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DOI: 10.1055/s-0035-1561499
Bismuth- and Iron-Catalyzed Three-Component Synthesis of α-Amino Acid Derivatives: A Simple and Convenient Route to α-Arylglycines
Publication History
Received: 07 June 2016
Accepted: 13 June 2016
Publication Date:
29 July 2016 (online)
‡ These authors contributed equally to this study.
Abstract
Efficient bismuth- and iron-catalyzed three-component syntheses of α-arylglycines have been developed. These methods provide a general, atom-economic route to various N-protected α-arylglycines starting from readily available amides (or carbamates), glyoxalates, and (hetero)arenes with water as the only by-product. Scope and limitations of bismuth- and iron-catalyzed reactions are discussed and compared. In addition, mechanistic investigations as well as initial forays into stereoselective three-component reactions are presented.
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Key words
multicomponent reactions - iron - bismuth - aza-Friedel–Crafts reaction - amino acids - homogeneous catalysisα-Amino acids are of fundamental importance for biology, biochemistry, and chemistry.[1] [2] They form the backbone of proteins, an essential part of every living organism, and are used as common feedstock for the production of biodegradable plastics, fertilizers, nutritional supplements, or drugs.[1,2] Many proteinogenic and nonproteinogenic α-amino acids have important biological, nonprotein-related functions, such as glutamate,[1] an important neurotransmitter or glycine,[3] the starting material for the biosynthesis of porphyrin-type cofactors. With the expansion of the genetic code and the discovery of protein-based drugs, nonproteinogenic (or unnatural) α-amino acids have gained increasing attention.[1] [2] Among these nonproteinogenic α-amino acids, α-arylglycines are of particular importance, as they are building blocks for various drugs, such as cardiovascular agents[4] and β-lactam antibiotics[5] like amoxicillin and norcardicin A (Figure [1]). The α-arylglycine moiety is also part of numerous natural products, such as vancomycin[6] or chloropeptin I[7] (Figure [1]). Expanding the organic chemist’s tool box with novel efficient, modular and practical methods for the synthesis of the α-arylglycine structure is therefore of great interest.[8] [9] Common procedures for the preparation of these compounds are based on the addition of a nucleophile to an imine species, such as the Mannich reaction,[10] the Strecker reaction,[11] the Petasis–(Borono–Mannich) reaction,[12] or aza-Friedel–Crafts-type reactions[13] (Scheme [1]).
However, these methods have some decisive drawbacks. Cyanides used in the Strecker reaction are highly toxic and the subsequent hydrolysis of the nitrile function under acidic conditions curtails the functional group tolerance (Scheme [1], path A). The Petasis–(Borono–Mannich) reaction and related processes require prefunctionalized and often expensive boronic acid derivatives (Scheme 1, path B). Another important approach is the direct amino- and amidoalkylation of unfunctionalized (hetero)arenes (Scheme [1], path C).[13] [14] These aza-Friedel–Crafts-type reactions are based on nucleophilic addition of arenes to highly electrophilic imines and especially N-acylimines. In combination with the in situ formation of the reactive N-acylimine species via condensation of an aldehyde and an amide, these methods enable the preparation of α-arylglycines with water as only by-product and offer a promising opportunity for the sustainable and atom-economic synthesis of this important compound class.[15] However, reported aza-Friedel–Crafts-type reactions are often limited to very reactive (hetero)arenes or require stoichiometric amounts of strong Brønsted or Lewis acids.[14] These restrictions lead to a rather small substrate scope and the formation of considerable amounts of waste and by-products.
In the course of our research on imine-based multicomponent reactions,[16] we were able to develop three-component reactions for the synthesis of α-arylglycines using inexpensive and nontoxic bismuth and iron catalysts.[16a] [b] These reactions provide straightforward access to a broad scope of α-(hetero)arylglycines. They utilize readily available starting materials and water is generated as the only by-product. Herein we report the full scope and limitations of both methods, together with comparison of the specific advantages and disadvantages as well as detailed mechanistic investigations.
Optimization and Scope
At the onset of our studies, we hypothesized that an ideal catalyst should be able to catalyze both the formation of a reactive N-acylimine via condensation of an amide with a glyoxylic acid derivative and the addition of an unreactive arene to the in situ formed N-acylimine. Small quantities of water formed in the condensation step should not lead to a significant catalyst deactivation. For the sake of practicality the glyoxalate was used in its more stable polymeric or hydrated form.[17]
To identify a suitable catalyst system, the reaction of benzamide (1a) with commercially available ethyl glyoxalate (2a)[18] and the moderately reactive m-xylene (3a)[19] was chosen using only 1 mol% of the catalyst (Table [1]). Preliminary results revealed that several Lewis and Brønsted acids are able to catalyze this reaction, albeit with various degrees of efficiency (Table [1]). Water-sensitive Lewis acids, such as BF3·OEt2 and AlCl3, or weak Brønsted acids, for example, TFA or (PhO)2P(O)OH, did not catalyze the reaction at all (yields <10%, results not shown).
 |
||
|
Entry |
Catalyst |
Yield (%)a |
|
1 |
Fe(ClO4)3·xH2O |
91 |
|
2 |
Bi(OTf)3 |
88 |
|
3 |
In(OTf)3 |
72 |
|
4 |
Yb(OTf)3 |
54 |
|
5 |
Sc(OTf)3 |
16 |
|
6 |
TfOH |
18 |
|
7 |
TfOH (5 mol%) |
49 |
|
8 |
TsOH |
12 |
a Yields are given for the isolated product. The product was obtained as a 98:2 mixture of regioisomers. Only the major regioisomer is shown.
The stronger Brønsted acids TfOH and TsOH provided the desired product in <20% yield (Table [1], entries 6 and 8). A higher loading of TfOH did not lead to a greatly improved yield (entry 7). Most promising results were obtained with Bi(OTf)3, In(OTf)3, and Yb(OTf)3 (entries 2–4). Other metal triflates such as Sc(OTf)3, Mg(OTf)2, or Zn(OTf)2 did not show a similar catalytic activity. Surprisingly, 1 mol% Fe(ClO4)3 furnished the α-arylglycine 4a in 91% yield (entry 1).
From an ecological and economic point of view, readily available, cheap, and nontoxic iron salts would be an ideal catalyst system for this three-component reaction.[20] [21] Therefore, iron-based catalysts were investigated in more detail. During our previous research on amidoalkylation reactions, Bi(OTf)3 was identified as a very active, nontoxic, and relatively cheap catalyst.[22,23] Thus, we decided to take focus on bismuth-catalyzed reactions as well. Although In(OTf)3 and Yb(OTf)3 showed promising catalytic activity (Table [1], entries 3 and 4), In- and Yb-based catalysts were not examined due to the toxicity and teratogenic potential of In(III) and Yb(III) salts.[24]
a Yields are given for the isolated product. The product was obtained as a 98:2 mixture of regioisomers. Only the major regioisomer is shown.
To optimize the reaction conditions for both bismuth- and iron-based conversions, the initial model reaction between benzamide (1a), ethyl glyoxalate (2a), and m-xylene (3a) was chosen. The results for the optimization of the iron catalyst are depicted in Table [2]. Both, iron chloride either in its anhydrous form or as hexahydrate, as well as iron perchlorate displayed high catalytic activities. Despite the fact that both Fe(ClO4)3 and FeCl3·6H2O gave similar yields during the initial optimization reactions (Table [2], entries 1 and 7), Fe(ClO4)3 led to higher yields in general. Additionally, for Fe(ClO4)3 the catalyst loading can be decreased without significant loss of efficiency (entry 9). Whereas 1 mol% Fe(ClO4)3 led to the desired product in 91% yield (entry 8), the yield with 1 mol% FeCl3 dropped to 18% (entry 5). The corresponding Fe2+ salts could catalyze the model reaction with similar efficiency (entries 6 and 11). However, as judged by the observed rapid color change, we assume a fast oxidation of Fe2+ to Fe3+ under our aerobic reaction conditions. To rule out a possible ‘hidden’ catalysis by Brønsted acids, the reaction was performed in the presence of the proton scavenger 2,6-di-tert-butylpyridine (dbpy, entry 12).[25] No significant decrease in yield was observed. Therefore, we concluded that a Fe3+ species is the active catalyst.
a Yields are given for the isolated product. The product was obtained as a 98:2 mixture of regioisomers. Only the major regioisomer is shown.
Next, different solvents were examined for our three-component reaction (Table [2], entries 13–16). Best results were obtained in nitromethane. All other tested solvents led to lower yields (1,2-dichloroethane, dichloromethane, or 1,4-dioxane) or complete shutdown of the reaction (THF, H2O, EtOAc). A similar screening of reaction parameters was performed with the Bi-catalyzed three-component synthesis. As shown in Table [3,] Bi(OTf)3 proved to be the optimal catalyst. Other bismuth salts like BiCl3 or BiBr3 afforded the product in lower yields (Table [3], entries 5 and 6). Notably, the catalyst loading of Bi(OTf)3 could be reduced to only 1 mol% without a significant change in yield and even with only 0.5 mol% of Bi(OTf)3 the product could be isolated in 77%. As shown in Table [1,] TfOH, a possible by-product from the hydrolysis of Bi(OTf)3, did not display a similar catalytic activity. To further exclude a possible Brønsted acid catalysis a control reaction with the proton scavenger dbpy was performed also in the case of Bi(OTf)3 (entry 7). Again no significant decrease in the catalytic activity was observed, indicating a Bi(III)-species as the active catalyst. In the case of the Bi-catalyzed reaction, nitromethane also proved to be the ideal solvent. While yields in 1,2-dichloroethane were still acceptable (entry 8), the use of other solvents led to significant lower yields (results not shown).
Scope of (Hetero)Arenes, Amides, and Glyoxalates
After identification of the ideal reaction conditions, the scope of our methods was explored. First, reactions of different arenes with benzamide (1a), and ethyl glyoxalate (2a) were investigated. Various electron-rich arenes are suitable substrates for both the Fe- and the Bi-catalyzed aza-Friedel–Crafts reaction (Scheme [2]). The combined results are shown in Scheme [2]. Both types of catalyst furnished different α-arylglycine derivatives in good to excellent yields. Interestingly N-pivalolyl-protected aniline 3m reacted chemoselectively and α-arylglycine 4m was isolated in 67% (Bi) and 80% (Fe) yield. The reactions of polycyclic arenes led to the formation of glycine derivatives 4q and 4r, useful building blocks for the synthesis of fluorescence labels,[26] in 49–64% yield. Less reactive arenes, such as benzene, did not react, even under harsh reaction conditions. In most cases only one regioisomer was obtained. However, in some cases, such as in the reaction with anisole, a mixture of regioisomers was isolated. To our surprise, the use of Bi(OTf)3, supposedly the more active catalyst, always led to higher regioselectivities. In certain cases, such as with anisole, only a small, negligible difference in the regioselectivity was observed (75:25 vs. 71:29 para/ortho). However, for reactions with other arenes, Bi(OTf)3 furnished the desired products with a significantly higher regioselectivity. This fact is exemplified by the arylglycines 4e (86:14 vs. 75:25), 4m (95:5 vs. 71:29), or 4p (67:33 vs 50:50). So far we do not have a conclusive explanation for this phenomenon.
Next, the reactions of different amides and carbamates with ethyl glyoxalate (2a) and mesitylene (3b) were examined (Scheme [3]). To our delight different benzamide derivatives were compatible with both catalysts systems and the desired products 5a–c were obtained in excellent yields (68–94%). Alkyl-substituted primary amides are also suitable substrates and arylglycine derivatives 5d–f were obtained in 70–88% yield with iron catalysis and in 79–81% yield with bismuth catalysis. Even acid-sensitive amides such as acrylamide were transformed into the desired product 5g in 82% (Bi) or 85% (Fe) yield. Carbamates are suitable substrates for the bismuth- and the iron-catalyzed three-component reactions. Different N-protected α-arylglycines 5h–k, such as 5i bearing a Cbz-protecting group or the Fmoc-derivative 5k, were obtained in high yields. Unfortunately reaction with tert-butyl carbamate did not furnish the desired Boc-protected arylglycine 5l. Sterically more demanding secondary amides or electron-deficient trifluoroacetyl amide proved to be unsuitable for our method and the desired products 5m and 5n could not be obtained.
Not only arenes but also heteroaromatic compounds are suitable substrates for the three-component reaction (Scheme [4]). The corresponding heteroarylglycines 7a–l were obtained in good to excellent yields with both Fe and Bi catalysis. In general, lower reaction temperatures were necessary to avoid direct addition of the heteroarene to the aldehyde (Scheme [5]).[27] Reaction of benzamide (1a) with ethyl glyoxalate (2a) and a heteroarene 6 as the nucleophilic component furnished different heteroarylglycines in 47 to 88% yield (Scheme [4]). Interestingly, reactions with carbamates, such as urethane, as the amide component, led to overall higher yields as well as improved regioselectivities. Improved regioselectivities can be rationalized by the decreased reactivity of the in situ formed N-carbamoylimine compared to the N-acylimine in the benzamide case. The low yields with benzamides are most probably associated with the instability of the formed amidoalkylated products under acidic conditions. We assume that these compounds decompose under acidic conditions via dissociation of the benzamide, thereby forming a stabilized heterobenzylic cation 9, which can react with excess of the heteroarene to the corresponding diarylmethane derivative 10.
Indeed, Bi(OTf)3-catalyzed reactions of very electron-rich heterocycles, such as benzofuran, N-tosylpyrrole, or -indole, with benzamide (1a) and ethyl glyoxalate (2a) led to the selective formation of the double addition products of type 10 (Scheme [5]). Using the less active iron catalyst, heteroarylglycines 7g, 7i, and 7k could be isolated in 51, 62, and 74% yield, respectively. Both methods are not limited to ethyl glyoxalate as the aldehyde component (Scheme [6]).[28] Reactions with different glyoxalates, such as isopropyl glyoxalate (2b) furnished the desired amino acid derivative 11a in 50 and 83% yield. Even free glyoxylic acid, used as aqueous solution, can be employed as aldehyde source, thereby providing the free acid 11b in 71 and 81% yield. Reactions with carbamates, such as urethane or the Fmoc-derivative, afforded the N-protected arylglycines 11c and 11d in 45–92% yield. Especially, the Fmoc-protected acid 11d would be an ideal starting material for solid-phase peptide synthesis with unnatural amino acid derivatives. In the case of the carbamates, iron catalysis proved to be more reliable and furnished the desired products in higher yields and purity.
Limitations
In general, similar yields were obtained with bismuth and iron catalysis. In the case of competing regioisomer formation, reactions with Bi(OTf)3 gave consistently higher regioselectivities. During our studies on the scope of the arene component, a significant difference was observed in the reactivity for very electron-rich as well as for unreactive aromatics (Scheme [7]). These differences in reactivity are most probably associated with the activity of the used catalyst. For very reactive, electron-rich arenes, such as dimethoxybenzenes, anthracene, or anisidine derivatives, the less active iron catalyst proved to be advantageous. The amidoalkylated arenes 12a–j were obtained in 63–89% yield. Reactions of electron-rich arenes in combination with the more active Bi(OTf)3 gave the corresponding products in lower yields or did not afford the product at all. In these cases, the competing formation of diarylmethane derivatives was observed in significant quantities (cf. Scheme [5]). For free phenols, such as 4-bromophenol, bismuth catalysis proved to be advantageous and furnished the glycine derivative 12g in 65% yield (vs 11% with Fe3+). With iron catalysts oxidative coupling reactions of the phenol were observed. In the case of less reactive arenes, such as o-xylene, the more active bismuth catalyst proved to be more efficient and afforded the arylglycine in 89% yield (vs 54% with Fe3+ catalysis). Bi(OTf)3 could even catalyze the reaction of toluene, furnishing product 12j in 50% yield. In the case of iron catalysis no product formation was observed with toluene. Although the lower catalytic activity of the iron salts might look like a disadvantage at the first glance, it proved to be a major advantage in terms of practicability. Commercially available, technical ethyl glyoxalate, is commonly provided as a solution of the polymer form in toluene. In the case of Bi-catalyzed reactions, toluene has to be removed prior to the reaction to avoid the formation of 12j as side-product. For iron-catalyzed reactions the commercially available solution can be used without further processing, thereby leading to a more straightforward procedure.
Also in the case of less reactive amide components, the higher catalytic activity of Bi(OTf)3 proved to be beneficial (Scheme [8]). Bi(OTf)3-catalyzed reactions with cyclic secondary amides or carbamates afforded the desired products 14a and 14b in 63 and 80% yield. No product formation with iron catalysts was observed. Acyclic secondary amides or carbamates proved to be unreactive using either bismuth or iron catalysis.
Interestingly, Bi(OTf)3 was able to catalyze reactions with different sulfonamides as amide component (Scheme [9]). The corresponding N-sulfonylated arylglycines 16a–c were obtained in 54–79% yield. Presumably, Bi(OTf)3 is active enough to catalyze the addition of arenes to in situ less electrophilic N-sulfonylimines.[14]
Investigations into Stereoselective Reactions
Since most of the natural α-arylglycines exist in one enantiomeric form, stereoselective synthesis of these compounds would be highly desirable. Therefore, we decided to investigate a possible asymmetric version of our three-component reactions (Scheme [10]). The most obvious approach would be the use of chiral ligands in our transformation. Hence various common chiral ligands were tested in combination with different Bi3+ or Fe3+ salts (Scheme [10]).[29] Unfortunately, no asymmetric induction was observed using various metal–ligand combinations, solvents, or temperatures (Scheme [10]). In further studies using different ligands and variations of the amide or arene component as well as In3+ and Yb3+, promising Lewis acids in our initial screening, were studied. Again no asymmetric induction was observed.
Since no enantioselective version of the three-component reaction could be realized with chiral catalysts, we decided to explore diastereoselective reactions with chiral amide components (Schemes 11–13).
For first tests chiral carbamates based on the Evans auxiliary were selected (Scheme [11]).[30] However, chiral oxazolidinones, such as 20a or 20b, did not furnish the desired products under our standard reaction conditions. Whereas 20b did not react at all, an interesting reactivity was observed for oxazolidinone 20a. The bismuth-catalyzed reaction of 20a furnished cyclic amino acid derivative 21 in 84% yield as single diastereomer (Scheme [12]). Formation of the cyclic product can be rationalized by an intramolecular addition of the phenyl moiety to the formed N-acylimine. Even in the presence of excess of mesitylene no intermolecular addition was observed. Therefore, we next selected chiral primary amides as potential chiral starting materials for our three-component reaction.
Reaction of phthalimide-protected valine amide 22 with ethyl glyoxalate (2a) and mesitylene (3b) furnished the expected product 23 in 84% with Bi(OTf)3 and 78% yield with FeCl3·6H2O (Scheme [13]). Only moderate diastereoselectivities (67:33 and 65:35) were observed. Variation of the temperature, solvent, or catalyst did not improve the stereoselectivity. Replacing the amide protecting group by a carbamate, led to a diminished diastereoselectivity and a drastic decrease in isolated yields. Reactions with amide-protected valine amides did not furnish any desired product at all. In summary, all our approaches to stereoselective reactions did not lead to the expected results. Only in the case of chiral amide components moderate stereoselectivities could be achieved. Therefore, further studies into the field of asymmetric three-component reactions were not pursued.
Mechanistic Investigations
In order to gain further insight into the reaction mechanism and the different catalytic activities of Bi(OTf)3 and Fe3+ salts, a series of experiments were performed. First the progress of the reaction between benzamide (1a), ethyl glyoxalate (2a), and mesitylene (3b) in the presence of different catalysts as well as catalyst loadings was monitored by gas chromatographic analysis (Scheme [14,] Figures [2] and 3).
In order to obtain a clearer distinction between the different systems, the reaction was performed at a slightly decreased temperature of 60 °C. Initially we compared the rates for conversion of the limiting starting material, benzamide (1a), and product formation with 5 mol% of Bi(OTf)3 and 5 mol% Fe(ClO4)3. In both cases an interesting observation was made: the rates of benzamide conversion and product formation deviate significantly from each other at the onset of the reaction (Figure [2]).
In the case of Fe(ClO4)3, a fast conversion of the benzamide (20% conversion after 10 min and 70% after 45 min) was observed. However, the rate of product formation was slower (<1% yield after 10 min and 50% yield after 45 min). Similar observations were made with 5 mol% of Bi(OTf)3 (20% and 45% conversion vs 2% yield and 30% yield after 10 and 45 min, respectively). Since in both cases the yield of α-arylglycine 4b exceeded 90% after 24 hours reaction time, no unproductive side-reactions of benzamide can account for the fast conversion of the amide component. Therefore, formation of some kind of productive intermediate, most probably by the reaction of two of the three components, has to take place.
As can be seen from Figure [3,] Fe(ClO4)3 catalyzes the reaction with a higher efficiency than Bi(OTf)3, both at high (5 mol%) and low (1 mol%) catalyst loading. With 5 mol% Fe(ClO4)3 64% of the amidoalkylated product is observed after 60 minutes, compared to only 28% with 5 mol% Bi(OTf)3. As expected, reduction of the catalyst loading to 1 mol% leads to a considerable decrease in the reaction rate (Figure [3]).
Interestingly, FeCl3·6H2O displays the lowest catalytic activity. After 50 minutes at 60 °C, only 5% product formation was observed with 5 mol% FeCl3·6H2O. Presumably, a facile dissociation of the noncoordinating counterions to form an active metal catalyst is crucial for a high activity.[31] We have to emphasize that under our standard reaction conditions (80 °C; 16 h, 24 h, respectively) all three catalysts [Fe(ClO4)3, FeCl3·6H2O, and Bi(OTf)3] give similar yields at 5 mol% and even 2 mol% loadings (>90% in all cases). To our surprise, Bi(OTf)3, the catalyst with the best performance with less reactive arenes, displayed an inferior activity compared to Fe(ClO4)3 in the reaction with mesitylene (Figure [3]). Therefore, Fe(ClO4)3 is the catalyst of choice for more reactive arenes, considering the activity and the economic and ecologic aspects of iron(III) salts.
As outlined in the introduction, our first rationale for the development of these three-component reactions was the in situ formation of a reactive N-acylimine species. Initial experiments indicated the formation of a two-component adduct of benzamide with one of the other starting materials (Figure [2]). Therefore, we examined the reaction between benzamide (1a) and ethyl glyoxalate (2a) in the presence of 5 mol% Fe(ClO4)3 or 5 mol% Bi(OTf)3 (Scheme [15]). At room temperature quantitative formation of N,O-hemiaminal 24a is observed within 24 hours (Scheme [15]). Longer reaction times (96 h) or heating to 80 °C led to the formation of bisamide 25a, insoluble in most common organic solvents, in almost quantitative yields. Indeed, the formation and precipitation of bisamide 25 could be observed in some of our three-component reactions. During the reaction bisamide 25a is consumed completely and at the end the reaction mixture becomes homogenous again. Due to the insolubility of bisamide 25a and the instability of bisamide 25a and hemiaminal 24a, we were not able to quantify the amount of both intermediates during the course of the reaction with the analytical methods available at our department (GC, HPLC, React-IR, or NMR). Neither were we able to detect any reactive N-acylimine species.[32] As expected, the reaction of benzamide (1a) and mesitylene (3b) in the presence of an iron or bismuth catalyst did not furnish any new product at all (Scheme [15]). Treatment of either hemiaminal 24a or bisamide 25a, both known precursors for acylimines,[14] with Bi(OTf)3 or Fe(ClO4)3 and mesitylene (3b) led to the expected formation of the aryl glycine derivative 4b in 85 and 83% yield. To elucidate further reaction pathways, the two-component reaction of mesitylene (3b) with ethyl glyoxalate (2a) was investigated next. Both 2 mol% Bi(OTf)3 and 2 mol% Fe(ClO4)3 furnished the double addition product 26 in 70–74% yield. Formation of such diarylmethane products was already observed in the case of more reactive (hetero)arenes (cf. Scheme [5]) and is described in the literature.[27] Addition of a ligand, 2,2′-bipyridine (bipy) to the iron-catalyzed reaction, enabled the controlled synthesis of monoaddition product 27 in 66% yield. Alcohol 27 is the presumed intermediate in the synthesis of diarylmethane products of type 26. We next examined alcohol 27 as a possible intermediate in our three-component reaction. Treatment of 27 with 1.0 equivalent of benzamide and 2.0 equivalents of mesitylene under our standard reaction conditions did furnish the expected product 4b and diarylmethane derivative 26 in less than 5% yield, using either Bi(OTf)3 or Fe(ClO4)3. These experiments indicate that alcohol 27 is not involved in the main reaction pathway. On the basis of these results, we assume the following mechanism (Scheme [15]). In the first step, the amide adds to the glyoxylic acid derivative 2 to form hemiaminal 24. Elimination of water furnishes a reactive acylimine species 28. Trapping of this highly electrophilic imine with a second molecule of the amide gives bisamide 25, observed intermediate in some of our three-component reactions. The fast addition of a second amide is not surprising, if one considers the higher nucleophilicity of the amide nitrogen.[18] Under the reaction conditions, bisamide 25, favored under kinetic control, can decompose to yield the reactive N-acylimine 28. In the presence of a suitable, nucleophilic arene, the N-acylimine can undergo an aza-Friedel–Crafts type reaction to afford the desired α-arylglycine product 4 containing a thermodynamically more stable C–C bond. The catalytic activity of the used catalyst greatly depends on two factors. On the one hand, the catalyst has to be stable in the presence of significant amounts of water, since up to 100 equivalents of water are generated during the course of the reaction (with respect to the catalyst).
On the other hand the catalyst has to promote the addition of the amide 1 to the glyoxalate 2 over the direct addition of the arene 3 to the aldehyde 2. Only the right combination of both reactivities leads to an efficient catalyst for these three-component reactions. In addition, the Lewis acidic catalyst could further activate the N-acylimine towards the addition of a nucleophile. This might partially explain the higher activity of Bi(OTf)3, a strong Lewis acid, in reactions with less nucleophilic arenes.[28] Another possible explanation for the high catalytic efficiency of bismuth as well as the observed improved regioselectivities is the activation of the arene component by the bismuth catalyst. Although Bi(III)-arene complexes have been reported in literature, we do not have any solid experimental evidence for an additional activation of the arene component.[33] We assume that two factors contribute to the observed low stereoselectivities in our asymmetric approaches. The high intrinsic reactivity of N-acylimines leads to a low selectivity in general, both for the diastereoselective and enantioselective reactions. As reported in the literature, coordination of a Lewis acid to the N-acylimine takes place at the oxygen atom.[34] This places the catalyst far away from the reactive center, thereby severely hampering any stereochemical induction by the ligand. Based on this assumption, one can rationalize that tailor-made sterically very demanding ligands should offer a solution to this problem. However, the catalytic activity of such encumbered systems might be too low for these types of multicomponent reactions.
Conclusion and Outlook
In summary, two general Bi(OTf)3- and Fe3+-catalyzed three-component reactions between amides, (hetero)arenes, and glyoxylic acid derivatives have been developed. Scope and limitations as well as advantages and disadvantages of both catalyst systems were investigated in detail. These investigations show that very cheap Fe3+ salts are the catalysts of choice in most reactions. The lower activity of iron-based catalysts offers an additional advantage in the case of very reactive arene components. On the other hand, the high activity of Bi(OTf)3 significantly expands the scope of the three-component reaction and allows the utilization of less reactive arenes and sulfonamides. Investigations into potential asymmetric versions of the three-component reaction were unsuccessful. No enantioselective reaction was realized and the diastereoselective induction with chiral amide components was low to moderate. Mechanistic investigations indicate a reaction pathway via formation of a reactive, highly electrophilic acylimine followed by an aza-Friedel–Crafts-type reaction with the arene as nucleophilic component. These practical and operationally simple reactions enable the efficient and straightforward synthesis of N-protected arylglycines from simple commercial available starting materials and nontoxic catalysts. With water as the only generated side-product, these methods constitute a promising approach towards the sustainable synthesis of important α-amino acids.
For reactions and column chromatography, solvents were obtained from different commercial suppliers in >97% purity and used as received.
All reactions were performed without any precautions to exclude ambient air or moisture. TLC was performed on precoated aluminum sheets (silica gel 60 F254). The spots were visualized by using UV radiation, I2, or cerium(IV) ammonium molybdate. Flash column chromatography was performed by using Silica 60 (0.04–0.063 mm, 230–400 mesh). All yields refer to isolated yields of compounds estimated to be >95% pure, as determined by 1H NMR spectroscopy. Melting points are uncorrected.
N-(m-Tolyl)pivalamide, N-(3-methoxyphenyl)pivalamide, 1-methoxy-3,5-dimethylbenzene, 2-methoxy-naphthalene, 1-tosyl-1H-pyrrole, 1-tosyl-1H-indole, N-(o-tolyl)pivalamide, N-(2-methoxy-phenyl)pivalamide, N-(4-methoxyphenyl)pivalamide, methanesulfonamide, 4-methylbenzenesulfonamide, 4-methoxybenzenesulfonamide, 4-bromobenzenesulfonamide, thiophene-2-sulfonamide, and 2-(1,3-dioxoisoindolin-2-yl)-3-methylbutanamide were synthesized according to literature.[16] Ethyl glyoxalate was obtained as 50 wt% solution in toluene. Glyoxylic acid was obtained as 50 wt% solution in H2O and used as received. All other starting materials were purchased from commercial sources and used without further purification. Fe(ClO4)3 was obtained as undefined hydrate (Fe(ClO4)3·xH2O, yellow form, reagent grade) from different providers. The exact H2O content was determined by elemental analysis. Depending on the provider and storage time (or even the time for weighting out a defined amount for elemental analysis) Fe(ClO4)3 contained from one up to ten molecules of H2O. Therefore, the amount of Fe(ClO4)3 used is always calculated on anhyd Fe(ClO4)3. No changes in catalytic activity were observed for different batches of Fe(ClO4)3 or upon prolonged storage times. No special precautions were taken to avoid exposure of Fe(ClO4)·xH2O to moisture. Caution! Perchlorate salts are known to be shock-sensitive and are potential explosives. They should be handled with care and the necessary precautions. Since most of these properties are associated with anhyd perchlorate salts, we strongly advise to use the hydrated form of Fe(ClO4)3 . Under no circumstances should Fe(ClO4)3 be dried or handled in its anhydrous form. Since similar yields are obtained even with the decahydrate Fe(ClO4)3·10H2O, this is not necessary. Special precautions should be taken to avoid accidental drying of the perchlorate, for example, by accidental evaporation of the solvent from the reaction. During our studies we never encountered problems associated with Fe(ClO4)3. Even prolonged heating of Fe(ClO4)3 in MeNO2 up to 120 °C did not lead to any decomposition. (In fact it is known the anhydrous LiClO4 is stable in Et2O at temperatures up to 140–150 °C. For further information on perchlorate safety and stability, we recommend the article of Long.[35]
Anhyd Bi(OTf)3 was obtained from different providers and used directly. No special precautions were taken to avoid exposure of Bi(OTf)3 to moisture. Therefore, we cannot rule out the formation of Bi(OTf)3·xH2O during storage. Indeed, depending on the provider and storage time (or even the time for weighting out a defined amount for elemental analysis) Bi(OTf)3 contained up to six molecules of water. However, no changes in catalytic activity and yield even upon prolonged storage (>1 year) were observed. Therefore, the amount of Bi(OTf)3 used is always calculated on anhyd Bi(OTf)3. The actual catalyst loading for particular reactions might be slightly lower, depending on the batch quality and storage time.
1H and 13C NMR spectra were recorded at 300, 400, or 500 MHz and 75, 101, or 126 MHz, respectively. Chemical shifts are reported as δ-values relative to the residual CDCl3 or DMSO-d 6 peak (δ = 7.26 for 1H and δ = 77.16 for 13C; δ = 2.50 for 1H and δ = 39.52 for 13C). Coupling constants (J) are given in Hz and standard abbreviations are used for signal multiplicities.
Mass spectra (MS) were measured using ESI (electrospray ionization) techniques. High-resolution mass spectra (HRMS) were measured using MALDI (Matrix-assisted Laser Desorption/Ionization) techniques.
IR spectra were recorded on an FTIR (Fourier transform infrared spectroscopy) spectrophotometer including a diamond universal ATR sampling technique (attenuated total reflectance) from 4000–400 cm–1. The absorption bands were reported in wave numbers (cm–1).
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Three-Component Synthesis of α-Arylglycines; General Procedure (GP)
A 10 mL screw cap vial was charged with the respective iron salt (1–5 mol%) or Bi(OTf)3 (1–5 mol%), the appropriate amide (1.0 equiv), and MeNO2 (4.0 mL/mmol amide) (or DCE wherever applicable). Ethyl glyoxalate (1.2 equiv) and the appropriate aromatic compound (3.0 equiv) were added under vigorous stirring. Ethyl glyoxalate was used as a 50 wt% solution in toluene (technical form) and used as received for the reactions with iron(III) salts. For the reaction with Bi(OTf)3 toluene was removed in vacuo (1 mbar, 3 h) in order to avoid side reactions. The resulting oil was redissolved in MeNO2. The reaction mixture was heated to 40–100 °C and stirred at this temperature. After cooling to r.t., the reaction mixture was diluted with EtOAc and filtered through a short plug of Celite and silica gel. The plug was rinsed with additional EtOAc. The combined filtrates were concentrated under reduced pressure. Purification of the crude residue by column chromatography (cyclohexane/EtOAc, then n-hexane/EtOAc) afforded the analytically pure product.
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Ethyl 2-Benzamido-2-(2,4-dimethylphenyl)acetate (4a)
Bi Catalysis : Compound 4a was synthesized according to the GP from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg, 1.2 mmol, 1.2 equiv), m-xylene (0.37 mL, 3.0 mmol, 3.0 equiv), and Bi(OTf)3 (13 mg, 0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the product as a colorless solid [276 mg, 89%; ratio of regioisomers (r.r.) = >98:2].
Fe Catalysis : Compound 4a was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.2 equiv), m-xylene (0.18 mL, 1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless solid (141 mg, 91%; r.r. = >98:2). Further purification of the major regioisomer could be achieved by precipitation from hexane/CH2Cl2 (only major regioisomer, as judged by 1H NMR). Analytical data were obtained for this purified regioisomer.
Mp 98.2 °C; Rf = 0.54 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3304 (w), 2985 (w), 2360 (w), 1745 (s), 1635 (s), 1601 (w), 1580 (w), 1523 (s), 1487 (m), 1371 (w), 1348 (m), 1324 (w), 1212 (s), 1189 (m), 1150 (m), 1095 (m), 1021 (m), 929 (w), 872 (w), 810 (w), 774 (w), 722 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 7.80 (dd, J = 5.3, 3.3 Hz, 2 H), 7.52–7.40 (m, 3 H), 7.17 (d, J = 7.8 Hz, 1 H), 7.07–6.96 (m, 3 H), 5.93 (d, J = 7.1 Hz, 1 H), 4.31–4.11 (m, 2 H), 2.52 (s, 3 H), 2.30 (s, 3 H), 1.23 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.8, 166.7, 138.4, 136.9, 133.9, 132.5, 131.9, 131.8, 128.7, 127.33, 127.3, 126.4, 62.0, 53.5, 21.2, 19.6, 14.2.
MS (ESI): m/z [M + H]+ calcd for C19H22NO3: 312.2; found: 312.2.
HRMS (MALDI): m/z [M + H]+ calcd for C19H22NO3: 312.1594; found: 312.1596.
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Ethyl 2-Benzamido-2-mesitylacetate (4b)
Bi Catalysis : Compound 4b was synthesized according to the GP from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 1 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the product as a colorless solid (308 mg, 95%).
Fe Catalysis : Compound 4b was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and FeCl3·6H2O (3 mg, 0.010 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless solid (153 mg, 94%).
Mp 77.6 °C; Rf = 0.50 (cyclohexane/EtOAc = 7:3)
IR (ATR): 3320 (m), 2980 (w), 1727 (s), 1632 (s), 1579 (m), 1525 (s), 1488 (m), 1382 (w), 1339 (w), 1311 (m), 1242 (s), 1136 (m), 1082 (m), 1020 (s), 929 (m), 852 (m), 800 (m), 713 (m), 689 (s), 622 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 7.5 Hz, 2 H), 7.47 (dt, J = 15.0, 7.2 Hz, 3 H), 7.18 (d, J = 6.1 Hz, 1 H), 6.85 (d, J = 7.8 Hz, 2 H), 6.19 (d, J = 6.6 Hz, 1 H), 4.34–4.12 (m, 2 H), 2.48 (s, 6 H), 2.25 (s, 3 H), 1.22 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.9, 166.6, 137.8, 137.1, 134.1, 131.8, 131.0, 130.2, 128.7, 127.2, 62.2, 52.8, 21.0, 20.5, 14.2.
MS (ESI): m/z [M + H]+ calcd for C20H24NO3: 326.2; found: 326.1.
HRMS (MALDI): m/z [M + H]+ calcd for C20H24NO3: 326.1751; found: 326.1751.
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Ethyl 2-Benzamido-2-(4-methoxyphenyl)acetate (4c)
Bi Catalysis : Compound 4c was synthesized according to the GP from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg, 1.2 mmol, 1.2 equiv), anisole (0.32 mL, 3.0 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 1 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the product as a colorless solid (236 mg, 75%; r.r. = 75:25).
Fe Catalysis : Compound 4c was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.2 equiv), anisole (0.16 mL, 1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.050 mmol, 5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless solid (105 mg, 67%; r.r. = 75:25). Further purification of the major regioisomer could be achieved by precipitation from hexane/CH2Cl2 (r.r. = 78:22, as judged by 1H NMR analysis). Analytical data were obtained for this purified mixture.
Mp 65.6 °C; Rf = 0.49 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3319 (w), 2964 (w), 1737 (s), 1633 (s), 1578 (w), 1530 (m), 1512 (s), 1490 (m), 1462 (w), 1366 (w), 1317 (m), 1248 (s), 1022 (m), 801 (m), 762 (m), 692 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ (major regioisomer) = 7.78–7.72 (m, 2 H), 7.47–7.28 (m, 5 H), 7.03 (d, J = 6.6 Hz, 1 H), 6.85–6.79 (m, 2 H), 5.63 (d, J = 7.0 Hz, 1 H), 4.24–4.07 (m, 2 H), 3.72 (s, 3 H), 1.20–1.14 (m, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.3, 166.5, 159.7, 133.8, 131.8, 131.6, 130.8, 129.8, 128.9, 128.7, 128.5 128.4, 127.1, 121.1, 114.4, 111.1, 62.0, 61.6, 56.3, 55.6, 55.3, 53.9, 14.0 (peaks not assigned to regioisomers).
MS (ESI): m/z [M + Na]+ calcd for C18H19NO4Na: 336.1; found: 336.4.
HRMS (MALDI): m/z [M + H]+ calcd for C18H20NO4 314.1387, found 314.1384.
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Ethyl 2-Benzamido-2-(4-methoxy-3-methylphenyl)acetate (4d)
Bi Catalysis : Compound 4d was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), 1-methoxy-2-methylbenzene (0.19 mL, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless solid (115 mg, 70%; r.r. = >98:2).
Fe Catalysis : Compound 4d was synthesized according to the GP from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.2 equiv), 1-methoxy-2-methylbenzene (0.37 mL, 3.0 mmol, 3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless solid (223 mg, 68%; r.r. = 94:6). Further purification of the major regioisomer could be achieved by precipitation from hexane/CH2Cl2 (only major regioisomer, as judged by 1H NMR analysis). Analytical data were obtained for this purified regioisomer.
Mp 95.0 °C; Rf = 0.51 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3323 (w), 2361 (w), 1733 (s), 1635 (s), 1579 (m), 1531 (m), 1508 (m), 1451 (w), 1347 (m), 1315 (m), 1278 (m), 1249 (s), 878 (m), 800 (m), 751 (m), 691 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 7.4 Hz, 2 H), 7.51 (t, J = 7.3 Hz, 1 H), 7.43 (t, J = 7.5 Hz, 2 H), 7.26 (m, 2 H), 7.06 (d, J = 6.6 Hz, 1 H), 6.80 (d, J = 8.4 Hz, 1 H), 5.66 (d, J = 7.0 Hz, 1 H), 4.34–4.13 (m, 2 H), 3.82 (s, 3 H), 2.21 (s, 3 H), 1.25 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.5, 166.6, 158.1, 134.0, 131.9, 129.7, 128.7, 128.4, 127.5, 127.3, 126.1, 110.3, 62.0, 56.5, 55.5, 16.4, 14.2.
MS (ESI): m/z [M + Na]+ calcd for C19H21NO4Na: 350.1; found: 350.3.
HRMS (MALDI): m/z [M + H]+ calcd for C19H22NO4: 328.1543; found: 328.1543.
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Ethyl 2-Benzamido-2-(4-methoxy-2-methylphenyl)acetate (4e)
Bi Catalysis : Compound 4e was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), 1-methoxy-3-methylbenzene (0.19 mL, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless solid (97 mg, 59%; r.r. = 80:20).
Fe Catalysis : Compound 4e was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.2 equiv), 1-methoxy-3-methylbenzene (0.19 mL, 1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless solid (121 mg, 63%; r.r. = 75:25). Further purification of the major regioisomer could be achieved by precipitation from hexane/CH2Cl2 (84:16 mixture of regioisomers, as judged by 1H NMR analysis). Analytical data were obtained for this purified mixture.
Mp 90.2 °C; Rf = 0.51 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3343 (w), 2937 (w), 1732 (s), 1638 (s), 1611 (m), 1579 (m), 1486 (m), 1347 (m), 1293 (m), 1252 (s), 1111 (m), 1079 (m), 925 (w), 862 (m), 761 (m), 691 (s), 626 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ (major regioisomer) = 7.89–7.73 (m, 2 H), 7.55–7.38 (m, 3 H), 7.23–7.15 (m, 1 H), 7.00 (d, J = 6.5 Hz, 1 H), 6.82–6.70 (m, 2 H), 5.89 (d, J = 6.9 Hz, 1 H), 4.32–4.11 (m, 2 H), 3.79 (s, 3 H), 2.53 (s, 3 H), 2.35 (s, 1 H), 1.27–1.16 (m, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.8, 166.7, 159.6, 138.7, 133.9, 131.9, 131.7, 130.7, 128.7, 128.6, 128.6, 127.8, 127.7, 127.3, 127.3, 121.8, 116.6, 112.2, 111.9, 62.0, 55.7, 55.4, 53.3, 21.8, 19.9, 14.2 (peaks not assigned to regioisomers).
MS (ESI): m/z [M + H]+ calcd for C19H22NO4: 328.2; found: 328.3.
HRMS (MALDI): m/z [M + H]+ calcd for C19H22NO4: 328.1543; found: 328.1543.
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Ethyl 2-Benzamido-2-(2-methoxy-5-methylphenyl)acetate (4f)
Bi Catalysis : Compound 4f was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), 1-methoxy-4-methylbenzene (0.19 mL, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless solid (102 mg, 62%; r.r. = >98:2).
Fe Catalysis : Compound 4f was synthesized according to the GP from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.2 equiv), 1-methoxy-4-methylbenzene (0.38 mL, 3.0 mmol, 3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless solid (205 mg, 63%; r.r. = >98:2).
Mp 100.3 °C; Rf = 0.51 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3263 (m), 2908 (w), 2832 (w), 1732 (s), 1637 (s), 1579 (w), 1524 (m), 1506 (m), 1461 (m), 1390 (w), 1365 (m), 1323 (s), 1254 (s), 1206 (s), 1135 (s), 1091 (s), 1033 (s), 978 (w), 874 (m), 805 (s), 761 (m), 717 (s), 690 (s), 604 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 7.82–7.77 (m, 2 H), 7.52–7.46 (m, 1 H), 7.42 (t, J = 7.4 Hz, 2 H), 7.29 (d, J = 8.1 Hz, 1 H), 7.25 (d, J = 1.9 Hz, 1 H), 7.10 (dd, J = 8.3, 1.7 Hz, 1 H), 6.80 (d, J = 8.3 Hz, 1 H), 5.89 (d, J = 8.3 Hz, 1 H), 4.25–4.16 (m, 2 H), 3.83 (s, 3 H), 2.30 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.3, 166.7, 155.1, 134.4, 131.7, 131.6, 130.6, 130.2, 128.6, 127.3, 125.5, 111.2, 61.7, 55.8, 54.1, 20.6, 14.3.
MS (ESI): m/z [M + Na]+ calcd for C19H21NO4Na: 350.1; found: 350.2.
HRMS (MALDI): m/z [M + H]+ calcd for C19H22NO4: 328.1543; found: 328.1543.
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Ethyl 2-Benzamido-2-(3-chloro-4-methoxyphenyl)acetate (4g)
Bi Catalysis : Compound 4g was synthesized according to the GP from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg, 1.2 mmol, 1.2 equiv), 2-chloroanisole (0.38 mL, 3.0 mmol, 3.0 equiv), and Bi(OTf)3 (13 mg, 0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless solid (266 mg, 77%; r.r. = >98:2).
Fe Catalysis : Compound 4g was synthesized according to the GP from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.2 equiv), 2-chloroanisole (0.38 mL, 3.0 mmol, 3.0 equiv) and FeCl3∙6H2O (14 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the product as colorless solid (235 mg, 68%; r.r. = >98:2).
Mp 89.0 °C; Rf = 0.49 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3310 (w), 2976 (w), 1730 (s), 1634 (s), 1604 (m), 1578 (m), 1525 (s), 1489 (s), 1372 (w), 1342 (m), 1292 (s), 1255 (s), 1188 (s), 1093 (s), 1063 (s), 1023 (s), 919 (w), 875 (m), 795 (m), 689 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 7.85–7.79 (m, 2 H), 7.55–7.41 (m, 4 H), 7.33 (dd, J = 8.5, 2.2 Hz, 1 H), 7.19 (d, J = 6.6 Hz, 1 H), 6.93–6.89 (m, 1 H), 5.67 (d, J = 6.8 Hz, 1 H), 4.32–4.15 (m, 2 H), 3.89 (s, 3 H), 1.25 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 170.8, 166.4, 155.1, 133.5, 131.9, 130.0, 128.9, 128.7, 127.2, 127.0, 123.0, 112.2, 62.3, 56.2, 55.9, 14.03.
MS (ESI): m/z [M + H]+ calcd for C18H19ClNO4: 348.1; found: 348.0.
HRMS (MALDI): m/z [M + H]+ calcd for C18H19ClNO4: 348.0997; found: 348.0996.
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Ethyl 2-Benzamido-2-(3-bromo-4-methoxyphenyl)acetate (4h)
Bi Catalysis : Compound 4h was synthesized according to the GP from benzamide (121 mg, 1.0 mmol), ethyl glyoxalate (122 mg, 1.2 mmol), 2-bromoanisole (0.37 mL, 3.0 mmol, 3.0 equiv), and Bi(OTf)3 (13 mg, 0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the product as a colorless solid (344 mg, 88%; r.r. = >98:2).
Fe Catalysis : Compound 4h was synthesized according to the GP from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.30 mL, 1.5 mmol, 1.5 equiv), 2-bromoanisole (0.37 mL, 3.0 mmol, 3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a colorless solid (289 mg, 74%; r.r. = >98:2).
Mp 103.7 °C; Rf = 0.51 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3387 (w), 2992 (w), 2942 (w), 1739 (s), 1654 (s), 1602 (w), 1580 (w), 1519 (m), 1498 (m), 1484 (s), 1443 (m), 1367 (w), 1342 (w), 1286 (m), 1261 (s), 1213 (s), 1179 (s), 1152 (m), 1096 (w), 1055 (m), 799 (m), 713 (s), 688 (m), 665 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 7.85–7.80 (m, 2 H), 7.61 (d, J = 2.2 Hz, 1 H), 7.52 (m, 1 H), 7.44 (dd, J = 10.2, 4.6 Hz, 2 H), 7.38 (dd, J = 8.5, 2.2 Hz, 1 H), 7.18 (d, J = 6.6 Hz, 1 H), 6.90–6.86 (m, 1 H), 5.68 (d, J = 6.7 Hz, 1 H), 4.32–4.16 (m, 2 H), 3.89 (s, 3 H), 1.25 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 170.9, 166.6, 156.2, 133.7, 132.1, 132.1, 130.6, 128.8, 127.9, 127.3, 112.3, 112.2, 62.4, 56.5, 55.9, 14.2.
MS (ESI): m/z [M + H]+ calcd for C18H19BrNO4: 392.0; found: 392.9.
HRMS (MALDI): m/z [M + H]+ calcd for C18H19BrNO4: 392.0492; found: 392.0491.
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Ethyl 2-Benzamido-2-(3-iodo-4-methoxyphenyl)acetate (4i)
Bi Catalysis : Compound 4i was synthesized according to the GP from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg, 1.2 mmol, 1.2 equiv), 2-iodoanisole (0.40 mL, 3.0 mmol, 3.0 equiv), and Bi(OTf)3 (13 mg, 0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the product as a colorless solid (355 mg, 81%; r.r. = >98:2).
Fe Catalysis : Compound 4i was synthesized according to the GP from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg, 1.2 mmol, 1.2 equiv), 2-iodoanisole (0.40 mL, 3.0 mmol, 3.0 equiv), and Fe(ClO4)3 (7 mg, 0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless solid (333 mg, 76%; r.r. = >98:2).
Mp 120.6 °C; Rf = 0.54 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3390 (w), 2362 (w), 1840 (s), 1655 (s), 1600 (w), 1579 (w), 1518 (m), 1483 (s), 1367 (w), 1343 (w), 1286 (m), 1259 (m), 1214 (s), 1180 (s), 1153 (m), 1097 (w), 1048 (m), 1012 (s), 927 (w), 799 (m), 714 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 7.86–7.78 (m, 3 H), 7.56–7.38 (m, 4 H), 7.17 (d, J = 6.6 Hz, 1 H), 6.80 (d, J = 8.5 Hz, 1 H), 5.65 (d, J = 6.8 Hz, 1 H), 4.32–4.15 (m, 2 H), 3.87 (s, 3 H), 1.25 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.0, 166.6, 158.4, 138.2, 133.7, 132.1, 131.1, 129.0, 128.8, 127.3, 111.1, 86.5, 62.4, 56.6, 55.7, 14.1.
MS (ESI): m/z [M]+ calcd for C18H18INO4: 439.0; found: 439.2.
HRMS (MALDI): m/z [M + H]+ calcd for C18H19INO4: 440.0353; found: 440.0345.
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Ethyl 2-Benzamido-2-(5-bromo-2-methoxyphenyl)acetate (4j)
Bi Catalysis : Compound 4j was synthesized according to the GP from benzamide (121 mg, 1.0 mmol), ethyl glyoxalate (122 mg, 1.2 mmol), 4-bromoanisole (0.38 mL, 3.0 mmol, 3.0 equiv), and Bi(OTf)3 (33 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 16 h at 100 °C. Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the product as a colorless solid (161 mg, 41%; r.r. = >98:2).
Fe Catalysis : Compound 4j was synthesized according to the GP from benzamide (121 mg, 1.0 mmol), ethyl glyoxalate (0.24 mL, 1.2 mmol), 4-bromoanisole (0.38 mL, 3.0 mmol, 3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 16 h at 100 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a colorless solid (132 mg, 34%; r.r. = >98:2).
Mp 129.2 °C; Rf = 0.56 (cyclohexane/EtOAc = 7:3).
IR (ATR): 1738 (m), 1638 (s), 1576 (m), 1520 (m), 1486 (s), 1365 (s), 1337 (m), 1315 (s), 1247 (s), 1188 (s), 1176 (s), 1131 (m), 1087 (s), 1026 (s), 900 (m), 868 (m), 801 (s), 759 (w), 718 (m), 688 (s), 669 (s), 653 (s), 618 (s), 590 (s), 539 (m), 500 cm–1 (w).
1H NMR (400 MHz, CDCl3): δ = 7.80 (d, J = 7.3 Hz, 2 H), 7.56 (d, J = 2.4 Hz, 1 H), 7.53–7.38 (m, 4 H), 7.28–7.24 (m, 1 H), 6.82–6.75 (m, 1 H), 5.88 (d, J = 8.0 Hz, 1 H), 4.27–4.17 (m, 2 H), 3.84 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 170.7, 166.7, 156.4, 134.1, 133.5, 132.5, 131.9, 128.7, 128.0, 127.3, 113.3, 113.0, 62.0, 56.1, 53.4, 14.2.
MS (ESI): m/z [M + H]+ calcd for C18H19BrNO4 392.1; found: 392.1.
Anal. Calcd for C18H18BrNO4: C, 55.12; H, 4.63; N, 3.57. Found: C, 54.86; H, 4.50; N, 3.42.
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Ethyl 2-Benzamido-2-(5-iodo-2-methoxyphenyl)acetate (4k)
Bi Catalysis : Compound 4k was synthesized according to the GP from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg, 1.2 mmol, 1.2 equiv), 4-iodoanisole (702 mg, 3.0 mmol, 3.0 equiv), and Bi(OTf)3 (33 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 16 h at 100 °C. Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the product as a colorless solid (261 mg, 59%; r.r. = >98:2).
Fe Catalysis : Compound 4k was synthesized according to the GP from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.2 equiv), 4-iodoanisole (702 mg, 3.0 mmol, 3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless solid (221 mg, 50%; r.r. = >98:2).
Mp 102.4 °C; Rf = 0.46 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3277 (w), 3054 (w), 2933 (w), 2835 (w), 1739 (s), 1637 (s), 1602 (w), 1578 (w), 1523 (m), 1486 (s), 1456 (m), 1391 (w), 1366 (w), 1336 (m), 1317 (m), 1294 (m), 1247 (s), 1188 (s), 1134 (m), 1093 (m), 1025 (s), 800 (m), 689 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 7.83–7.75 (m, J = 13.0, 7.6 Hz, 2 H), 7.75–7.68 (m, 1 H), 7.63–7.37 (m, 4 H), 7.31–7.20 (m, 1 H), 6.71–6.64 (m, 1 H), 5.86 (d, J = 8.0 Hz, 1 H), 4.26–4.15 (m, 2 H), 3.82 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 170.7, 166.7, 157.2, 139.2, 138.6, 134.1, 131.9, 128.7, 128.4, 127.3, 113.5, 83.2, 62.0, 55.9, 53.3, 14.3.
MS (ESI): m/z [M + Na]+ calcd for C18H18INO4Na: 462.0; found: 462.2.
HRMS (MALDI): m/z [M + H]+ calcd for C18H19INO4: 440.0353; found: 440.0347.
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Ethyl 2-Benzamido-2-(2,5-dimethylphenyl)acetate (4l)
Bi Catalysis : Compound 4l was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), p-xylene (0.19 mL, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless oil (62 mg, 40%).
Fe Catalysis : Compound 4l was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.2 equiv), p-xylene (0.19 mL, 1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless oil (53 mg, 32%); Rf = 0.38 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3338 (w), 2977 (w), 2925 (w), 2869 (w), 1737 (s), 1638 (s), 1578 (w), 1531 (s), 1489 (m), 1366 (w), 1344 (s), 1285 (m), 1219 (m), 1198 (s), 1077 (w), 1021 (m), 808 (w), 689 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 7.4 Hz, 2 H), 7.55–7.41 (m, 3 H), 7.13–7.01 (m, 4 H), 5.93 (d, J = 7.0 Hz, 1 H), 4.35–4.11 (m, 2 H), 2.51 (s, 3 H), 2.30 (s, 3 H), 1.29–1.19 (m, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.6, 166.5, 136.1, 135.0, 133.8, 133.7, 131.8, 130.9, 129.2, 128.6, 127.2, 127.0, 61.9, 53.6, 21.0, 19.1, 14.0.
MS (ESI): m/z [M + H]+ calcd for C19H22NO3: 312.2; found: 312.2.
HRMS (MALDI): m/z [M + H]+ calcd for C19H22NO3: 312.1594; found 312.1595.
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Ethyl 2-Benzamido-2-(3-methyl-5-pivalamidophenyl)acetate (4m)
Bi Catalysis : Compound 4m was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), 3-methylpivalanilide (287 mg, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (16 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 100 °C. Purification by chromatography (n-hexane/EtOAc 4:1) yielded the product as a yellow solid (13 mg, 67%; r.r. = >98:2).
Fe Catalysis : Compound 4m was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.0 equiv), 3-methylpivalanilide (287 mg, 1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 100 °C. Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the product as a yellow solid (158 mg, 80%; r.r. = 71:29).
Mp 157–159 °C; Rf = 0.5 (n-hexane/EtOAc = 1:1).
IR (ATR): 3244 (w), 2962 (w), 1742 (s), 1666 (m), 1638 (s), 1600 (m), 1582 (w), 1524 (s), 1505 (s), 1481 (m), 1443 (m), 1399 (m), 1387 (m), 1369 (m), 1335 (s), 1252 (m), 1194 (s), 1158 (s), 1105 (m), 1076 (m), 1019 (m), 949 (w), 911 (m), 872 (m), 839 (w), 829 (w), 814 (w), 796 (w), 769 (m), 691 (s), 665 (m), 596 (m), 567 (w), 519 (w), 489 cm–1 (w).
1H NMR (400 MHz, CDCl3): δ (major regioisomer) = 7.80–7.78 (m, 2 H), 7.52–7.48 (m, 1 H), 7.44–7.37 (m, 4 H), 7.31 (br s, 1 H), 7.23 (d, J = 8.2 Hz, 1 H), 7.08 (br d, J = 6.7 Hz, 1 H), 5.90 (d, J = 6.9 Hz, 1 H), 4.27–4.12 (m, 2 H), 2.53 (s, 3 H), 1.30 (s, 9 H), 1.22 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ (major regioisomer) = 176.8, 171.6, 166.7, 138.2, 138.1, 133.8, 131.9, 131.2, 128.7, 127.2, 127.2, 122.3, 118.1, 62.1, 53.4, 39.7, 27.7, 19.7, 14.1.
MS (ESI): m/z [M + H]+ calcd for C23H28N2O4: 396.2; found: 419.1.
HRMS (MALDI): m/z [M + H]+ calcd for C23H28N2O4: 397.2122; found: 397.2182.
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Ethyl 3-(1-Benzamido-2-ethoxy-2-oxoethyl)-4-methoxybenzoate (4n)
Bi Catalysis : Compound 4n was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), ethyl 4-methoxybenzoate (360 mg, 2.0 mmol, 4.0 equiv), and Bi(OTf)3 (16 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 72 h at 100 °C. Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the product as a yellow oil (77 mg, 40%; r.r. = >98:2).
Fe Catalysis : Compound 4n was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.0 equiv), ethyl 4-methoxybenzoate (270 mg, 1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 100 °C. Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the product as a yellow oil (128 mg, 66%; r.r. = 71:28); Rf = 0.3 (hexane/EtOAc = 7:3).
IR (ATR): 3342 (w), 2981 (w), 2843 (w), 1741 (m), 1711 (s), 1650 (s), 1608 (m), 1580 (m), 1506 (m), 1484 (m), 1465 (m), 1445 (m), 1391 (w), 1368 (m), 1322 (m), 1297 (m), 1265 (s), 1238 (s), 1204 (s), 1188 (s), 1130 (s), 1103 (m), 1023 (s), 913 (m), 862 (m), 831 (m), 801 (m), 771 (m), 713 (s), 692 (m), 647 (m), 630 (m), 589 (m), 541 (m), 473 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 8.13 (d, J = 2.1 Hz, 1 H), 8.04 (dd, J = 8.6, 2.2 Hz, 1 H), 7.82–7.79 (m, 2 H), 7.53–7.43 (m, 3 H), 7.27 (br s, 1 H), 6.93 (d, J = 8.7 Hz, 1 H), 6.00 (d, J = 8.0 Hz, 1 H), 4.35 (q, J = 7.1 Hz, 2 H), 4.20 (q, J = 7.1 Hz, 2 H), 3.92 (s, 3 H), 1.38 (t, J = 7.1 Hz, 3 H), 1.20 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.86, 166.73, 166.11, 160.76, 134.16, 132.20, 132.13, 131.84, 128.69, 127.31, 125.93, 123.56, 110.71, 61.98, 61.01, 56.06, 53.61, 14.53, 14.23.
MS (ESI): m/z [M + Na]+ calcd for C21H23NO6Na: 408.1; found: 408.1.
HRMS (MALDI): m/z [M + H]+ calcd for C21H24NO6 386.1598; found: 386.1600.
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Ethyl 2-Benzamido-2-(3,4,5-trimethoxyphenyl)acetate (4o)
Bi Catalysis : Compound 4o was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), 1,2,3-trimethoxybenzene (253 mg, 3.0 mmol, 3.0 equiv), Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%), and in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 7:3) yielded the product as a colorless oil (127 mg, 68%; r.r. = >98:2).
Fe Catalysis : Compound 4o was synthesized according to the GP from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.2 equiv), 1,2,3-trimethoxybenzene (505 mg, 3.0 mmol, 3.0 equiv), Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%), and 2,2′-bipyridine (0.06 mmol, 6 mol%, 9 mg) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 100 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 7:3) yielded the product as a colorless oil (216 mg, 58%; r.r. = >98:2); Rf = 0.23 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3347 (w), 2979 (w), 2939 (w), 2837 (w), 1721 (m), 1670 (m), 1600 (m), 1581 (m), 1516 (m), 1494 (s), 1465 (w), 1418 (m), 1369 (m), 1313 (m), 1278 (s), 1244 (s), 1203 (s), 1172 (s), 1092 (s), 1055 (s), 1015 (s), 964 (m), 909 (m), 873 (m), 798 (m), 746 (m), 713 (m), 692 (m), 667 (m), 570 (m), 514 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 7.83–7.79 (m, 2 H), 7.52–7.47 (m, 1 H), 7.45–7.40 (m, 2 H), 7.32 (d, J = 7.8 Hz, 1 H), 7.12 (d, J = 8.6 Hz, 1 H), 6.67–6.64 (m, 1 H), 5.86 (d, J = 7.9 Hz, 1 H), 4.31–4.15 (m, 2 H), 3.95 (s, 3 H), 3.86 (s, 3 H), 3.86 (s, 3 H), 1.23 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.5, 166.7, 154.3, 151.8, 142.2, 134.3, 131.8, 128.7, 127.3, 124.6, 123.5, 107.3, 61.9, 61.1, 60.9, 56.1, 53.6, 14.3.
MS (ESI): m/z [M + Na]+ calcd for C20H23NO6Na: 396.1; found: 396.3.
HRMS (MALDI): m/z [M + H]+ calcd for C21H24NO6: 374.1598; found: 374.15988.
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Ethyl 2-Benzamido-2-(4-methoxy-2,6-dimethylphenyl)acetate (4p)
Bi Catalysis : Compound 4p was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), 1-methoxy-3,5-dimethylbenzene (204 mg, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (n-hexane/EtOAc = 9:1 → 4:1) yielded the product as a colorless oil (84 mg, 50%; r.r. = 67:33).
Fe Catalysis : Compound 4p was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.2 equiv), 1-methoxy-3,5-dimethylbenzene (204 mg, 1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 100 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a yellowish oil (106 mg, 62%; r.r. = 50:50); Rf = 0.57 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3449 (w), 3319 (s), 2977 (m), 2840 (w), 2099 (s), 1739 (s), 1655 (s), 1651 (s), 1624 (m), 1599 (m), 1580 (m), 1512 (s), 1482 (s), 1446 (m), 1367 (m), 1318 (s), 1251 (s), 1207 (s), 1186 (s), 1147 (s), 1094 (s), 1024 (s), 1002 (m), 973 (m), 931 (m), 906 (m), 887 (m), 862 (m), 848 (m), 810 (s), 745 (m), 709 (s), 691 (s), 672 (m), 645 (m), 608 (m), 590 (m), 546 (m), 526 (m), 502 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 7.82–7.77 (m, 2 H), 7.50–7.39 (m, 3 H), 7.17 (d, J = 6.1 Hz, 1 H), 6.75–6.44 (m, 2 H), 6.23–6.12 (m, 1 H), 4.32–4.10 (m, 2 H), 3.85–3.74 (m, 3 H), 2.56 (s, 2 H), 2.49 (s, 2 H), 2.31 (s, 2 H), 1.28–1.15 (m, 3 H) (peaks not assigned to regioisomers).
13C NMR (101 MHz, CDCl3): δ = 171.9, 171.5, 166.6, 166.4, 158.7, 157.5, 139.0, 138.3, 134.5, 133.9, 131.7, 131.5, 128.6, 128.5, 127.2, 127.1, 126.3, 124.2, 122.2, 114.4, 109.7, 62.0, 61.4, 55.5, 55.0, 52.5, 50.2, 21.5, 20.8, 19.9, 14.2, 14.1 (peaks not assigned to regioisomers).
MS (ESI): m/z [M + H]+ calcd for C20H24NO4: 342.1; found: 342.2.
HRMS (MALDI): m/z [M + H]+ calcd for C20H24NO4: 342.1053; found: 342.1696.
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Ethyl 2-Benzamido-2-(2-methoxynaphthalen-1-yl)acetate (4q)
Bi Catalysis : Compound 4q was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), 2-methoxynaphthalene (237 mg, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the product as an orange oil (89 mg, 49%).
Fe Catalysis : Compound 4q was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.2 equiv), 2-methoxynaphthalene (237 mg, 1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as an orange oil (123 mg, 64%); Rf = 0.31 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3446 (w), 2979 (w), 2841 (w), 2099 (w), 1739 (s), 1651 (s), 1626 (m), 1598 (m), 1580 (m), 1560 (m), 1512 (s), 1482 (s), 1473 (s), 1445 (m), 1386 (s), 1367 (m), 1319 (m), 1267 (s), 1251 (s), 1204 (s), 1185 (s), 1147 (s), 1086 (s), 1024 (s), 906 (m), 888 (w), 864 (m), 848 (m), 810 (s), 783 (m), 709 (s), 692 (s), 672 (m), 645 (m), 605 (m), 589 (m), 546 (m), 526 (m), 502 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 8.36 (d, J = 8.7 Hz, 1 H), 7.88 (d, J = 9.0 Hz, 1 H), 7.84–7.78 (m, 3 H), 7.62–7.57 (m, 1 H), 7.50–7.36 (m, 5 H), 7.30 (d, J = 9.0 Hz, 1 H), 6.86 (d, J = 8.9 Hz, 1 H), 4.23–4.16 (m, 2 H), 3.99 (s, 3 H), 1.16 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.8, 167.0, 155.3, 134.4, 132.6, 131.7, 130.8, 129.6, 128.7, 128.6, 127.8, 127.4, 124.1, 123.1, 119.5, 113.1, 61.7, 56.6, 49.0, 14.3.
MS (ESI): m/z [M + H]+ calcd for C22H22NO4: 364.2; found: 364.3.
HRMS (MALDI): m/z [M + H]+ calcd for C22H22NO4: 364.1543; found: 364.1544.
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Ethyl 2-Benzamido-2-(pyren-4-yl)acetate (4r)
Bi Catalysis : Compound 4r was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), pyrene (303 mg, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the product as a colorless solid (111 mg, 54%; r.r. = >98:2).
Fe Catalysis : Compound 4r was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.2 equiv), pyrene (303 mg, 1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 20:1 → 9:1 → 4:1) yielded the product as a colorless solid (115 mg, 57%; r.r. = >98:2).
Mp 207.3 °C; Rf = 0.48 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3331 (w), 2985 (w), 2360 (w), 2342 (w), 1740 (s), 1635 (s), 1602 (w), 1579 (w), 1517 (w), 1489 (m), 1374 (w), 1349 (m), 1313 (w), 1204 (s), 1183 (m), 1150 (m), 1089 (m), 1021 (m), 845 (s), 824 (m), 692 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 8.61–8.54 (m, 1 H), 8.25–8.01 (m, 8 H), 7.86–7.79 (m, 2 H), 7.49 (dd, J = 14.0, 6.6 Hz, 1 H), 7.40 (t, J = 7.5 Hz, 2 H), 7.26 (s, 1 H), 6.83 (d, J = 7.3 Hz, 1 H), 4.36–4.15 (m, 2 H), 1.18 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.8, 166.9, 133.8, 132.0, 131.8, 131.4, 130.9, 130.1, 129.3, 128.9, 128.7, 128.2, 127.4, 127.3, 126.4, 125.8, 125.7, 125.4, 125.2, 125.1, 124.8, 122.8, 62.3, 54.3, 14.2.
MS (ESI): m/z [M]+ calcd for C27H21NO3: 407.2; found: 407.2.
HRMS (MALDI): m/z [M]+ calcd for C27H21NO3: 407.1516; found: 407.1513.
#
Ethyl 2-Mesityl-2-(4-methoxybenzamido)acetate (5a)
Bi Catalysis : Compound 5a was synthesized according to the GP from 4-methoxybenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless solid (145 mg, 81%).
Fe Catalysis : Compound 5a was synthesized according to the GP from 4-methoxybenzamide (73 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and FeCl3·6H2O (3 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1 → 7:3) yielded the product as a colorless solid (166 mg, 94%).
Mp 109.8 °C; Rf = 0.36 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3432 (w), 2921 (m), 2851 (m), 1726 (m), 1652 (s), 1605 (m), 1524 (w), 1486 (s), 1366 (m), 1349 (m), 1306 (m), 1252 (s), 1214 (w), 1193 (s), 1175 (s), 1088 (m), 1021 (s), 845 (m), 767 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 8.7 Hz, 2 H), 7.08 (d, J = 6.3 Hz, 1 H), 6.92 (d, J = 8.7 Hz, 2 H), 6.85 (s, 2 H), 6.18 (d, J = 6.5 Hz, 1 H), 4.32–4.11 (m, 2 H), 3.84 (s, 3 H), 2.47 (s, 6 H), 2.25 (s, 3 H), 1.22 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 172.1, 166.1, 162.5, 137.7, 137.1, 131.1, 130.1, 129.0, 126.3, 113.9, 62.1, 55.5, 52.8, 21.0, 20.5, 14.2.
MS (ESI): m/z [M + H]+ calcd for C21H26NO4 356.2; found: 356.2.
HRMS (MALDI): m/z [M + H]+ calcd for C21H26NO4 356.1856; found: 356.1856.
#
Ethyl 2-(4-Bromobenzamido)-2-mesitylacetate (5b)
Bi Catalysis : Compound 5b was synthesized according to the GP from 4-bromobenzamide (100 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless solid (161 mg, 80%).
Fe Catalysis : Compound 5b was synthesized according to the GP from 4-bromobenzamide (100 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and FeCl3·6H2O (3 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a colorless solid (172 mg, 85%).
Mp 89.5 °C; Rf = 0.70 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3427 (w), 2969 (w), 1731 (s), 1660 (s), 1607 (w), 1588 (m), 1566 (w), 1506 (s), 1473 (s), 1366 (m), 1352 (w), 1309 (s), 1256 (m), 1212 (w), 1189 (s), 1159 (m), 881 (m), 848 (m), 777 (m), 751 (s), 613 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 7.71–7.51 (m, 4 H), 7.14 (d, J = 6.2 Hz, 1 H), 6.86 (s, 2 H), 6.15 (d, J = 6.5 Hz, 1 H), 4.33–4.12 (m, 2 H), 2.46 (s, 6 H), 2.25 (s, 3 H), 1.22 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.8, 165.6, 137.9, 137.1, 132.89, 132.0, 130.8, 130.2, 128.8, 126.6, 62.3, 52.9, 21.0, 20.5, 14.2.
MS (ESI): m/z [M + Na]+ calcd for C20H22BrNO3Na: 428.1; found 428.2.
HRMS (MALDI): m/z [M + H]+ calcd for C20H23BrNO3: 404.0856; found: 404.0854.
#
Ethyl 2-Mesityl-2-(4-nitrobenzamido)acetate (5c)
Bi Catalysis : Compound 5c was synthesized according to the GP from 4-nitrobenzamide (83 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless solid (125 mg, 68%).
Fe Catalysis : Compound 5c was synthesized according to the GP from 4-nitrobenzamide (166 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), and FeCl3·6H2O (14 mg, 0.050 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a colorless solid (329 mg, 89%).
Mp 119.2 °C; Rf = 0.36 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3349 (w), 2978 (w), 1731 (s), 1634 (m), 1598 (m), 1525 (s), 1488 (m), 1460 (w), 1343 (m), 1297 (m), 1240 (s), 1148 (w), 1077 (m), 1024 (m), 928 (w), 876 (m), 853 (m), 799 (m), 761 (w), 720 (s), 679 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 8.28 (d, J = 8.7 Hz, 2 H), 7.95 (d, J = 8.7 Hz, 2 H), 7.27–7.22 (m, 1 H), 6.87 (s, 2 H), 6.15 (d, J = 6.4 Hz, 1 H), 4.34–4.12 (m, 2 H), 2.46 (s, 6 H), 2.26 (s, 3 H), 1.23 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.6, 164.6, 149.9, 139.6, 138.2, 137.1, 130.4, 130.3, 128.4, 124.0, 62.5, 53.1, 21.0, 20.5, 14.2.
MS (ESI): m/z [M + Na]+ calcd for C20H22N2O5Na: 393.1; found: 393.3.
HRMS (MALDI): m/z [M + Na]+ calcd for C20H22N2O5Na: 393.1421; found: 393.1421.
#
Ethyl 2-(2-Chloroacetamido)-2-mesitylacetate (5d)
Bi Catalysis : Compound 5d was synthesized according to the GP from 2-chloroacetamide (47 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1 → 7:3) yielded the product as a colorless oil (121 mg, 81%).
Fe Catalysis : Compound 5d was synthesized according to the GP from 2-chloroacetamide (47 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and FeCl3·6H2O (3 mg, 0.010 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1 → 7:3) yielded the product as a colorless oil (131 mg, 88%); Rf = 0.30 = (cyclohexane/ EtOAc = 7:3).
IR (ATR): 3307 (w), 2975 (w), 1733 (s), 1660 (m), 1519 (m), 1463 (w), 1370 (w), 1311 (m), 1195 (s), 1150 (m), 1096 (m), 1017 (s), 925 (w), 853 (m), 769 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 6.2 Hz, 1 H), 6.87–6.82 (m, 2 H), 5.99 (d, J = 7.2 Hz, 1 H), 4.32–3.97 (m, 4 H), 2.40 (s, 6 H), 2.25 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.1, 165.3, 138.4, 137.1, 130.4, 130.2, 129.9, 69.3, 62.2, 52.5, 42.7, 21.0, 20.4, 20.1, 14.2.
MS (ESI): m/z [M + Na]+ calcd for C15H20ClNO3Na: 320.1; found: 320.2.
HRMS (MALDI): m/z [M + H]+ calcd for C15H21ClNO3: 298.1205; found: 298.1202.
#
Ethyl 2-Acetamido-2-mesitylacetate (5e)
Bi Catalysis : Compound 5e was synthesized according to the GP from acetamide (59 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg, 1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), and Bi(OTf)3 (33 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1 → 1:1) yielded the product as a colorless solid (209 mg, 79%).
Fe Catalysis : Compound 5e was synthesized according to the GP from acetamide (30 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), and FeCl3·6H2O (7 mg, 0.020 mmol, 2 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1 → 1:1) yielded the product as a colorless solid (93 mg, 70%).
Mp 95.8 °C; Rf = 0.29 (cyclohexane/EtOAc = 1:1).
IR (ATR): 3302 (m), 2976 (w), 2360 (w), 1748 (s), 1649 (s), 1524 (s), 1366 (m), 1310 (w), 1281 (w), 1211 (s), 1192 (s), 1149 (m), 1124 (m), 1022 (m), 855 (m), 832 (w), 797 (w), 644 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 6.84 (s, 2 H), 6.40 (d, J = 6.4 Hz, 1 H), 6.02 (d, J = 7.2 Hz, 1 H), 4.28–4.07 (m, 2 H), 2.38 (s, 6 H), 2.25 (s, 3 H), 2.01 (s, 3 H), 1.19 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.9, 169.4, 137.8, 137.0, 131.2, 130.1, 62.0, 52.2, 23.2, 21.0, 20.4, 14.2.
MS (ESI): m/z [M + Na]+ calcd for C15H21NO3Na: 286.1; found: 286.2.
HRMS (MALDI): m/z [M + H]+ calcd for C15H22NO3: 264.1594; found: 264.1597.
#
Ethyl 2-Mesityl-2-pivalamidoacetate (5f)
Bi Catalysis : Compound 5f was synthesized according to the GP from pivalamide (100 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg, 1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 1 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless oil (248 mg, 81%).
Fe Catalysis : Compound 5f was synthesized according to the GP from pivalamide (50 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv) and FeCl3·6H2O (3 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless oil (122 mg, 80%); Rf = 0.44 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3448 (w), 2961 (m), 1731 (s), 1670 (s), 1611 (w), 1494 (s), 1395 (w), 1366 (m), 1308 (m), 1257 (m), 1185 (s), 1100 (m), 1016 (m), 907 (w), 852 (m), 770 cm–1 (w).
1H NMR (300 MHz, CDCl3): δ = 6.83 (s, 2 H), 6.68 (d, J = 6.0 Hz, 1 H), 5.96 (d, J = 6.7 Hz, 1 H), 4.30–4.06 (m, 2 H), 2.40 (s, 6 H), 2.24 (s, 3 H), 1.24–1.16 (m, 12 H).
13C NMR (101 MHz, CDCl3): δ = 177.7, 172.0, 137.60, 137.0, 131.1, 130.1, 62.0, 52.4, 38.9, 27.7, 21.0, 20.4, 14.2.
MS (ESI): m/z [M + H]+ calcd for C18H28NO3: 306.2; found: 306.2.
HRMS (MALDI): m/z [M + H]+ calcd for C18H28NO3: 306.2064; found: 306.2064.
#
Ethyl 2-Acrylamido-2-mesitylacetate (5g)
Bi Catalysis : Compound 5g was synthesized according to the GP from acrylamide (71 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg, 1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 1 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless solid (226 mg, 82%).
Fe Catalysis : Compound 5g was synthesized according to the GP from acrylamide (71 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), and FeCl3·6H2O (7 mg, 0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 7:3) yielded the product as a colorless solid (233 mg, 85%).
Mp 117.2 °C; Rf = 0.43 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3304.43 (s), 2983 (s), 1748 (s), 1652 (m), 1614 (m), 1519 (s), 1404 (m), 1368 (s), 1311 (s), 1209 (m), 1187 (s), 1148 (m), 1113 (m), 1072 (s), 1023 (m), 990 (m), 958 (s), 856 (m), 810 (m), 604 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 6.84 (s, 2 H), 6.59 (t, J = 16.2 Hz, 1 H), 6.29 (dd, J = 16.9, 1.0 Hz, 1 H), 6.16 (dd, J = 17.0, 10.1 Hz, 1 H), 6.07 (d, J = 6.9 Hz, 1 H), 5.66 (dd, J = 10.1, 1.0 Hz, 1 H), 4.30–4.09 (m, 2 H), 2.40 (s, 6 H), 2.24 (s, 3 H), 1.20 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.8, 164.7, 137.8, 137.1, 130.9, 130.4, 130.1, 127.4, 62.1, 52.4, 21.0, 20.4, 14.2.
MS (ESI): m/z [M + H]+ calcd for C16H22NO3: 276.2; found: 276.2.
HRMS (MALDI): m/z [M + H]+ calcd for C16H22NO3: 276.1594; found: 276.1595.
#
Ethyl 2-[(Ethoxycarbonyl)amino]-2-mesitylacetate (5h)
Bi Catalysis : Compound 5h was synthesized according to the GP from ethyl carbamate (45 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as colorless crystals (126 mg, 86%).
Fe Catalysis : Compound 5h was synthesized according to the GP from ethyl carbamate (45 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and FeCl3·6H2O (3 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a colorless solid (121 mg, 83%).
Mp 54.1 °C; Rf = 0.40 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3374 (m), 2964 (s), 1705 (s), 1612 (w), 1509 (m), 1391 (w), 1366 (m), 1308 (s), 1263 (w), 1220 (m), 1173 (w), 1091 (m), 1053 (s), 947 (w), 847 (w), 781 (m), 732 (w), 694 (w), 639 cm–1 (w).
1H NMR (500 MHz, CDCl3): δ = 6.84 (s, 2 H), 5.83–5.71 (m, 1 H), 5.67 (d, J = 6.1 Hz, 1 H), 4.16 (d, J = 91.0 Hz, 4 H), 2.37 (s, 6 H), 2.25 (s, 3 H), 1.27–1.17 (m, 6 H).
13C NMR (126 MHz, CDCl3): δ = 171.6, 155.8, 137.5, 136.7, 131.2, 129.8, 61.7, 61.0, 53.3, 20.7, 20.0, 14.4, 14.0.
MS (ESI): m/z [M + H]+ calcd for C16H24NO4: 294.2; found: 294.2.
HRMS (MALDI): m/z [M + H]+ calcd for C16H24NO4: 294.1700; found: 294.1700.
#
Ethyl 2-{[Benzyloxy)carbonyl]amino}-2-mesitylacetate (5i)
Bi Catalysis : Compound 5i was synthesized according to the GP from benzyl carbamate (76 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a colorless solid (116 mg, 65%).
Fe Catalysis : Compound 5i was synthesized according to the GP from benzyl carbamate (76 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and FeCl3·6H2O (3 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a colorless solid (91 mg, 51%).
Mp 73.5 °C; Rf = 0.38 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3363 (m), 2957 (s), 2360 (m), 1728 (m), 1701 (s), 1521 (s), 1479 (w), 1455 (w), 1370 (w), 1306 (m), 1231 (s), 1048 (s), 986 (m), 916 (w), 824 (m), 794 (m), 752 (s), 700 (s), 606 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 7.43–7.01 (m, 5 H), 6.85 (s, 2 H), 5.88–5.55 (m, 2 H), 5.17–4.99 (m, 2 H), 4.29–4.06 (m, 2 H), 2.38 (s, 6 H), 2.26 (s, 3 H), 1.19 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.7, 155.8, 137.8, 136.9, 136.4, 131.3, 130.1, 130.1, 128.7, 128.3, 67.2, 62.0, 53.7, 21.0, 20.3, 14.2.
MS (ESI): m/z [M + Na]+ calcd for C21H25NO4Na: 378.2; found: 378.3.
HRMS (MALDI): m/z [M + Na]+ calcd for C21H25NO4Na: 378.1677; found: 378.1681.
#
Ethyl 2-{[(Allyloxy)carbonyl]amino}-2-mesitylacetate (5j)
Bi Catalysis : Compound 5j was synthesized according to the GP from allyloxycarbamate (51 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the product as a colorless oil (128 mg, 84%).
Fe Catalysis : Compound 5j was synthesized according to the GP from allyloxycarbamate (102 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), and FeCl3·6H2O (14 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 20:1 → 9:1 → 4:1) yielded the product as a colorless oil (215 mg, 70%); Rf = 0.63 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3376 (w), 2981 (w), 1831 (w), 1718 (s), 1649 (w), 1611 (w), 1498 (m), 1369 (m), 1305 (m), 1195 (s), 1093 (m), 1053 (s), 932 (m), 852 (m), 775 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 6.84 (s, 2 H), 5.98–5.68 (m, 3 H), 5.35–5.15 (m, 2 H), 4.63–4.47 (m, 2 H), 4.30–4.07 (m, 2 H), 2.37 (s, 6 H), 2.25 (s, 3 H), 1.20 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 171.8, 155.6, 137.8, 136.9, 132.8, 131.3, 130.1, 118.0, 66.0, 62.0, 53.7, 21.0, 20.3, 14.2.
MS (ESI): m/z [M + H]+ calcd for C17H24NO4: 306.2; found: 306.2.
HRMS (MALDI): m/z [M + H]+ calcd for C17H24NO4: 306.1700; found: 306.1700.
#
Ethyl 2-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-2-mesitylacetate (5k)
Bi Catalysis : Compound 5k was synthesized according to the GP from (9H-fluoren-9-yl)methyl carbamate (120 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 3.0 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the product as a colorless oil (185 mg, 83%).
Fe Catalysis : Compound 5k was synthesized according to the GP from (9H-fluoren-9-yl)methyl carbamate (239 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), and FeCl3·6H2O (5 mg, 0.020 mmol, 2 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1) yielded the product as a colorless oil (332 mg, 75%); Rf = 0.69 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3368 (w), 2956 (w), 1718 (s), 1611 (w), 1498 (m), 1448 (m), 1305 (m), 1195 (s), 1050 (s), 852 (m), 739 (s), 621 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 7.75 (d, J = 7.5 Hz, 2 H), 7.63–7.47 (m, 2 H), 7.45–7.26 (m, 4 H), 6.86 (s, 2 H), 5.90–5.49 (m, 2 H), 4.44–4.11 (m, 5 H), 2.35 (s, 6 H), 2.27 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 171.7, 155.7 144.1, 143.9, 141.4, 137.9, 137.0, 131.1, 130.2, 127.8, 127.2, 125.2, 120.1, 67.3, 62.1, 53.8, 47.3, 21.0, 20.4, 14.2.
MS (ESI): m/z [M + Na]+ calcd for C28H29NO4Na: 466.2; found: 466.0.
HRMS (MALDI): m/z [M + Na]+ calcd for C28H29NO4Na: 466.1989; found: 466.1993.
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Ethyl 2-Benzamido-2-(5-bromothiophen-2-yl)acetate (7a)
Bi Catalysis : Compound 7a was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), 2-bromothiophene (0.15 mL, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 60 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a yellow solid (102 mg, 55%; r.r. = >98:2).
Fe Catalysis : Compound 7a was synthesized according to the GP from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.2 equiv), 2-bromothiophene (0.29 mL, 3.0 mmol, 3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a yellow solid (219 mg, 60%; r.r. = >98:2).
Mp 95.2 °C; Rf = 0.58 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3309 (w), 2995 (w), 2929 (w), 1738 (s), 1636 (s), 1604 (w), 1570 (w), 1525 (s), 1488 (m), 1371 (m), 1292 (s), 1205 (s), 1171 (m), 1123 (w), 1083 (m), 1012 (m), 810 (m), 755 (m), 716 (s), 691 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 7.7 Hz, 2 H), 7.57–7.51 (m, 1 H), 7.49–7.43 (m, 2 H), 7.16–7.08 (m, 1 H), 6.94–6.77 (m, 2 H), 5.99–5.92 (m, 1 H), 4.37–4.23 (m, 2 H), 1.32 (t, J = 7.1 Hz, 3 H) (peaks not assigned to regioisomers).
13C NMR (75 MHz, CDCl3): δ = 169.6, 166.7, 140.7, 137.8, 133.4, 132.3, 130.0, 128.8, 127.3, 126.6, 126.2, 125.7, 112.7, 62.8, 52.6, 14.2 (peaks not assigned to regioisomers).
MS (ESI): m/z [M + Na]+ calcd for C15H14BrNO3SNa: 390.0; found: 390.1.
HRMS (MALDI): m/z [M + H]+ calcd for C15H14BrNO3S: 367.9952; found: 367.9951.
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Ethyl 2-(5-Bromothiophen-2-yl)-2-[(ethoxycarbonyl)amino]acetate (7b)
Bi Catalysis : Compound 7b was synthesized according to the GP from urethane (67 mg, 0.75 mmol, 1.5 equiv), ethyl glyoxalate (51 mg, 0.5 mmol, 1.0 equiv), 2-bromothiophene (0.16 mL, 1.5 mmol), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (1.0 mL). The reaction mixture was stirred for 16 h at 60 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a yellow solid (130 mg, 77%; r.r. = >98:2).
Fe Catalysis : Compound 7b was synthesized according to the GP from urethane (89 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.2 equiv), 2-bromothiophene (0.28 mL, 3.0 mmol), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 48 h at 40 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a yellow solid (249 mg, 74%; r.r. = >98:2).
Mp 48.8 °C; Rf = 0.56 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3305 (m), 2983 (w), 2951 (w), 2904 (w), 1741 (s), 1686 (s), 1526 (m), 1499 (w), 1433 (m), 1372 (m), 1312 (m), 1295 (m), 1257 (m), 1216 (s), 1107 (s), 1061 (s), 1038 (s), 963 (s), 810 (w), 800 (w), 780 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 6.91 (d, J = 3.8 Hz, 1 H), 6.82 (d, J = 3.7 Hz, 1 H), 5.68 (s, 1 H), 5.53 (d, J = 7.4 Hz, 1 H), 4.31–4.20 (m, 2 H), 4.19–4.11 (m, 2 H), 1.31–1.23 (m, 6 H).
13C NMR (101 MHz, CDCl3): δ = 169.5, 155.6, 141.1, 129.9, 126.3, 112.6, 62.6, 61.7, 53.8, 14.6, 14.2.
MS (ESI): m/z [M + Na]+ calcd for C11H14BrNO4SNa: 358.0; found: 358.1.
HRMS (MALDI): m/z [M + K]+ calcd for C11H14BrNO4SK: 373.9464; found: 373.9453.
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Ethyl 2-Benzamido-2-(5-chlorothiophen-2-yl)acetate (7c)
Bi Catalysis : Compound 7c was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), 2-chlorothiophene (0.15 mL, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 60 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a yellow solid (119 mg, 37%; r.r. = >98:2).
Fe Catalysis : Compound 7c was synthesized according to the GP from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.2 equiv), 2-chlorothiophene (0.28 mL, 3.0 mmol, 3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a yellow low-melting solid (161 mg, 50%; r.r. = 63:37).
Rf = 0.58 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3300 (w), 2978 (w), 2929 (w), 1983 (w), 1983 (w), 1739 (s), 1635 (s), 1604 (w), 1579 (w), 1525 (s), 1587 (m), 1443 (m), 1369 (m), 1324 (m), 1290 (s), 1204 (s), 1166 (m), 1125 (m), 1086 (m), 1021 (m), 989 (m), 881 (m), 810 (m), 754 (m), 715 (s), 690 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 7.6 Hz, 2 H), 7.57–7.42 (m, 3 H), 7.12 (d, J = 6.3 Hz, 1 H), 6.95–6.76 (m, 2 H), 5.99–5.91 (m, 1 H), 4.37–4.23 (m, 2 H), 1.32 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 169.7, 166.7, 140.7, 137.8, 133.4, 132.3, 130.5, 130.0, 128.9, 127.3, 126.6, 126.2, 125.7, 62.8, 52.6, 52.6, 14.2 (peaks not assigned to regioisomers).
MS (ESI): m/z [M + Na]+ calcd for C15H14ClNO3SNa: 346.0; found: 346.2.
HRMS (MALDI): m/z [M + H]+ calcd for C15H15ClNO3S: 324.0456; found: 324.0454.
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Ethyl 2-(5-Chlorothiophen-2-yl)-2-[(ethoxycarbonyl)amino]acetate (7d)
Bi Catalysis : Compound 7d was synthesized according to the GP from urethane (67 mg, 0.75 mmol, 1.5 equiv), ethyl glyoxalate (51 mg, 0.5 mmol, 1.0 equiv), 2-chlorothiophene (0.16 mL, 1.5 mmol), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (1.0 mL). The reaction mixture was stirred for 16 h at 60 °C. Purification by chromatography (cyclohexane/EtOAc 9:1 → 4:1) yielded the product as a yellow solid (76 mg, 52%; r.r. = >98:2).
Fe Catalysis : Compound 7d was synthesized according to the GP from urethane (89 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.2 equiv), 2-chlorothiophene (0.29 mL, 3.0 mmol, 3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 48 h at 40 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a yellow solid (219 mg, 75%; r.r. = >98:2).
Mp 46.9 °C; Rf = 0.56 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3310 (m), 2985 (w) 1741 (s), 1686 (s), 1528 (m), 1443 (m), 1371 (m), 1355 (m), 1206 (s), 1045 (s), 986 (s), 964 (w), 869 (w), 780 (m), 664 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 6.84–6.82 (m, 1 H), 6.77 (d, J = 3.8 Hz, 1 H), 5.68 (s, 1 H), 5.51 (d, J = 7.3 Hz, 1 H), 4.31–4.10 (m, 4 H), 1.34–1.14 (m, 6 H).
13C NMR (75 MHz, CDCl3): δ = 169.5 155.6, 138.2, 130.4, 126.2, 125.4, 62.6, 61.7, 53.9, 14.6, 14.1.
MS (ESI): m/z [M + Na]+ calcd for C11H14ClNO4SNa: 314.0; found: 314.2.
HRMS (MALDI): m/z [M + K]+ calcd for C11H14ClNO4SK: 329.9964; found: 329.9970.
#
Ethyl 2-Benzamido-2-(5-methylthiophen-2-yl)acetate (7e)
Bi Catalysis : Compound 7e was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), 2-methylthiophene (0.15 mL, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (1.0 mL). The reaction mixture was stirred for 16 h at r.t. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless solid (97 mg, 64%; r.r. = 89:11).
Fe Catalysis : Compound 7e was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.2 equiv), 2-methylthiophene (0.15 mL, 1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 60 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a yellow solid (72 mg, 47%; r.r. = 88:12).
Mp 66–68 °C; Rf = 0.3 (cyclohexane/EtOAc = 4:1).
IR (ATR): 3315 (w), 2981 (w), 2917 (w), 1737 (s), 1637 (s), 1603 (m), 1579 (m), 1523 (s), 1486 (s), 1446 (m), 1369 (m), 1327 (m), 1294 (m), 1229 (m), 1204 (s), 1172 (s), 1122 (m), 1083 (m), 1019 (s), 976 (m), 929 (w), 883 (w), 803 (m), 754 (m), 714 (s), 691 (s), 672 (s), 622 (m), 601 (s), 579 (s), 557 (s), 537 (s), 522 (s), 505 (m), 480 (m), 472 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ (major regioisomer) = 7.83–7.79 (m, 2 H), 7.54–7.41 (m, 3 H), 7.05 (br d, J = 5.5 Hz, 1 H), 6.92–6.89 (m, 1 H), 6.64–6.60 (m, 1 H), 5.95 (d, J = 7.4 Hz, 1 H), 4.36–4.18 (m, 2 H), 2.44 (s, 3 H), 1.32–1.22 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ (major regioisomer) = 171.21, 170.29, 166.66, 140.68, 136.33, 133.80, 133.68, 132.04, 131.94, 128.73, 127.32, 127.25, 126.37, 125.81, 125.26, 122.71, 62.39, 62.09, 52.63, 50.95, 15.43, 14.17, 13.25.
MS (ESI): m/z [M + H]+ calcd for C16H18NO3: 303.1; found: 304.3.
HRMS (MALDI): m/z [M + Na]+ calcd for C16H17NO3SNa: 326.0821; found: 326.0821.
#
Ethyl 2-[(Ethoxycarbonyl)amino]-2-(5-methylthiophen-2-yl)acetate (7f)
Bi Catalysis : Compound 7f was synthesized according to the GP from urethane (67 mg, 0.75 mmol, 1.5 equiv), ethyl glyoxalate (51 mg, 0.5 mmol, 1.0 equiv), 2-methylthiophene (0.15 mL, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in DCE (4.0 mL). The reaction mixture was stirred for 16 h at 60 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a colorless oil (97 mg, 72%; r.r. = >98:2).
Fe Catalysis : Compound 7f was synthesized according to the GP from urethane (89 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.2 equiv), 2-methylthiophene (0.29 mL, 3.0 mmol, 3.0 equiv) and Fe(ClO4)3 (18 mg, 0.050 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 48 h at 40 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a yellow oil (211 mg, 78%; r.r. = 93:7); Rf = 0.56 cyclohexane/EtOAc = 7:3).
IR (ATR): 3326 (w), 2985 (w), 2933 (w), 1710 (s), 1506 (s), 1370 (m), 1317 (m), 1200 (s), 1094 (w), 1053 (s), 862 (w), 798 (m), 778 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ (major regioisomer) = 6.87–6.77 (m, 1 H), 6.62–6.51 (m, 1 H), 5.66–5.41 (m, 2 H), 4.31–4.09 (m, 4 H), 2.44 (s, 3 H), 1.29–1.19 (m, 6 H).
13C NMR (75 MHz, CDCl3): δ (major regioisomer) = 170.3, 155.7, 140.6, 136.6, 126.1, 125.2, 62.2, 61.5, 53.8, 15.4, 14.6, 14.2.
MS (ESI): m/z [M + Na]+ calcd for C12H17NO4SNa: 294.1; found: 294.4.
HRMS (MALDI): m/z [M + K]+ calcd for C12H17NO4SK: 310.0510; found: 310.0511.
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Ethyl 2-Benzamido-2-(benzofuran-2-yl)acetate (7g)
Fe Catalysis : Compound 7g was synthesized according to the GP from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.2 equiv), benzofuran (0.33 mL, 3.0 mmol, 3.0 equiv), and Fe(ClO4)3 (18 mg, 0.050 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 60 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1) yielded the product as a yellow solid (166 mg, 51%, r.r. = >98:2).
Mp 79.4 °C; Rf = 0.59 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3299 (w), 3057 (w), 2991 (w), 1751 (s), 1639 (s), 1602 (w), 1579. (w), 1526 (s), 1488 (m), 1454 (m), 1369 (w), 1336 (m), 1241 (m), 1206 (s), 1156 (s), 1094 (m), 1016 (m), 961 (m), 820 (m), 749 (s), 716 (s), 689 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 7.89–7.82 (m, 2 H), 7.60–7.42 (m, 5 H), 7.35–7.19 (m, 3 H), 6.85 (s, 1 H), 6.09 (d, J = 7.7 Hz, 1 H), 4.37–4.21 (m, 2 H), 1.28 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 168.7, 166.8, 155.1, 151.5, 133.6, 132.2, 128.8, 128.1, 127.4, 124.9, 123.3, 121.5, 111.5, 106.1, 62.8, 51.3, 14.2.
MS (ESI): m/z [M + Na]+ calcd for C19H17NO4Na: 346.1; found: 346.2.
HRMS (MALDI): m/z [M + H]+ calcd for C19H18NO4: 324.1230; found: 324.1229.
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Ethyl 2-(Benzofuran-2-yl)-2-[(ethoxycarbonyl)amino]acetate (7h)
Bi Catalysis : Compound 7h was synthesized according to the GP from urethane (46 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), benzofuran (0.16 mL, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 16 h at 60 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a yellow solid (128 mg, 88%; r.r. = >98:2).
Fe Catalysis : Compound 7h was synthesized according to the GP from urethane (89 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.2 equiv), benzofuran (0.32 mL, 3.0 mmol, 3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 60 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a yellow solid (219 mg, 75%; r.r. = 80:20). Further purification of the major regioisomer could be achieved by precipitation from hexane/CH2Cl2 (91:9 mixture of regioisomers, as judged by 1H NMR analysis). Analytical data were obtained for this purified mixture.
Mp 60.3 °C; Rf = 0.56 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3263 (w), 2983 (w), 1742 (m), 1688 (s), 1605 (w), 1533 (m), 1453 (m), 1369 (m), 1319 (s), 1245 (s), 1200 (s), 1093 (m), 1049 (s), 953 (m), 937 (m), 753 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ (major regioisomer) = 7.57–7.52 (m, 1 H), 7.49–7.42 (m, 1 H), 7.32–7.19 (m, 2 H), 6.76 (s, 1 H), 5.85–5.72 (m, 1 H), 5.71–5.58 (m, 1 H), 4.32–4.10 (m, 4 H), 1.29–1.22 (m, 6 H).
13C NMR (75 MHz, CDCl3): δ = 168.7, 155.8, 155.0, 151.8, 128.0, 124.9, 123.2, 121.4, 111.5, 105.5, 62.6, 61.7, 52.6, 14.6, 14.2 (peaks not assigned to regioisomers).
MS (ESI): m/z [M + Na]+ calcd for C15H17NO5Na: 314.1; found: 314.2.
HMRS (MALDI): m/z [M + H]+ calcd for C15H18NO5: 292.1180; found: 292.1177.
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Ethyl 2-(Benzamido)-2-(1-tosyl-1H-pyrrol-2-yl)acetate (7i)
Fe Catalysis : Compound 7i was synthesized according to the GP from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.2 equiv), N-tosylpyrrole (664 mg, 3.0 mmol, 3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 60 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1) yielded the product as a yellow oil (265 mg, 62%; r.r. = >98:2); Rf = 0.57 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3365 (w), 1725 (m), 1662 (m), 1599 (w), 1505 (w), 1482 (m), 1404 (w), 1363 (m), 1345 (m), 1281 (w), 1246 (w), 1211 (m), 1188 (m), 1172 (s), 1155 (s), 1123 (m), 1091 (m), 1056 (m), 1017 (m), 864 (w), 808 (m), 750 (s), 716 (m), 702 (m), 673 (s), 627 (m), 584 (s), 562 (s), 542 (s), 511 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 7.68–7.58 (m, 4 H), 7.53–7.36 (m, 3 H), 7.33–7.28 (m, 1 H), 7.18–7.11 (m, 2 H), 6.88 (d, J = 7.5 Hz, 1 H), 6.48–6.41 (m, 1 H), 6.31–6.22 (m, 2 H), 4.23–4.06 (m, 2 H), 2.26 (s, 3 H), 1.19 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 169.6, 166.5, 145.2, 136.4, 133.5, 131.9, 130.1, 129.7, 128.6, 127.3, 126.8, 124.6, 116.9, 112.1, 62.3, 50.1, 21.6, 14.1.
MS (ESI): m/z [M + Na]+ calcd for C22H22N2O5SNa: 449.1; found: 449.1.
HRMS (MALDI): m/z [M + Na]+ calcd for C22H22N2O5SNa: 449.1142; found: 449.1146.
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Ethyl 2-[(Ethoxycarbonyl)amino]-2-(1-tosyl-1H-pyrrol-2-yl)acetate (7j)
Bi Catalysis : Compound 7j was synthesized according to the GP from urethane (46 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), N-tosylpyrrole (332 mg, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in DCE (2.0 mL). The reaction mixture was stirred for 16 h at 60 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4.1) yielded the product as a yellow solid (123 mg, 62%; r.r. = >98:2).
Fe Catalysis
Compound 7j was synthesized according to the GP from urethane (89 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.2 equiv), N-tosylpyrrole (664 mg, 3.0 mmol, 3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 40 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a yellow solid (302 mg, 75%; r.r. = >98:2).
Mp 138.9 °C; Rf = 0.63 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3367 (w), 3161 (w), 2985 (w), 1722 (m), 1709 (s), 1596 (w), 1515 (m), 1469 (m), 1407 (w), 1364 (m), 1329 (m), 1213 (m), 1176 (s), 1154 (s), 1124 (m), 1090 (m), 1048 (s), 899 (m), 813 (m), 739 (m), 702 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 8.3 Hz, 2 H), 7.31–7.21 (m, 3 H), 6.30 (s, 1 H), 6.25–6.22 (m, 1 H), 5.84 (d, J = 8.1 Hz, 1 H), 5.43 (d, J = 6.5 Hz, 1 H), 4.22–4.03 (m, 4 H), 2.40 (s, 3 H), 1.20 (m, 6 H).
13C NMR (101 MHz, CDCl3): δ = 169.9, 155.7, 145.2, 136.3, 130.0, 129.9, 127.1, 124.3, 116.1, 111.9, 62.1, 61.4, 51.3, 21.7, 14.7, 14.1.
MS (ESI): m/z [M + Na]+ calcd for C18H22N2O6SNa: 417.1; found: 417.2.
HRMS (MALDI): m/z [M + Na]+ calcd for C18H22N2O6SNa: 417.1096; found: 417.1099.
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Ethyl 2-Benzamido-2-(1-tosyl-1H-indol-3-yl)acetate (7k)
Fe Catalysis : Compound 7k was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.2 equiv), N-tosylindole (407 mg, 1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 60 °C. Purification by chromatography (n-hexane/EtOAc = 9:1 → 4.1 → 7:3) yielded the product as a white low-melting foam (177 mg, 74%; r.r. = 82:18).
Rf = 0.40 (n-hexane/EtOAc = 7:3).
IR (ATR): 1739 (w), 1644 (w), 1520 (w), 1486 (w), 1447 (w), 1367 (m), 1171 (s), 1120 (m), 1089 (m), 1019 (m), 979 (m), 812 (w), 746 (m), 703 (s), 666 (s), 570 (s), 536 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 8.00–6.90 (m, 15 H), 6.05 (d, J = 7.4 Hz, 1 H), 4.40–4.12 (m, 2 H), 2.33 (s, 3 H), 1.23 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 170.6, 166.9, 145.4, 135.3, 135.1, 133.6, 132.1, 130.1, 129.9, 128.8, 127.3, 127.1, 125.4, 125.1, 123.8, 120.2, 118.0, 113.9, 62.4, 49.6, 21.7, 14.2.
MS (ESI): m/z [M + Na]+ calcd for C26H24N2O5SNa: 499.1; found: 499.1.
HRMS (MALDI): m/z [M + Na]+ calcd for C26H24N2O5SNa: 499.1298; found: 499.1291.
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Ethyl 2-[(Ethoxycarbonyl)amino]-2-(1-tosyl-1H-indol-3-yl)acetate (7l)
Bi Catalysis : Compound 7l was synthesized according to the GP from urethane (46 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), N-tosylindole (203 mg, 0.75 mmol, 1.5 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in DCE (4.0 mL). The reaction mixture was stirred for 16 h at 60 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4.1) yielded the product as a colorless oil (171 mg, 78%; r.r. = >98:2).
Fe Catalysis : Compound 7l was synthesized according to the GP from urethane (89 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.2 equiv), N-tosylindole (814 mg, 3.0 mmol, 3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 60 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4.1) yielded the product as a colorless oil (369 mg, 83%; r.r. = >98:2). Compound 7l is very sensitive, especially towards light or acid and decomposes rapidly. Partial decomposition (<5%) is observed upon silica gel chromatography. Analytically pure 7l could be obtained by preparative HPLC (column: Machery Nagel Nuc 50-100/250 × 20 mm, hexane/EtOAc/CH2Cl2 = 10:1.5:2, flow rate 8 mL/min) and has to be stored under argon, protected from light at or below –20 °C.
Rf = 0.59 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3383 (w), 2981 (w), 1714 (m), 1596 (w), 1514 (w), 1446 (m), 1368 (m), 1301 (m), 1218 (m), 1171 (s), 1200 (m), 1093 (m), 1050 (m), 1019 (m), 976 (m), 856 (w), 812 (m), 745 (s), 704 (m), 663 cm–1 (s).
1H NMR (500 MHz, CDCl3): δ = 7.95 (d, J = 8.3 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 2 H), 7.64 (d, J = 7.9 Hz, 1 H), 7.58 (s, 1 H), 7.27 (t, J = 32.8 Hz, 4 H), 5.68–5.42 (m, 2 H), 4.27–4.08 (m, 4 H), 2.34 (s, 3 H), 1.27–1.16 (m, 6 H).
13C NMR (126 MHz, CDCl3): δ = 170.5, 155.8, 145.3, 135.3, 135.1, 130.1, 128.6, 127.0, 125.3, 124.8, 123.6, 120.2, 118.2, 113.8, 62.2, 61.5, 50.8, 21.7, 14.6, 14.1.
MS (ESI): m/z [M + Na]+ calcd for C22H24N2O6SNa: 467.1; found: 467.2.
HRMS (MALDI): m/z [M + Na]+ calcd for C22H24N2O6SNa: 467.1247; found: 467.1239.
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Isopropyl 2-Benzamido-2-mesitylacetate (11a)
Bi Catalysis : Compound 11a was synthesized according to the GP from benzamide (66 mg, 0.55 mmol, 1.0 equiv), isopropyl 2-oxoacetate (75 mg 0.65 mmol, 1.18 equiv), mesitylene (0.21 mL, 3.0 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1 → 1:1) yielded the product as colorless solid (94 mg, 50%).
Fe Catalysis : Compound 11a was synthesized according to the GP from benzamide (121 mg, 1.0 mmol, 1.0 equiv), isopropyl 2-oxoacetate (174 mg, 1.5 mmol, 1.5 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), and Fe(ClO4)3 (18 mg, 0.050 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 60 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1 → 1:1) yielded the product as a colorless solid (281 mg, 83%).
Mp 101.2 °C; Rf = 0.56 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3317 (m), 2975 (w), 2932 (w), 1747 (s), 1633 (s), 1579 (w), 1530 (s), 1490 (m), 1462 (m), 1360 (m), 1212 (s), 1154 (m), 1108 (s), 1089 (s), 973 (w), 852 (m), 828 (w), 787 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 7.82–7.78 (m, 2 H), 7.53–7.39 (m, 3 H), 7.18 (d, J = 6.2 Hz, 1 H), 6.83 (s, 2 H), 6.15 (d, J = 6.6 Hz, 1 H), 5.08 (hept, J = 6.3 Hz, 1 H), 2.47 (s, 6 H), 2.25 (s, 3 H), 1.25 (d, J = 6.3 Hz, 3 H), 1.12 (d, J = 6.2 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.4, 166.6, 137.6, 137.0, 134.2, 131.8, 131.1, 130.1, 128.7, 127.2, 69.9, 53.0, 21.8, 21.6, 21.0, 20.5.
MS (ESI): m/z [M + Na]+ calcd for C21H25NO3Na: 362.2; found: 362.3.
HRMS (MALDI): m/z [M + H]+ calcd for C21H26NO3: 340.1907; found: 340.1905.
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2-Benzamido-2-mesitylacetic Acid (11b)
Fe Catalysis : Compound 11b was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), glyoxylic acid (50% w/w in H2O, 0.07 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and FeCl3·6H2O (7 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (CH2Cl2/MeOH = 20:1 → 9:1) yielded the product as a low-melting solid (120 mg, 81%).
Bi Catalysis : Compound 11b was synthesized according to the GP from benzamide (121 mg, 1.0 mmol, 1.0 equiv), glyoxylic acid (50% w/w in H2O, 0.13 mL, 1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), and Bi(OTf)3 (13 mg, 0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 21 h at 80 °C. After cooling to r.t., aq 1 M NaOH (15 mL) was added to the reaction mixture. The aqueous phase was washed with EtOAc (2 × 10 mL), acidified with aq 2 N HCl to pH 4, and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (anhyd MgSO4), filtered, and evaporated to dryness. Purification by chromatography (CH2Cl2/MeOH = 20:1 → 9:1) yielded the product as a low-melting solid (211 mg, 71%).
Mp <30 °C; Rf = 0.41 (CH2Cl2/MeOH = 9:1).
IR (ATR): 3412 (w), 2920 (w), 2520 (w), 1732 (m), 1612 (s), 1575 (m), 1514 (s), 1485 (s), 1344 (w), 1308 (w), 1240 (m), 1193 (m), 1085 (w), 976 (w), 851 (m), 746 (m), 713 cm–1 (s).
1H NMR (300 MHz, DMSO-d 6): δ = 8.50 (d, J = 6.7 Hz, 1 H), 7.88 (d, J = 7.0 Hz, 2 H), 7.56–7.42 (m, 3 H), 6.85 (s, 2 H), 5.94 (d, J = 6.7 Hz, 1 H), 2.35 (s, 6 H), 2.21 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 172.5, 166.4, 137.2, 136.5, 133.8, 131.4, 131.4, 129.3, 128.2, 127.7, 52.2, 20.4, 20.1.
MS (ESI): m/z [M + H]+ calcd for C18H20NO3: 298.1; found: 298.5.
HRMS (MALDI): m/z [M + H]+ calcd for C18H20NO3: 298.1438; found: 298.1440.
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2-[(Ethoxycarbonyl)amino]-2-mesitylacetic Acid (11c)
Bi Catalysis : Compound 11c was synthesized according to the GP from urethane (45 mg, 0.5 mmol, 1.0 equiv), glyoxylic acid (0.07 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (CH2Cl2/MeOH = 50:1 → 20:1) yielded the product as a colorless solid (66 mg, 50%).
Fe Catalysis : Compound 11c was synthesized according to the GP from urethane (45 mg, 0.5 mmol, 1.0 equiv), glyoxylic acid (0.07 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and FeCl3·6H2O (7 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (CH2Cl2/MeOH = 50:1 → 20:1) yielded the product as a colorless solid (122 mg, 92%).
Mp 144.5 °C; Rf = 0.23 (CH2Cl2/MeOH = 9:1).
IR (ATR): 3267 (w), 3027 (w), 2918 (w), 2530 (w), 1725 (s), 1655 (m), 1613 (m), 1513 (w), 1426 (w), 1336 (m), 1226 (w), 1196 (m), 1067 (m), 925 (m), 851 cm–1 (m).
1H NMR (400 MHz, DMSO): δ = 12.78 (s, 1 H), 7.42 (d, J = 7.2 Hz, 1 H), 6.81 (s, 2 H), 5.52 (d, J = 7.7 Hz, 1 H), 4.09–3.94 (m, 2 H), 2.26 (s, 6 H), 2.19 (s, 3 H), 1.16 (t, J = 7.0 Hz, 3 H).
13C NMR (101 MHz, DMSO): δ = 172.8, 156.1, 136.7, 136.4, 132.0, 129.2, 60.0, 52.9, 20.4, 19.9, 14.6.
MS (ESI): m/z [M]+ calcd for C14H19NO4: 265.1; found: 264.2.
HRMS (MALDI): m/z [M + Na]+ calcd for C14H19NO4Na: 288.1206; found: 288.1208.
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2-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-2-mesitylacetic Acid (11d)
Bi Catalysis : Compound 11d was synthesized according to the GP from 9H-fluoren-9-yl carbamate (113 mg, 0.5 mmol, 1.0 equiv), glyoxylic acid (0.07 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc =7:3 → 1:1) yielded the product as a colorless oil (94 mg, 45%).
Fe Catalysis : Compound 11d was synthesized according to the GP from 9H-fluoren-9-yl carbamate (113 mg, 0.5 mmol, 1.0 equiv), glyoxylic acid (0.07 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and FeCl3·6H2O (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc =7:3 → 1:1) yielded the product as a colorless oil (177 mg, 85%); Rf = 0.35 (EtOAc).
IR (ATR): 3347 (w), 2953 (w), 1717 (s), 1598 (w), 1512 (m), 1443 (m), 1323 (m), 1194 (s), 1052 (s), 853 (m), 747 (s), 616 cm–1 (m).
1H NMR (500 MHz, DMSO-d 6): δ = 12.84 (s, 1 H), 7.90–7.86 (m, 2 H), 7.86–7.81 (m, 1 H), 7.81–7.70 (m, 2 H), 7.44–7.38 (m, 2 H), 7.35–7.26 (m, 2 H), 6.83 (s, 2 H), 5.52 (d, J = 7.6 Hz, 1 H), 4.32–4.16 (m, 3 H), 2.28 (s, 6 H), 2.20 (s, 3 H).
13C NMR (126 MHz, DMSO-d 6): δ = 172.8, 156.1, 144.0, 143.7, 140.7, 136.9, 136.5), 131.9, 129.3, 127.7, 127.1, 127.0, 125.5, 120.1, 65.9, 53.1, 46.7, 20.4, 20.0.
MS (ESI): m/z [M + H]+ calcd for C26H26NO4: 416.2; found: 416.4.
HRMS (MALDI): m/z [M + Na]+ calcd for C26H25NO4Na: 438.1676; found: 438.1674.
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Ethyl 2-Benzamido-2-(2-methoxy-5-pivalamidophenyl)acetate (12a)
Fe Catalysis : Compound 12a was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.2 equiv), N-(4-methoxyphenyl)pivalamide (311 mg, 1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1 → 7:3 → 1:1) yielded the product as a colorless solid (184 mg, 89%; r.r.= >98:2).
Bi Catalysis : Compound 12a was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), N-(4-methoxyphenyl)pivalamide (311 mg, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1 → 7:3 → 1:1) yielded the product as a colorless solid (128 mg, 62%; r.r. = >98:2).
Mp 90.2 °C; Rf = 0.20 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3302 (w), 2948 (w), 1743 (m), 1638 (s), 1603 (w), 1526 (s), 1414 (w), 1369 (w), 1328 (m), 1216 (s), 1149 (m), 1096 (m), 1029 (m), 932 (w), 859 (w), 806 (w), 725 (m), 693 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 7.84–7.76 (m, 3 H), 7.52–7.39 (m, 3 H), 7.34–7.30 (m, 2 H), 6.86 (d, J = 8.9 Hz, 1 H), 5.84 (d, J = 8.0 Hz, 1 H), 4.25–4.16 (m, 2 H), 3.83 (s, 3 H), 1.30 (s, 9 H), 1.20 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 176.7, 171.9, 166.7, 153.8, 134.2, 131.8, 131.5, 128.7, 127.3, 126.1, 123.2, 122.2, 111.7, 61.9, 56.0, 53.9, 39.6, 27.8, 14.3.
MS (ESI): m/z [M + H]+ calcd for C23H29N2O5: 413.2; found: 413.9.
HRMS (MALDI): m/z [M + H]+ calcd for C23H29N2O5: 413.2071; found: 413.2071.
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Ethyl 2-Benzamido-2-(4-methoxy-3-pivalamidophenyl)acetate (12b)
Fe Catalysis : Compound 12b was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.2 equiv), N-(2-methoxyphenyl)pivalamide (311 mg, 1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mol, 5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 100 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1 → 7:3 → 1:1) yielded the product as a colorless solid (164 mg, 80%, obtained as a 1.6:1 mixture of regioisomers). Further purification of the major regioisomer could be achieved by precipitation from hexane/CH2Cl2 (92:8 mixture of regioisomers, as judged by 1H NMR analysis). Analytical data were obtained for this purified mixture.
Mp 127.6 °C; Rf = 0.34 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3443 (w), 3283 (w), 2959 (w), 2361 (w), 1743 (m), 1668 (m), 1632 (m), 1600 (w), 1579 (w), 1525 (s), 1484 (s), 1430 (m), 1394 (w), 1339 (m), 1267 (m), 1198 (m), 1153 (m), 1122 (m) 1093 (w), 1027 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 8.54 (d, J = 2.2 Hz, 1 H), 8.10 (s, 1 H), 7.85–7.79 (m, 2 H), 7.52–7.39 (m, 3 H), 7.19–7.11 (m, 2 H), 6.86 (d, J = 8.4 Hz, 1 H), 5.68 (d, J = 7.0 Hz, 1 H), 4.33–4.12 (m, 2 H), 3.89 (s, 3 H), 1.31 (s, 9 H), 1.24 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 176.6, 171.1, 166.7, 148.1, 134.0, 131.8, 129.7, 128.7, 128.5, 127.4, 123.10, 118.2, 110.1, 62.1, 56.9, 56.1, 40.2, 27.8, 14.2.
MS (ESI): m/z [M + Na]+ calcd for C23H28N2O5Na: 435.2; found: 435.3.
HRMS (MALDI): m/z [M + H]+ calcd for C23H29N2O5: 413.2071; found: 413.2072.
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Ethyl 2-Benzamido-2-(4-methyl-3-pivalamidophenyl)acetate (12c)
Bi Catalysis : Compound 12c was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), 2-methylpivalanilide (287 mg, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (16 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 100 °C. Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the product as a yellow solid (89 mg, 45%; r.r. = >98:2).
Fe Catalysis : Compound 12c was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.2 equiv), 2-methylpivalanilide (287 mg, 1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 100 °C. Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the product as a yellow solid (152 mg, 77%; r.r. = 91:9).
Mp 123–125 °C; Rf = 0.5 (n-hexane/EtOAc = 1:1).
IR (ATR): 2959 (w), 2923 (m), 2853 (w), 1744 (s), 1661 (s), 1643 (s), 1615 (w), 1602 (w), 1580 (w), 1519 (s), 1489 (s), 1446 (m), 1417 (w), 1399 (w), 1367 (m), 1340 (s), 1299 (s), 1265 (s), 1218 (m), 1194 (s), 1170 (s), 1092 (m), 1023 (m), 947 (w), 923 (w), 880 (w), 800 (w), 777 (m), 749 (w), 714 (s), 691 (s), 620 (s), 608 (s), 584 (s), 540 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 7.91 (d, J = 9.0 Hz, 1 H), 7.82–7.79 (m, 2 H), 7.51–7.41 (m, 3 H), 7.28 (s, 2 H), 7.23 (br s, 1 H), 7.12 (br d, J = 6.8 Hz, 1 H), 5.68 (d, J = 6.9 Hz, 1 H), 4.30–4.13 (m, 2 H), 2.26 (s, 3 H), 1.33 (s, 9 H), 1.24 (t, J = 5.8 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 176.6, 171.2, 166.6, 136.3, 133.9, 133.1, 132.0, 129.7, 129.14, 128.7, 127.3, 125.8, 123.2, 62.2, 56.6, 40.0, 27.8, 17.8, 14.2.
MS (ESI): m/z [M + Na]+ calcd for C23H28N2O4Na: 420.0; found: 420.0.
HRMS (MALDI): m/z [M + K]+ calcd for C23H28N2O4K: 435.1681; found: 435.1674.
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Ethyl 2-Benzamido-2-(2,5-dimethoxyphenyl)acetate (12d)
Fe Catalysis : Compound 12d was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.2 equiv), 1,4-dimethoxybenzene (207 mg, 1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless solid (128 mg, 74%).
Mp 75.4 °C; Rf = 0.33 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3299 (w), 2954 (w), 2835 (w), 1727 (m), 1636 (m), 1581 (w), 1503 (s), 1458 (m), 1327 (m), 1207 (s), 1153 (s), 1045 (s), 1022 (s), 925 (m), 822 (m), 755 (m), 715 (m), 635 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 7.82–7.78 (m, 2 H), 7.51–7.46 (m, 1 H), 7.42 (t, J = 7.4 Hz, 2 H), 7.31 (d, J = 8.1 Hz, 1 H), 7.01 (s, 1 H), 6.84 (d, J = 1.3 Hz, 2 H), 5.90 (d, J = 8.3 Hz, 1 H), 4.26–4.16 (m, 2 H), 3.82 (s, 3 H), 3.78 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.1, 166.7, 153.9, 151.4, 134.3, 131.7, 128.7, 127.3, 126.7, 116.7, 114.5, 112.4, 61.8, 56.3, 55.9, 54.1, 14.3.
MS (ESI): m/z [M + Na]+ calcd for C19H21NO5Na: 366.1; found: 366.2.
HRMS (MALDI): m/z [M + H]+ calcd for C19H22NO5: 344.1493; found: 344.1491.
Anal. Calcd for C19H21NO5: C, 66.46; H, 6.16; N, 4.08. Found: C, 66.20, H, 6.11; N, 3.80.
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Ethyl 2-Benzamido-2-(3,4-dimethoxyphenyl)acetate (12e)
Fe Catalysis : Compound 12e was synthesized according to the GP from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.2 equiv), veratrole (0.38 mL, 3.0 mmol, 3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a colorless oil (216 mg, 63%; r.r. = >98:2).
Rf = 0.32 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3338 (w), 2980 (w), 1732 (s), 1634 (s), 1595 (w), 1578 (w), 1520 (s), 1488 (m), 1467 (m), 1356 (m), 1332 (m), 1255 (s), 1238 (m), 1203 (m), 1183 (m), 1165 (m), 1139 (s), 1097 (m), 1017 (s), 923 (w), 878 (w), 851 (m), 799 (m), 752 (m), 714 (s), 691 (m), 633 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 7.3 Hz, 2 H), 7.51 (t, J = 7.3 Hz, 1 H), 7.44 (t, J = 7.5 Hz, 2 H), 7.11 (d, J = 6.7 Hz, 1 H), 7.02–6.94 (m, 2 H), 6.85 (d, J = 8.2 Hz, 1 H), 5.69 (d, J = 7.0 Hz, 1 H), 4.33–4.15 (m, 2 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 1.25 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.3, 166.7, 149.4, 149.4, 133.9, 132.0, 129.3, 128.8, 127.3, 119.7, 111.5, 110.7, 62.1, 56.7, 56.1, 56.1, 14.2.
MS (ESI): m/z [M + Na]+ calcd for C19H21NO5Na: 366.1; found: 366.3.
HRMS (MALDI): m/z [M + H]+ calcd for C19H22NO5: 344.1493; found: 344.1490.
Anal. Calcd for C19H21NO5: C, 66.46; H, 6.16; N, 4.08. Found: C, 66.31; H, 6.18; N, 3.98.
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Ethyl 2-(Anthracen-9-yl)-2-benzamidoacetate (12f)
Bi Catalysis : Compound 12f was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), anthracene (267 mg, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 20:1 → 9:1 → 4:1) yielded the product as a yellow solid (92 mg, 48%; r.r. = >98:2).
Fe Catalysis : Compound 12f was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.2 equiv), anthracene (267 mg, 1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 20:1 → 9:1 → 4:1) yielded the product as a yellow solid (157 mg, 82%; r.r. = >98:2).
Mp 128.6 °C; Rf = 0.59 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3355 (w), 3058 (w), 2979 (w), 1721 (s), 1640 (s), 1579 (w), 1520 (s), 1488 (m), 1450 (m), 1367 (w), 1314 (s), 1210 (s), 1142 (m), 1092 (m), 1044 (m), 901 (m), 845 (m), 727 (s), 713 (s), 690 cm–1 (s).
1H NMR (500 MHz, CDCl3): δ = 8.55–8.43 (m, 3 H), 8.06 (d, J = 8.4 Hz, 2 H), 7.78 (d, J = 8.5 Hz, 2 H), 7.64–7.34 (m, 9 H), 7.31 (d, J = 7.2 Hz, 1 H), 4.25–4.09 (m, 2 H), 1.04 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 172.3, 167.3, 133.8, 131.9, 131.8, 130.3, 129.8, 129.4, 128.7, 128.1, 127.37, 127.3, 125.3, 123.6, 62.3, 51.4, 14.1.
MS (ESI): m/z [M + H]+ calcd for C25H22NO3: 384.2; found: 385.0.
HRMS (MALDI): m/z [M] calcd for C25H21NO3: 383.1521; found: 383.1501.
#
Ethyl 2-Benzamido-2-(5-bromo-2-hydroxyphenyl)acetate (12g)
Bi Catalysis : Compound 12g was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), 4-bromophenol (260 mg, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (3 mg, 0.005 mmol, 1 mol%) in DCE (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a low-melting solid (123 mg, 65%; r.r. = >98:2).
Fe Catalysis : Compound 12g was synthesized according to the GP from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.2 equiv), 4-bromophenol (516 mg, 3.0 mmol, 3.0 equiv), and Fe(ClO4)3 (7 mg, 0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a low-melting solid (39 mg, 11%; r.r. = >98:2).
Rf = 0.46 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3368, 3099, 2920, 2852, 1736, 1622, 1576, 1530 (s), 1488 (m), 1430 (m), 1363, 1344 (m), 1310 (m), 1278 (s), 1236 (m), 1198 (m), 1120 (m), 1090 (s), 1022 (m), 877 (m), 813 (s), 727 (s), 692 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 9.47 (s, 1 H), 7.86–7.76 (m, 2 H), 7.61 (d, J = 6.7 Hz, 1 H), 7.58–7.52 (m, 1 H), 7.49–7.43 (m, 2 H), 7.35–7.31 (m, 1 H), 7.13 (d, J = 2.4 Hz, 1 H), 6.92 (d, J = 8.7 Hz, 1 H), 5.83 (d, J = 6.9 Hz, 1 H), 4.39–4.30 (m, 2 H), 1.30 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 170.6, 168.3, 155.0, 133.3, 132.7, 132.0, 129.9, 128.8, 127.3, 126.1, 121.3, 112.6, 62.9, 51.8, 14.0.
MS (ESI): m/z [M + Na]+ calcd for C17H16BrNO4Na: 400.0; found: 400.1.
HRMS (MALDI): m/z [M + H]+ calcd for C17H17BrNO4: 378.0335; found: 378.0335.
#
Ethyl 2-Benzamido-2-(3,4-dimethylphenyl)acetate (12h)
Bi Catalysis : Compound 12h was synthesized according to the GP from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg, 1.2 mmol, 1.2 equiv), o-xylene (0.36 mL, 3.0 mmol, 3.0 equiv), and Bi(OTf)3 (13 mg, 0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the product as a colorless solid (278 mg, 89%; r.r. = 89:11).
Fe Catalysis : Compound 12h was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.2 equiv), o-xylene (0.18 mL, 1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless solid (88 mg, 54%; r.r. = 80:20). Further purification of the major regioisomer could be achieved by precipitation from hexane/CH2Cl2 (87:13 mixture of regioisomers, as judged by 1H NMR analysis). Analytical data were obtained for this purified mixture.
Mp 70–72 °C; Rf = 0.31 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3285 (w), 2981 (w), 1741 (s), 1635 (s), 1602 (w), 1579 (w), 1527 (s), 1488 (s), 1446 (w), 1370 (w), 1345 (m), 1302 (m), 1263 (m), 1189 (s), 1153 (s), 1093 (m), 1022 (m), 819 (w), 689 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ (major regioisomer) = 7.82 (d, J = 7.3 Hz, 2 H), 7.54–7.39 (m, 3 H), 7.22–6.95 (m, 4 H), 5.71 (d, J = 7.1 Hz, 1 H), 4.34–4.10 (m, 2 H), 2.26 (s, 3 H), 2.25 (s, 3 H), 1.27–1.21 (m, 3 H).
13C NMR (101 MHz, CDCl3): δ (major regioisomer) = 171.4, 166.6, 137.5, 137.2, 134.3, 134.0, 131.9, 130.3, 128.7, 127.3, 124.8, 124.4, 62.1, 56.8, 20.0, 19.6, 14.2.
MS (ESI): m/z [M + H]+ calcd for C19H22NO3: 312.2; found: 312.2.
HRMS (MALDI): m/z [M + H]+ calcd for C19H22NO3: 312.1594; found: 312.1595.
#
Ethyl 2-Benzamido-2-(5-chloro-2-methoxyphenyl)acetate (12i)
Bi Catalysis : Compound 12i was synthesized according to the GP from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg, 1.2 mmol, 1.2 equiv), 4-chloroanisole (0.49 mL, 4.0 mmol, 4.0 equiv), and Bi(OTf)3 (32 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 16 h at 100 °C. Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the product as a colorless solid (310 mg, 89%; r.r. = >98:2).
Fe Catalysis : Compound 12i was synthesized according to the GP from benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.2 equiv), 4-chloroanisole (0.37 mL, 3.0 mmol, 3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a colorless solid (116 mg, 34%; r.r. = >98:2).
Mp 88.8 °C; Rf = 0.55 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3257 (w), 2959 (w), 1737 (s), 1638 (s), 1602 (w), 1579 (w), 1523 (m), 1488 (s), 1458 (m), 1365 (w), 1320 (m), 1247 (s), 1190 (s), 1130 (m), 1093 (s), 1026 (s), 979 (w), 804 (m), 719 (m), 658 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 7.79 (dd, J = 5.2, 3.3 Hz, 2 H), 7.53–7.40 (m, 4 H), 7.30–7.23 (m, 2 H), 6.83 (d, J = 8.8 Hz, 1 H), 5.88 (d, J = 8.0 Hz, 1 H), 4.24–4.17 (m, 2 H), 3.85 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 170.6, 166.5, 155.7, 134.0, 131.7, 130.6, 129.4, 128.6, 127.4, 127.2, 125.9, 112.3, 61.9, 56.0, 53.3, 14.1.
MS (ESI): m/z [M + H]+ calcd for C18H19ClNO4: 348.1; found: 348.2.
HRMS (MALDI): m/z [M + H]+ calcd for C18H19ClNO4: 348.0997; found: 348.0995.
#
Ethyl 2-Benzamido-2-(p-tolyl)acetate (12j)
Bi Catalysis : Compound 12j was synthesized according to the GP from benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), toluene (0.22 mL, 2.1 mmol, 4.2 equiv), and Bi(OTf)3 (7 mg, 0.005 mmol, 2 mol%) in DCE (2.0 mL). The reaction mixture was stirred for 16 h at 100 °C. Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the product as a colorless solid (74 mg, 50%; r.r. = 75:25).
Mp 99–101 °C; Rf = 0.4 (n-hexane/EtOAc 4:1).
IR (ATR): 3290 (w), 1743 (s), 1636 (s), 1603 (m), 1581 (m), 1527 (s), 1488 (s), 1447 (m), 1372 (m), 1348 (m), 1330 (m), 1300 (w), 1275 (w), 1252 (m), 1206 (s), 1178 (s), 1153 (s), 1096 (m), 1075 (w), 1021 (s), 928 (w), 815 (m), 803 (w), 791 (w), 759 (m), 723 (s), 711 (s), 691 (s), 634 (m), 615 (m), 587 (s), 573 (m), 512 (m), 487 (m), 459 cm–1 (w).
1H NMR (300 MHz, CDCl3): δ (major regioisomer) = 7.83–7.80 (m, 2 H), 7.54–7.40 (m, 3 H), 7.35–7.32 (m, J = 8.1 Hz, 2 H), 7.24–7.16 (m, J = 15.2, 5.8 Hz, 2 H), 7.11 (br d, J = 6.9 Hz, 1 H), 5.73 (d, J = 7.0 Hz, 1 H), 4.33–4.11 (m, 2 H), 2.34 (s, 3 H), 1.29–1.19 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 171.33, 166.61, 138.51, 137.19, 135.48, 133.94, 131.93, 131.17, 129.81, 128.73, 128.60, 127.34, 127.28, 126.67, 126.45, 62.12, 56.75, 53.71, 21.30, 19.68, 14.18. (peaks are not assigned to regioisomers).
MS (ESI): m/z [M + H]+ calcd for C18H20NO3: 298.5; found: 298.5.
HRMS (MALDI): m/z [M + H]+ calcd for C18H20NO3: 298.1438; found: 298.1439.
#
Ethyl 2-Mesityl-2-(2-oxopyrrolidin-1-yl)acetate (14a)
Bi Catalysis : Compound 14a was synthesized according to the GP from pyrrolidin-2-one (85 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg, 1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), and Bi(OTf)3 (13 mg, 0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless solid (182 mg, 63%).
Fe Catalysis : Compound 14a was synthesized according to the GP from pyrrolidin-2-one (43 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and FeCl3·6H2O (3 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless solid (12 mg, 8%).
Mp 141–142 °C; Rf = 0.2 (cyclohexane/EtOAc = 7:3).
IR (ATR): 2988 (w), 2926 (w), 1743 (s), 1681 (s), 1610 (m), 1491 (m), 1460 (m), 1245 (m), 1187 (s), 1023 (m), 903 (w), 860 (m), 673 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 6.87 (s, 2 H), 6.12 (s, 1 H), 4.33–4.11 (m, 2 H), 3.66 (m, 1 H),
2.93 (m, 1 H), 2.56–2.35 (m, 2 H), 2.26 (d, J = 4.5 Hz, 9 H), 2.10–1.99 (m, 1 H), 1.86–1.79 (m,
1 H), 1.24 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 175.3, 171.7, 138.1, 130.1, 128.2, 61.8, 54.0, 44.2, 30.8, 21.0, 20.6, 18.3, 14.2.
MS (ESI): m/z [M + H]+ calcd for C17H24NO3: 290.2; found: 290.2.
Anal. Calcd for C17H23NO3: C, 70.56; H, 8.01; N, 4.84. Found: C, 70.47; H, 7.97; N, 4.66.
#
Ethyl 2-Mesityl-2-(2-oxooxazolidin-3-yl)acetate (14b)
Bi Catalysis : Compound 14b was synthesized according to the GP from oxazolidin-2-one (87 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg, 1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), and Bi(OTf)3 (13 mg, 0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless solid (234 mg, 80%).
Mp 127–128 °C; Rf = 0.2 (cyclohexane/EtOAc = 7:3).
IR (ATR): 2921 (w), 1732 (s), 1611 (w), 1486 (w), 1447 (m), 1239 (m), 1144 (w), 1023 (s), 884 (m), 738 (w), 699 (m), 676 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 6.89 (s, 2 H), 5.88 (s, 1 H), 4.45–4.14 (m, 4 H), 3.93 (m, 1 H), 3.13 (m, 1 H), 2.28 (d, J = 2.7 Hz, 9 H), 1.26 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 171.4, 158.4, 138.6, 137.9, 130.3, 127.8, 62.5, 62.1, 55.6, 41.9, 21.0, 20.5, 14.3.
MS (ESI): m/z [M + H]+ calcd for C16H22NO4: 292.2; found: 292.2.
Anal. Calcd for C16H21NO4: C, 65.96; H, 7.27; N, 4.81. Found: C, 65.82; H, 7.25; N, 4.69.
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Ethyl 2-Mesityl-2-(methylsulfonamido)acetate (16a)
Bi Catalysis : Compound 16a was synthesized according to the GP from methanesulfonamide (49 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 20 h at 80 °C. Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the product as a colorless solid (81 mg, 54%).
Mp 126–128 °C; Rf = 0.5 (n-hexane/EtOAc 7:3).
IR (ATR): 3298 (w), 2966 (w), 2927 (w), 2111 (w), 1732 (s), 1609 (w), 1464 (w), 1413 (m), 1401 (m), 1366 (w), 1327 (s), 1311 (s), 1289 (s), 1254 (m), 1219 (s), 1199 (s), 1161 (s), 1145 (s), 1096 (s), 1021 (m), 987 (s), 970 (s), 909 (w), 872 (m), 855 (s), 827 (m), 784 (w), 762 (s), 721 (w), 636 (w), 602 (m), 555 (m), 528 (s), 513 (s), 475 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 6.86 (s, 2 H), 5.64 (d, J = 4.0 Hz, 1 H), 5.41 (br d, J = 3.5 Hz, 1 H), 4.29–4.13 (m, 2 H), 2.61 (s, 3 H), 2.35 (s, 6 H), 2.26 (s, 3 H), 1.20 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 171.21, 138.51, 137.35, 130.28, 129.78, 62.68, 55.24, 42.03, 21.04, 20.10, 14.20.
MS (ESI): m/z [M + Na] calcd for C14H21NO4SNa: 322.1; found: 322.0.
HRMS (MALDI): m/z [M + K]+ calcd for C14H21NO4SK: 338.0823; found: 338.0823.
#
Ethyl 2-Mesityl-2-(4-methylphenylsulfonamido)acetate (16b, R = Me)
Bi Catalysis : Compound 16b was synthesized according to the GP from 4-methylbenzenesulfonamide (87 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (n-hexane/EtOAc = 9:1 → 4:1) yielded the product as a colorless solid (148 mg, 79%).
Mp 138–140 °C; Rf = 0.3 (cyclohexane/EtOAc = 4:1).
IR (ATR): 3275 (w), 2923 (w), 1735 (s), 1611 (w), 1597 (w), 1451 (w), 1407 (w), 1367 (w), 1330 (m), 1289 (m), 1265 (m), 1228 (m), 1187 (w), 1163 (s), 1119 (w), 1095 (w), 1065 (m), 1023 (m), 972 (w), 938 (w), 911 (m), 870 (m), 838 (w), 825 (w), 809 (s), 778 (w), 721 (m), 705 (w), 670 (m), 586 (s), 552 (s), 530 (m), 486 cm–1 (w).
1H NMR (300 MHz, CDCl3): δ = 7.44 (d, J = 8.3 Hz, 2 H), 7.07 (d, J = 8.1 Hz, 2 H), 6.65 (s, 2 H), 5.69 (d, J = 4.6 Hz, 1 H), 5.51 (d, J = 4.7 Hz, 1 H), 4.20–4.03 (m, 2 H), 2.34 (s, 3 H), 2.21 (s, 6 H), 2.21 (s, 3 H), 1.12 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.93, 143.13, 137.99, 137.18, 137.13, 129.84, 129.46, 129.17, 126.99, 62.55, 55.01, 21.59, 20.92, 20.12, 14.10.
MS (ESI): m/z [M + Na]+ calcd for C20H25NO4SNa: 398.1; found: 398.1.
HRMS (MALDI): m/z [M + K]+ calcd for C20H25NO4SK: 414.1136; found: 414.1133.
#
Ethyl 2-(4-Bromophenylsulfonamido)-2-mesitylacetate (16b, R = Br)
Bi Catalysis : Compound 16b (R = Br) was synthesized according to the GP from 4-bromobenzenesulfonamide (120 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 100 °C. Purification by chromatography (n-hexane/EtOAc 4:1 → 7:3) yielded the product as a colorless solid (118 mg, 54%).
Mp 114–116 °C; Rf = 0.6 (n-hexane/EtOAc = 4:1).
IR (ATR): 3309 (w), 2965 (w), 1732 (s), 1610 (w), 1577 (w), 1473 (w), 1449 (w), 1391 (m), 1370 (m), 1323 (s), 1299 (m), 1278 (s), 1247 (m), 1223 (m), 1200 (m), 1159 (s), 1147 (s), 1090 (s), 1071 (s), 1033 (m), 1012 (m), 975 (w), 925 (m), 852 (m), 818 (s), 764 (w), 740 (s), 724 (m), 703 (w), 615 (s), 593 (m), 562 (s), 553 (s), 532 (m), 475 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 7.37–7.30 (m, 4 H), 6.63 (s, 2 H), 5.84 (br d, J = 4.2 Hz, 1 H), 5.57 (d, J = 4.3 Hz, 1 H), 4.23–4.06 (m, 2 H), 2.20 (s, 6 H), 2.19 (s, 3 H), 1.14 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.65, 139.23, 138.40, 137.17, 131.58, 129.83, 128.78, 128.32, 127.12, 62.68, 55.01, 20.88, 20.01, 14.09.
MS (ESI): m/z [M + Na]+ calcd for C19H22BrNO4SNa: 462.0; found: 462.0.
HRMS (MALDI): m/z [M + K]+ calcd for C19H22BrNO4SK: 478.0085; found: 478.0069.
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Ethyl 2-Mesityl-2-(4-methoxyphenylsulfonamido)acetate (16b, R = OMe)
Bi Catalysis : Compound 16b (R = OMe) was synthesized according to the GP from 4-methoxybenzenesulfonamide (196 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 18 h at 80 °C. Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the product as a colorless solid (126 mg, 64%).
Mp 173–175 °C; Rf = 0.5 (n-hexane/EtOAc 4:1).
IR (ATR): 3274 (w), 2923 (w), 1738 (m), 1594 (m), 1496 (m), 1437 (w), 1412 (m), 1329 (m), 1311 (w), 1288 (w), 1263 (s), 1228 (m), 1183 (m), 1157 (m), 1119 (w), 1096 (m), 1063 (m), 1024 (s), 939 (w), 913 (m), 870 (m), 828 (s), 801 (m), 779 (m), 722 (m), 674 (s), 628 (w), 585 (s), 559 cm–1 (s).
1H NMR (300 MHz, CDCl3): δ = 7.50–7.45 (m, 2 H), 6.75–6.70 (m, 2 H), 6.66 (s, 2 H), 5.67 (br d, J = 4.5 Hz, 1 H), 5.51 (d, J = 4.6 Hz, 1 H), 4.20–4.04 (m, 2 H), 3.80 (s, 3 H), 2.21 (s, 6 H), 2.19 (s, 3 H), 1.13 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.95, 162.74, 137.90, 137.17, 131.85, 129.87, 129.42, 129.09, 113.71, 62.55, 55.66, 55.00, 20.92, 20.13, 14.12.
MS (ESI): m/z [M + Na]+ calcd for C20H25NO5SNa: 414.1; found: 414.08.
HRMS (MALDI): m/z [M + Na]+ calcd for C20H25NO5SNa: 414.1346; found: 414.1338.
#
Ethyl 2-Mesityl-2-(thiophene-2-sulfonamido)acetate (16c)
Bi Catalysis : Compound 16c was synthesized according to the GP from 2-thiophenesulfonamide (82 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 1.5 equiv) and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purification by chromatography (n-hexane/EtOAc 9:1 → 4:1) yielded the product as a colorless solid (123 mg, 67%).
Mp 158–160 °C; Rf = 0.3 (n-hexane/EtOAc = 4:1).
IR (ATR): 3314 (w), 3115 (w), 2967 (w), 2083 (w), 1739 (s), 1612 (w), 1509 (w), 1480 (w), 1463 (w), 1407 (m), 1367 (w), 1329 (s), 1287 (s), 1225 (m), 1197 (m), 1157 (s), 1144 (s), 1091 (s), 1033 (m), 1014 (s), 976 (w), 925 (w), 852 (s), 828 (m), 782 (w), 739 (m), 729 (s), 666 (s), 641 (w), 608 (s), 589 (s), 570 (s), 546 (s), 528 (s), 468 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 7.44 (dd, J = 5.0, 1.2 Hz, 1 H), 7.24 (dd, J = 3.8, 1.3 Hz, 1 H), 6.88–6.85 (m, 1 H), 6.72 (s, 2 H), 5.87 (br d, J = 4.9 Hz, 1 H), 5.59 (d, J = 5.0 Hz, 1 H), 4.22–4.05 (m, 2 H), 2.26 (s, 6 H), 2.21 (s, 3 H), 1.14 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.78, 141.13, 138.13, 137.21, 132.19, 131.93, 129.96, 129.35, 127.00, 62.67, 55.28, 20.96, 20.16, 14.11.
MS (ESI): m/z [M + H]+ calcd for C17H22NO4S2: 368.1; found: 368.5.
HRMS (MALDI): m/z [M + K]+ calcd for C17H21NO4S2K: 406.0544; found: 406.0543.
#
Ethyl 3,5,10,10a-Tetrahydro-3-oxo-1H-oxazolo[3,4-b]isoquinoline-5-carboxylate (21)
Bi Catalysis : Compound 21 was synthesized according to the GP from (R)-4-benzyloxazolidin-2-one (59 mg, 0.3 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 2.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1) yielded the product as a colorless solid (72 mg, 84%).
Mp 58–59 °C; Rf = 0.2 (cyclohexane/EtOAc = 7:3).
IR (ATR): 2980 (w), 2936 (w), 2084 (w), 1760 (s), 1726 (s), 1477 (m), 1454 (m), 1408 (m), 1393 (m), 1365 (m), 1340 (m), 1322 (m), 1272 (s), 1237 (s), 1227 (s), 1205 (s), 1186 (s), 1167 (m), 1115 (m), 1099 (m), 1063 (s), 1017 (s), 983 (m), 938 (m), 917 (w), 892 (m), 876 (m), 824 (m), 810 (m), 759 (s), 745 (m), 715 (w), 697 (m), 671 (m), 620 (w), 585 (w), 534 (m), 509 (w), 495 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 7.61–7.56 (m, 1 H), 7.28–7.25 (m, 3 H), 7.18–7.15 (m, 1 H), 5.46 (s, 1 H), 4.72–4.67 (m, 1 H), 4.52–4.45 (m, 1 H), 4.27–4.12 (m, 3 H), 3.06–2.99 (m, 1 H), 2.93–2.84 (m, 1 H), 1.31 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.09, 157.14, 132.04, 129.88, 128.95, 128.31, 127.65, 127.31, 69.38, 62.16, 55.07, 49.62, 33.78, 14.25.
The structure was assigned by COSY.
MS (ESI): m/z [M + H]+ calcd for C14H16NO4: 262.1; found: 262.2.
Anal. Calcd for C14H15NO4: C, 64.36; H, 5.79; N, 5.36. Found: C, 63.95; H, 5.82; N, 5.20.
#
Ethyl 2-(3-Methyl-(1,3-dioxoisoindolin-2-yl)butanamido)-2-mesitylacetate (23, PG = Phth)
Bi Catalysis : Compound 23 (PG = Phth) was synthesized according to the GP from 3-methyl-2(1,3-dioxoisoindolin-2-yl)butanamide (246 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg, 1.2 mmol, 1.2 equiv), mesitylene (0.41 mL, 3.0 mmol, 3.0 equiv), and Bi(OTf)3 (13 mg, 0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the product as a colorless solid (393 mg, 87%; r.r. = 67:33).
IR (ATR): 3348 (w), 2966 (w), 2873 (w), 2050 (w), 1979 (w), 1776 (w), 1765 (w), 1730 (m), 1705 (s), 1676 (s), 1608 (w), 1525 (s), 1466 (m), 1383 (s), 1360 (m), 1331 (m), 1279 (m), 1240 (s), 1153 (m), 1099 (m), 1063 (s), 1026 (s), 982 (w), 947 (w), 908 (w), 885 (m), 868 (w), 854 (m), 827 (w), 806 (w), 766 (w), 725 (s), 708 (m), 688 (w), 613 (s), 604 cm–1 (s).
#
Diastereomer a
Mp 63–65 °C; Rf = 0.2 (n-hexane/EtOAc = 4:1).
1H NMR (300 MHz, CDCl3): δ = 8.10 (br d, J = 7.2 Hz, 1 H), 7.90–7.88 (m, 2 H), 7.77–7.74 (m, 2 H), 6.83 (s, 2 H), 5.99 (d, J = 7.3 Hz, 1 H), 4.44 (d, J = 11.5 Hz, 1 H), 4.20–4.03 (m, 2 H), 2.86–2.74 (m, 1 H), 2.39 (s, 6 H), 2.25 (s, 3 H), 1.11 (t, J = 7.1 Hz, 3 H), 0.92 (d, J = 6.7 Hz, 3 H), 0.83 (d, J = 6.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 171.38, 168.61, 168.33, 137.69, 137.05, 134.54, 131.57, 130.90, 130.01, 123.88, 63.58, 61.85, 52.40, 27.89, 21.01, 20.29, 19.62, 14.11.
#
Diastereomer b
Mp 136–138 °C; Rf = 0.3 (n-hexane/EtOAc = 4:1).
1H NMR (300 MHz, CDCl3): δ = 7.95 (br d, J = 7.4 Hz, 1 H), 7.85–7.82 (m, 2 H), 7.74–7.71 (m, 2 H), 6.79 (s, 2 H), 6.04 (d, J = 7.5 Hz, 1 H), 4.45 (d, J = 11.3 Hz, 1 H), 4.24–4.09 (m, 2 H), 3.03–2.90 (m, 1 H), 2.36 (s, 6 H), 2.21 (s, 3 H), 1.20–1.14 (m, 6 H), 0.86 (d, J = 6.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 171.43, 168.54, 168.50, 137.72, 137.08, 134.52, 131.51, 130.82, 129.99, 123.84, 63.29, 61.88, 52.10, 27.96, 20.97, 20.28, 19.91, 19.72, 14.18.
MS (ESI): m/z [M + H]+ calcd for C26H31N2O5: 451.2; found: 451.4.
HRMS (MALDI): m/z [M + H]+ calcd for C26H31N2O5: 451.2228; found: 451.2224.
#
Ethyl 2-Benzamido-2-hydroxyacetate (24a)
Fe Catalysis : Compound 24a was synthesized according to the GP from benzamide (61 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL, 1.2 mmol, 1.2 equiv), and FeCl3·6H2O (13 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at r.t. Purification by chromatography (n-hexane/EtOAc = 4:1) yielded the product as a colorless solid (96 mg, 99%).
Mp 54.8 °C; Rf = 0.30 (n-hexane/EtOAc = 7:3).
1H NMR (400 MHz, CDCl3): δ = 7.84–7.79 (m, 2 H), 7.51 (d, J = 51.2 Hz, 3 H), 7.36 (d, J = 5.8 Hz, 1 H), 5.78 (dd, J = 6.9, 6.0 Hz, 1 H), 4.35 (q, J = 7.1 Hz, 2 H), 4.15 (d, J = 5.8 Hz, 1 H), 1.36 (t, J = 7.1 Hz, 3 H).
Analytical and spectral data are consistent with those reported in the literature.[36]
#
Ethyl 2,2-Bis(benzamido)acetate (25a)
Fe Catalysis : Compound 25a was synthesized according to the GP from benzamide (242 mg, 2.0 mmol, 2.0 equiv), ethyl glyoxalate (0.10 mL, 1.0 mmol, 1.0 equiv), and FeCl3·6H2O (13 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). After stirring for 24 h at 80 °C, the white precipitate was filtered, and dried under reduced pressure. The desired product was isolated as a white solid (325 mg, ~100%).
Mp (decomp.); Rf = 0.26 (n-hexane/EtOAc = 7:3).
1H NMR (400 MHz, CDCl3): δ = 8.00–7.70 (m, 6 H), 7.55–7.42 (m, 6 H), 5.88 (t, J = 6.7 Hz, 1 H), 4.33 (dd, J = 14.1, 7.0 Hz, 2 H), 1.30 (t, J = 7.1 Hz, 3 H).
Analytical and spectral data are consistent with those reported in the literature.[37]
#
Ethyl 2,2-Dimesitylacetate (26)
Fe Catalysis : Compound 26 was synthesized according to the GP from ethyl glyoxalate (0.10 mL, 1.0 mmol, 1.0 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), and FeCl3·6H2O (13 mg, 0.025 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (n-hexane/EtOAc = 20:1 → 9:1) yielded the product as a colorless solid (320 mg, 99%).
Mp 100–106 °C; Rf = 0.72 (n-hexane/EtOAc = 9:1).
1H NMR (400 MHz, CDCl3): δ = 6.79 (s, 4 H), 4.24 (q, J = 7.1 Hz, 2 H), 2.24 (s, 6 H), 2.07 (s, 12 H), 1.27 (t, J = 7.1 Hz, 3 H).
Analytical and spectral data are consistent with those reported in the literature.[38]
#
Ethyl 2-Hydroxy-2-mesitylacetate (27)
Fe Catalysis : Compound 27 was synthesized according to the GP from ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.0 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), 2,2′-bipyridine (5 mg, 0.03 mmol, 3 mol%), and Fe(ClO4)3 (7 mg, 0.02 mmol, 2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purification by chromatography (hexane/EtOAc = 4:1) yielded the product as a colorless oil (176 mg, 66%).
Rf = 0.51 (n-hexane/EtOAc = 7:3).
1H NMR (400 MHz, CDCl3): δ = 6.84 (s, 2 H), 5.52 (d, J = 2.8 Hz, 1 H), 4.34–4.11 (m, 2 H), 3.22 (d, J = 2.8 Hz, 1 H), 2.33 (s, 6 H), 2.26 (s, 3 H), 1.22 (t, J = 7.1 Hz, 3 H).
Analytical data are consistent with those reported in the literature.[39]
#
#
Acknowledgment
This work was financially supported by the Fonds der Chemischen Industrie (Liebig Fellowship to G.M. and A.E.S.), the Evonik Stiftung (Fellowship to J.H.), the Stiftung Polytechnische Gesellschaft Frankfurt am Main (Fellowship to T.B.), and the Goethe-University Frankfurt (Nachwuchs im Fokus-Program). We would like to thank Prof. Michael Göbel (Goethe-University Frankfurt) for his support as well as Rockwood Lithium GmbH (Frankfurt) and Evonik Industries AG (Hanau) for the generous gift of chemicals.
Supporting Information
- Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0035-1561499.
- Supporting Information
-
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For reviews on asymmetric arylglycine synthesis, see:
For recent examples, see:
For the iron-catalyzed addition of thiophenes to preformed glyoxalate imines, see:
For recent reviews, see:
For a recent review, see:
Atom economic:
Sustainable synthesis:
For reviews, see:
For selected recent examples of iron catalysis in organic synthesis, see:
For reviews, see:
For selected recent examples of bismuth catalysis in organic synthesis, see:
For the use of dbpy as a mechanistic probe to determine between Lewis and Brønsted acid catalysis, see:
For examples of asymmetric Bi- and Fe-catalyzed transformations, see:
-
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For reviews on asymmetric arylglycine synthesis, see:
For recent examples, see:
For the iron-catalyzed addition of thiophenes to preformed glyoxalate imines, see:
For recent reviews, see:
For a recent review, see:
Atom economic:
Sustainable synthesis:
For reviews, see:
For selected recent examples of iron catalysis in organic synthesis, see:
For reviews, see:
For selected recent examples of bismuth catalysis in organic synthesis, see:
For the use of dbpy as a mechanistic probe to determine between Lewis and Brønsted acid catalysis, see:
For examples of asymmetric Bi- and Fe-catalyzed transformations, see:
