Keywords
amino acid - catalyst-free - metal-free - chemoselective - secondary amide - transamidation
The interconversion of one amide to another amide is known as the transamidation reaction. The transamidation reactions are one of the most fundamental transformations in synthetic organic chemistry because amides are ubiquitous in nature and are most important functional molecules in industry.[1] However, the notorious stability[2] of the amide group is a major challenge arising out of the high kinetic barrier, the thermodynamic factor to break the C–N bond, and the resonance stabilization of the amide group.[3] In spite of this, notable headway has been made with transamidation of primary amides.[4] Recently several successful attempts have been reported for transamidation reactions of secondary amides.[5] The Lewis acid catalyzed transamidation reaction of secondary amide is accomplished by the activation of the amide carbonyl group.[6] Gellman and co-workers reported the use of dimeric aluminum complex[6a] and Bertrand reported the use of excess AlCl3 for simple substrates.[6b] Garg and co-workers achieved transamidation of Boc-activated aliphatic and aryl substituted secondary amides in a two-step process using nickel catalysis (Scheme [1a]).[7] More recently, a metal-free transamidation involving triethylamine[8a]
[b] and a Pd-NHC complex-mediated[8c] transamidation of secondary amides were reported by Szostak (Scheme [1b]).[8] Despite these reports, a more general approach to the problem of transamidation has remained a challenge and a more sustainable green methodology is warranted. Herein, we describe the results of a successful approach and report a highly selective methodology for transamidation of secondary amides under catalyst-free conditions in ethanol or water as solvent (Scheme [1c]). The N-functionalized substrates with appropriate activating groups such as Boc or Ts or aryl sulfonyl groups generally undergo an efficient transamidation reaction smoothly (Scheme [1c]).[9]
Scheme 1 Transamidation of secondary amides
Initially, when the transamidation was performed with activated secondary benzamide 1a (1 equiv) and piperidine (2a; 1.3 equiv) at room temperature there was no reaction in ethanol or dichloromethane (Table [1], entries a, b) even after 24 hours. The above reaction performed at 45 °C in dichloromethane gave the transamidation product 3a in 68% yield after 12 hours (entry c). Encouraged by this initial result, the reaction was tested in other solvents like toluene and THF at higher temperatures (45–80 °C) and the product 3a was obtained in moderate yields (entries d, e). Interestingly, the transamidation reaction was found to occur when performed in water at 60 °C, affording the secondary amide 3a in 58% yield (entry f). Finally, when the transamidation reaction was performed in ethanol at 45 °C it gave an excellent yield (99%) of 3a in 1.5 hours (entry g). It is pertinent to point out that the reaction of unactivated amides like N-benzyl-N-methylbenzamide with piperidine under the same reaction conditions does not provide any transamidation product.
Table 1 Optimization of Reaction Conditionsa
|
|
Entry
|
Solvent
|
Temp (°C)
|
Time (h)
|
Yield (%)b
|
|
a
|
EtOH
|
r.t.
|
24
|
0
|
|
b
|
CH2Cl2
|
r.t.
|
24
|
0
|
|
c
|
CH2Cl2
|
45
|
12
|
68
|
|
d
|
toluene
|
45
|
12
|
61
|
|
e
|
THF
|
80
|
24
|
59
|
|
f
|
H2O
|
60
|
12
|
58c
|
|
g
|
EtOH
|
45
|
1.5
|
99
|
a Reaction conditions: activated secondary amide substrate 1a (1 equiv), amine (1.3 equiv), EtOH (1 mL).
b Isolated yields.
c Reaction was performed with activated secondary amide substrate 1a (1 equiv) and amine (1.3 equiv) in H2O (1 mL).
With optimized conditions in hand, the scope and generality of the transamidation protocol were explored with a variety of primary and secondary amine partners with different activated amides 1 (Figure [1], Scheme [2]). The cyclic secondary amines such as pyrrolidine and morpholine could be utilized for the transamidation reaction with 1a to furnish the corresponding products 3b and 3c, respectively, in excellent yields (97% and 99%). Substrates with electron-donating substituents on the aryl ring of activated secondary amides 1b,c readily undergo transamidation to give products 3d,e in excellent yields. Interestingly, this green protocol tolerates several functional groups such as bromo and iodo that would be problematic substrates in the metal-catalyzed transamidation to form 3f–i.[8]
[10] Further, the N-activated heterocyclic secondary amides 1f–h also furnished the corresponding transamidation products 3j–l in excellent yields. The reaction of secondary amide with N-methylaniline also gave the transamidation product 3m in 95% yield.
Figure 1 Activated amides used in this work
Further, we examined the scope of reaction with different anilines as shown by the formation of secondary amides 3n–p. In all the cases, the reactions occur very smoothly without affecting the yield.[8] Reaction of benzylamine with activated amide 1a also furnished the secondary amide 3q in high yield. Additionally, propargylamine could also be used to form the secondary amide 3r in 97% yield. Cyclohexylamine or hindered 1-adamantylamine also undergo smooth transamidation with 1a to furnish the corresponding secondary amides 3s,t in 98% and 94% yield, respectively. The results of this study are summarized in Scheme [2].
Scheme 2 Transamidation of tosyl-activated N-benzylamide 1 with various amines 2. Reagents and conditions: activated secondary amide substrate 1a (1 equiv), amine (1.3 equiv), EtOH (1 mL). Isolated yields are shown.
The scope of this methodology was then extended to tosyl-activated N-methylamide derivatives 4 with piperidine and α-branched amines. The amide substrates 4a,b containing either electron-donating substituents or electron-withdrawing substituents on the aryl ring furnish the corresponding amides 5a,b in excellent yields. α-Branched amine such as isopropylamine and primary amine like n-butylamine also react with amide 4c leading to the formation of the desired secondary amides 5c,d in high yields (Scheme [3]).
Scheme 3 Transamidation of tosyl-activated N-methylamide 4 with amines 2. Reagents and conditions: activated secondary amide substrate 5 (1 equiv), amine (1.3 equiv), EtOH (1 mL). Isolated yields are shown.
It was of interest to study the reaction of amides activated with N-Boc group in the transamidation reaction. Reaction of N-Boc-activated amides 6a,b with secondary or primary amines was explored in ethanol at 45 °C and the results are presented in the Scheme [4]. The reactions generally yielded the expected products 7a–f in almost quantitative yield.
Scheme 4 Transamidation of Boc-activated N-methylamide 6 with amines 2. Reagents and conditions: Boc-activated secondary amide 7 (1 equiv), amine (1.3 equiv), EtOH (1 mL). Isolated yields are shown.
To evaluate the efficiency of this protocol, the transamidation of activated secondary amide substrate 1a was performed with amino acid and amino alcohol derived nucleophiles. All the nucleophiles derived from amino acids, phenylalanine, alanine, and methionine, and the amino alcohols could be utilized for the reaction, leading to the corresponding secondary amides 8a–d, respectively in high yields (Scheme [5]). It is of interest to note that the reaction is chemoselective in that only N-nucleophiles react in the presence of O-nucleophiles in amino alcohols. This selectivity is not known with nickel-catalyzed[7] transamidation reactions.
Scheme 5 Transamidation of Ts-activated N-benzylamide 1a with amino acids and amino alcohols. Reagents and conditions: amide 1a (1 equiv), amino acid, or amino alcohol (1.5 equiv), EtOH (1 mL) at 60 °C. Isolated yields are shown.
At this stage, we decided to test the feasibility of this transamidation in water. Our initial studies with 1a and piperidine (1.5 equiv) in water gave only 58% the product 3a. When the stoichiometry of the amine was increased to 4 equivalents at 60 °C, the yield of the product 3a went up to to 97%. Some of the successful experiments in water are presented in Scheme [6].
Scheme 6 Transamidation of activated secondary amides in water. Reagents and conditions: Amide 1a–b,f (1 equiv), amine 2 (4 equiv), H2O (1 mL) at 60 °C; amide 6b (1 equiv), amine 2 (4 equiv), H2O (1 mL) at 60 °C. Isolated yields are shown.
Having successfully carried out many transamidation reactions under catalyst-free, metal-free conditions, we decided to compare our results with similar transamidation reaction reported in the literature recently under nickel-catalyzed[7] condition as well the reaction performed in the presence of triethylamine.[8]
The Boc-activated amide 11a on transamidation with sterically hindered 1-adamantylamine and 2,6-dimethylaniline in Et3N is reported to give no product while under Ni-catalyzed condition[7] gave 58% and 49% of corresponding amides (3t and 12a). Under our reaction condition both the amines reacted with 11a to give 73% and 69% yield of products (Table [2], entries 1, 2). While the reaction of benzylamine and morpholine with 11b has not been reported under nickel catalysis,[7] under Et3N catalysis benzylamine afforded excellent yield of the product 12b (Table [2], entries 3,4).[8] In the present protocol, both the amines react with 11b to give higher yield of the transamidation products 3g and 12b.
Table 2 Comparison Table of Transamidation of N-Activated 2° Amides Using [Ni] Catalysis, Metal-Free Conditions and Our Protocola
|
|
Entry
|
Amide
|
Amine
|
Product
|
Ni catalyst[7]
|
Et3N[8]
|
Metal-free[11]
|
Our workb
|
|
1
|
11a
|
1-adamantylamine
|
3t
|
58
|
no reaction
|
not reported
|
73
|
|
2
|
11a
|
2,6-dimethylaniline
|
12a
|
49
|
no reaction
|
not reported
|
69
|
|
3
|
11b
|
benzylamine
|
12b
|
not reported
|
98
|
not reported
|
96
|
|
4
|
11b
|
morpholine
|
3g
|
not reported
|
not reported
|
not reported
|
78
|
|
5
|
10
|
(R)-1-methylbenzylaminec
|
12c
|
not reported
|
not reported
|
52
|
88
|
a Reaction conditions: Amide 11 (1 equiv), amine 2 (1.3 equiv), EtOH (1 mL) at 45–60 °C.
b Isolated yields.
c Amide 10 (1 equiv), amine 2 (1.5 equiv), EtOH (1 mL) at 60 °C, 6 h.
Verho reported[11] a protocol where they find that the reaction of 10 with (R)-1-methylbenzylamine (5 equiv) gave the corresponding amide in 52% yield after 24 hours. However, using our methodology the same reaction of 10 with chiral amine (R)-1-methylbenzylamine (1.5 equiv) gave the product 12c without loss of optical purity in 88% yield in 6 hours (Table [2], entry 5). Thus our methodology appears to be as good as the other reported transamidations in the literature and in some cases better.
Mechanistic Studies
A series of competitive experiments were performed using N-activated amide 1a with various amine nucleophiles to identify the selectivity patterns of the transamidation (Scheme [7]). To study the effect of ring size, we compared the reaction of cyclic amines piperidine and pyrrolidine with 1a. The major product obtained was 3c (reaction with pyrrolidine) in 66% yield while 3a was found to be the minor product.
Scheme 7 Competitive reactivity of various amines
The reaction of aryl- versus alkylamine was tested by the reaction of aniline and cyclohexylamine with 1a. The product 3s derived from cyclohexylamine was found to be the major product (81%). The involvement of the steric factors in the reaction was tested using n-butylamine and tert-butylamine as partners for transamidation. The only product obtained in this case was the amide 5d resulting from the reaction of n-butylamine.
The study of selectivity and reactivity of Ts- and Boc-activated amides containing electron-donating or electron-withdrawing substituents with piperidine was carried out (Scheme [8]). When a 1:1 mixture of Ts-activated amides 4a and 4b was treated with piperidine (EtOH, 45 °C, 1.5 h) the major product was found to be 5a. Similarly, the reaction of a 1:1 mixture of Boc-activated amides 6a and 6b with piperidine gave 7d as the major product. Additionally we tested the competitive reactivity of Ts-activated amide 1a and Boc-activated amide 11a with piperidine at different time intervals. The amide 11a started to react with piperidine only after 1 hour but 1a was already fully consumed. It shows that N-Ts-activated amide 1a reacts faster than Boc-activated amide 11a.
Scheme 8 Competition studies with N-Ts- and N-Boc-activated amides
Based on the above observations we propose a reaction mechanism, which is similar to the one proposed by Szostak.[8a]
[b] The transamidation of secondary amides is achieved by exothermic nucleophilic addition of amine to form intermediate 13. Subsequent release of the N-functionalized amine 14, which is less nucleophilic than the amine involved in the transamidation reaction leads to the formation of product 3 (Scheme [9]).
Scheme 9 Proposed Mechanism
Conclusion
In summary, we have developed a simple protocol for the transamidation of a number of activated secondary amides using a broad range of amines in ethanol as solvent under catalyst-free and metal-free conditions. We have also extended the scope of the transamidation to water medium. This effective procedure is highly chemoselective as shown in the reaction of amino acid and amino alcohols. The stereochemical integrity of the amino acid and amino alcohol derivatives is preserved in the reaction. The present methodology appears to be better than other catalyzed transamidations reported in the literature recently.
Melting points were determined using a capillary melting point apparatus and are uncorrected. All the transamidation reactions were performed using sealed vial under air atmosphere, unless stated otherwise. The starting materials were prepared based on the previously reported literature method. The solvents purchased were of the laboratory grade (LR) and used as received or purified by distillation following standard procedure. All other chemicals were purchased from Sigma-Aldrich, Alfa Acer, and TCI. 1HNMR spectra were recorded on a Bruker Avance at 400 MHz using CDCl3 or DMSO-d
6 in ppm (δ) related to TMS (δ = 0.00) as an internal standard and are reported as follows; chemical shift (ppm), multiplicity (standard abbreviations), coupling constant (Hz), and integration. 13C NMR spectra were recorded at 100 MHz in CDCl3 or DMSO-d
6. Chemical shifts are reported in delta (δ) units, parts per million (ppm) relative to the center of the triplet at 77.7 ppm for CDCl3 or 39.5 ppm for DMSO-d
6. Carbon types were determined from 13C NMR and DEPT experiments. Mass spectra were measured with Micromass Q-Tof (ESI-HRMS). Optical rotations were measured on JASCO P-2000 polarimeter at r.t. using 50 mm cell of 1 mL capacity. TLC was performed on silica gel GF-254 and components visualized by observation under I2/UV light at 254 nm. Column chromatography was performed on silica gel (230–400 mesh).
N-Ts-Activated Secondary Amides; General Procedure
N-Ts-Activated Secondary Amides; General Procedure
An oven-dried 100 mL round-bottomed flask was charged with N-benzyl-4-methylbenzenesulfonamide (1.0 mmol, 1.0 equiv), and NaH (1.5 mmol, 1.5 equiv) in anhyd THF (20 mL). A solution of the respective acyl chloride (1.0 mmol, 1.0 equiv) in anhyd THF (10 mL) was added at 0 °C. The reaction mixture was stirred at r.t. (25 °C) for 3 h. The reaction was monitored by TLC. After completion of the reaction, the mixture was quenched with H2O and extracted with CH2Cl2 (3 × 25 mL). The combined organic layers were washed with brine (20 mL), dried (anhyd Na2SO4), and the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (EtOAc/PE) to afford the desired N-tosyl-activated secondary amide.
N-Benzyl-N-tosylbenzamide (1a)[12]
N-Benzyl-N-tosylbenzamide (1a)[12]
Eluent: PE/EtOAc (90:10); white solid; yield: 1.29 g (92%); mp 95–97 °C.
1H NMR (CDCl3, 400 MHz): δ = 2.41 (s, 3 H, CH3), 5.01 (s, 2 H, CH2), 7.21–7.26 (m, 7 H, ArH), 7.34 (t, J = 7.2 Hz, 2 H, ArH), 7.46 (t, J = 7.6 Hz, 3 H, ArH), 7.63 (d, J = 8.0 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 21.61, 51.25, 127.75, 127.91, 128.18, 128.50, 128.55, 129.37, 130.14, 131.70, 133.72, 134.90, 135.85, 136.21, 144.70, 171.56.
N-Benzyl-4-methyl-N-tosylbenzamide (1b)[12]
N-Benzyl-4-methyl-N-tosylbenzamide (1b)[12]
Eluent: PE/EtOAc (90:10); colorless oil; yield: 256 mg (88%).
1H NMR (CDCl3, 400 MHz): δ = 2.35 (s, 3 H, CH3), 2.40 (s, 3 H, CH3), 4.94 (s, 2 H, CH2), 7.14 (d, J = 8.0 Hz, 2 H, ArH), 7.19–7.25 (m, 7 H, ArH), 7.41 (d, J = 7.6 Hz, 2 H, ArH), 7.60 (d, J = 8.0 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 21.56, 21.59, 51.32, 127.68, 127.93, 128.47, 128.50, 128.60, 128.86, 129.33, 132.05, 135.89, 136.18, 142.61, 144.54, 171.65.
N-Benzyl-4-methoxy-N-tosylbenzamide (1c)
N-Benzyl-4-methoxy-N-tosylbenzamide (1c)
Eluent: PE/EtOAc (85:15); white solid; yield: 269 mg (89%); mp 121–123 °C.
1H NMR (CDCl3, 400 MHz): δ = 2.40 (s, 3 H, CH3), 3.81 (s, 3 H, CH3), 4.88 (s, 2 H, CH2), 6.84 (d, J = 8.8 Hz, 2 H, ArH), 7.21–7.24 (m, 7 H, ArH), 7.56 (d, J = 8.8 Hz, 2 H, ArH), 7.61 (d, J = 8.0 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 21.58, 51.33, 55.40, 113.47, 127.12, 127.68, 128.02, 128.32, 128.49, 129.41, 131.26, 135.82, 136.12, 144.48, 162.89, 171.26.
HRMS: m/z calcd for C22H21NO4SNa [M + Na]+: 418.1089; found: 418.1089.
N-Benzyl-4-bromo-N-tosylbenzamide (1d)
N-Benzyl-4-bromo-N-tosylbenzamide (1d)
Eluent: PE/EtOAc (90:10); white solid; yield: 292 mg (86%); mp 131–133 °C.
1H NMR (CDCl3, 400 MHz): δ = 2.41 (s, 3 H, CH3), 4.92 (s, 2 H, CH2), 7.20–7.26 (m, 7 H, ArH), 7.31 (d, J = 8.4 Hz, 2 H, ArH), 7.46 (d, J = 8.4 Hz, 2 H, ArH), 7.56 (d, J = 8.0 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 21.62, 50.98, 126.57, 127.86, 127.95, 128.33, 128.60, 129.51, 129.89, 131.37, 133.90, 135.60, 135.92, 144.91, 170.68.
HRMS: m/z calcd for C21H18BrNO3SNa [M + Na]+: 466.0088; found: 466.0094.
N-Benzyl-2-iodo-N-tosylbenzamide (1e)
N-Benzyl-2-iodo-N-tosylbenzamide (1e)
Eluent: PE/EtOAc (88:12); white solid; yield: 320 g (85%); mp 146–148 °C.
1H NMR (CDCl3, 400 MHz): δ = 2.42 (s, 3 H, CH3), 4.93 (s, 2 H, CH2), 7.23–7.33 (m, 9 H, ArH), 7.47 (d, J = 7.6 Hz, 2 H, ArH), 7.57 (d, J = 7.2 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 21.63, 51.01, 126.56, 127.27, 127.86, 127.96, 128.34, 128.39, 128.61, 129.53, 129.89, 129.99, 131.38, 133.91, 135.61, 135.95, 144.92, 170.67.
HRMS: m/z calcd for C21H18INO3SNa [M + Na]+: 513.9950; found: 513.9947.
N-Benzyl-N-tosylfuran-2-carboxamide (1f)[12]
N-Benzyl-N-tosylfuran-2-carboxamide (1f)[12]
Eluent: PE/EtOAc (85:15); light yellow solid; yield: 242 mg (89%); mp 113–115 °C.
1H NMR (CDCl3, 400 MHz): δ = 2.45 (s, 3 H, CH3), 5.27 (s, 2 H, CH2), 6.48 (d, J = 2.0 Hz, 1 H, ArH), 7.15 (d, J = 3.2 Hz, 1 H, ArH), 7.25–7.30 (m, 7 H, ArH), 7.52 (s, 1 H, ArH), 7.80 (d, J = 8.0 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 21.61, 50.49, 112.17, 120.42, 127.16, 127.58, 128.57, 128.80, 129.30, 135.86, 136.48, 144.73, 146.01, 146.53, 159.48.
N-Benzyl-N-tosylthiophene-2-carboxamide (1g)
N-Benzyl-N-tosylthiophene-2-carboxamide (1g)
Eluent: PE/EtOAc (85:15); white solid; yield: 259 mg 91%); mp 86–88 °C.
1H NMR (CDCl3, 400 MHz): δ = 2.41 (s, 3 H, CH3), 5.06 (s, 2 H, CH2), 6.98 (t, J = 4.4 Hz, 1 H, ArH), 7.25–7.29 (m, 7 H, ArH), 7.53 (d, J = 4.4 Hz, 2 H, ArH), 7.73 (d, J = 8.0 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 21.62, 51.66, 127.46, 127.48, 127.74, 128.65, 128.66, 129.44, 133.19, 133.33, 135.60, 136.14, 137.29, 144.73, 164.66.
HRMS: m/z calcd for C19H17NO3S2Na [M + Na]+: 394.0548; found: 394.0548.
N-Benzyl-5-bromo-N-tosylfuran-2-carboxamide (1h)
N-Benzyl-5-bromo-N-tosylfuran-2-carboxamide (1h)
Eluent: PE/EtOAc (80:20); white solid; yield: 283 mg (85%); mp 119–121 °C.
1H NMR (CDCl3, 400 MHz): δ = 2.41 (s, 3 H, CH3), 5.17 (s, 2 H, CH2), 6.36 (d, J = 3.6 Hz, 1 H, ArH), 7.02 (d, J = 3.6 Hz, 1 H, ArH), 7.20–7.29 (m, 7 H, ArH), 7.78 (d, J = 8.0 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 21.64, 50.51, 114.23, 122.46, 127.24, 127.52, 127.64, 128.60, 128.74, 129.43, 135.66, 136.18, 144.89, 148.10, 158.30.
HRMS: m/z calcd for C19H16BrNO4SNa [M + Na]+: 455.9881; found: 455.9881.
N-Benzyl-N-tosylacetamide (1i)[13]
N-Benzyl-N-tosylacetamide (1i)[13]
Eluent: PE/EtOAc (90:10); colorless oil; yield: 195 mg (84%).
1H NMR (CDCl3, 400 MHz): δ = 2.32 (s, 3 H, CH3), 2.45 (s, 3 H, CH3), 5.11 (s, 2 H, CH2) 7.29–7.36 (m, 6 H, ArH), 7.39 (t, J = 7.6 Hz, 2 H, ArH), 7.64 (d, J = 8.4 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 21.56, 24.86, 49.48, 127.71, 127.83, 127.93, 128.57, 128.66, 129.71, 136.49, 136.63, 144.88, 170.33.
4-Methoxy-N-methyl-N-tosylbenzamide (4a)[14]
4-Methoxy-N-methyl-N-tosylbenzamide (4a)[14]
Eluent: PE/EtOAc (90:10); white solid; yield: 785 mg (91%); mp 46–48 °C.
1H NMR (CDCl3, 400 MHz): δ = 2.42 (s, 3 H, CH3), 3.24 (s, 3 H, NCH3), 3.83 (s, 3 H, OCH3), 7.89 (d, J = 7.6 Hz, 2 H, ArH), 7.32 (d, J = 7.6 Hz, 2 H, ArH), 7.61 (d, J = 7.6 Hz, 2 H, ArH), 7.84 (d, J = 8.0 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 21.61, 35.90, 55.44, 113.55, 126.24, 128.35, 129.57, 131.30, 134.97, 144.74, 162.91, 171.20.
N-Methyl-4-nitro-N-tosylbenzamide (4b)[14]
N-Methyl-4-nitro-N-tosylbenzamide (4b)[14]
Eluent: PE/EtOAc (85:15); light yellow solid; yield: 794 mg (88%); mp 114–116 °C.
1H NMR (CDCl3, 400 MHz): δ = 2.47 (s, 3 H, CH3), 3.27 (s, 3 H, NCH3), 7.36 (d, J = 8.4 Hz, 2 H, ArH), 7.69 (t, J = 9.6 Hz, 4 H, ArH), 8.26 (d, J = 8.8 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 21.67, 34.62, 123.32, 128.01, 129.16, 129.95, 134.55, 140.88, 145.59, 149.28, 169.55.
N-Methyl-N-tosylbenzamide (4c)[14]
N-Methyl-N-tosylbenzamide (4c)[14]
Eluent: PE/EtOAc (85:15); white solid; yield: 672 mg (86%); mp 65–67 °C.
1H NMR (CDCl3, 400 MHz): δ = 2.42 (s, 3 H, CH3), 3.27 (s, 3 H, NCH3), 7.32 (d, 2 H, J = 8.0 Hz, ArH), 7.39 (t, 2 H, J = 7.6 Hz, ArH), 7.49 (dd, J
1 = 7.0 Hz, J
2 = 1.2 Hz, 1 H, ArH), 7.53 (dd, J
1 = 7.8 Hz, J
2 = 1.2 Hz, 2 H, ArH), 7.83 (d, J = 7.0 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 21.63, 35.61, 128.28, 128.38, 128.43, 129.61, 130.09, 131.94, 134.47, 135.18, 144.93, 171.45.
N-Phenyl-N-tosylbenzamide (4d)[8d]
N-Phenyl-N-tosylbenzamide (4d)[8d]
Eluent: PE/EtOAc (85:15); white solid; yield: 2.44 g (86%); mp 151–153 °C.
1H NMR (CDCl3, 400 MHz): δ = 2.43 (s, 3 H, CH3), 7.14–7.15 (m, 3 H, ArH), 7.26–7.30 (m, 5 H, ArH), 7.42 (d, J = 7.2 Hz, 2 H, ArH), 7.82 (d, J = 8.4 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 21.67, 127.95, 129.01, 129.07, 129.22, 129.42, 130.35, 131.71, 133.60, 135.17, 137.36, 144.81, 169.87.
N-Boc-Activated Secondary Amides; General Procedure
N-Boc-Activated Secondary Amides; General Procedure
To an oven-dried 100 mL round-bottomed flask containing a secondary amide substrate (1.0 mmol, 1.0 equiv) and DMAP (0.1 mmol, 0.1 equiv) in CH2Cl2 (20 mL) was added Boc2O (1.3 mmol, 1.3 equiv) in one portion and the reaction mixture was allowed to stir at r.t. After the indicated time, the mixture was quenched with aq NaHCO3 (10 mL), and extracted with EtOAc (3 × 20 mL). the combined organic layers were washed with H2O (20 mL) and brine (20 mL), dried (anhyd Na2SO4), and concentrated. The crude product was purified by column chromatography (EtOAc/PE) to afford the pure product.
tert-Butyl (4-Methoxybenzoyl)(methyl)carbamate (6a)[8d]
tert-Butyl (4-Methoxybenzoyl)(methyl)carbamate (6a)[8d]
Eluent: PE/EtOAc (85:15); colorless oil; yield: 715 mg (89%).
1H NMR (CDCl3, 400 MHz): δ = 1.19 (s, 9 H, 3 × CH3), 3.24 (s, 3 H, NCH3), 3.81 (s, 3 H, OCH3), 6.85 (d, J = 8.8 Hz, 2 H, ArH), 7.49 (d, J = 8.8 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 27.46, 32.75, 55.36, 82.58, 133.14, 129.69, 129.90, 153.77, 162.06, 173.13.
tert-Butyl Methyl[4-(trifluoromethyl)benzoyl]carbamate (6b)[8d]
tert-Butyl Methyl[4-(trifluoromethyl)benzoyl]carbamate (6b)[8d]
Eluent: PE/EtOAc (90:10); white solid; yield: 627 mg (84%); mp 147–149 °C.
1H NMR (CDCl3, 400 MHz): δ = 1.16 (s, 9 H, 3 × CH3), 3.31 (s, 3 H, NCH3), 7.57 (d, J = 8.0 Hz, 2 H, ArH), 7.64 (d, J = 8.0 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 27.33, 32.37, 83.63, 124.98, 127.40, 141.29, 152.92, 172.04.
tert-Butyl Benzoyl(benzyl)carbamate (11a)[8d]
tert-Butyl Benzoyl(benzyl)carbamate (11a)[8d]
Eluent: PE/EtOAc (90:10); colorless oil; yield: 1.31 g (89%).
1H NMR (CDCl3, 400 MHz): δ = 1.11 (s, 9 H, 3 × CH3), 4.99 (s, 2 H, CH2), 7.24 (t, J = 6.4 Hz, 1 H, ArH), 7.29–7.37 (m, 4 H, ArH), 7.42 (t, J = 6.0 Hz, 3 H, ArH), 7.50 (d, J = 7.2 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 27.31, 48.84, 83.10, 127.38, 127.44, 128.04, 128.14, 128.43, 131.02, 137.71, 137.86, 153.42, 173.03.
tert-Butyl Benzyl(4-bromobenzoyl)carbamate (11b)
tert-Butyl Benzyl(4-bromobenzoyl)carbamate (11b)
Eluent: PE/EtOAc (90:10); colorless oil; yield: 504 mg (75%).
1H NMR (CDCl3, 400 MHz): δ = 1.16 (s, 9 H, 3 × CH3), 4.95 (s, 2 H, CH2), 7.25–7.27 (m, 2 H, ArH), 7.32 (t, J = 7.6 Hz, 2 H, ArH), 7.38 (t, J = 6.4 Hz, 3 H, ArH), 7.52 (dd, J
1 = 7.8 Hz, J
2 = 1.2 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 27.39, 48.88, 83.53, 125.51, 127.46, 128.06, 128.45, 129.02, 131.26, 136.40, 137.60, 153.16, 172.07.
HRMS: m/z calcd for C19H20BrNO3Na [M + Na]+: 412.0524; found: 412.0527.
Transamidation of Activated Amides; General Procedure
Transamidation of Activated Amides; General Procedure
The amide substrate 1, 4, 6, 10, or 11 (1.0 mmol, 1.0 equiv) and the respective amine 2 (1.3 mmol, 1.3 equiv) in EtOH (1 mL) were taken in a vial and the reaction mixture was stirred at 45 °C. The reaction was monitored by TLC. After completion of the reaction, the mixture was concentrated in vacuo and the residue was purified by column chromatography using silica gel (EtOAc/PE) to give the corresponding transamidation product.
Phenyl(piperidin-1-yl)methanone (3a)
[8d]
Eluent: PE/EtOAc (75:25); colorless oil; yield: 51.3 mg (99%).
1H NMR (CDCl3, 400 MHz): δ = 1.47 (s, 2 H, CH2), 1.63 (s, 4 H, CH2), 3.29 (s, 2 H, CH2), 3.67 (s, 2 H, CH2), 7.35 (d, J = 4.0 Hz, 5 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 24.51, 25.57, 26.46, 29.62, 43.03, 48.69, 126.70, 128.32, 129.27, 136.43, 170.22.
Morpholino(phenyl)methanone (3b)[8d]
Morpholino(phenyl)methanone (3b)[8d]
Eluent: PE/EtOAc (85:15); colorless oil; yield: 50.7 mg (97%).
1H NMR (CDCl3, 400 MHz): δ = 2.28–3.59 (m, 8 H, CH2), 7.26 (d, J = 7.6 Hz, 5 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 42.45, 48.04, 66.66, 126.98, 128.12, 128.41, 129.75, 132.64, 135.12, 170.26.
Phenyl(pyrrolidin-1-yl)methanone (3c)[8d]
Phenyl(pyrrolidin-1-yl)methanone (3c)[8d]
Eluent: PE/EtOAc (75:25); colorless oil; yield: 47.5 mg (99%).
1H NMR (CDCl3, 400 MHz): δ = 1.68–1.73 (m, 2 H, CH2), 1.76–1.81 (m, 2 H, CH2), 3.26 (t, 2 H, J = 6.4 Hz, CH2), 3.50 (t, J = 6.8 Hz, 2 H, CH2), 7.23–7.25 (m, 3 H, ArH), 7.37–7.39 (m, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 24.29, 26.22, 46.08, 49.49, 126.95, 128.03, 128.09, 129.67, 130.81, 132.43, 136.95, 169.60.
Piperidin-1-yl(p-tolyl)methanone (3d)[15]
Piperidin-1-yl(p-tolyl)methanone (3d)[15]
Eluent: PE/EtOAc (85:15); colorless oil; yield: 53.4 mg (96%).
1H NMR (CDCl3, 400 MHz): δ = 1.44 (s, 2 H, CH2), 1.59 (s, 4 H, CH2), 2.29 (s, 3 H, CH3), 3.29 (s, 2 H, CH2), 3.63 (s, 2 H, CH2), 7.12 (d, J = 6.8 Hz, 2 H, ArH), 7.22 (dd, J
1 = 7.4 Hz, J
2 = 1.2 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 21.29, 24.53, 25.59, 26.43, 43.11, 48.75, 126.83, 128.90, 133.40, 139.33, 170.44.
(4-Methoxyphenyl)(morpholino)methanone (3e)[16]
(4-Methoxyphenyl)(morpholino)methanone (3e)[16]
Eluent: PE/EtOAc (85:15); colorless oil; yield: 53.1 mg (95%).
1H NMR (CDCl3, 400 MHz): δ = 3.66 (m, 8 H, CH2), 3.79 (s, 3 H, OCH3), 6.87–6.89 (m, 2 H, ArH), 7.34–7.36 (m, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 55.31, 66.87, 113.72, 127.25, 129.15, 160.83, 170.35.
(4-Bromophenyl)(piperidin-1-yl)methanone (3f)[17]
(4-Bromophenyl)(piperidin-1-yl)methanone (3f)[17]
Eluent: PE/EtOAc (85:15); white solid; yield: 56.5 mg (94%); mp 93–95 °C.
1H NMR (CDCl3, 400 MHz): δ = 1.47 (s, 2 H, CH2), 1.63 (s, 4 H, CH2), 3.28 (s, 2 H, CH2), 3.65 (s, 2 H, CH2), 7.23 (dd, J
1 = 8.0 Hz, J
2 = 0.8 Hz, 2 H, ArH), 7.49 (dd, J
1 = 8.0 Hz, J
2 = 0.8 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 24.46, 25.55, 43.19, 48.72, 123.54, 128.52, 131.57, 135.25, 169.16
(4-Bromophenyl)(morpholino)methanone (3g)[16]
(4-Bromophenyl)(morpholino)methanone (3g)[16]
Eluent: PE/EtOAc (85:15); colorless oil; yield: 55.3 mg (91%).
1H NMR (CDCl3, 400 MHz): δ = 3.44–3.71 (m, 8 H, CH2), 7.29 (d, J = 8.0 Hz, 2 H, ArH), 7.55 (d, J = 8.0 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 42.60, 48.09, 66.74, 124.14, 128.85, 131.75, 134.09, 169.25.
(2-Iodophenyl)(piperidin-1-yl)methanone (3h)
[18]
Eluent: PE/EtOAc (85:15); colorless oil; yield: 59.7 mg (93%).
1H NMR (CDCl3, 400 MHz): δ = 1.41–1.71 (m, 6 H, CH2), 3.08–3.21 (m, 2 H, CH2), 3.65–3.79 (m, 2 H, CH2), 7.03 (td, J
1 = 7.4 Hz, J
2 = 2.0 Hz, 1 H, ArH), 7.16 (dd, J
1 = 7.6 Hz, J
2 = 1.6 Hz, 1 H, ArH), 7.35 (td, J
1 = 7.6 Hz, J
2 = 0.8 Hz, 1 H, ArH), 7.79 (dd, J
1 = 7.6 Hz, J
2 = 0.8 Hz, 1 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 24.45, 25.36, 26.22, 42.46, 47.91, 92.47, 126.78, 128.27, 129.90, 139.13, 142.76, 169.14.
(2-Iodophenyl)(morpholino)methanone (3i)[19]
(2-Iodophenyl)(morpholino)methanone (3i)[19]
Eluent: PE/EtOAc (85:15); white solid; yield: 59.4 mg (91%); mp 82–84 °C.
1H NMR (CDCl3, 400 MHz): δ = 3.15 (s, 1 H, CH2), 3.22 (s, 1 H, CH2), 3.55 (s, 1 H, CH2), 3.72–3.79 (m, 5 H, CH2), 7.04 (t, J = 7.6 Hz, 1 H, ArH), 7.16 (d, J = 7.2 Hz, 1 H, ArH), 7.35 (t, J = 7.2 Hz, 1 H, ArH), 7.89 (t, J = 7.6 Hz, 1 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 41.95, 47.20, 66.52, 66.63, 92.38, 127.04, 128.45, 130.38, 139.20, 141.62, 169.38.
Furan-2-yl(piperidin-1-yl)methanone (3j)[20]
Furan-2-yl(piperidin-1-yl)methanone (3j)[20]
Eluent: PE/EtOAc (85:15); white solid; yield: 48.9 mg (97%); mp 46–48 °C.
1H NMR (CDCl3, 400 MHz): δ = 1.48–1.55 (m, 6 H, CH2), 3.55 (s, 4 H, CH2), 6.31–6.33 (m, 1 H, ArH), 6.79 (dd, J
1 = 3.4 Hz , J
2 = 0.8 Hz, 1 H, ArH), 7.34 (d, J = 0.8 Hz, 1 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 24.51, 25.99, 29.52, 43.88, 47.57, 110.94, 115.38, 143.34, 147.94, 159.10.
(5-Bromofuran-2-yl)(piperidin-1-yl)methanone (3k)[21]
(5-Bromofuran-2-yl)(piperidin-1-yl)methanone (3k)[21]
Eluent: PE/EtOAc (85:15); white solid; yield: 57.1 mg (96%); mp 53–55 °C.
1H NMR (CDCl3, 400 MHz): δ = 1.61–1.69 (m, 6 H, CH2), 3.65 (s, 4 H, CH2), 6.37 (d, J = 3.6 Hz, 1 H, ArH), 6.88 (d, J = 3.6 Hz, 1 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 24.57, 25.71, 29.65, 113.05, 118.03, 123.71, 149.85, 157.91.
Piperidin-1-yl(thiophen-2-yl)methanone (3l)[20]
Piperidin-1-yl(thiophen-2-yl)methanone (3l)[20]
Eluent: PE/EtOAc (85:15); white solid; yield: 50.9 mg (96%); mp 55–57 °C.
1H NMR (CDCl3, 400 MHz): δ = 1.59–1.60 (m, 4 H, CH2), 1.65–1.67 (m, 2 H, CH2), 3.61–3.64 (m, 4 H, CH2), 6.99 (td, J
1 = 4.0 Hz, J
2 = 0.8 Hz, 1 H, ArH), 7.22 (d, J = 3.2 Hz, 1 H, ArH), 7.38 (d, J = 5.2 Hz, 1 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 24.56, 26.08, 26.29, 29.63, 126.49, 128.03, 128.20, 137.56, 163.41.
N-Methyl-N-phenylbenzamide (3m)[15]
N-Methyl-N-phenylbenzamide (3m)[15]
Eluent: PE/EtOAc (90:10); white solid; yield: 54.9 mg (95%); mp 61–63 °C.
1H NMR (CDCl3, 400 MHz): δ = 3.46 (s, 3 H, CH3), 6.99 (d, J = 7.6 Hz, 2 H, ArH), 7.11 (t, J = 8.0 Hz, 3 H, ArH), 7.16–7.17 (m, 3 H, ArH), 7.26 (d, J = 7.6 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 38.37, 126.47, 126.85, 127.68, 128.65, 129.10, 129.56, 135.82, 144.79, 170.68.
N-Phenylbenzamide (3n)[7a]
N-Phenylbenzamide (3n)[7a]
Eluent: PE/EtOAc (70:30); brownish solid; yield: 51.8 mg (96%); mp 160–162 °C.
1H NMR (CDCl3, 400 MHz): δ = 7.14 (td, J
1 = 7.0 Hz, J
2 = 0.4 Hz, 1 H, ArH), 7.35 (t, J = 7.6 Hz, 2 H, ArH), 7.45 (t, J = 8.0 Hz, 2 H, ArH), 7.52 (td, J
1 = 7.4 Hz, J
2 = 0.4 Hz, 1 H, ArH), 7.63 (d, J = 8.0 Hz, 2 H, ArH), 7.85 (t, J = 7.6 Hz, 2 H, ArH), 7.98 (s, 1 H, NH).
13C NMR (CDCl3, 100 MHz): δ = 120.26, 124.56, 127.02, 128.41, 128.73, 129.04, 130.12, 131.80, 134.91, 137.87, 165.87.
N-(4-Iodophenyl)benzamide (3o)[22]
N-(4-Iodophenyl)benzamide (3o)[22]
Eluent: PE/EtOAc (70:30); white solid; yield: 81.3 mg (92%); mp 214–216 °C.
1H NMR (DMSO-d
6, 400 MHz): δ = 7.46–7.41 (m, 2 H, ArH), 7.54–7.59 (m, 3 H, ArH), 7.65 (d, J = 8.8 Hz, 2 H, ArH), 7.89 (d, J = 7.2 Hz, 2 H, ArH), 10. 32 (s, 1 H, NH).
13C NMR (DMSO-d
6, 100 MHz): δ = 122.96, 128.05, 128.86, 128.99, 129.66, 132.17, 135.03, 137.69, 139.56, 166.15.
N-(3,5-Dichlorophenyl)benzamide (3p)[23]
N-(3,5-Dichlorophenyl)benzamide (3p)[23]
Eluent: PE/EtOAc (70:30); white solid; yield: 65.5 mg (90%); mp 148–150 °C.
1H NMR (CDCl3, 400 MHz): δ = 7.46 (td, J
1 = 7.4 Hz, J
2 = 0.4 Hz, 3 H, ArH), 7.61 (td, J
1 = 6.6 Hz, J
2 = 1.2 Hz, 2 H, ArH), 8.13 (dd, 3 H, J
1 = 7.8 Hz, J
2 = 1.2 Hz, ArH), 10.60 (br, 1 H, NH).
13C NMR (CDCl3, 100 MHz): δ = 128.46, 129.29, 130.18, 133.79, 172.42.
N-Benzylbenzamide (3q)[8d]
N-Benzylbenzamide (3q)[8d]
Eluent: PE/EtOAc (75:25); white solid; yield: 56.6 mg (98%); mp 105–107 °C.
1H NMR (CDCl3, 400 MHz): δ = 4.64 (d, J = 5.6 Hz, 2 H, ArH), 6.57 (s, 1 H, NH), 7.23–7.36 (m, 5 H, ArH), 7.42 (td, J
1 = 7.2 Hz, J
2 = 1.2 Hz, 2 H, ArH), 7.50 (td, J
1 = 7.8 Hz, J
2 = 1.2 Hz, 1 H, ArH), 7.80 (dd, J
1 = 8.0 Hz, J
2 = 0.8 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 44.08, 126.93, 127.58, 127.87, 128.55, 128.74, 131.52, 134.30, 138.14, 167.37.
N-(Prop-2-yn-1-yl)benzamide (3r)[24]
N-(Prop-2-yn-1-yl)benzamide (3r)[24]
Eluent: PE/EtOAc (85:15); colorless oil; yield: 42.7 mg (97%).
1H NMR (CDCl3, 400 MHz): δ = 2.22 (t, J = 2.4 Hz, 1 H, CH), 4.18 (dd, J
1 = 5.2 Hz, J
2 = 2.4 Hz, 2 H, CH2), 7.01 (s, 1 H, NH), 7.35 (td, J
1 = 7.6 Hz, J
2 = 0.4 Hz, 2 H, ArH), 7.44 (td, J
1 = 7.0 Hz, J
2 = 1.2 Hz, 1 H, ArH), 7.78 (d, J = 7.2 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 29.66, 71.54, 79.66, 127.16, 128.48, 131.69, 133.67, 167.44
N-Cyclohexylbenzamide (3s)[25]
N-Cyclohexylbenzamide (3s)[25]
Eluent: PE/EtOAc (80:20); white solid; yield: 54.2 mg (98%); mp 153–155 °C.
1H NMR (CDCl3, 400 MHz): δ = 1.13–1.26 (m, 3 H, CH2), 1.34–1.44 (m, 2 H, CH2), 1.63 (d, J = 12.8 Hz, 1 H, CH), 1.71–1.74 (m, 2 H, CH2), 1.99 (d, J = 11.6 Hz, 2 H, CH2), 3.91–3.98 (m, 1 H, CH), 6.06 (s, 1 H, NH), 7.36–7.74 (m, 2 H, ArH), 7.43–7.47 (m, 1 H, ArH), 7.73 (d, J = 7.2 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 24.91, 25.49, 33.10, 48.67, 126.85, 128.39, 131.12, 135.02, 166.65.
N-[(3s,5s,7s)-Adamantan-1-yl]benzamide (3t)[7a]
N-[(3s,5s,7s)-Adamantan-1-yl]benzamide (3t)[7a]
Eluent: PE/EtOAc (80:20); white solid; yield: 65.7 mg (94%); mp 125–127 °C.
1H NMR (CDCl3, 400 MHz): δ = 1.68 (s, 6 H), 2.09 (m, 9 H), 5.87 (s, 1 H, NH), 7.34 (t, J = 7.6 Hz, 2 H, ArH), 7.41 (t, J = 7.2 Hz, 1 H, ArH), 7.68 (d, J = 7.2 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 29.44, 36.32, 41.57, 52.20, 126.68, 128.35, 130.94, 135.95, 166.60.
N-Dodecylbenzamide (3u)[8d]
N-Dodecylbenzamide (3u)[8d]
Eluent: PE/EtOAc (90:10); white solid; yield: 73.4 mg (97%); mp 83–85 °C.
1H NMR (CDCl3, 400 MHz): δ = 0.83 (t, J = 6.8 Hz, 3 H, CH3), 1.21–1.36 (m, 16 H, CH2), 1.55–1.58 (m, 2 H, CH2), 3.03 (q, J = 7.6; 7.2 Hz, 2 H, CH2), 3.39 (q, J = 6.8; 6.4 Hz, 2 H, CH2), 6.38 (s, 1 H, NH), 7.37 (t, J = 6.8 Hz, 2 H, ArH), 7.43 (d, J = 7.2 Hz, 1 H, ArH), 7.73 (d, J = 7.2 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): d = 08.55, 14.06, 22.62, 26.96, 29.28, 29.50, 29.53, 29.58, 31.85, 40.06, 45.74, 126.83, 128.42, 131.19, 134.80, 167.49.
N-Dodecylacetamide (3v)[26]
N-Dodecylacetamide (3v)[26]
Eluent: PE/EtOAc (90:10); white solid; yield: 71.2 mg (95%); mp 52–54 °C.
1H NMR (CDCl3, 400 MHz): δ = 0.84 (t, J = 6 Hz, 3 H, CH3), 1.22–1.25 (m, 18 H, CH2), 1.45 (t, J = 6.8 Hz, 2 H, CH2), 1.94 (s, 3 H, CH3), 3.19 (q, J = 6.8; 6.4 Hz, 2 H, CH2), 5.64 (s, 1 H, NH).
13C NMR (CDCl3, 100 MHz): δ = 14.06, 22.62, 23.27, 26.87, 29.25, 29.28, 29.49, 29.53, 29.56, 29.58, 31.85, 39.65, 170.03.
(4-Methoxyphenyl)(piperidin-1-yl)methanone (5a)[20]
(4-Methoxyphenyl)(piperidin-1-yl)methanone (5a)[20]
Eluent: PE/EtOAc (80:20); white solid; yield: 66.9 mg (96%); mp 36–38 °C.
1H NMR (CDCl3, 400 MHz): δ = 1.51–1.59 (m, 6 H, CH2), 3.36–3.56 (m, 4 H, CH2), 3.75 (s, 3 H, OCH3), 6.82 (d, J = 8.4 Hz, 2 H, ArH), 7.29 (d, J = 8.8 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 24.59, 55.27, 113.55, 128.52, 128.80, 160.43, 170.25.
(4-Nitrophenyl)(piperidin-1-yl)methanone (5b)[20]
(4-Nitrophenyl)(piperidin-1-yl)methanone (5b)[20]
Eluent: PE/EtOAc (80:20); light yellow solid; yield: 62.4 mg (89%); mp 121–123 °C.
1H NMR (CDCl3, 400 MHz): δ = 1.43 (s, 2 H, CH2), 1.60 (s, 4 H, CH2), 3.19 (s, 2 H, CH2), 3.63 (s, 2 H, CH2), 7.46 (d, J = 6.8 Hz, 2 H, ArH), 8.15–8.18 (m, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 24.32, 25.43, 26.43, 43.11, 48.58, 123.78,127.74, 142.67, 148.07, 167.79.
N-Isopropylbenzamide (5c)[8a]
N-Isopropylbenzamide (5c)[8a]
Eluent: PE/EtOAc (85:15); white solid; yield: 53.0 mg (94%); mp 97–99 °C.
1H NMR (CDCl3, 400 MHz): δ = 1.23 (s, 3 H, CH3), 1.25 (s, 3 H, CH3), 4.23–4.31 (m, 1 H, CH), 6.01 (s, 1 H, NH), 7.39 (t, J = 8.0 Hz, 2 H, ArH), 7.46 (t, J = 7.6 Hz, 1 H, ArH), 7.73 (d, J = 7.2 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 22.82, 41.84, 126.76, 128.45, 131.21, 134.92, 166.65.
N-Butylbenzamide (5d)[8d]
N-Butylbenzamide (5d)[8d]
Eluent: PE/EtOAc (90:10); colorless oil; yield: 60.1 mg (98%).
1H NMR (CDCl3, 400 MHz): δ = 0.92 (s, 3 H, CH3), 1.31–1.42 (m, 2 H, CH2), 1.53–1.60 (m, 2 H, CH2), 3.39–3.44 (q, J = 7.2; 6.8 Hz, 2 H, CH2), 6.32 (s, 1 H, NH), 7.38 (td, J
1 = 7.2 Hz, J
2 = 1.2 Hz, 2 H, ArH), 7.45 (td, J
1 = 6.8 Hz, J
2 = 0.8 Hz, 1 H, ArH), 7.74 (dd, J
1 = 8.0 Hz, J
2 = 1.6 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 13.75, 20.11, 31.68, 39.77, 126.81, 128.46, 131.23, 134.79, 167.55.
N-(tert-Butyl)benzamide (5e)[27]
N-(tert-Butyl)benzamide (5e)[27]
Eluent: PE/EtOAc (90:10); white solid; yield: 48.4 mg (79%); mp 131–133 °C.
1H NMR (CDCl3, 400 MHz): δ = 1.23 (s, 9 H, 3 × CH3), 5.96 (s, 1 H, NH), 7.31 (t, J = 7.6 Hz, 2 H, ArH), 7.38 (t, J = 7.2 Hz, 1 H, ArH), 7.64 (dd, J
1 = 7.2 Hz, J
2 = 1.6 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 22.82, 41.84, 126.76, 128.45, 131.21, 134.92, 166.65.
N-Benzyl-4-methoxybenzamide (7a)[8d]
N-Benzyl-4-methoxybenzamide (7a)[8d]
Eluent: PE/EtOAc (80:20); white solid; yield: 86.4 mg (95%); mp 122–124 °C.
1H NMR (CDCl3, 400 MHz): δ = 3.80 (s, 3 H, OCH3), 4.56 (d, J = 6 Hz, 2 H, CH2), 6.75 (br, 1 H, NH), 6.84–6.87 (m, 2 H, ArH), 7.23–7.30 (m, 5 H, ArH), 7.75 (d, J = 8.4 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 43.91, 55.34, 113.65, 126.59, 127.38, 127.78, 128.64, 128.83, 138.49, 162.12, 166.96.
N-Benzyl-4-(trifluoromethyl)benzamide (7b)[8d]
N-Benzyl-4-(trifluoromethyl)benzamide (7b)[8d]
Eluent: PE/EtOAc (80:20); white solid; yield: 86.6 mg (94%); mp 149–151 °C.
1H NMR (CDCl3, 400 MHz): δ = 4.64 (d, J = 5.6 Hz, 2 H, CH2), 6.61 (br, 1 H, NH), 7.29–7.38 (m, 5 H, ArH), 7.67 (d, J = 8.4 Hz, 2 H, ArH), 7.88 (d, J = 8.0 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 44.77, 122.74, 125.45, 126.11 (J = 3.6 Hz), 128.29, 134.78 (J = 33.8 Hz), 138.09, 138.9, 138.19, 166.56.
N-Cyclohexyl-4-(trifluoromethyl)benzamide (7c)[28]
N-Cyclohexyl-4-(trifluoromethyl)benzamide (7c)[28]
Eluent: PE/EtOAc (75:25); white solid; 85.0 g (95%); mp 167–169 °C.
1H NMR (CDCl3, 400 MHz): δ = 1.16–1.28 (m, 3 H, CH2), 1.36–1.46 (m, 2 H, CH2), 1.63–1.67 (m, 1 H, CH), 1.75 (dt, J
1 = 13.6 Hz, J
2 = 3.6 Hz, 2 H, CH2), 2.02 (dd, J
1 = 12.4 Hz, J
2 = 3.2 Hz, 2 H, CH2), 3.91–4.01 (m, 1 H, CH), 6.03 (br, 1 H, NH) 7.66 (d, J = 8.0 Hz, 2 H, ArH), 7.83 (d, J = 8.4 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 25.35, 25.97, 33.62, 49.47, 122.79, 125.51, 126.042 (J = 3.4 Hz), 127.79, 133.47 (J = 32.5 Hz), 138.84, 165.83.
Piperidin-1-yl[4-(trifluoromethyl)phenyl]methanone (7d)[20]
Piperidin-1-yl[4-(trifluoromethyl)phenyl]methanone (7d)[20]
Eluent: PE/EtOAc (85:15); white solid; yield: 84.0 g (99%); mp 98–100 °C.
1H NMR (CDCl3, 400 MHz): δ = 1.43 (s, 2 H, CH2), 1.60 (s, 4 H, CH2), 3.32 (s, 2 H, CH2), 3.64 (s, 2 H, CH2), 7.42 (d, J = 8.0 Hz, 2 H, ArH), 7.58 (d, J = 8.0 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 24.88, 25.97, 26.94, 43.56, 49.09, 122.88, 125.58, 125.95 (J = 3.7 Hz), 127.58, 13.72 (J = 32.6 Hz), 140.55, 169.20.
Morpholino[4-(trifluoromethyl)phenyl]methanone (7e)[7a]
Morpholino[4-(trifluoromethyl)phenyl]methanone (7e)[7a]
Eluent: PE/EtOAc (80:20); white solid; yield: 81.2 mg (97%); mp 47–49 °C.
1H NMR (CDCl3, 400 MHz): δ = 3.32 (s, 2 H, CH2), 3.54 (s, 2 H, CH2), 3.71 (s, 4 H, CH2), 7.46 (d, J = 7.6 Hz, 2 H, ArH), 7.61 (d, J = 8.0 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 42.42, 47.99, 66.68, 119.53, 122.24, 124.95, 125.60 (J = 3.5 Hz), 127.40, 131.68 (J = 31.6 Hz), 138.82, 168.81.
Pyrrolidin-1-yl[4-(trifluoromethyl)phenyl]methanone (7f)[24]
Pyrrolidin-1-yl[4-(trifluoromethyl)phenyl]methanone (7f)[24]
Eluent: PE/EtOAc (85:15); white solid; yield: 77.8 mg (97%); mp 80–82 °C.
1H NMR (CDCl3, 400 MHz): δ = 1.84 (pent, J = 6.5 Hz, 2 H, CH2), 1.93 (pent, J = 6.7 Hz, 2 H, CH2), 3.34 (t, J = 6.4.0 Hz, 2 H, CH2), 3.61 (t, J = 6.8 Hz, 2 H, CH2), 7.67–7.63 (m, 4 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 24.84, 26.81, 46.70, 49.93, 125.58, 125.81 (J = 3.6 Hz), 127.90, 132.08 ( J = 32.7 Hz), 141.15, 168.68.
Transamidation of Activated Amide 1a with Amino Acids and Amino Alcohols
Transamidation of Activated Amide 1a with Amino Acids and Amino Alcohols
The amide substrate 1a (0.273 mmol) and the respective amino acid or amino alcohol (0.356 mmol) in EtOH (1 mL) were taken in a vial and the reaction mixture was stirred at 60 °C (1–3 h). The mixture was concentrated in vacuo and the crude product was purified by column chromatography as described in the general procedure to give the corresponding transamidation product 8a–d.
Methyl Benzoyl-l-phenylalaninate (8a)[29]
Methyl Benzoyl-l-phenylalaninate (8a)[29]
Eluent: PE/EtOAc (85:15); white solid; yield: 75.1 mg (97%); mp 84–86 °C; [α]D
20 +65.56 (c 0.1, CHCl3).
1H NMR (CDCl3, 400 MHz): δ = 3.19–3.31 (m, 2 H, CH2), 3.75 (s, 3 H, OCH3), 5.08 (q, J = 5.6 Hz, 1 H, CH), 6.57 (d, J = 5.6 Hz, 1 H, NH), 7.12 (d, J = 7.2 Hz, 2 H, ArH), 7.24–7.30 (m, 3 H, ArH), 7.41 (t, J = 7.2 Hz, 2 H, ArH), 7.49 (t, J = 7.2 Hz, 1 H, ArH), 7.71 (d, J = 7.6 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 37.80, 53.40, 53.56, 127.02, 127.15, 128.56, 128.59, 129.29, 131.76, 133.78, 135.88, 166.93, 172.10.
Methyl Benzoyl-l-methioninate (8b)[30]
Methyl Benzoyl-l-methioninate (8b)[30]
Eluent: PE/EtOAc (85:15); white solid; yield: 68.8 mg (94%); mp 87–89 °C; [α]D
20 +19.5 (c 0.1, CHCl3).
1H NMR (CDCl3, 400 MHz): δ = 2.08 (s, 4 H, CH2), 2.26 (s, 1 H, CH), 2.56 (s, 2 H, CH2), 3.76 (s, 3 H, OCH3), 4.906 (s, 1 H, CH), 6.99 (s, 1 H, NH), 7.24–7.48 (m, 3 H, ArH), 7.79 (s, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 15.47, 30.03, 31.49, 52.01, 52.60, 127.05, 128.57, 131.81, 133.64, 167.05, 172.55.
Ethyl Benzoyl-l-alaninate (8c)[31]
Ethyl Benzoyl-l-alaninate (8c)[31]
Eluent: PE/EtOAc (85:15); white solid; yield: 53.3 mg (94%); mp 76–78 °C; [α]D
20 +30.14 (c 0.1, CHCl3).
1H NMR (CDCl3, 400 MHz): δ = 1.29 (t, J = 7.2 Hz, 3 H, CH2), 1.50 (d, J = 7.2 Hz, 3 H, CH3), 5.72 (q, J = 7.2 Hz, 2 H, CH2), 4.76 (pent, J = 7.2 Hz, 1 H, CH), 6.79 (s, 1 H, NH), 7.41 (t, J = 7.2 Hz, 2 H, ArH), 7.49 (d, J = 7.2 Hz, 1 H, ArH), 7.79 (d, J = 7.2 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 14.10, 18.66, 48.51, 61.62, 126.98, 128.53, 131.66, 133.91, 166.77, 173.25.
N-[(2R,3R)-1-Hydroxy-3-methylpentan-2-yl]benzamide (8d)
N-[(2R,3R)-1-Hydroxy-3-methylpentan-2-yl]benzamide (8d)
Eluent: PE/EtOAc (80:20); white solid; yield: 53.9 mg (89%); mp 79–81 °C; [α]D
20 –8.28 (c 0.1, CHCl3).
1H NMR (CDCl3, 400 MHz): δ = 0.91 (t, J = 7.2 Hz, 3 H, CH3), 0.97 (d, J = 6.8 Hz, 3 H, CH3), 1.16–1.27 (m, 2 H, CH2), 1.53–1.61 (m, 1 H, CH), 1.75–1.76 (m, 1 H, CH), 3.73–3.80 (m, 2 H, CH2), 3.99 (t, J = 7.2 Hz, 1 H, OH), 6.48 (d, J = 7.2 Hz, 1 H, NH), 7.39 (t, J = 7.6 Hz, 2 H, ArH), 7.47 (t, J = 7.2 Hz, 1 H, ArH), 7.74 (d, J = 7.2 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 11.34, 15.60, 25.63, 35.73, 56.25, 63.53, 126.93, 128.54, 131.54, 134.41, 168.34.
HRMS: m/z calcd for C13H19NO2Na [M + Na]+: 244.1313; found: 244.1318.
Transamidation of Activated Secondary Amides in Water; General Procedure
Transamidation of Activated Secondary Amides in Water; General Procedure
The amide substrate 1 or 6b (1 equiv) and the respective amine (4 equiv) in H2O (1 mL) were taken in a vial and the reaction mixture was stirred at 60 °C (1–2 h). After the reaction was complete, EtOAc (20 mL) was added. The organic layer was separated, dried (anhyd Na2SO4), and the filtrate was concentrated. The crude product was purified by column chromatography on silica gel to afford the corresponding transamidation product.
Furan-2-yl(morpholino)methanone (9)[32]
Furan-2-yl(morpholino)methanone (9)[32]
According to the general procedure, the reaction of 1f (0.28 mmol) and morpholine (1.13 mmol) in H2O (1 mL) at 60 °C for 2 h, afforded the corresponding transamidation product 9 (46.9 mg, 92%) after column chromatography (PE/EtOAc, 85:15); white solid; mp 51–53 °C.
1H NMR (CDCl3, 400 MHz): δ = 3.69–3.77 (m, 8 H, CH2), 6.44–6.45 (m, 1 H, ArH), 6.98 (d, J = 3.6 Hz, 1 H, ArH), 7.43–7.44 (m, 1 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 66.89, 111.32, 116.73, 143.73, 147.66, 159.04.
Comparative Studies
The amide substrate 10 or 11 (1.0 equiv) and the respective amine (1.3 equiv) in ethanol (1 mL) were taken in a vial and the reaction mixture was stirred at 45–60 °C (1–12 h). After completion of the reaction, the mixture was concentrated. The crude product was purified by column chromatography (PE/EtOAc) on SiO2 to give the corresponding transamidation product.
N-(2,6-Dimethylphenyl)benzamide (12a)[7a]
N-(2,6-Dimethylphenyl)benzamide (12a)[7a]
Eluent: PE/EtOAc (85:15); white solid; yield: 49.9 mg (69%); mp 155–157 °C.
1H NMR (CDCl3, 400 MHz): δ = 2.27 (s, 6 H, CH3), 7.12 (m, 3 H, ArH), 7.38 (s, 1 H, ArH), 7.49 (t, J = 7.6 Hz, 1 H, ArH), 7.56 (t, J = 7.2 Hz, 1 H, ArH), 7.91 (d, J = 7.2 Hz, 1 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 18.42, 127.21, 127.34, 128.21, 128.67, 131.69, 133.93, 134.43, 135.58, 165.91.
N-Benzyl-4-bromobenzamide (12b)[8d]
N-Benzyl-4-bromobenzamide (12b)[8d]
Eluent: PE/EtOAc (80:20); white solid; yield: 71.4 mg (96%); mp 125–127 °C.
1H NMR (CDCl3, 400 MHz): δ = 4.62 (d, J = 5.2 Hz, 2 H, CH2), 6.62 (s, 1 H, NH), 7.28–7.35 (m, 5 H, ArH), 7.55 (d, J = 8.0 Hz, 2 H, ArH), 7.66 (d, J = 8.4 Hz, 2 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 44.68,126.71, 128.19, 128.39, 129.08, 129.30, 132.28, 133.64, 138.38, 166.91.
(S)-3,3-Diphenyl-N-(1-phenylethyl)propanamide (12c)[11]
(S)-3,3-Diphenyl-N-(1-phenylethyl)propanamide (12c)[11]
Eluent: PE/EtOAc (90:10); yellowish solid; yield: 64.2 mg (88%); mp 121–123 °C; [α]D
20 +46.18 (c 0.1, CHCl3).
1H NMR (CDCl3, 400 MHz): δ = 1.25 (d, J = 7.2 Hz, 3 H, CH3), 2.90 (d, J = 8.0 Hz, 2 H, CH2), 4.56 (t, J = 7.6 Hz, 1 H, CH), 4.98 (pent, J = 7.2 Hz, 1 H, CH), 5.65 (s, 1 H, NH), 6.98 (d, J = 7.6 Hz, 2 H, ArH), 7.21–7.31 (m, 12 H, ArH).
13C NMR (CDCl3, 100 MHz): δ = 21.31, 43.51, 47.62, 48.37, 125.97, 126.52, 127.08, 127.77, 128.47, 128.60, 142.80, 143.48, 143.66, 170.14.
