Regioselective C–H Activation of Substituted Pyridines and other Azines using Mg- and Zn-TMP-Bases

Abstract

The metalation of substituted pyridines, diazines and related N-heterocycles using TMPMgCl·LiCl, TMP₂Mg·2LiCl, TMPZnCl·LiCl or TMP₂Zn·2LiCl₂·2MgCl₂ (TMP = 2,2,6,6-tetramethylpiperidyl) in the presence or absence of a Lewis acid is reviewed.

Contents

1 Introduction

2 Magnesiation of Pyridines and Related Azines

2.1 Magnesiations using TMPMgCl·LiCl

2.2 Magnesiations using TMP₂Mg·2LiCl and Related Bases

2.3 BF₃·OEt₂ Promoted Metalations of Pyridines

3 Zincation of Pyridines and Related Azines using TMPZnCl·LiCl and TMP₂Zn·2LiCl·2MgCl₂

4 Metalation of Pyridines using other TMP-Bases

5 Magnesiation and Zincation of Diazines

6 Conclusion

Key words

azines - metalation - N-heterocycles - pyridine - TMP bases

Biographical Sketches

Paul Knochel was born in 1955 in Strasbourg (France). He studied at the University of Strasbourg (France) and did his Ph.D at the ETH-Zürich (D. Seebach). He spent four years at the University Pierre and Marie Curie in Paris (J.-F. Normant) and one year at Princeton University (M. F. Semmelhack). In 1987, he was Professor at the University of Michigan. In 1992, he moved to Philipps-University at Marburg (Germany). In 1999, he then moved to the Chemistry Department of Ludwig-Maximilians­-University in Munich (Germany). His research interests include the development of novel organometallic reagents and methods for use in organic synthesis, asymmetric catalysis and natural product synthesis. Prof. Knochel has received many distinguished prizes including the Berthelot Medal of the Academie des Sciences (Paris), the IUPAC Thieme Prize, the Otto-Bayer-Prize, the Leibniz-Prize, the Arthur C. Cope Scholar Award, Karl-Ziegler-Prize, the Nagoya Gold Medal, the H. C. Brown Award and Paul Karrer gold medal. He is member of the Académie des Sciences, the Bavarian Academy of Science, the German Academy of Sciences Leopodina. He is author of over 900 publications.

Moritz Balkenhohl was born in 1992 in Speyer (Germany). He studied chemistry at the Julius­-Maximilians-Universität Würzburg and at Imperial College London. In 2015 he joined the group of Prof. Paul Knochel for his Master thesis in Munich and started his PhD thesis in 2016. His research focuses on the functionalization of challenging­ heterocycles and transition-metal-free amination reactions.

1

Introduction

The regioselective functionalization of azines, especially pyridines, is an important synthetic challenge because of the importance of these N-heterocycles as pharmaceuticals and agrochemicals.[1] The use of lithium bases for achieving regioselective lithiations has been pioneered by Snieckus,[2] Schlosser,[3] Quéginer[4] and Mongin[4h] [i] [j] ^, [5] as well as Gros.[6] These powerful bases produce lithiated N-heterocycles, which are often only stable at low temperature, although the performance of such metalations in continuous flow may avoid such low temperatures.[7] Furthermore, the use of lithium magnesiate or zincate bases pioneered by Mulvey,[8] Mongin,[8b] [9] Uchiyama[8b] ^, [9b] [e] [g] [l] ^, [10] and Kondo[8b] ^, [10a] [b] [c] ^, [11] has considerably broadened the scope of metalations for the functionalizations of pyridines and other azines. Recently, it became clear that highly reactive magnesium and zinc bases can be obtained by mixing sterically hindered magnesium and zinc bases (derived mostly from 2,2,6,6-tetramethylpiperidine (TMP-H)) with LiCl.[12] The resulting, highly THF-soluble bases[13] are mostly monomeric and kinetically highly active for the magnesiation and zincation of various functionalized pyridines or sensitive azines.[12] Furthermore, in such metalations, only magnesiated or zincated heterocycles are produced, which are compatible with a range of functional groups at moderate to low temperatures. In the case of the zincation of azines, either ambient or elevated temperature (up to 120 °C)[14] can be used, offering considerable potential for industrial applications. Since the metalation of azines using magnesiate or zincate bases has already been reported extensively,[8] [9] [10] [11] this review will focus on recent advances describing the most practical and regioselective C–H activations[15] of functionalized pyridines and other azines, using mostly zinc and magnesium TMP-bases.[16]

2

Magnesiation of Pyridines and Related Azines

2.1

Magnesiations using TMPMgCl·LiCl (1)

Usually, magnesium amides of type R₂NMgX or (R₂N)₂Mg are aggregated and relatively slow deprotonation reagents, partially because of their moderate solubility.[17] Mulzer pioneered the use of TMPMgCl for the magnesiation of an azine.[18] A base with higher activity and higher solubility in THF was obtained by using TMPMgCl with LiCl (1 equiv). Thus, mixing of TMP-H with i-PrMgCl·LiCl in THF (25 °C, 24 h) provides a ca. 1.4 M soluble base TMPMgCl·LiCl (1).[12] [13]

This base magnesiates a range of functionalized pyridines and quinolines under mild conditions. Since magnesium reagents are produced, there is no need for low temperatures as it is often the case with corresponding lithiations.[19] [20] Thus, the magnesiation of 2-bromoquinoline 2 with TMPMgCl·LiCl (1) at –20 °C for 2 h provides the ortho-magnesiated product 3 (Scheme [1]). After bromolysis, the dibromoquinoline 4 is obtained in 65% yield.[21] Pyridines bearing less sensitive functional groups, such as 3,5-dibromopyridine (5) or 2,6-dichloropyridine (6), are magnesiated at convenient temperatures (–25 °C or 25 °C), regioselectively providing the pyridylmagnesium derivatives 7 and 8. Quenching with various electrophiles, such as N,N-dimethylformamide (DMF) or 4-methoxybenzaldehyde, affords the polyfunctional pyridines 9 and 10 in 85–92% yield (Scheme [1]).[12]

Scheme 1 Regioselective magnesiation of halogenoazines using TMPMgCl·LiCl (1)

The last reaction can be readily scaled up to a 100 mmol-scale with no yield loss.[22] Aminopyridines are converted into the corresponding trifluoroacetamides such as 11. Deprotonation of the amide function with MeMgCl and ring-magnesiation with TMPMgCl·LiCl (1) furnishes the Grignard reagent 12, which, after a transmetalation with ZnCl₂ and Negishi cross-coupling,[23] [24] affords the 4-arylated pyridine 13 in 80% yield (Scheme [2]).[25] The trifluoroacetamido group of 11 is an excellent directing group. Similarly, a sulfoxide function directs a magnesiation in the ortho-position­ with high efficiency. Thus, pyridine 14, bearing a sulfoxide function at position C4, is magnesiated at –30 °C with TMPMgCl·LiCl (1) within 20 min (Scheme [3]). Addition of ZnCl₂ and Negishi cross-coupling with p-iodoanisole catalyzed by 5% Pd(PPh₃)₄ (50 °C, 2 h) furnishes the tetrasubstituted pyridine 15 in 68% yield. The sulfoxide group can then be converted into a new magnesium reagent through sulfoxide–magnesium exchange[26] in 2-methyl-THF[27] triggered by i-PrMgCl·LiCl (–50 °C, 5 min). Transmetalation with ZnCl₂ followed by a Negishi cross-coupling with ethyl 5-bromonicotinate (16), catalyzed by 2% Pd(PPh₃)₄ (50 °C, 5 h), leads to the complex bis-pyridine 17 in 82% yield (Scheme [3]).[28]

Scheme 2 Magnesiation of a trifluoroamidopyridine using TMPMgCl·LiCl (1)

Scheme 3 ortho-Magnesiation of a pyridyl sulfoxide, followed by a sulfoxide–magnesium exchange

Likewise, sulfonamides are excellent directing groups[2c] [d] ^, [29] and can undergo amination reactions when treated with an excess of a magnesium amide. Thus, sulfonamides 18 and 19 are magnesiated with TMPMgCl·LiCl (1; THF, 0 °C, 2 h). After iodolysis and amination at 25 °C (2 h) with piperidylmagnesium chloride, aminoquinolines 20 and 21 are obtained in 52–59% yield over two steps (Scheme [4]).[30]

TMPMgCl·LiCl (1) also proves to be an excellent base for the C–H activation of 3-methoxypyridine (22). Thus, treatment of 22 with 10% FeCl₃ and 25% diamine (23) and an excess of TMPMgCl·LiCl (1) at 25 °C for 2 h allows facile alkylation with various alkyl bromides such as 5-bromopentene (24), providing the alkylated product 25 in 85% yield (Scheme [5]).[31]

The N,N,N′,N′-tetramethylphosphordiamidate group (OP(O)(NMe₂)₂) was found to be a more powerful directing group than the methoxy group,[32] which allows efficient magnesiations with TMPMgCl·LiCl (1). Thus, the 4-substituted pyridine 26 is magnesiated with 1 (1.5 equiv, 0 °C, 1 h) and subsequently thiolated by reaction with MeSSO₂Me, affording the disubstituted pyridine 27 in 88% yield.

Scheme 4 ortho-Metalation, functionalization and amination of quinoline-sulfonamides

Scheme 5 Iron-catalyzed alkylation of 3-methoxypyridine (22)

Scheme 6 ortho-Magnesiation of a phosphordiamidate substituted pyridine and quinoline using TMPMgCl·LiCl (1)

Similarly, quinoline 28 was magnesiated with TMPMgCl·LiCl (1) at 0 °C within 1 h and acylated in the presence of a copper(I)-catalyst (CuCN·2LiCl), furnishing the ketone 29 in 62% yield (Scheme [6]).[33] This method has been used to prepare the pyridine based COX-2 inhibitor etoricoxib 30 [34] starting from the phosphordiamidate substituted pyridine 31. Thus, the magnesiation of 31 with TMPMgCl·LiCl (1) in THF at 0 °C for 1 h, followed by a transmetalation with ZnCl₂ and Negishi cross-coupling with aryl bromide 32 using 1% Pd₂(dba)₃ (dba = dibenzylideneacetone) and 2% RuPhos[35] provides the arylated pyridine 33 in 88% yield. Standard transformations and Stille cross-coupling[36] provides the desired pharmaceutical 30 (Scheme [7]).[33]

Scheme 7 Synthesis of Etoricoxib (30) using TMPMgCl·LiCl (1)

2.2

Magnesiations using TMP₂Mg·2LiCl (34) and Related Bases

Although TMPMgCl·LiCl (1) is a very powerful magnesiation reagent, in the case of substrates bearing weakly acidic or sterically hindered protons, the magnesiation is advantageously performed using TMP₂Mg·2LiCl (34).[37] Often, the presence of sensitive functional groups, such as a carboethoxy group, requires low magnesiation temperatures, since higher temperatures lead to considerable side reactions. TMP₂Mg·2LiCl (34), which is prepared in quantitative yield by treating TMPLi with 1, can be stored at 25 °C for several hours. A degradation after several days is however observed. This base readily magnesiates 4-carbethoxypyridine (35) at –40 °C for 12 h, leading to 36, furnishing, after iodolysis, the iodopyridine 37 in 66% yield (Scheme [8]).[37] The phosphordiamidate substituted quinoline 38 was magnesiated­ with 34, yielding the magnesium reagent 39 (–50 °C, 1 h). After transmetalation with ZnCl₂ and Negishi cross-coupling using PhI, 5% Pd(dba)₂ and 10% P(o-furyl)₃ as catalyst,[38] the arylated quinoline 40 is obtained in 81% yield. Interestingly, the quinoline 40 can now be magnesiated with TMPMgCl·LiCl (1) at 25 °C within 1 h. The presence of the phenyl group at position 2 avoids nucleophilic additions to the quinoline ring and allows higher metalation temperatures (25 °C instead of –50 °C). Quenching with NC-CO₂Et­ produces the 2,3,4-trisubstituted quinoline 41, which is further converted into Talnetant (42), an NK₃ receptor antagonist, in 86% yield (Scheme [8]).[33]

Scheme 8 Azine functionalization using TMP₂Mg·2LiCl (34)

An alternative base with enhanced thermal stability derived­ from t-butyl-isopropylamine (tBu(iPr)NH, 43) was obtained by treating 43 with n-BuLi, giving 44, followed by the addition of tBu(iPr)NMgCl·LiCl (45), affording the magnesium­ bis-amide 46 in >90% yield (Scheme [9]).[39] The metalation of 4-t-butoxycarbonylpyridine (47) with 46 provides the expected pyridine 48 in 68% yield (Scheme [9]).[39]

Scheme 9 Preparation of 46 and magnesiation of 47 with [iPr(tBu)N]₂Mg·2LiCl (46)

2.3

BF₃·OEt₂-Promoted Metalations of Pyridines

A typical mono-substituted pyridine, 3-fluoropyridine (49), can be metalated in two complementary positions (position C2 or position C4) with TMPMgCl·LiCl (1), either in the absence or in the presence of the strong Lewis acid BF₃·OEt₂ (Scheme [10]). Preliminary experiments showed that BF₃·OEt₂ does not react in an irreversible manner with TMPMgCl·LiCl (1) at temperatures below –30 °C. Also, the 3-fluoro substituent considerably acidifies the adjacent positions C2 and C4 of 49. The position of the metalation is determined by the nature of the complexation with the TMP-base.[40] Thus, by adding TMPMgCl·LiCl (1) to 49, a complexation of 1 to the heterocyclic N-atom takes place, leading to a complex of type 50, which favors metalation at position C2. On the other hand, in the presence of BF₃·OEt₂, this strong Lewis acid forms a complex with the N-atom of the pyridine ring and the base 1 may, if at all, only complex the fluorine substituent.

Scheme 10 Regioselective metalation of 3-fluoropyridine 49 in the presence or absence of BF₃·OEt₂

This favors a metalation at position C4 (see 51). Thus, the presence or absence of BF₃·OEt₂ allows the arylation of 3-fluoropyridine (49) either in position C2 or C4, leading to the expected products 52 and 53 (Scheme [10]).[40] The exact nature of the organometallic species obtained after the metalation of 49 in the presence of BF₃·OEt₂ has been examined by ¹³C NMR spectroscopy.[40] [41] This regioselectivity switch is observed for a range of pyridines. An unexpected regioselectivity is observed in the case of 2-phenylpyridine (54). Thus, the treatment of 54 with TMPMgCl·LiCl (1) at 55 °C provides the magnesiated pyridine 55. After iodolysis, pyridine 56 is obtained in 85% yield. Alternatively, the treatment of 54 with BF₃·OEt₂, followed by TMPMgCl·LiCl (1), furnishes, after iodolysis, the 2,6-disubstituted pyridine 57 in 83% yield (Scheme [11]).[40]

Scheme 11 Regioselective metalation of 2-phenylpyridine (54) with or without BF₃·OEt₂

This methodology also allows the functionalization of 4-dimethylaminopyridine (58) in position 2. In this case, the coordination with BF₃·OEt₂ greatly acidifies all the heterocyclic hydrogen atoms, especially those in position C2. Thus, treatment of 58 with BF₃·OEt₂ in THF, followed by TMPMgCl·LiCl (1) at 0 °C for 1 h, furnishes the magnesium derivative 59 or, after metallotropy, the trifluoroborate derivative 60. After a copper(I)-catalyzed acylation, the 2-ketopyridine­ 61 is obtained in 68% yield.[42] Similarly, 2-chloro-4-dimethylaminopyridine (62) is allylated via the organometallic intermediate 63, furnishing the trisubstituted pyridine 64 in 78% yield (Scheme [12]).[42]

Scheme 12 Functionalization of 4-dimethylaminopyridine (58) using TMPMgCl·LiCl (1) and BF₃·OEt₂

Furthermore a regioselective functionalization of (S)-nicotine (65) via the organometallic intermediate 66, leading to 6-functionalized nicotine derivatives, such as 67, is feasible.[42] Similarly, the metalation of quinine (68) can be tuned depending on the reaction conditions used. Thus, the formation of the lithium alcoholate of quinine followed by the addition of BF₃·OEt₂ (2 equiv) is tentatively thought to provide intermediate 69, which leads to a complexation of 1 at the basic tertiary nitrogen atom and therefore leads to the 3-iodinated quinoline 70 in 65% yield (Scheme [13]).[42]

Scheme 13 BF₃·OEt₂-triggered metalation of (S)-nicotine (65) and quinine (68) using TMPMgCl·LiCl (1)

By tuning the protecting groups attached to quinine (68), a switch of the metalation is observed. Thus, the conversion of 68 into the TBDMS-silyl enol ether 71 followed by addition of BF₃·OEt₂ (1 equiv) now leads to the BF₃-adduct­ 72, which can be metalated with TMPMgCl·LiCl (1) exclusively at the position C2, providing, after iodolysis, the 2-iodoquinine derivative 73 in 44% yield (Scheme [14]).[42]

Scheme 14 BF₃·OEt₂-triggered metalation of a silyl-derivative of quinine (71)

The regioselectivity of the metalation of pyridines and quinolines is the result of steric and electronic factors, often leading to kinetically controlled products. Thus, the bis-trimethylsilylmethyl group, which is readily attached to the pyridine scaffold, directs the metalation by steric effects. Therefore, the 3-substituted pyridine 74 was activated with BF₃·OEt₂ (0 °C, 15 min) and magnesiated with TMP₂Mg·2LiCl (34), since the magnesiation with 1 proved to be ineffective. The BF₃-adduct 75 is exclusively metalated at position C6, providing, after a Negishi cross-coupling with an iodopyrimidine, the bis-azine 76 in 65% yield (Scheme [15]).[43] Interestingly, 6-bromo-3-bis(trimethylsilylmethyl)pyridine (77) can be directly metalated by TMP₂Mg·2LiCl (34) at 0 °C for 25 h, affording the magnesium derivative 78. Due to the steric hindrance of the silyl-substituent at position C3, no magnesiation occurs at position C2, and only a magnesiation is observed at position C5. Subsequent acylation with an acid chloride, after transmetalation to copper(I) with CuCN·2LiCl, provides ketone 79 in 60% yield (Scheme [15]).[43]

Scheme 15 Metalation of sterically hindered pyridines bearing a bis-trimethylsilylmethyl substituent

3

Zincation of Pyridines and Related Azines using TMPZnCl·LiCl and TMP₂Zn·2LiCl·2MgCl₂

The availability of kinetically active zinc amides further extends the scope of directed metalations of functionalized azines. Two complementary zinc bases TMPZnCl·LiCl (80) and TMP₂Zn·2LiCl·2MgCl₂ (81) are obtained from TMPLi and ZnCl₂ or TMPMgCl·LiCl (1) and ZnCl₂ (Scheme [16]).[11] [44] [45] Since the carbon–zinc bond is much more covalent than the carbon–magnesium bond, electrophilic functional groups are much better tolerated in such zinc organometallics and the directed zincation of various functionalized pyridines such as 82 and 83 is readily achieved.[14] As the carbon–zinc bond in heteroarylzinc reagents is stable up to 100 °C, directed zincations of pyridines 82–83 have been performed under microwave irradiation under elevated temperatures (60–80 °C), providing the corresponding dipyridylzinc reagents 84–85 in high yields. After quenching with electrophiles such as allylic bromides or acyl chlorides in the presence of a copper(I) catalyst, the expected products 86–87 are obtained in 68–80% yield (Scheme [16]).[14]

Scheme 16 Preparation of the TMP-zinc bases TMPZnCl·LiCl (80) and TMP₂Zn·2LiCl·2MgCl₂ (81) and of polyfunctional pyridylzinc reagents using 81

Furthermore, pyridylzinc organometallics do not undergo electron-transfer reactions. Therefore, the electron-deficient nitro group is well tolerated in the zincation of nitro-substituted pyridines such as 88. In this case, the zincation proceeds at –40 °C within 1.5 h, leading to the bis-pyridylzinc 89. After a copper-catalyzed allylation with 3-bromocyclohexene, the trisubstituted pyridine 90 is obtained in 80% yield (Scheme [17]).[44] Alternatively, the milder zinc base TMPZnCl·LiCl (80) can be used to zincate 88 at 25 °C within 5 h and does not require low temperature metalations[45] [46] leading to the acylated pyridine 91 in 77% yield on 50 mmol scale (Scheme [17]).[46]

Highly oxidized pyridines, such as pyridine N-oxides, are smoothly zincated with TMPZnCl·LiCl (80) at 25 °C and such functionalizations of pyridines are possible in large scale (20 mmol) in high yields.

Scheme 17 Zincation of nitro-substituted pyridine 88 using TMPZnCl·LiCl (80) or TMP₂Zn·2LiCl·2MgCl₂ (81)

Thus, a room-temperature zincation of pyridine N-oxide 92 with TMPZnCl·LiCl (80), and subsequent cross-coupling with the heteroaryl bromide 93, provides the desired cross-coupling product 94 in 95% yield. Remarkably, this reaction has been extended to diazine N-oxides such as pyridazine N-oxide 95, providing, after cross-coupling with the heterocyclic bromide 96, the complex heterocycle 97 in 66% yield (Scheme [18]).[47]

Scheme 18 Metalation of azine N-oxides using TMPZnCl·LiCl (80)

The use of TMPZnCl·LiCl (80) is compatible with electrophilic aminations as shown by Wang.[48] [49] Thus, TMPZnCl·LiCl (80) regioselectively zincates 3-fluoropyridine (49) at 25 °C. Addition of a Cu(II)-catalyst (5 mol% Cu(OAc)₂) at 50 °C for 18 h in the presence of the electrophilic amination reagent, a benzoyloxypiperazine derivative (98), provides the amination product 99 in 53% yield at a 60 mmol scale. A related cobalt(II)-catalyzed amination can be performed under milder conditions using CoCl₂·2LiCl as catalyst (2.5%). In this case, the amination proceeds at 25 °C. Thus, pyridylzinc pivalate 100 and 101,[50] obtained by the magnesiation of the corresponding azine and diazine 102 and 103 with TMPMgCl·LiCl (1) followed by the addition of Zn(OPiv)₂, are treated with N-hydroxymorpholine benzoate in THF at 25 °C for 2 h, furnishing the aminated derivatives 104 and 105 in 91–95% yield (Scheme [19]).[51]

The performance of lateral zincations of pyridines has been achieved by using TMP₂Zn·2LiCl·2MgCl₂ (81). Thus, the treatment of the cyanohydrine derivative 106 with TMP₂Zn·2LiCl·2MgCl₂ (81) at 0 °C for 1 h provides the benzylic pyridylzinc derivative 107.

Scheme 19 Electrophilic aminations of zincated azines using TMPZnCl·LiCl (80), TMPMgCl·LiCl (1) and Zn(OPiv)₂

This zinc reagent can be acylated with cyclopropanecarbonyl chloride in the presence of 20% CuCN·2LiCl, affording, after tetrabutylammonium fluoride (TBAF) treatment, ketone 108 in 80% yield (Scheme [20]).[52]

Scheme 20 Lateral zincation of a pyridine cyanohydrine 106 using TMP₂Zn·2LiCl·2MgCl₂ (81)

The scope of azine zincations has been extended by performing a Barbier type zincation in which the metalation is performed with TMPLi in the presence of ZnCl₂·2LiCl at low temperature. Thus, to a mixture of ZnCl₂·2LiCl and the substrate pyridine 109, a THF solution of TMPLi (ca. 1.5 equiv) is added at –78 °C. Under these conditions, the directed lithiation of 109 is fast, producing the ortho-lithiated pyridine 110, which is a highly reactive intermediate, that is transmetalated in situ with the soluble ZnCl₂·2LiCl, providing the stable pyridylzinc reagent 111. Quenching with an electrophile (E-X) under appropriate reaction conditions furnishes then the functionalized pyridine 112 (Scheme [21]).[53]

Scheme 21 Barbier type metalation of pyridine 81 using TMPLi in the presence of ZnCl₂·2LiCl

That such a Barbier reaction proceeds properly relies on the slow transmetalation between TMPLi and ZnCl₂·2LiCl at –78 °C. On the other hand, the directed lithiation and transmetalation steps are required to be fast.[53] This reaction setup has a good reaction scope and the functionalized pyridines 113–115 are smoothly metalated under these in situ trapping conditions, using either ZnCl₂·2LiCl or MgCl₂·2LiCl as trapping salts, providing the zincated pyridine derivatives 116–118. After quenching with various electrophiles (aldehydes or aryl halides in the presence of a Pd-catalyst) the polyfunctionalized pyridines 119–121 are obtained in 79–94% yield (Scheme [22]).[53]

Scheme 22 In situ trapping metalations of polyfunctional pyridines 113–115

The drawback of these metalations are the required low reaction temperatures. This problem was overcome by using a continuous-flow setup (Scheme [23]).[7a] Thus, pyridine substrates bearing a directing group (DG) are mixed with a metallic salt (ZnCl₂·2LiCl; MgCl₂·2LiCl or CuCN·2LiCl), and added to a TMPLi solution in THF. These solutions were combined in a commercial flow setup from Uniqsis (1.80 mL/min) at 0 °C for 40 s. This continuous-flow setup has several advantages, such as enabling a reaction temperature of 0 °C and a short reaction time of 40 s. Also, the reaction can be readily scaled-up by pumping the solutions longer (Scheme [23]).[7a]

Scheme 23 Continuous-flow setup for in situ trapping metalations

By using this procedure, a range of pyridines such as 122–123 are readily functionalized via the intermediate organometallics 124–125 leading to the expected products 126–127 in 80–98% yield (Scheme [24]).[7a]

Scheme 24 Continuous-flow metalation of pyridines 122–123 using TMPLi in the presence of a metallic salt

In some cases, this procedure may be performed by replacing TMPLi with the 100 times cheaper lithium bis-cyclo­hexylamide (Cy₂NLi).[54] For example, the ethyl nicotinate 115 was metalated with Cy₂NLi (1.5 equiv) at 0 °C within 40 s and further allylated under copper(I)-catalysis in batch, leading to the pyridine 128 in 88% yield (Scheme [25]).[54]

Scheme 25 Continuous-flow metalation of pyridine 115 in the presence of ZnCl₂·2LiCl using Cy₂NLi as a cheap lithium amide

The combined use of TMP-zinc and magnesium bases (TMPMgCl·LiCl (1), TMPZnCl·LiCl (80) and TMP₂Zn·2LiCl· 2MgCl₂ (81)) in several cases allows a full functionalization of the pyridine scaffold. Thus, the treatment of 5-bromo-2-chloropyridine (129) with TMPMgCl·LiCl (1) in THF (–40 °C, 3 h), followed by the addition of tosyl cyanide furnishes the regioselective product 130 in 68% yield.[42] Remarkably, the pyridine 130 is magnesiated at low temperature with TMPMgCl·LiCl (1), affording the 4-magnesiated pyridine 131. The regioselectivity of this magnesiation may be explained by a preferential complexation of TMPMgCl·LiCl (1) to the bromo-substituent, triggering a metalation in position C4. Quenching with MeSO₂SMe provides thioether 132 in 81% yield. The last metalation is best performed with TMP₂Zn·2LiCl·2MgCl₂ (81), leading to the bis-pyridylzinc 133, which was transmetalated to the copper derivative with CuCN·2LiCl and benzoylated with PhCOCl, leading to the pentasubstituted pyridine 134 in 61% yield (Scheme [26]).[42]

Scheme 26 Full functionalization of the pyridine scaffold

4

Metalation of Pyridines using other TMP-Bases

It should be mentioned that related TMP-amide base derivatives from manganese,[55] aluminum,[56] and lanthanum[57] have been reported. Thus, 2-chloro-5-fluoropyridine 135 can be treated with TMP₂Mn·4LiCl₂ (THF, 0 °C, 4 h), leading to the bis-pyridylmanganese species 136. After the addition of chloranil (1 equiv) at –40 °C for 0.5 h, the bis-pyridine 137 is obtained in 64% yield.[55c] The reaction of the 3-cyanopyridine 113 with TMP₂Mn·4LiCl (THF, 0 °C, 0.5 h) affords an intermediate manganese-species 138, which, after transmetalation with CuCl·2LiCl, followed by the addition of LiN(SiMe₃)₂, leads to 139 and oxidative amination with chloranil gives the 4-aminopyridine 140 in 75% yield (Scheme [27]).[55a]

Scheme 27 Magnesiation of pyridine derivatives using TMP₂Mn·4LiCl

Aluminum-TMP amides have proven to be especially useful for the metalation of electron-rich pyridines. Thus, the treatment of TMPLi with AlCl₃ provides the corresponding TMP₃Al·3LiCl base (141) as a 0.3 M solution in THF. This base readily aluminates the 2-methoxypyridine 142 leading to the tris-arylaluminum 143, which provides, after transmetalation to zinc and to copper, and acylation, the expected ketone 144 in 90% yield (Scheme [28]).[56]

Scheme 28 Alumination of an electron-rich pyridine 142 using TMP₃Al·3LiCl (141)

The treatment of TMPMgCl·LiCl with LaCl₃·2LiCl[58] [59] and its addition to a functionalized pyridine such as 115 leads to an organometallic intermediate best represented as 145. From recent results,[59] the reagent 145 may be better represented as a magnesium reagent complexed with LaCl₃, rather than a true aryllanthanum species.[59] However, the reaction of 145 with the sterically hindered ketone 146 leads to the expected addition product 147 in 74% yield (Scheme [29]).[57]

Scheme 29 Metalation of the functionalized pyridine 115 using TMPMgCl­·LaCl₃·nLiCl

5

Magnesiation and Zincation of Diazines

Whereas the metalation of pyridines and quinolones is relatively well explored, the metalation of diazines such as pyrimidine (148), pyrazine (149), and pyridazine (150) is much less studied, and the functionalization of these N-heterocycles remains a challenge, as the predictability of the appropriate base for their metalation is still difficult (Figure [1]).

Figure 1 Diazine scaffolds

Nevertheless, the TMP-bases TMPMgCl·LiCl (1), TMP₂Mg·2LiCl (34), TMPZnCl·LiCl (80) and TMP₂Zn·2LiCl·2MgCl₂ (81) have proven to be a set of very useful metalation reagents, especially well-suited for the functionalization of diazines and annulated analogues. These bases also constitute an automated strong base screening platform, as recently shown by Boga and Christensen.[60] Some recent applications are shown below, as well as guidelines for rationalizing the metalations of various diazines. Whereas pyrimidine itself has a high propensity to add magnesium nucleophiles, substituted pyrimidines are better substrates for metalations. Thus, 2-bromopyrimidine (151) undergoes a smooth magnesiation with TMPMgCl·LiCl (1) at –55 °C within 1.5 h and produces the 4-magnesiated pyrimidine 152 in >90% yield. After thiolation of 152 with MeSO₂SMe, the corresponding thioether 153 is obtained in 81% yield.[61] [62] The methylthio substituent has a highly stabilizing effect and considerably stabilizes the pyrimidine towards unwanted nucleophilic additions. Thus, further magnesiation of 153 may now be performed at room temperature and the metalation is complete within 5 min, producing the magnesiated pyrimidine 154, which, after chlorination, provides the trisubstituted pyrimidine 155 in 76% yield. The last position of the ring is magnesiated under similar conditions furnishing, after copper(I)-mediated benzoylation, the ketone 156 in 81% yield (Scheme [30]).[61]

Scheme 30 Regioselective magnesiations of 2-bromopyrimidine (151) using TMPMgCl·LiCl (1)

This methodology has been applied to the functionalization of 2-chloropyrimidine (157), providing a convenient synthesis of the fungicide mepanipyrim 158.[63] Thus, the magnesiation of 157 at –60 °C is complete within 2 h using TMPMgCl·LiCl (1). Transmetalation with ZnCl₂ and iodolysis affords the bis-halogenated pyrimidine 159 in 91% yield. Subsequent magnesiation with TMPMgCl·LiCl (1; –60 °C, 1 h) followed by a bromination with 1,2-dibromotetrachloroethane affords the tri-halogenated pyrimidine 160 in almost quantitative yield (96%). Negishi cross-coupling of the most reactive iodine-substituent at 160 using MeZnBr furnishes the pyrimidine 161 in 58% yield. Sonogashira cross-coupling with propyne gives the alkynylpyrimidine 162 in 97% yield. Finally, Pd-catalyzed amination of 162 with aniline furnishes mepanipyrim 158 in 81% yield (Scheme [31]).[63]

The amination of the pyrimidine scaffold can also be achieved using TMPMgCl·LiCl (1). Thus, the magnesiation of dichloropyrimidine 163 with 1 at 25 °C for 0.5 h produces the magnesium reagent 164. Its transmetalation with CuCl·2LiCl followed by the addition of N-lithiomorpholine (165) leads to the lithium amidocuprate 166, which, after oxidative amination using chloranil, leads to the 5-aminopyrimidine 167 in 68% yield (Scheme [32]).[63] [64]

The regioselectivity of the metalation of uracil may be controlled by the bases used.[65] [66] [67] Thus, the deprotonation of 2,4-dimethoxypyrimidine 168 with TMPLi proceeds through precomplexation of the lithium base at oxygen and leads to an ortho-lithiation (169). On the other hand, magnesiation with TMPMgCl·LiCl (1) in THF is triggered by a complexation of the magnesium base 1 at the heterocyclic N-atom and therefore leads to a magnesiation at the ortho-position to nitrogen, providing the magnesium derivative 170.[57] After quenching with ethyl cyanoformate, the uracil 171 is obtained in 71% yield. Subsequent magnesiation leads to 172 and a copper(I)-mediated benzoylation gives ketone 173 in 78% yield (Scheme [33]).[67] [68]

Scheme 31 Synthesis of the fungicide mepanipyrim 158 starting from 2-chloropyrimidine (157) using TMPMgCl·LiCl (1)

Scheme 32 Amination of the pyrimidine scaffold using TMPMgCl·LiCl (1)

Scheme 33 Selective magnesiation of the protected uracil 168 using TMPMgCl·LiCl (1)

The magnesiation of dichloropyrimidine 163 (25 °C, 0.5 h) with TMPMgCl·LiCl (1) provides the magnesium derivative 164 as shown in Scheme [32]. Its treatment with chiral sulfamidate 174 for 1 h at 25 °C followed by acidification with trifluoroacetic acid (TFA) and heating with Et₃N (4 equiv) in MeCN for 0.5 h at 80 °C leads to the chiral heterocycle 175 in 85% yield. Using the sulfamidate 176 provides tetrahydropyridopyrimidine 177, which is a precursor for various unsaturated heterocycles (Scheme [34]).[69]

Scheme 34 Preparation of annulated pyrimidine 175 and 177

The use of magnesium intermediates in some cases leads to rearrangements,[70] [71] as shown by the magnesiation of indolizine 178 using TMPMgCl·LiCl (1) at 25 °C for 1 h. Under these conditions, a dynamic equilibrium between the two isomeric magnesium species 179 and 180 is observed. Whereas more reactive electrophiles such as iodine and aldehydes provide the products of type 181, less reactive electrophiles such as Cl₃CCCl₃ or a Negishi cross-coupling­ provide products of type 182 (Scheme [35]).[70]

Scheme 35 Electrophile controlled regioselectivity in the functionalization of indolizine 178 using TMPMgCl·LiCl (1)

An in situ trapping procedure in several cases avoids side-reactions and provides high yields of products. Thus, the functionalization of the quinoxaline scaffold is possible using TMPLi. The treatment of dichloroquinoxaline 183 with TMPLi (2.4 equiv) in the presence of an excess of TMSCl furnishes the bis-silyl derivative 184 in 74% yield. After the addition of ICl (1 equiv) the mono-iodinated quinoxaline derivative 185 is obtained in 63% yield.[72] Similarly, the 2,7-naphthyridine 186 can be converted into silyl derivative 187 in 73% yield (Scheme [36]).[73]

Scheme 36 Functionalization of quinoxalines and 2,7-naphthyridines using TMPLi

The 1,5-naphthyridine scaffold (188) has been examined in more detail. Complexation of TMP₂Mg·2LiCl (34) to the nitrogen-atom N1 of 188 leads to a selective metalation in position C8. This magnesiation has to be performed at –78 °C (for 5 min) to avoid decomposition of the metalated species. The resulting magnesium species 189 can be functionalized with various electrophiles E¹-X providing products of type 190. The mono-substituted naphthyridines 190 can be regioselectively functionalized using either TMPMgCl·LiCl (1) or the combination of 1 and BF₃·OEt₂. In the first case, complexation of the base 1 occurs at the sterically most accessible N5, leading to a magnesiation and thus functionalization at position C4 (191).

On the other hand, the addition of BF₃·OEt₂ prior to the addition of 1 blocks a complexation of the magnesium base at N5 and, since N1 is also inaccessible due to the substituent E¹, leads to a complexation of 1 to the BF₃ unit and a deprotonation of the most acidic hydrogen at position C6. After quenching with an electrophile E²-X the disubstituted 1,5-naphthyridine 192 is obtained (Scheme [37]).[74] The products of type 192 may be further metalated, although a very strong lithium base (TMPLi) is required. Thus, the reaction of 192a with TMPLi at –78 °C for 0.5 h provides the lithium intermediate 193, which is trapped with iodine, furnishing the adduct 194 in 70% yield. The use of TMPLi also allows a fourth functionalization and the reaction of 194 with TMPLi at –78 °C for 90 s (!) leads to an ortho-lithiation, providing the lithium reagent 195, which gives the more stable lithium derivative 196 through an intramolecular iodine–lithium exchange. After quenching with an electrophile such as an acid chloride in the presence of stoichiometric amounts of CuCN·2LiCl, the corresponding ketone 197 is obtained in 70% yield (Scheme [38]).[74] This methodology can be applied for the synthesis of an antibacterial agent such as 198. Thus, the magnesiation of 1,5-naphthyridine 188 with TMP₂Mg·2LiCl (34) from –40 to –20 °C for 4 h, followed by a transmetalation with ZnCl₂ and Pd(0)-catalyzed cross-coupling with 4-tert-butylphenyl iodide, provides the arylated naphthyridine 199 in 88% yield. TMPLi­-lithiation at position C4 followed by a methylation with methyl triflate affords the disubstituted naphthyridine 200 in 53% yield. This naphthyridine can be converted into the antibacterial drug candidate 198 (Scheme [39]).[74] [75]

Scheme 37 Regioselective magnesiation and functionalization of 1,5-naphthyridines using TMP₂Mg·2LiCl (34) and TMPMgCl·LiCl (1) in the presence or absence of BF₃·OEt₂

Scheme 38 Tri- and tetra-functionalization of 1,5-naphthyridines using TMPLi

Scheme 39 Preparation of the antibacterial agent 198 through successive metalations of 1,5-naphthyridine 188

TMPMgCl·LiCl (1) can be used to magnesiate highly functionalized 2,7-naphthyridines such as 201. Thus, the treatment of 201 triggered by a coordination at N2, affords the magnesium derivative 202, which undergoes an intramolecular addition to the carbethoxy function, providing the alkaloid sampangine 203 in 35% yield (Scheme [40]).[76]

Bracher has extended this strategy to a marine pyridoacridine alkaloid demethyldeoxyamphimedine (204). Thus, the magnesiation of ethyl nicotinate 205 with TMPMgCl·LiCl (1) in the presence of BF₃·OEt₂, followed by transmetalation with ZnCl₂, furnishes the zinc reagent 206, which, after cross-coupling with 2-iodoaniline in the presence of a palladium-catalyst, furnishes the lactam 207 in 50% yield. Conversion into the corresponding bromide 208 using POBr₃, followed by a second cross-coupling with the zincated ethyl nicotinate 206, produces the naphthyridine 209 in 78% yield. Cyclization of 209 with TMPMgCl·LiCl (1) furnishes the desired marine pyridoacridine alkaloid 204 in 28% yield (Scheme [41]).[77]

Scheme 40 TMPMgCl·LiCl (1) magnesiation of the 2,7-naphthyridine 201 leading to the alkaloid sampangine 203

Scheme 41 Preparation of the alkaloid demethyldeoxyamphimedine 204 using TMPMgCl·LiCl (1)

The metalation of the cinnoline scaffold (210) can also be realized using TMP₂Mg·2LiCl (34). Thus, the reaction of 210 first with BF₃·OEt₂, followed by the addition of TMP₂Mg·2LiCl (34) at –78 °C for 10 min, leads to a regio­selective magnesiation at C3. This regioselectivity can be explained by assuming that BF₃·OEt₂ complexes at the most readily available nitrogen N2 and that TMP₂Mg·2LiCl coordinates at BF₃ leading to a metalation at C3 (see 211). After Pd(0)-catalyzed cross-couplings, the desired arylated products of type 212 are obtained. Alternatively, the metalation of 210 with TMP₂Zn·2LiCl·2MgCl₂ (49) in the presence of MgCl₂ leads to a preferential complexation at N1 of the base and at N2 of MgCl₂, favoring a zincation at C8 via a transition state of type 213. After palladium-catalyzed arylation with various aryl iodides, 8-arylated cinnolines of type 214 are obtained (Scheme [42]).[78]

Scheme 42 Regioselective metalation of the cinnoline scaffold using TMP₂Mg·2LiCl (34) and TMP₂Zn·2LiCl·2MgCl₂ (81)

As shown above, the presence or absence of a Lewis acid such as BF₃·OEt₂ or MgCl₂ is essential for achieving a high regioselectivity in metalations with TMP-bases. This has been demonstrated for various heterocyclic metalations.[79] [80] [81] Especially relevant in the frame of this review is the regioselective metalation of the pyrazine scaffold. Thus, the introduction of a bulky bis-trimethylsilylmethyl-substituent to the pyrazine core is readily realized by treating chloropyrazine 215 with the magnesium reagent 216. The resulting silyl-substituted pyrazine 217 proved to be difficult to magnesiate using TMP-magnesium bases such as 1 or 34. However, a precomplexation with BF₃·OEt₂ sufficiently acidifies the ring hydrogen atoms, allowing a regioselective metalation at the least sterically hindered position at C5 (see 218, Scheme [43]).[81]

Scheme 43 Regioselective functionalization of the pyrazine scaffold

The resulting magnesium reagent 219 reacts with various electrophiles. Chlorination with PhSO₂Cl provides the chloropyrazine 220 in 61% yield. This pyrazine is readily magnesiated in a subsequent step. Remarkably, the inductive effect of the chlorine substituent is sufficient for a magnesiation to be achieved with TMP₂Mg·2LiCl (34) in the absence of BF₃·OEt₂. The resulting magnesiated pyrazine 221 can be brominated with 1,2-dibromotetrachloroethane providing the bis-halogenated pyrazine 222 in 93% yield. Finally, the last ring hydrogen of 222 can again be metalated with TMP₂Mg·2LiCl (34), leading to the magnesium species 223, which, after iodolysis, provides the tri-halogenated pyrazine 224 in 83% yield (Scheme [44]).[81]

Scheme 44 Successive magnesiation of the pyrazine scaffold using TMP₂Mg·2LiCl (34)

The metalation of the pyrazine and the pyridazine scaffolds remains a challenge and usually quite strong bases are required for these metalations. Especially for the pyridazine scaffold, either yields are low or the electrophile scope is narrow.[8f] [9a] The presence of two chlorine substituents in 3,6-dichloropyrazine 225 facilitates the metalation and now TMP₂Zn·2LiCl·2MgCl₂ (81) leads to a zincation at –78 °C.[82] Also, a more convenient zincation of pyridazine 225 can be realized at 25 °C with TMPZnCl·LiCl (80). The resulting zinc reagent 226 can be acylated after a transmetalation with CuCN·2LiCl, leading to the corresponding ketone 227 (Scheme [45]).[45] Similarly, the corresponding dibromopyridazine 228 is zincated with TMPZnCl·LiCl (80) under the same conditions, furnishing the zincated heterocycle 229, which is benzoated, after transmetalation with CuCN·2LiCl, leading to the ketone 230 in 86% yield (Scheme [45]).[46] [83]

Scheme 45 Zincations of the halogenopyridazines 225 and 228

Finally, zinc-TMP-bases are especially efficient for the zincation of 2-pyridones and 2,7-naphthyridones. Thus, treatment of functionalized 2-pyridone 231 with TMP₂Zn·2LiCl (81) at –10 °C for 72 h leads to the zincated pyridone 232, which, after iodolysis, affords the iodopyridone 233 in 80% yield. Similarly, naphthyridone 234 is zincated regioselectively and Pd-catalyzed cross-coupling with 4-iodoaniline provides the cross-coupling product 235 in 76% yield (Scheme [46]).[84]

Scheme 46 Functionalization of 2-pyridones and 2-naphthyridones using TMP₂Zn·2LiCl·2MgCl₂ (81)

6

Conclusion

The functionalization of azines and diazines is an important task for pharmaceutical and agro-chemical research. Herein, we have summarized recent developments in the field of azine metalation using TMPMgCl·LiCl (1), TMP₂Mg·2LiCl (34), TMPZnCl·LiCl (80), and TMP₂Zn·2LiCl·2MgCl₂ (81), and have shown that they are excellent bases for the functionalization of N-heterocycles. The additional use of BF₃·OEt₂ or MgCl₂ as Lewis acids considerably expands the scope of these bases. Furthermore, the performance of such metalations not in batch, but in continuous flow, allows further tuning of the reaction conditions, so that more convenient reaction temperatures and short reaction times can be achieved. In the future, the combination of these methods will certainly facilitate the functionalization of diazines and benzo-analogues further, since this research is still in its infancy.

Acknowledgment

We would like to thank Albemarle (Hoechst, Germany) for the generous donation of chemicals.

• References

• 1a Li X.-Q. Andersson TB. Ahlström M. Weidolf L. Drug Metab. Dispos. 2004; 32: 821
• 1b Manolikakes SM. Barl NM. Sämann C. Knochel P. Z. Naturforsch., B 2013; 68: 411
• 1c Lamberth C. Pest Manage. Sci. 2013; 69: 1106
• 1d Dinesh K. Subheet KJ. Curr. Med. Chem. 2016; 23: 4338
• 1e Taylor AP. Robinson RP. Fobian YM. Blakemore DC. Jones LH. Fadeyi O. Org. Biomol. Chem. 2016; 14: 6611
• 2a Beak P. Snieckus V. Acc. Chem. Res. 1982; 15: 306
• 2b Snieckus V. Chem. Rev. 1990; 90: 879
• 2c Alessi M. Larkin AL. Ogilvie KA. Green LA. Lai S. Lopez S. Snieckus V. J. Org. Chem. 2007; 72: 1588
• 2d Schneider C. Broda E. Snieckus V. Org. Lett. 2011; 13: 3588
• 2e Board J. Cosman JL. Rantanen T. Singh SP. Snieckus V. Platinum Met. Rev. 2013; 57: 234
• 3a Schlosser M. Jung HC. Takagishi S. Tetrahedron 1990; 46: 5633
• 3b Marzi E. Bigi A. Schlosser M. Eur. J. Org. Chem. 2001; 1371
• 3c Schlosser M. Eur. J. Org. Chem. 2001; 3975
• 3d Schlosser M. Rausis T. Eur. J. Org. Chem. 2004; 1018
• 3e Schlosser M. Angew. Chem. Int. Ed. 2005; 44: 376
• 4a Marsais F. Queguiner G. Tetrahedron 1983; 39: 2009
• 4b Trécourt F. Mallet M. Marsais F. Queguiner G. J. Org. Chem. 1988; 53: 1367
• 4c Rocca P. Cochennec C. Marsais F. Thomas-dit-Dumont L. Mallet M. Godard A. Queguiner G. J. Org. Chem. 1993; 58: 7832
• 4d Trécourt F. Mallet M. Mongin O. Gervais B. Quéguiner G. Tetrahedron 1993; 49: 8373
• 4e Gros P. Fort Y. Queguiner G. Caubère P. Tetrahedron Lett. 1995; 36: 4791
• 4f Cochennec C. Rocca P. Marsais F. Godard A. Quéguiner G. Synthesis 1995; 321
• 4g Arzel E. Rocca P. Marsais F. Godard A. Quéguiner G. Tetrahedron Lett. 1998; 39: 6465
• 4h Mongin F. Quéguiner G. Tetrahedron 2001; 57: 4059
• 4i Turck A. Plé N. Mongin F. Quéguiner G. Tetrahedron 2001; 57: 4489
• 4j Awad H. Mongin F. Trécourt F. Quéguiner G. Marsais F. Tetrahedron Lett. 2004; 45: 7873
• 5a Chevallier F. Mongin F. Chem. Soc. Rev. 2008; 37: 595
• 5b Tilly D. Chevallier F. Mongin F. Gros PC. Chem. Rev. 2014; 114: 1207
• 6 Gros PC. Fort Y. Eur. J. Org. Chem. 2009; 4199
• 7a Becker MR. Knochel P. Angew. Chem. Int. Ed. 2015; 54: 12501
• 7b Ketels M. Konrad DB. Karaghiosoff K. Trauner D. Knochel P. Org. Lett. 2017; 19: 1666
• 8a Mulvey RE. Organometallics 2006; 25: 1060
• 8b Mulvey RE. Mongin F. Uchiyama M. Kondo Y. Angew. Chem. Int. Ed. 2007; 46: 3802
• 8c Mulvey RE. Acc. Chem. Res. 2009; 42: 743
• 8d Armstrong DR. Kennedy AR. Mulvey RE. Parkinson JA. Robertson SD. Chem. Sci. 2012; 3: 2700
• 8e Mulvey RE. Dalton Trans. 2013; 6676
• 8f Uzelac M. Kennedy AR. Hevia E. Mulvey RE. Angew. Chem. Int. Ed. 2016; 55: 13147
• 9a Seggio A. Chevallier F. Vaultier M. Mongin F. J. Org. Chem. 2007; 72: 6602
• 9b L’Helgoual’ch J.-M. Bentabed-Ababsa G. Chevallier F. Yonehara M. Uchiyama M. Derdour A. Mongin F. Chem. Commun. 2008; 5375
• 9c Bentabed-Ababsa G. Blanco F. Derdour A. Mongin F. Trécourt F. Quéguiner G. Ballesteros R. Abarca B. J. Org. Chem. 2009; 74: 163
• 9d Nguyen TT. Chevallier F. Jouikov V. Mongin F. Tetrahedron Lett. 2009; 50: 6787
• 9e Snégaroff K. L’Helgoual’ch J.-M. Bentabed-Ababsa G. Nguyen TT. Chevallier F. Yonehara M. Uchiyama M. Derdour A. Mongin F. Chem. Eur. J. 2009; 15: 10280
• 9f Dayaker G. Chevallier F. Gros PC. Mongin F. Tetrahedron 2010; 66: 8904
• 9g Snégaroff K. Komagawa S. Chevallier F. Gros PC. Golhen S. Roisnel T. Uchiyama M. Mongin F. Chem. Eur. J. 2010; 16: 8191
• 9h Nguyen TT. Marquise N. Chevallier F. Mongin F. Chem. Eur. J. 2011; 17: 10405
• 9i Nagaradja E. Chevallier F. Roisnel T. Jouikov V. Mongin F. Tetrahedron 2012; 68: 3063
• 9j Kadiyala RR. Tilly D. Nagaradja E. Roisnel T. Matulis VE. Ivashkevich OA. Halauko YS. Chevallier F. Gros PC. Mongin F. Chem. Eur. J. 2013; 19: 7944
• 9k Marquise N. Harford PJ. Chevallier F. Roisnel T. Dorcet V. Gagez A.-L. Sablé S. Picot L. Thiéry V. Wheatley AE. H. Gros PC. Mongin F. Tetrahedron 2013; 69: 10123
• 9l Harford PJ. Peel AJ. Chevallier F. Takita R. Mongin F. Uchiyama M. Wheatley AE. H. Dalton Trans. 2014; 14181
• 9m Marquise N. Bretel G. Lassagne F. Chevallier F. Roisnel T. Dorcet V. Halauko YS. Ivashkevich OA. Matulis VE. Gros PC. Mongin F. RSC Adv. 2014; 4: 19602
• 9n Messaoud MY. A. Bentabed-Ababsa G. Hedidi M. Derdour A. Chevallier F. Halauko YS. Ivashkevich OA. Matulis VE. Picot L. Thiéry V. Roisnel T. Dorcet V. Mongin F. Beilstein J. Org. Chem. 2015; 11: 1475
• 9o Nagaradja E. Bentabed-Ababsa G. Scalabrini M. Chevallier F. Philippot S. Fontanay S. Duval RE. Halauko YS. Ivashkevich OA. Matulis VE. Roisnel T. Mongin F. Bioorg. Med. Chem. 2015; 23: 6355
• 9p Hedidi M. Bentabed-Ababsa G. Derdour A. Halauko YS. Ivashkevich OA. Matulis VE. Chevallier F. Roisnel T. Dorcet V. Mongin F. Tetrahedron 2016; 72: 2196
• 9q Hedidi M. Erb W. Lassagne F. Halauko YS. Ivashkevich OA. Matulis VE. Roisnel T. Bentabed-Ababsa G. Mongin F. RSC Adv. 2016; 6: 63185
• 9r Peel AJ. Hedidi M. Bentabed-Ababsa G. Roisnel T. Mongin F. Wheatley AE. H. Dalton Trans. 2016; 6094
• 10a Kondo Y. Shilai M. Uchiyama M. Sakamoto T. J. Am. Chem. Soc. 1999; 121: 3539
• 10b Imahori T. Uchiyama M. Sakamoto T. Kondo Y. Chem. Commun. 2001; 2450
• 10c Uchiyama M. Miyoshi T. Kajihara Y. Sakamoto T. Otani Y. Ohwada T. Kondo Y. J. Am. Chem. Soc. 2002; 124: 8514
• 10d Tezuka N. Shimojo K. Hirano K. Komagawa S. Yoshida K. Wang C. Miyamoto K. Saito T. Takita R. Uchiyama M. J. Am. Chem. Soc. 2016; 138: 9166
• 11 Imahori T. Kondo Y. J. Am. Chem. Soc. 2003; 125: 8082
• 12a Haag B. Mosrin M. Ila H. Malakhov V. Knochel P. Angew. Chem. Int. Ed. 2011; 50: 9794
• 12b Krasovskiy A. Krasovskaya V. Knochel P. Angew. Chem. Int. Ed. 2006; 45: 2958
• 12c Klatt T. Markiewicz JT. Sämann C. Knochel P. J. Org. Chem. 2014; 79: 4253
• 13 García-Álvarez P. Graham DV. Hevia E. Kennedy AR. Klett J. Mulvey RE. O’Hara CT. Weatherstone S. Angew. Chem. Int. Ed. 2008; 47: 8079
• 14 Wunderlich S. Knochel P. Org. Lett. 2008; 10: 4705

For recent reviews on C–H activation, see:
• 15a Chen Z. Wang B. Zhang J. Yu W. Liu Z. Zhang Y. Org. Chem. Front. 2015; 2: 1107
• 15b Crabtree RH. Lei A. Chem. Rev. 2017; 117: 8481
• 15c Murakami K. Yamada S. Kaneda T. Itami K. Chem. Rev. 2017; 117: 9302

For previous reviews, see:
• 16a Bresser T. Mosrin M. Monzon G. Knochel P. J. Org. Chem. 2010; 75: 4686
• 16b Knochel P. Schade MA. Bernhardt S. Manolikakes G. Metzger A. Piller FM. Rohbogner CJ. Mosrin M. Beilstein J. Org. Chem. 2011; 7: 1261
• 16c Manolikakes SM. Barl NM. Sämann C. Knochel P. Z. Naturforsch., B 2013; 68: 411
• 16d Klatt T. Markiewicz JT. Sämann C. Knochel P. J. Org. Chem. 2014; 79: 4253
• 17a Hauser CR. Walker HG. J. Am. Chem. Soc. 1947; 69: 295
• 17b Henderson KW. Kerr WJ. Chem. Eur. J. 2001; 7: 3430
• 17c Eaton PE. Xiong Y. Gilardi R. J. Am. Chem. Soc. 1993; 115: 10195
• 17d Eaton PE. Lukin KA. J. Am. Chem. Soc. 1993; 115: 11370
• 17e Zhang M.-X. Eaton PE. Angew. Chem. Int. Ed. 2002; 41: 2169
• 18a Schlecker W. Huth A. Ottow E. Mulzer J. J. Org. Chem. 1995; 60: 8414
• 18b Schlecker W. Huth A. Ottow E. Mulzer J. Liebigs Ann. 1995; 1441
• 18c Schlecker W. Huth A. Ottow E. Mulzer J. Synthesis 1995; 1225
• 19a Gribble GW. Saulnier MG. Tetrahedron Lett. 1980; 21: 4137
• 19b Verbeek J. Brandsma L. J. Org. Chem. 1984; 49: 3857
• 19c Verbeek J. George AV. E. de Jong RL. P. Brandsma L. J. Chem. Soc., Chem. Commun. 1984; 257
• 19d Subota AI. Grygorenko OO. Valter YB. Tairov MA. Artamonov OS. Volochnyuk DM. Ryabukhin SV. Synlett 2015; 26: 408

In the case of a stabilized pyridine such as 2-methoxy pyridine, higher temperatures are possible, see:
• 20a Trecourt F. Mallet M. Marsais F. Queguiner G. J. Org. Chem. 1988; 53: 1367
• 20b Khartabil HK. Gros PC. Fort Y. Ruiz-López MF. J. Am. Chem. Soc. 2010; 132: 2410; and ref. 4d
• 21 Boudet N. Lachs JR. Knochel P. Org. Lett. 2007; 9: 5525
• 22 Wunderlich SH. Rohbogner CJ. Unsinn A. Knochel P. Org. Process Res. Dev. 2010; 14: 339
• 23 Negishi E. Acc. Chem. Res. 1982; 15: 340
• 24 Haas D. Hammann JM. Greiner R. Knochel P. ACS Catal. 2016; 6: 1540
• 25 Monzón G. Tirotta I. Nishii Y. Knochel P. Angew. Chem. Int. Ed. 2012; 51: 10624
• 26a Ogawa S. Furukawa N. J. Org. Chem. 1991; 56: 5723
• 26b Capozzi MA. M. Cardellicchio C. Naso F. Spina G. Tortorella P. J. Org. Chem. 2001; 66: 5933
• 27a Rauhut CB. Melzig L. Knochel P. Org. Lett. 2008; 10: 3891
• 27b Melzig L. Rauhut CB. Knochel P. Synthesis 2009; 1041
• 27c Melzig L. Rauhut CB. Knochel P. Chem. Commun. 2009; 3536
• 28 Melzig L. Rauhut CB. Naredi-Rainer N. Knochel P. Chem. Eur. J. 2011; 17: 5362
• 29 MacNeil SL. Familoni OB. Snieckus V. J. Org. Chem. 2001; 66: 3662
• 30 Balkenhohl M. François C. Sustac RD. Quinio P. Knochel P. Org. Lett. 2017; 19: 536
• 31 Tran LD. Daugulis O. Org. Lett. 2010; 12: 4277
• 32 Rohbogner CJ. Clososki GC. Knochel P. Angew. Chem. Int. Ed. 2008; 47: 1503
• 33 Rohbogner CJ. Wirth S. Knochel P. Org. Lett. 2010; 12: 1984
• 34 Sorbera LA. Castaner RM. Silvestre J. Castaner J. Drugs Future 2001; 26: 346
• 35 Milne JE. Buchwald SL. J. Am. Chem. Soc. 2004; 126: 13028
• 36a Milstein D. Stille JK. J. Am. Chem. Soc. 1978; 100: 3636
• 36b Cordovilla C. Bartolomé C. Martínez-Ilarduya JM. Espinet P. ACS Catal. 2015; 5: 3040
• 37 Clososki GC. Rohbogner CJ. Knochel P. Angew. Chem. Int. Ed. 2007; 46: 7681
• 38 Farina V. Krishnan B. J. Am. Chem. Soc. 1991; 113: 9585
• 39 Rohbogner CJ. Wunderlich SH. Clososki GC. Knochel P. Eur. J. Org. Chem. 2009; 1781
• 40 Jaric M. Haag BA. Unsinn A. Karaghiosoff K. Knochel P. Angew. Chem. Int. Ed. 2010; 49: 5451
• 41 Manolikakes SM. Jaric M. Karaghiosoff K. Knochel P. Chem. Commun. 2013; 2124
• 42 Jaric M. Haag BA. Manolikakes SM. Knochel P. Org. Lett. 2011; 13: 2306
• 43 Klatt T. Werner V. Maximova MG. Didier D. Apeloig Y. Knochel P. Chem. Eur. J. 2015; 21: 7830
• 44 Wunderlich SH. Knochel P. Angew. Chem. Int. Ed. 2007; 46: 7685
• 45 Mosrin M. Knochel P. Org. Lett. 2009; 11: 1837
• 46 Bresser T. Monzon G. Mosrin M. Knochel P. Org. Process Res. Dev. 2010; 14: 1299
• 47 Gosselin F. Savage SJ. Blaquiere N. Staben ST. Org. Lett. 2012; 14: 862
• 48 McDonald SL. Hendrick CE. Wang Q. Angew. Chem. Int. Ed. 2014; 53: 4667
• 49 McDonald SL. Hendrick CE. Bitting KJ. Wang Q. Org. Synth. 2015; 92: 356
• 50 Manolikakes SM. Ellwart M. Stathakis CI. Knochel P. Chem. Eur. J. 2014; 20: 12289
• 51 Chen Y.-H. Graßl S. Knochel P. Angew. Chem. Int. Ed. 2018; 57: 1108
• 52 Castelló-Micó A. Knochel P. Synthesis 2018; 50: 155
• 53 Frischmuth A. Fernández M. Barl NM. Achrainer F. Zipse H. Berionni G. Mayr H. Karaghiosoff K. Knochel P. Angew. Chem. Int. Ed. 2014; 53: 7928
• 54 Becker MR. Ganiek MA. Knochel P. Chem. Sci. 2015; 6: 6649
• 55a Wunderlich SH. Kienle M. Knochel P. Angew. Chem. Int. Ed. 2009; 48: 7256
• 55b Wunderlich SH. Bresser T. Dunst C. Monzon G. Knochel P. Synthesis 2010; 2670
• 55c Haas D. Hammann JM. Moyeux A. Cahiez G. Knochel P. Synlett 2015; 26: 1515
• 56 Wunderlich SH. Knochel P. Angew. Chem. Int. Ed. 2009; 48: 1501
• 57 Wunderlich SH. Knochel P. Chem. Eur. J. 2010; 16: 3304
• 58 Krasovskiy A. Kopp F. Knochel P. Angew. Chem. Int. Ed. 2006; 45: 497
• 59 Benischke AD. Anthore-Dalion L. Berionni G. Knochel P. Angew. Chem. Int. Ed. 2017; 56: 16390
• 60 Boga SB. Christensen M. Perrotto N. Krska SW. Dreher S. Tudge MT. Ashley ER. Poirier M. Reibarkh M. Liu Y. Streckfuss E. Campeau L.-C. Ruck RT. Davies IW. Vachal P. React. Chem. Eng. 2017; 2: 446
• 61 Mosrin M. Knochel P. Org. Lett. 2008; 10: 2497
• 62 Mosrin M. Petrera M. Knochel P. Synthesis 2008; 3697
• 63 Mosrin M. Knochel P. Chem. Eur. J. 2009; 15: 1468
• 64 Del Amo V. Dubbaka SR. Krasovskiy A. Knochel P. Angew. Chem. Int. Ed. 2006; 45: 7838
• 65 Wada A. Yamamoto J. Kanatomo S. Heterocycles 1987; 26: 585
• 66 Turck A. Plé N. Quéguiner G. Heterocycles 1994; 37: 2149
• 67 Mosrin M. Boudet N. Knochel P. Org. Biomol. Chem. 2008; 6: 3237
• 68 Soorukram D. Boudet N. Malakhov V. Knochel P. Synthesis 2007; 3915
• 69 Moss TA. Hayter BR. Hollingsworth IA. Nowak T. Synlett 2012; 23: 2408
• 70 Amaral MF. Z. J. Baumgartner AA. Vessecchi R. Clososki GC. Org. Lett. 2015; 17: 238
• 71 Barl NM. Sansiaume-Dagousset E. Karaghiosoff K. Knochel P. Angew. Chem. Int. Ed. 2013; 52: 10093
• 72 Nafe J. Herbert S. Auras F. Karaghiosoff K. Bein T. Knochel P. Chem. Eur. J. 2015; 21: 1102
• 73 Greiner R. Blanc R. Petermayer C. Karaghiosoff K. Knochel P. Synlett 2016; 27: 231
• 74 Balkenhohl M. Greiner R. Makarov IS. Heinz B. Karaghiosoff K. Zipse H. Knochel P. Chem. Eur. J. 2017; 23: 13046
• 75 Ioannidou HA. Martin A. Gollner A. Koutentis PA. J. Org. Chem. 2011; 76: 5113
• 76 Plodek A. König M. Bracher F. Eur. J. Org. Chem. 2015; 1302
• 77 Melzer B. Plodek A. Bracher F. J. Org. Chem. 2014; 79: 7239
• 78 Klatt T. Roman DS. León T. Knochel P. Org. Lett. 2014; 16: 1232
• 79 Klier L. Aranzamendi E. Ziegler D. Nickel J. Karaghiosoff K. Carell T. Knochel P. Org. Lett. 2016; 18: 1068
• 80 Klier L. Bresser T. Nigst TA. Karaghiosoff K. Knochel P. J. Am. Chem. Soc. 2012; 134: 13584
• 81 Groll K. Manolikakes SM. du Jourdin XM. Jaric M. Bredihhin A. Karaghiosoff K. Carell T. Knochel P. Angew. Chem. Int. Ed. 2013; 52: 6776
• 82 Wunderlich S. Knochel P. Chem. Commun. 2008; 6387
• 83 Unsinn A. Ford MJ. Knochel P. Org. Lett. 2013; 15: 1128
• 84 Ziegler DS. Greiner R. Lumpe H. Kqiku L. Karaghiosoff K. Knochel P. Org. Lett. 2017; 19: 5760