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Letter
Nickel-Catalyzed Reductive Transamidation of Secondary Amides with Nitroarenes Chi Wai Cheung, Marten Ploeger, and Xile Hu ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02859 • Publication Date (Web): 18 Sep 2017 Downloaded from http://pubs.acs.org on September 19, 2017
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ACS Catalysis
Nickel-Catalyzed Reductive Transamidation of Secondary Amides with Nitroarenes Chi Wai Cheung, Marten Leendert Ploeger, and Xile Hu* Laboratory of Inorganic Synthesis and Catalysis, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), ISIC-LSCI, BCH 3305, Lausanne 1015 (Switzerland) ABSTRACT: Transmidation is an attractive method for amide synthesis. However, transamidation of secondary amides is challenging. Here, we describe a reductive transamidation method that employs readily available nitro(hetero)arenes as the nitrogen sources, zinc or manganese as reductant, and simple nickel salt and ligand as catalyst system. The scope of amides includes both alkyl and aryl secondary amides, with high functional group compatibility.
KEYWORDS: transamidation, nickel catalysis, reductive coupling, amide synthesis, nitroarenes
Amides are ubiquitous in nature and are among the most important functional molecules in industries.1,2 The prevalence and stability of amides make them attractive reagents in organic synthesis.3 Among various transformations of amides, transamidation is particularly useful as it provides a direct and rapid means to diversify amides. However, the amide C-N bond is very strong and difficult to cleave due to the resonance stabilization.1,4,5 While efficient catalytic methods are available for the transamidation of primary amides,3a,6 secondary transamidation remains challenging because this process is mostly thermo-neutral and tends to give an equilibrium mixture of reagent and product amides (Figure 1a).7,8 Recently, Garg and co-workers reported a two-step approach to effect transamidation of secondary aryl9 and alkyl10 amides (Figure 1b). By activating the amides with tert-butyloxycarbonyl (Boc) group using di-tert-butyl carbonate (Boc2O), transamidation with amines was achieved using nickel catalysis. Szostak and coworker showed that transamidation of similar Boc-activated aryl amides with alkylamines and arylamines could be obtained using 3 equivalents of Et3N as promotor11 and Pd12 catalysis, respectively (Figure 1b). These recent developments have considerably advanced the transamidation methodology.
We13,14 and others15 have recently reported amination and amidation reactions using nitroarenes as the nitrogen sources. Compared to anilines, nitroarenes are more attractive nitrogen sources thanks to their lower cost, easier accessibility, and higher stability.13-15 Here, we describe a method for transamidation with nitroarenes under reductive conditions (Figure 1c). Both Boc-activated secondary alkyl and aryl amides are suitable substrates. Broad scope and high functional group tolerance are demonstrated.
Figure 1. Various methods of transamidation.
In our previous work on Ni-catalyzed amidation of esters with nitroarenes,14 we identified diazoarene as the most probable intermediate, which was formed by reduction of a nitroarene with zinc in the presence of chlorotrimethylsilane (TMSCl). This intermediate then reacted with a Ni(0) species to give a Ni(II) nitrene-type species, which then reacted with an ester to give an amide (Figure 2). An analogous Nicatalyzed reductive transamidation with nitroarenes might be developed if amides can be used as the substrates in place of esters (Figure 2). This replacement is not trivial because amides are normally more inert than esters.
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likely in the deprotonated forms, did not interfere the transamidation, again suggesting that the reactions did not involve anilines as intermediates. While amides bearing primary alkyl substituents transamidate smoothly, the use of amides bearing more sterically bulky secondary alkyl groups were problematic, due to the difficulty in preparation of bulky Boc-activated amide substrates or the low yields of transamidation products.
Table 1. Optimization of reductive transamidation of Bocactivated secondary alkyl amide. Figure 2. Proposed mechanisms for Ni-catalyzed reductive amidation and transamidation with nitroarene.
Inspired by the two-step approach of transamidation of Garg et al.,9,10 we initially focused on transamidation of Bocactivated N-benzyl decanoamide (1a) with nitrobenzene (2a). The conditions for amidation of esters with nitroarenenes14 were the starting point of optimization. After screening of various reaction parameters, the optimized conditions were found to involve N-methyl-2-pyrrolidone (NMP) as solvent, Ni(glyme)Cl2 (10 mol %) as catalyst, 1,10-phenanthroline (phen, 10 mol %) as ligand, Zn powder (5 equiv) as reductant, and chlorotrimethylsilane (TMSCl, 1.5 equiv) as additive (Table 1, entry 1). The optimal loading of 2a was 1.5 equiv., and the reaction was completed after 16 h at 100 oC. After an acidic workup, the desired amide product, N-phenyl decanoate, was obtained in 80% yield (Table 1, entry 1). Table 1 and Table S1 in the Supporting Information lists the yields obtained when the reaction parameters were systemically varied. Whereas the influence of ligands in the yields of reaction was small (Table 1, entries 2-7), both the Ni catalyst and TMSCl were essential (Table 1, entries 16 and 17). Other anhydrous Ni salts such as Ni(diglyme)Br2 and NiCl2 could be used as catalysts, leading to slightly lower yields (Table 1, entries 8 and 9). However, FeBr2, CoBr2, CuBr2, and Mn(OTf)2 (OTf = triflate) were all much inferior catalysts (Table 1, entries 1013). The use of Mn reductant instead of Zn resulted in a lower yield (Table 1, entry 14). Because some reduction of nitrobenzene to aniline was occurring as a side reaction, a slight excess (1.5 equiv.) of nitrobenzene was needed. Lowering the loading of nitrobenzene led to a diminished yield (Table 1, entry 15). When aniline was used instead of 2a, the yield was below 30% (Table 1, entries 18 and 19), consistent with the previous result indicating diazobenzene rather than aniline as the intermediate in the analogous amidation reaction of esters.14 The optimization conditions in Table 1 could be applied for the transamidation of various secondary alkyl amides bearing a Boc group (Figure 3). Both non-functionalized and functionalized alkyl groups on the amide reaction partners could be tolerated (P1-P7, 3a-3o). Heterocyclic groups such as quinoline (3a), benzothiophene (3b), pyrazole (3c), benzoxazole (3d), and indole (3e) could also be included in the nitroarene partners. Sterically-encumbered, ortho-substituted nitroarene was also a suitable substrate (3o). Functional groups, including olefins (3i, 3j), chloroalkyl (3l), chloroaryl (3m), ketone (3n), ether (P-5, 3g), thio (P-6, 3h), and trifluoromethyl groups (P7), were compatible. In some of these transamidation reactions, amines originated from the starting amide reagents could be observed after the workup. Apparently, these amines,
entry
variation from ‘standard conditions’
1 2
none L2 instead of L1
3
L3 instead of L1
4
L4 instead of L1
5
L5 instead of L1
6
L6 instead of L1
7
L7 instead of L1
8
Ni(diglyme)Br2 instead of Ni(glyme)Cl2
9
NiCl2 instead of Ni(glyme)Cl2
10
FeBr2 (10 mol %) instead of Ni(glyme)Cl2 CoBr2 (10 mol %) instead of Ni(glyme)Cl2 CuBr2 (10 mol %) instead of Ni(glyme)Cl2 Mn(OTf)2 (10 mol %) instead of Ni(glyme)Cl2 Mn instead of Zn PhNO2 (1.3 equiv) instead of (1.5 equiv) No Ni(glyme)Cl2 no TMSCl PhNH2 instead of PhNO2 PhNH2 instead of PhNO2b
11 12 13 14 15 16 17 18 19
yield/%a 80
63 78 60 67 61 55 71 70 25 27 9 7 47 66 6
