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Synlett 2021; 32(16): 1642-1646
DOI: 10.1055/a-1517-5895
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Modern Nickel-Catalyzed Reactions

Nickel-Catalyzed Oxidative Transamidation of Tertiary Aromatic Amines with N-Acylsaccharins

Shengzhang Liu‡
a   College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, Jiangxi 330022, P. R. of China
,
Lingyun Yang‡
a   College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, Jiangxi 330022, P. R. of China
,
Jiasi Tao
a   College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, Jiangxi 330022, P. R. of China
,
Weijie Yu
a   College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, Jiangxi 330022, P. R. of China
,
Tao Wang∗
a   College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, Jiangxi 330022, P. R. of China
b   National Research Center for Carbohydrate Synthesis, Jiangxi Province’s Key Laboratory of Chemical Biology, Jiangxi Normal University, Nanchang, Jiangxi 330022, P. R. of China
,
Junkai Fu  ∗
a   College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, Jiangxi 330022, P. R. of China
b   National Research Center for Carbohydrate Synthesis, Jiangxi Province’s Key Laboratory of Chemical Biology, Jiangxi Normal University, Nanchang, Jiangxi 330022, P. R. of China
› Author Affiliations

We gratefully acknowledge financial support from the National Natural Science Foundation of China (21762025, 21562026) and the Key Projects of Natural Science Foundation of Jiangxi Province (20192ACBL20026).
› Further Information
 
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Abstract

The use of tertiary amines as surrogates for secondary amines has prominent advantages in terms of stabilization and ease of handling. A Ni-catalyzed transamidation of N-acylsaccharins with tertiary aromatic amines is reported. By using tert-butyl hydroperoxide as the terminal oxidant, this reaction permits selective cleavage of the C(sp3)–N bonds of unsymmetrical tertiary aromatic amines depending on the sizes of the alkyl substituents.


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Key words

transamidation - nickel catalysis - amides - tertiary amines - C–N bond cleavage

Due to the prevalence of amides in protein chemistry, organic synthesis, drug discovery, and polymer chemistry,[1] the development of methods for the construction of amide bonds is consistently a hot topic for chemists.[2] Conventional methods for accessing amides rely on condensation of carboxylic acids with secondary or primary amines (Scheme [1a]).[3] However, this reaction is considered challenging due to competing acid–base interactions. Consequently, prefunctionalized carboxylic acid derivatives are frequently employed, or a stoichiometric coupling reagent is needed to activate the carboxylic acid component and to drive the dehydration reaction.[4] Moreover, the amine component is difficult to separate and purify and it is easily oxidized when exposed to air. In this context, searching for supplementary methods to construct C–N bonds and, ultimately, to obtain amides is deemed a worthy pursuit.

Zoom Image
Scheme 1 Transamidation with tertiary aromatic amines

Transamidation has recently emerged as a convenient and straightforward alternative strategy for preparing amides that avoids the use of carboxylic acids.[5] The high stability of the readily available amide component means that the amide moiety can undergo multistep transformations and can serve as an acyl resource in late-stage modifications of molecules. However, a concomitant challenge lies in the difficulty of activating inert N−C(O) amide bonds as a result of nN→π*C=O conjugation.[1a] [6] This issue was overcome by Kirby and co-workers,[7] Tani and Stoltz,[8] and others[9] through the design of conformationally locked bridged lactams to disrupt the amide bond resonance. In recent years, another tool has emerged, that of steric and electronic distortion of N−C(O) amide bonds.[10] The pioneering work by Meng and Szostak[11] and by the Garg group[12] showed that acyclic nonplanar N−C(O) bonds can be activated by transition metals (e.g., Pd or Ni) to serve as new acyl or aryl sources. Subsequently, a great deal of elegant work on transamidation of nonplanar amides by other secondary or primary amines has emerged from the groups of Szostak,[13] Lee,[14] Garg,[15] and others.[16]

Attracted by this beautiful chemistry, we wonder whether secondary amine components in transamidations could be replaced by readily available tertiary amines, which would be more stable and more readily available. It is well known that tertiary amines can be degraded to the corresponding secondary amines under oxidative conditions.[17] [18] During our researches, Lee and co-workers reported the first example of the transamidation of nonplanar amides with symmetrically substituted tertiary alkylamines with a Pd catalyst and di-tert-butyl peroxide (DTBP; Scheme [1b]).[19] However, no study has been reported of the corresponding reaction of unsymmetrically substituted tertiary amines, which might produce a mixture of amide products due to the difficulties in the selective cleavage of C(sp3)–N bonds. Here, we reported a supplementary method for the transamidation of N-acylsaccharins and tertiary aromatic amines with a Ni catalyst[20] and tert-butyl hydroperoxide (TBHP) as the terminal oxidant. One major advantage of this method is that it permits selective C(sp3)–N bond cleavage of unsymmetrically substituted tertiary amines depending on the size of the alkyl substituents, to deliver single amide products.

We began our optimization investigations by studying the reaction of N-benzoylsaccharin (1a) with N,N-dimethylaniline (2a)[21] in the presence of Ni(OAc)2 and TBHP (70% wt. aqueous) in stirred chlorobenzene at 100 °C for 12 hours. This gave the corresponding amide 3a in 28% yield (Table [1], entry 1). In an attempt to increase the yield, various nickel salts were tested (entries 2–4). The reaction with NiCl2 gave a similar yield of 30%, whereas Ni(acac)2 proved to be inefficient. Fortunately, the yield was improved to 54% when Ni(OTf)2 was used. When carried out with a palladium catalyst, the reaction gave a low yield of 19% (entry 5). The choice of solvent was found to be crucial for the efficiency of this reaction (entries 6–10). Moderate yields of 44% and 47% were obtained in acetonitrile and tetrahydrofuran, respectively, whereas none of the desired amide product 3a was detected for the reactions in DMSO or toluene. However, a good yield of 68% was obtained when the reaction was carried out in 1,4-dioxane. The oxidant is an essential component for the reaction, so various oxidants were then tested. The strong oxidant K2S2O8 proved to be ineffective for this reaction and most of the substrate 1a was recovered (entry 11). Mild oxidants such as DDQ, H2O2, and DTBP, or an oxygen atmosphere gave product 3a in yields of 16–44% (entries 12–15). When the reaction was exposed to air without any additional oxidant, only a trace of the desired product 3a was obtained (entry 16). Concomitantly, the reaction temperature was also shown to be fairly significant in ensuring a satisfactory yield (entries 17–18). The reaction at 80 °C gave a slightly lower yield of 66%, whereas the desired reaction pathway was totally suppressed at room temperature. In addition, the reaction yield was further improved to 76% by increasing the loading of the Ni catalyst to 10 mol% (entry 19), whereas a control experiment in the absence of Ni catalyst afforded only a trace of the desired product, showing the importance of the nickel salt for the transformation (entry 20). Thus, the optimal conditions involved treating substrates 1a and 2a with 10 mol% Ni(OTf)2 and 1.5 equivalents of TBHP in 1,4-dioxane at 100 °C under a nitrogen atmosphere for 12 hours.[22]

Table 1 Screening of the Reaction Conditionsa

Entry

Catalyst

Solvent

Oxidant

Temp (°C)

Yieldb (%)

 1

Ni(OAc)2

PhCl

TBHP

100

28

 2

NiCl2

PhCl

TBHP

100

30

 3

Ni(acac)2

PhCl

TBHP

100

 0

 4

Ni(OTf)2

PhCl

TBHP

100

54

 5

PdCl2

PhCl

TBHP

100

19

 6

Ni(OTf)2

CH3CN

TBHP

 80

44

 7

Ni(OTf)2

THF

TBHP

 60

47

 8

Ni(OTf)2

DMSO

TBHP

100

 0

 9

Ni(OTf)2

toluene

TBHP

100

 0

10

Ni(OTf)2

1,4-dioxane

TBHP

100

68

11

Ni(OTf)2

1,4-dioxane

K2S2O8

100

 0

12

Ni(OTf)2

1,4-dioxane

DDQ

100

16

13

Ni(OTf)2

1,4-dioxane

O2

100

44

14

Ni(OTf)2

1,4-dioxane

H2O2

100

38

15

Ni(OTf)2

1,4-dioxane

DTBP

100

43

16

Ni(OTf)2

1,4-dioxane

air

100

trace

17

Ni(OTf)2

1,4-dioxane

TBHP

 r.t.

 0

18

Ni(OTf)2

1,4-dioxane

TBHP

 80

66

19c

Ni(OTf)2

1,4-dioxane

TBHP

100

76

20

–

1,4-dioxane

TBHP

100

trace

a Reaction conditions: 1a (0.2 mmol), 2a (0.22mmol), nickel salt (5 mol%), oxidant (0.3 mmol), solvent (3 mL), under N2, 12 h.

b Isolated yield.

c Ni(OTf)2 (10 mol%).

To investigate the activating effect of substituents on the nitrogen atom of the amide, several frequently used nonplanar amides were evaluated (Scheme [2]). Whereas N-benzoylsaccharin (1a) exhibited a high reactivity, N-benzoylglutarimide (1a-I), containing a highly distorted amide bond,[23] gave the desired transamidation product 3a in only 18% yield, showing a distinction between the present method and Idris and Lee’s Pd-catalyzed system.[19] Under the standard reaction conditions, two other nonplanar amides, N-benzoylphthalimide (1a-II) and N-phenyl-N-tosyl-benzamide (1a-III), gave 3a in yields of 34 and 10%, respectively, whereas N,N-di-Boc-benzamide (1a-IV) and N-benzoylpyrazole (1a-V) all failed to give the desired transamidation product.

Zoom Image
Scheme 2 Tests with various nonplanar amides

Having established the standard reaction conditions, we explored the substrate scope with a variety of N-acylsaccharins 1 (Scheme [3]). N-Benzoylsaccharin derivatives with electronically neutral substituents (e.g., methyl or butyl groups) on the phenyl rings all reacted with N,N-dimethylaniline (2a) to give the desired amides 3b–d in good yields. The effects of electron-donating (methoxy) or electron-withdrawing (chloro or bromo) substituents on the benzoyl moiety were then evaluated. The amides all underwent transamidation with N,N-dimethylaniline to produce the corresponding amides 3e–g in yields of 65–70%. Because of the prevalence of fluorine-containing motifs and their ability to modulate such molecular properties as lipophilicity, permeability, pharmacokinetics, and metabolic stability,[24] we tested several fluorine-containing N-benzoylsaccharins. 4-Fluorobenzoyl, perfluorobenzoyl, and 4-trifluoromethylbenzoyl derivatives were successfully transformed into the amides 3h–j. In addition, this transformation was compatible with N-naphthoylsaccharin and several heteroaromatic-ring-based N-acylsaccharins, including furyl, thienyl, 2-bromofuryl, and 2-chlorothienyl derivatives, giving amides 3k–o. Note that the R group in amide substrates 1 was not limited to an aryl group, but could also be an alkyl group; for example, the benzyl derivative gave product 3p in 68% yield.

Zoom Image
Scheme 3 Substrate scope of N-acyl saccharins. Reagents and conditions: 1 (0.2 mmol), 2a (0.22mmol), Ni(OTf)2 (10 mol%), TBHP (0.3 mmol), 1,4-dioxane (3 mL), under N2, 100 °C, 12 h. Isolated yields are reported.

Next, the reactions of a range of tertiary aromatic amines 2 with N-acylsaccharins 1 were examined (Scheme [4]). First, effects of substituents on the aromatic ring of the N,N-dimethylaniline were investigated. The para-, meta-, and ortho-methyl N,N-dimethylanilines 2b–d all reacted readily with N-benzoylsaccharin (1a) to give the corresponding amides 4a–c in good yields, showing there was little steric influence on this transamidation. Fluoro or chloro atoms could also be incorporated in the aromatic amine substrate to give amide products 4d and 4e in yields of 78 and 60%, respectively. Moreover, N,N-diethylaniline (2g) underwent cleavage of an ethyl group to give amide 4f. For unsymmetric tertiary aromatic amines, one major advantage of this method lies in the selective cleavage of the C(sp3)–N bonds. When N-methyl-N-ethylaniline (2h) was subjected to the standard reaction conditions, the methyl group was selectively cleaved to give 4f as a single product. This selectivity was also observed for N-methyl-N-butylaniline 2i and N-ethyl-N-butylaniline 2j, in which the smaller methyl or ethyl group was cleaved in the presence of the larger butyl group to give the common product 4g. Amide 4g could also be accessed in 57% yield by the reaction of N,N-dibutylaniline (2k) with N-benzoylsaccharin. N,N-Dimethylaniline derivatives reacted with heteroaromatic ring-based N-acylsaccharins, demonstrating a potential application of this transformation in complex systems. N,N,3-Trimethylaniline (2c) underwent transamidation with N-(2-thienoyl)saccharin or its 5-chloro derivative to afford amides 4h and 4i, respectively, whereas the reaction of the N,N-dimethylaniline derivative 2l bearing a free para-hydroxy group led to the formation of 4j. The reaction of N-ethyl-N,4-dimethylaniline (2m) with heteroaromatic ring-based N-acylsaccharins again showed selective cleavage of the smaller methyl group to provide the corresponding amide products 4k–m.

Zoom Image
Scheme 4 Substrate scope of tertiary aromatic amines. Reagents and conditions: 1 (0.2 mmol), 2 (0.22 mmol), Ni(OTf)2 (10 mol%), TBHP (0.3 mmol), 1,4-dioxane (3 mL), under N2, 100 °C, 12 h. Isolated yields are reported.

Under the standard reaction conditions in the absence of N-benzoylsaccharin (1a), N,N-dimethylaniline (2a) gave a trace amount of N-methylaniline, which could be detected by GC (Scheme [5]), This showed that dealkylation of the N,N-dimethylaniline occurred, possibly in equilibrium, when further transformation was hampered. Based on this experimental result and previous reports in the literature,[10] [20] a plausible mechanism is proposed for this transformation. Ni(II) salt is first reduced by TBHP to generate an active Ni(I) catalyst and a tert-butylperoxyl radical. The tert-butylperoxyl radical then abstracts hydrogen from the tertiary aromatic amine 2 to generate a radical I.[18d] [25] Intermediate I can be further oxidized by TBHP to form a carbon cation II, which exists in equilibrium with the iminium compound III. The accompanying tert-butoxyl radical reacts with another TBHP molecule to regenerate a tert-butylperoxyl radical with the release of tert-butanol. Iminium III is readily hydrolyzed to produce an aldehyde and a secondary amine IV. This secondary amine undergoes a ligand exchange with the Ni(III) intermediate V, formed by oxidative addition of Ni(I) to the nonplanar amide 1, to give intermediate VI.[20] Finally, reductive elimination of VI leads to the formation of the amide product 3 or 4 with regeneration of the Ni(I) catalyst.

Zoom Image
Scheme 5 Control experiment and the proposed mechanism

In summary, we have developed a Ni-catalyzed transamidation of N-acylsaccharins with tertiary aromatic amines. TBHP was employed as the terminal oxidant to drive the tertiary aromatic amines as surrogates for secondary amines. In the case of unsymmetric tertiary aromatic amines, this reaction protocol features a selective cleavage of the C(sp3)–N bonds, leading to the formation of single transamidation products. Further mechanistic studies focusing on the origin of this cleaving selectivity are in progress in our laboratory.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1517-5895.
  • Supporting Information

Corresponding Authors

Tao Wang
National Research Center for Carbohydrate Synthesis, Jiangxi Province’s Key Laboratory of Chemical Biology, Jiangxi Normal University
Nanchang, Jiangxi 330022
P. R. of China   

Jukai Fu
College of Chemistry and Chemical Engineering, Jiangxi Normal University
Nanchang, Jiangxi 330022
P. R. of China   

Publication History

Received: 30 April 2021

Accepted after revision: 25 May 2021

Accepted Manuscript online:
25 May 2021

Article published online:
09 June 2021

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Zoom Image
Scheme 1 Transamidation with tertiary aromatic amines
Zoom Image
Scheme 2 Tests with various nonplanar amides
Zoom Image
Scheme 3 Substrate scope of N-acyl saccharins. Reagents and conditions: 1 (0.2 mmol), 2a (0.22mmol), Ni(OTf)2 (10 mol%), TBHP (0.3 mmol), 1,4-dioxane (3 mL), under N2, 100 °C, 12 h. Isolated yields are reported.
Zoom Image
Scheme 4 Substrate scope of tertiary aromatic amines. Reagents and conditions: 1 (0.2 mmol), 2 (0.22 mmol), Ni(OTf)2 (10 mol%), TBHP (0.3 mmol), 1,4-dioxane (3 mL), under N2, 100 °C, 12 h. Isolated yields are reported.
Zoom Image
Scheme 5 Control experiment and the proposed mechanism