Deprotonative Coupling of Pyridines with Aldehydes Catalyzed by an HMDS-Amide Base Generated in Situ

Abstract

Herein, the deprotonative functionalization of pyridine derivatives with aldehydes under ambient conditions has been demonstrated using an amide base generated in situ from a catalytic amount of CsF and a stoichiometric amount of tris(trimethylsilyl)amine (N(TMS)₃). Pyridine substrates bearing two electron-withdrawing substituents (i.e., fluoro, chloro, bromo, and trifluoromethyl moieties) at the 3- and 5-positions efficiently react at the 4-position with various aldehydes including arylaldehydes, pivalaldehyde, and cyclohexanecarboxaldehyde.

Introduction

Pyridine is a key structural motif in pharmaceutical, agrochemical, and materials science. The deprotonative functionalization of pyridines with electrophiles has been widely used to synthesize a variety of pyridine derivatives.^1–10) Strong Brønsted bases such as n-BuLi, sec-BuLi, lithium diisopropylamide (LDA), and lithium tetramethylpiperidide (LiTMP) are employed in the deprotonation step to prepare the requisite pyridyl lithium species (Fig. 1a, upper scheme).^1–6) The reactions are usually performed under cryogenic conditions, which aim at inhibiting the temperature increase observed during this exothermic process and to restrain any side-reactions involving the lithiated species, such as nucleophilic addition onto an electrophilic substituent as well as the halogen dance reaction and aryne formation in the case of halogenated substrates. Protocols using milder bases, such as magnesium- and zinc-derived reagents, have also been developed, which can be conducted at near ambient conditions with high functional group tolerance (Fig. 1a, lower scheme).^6,7,11–23) However, the preparation of these reagents requires the use of stoichiometric amounts of several chemical reagents. Hence, further development of an efficient protocol to perform this transformation is still imperative in organic chemistry.

Fig. 1. Deprotonative Functionalization of Pyridine Derivatives with Electrophiles

Our group has previously reported the deprotonative functionalization of C–H bonds in pronucleophiles using a hexamethyldisilazide (HMDS)-amide base generated in situ using a catalytic amount of a fluoride or alkoxide salt and a stoichiometric amount of tris(trimethylsilyl)amine (N(TMS)₃).^24–34) The system efficiently catalyzes the reaction of heteroarenes, methyl(hetero)arenes, acetate, and terminal alkynes with electrophiles such as carbonyl and polyfluoroarene compounds. The heteroarenes employed in the reaction include five-membered heterocyclic compounds such as (benzo)thiophene, benzofuran, benzothiazole, and indole derivatives. Herein, we report that this reaction system is applicable toward the transformation of pyridine derivatives; for example, 3,5-dihalopyridines react with a variety of aldehydes (1.1 equiv) under ambient conditions (Fig. 1b).

Results and Discussion

At the beginning of this research project, the reaction conditions were investigated using 3,5-dibromopyridine (1a) and benzaldehyde (2a) as model substrates³⁵⁾ (Table 1). Among the fluoride salts examined, CsF was the most effective and formed the desired coupling product (3aa) in quantitative yield (entries 1-5). Alkoxide salts including NaOEt, NaO-t-Bu, and KO-t-Bu can also be used in the reaction, however, they were inferior to CsF (entries 6–8). CsCl and CsI did not give 3aa (entries 9 and 10). Subsequently, the solvent effect on the reaction was examined (entries 11–17). Using aprotic polar solvents such as N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), 1-methyl-2-pyrrolidone (NMP), and 1,3-dimethyl-2-imidazolidinone (DMI) afforded the target product in good yields, while the reaction did not proceed in tetrahydrofuran (THF), Et₂O, and toluene. Finally, when the reaction was conducted using decreased amounts of CsF (15 mol%) and N(TMS)₃ (1.5 equiv) for a shorter reaction time (6 h), 3aa was still isolated in a high yield (97%) (entry 18).

Table 1. Optimization of the Coupling Reaction between 1a and 2a^a)

Entry	Fluoride or alkoxide salt	Solvent	Yield (%)b)
1	KF	DMF	0
2	RbF	DMF	32
3	CsF	DMF	quant.
4	TMAFc)	DMF	38
5	TBATd)	DMF	93
6	NaOEt	DMF	69
7	NaO-t-Bu	DMF	85
8	KO-t-Bu	DMF	81
9	CsCl	DMF	0
10	CsI	DMF	0
11	CsF	DMA	76
12	CsF	DMSO	95
13	CsF	NMP	77
14	CsF	DMI	87
15	CsF	THF	trace
16	CsF	Et2O	0
17	CsF	Toluene	0
18	CsF	DMF	quant. (97)e,f)

a) Reactions were conducted on a 0.2 mmol scale. b) Yields were determined by ¹H-NMR analysis. c) Tetramethylammonium fluoride. d) Tetrabutylammonium difluorotriphenylsilicate. e) The yield reported in the parenthesis denotes the isolated yield. f) Reaction was conducted using CsF (15 mol%) and N(TMS)₃ (1.5 equiv) for 6 h.

With the optimal conditions in hand, the substrate scope of the reaction was investigated using a range of pyridine (1) and carbonyl (2) compounds (Fig. 2). 3,5-Dichloropyridine (1b) and 3,5-difluoropyridine (1c) coupled with 2a to provide the target products in 94 and 74% yields, respectively. 3-Chloro-5-(trifluoromethyl)pyridine (1d) also reacted with 2a to form the desired product in 42% yield. The reactions of 1a and 1b with pivalaldehyde (2b) furnished 3ab and 3bb in 98% and 94% yields, respectively. Mono-halogenated pyridines 1e and 1f were also employed in the reaction, however, the target products were produced in low yields (12% and 14%, respectively). Arylaldehydes other than 2a were also applied in the reaction. Ortho- and para-methyl-substituted 2c and 2d reacted with 1a to form 3ac and 3ad in 98 and 82% yields, respectively. Compounds 2e and 2f bearing electron-donating methoxy and dimethylamino groups also underwent the reaction to give their corresponding products in 91% and 80% yields, respectively. Chloro- and bromo-substituents were tolerated in the reaction and gave alcohols 3ag and 3ah in 92% and 80% yields, respectively. When employing substrate 2i bearing an ester moiety in the reaction, product 3ai was isolated in 45% yield. 2-Naphthaldehyde (2j) furnished product 3aj in 92% yield. Reaction of 2,6-dimethylbenzaldehyde (2k) also took place in 78% yield. The use of heteroarylaldehydes, 2-formylbenzothiophene (2l) and 3-formylpyridine (2m), led to the formations of 3al and 3am in 47% and 69% yields, respectively. Enolizable cyclohexanecarboxaldehyde (2n) was also used in the reaction and resulted in the formation of product 3an in 73% yield.³⁶⁾

Fig. 2. Substrate Scope of the Deprotonative Functionalization Reaction of Pyridine Derivatives^a,b)

^a) Reactions were conducted on a 0.2 mmol scale. ^b) Isolated yields. ^c) Reactions were conducted using CsF (20 mol %) and N(TMS)₃ (2.0 equiv).

The proposed mechanism for the deprotonative functionalization reaction is shown in Fig. 3. Initially, amide-base A is generated in situ from CsF and N(TMS)₃,³¹⁾ which performs the deprotonation of 1a to give pyridyl anion species B. Subsequently, B couples with 2a to form alkoxide C. Then, the reaction of C and N(TMS)₃ occurs to provide silyl ether D and regenerate A to complete the catalytic cycle.³⁷⁾

Fig. 3. Proposed Mechanism for the Deprotonative Functionalization of Pyridine Derivatives

In summary, a catalytic system consisting of an amide-base generated in situ allows the coupling of a range of pyridine derivatives to be performed under ambient conditions. 3,5-Dihalopyridines and 3-chloro-5-(trifluoromethyl)pyridine react efficiently under these reaction conditions. In addition, a diverse range of aldehydes, which include arylaldehydes bearing a variety of substituents (i.e., methyl, methoxy, dimethylamino, chloro, bromo, and ester moieties) and heteroarylaldehydes as well as pivalaldehyde and cyclohexanecarboxaldehyde, were used in the reaction.

Acknowledgments

This work was financially supported by JSPS KAKENHI Grant Number 19H03346 (YK), JSPS KAKENHI Grant Number 17K15419 (MS), JSPS KAKENHI Grant Number 19K06967 (MS), Grand for Basic Science Research Projects from The Sumitomo Foundation (MS), Yamaguchi Educational and Scholarship Foundation (MS), NIPPON SHOKUBAI Award in Synthetic Organic Chemistry, Japan (MS), and also the Platform Project for Supporting Drug Discovery and Life Science Research funded by Japan Agency for Medical Research and Development (AMED) (MS, KNK, and YK).

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

The online version of this article contains supplementary materials.

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