Palladium-catalyzed arylation of β-methylene C(sp³)–H bonds at room temperature: desymmetrization of simple cycloalkyl carboxylic acids

Abstract

A new protocol for Pd-catalyzed β methylene C–H arylation of N-quinolyl cycloalkylcarboxamides with aryl iodides at room temperature is reported. The β methylene C–H bonds of symmetrical cycloalkylcarboxamides of varied ring size can be arylated in moderate to good yields and monoselectivity with excellent diastereoselectivity. This mono-selective β methylene C–H arylation reaction enabled the rapid synthesis of complex carbocycle products from easily accessible symmetrical cycloalkyl carboxylic acids via sequential C–H functionalization.

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G. Chen

Gong Chen received his B.S. degree from Nanjing University in China, and his Ph.D. degree in bioorganic chemistry from Columbia University under the guidance of Professor Dalibor Sames. He then became a postdoctoral research fellow at the Memorial Sloan-Kettering Cancer Center with Professor Samuel Danishefsky. He joined the faculty at Pennsylvania State University in 2008 and recently took a faculty position at Nankai University in China. His research interests include the chemical synthesis and biological study of complex carbohydrates and peptides, as well as C–H functionalization methods.

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Reactions based on palladium-catalyzed sp³ C–H functionalization of aliphatic carboxamides bearing the aminoquinoline (AQ) auxiliary have quickly advanced over the past ten years.¹ Among these reactions, sp³ C–H arylation with aryl halides has been shown to be particularly useful for constructing various alkylarene motifs from readily available precursors.² Compared with other amide-linked directing groups, the AQ group is unique for its effectiveness at functionalizing β methylene C–H bonds of carboxamide substrates.^3–10 However, the high efficiency of methylene C–H functionalization in these AQ-directed reaction systems sometimes presents unique challenges. For instance, arylation of the Phth-protected AQ-coupled alanine substrate with aryl iodides under typical reaction conditions at elevated temperatures does not give mono-arylated β-aryl α-amino acids, but instead forms symmetrically β-di-arylated α-amino acids as the major products (Scheme 1A).^4a Recently, we demonstrated that mono-selective β C–H arylation of alanine substrates with aryl iodides could be achieved with high efficiency at room temperature via kinetic control.^6a Cycloalkyl carboxamides represent another class of useful substrates for Pd-catalyzed C–H arylation reactions.¹¹ Several groups have demonstrated that N-quinolyl cycloalkylcarboxamides can readily undergo β methylene C–H arylation, however β,β′-diarylated products are typically obtained (Scheme 1B).^3a,b,4d,7,8 Herein, we report a new protocol for Pd-catalyzed β methylene C–H arylation of N-quinolyl cycloalkylcarboxamides with aryl iodides at room temperature. The β methylene C–H bonds of symmetrical cycloalkylcarboxamides of varied ring size can be arylated in moderate to good yields and monoselectivity with excellent diastereoselectivity.

Scheme 1 Pd-catalyzed AQ-directed C(sp³)–H arylation.

As shown in Table 1, we commenced our study with arylation of cyclopentyl carboxamide 1 with 2 equiv. of 4-iodoanisole under various Pd-catalyzed conditions. Reaction of 1 under previously reported conditions at elevated temperatures gave the di-arylated product 2d as the major product (entries 1 and 2). Reaction of 1 under our room temperature conditions for C–H arylation of alanine with AgTFA in dioxane gave little product (entries 3–6).⁶ To our delight, further optimization revealed that the use of 1 equiv. of Ag₂CO₃ in dichloromethane (DCM) or 1,1,2,2-tetrachloroethane (TCE) at room temperature for 2 days gave the desired mono-arylated product 2m in excellent yield and selectivity (entry 7). Various carboxylic acid additives have no useful promoting effect (entries 12–14). DCM is used as a solvent in the subsequent experiments due to its lower cost and toxicity than TCE.

Table 1 Pd-catalyzed β-C(sp³)–H arylation of 1

Entry	Reagents (equiv.)	Solvents	t (°C)/time (h)	Yield^a (%)
				2m	2d
a Yields are based on ^1H-NMR analysis on a 0.2 mmol scale, under an ambient atmosphere. b Isolated yield.
1	AgOAc	Neat	70/24	<5%	73%
2	AgOAc (2)	Toluene	110/24	38%	62%
3	AgTFA (2)	Dioxane	rt/48	<5%	<5%
4	AgOAc (2), TFA (2)	Dioxane	rt/48	<5%	<5%
5	AgTFA (2)	tAmylOH	rt/48	<5%	<5%
6	AgTFA (2)	DCM	rt/48	<5%	<5%
7	Ag2CO3 (1)	DCM	rt/48	85 (80^b)	<5%
8	Ag2CO3 (1)	Toluene	rt/48	21	<5%
9	Ag2CO3 (1)	Dioxane	rt/48	11	<5%
10	Ag2CO3 (1)	tAmylOH	rt/48	15	<5%
11	Ag2CO3 (1)	TCE	rt/48	85	<5%
12	Ag2CO3 (1), TFA (1)	DCM	rt/48	<5%	<5%
13	Ag2CO3 (1), AcOH (1)	DCM	rt/48	71%	<5%
14	Ag2CO3 (1), PivOH (1)	DCM	rt/48	68%	<5%

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Next, we proceeded to evaluate the substrate scope of the Pd-catalyzed β C–H arylation of symmetric cycloalkyl carboxamides of varied ring size and other related structures under the optimized conditions at rt (Scheme 2). All C–H arylation reactions of symmetric cycloalkyl carboxamides provided exclusive cis diastereoselectivity under rt conditions. Electron rich aryl iodides gave higher arylation yield than electron deficient aryl iodides (e.g.2mvs.7m). Sterically more hindered aryl iodides gave lower yields (e.g.6m). The ring size has a notable effect on reactivity. Reactions of cyclopentyl carboxamide 1 gave moderate to good yields with excellent monoselectivity. Arylation of cyclobutyl carboxamides proceeded with higher yield but decreased mono-selectivity (see 8m and 8d). Reactions of cyclohexyl and cycloheptyl carboxamides had reactivity similar to cyclopentyl carboxamides, and proceeded with moderate yield and selectivity (see 11m and 14m). Cyclopropyl carboxamide 18 was completely unreactive. 2-Ethylbutyramide, the ring-opened analog of 1, gave comparable arylation yield but reduced mono- and diastereo-selectivity (see 15m). Interestingly, pivalamide 21 was completely unreactive under rt conditions.

Scheme 2 Substrate scope of the arylation at rt. (a) Isolated yield on a 0.2 mmol scale.

As shown in Scheme 3, several mono-arylated products were subjected to a sequential Pd-catalyzed, AQ-directed C–H functionalization including C–H arylation, alkylation, and alkenylation at the remaining β C–H position to give cycloalkyl products with three contiguous stereocenters with cis stereochemistry. Interestingly, the attempted acetoxylation of 11m resulted in the formation of the β-lactam product 26via intramolecular dehydrogenative C–H amination (IDCA) along with a small amount of the acetoxylated product 27.¹² Similarly, 9m can undergo IDCA to give a highly strained β-lactam 28 in high yield. As shown in Scheme 3E, the AQ group of the mono-arylated product 8m can be easily removed in two steps under mild conditions to give the carboxylic acid product 29.

Scheme 3 Pd-catalyzed sequential C–H functionalization of cycloalkyl carboxamides. (a) Isolated yields on a 0.2 mmol scale.

Previous work has suggested that AQ-directed, Pd-catalyzed C–H arylations with aryl iodides proceed through a Pd(II)/Pd(IV) catalytic cycle.^3b A primary KIE of ∼4.4 was observed from the parallel arylation of 30 and 1 with PhI under our rt conditions, suggesting that C–H palladation is the rate-limiting step (Scheme 4). This is in sharp contrast to a small KIE observed in our previously reported Pd-catalyzed C–H arylation of Phth-protected AQ-coupled alanine at rt.^6a As exemplified by the markedly different arylation performance of Boc protected trans- and cis-4-amino cyclohexanecarboxamides 31 and 33, the stereochemical configuration of cycloalkane rings strongly influences their reactivity towards C–H arylation. However, the details of this stereochemical influence are not clearly understood.

Scheme 4 Mechanistic observations.

In summary, we have developed a new protocol for Pd-catalyzed β methylene C–H arylation of N-quinolyl cycloalkylcarboxamides with aryl iodides that proceeds at room temperature. Symmetrical cycloalkylcarboxamides of varied ring size can be arylated at the β methylene C–H position in good yield and with good mono- and diastereo-selectivity. This β mono-selective methylene C–H arylation enabled the rapid synthesis of complex carbocycle products from easily accessible symmetrical cycloalkyl carboxylic acids via sequential C–H functionalization. Further experiments concerning other C–H functionalization reactions of cycloalkylcarboxamides, as well as mechanistic studies, are underway.

We gratefully thank Pennsylvania State University and Nankai University for financial support of this work.

Notes and references

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2. Selected examples of auxiliary-directed Pd-catalyzed C(sp³)–H arylation with Ar–X: (a) N. Rodríguez, J. A. Romero-Revilla, M. Á. Fernández-Ibáñez and J. C. Carretero, Chem. Sci., 2013, 4, 175; (b) M. Fan and D. Ma, Angew. Chem., Int. Ed., 2013, 52, 12152; (c) Q. Zhang, K. Chen, W. Rao, Y. Zhang, F.-J. Chen; and B.-F. Shi, Angew. Chem., Int. Ed., 2013, 52, 13588; (d) J. He, S. Li, Y. Deng, H. Fu, B. N. Laforteza, J. E. Spangler, A. Homes and J.-Q. Yu, Science, 2014, 343, 1216; (e) C. Wang, C. Chen, J. Zhang, J. Han, Q. Wang, K. Guo, P. Liu, M. Guan, Y. Yao and Y.-S. Zhao, Angew. Chem., Int. Ed., 2014, 53, 9884; (f) Y.-F. Zhang, H.-W. Zhao, H. Wang, J.-B. Wei and Z.-J. Shi, Angew. Chem., Int. Ed., 2015, 54, 13686; (g) K. Chen, Z.-W. Li, P.-X. Shen, H.-W. Zhao and Z.-J. Shi, Chem. – Eur. J., 2015, 21, 7389.
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Footnote

† Electronic supplementary information (ESI) available. CCDC 1451082. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5qo00421g

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