Rhenium and base co-catalyzed [3 + 2] annulations of N–H ketimines and alkynes to access unprotected tertiary indenamines through C–H bond activation

Abstract

Herein, a rhenium-catalyzed [3 + 2] carbocyclization of N–H ketimines and alkynes through C–H bond activation to afford unprotected tertiary indenamines is described. Notably, the catalytic use of a cheap base, sodium carbonate, was demonstrated to be crucial to the success of this reaction. The protocol is also highlighted by a high atom-economy, a broad substrate scope, and excellent regioselectivity for unsymmetrical alkynes.

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Congyang Wang

Congyang Wang was born in Jiangsu province, China in 1977. He obtained his BS degree from Nanjing University in 2000 and a Ph.D. degree from Peking University under the guidance of Professor Zhenfeng Xi in 2005. After a postdoctoral stay of two more years in the same group, he moved to the University of Münster, Germany working with Professor Frank Glorius as an Alexander von Humboldt Research Fellow. In 2010, he started his independent research at the Institute of Chemistry, Chinese Academy of Sciences (ICCAS) as a professor. His research interests include organometallic chemistry, transition metal catalysis, and synthesis of functional molecules. Currently, his group is focusing on manganese-group-metal catalysis.

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Due to the ubiquitous nature of C–H bonds in organic compounds and the inherent atom- and step-economies of direct C–H bond transformations, C–H bond activation has recently attracted immense efforts from chemical communities. As a result, it has evolved as an important tool for new chemical bond formation and the efficient construction of complex molecules. Transition metal catalysis is among the most powerful tool kits for C–H bond activation because of the versatile modes of C–H bond breakage promoted by transition metal catalysts, such as oxidative addition, concerted metalation/deprotonation, σ-bond metathesis, and so on.¹ Late transition metal (e.g. Pd, Rh, Ru, Ir) catalysts are the predominant players in this field and have witnessed an explosive progress in a large variety of C–H activation reactions during the past three decades.¹ In sharp contrast, early transition metal compounds are far less explored as efficient catalysts for C–H bond transformations. As a prominent example of early transition metals, rhenium has demonstrated intriguing reactivity toward inert C–H bond activation in particular for cyclization reactions.^2–4 In 2005, Takai and Kuninobu et al. reported rhenium-catalyzed annulations of aromatic aldimines and alkynes leading to conjugated indenamines via a C–H addition/cyclization/isomerization sequence (Scheme 1a).⁴ An oxidative addition pathway was proposed for the C–H bond activation step in this reaction. Very recently, we have reported manganese-catalyzed [4 + 2] annulations of N–H ketimines and alkynes to approach diverse isoquinolines with the evolution of hydrogen gas (Scheme 1b).^5a,6 Of note, only MnBr(CO)₅ was used as the catalyst for this reaction without the need for any oxidant, external ligand, or additive. It remains a question whether the reaction of N–H ketimines and alkynes employing a congeneric rhenium catalyst would form the same isoquinoline products via [4 + 2] annulation or, alternatively, indenamine products through [3 + 2] cyclization. To address this query and based on our continuous interest in rhenium-catalysis,^3,7 herein we describe rhenium-catalyzed [3 + 2] annulations of N–H ketimines and alkynes to access unprotected indenamines bearing a quaternary carbon center (Scheme 1c).^8,9 Importantly, the catalytic use of a cheap base, sodium carbonate, is essential to the success of this transformation. Mechanistically, a base-assisted deprotonation pathway operates in the key C–H activation step, which is in sharp contrast to the previous work in Scheme 1a.⁴ Also, the reaction features a high atom-economy, excellent regioselectivity for unsymmetrical alkynes, and a broad substrate scope for both ketimines and alkynes.

Scheme 1 Manganese-group-metal catalyzed annulations of imines and alkynes via C–H bond activation. (a) Re-catalyzed annulations of aldimines and alkynes: Kuninobu and Takai. (b) Mn-catalyzed annulations of N–H ketimines and alkynes: our previous work. (c) Re-base co-catalyzed annulations of N–H ketimines and alkynes: this work.

At the outset, we selected the model reaction of ketimine 1c and diphenylacetylene 2a to screen the reaction parameters (Table 1).¹⁰ No products were observed with the mere use of ReBr(CO)₅ as a catalyst (entry 1). Inspired by our recent findings on acetate-accelerated Re-catalyzed C–H activation reactions,^3c,e we tested the addition of a series of different bases in the current reaction. To our delight, with a 30 mol% amount of NaOAc the [3 + 2] annulation product 3ca was obtained in 20% ¹H NMR yield without the formation of the [4 + 2] cyclization product 4ca (entry 2), which is in contrast to the reaction catalyzed by MnBr(CO)₅.⁵ It was further shown that strong bases were detrimental to the reaction (entries 3–6), while relatively weak bases gave better results with Na₂CO₃ being the optimal (entries 7–10). Variations on the solvents showed that the use of 1,4-dioxane gave a nearly quantitative yield of 3ca comparable to that in THF (entries 11–13).¹⁰ As a result, 1,4-dioxane was selected as the optimal solvent because of its suitable boiling point for the reaction. Other rhenium and manganese carbonyl catalysts gave no better results in the reaction (entries 14–16). Further tunings on the reaction conditions demonstrated that the catalyst loading could be lowered to 2.5 mol% while maintaining equal reactivity (entry 17). Finally, 3ca was isolated as a pure compound in 95% yield. Of note, no excessive amount of either ketimine 1c or alkyne 2a was required in this reaction.

Table 1 Optimization of reaction conditions^a

Entry	Cat. (5 mol%)	Additive (30 mol%)	Solvent	Yield of 3ca ^b (%)
a Reaction conditions unless otherwise noted: 1c (0.2 mmol), 2a (0.2 mmol), catalyst (0.01 mmol), base (0.06 mmol), solvent (2 mL), 150 °C, 24 h. b Yields determined by ^1H NMR analysis with an internal standard. c 140 °C. d No additive. e Isoquinoline 4ca was formed in 21% ^1H NMR yield. f ReBr(CO)5 (2.5 mol%). g Isolated yield on the 1.0 mmol scale. PMP = p-methoxyphenyl.
1^c	ReBr(CO)5	—^d	THF	0
2^c	ReBr(CO)5	NaOAc	THF	20
3^c	ReBr(CO)5	PhLi	THF	0
4^c	ReBr(CO)5	PhMgBr	THF	0
5^c	ReBr(CO)5	NaH	THF	Trace
6^c	ReBr(CO)5	KO^tBu	THF	Trace
7^c	ReBr(CO)5	LiO^tBu	THF	85
8^c	ReBr(CO)5	Cs2CO3	THF	54
9^c	ReBr(CO)5	CsF	THF	96
10^c	ReBr(CO)5	Na2CO3	THF	98
11	ReBr(CO)5	Na2CO3	Toluene	87
12	ReBr(CO)5	Na2CO3	1,4-Dioxane	98
13	ReBr(CO)5	Na2CO3	DMSO	88
14	ReCl(CO)5	Na2CO3	1,4-Dioxane	61
15	Re2(CO)10	Na2CO3	1,4-Dioxane	74
16	MnBr(CO)5	Na2CO3	1,4-Dioxane	Trace^e
17^f	ReBr(CO)5	Na2CO3	1,4-Dioxane	97 (95)^g

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With the optimized conditions in hand, we first examined the reaction scope with regard to N–H ketimines as shown in Scheme 2. Both electron-donating and -withdrawing groups on the benzene moiety of N–H ketimines were well tolerated leading to products 3aa–ea in moderate to excellent yields. It was shown that electron-rich ketimines had better reactivity than the electron-deficient ones. Primary, secondary, and tertiary alkyl aryl N–H ketimines with increasing steric hindrance were all suitable substrates for this reaction giving the corresponding products 3fa–ha smoothly. The ortho-methyl substituent had no severe influence on the reaction yield of 3ia, which contrasted obviously with the reaction of aldimines and alkynes.⁴ When meta-substituted aromatic ketimine 1j was employed in the reaction, the sterically less congested C–H bond was preferably annulated affording indenamine 3ja as the major product. Of note, two regioisomeric products 3ka and 3ka′ were formed in the case of the unsymmetrical diaryl ketimine 1k. Finally, conjugated indenamine 3la was also obtained successfully from the annulation of aldimine 1l and diphenylacetylene 2a under slightly modified conditions.⁴

Scheme 2 Substrate scope of N–H ketimines. ^aReaction conditions: 1 (1.0 mmol), 2a (1.0 mmol), ReBr(CO)₅ (2.5 mol%), Na₂CO₃ (30 mol%), 1,4-dioxane (1.5 mL), 150 °C, 24 h. ^bIsolated yields of 3 are shown. ^cRe₂(CO)₁₀ (2.5 mol%) was used.

Next, we explored the substrate scope of alkynes with ketimine 1c as the reaction partner (Scheme 3). It turned out that the electronic variations on the diaryl alkynes showed no obvious effect on the reaction outcome (3cb and 3cc). Importantly, halogen functionalities such as F, Cl, and Br were all compatible with the reaction conditions (3cd–f). ortho- and meta-substituted diaryl alkynes gave the corresponding products successfully (3cg–h). As an example of heteroaryl alkynes, dithiophenylacetylene delivered the expected indenamine (3ci) in excellent yield. Furthermore, perfect regioselectivity was obtained when unsymmetrical aryl alkyl alkynes were employed in this reaction with the aryl group posed adjacent to the free amino functionality (3ak, 3cj, 3ck). The structure of 3ak was confirmed by comparison with known spectral data in the literature.¹⁰ Of particular note, 4-octyne bearing no aryl group was also amenable to this annulation protocol which again demonstrated its wider substrate scope than that of the reaction between aldimines and alkynes.⁴

Scheme 3 Substrate scope of alkynes. ^aReaction conditions: 1c (1.0 mmol), 2 (1.0 mmol), ReBr (CO)₅ (2.5 mol%), Na₂CO₃ (30 mol%), 1,4-dioxane (1.5 mL), 150 °C, 24 h. ^bIsolated yields of 3 are shown. ^cSingle isomer was detected.

To shed light on the possible reaction mechanism, competition experiments between two ketimines and alkynes bearing electronically varied groups were investigated. It turned out that ketimine 1c containing an electron-donating group (OMe) exhibited much better reactivity than that of ketimine 1e with an electron-withdrawing group (CF₃) (Scheme 4a). This result might originate from the stronger coordination ability of the imino functionality of 1c with the rhenium center, which facilitated the following C–H activation step. On the other hand, alkyne 2c bearing an electron-withdrawing group (CF₃) was slightly preferred to alkyne 2b having an electron-donating group (OMe) (Scheme 4b), which might arise from the higher propensity of 2c toward nucleophilic attack by the cyclic rhenium species formed after the C–H activation (vide infra).

Scheme 4 Competition experiments. (a) Competition experiments of ketimines; (b) competition experiments of alkynes.

Furthermore, the deuterium-labeling experiments were carried out. First, decadeuterated ketimine 1a-d₁₀ was synthesized and subjected to a reaction with alkyne 2a (Scheme 5a). After 6 h, the reaction was stopped and analyzed. It was shown that partial deuterium-loss occurred at the ortho-positions of the indenamine product 3aa-d₉. A similar phenomenon was found in the deuterated ketone 5a-d₁₀ isolated from the hydrolysis of unconverted ketimine. These results suggested a reversible deprotonative C–H activation step, which is in agreement with the previously reported mechanism in Re/base systems.³ In addition, a competition experiment as well as two parallel reactions for KIE measurements between 1a and 1a-d₁₀ were conducted (Scheme 5b and c). The results indicated that the cleavage of the C–H bond might be involved in the rate-determining step of the reaction.

Scheme 5 Deuterium-labeling experiments. (a) H/D scrambling experiment; (b) KIE determined from intermolecular competition; (c) KIE determined by two parallel reactions.

Based on these results and the literature clues,^3,4 a tentative reaction mechanism was proposed in Scheme 6. First, ReBr(CO)₅ reacted with ketimine 1a in the presence of Na₂CO₃ to generate rhenacycle A. The ligand exchange of CO with alkyne 2a gave the rhenium-alkyne complex B, which led to the seven-membered rhenacycle C through a migratory insertion of the alkyne. The intramolecular nucleophilic attack of the C–Re bond on the imino group in C resulted in the formation of intermediate D. Protonation of D gave the target [3 + 2] annulation product 3aa and formed the rhenium species E, which promoted the C–H bond cleavage of 1a with the assistance of the base regenerating rhenacycle A. The base, Na₂CO₃, acting as a proton shuttle in the reaction, facilitated the deprotonative C–H activation of 1a and the protonation of species D.

Scheme 6 A tentative reaction mechanism.

In conclusion, we have developed rhenium and base co-catalyzed [3 + 2] annulations of N–H ketimines and alkynes to approach the unprotected tertiary indenamines through C–H bond activation. The reaction demonstrates a high atom-economy, a broad substrate scope for both ketimines and alkynes, and excellent regioselectivity for unsymmetrical alkyne insertion. Mechanistic studies suggested a base-assisted deprotonation pathway occurring in the C–H bond activation step. Further implementations of rhenium/base co-catalysis in novel C–H transformations are underway in our laboratory.

Financial support from the National Basic Research Program of China (973 Program) (No. 2012CB821600) and the National Natural Science Foundation of China (21322203, 21272238, 21472194) is gratefully acknowledged.

Notes and references

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10. For more details, see the ESI.†.

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Footnote

† Electronic supplementary information (ESI) available: Experimental details, characterization data and NMR spectra of all new compounds. See DOI: 10.1039/c5qo00336a

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