Cp*Co(III)-catalyzed vinylic C–H bond activation under mild conditions: expedient pyrrole synthesis via (3 + 2) annulation of enamides and alkynes

Abstract

Cobalt(III)-catalyzed (3 + 2) oxidative annulation of enamides and alkynes for the synthesis of pyrroles has been developed under exceedingly mild conditions. The reaction works well with various internal alkynes with broad scope and functional group tolerance. In most cases, the reaction proceeds at room temperature leading to N-acetyl pyrroles in excellent yields. Synthetically useful N-H pyrroles can also be obtained at elevated temperature.

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Introduction

Recent years have witnessed tremendous developments in the area of Cp*Co(III) catalysis for C–H functionalization.^1,2 After the seminal work of the Kanai/Matsunaga group,³ various other groups including those of Ackermann,⁴ Glorius,⁵ Chang,⁶ Ellman⁷ and others⁸ have also contributed to further advancing this field. The major advantages of Cp*Co(III) catalysis are (i) the use of earth abundant and less toxic first row transition metal,⁹ (ii) similar catalytic activity like precious transition metals such as Ru, Rh and Ir, and (iii) easily synthesized and air stable Co(III) complexes. Due to these advantages; Cp*Co(III) catalysis has became very popular within a short period of time.

On the other hand, nitrogen containing heterocycles are privileged structures in organic chemistry.¹⁰ Most of them are found in wide range of natural products, pharmaceuticals and agrochemicals. Recently, Cp*Co(III) catalysis has been extensively applied in the preparation of various important heterocyclic compounds such as pyrroloindolones,^3d isoquinolines,¹¹ quaternary ammonium salts of heterocyclic nitrogen compounds,¹² indoles,¹³ quinolines^13b,14 and isoquinolones,¹⁵ which involves the annulation of alkynes with appropriate aromatic nitrogen compounds (Scheme 1). However, most of these reports are based on arene C–H bond functionalization and require higher temperatures for generation of the desired products (above 80 °C). Moreover, Cp*Co(III)-catalyzed pyrrole synthesis via the (3 + 2) annulation of enamides and alkynes via olefinic C–H bond functionalization has not been studied.¹⁶ There are several examples of Co(III)-catalyzed olefinic C–H bond functionalization. However, to the best of our knowledge, there is only one report of Cp*Co(III)-catalyzed vinylic C–H bond activation at room temperature.^8b

Scheme 1 Cp*Co(III)-catalyzed synthesis of various nitrogen containing heterocycles.

Pyrrole represents one of the most ubiquitous structural motifs in organic chemistry, which is often encountered in various bioactive natural products and pharmaceuticals.¹⁷ So far, transition metals such as Rh,^18a–c Ru^18d,e and Pd^18f,g has been employed for the synthesis of pyrroles via the (3 + 2) annulation of enamides and alkynes. The major drawbacks of these methods are the high cost of the metal catalysts and in case of Ru and Pd, the reaction being carried out at higher temperatures. Therefore, it is highly desirable to develop a much milder protocol for these scaffolds using an inexpensive catalyst. In continuation of our interest in Cp*Co(III) catalysis,¹⁹ herein we report a Co(III)-catalyzed pyrrole synthesis to afford N-Ac and N-H pyrroles. The developed reaction conditions are extremely mild, furnishing a number of N-Ac pyrroles even at room temperature.

Results and discussion

We started our studies with enamide 1a as our starting substrate and diphenylacetylene 2a as a coupling partner (Table 1). When enamide 1a was treated with diphenylacetylene 2a in the presence of Cp*Co(CO)I₂ (5 mol%) and Cu(OAc)₂·H₂O (50 mol%) in TFE at room temperature for 14 h, it did not furnish any product (Table 1, entry 1).

Table 1 Optimization studies^a

Entry	Additive	Oxidant	Solvent	Temp (°C)	Yield^b (%)
					3aa	4aa
a Reaction conditions: 1a (0.10 mmol), 2a (1.2 equiv.), Cp*Co(CO)I2 (5 mol%), additive (10 mol%), oxidant (1.0 equiv.) in solvent (0.6 mL) for 14 h. b Yields are based ^1H NMR analysis of the crude reaction mixture (internal standard: 1,1,2,2 tetrachloroethane). c Cu(OAc)2·H2O (50 mol%). n.d. = Not detected. TFE = 2,2,2-trifluoroethanol.
1^c	—	Cu(OAc)2·H2O	TFE	rt	n.d	n.d
2^c	AgSbF6	Cu(OAc)2·H2O	TFE	rt	67	n.d.
3	AgSbF 6	Cu(OAc) 2 ·H 2 O	TFE	rt	95	4
4	AgOAc	Cu(OAc)2·H2O	TFE	rt	36	n.d.
5	Ag2CO3	Cu(OAc)2·H2O	TFE	rt	38	n.d.
6	AgSbF6	AgOAc	TFE	rt	8	n.d.
7	AgSbF6	Ag2CO3	TFE	rt	12	n.d.
8	AgSbF6	Cu(OAc)2·H2O	MeOH	rt	n.d.	n.d.
9	AgSbF6	Cu(OAc)2·H2O	^tAmOH	rt	33	n.d.
10	AgSbF6	Cu(OAc)2·H2O	1,2-DCE	rt	80	n.d.
11	AgSbF6	Cu(OAc)2·H2O	TFE	80	36	54
12	AgSbF6	Cu(OAc)2·H2O	TFE	100	16	78
13	AgSbF 6	Cu(OAc) 2 ·H 2 O	TFE	120	n.d	92

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We were pleased to see that pyrrole 3aa formed in 67% yield after the introduction of 10 mol% AgSbF₆ (entry 2). This indicates the role of cationic cobalt species in the reaction.^3c When the amount of Cu(OAc)₂·H₂O was increased to 1.0 equiv., pyrrole 3aa was formed in almost quantitative yield along with traces of 4aa (entry 3). The replacement of AgSbF₆ with other silver salts such as AgOAc and Ag₂CO₃ resulted in poor yields (entries 4 and 5). Instead of Cu(OAc)₂·H₂O, silver based oxidants were examined (AgOAc and Ag₂CO₃). However, they showed diminished yields of the product 3aa (entries 6 and 7). The use of other protic solvents such as MeOH or ^tAmOH gave poor yields of the pyrrole (entries 8 and 9). However, 1,2-DCE also furnished the pyrrole in good yield, but less compared to TFE (entry 10). Since we have observed the formation of a trace amount of 4aa at room temperature, we envisioned that an increase in reaction temperature might lead to an increase in the yield of N-H pyrrole 4aa. Indeed, we were excited to see that the amount of 4aa was gradually increased as the reaction temperature was increased (entries 11 and 12). We could observe the formation of 4aa in 92% yield at 120 °C (entry 13). Thus, by simple tuning of the reaction temperature we could be able to obtain both N-Ac and N-H pyrroles under identical catalytic conditions.

With the optimized conditions in hand, we initially investigated the Cp*Co(III)-catalyzed synthesis of various N-acetyl pyrroles using different internal alkynes (Table 2).²⁰ The alkynes with electron donating groups such as Me and OMe furnished the corresponding pyrroles in excellent yields (3ab–3ac). Halogen containing alkynes were also found to be compatible, furnishing annulated pyrroles in high yields (3ad–3ae). Electron withdrawing groups such as CF₃ and acetyl did not inhibit the reaction and produced pyrroles in good yields (4af and 3ag). Interestingly, in the case of the CF₃ group we observed N-deacetylation during column chromatography (4af). The meta-substituted alkynes also underwent reaction to furnish the corresponding products in high yields (3ah–3ai). The ortho-methyl group also did not deteriorate product formation (3aj). Heteroaryl alkynes such as di(2-thiophenyl)ethylene (2k) underwent cyclization in good yields (3ak). Dialkyl substituted alkynes such as 3-hexyne and 4-octyne also furnished the products in excellent yields at slightly elevated temperatures (3al–3am). The unsymmetrical dialkyl alkyne, 2-pentyne (2l), produced an inseparable mixture of regioisomers (3an–3an′) with a 1.0 : 0.6 ratio in 65% yield wherein the product that has a methyl group adjacent to the pyrrole nitrogen is the major product.²¹ Then, we turned our attention towards unsymmetrical aryl–alkyl alkynes such as 1-phenyl-1-propyne (2o), 1-phenyl-1-butyne (2p) and 1-phenyl-1-pentyne (2q) for regioselective annulation. These alkynes smoothly underwent annulation at 50 °C with good regioselectivity (3ao–3aq). Ethyl phenylpropiolate (2r) also furnished the corresponding pyrrole in moderate yield (3ar). The alkyne with a free hydroxyl group was also tolerated under the present reaction conditions (3as); thus showcasing the functional group tolerance of the present protocol. However, our attempt to employ terminal alkynes such as phenylacteylene as a coupling partner was unsuccessful.

Table 2 Co(III)-catalyzed synthesis of N-acetyl pyrroles^a

a Reaction conditions: 1a (0.20 mmol), 2 (1.2 equiv.), Cp*Co(CO)I₂ (5 mol%), AgSbF₆ (10 mol%), and Cu(OAc)₂·H₂O (1.0 equiv.) in TFE (1.2 mL) at rt for 14 h. b At 50 °C. c N-Deacetylation was observed during column chromatography. d Major isomer shown. e Run for 24 h; isolated yields are given.

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After successfully synthesizing diverse N-acetyl pyrroles, we were interested in expanding the scope of the cobalt catalytic system for the synthesis of synthetically useful N-H pyrroles (Table 3). As described in the optimization table, N-H pyrroles can be obtained by simply heating the reaction mixture at a higher temperature (Table 1, entry 13). Initially, the functional group tolerance of the presented reaction was tested by employing alkynes with various functional groups such as Me, Cl, Ac and ester. Gratifyingly, they gave the corresponding N-H pyrroles in high yields (4ab, 4ae, 4ag and 4at). The meta-substituted alkynes were also coupled efficiently (4ah & 4au). The alkyne with heteroaryl substituents was also well tolerated under the present reaction conditions furnishing the corresponding N-H pyrrole in good yield (4ak). This protocol was further applied to dialkyl alkynes without any difficulties (4al–4am). Li et al. in their Ru-catalyzed pyrrole synthesis have also reported the formation of N-H pyrrole.^18d However, they had to employ a mixed solvent system in order to generate these products. However, the present reaction works well in TFE as a single solvent; which makes this procedure operationally friendly.

Table 3 Co(III)-catalyzed synthesis of N-H pyrroles^a

a Reaction conditions: 1a (0.20 mmol), 2 (1.2 equiv.), Cp*Co(CO)I₂ (5 mol%), AgSbF₆ (10 mol%), and Cu(OAc)₂·H₂O (1.0 equiv.) in TFE (1.2 mL) at 120 °C for 14 h; isolated yields are given.

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In order to check the practical applicability of the present protocol, a gram scale synthesis of pyrrole was carried out at room temperature (Scheme 2). We were pleased to see that when 1.0 g of enamide 1a was treated with diphenylacetylene 2a under Cp*Co(III) catalysis, it delivered the corresponding pyrrole 3aa in 72% yield.

Scheme 2 Large scale pyrrole synthesis.

In order to gain insight into the mechanism, some control experiments were carried out (Scheme 3).²¹ Initially, when enamide 1a was subjected to standard reaction conditions in the absence of Cu(OAc)₂·H₂O for 14 h at room temperature, it resulted in the formation of 3aa in <5% NMR yield. Afterwards, the addition of 1.0 equiv. of Cu(OAc)₂·H₂O to the reaction mixture and further stirring of the reaction mixture at room temperature for another 14 h led to the formation of 3aa in 54% yield (Scheme 3). This result clearly indicate that Cu(II) does not play any role in product formation and it acts as a oxidant.^18b,d However, at present we cannot rule out the possibility of carboxylate assistance by Cu(OAc)₂. An intermolecular competitive experiment with differently functionalized alkynes (2b and 2e) revealed that the more electron rich alkyne 2b reacted solely with respect to the alkyne 2e with an electron withdrawing group.

Scheme 3 Control experiments.

Based on the control experiments and previous cobalt(III)-catalyzed annulation reactions;^11–14 a plausible mechanism for the present study is depicted in Scheme 4. Initially Cp*Co(CO)I₂ reacts with AgSbF₆ in the presence of Cu(OAc)₂·H₂O to generate the catalytically active species A; which undergoes cyclometalation via vinylic C–H bond activation to form cobaltacycle B. This is followed by migratory insertion of alkyne into B to form the six-membered cobaltacyclic intermediate C, which undergoes reductive elimination to furnish the pyrrole and cobalt(I) species D. The Co(I) in species D is oxidized to catalytically active Co(III) species A by Cu(OAc)₂. The N-acetyl group may be deprotected in the presence of AgSbF₆ at elevated temperature to produce N-H pyrroles.^18d

Scheme 4 Plausible mechanism.

Conclusions

In conclusion, we have developed a Co(III)-catalyzed (3 + 2) annulation of enamides and alkynes via vinylic C–H bond activation. Most of the N-acetyl pyrroles were formed at room temperature, thus showcasing the power of Cp*Co(III) catalysis. The reaction shows broad scope and excellent functional group tolerance with high yields of the pyrroles. The simple tuning of temperature led to the formation of synthetically useful N-H pyrroles under an identical catalytic system. The practicability of the present protocol is shown by a gram scale synthesis of the pyrrole.

Acknowledgements

A. B. P thanks the Department of Science and Technology (DST), New Delhi, India for the INSPIRE Faculty Award (CH-157, GAP 0520). D. M. L thanks CSIR for the senior research fellowship. We thank Dr S. Chandrasekhar (Director, CSIR-IICT) for his support and encouragement.

Notes and references

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20. Traces of N-deacetylation was observed during silica gel column chromatography.
21. See the ESI† for details.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6qo00108d

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