Letter pubs.acs.org/OrgLett
Cp*Co(III)-Catalyzed C−H Functionalization Cascade of N‑Methoxyamides with Alkynedione for the Synthesis of Indolizidines Lahu N. Chavan,†,‡ Krishna Kumar Gollapelli,† Rambabu Chegondi,*,†,‡ and Amit B. Pawar*,† †
Division of Natural Product Chemistry, CSIR−Indian Institute of Chemical Technology, Hyderabad 500007, India Academy of Scientific and Innovative Research (AcSIR), New Delhi 110020, India
‡
S Supporting Information *
ABSTRACT: Cp*Co(III)-catalyzed C−H functionalization cascade of N-methoxyamides with alkynedione has been reported for the synthesis of indolizidine scaffolds under redox-neutral conditions. The reaction displays broad functional group tolerance along with excellent yield. The reaction proceeds with kinetically relevant C−H bond activation through carboxylate assistance with excellent diastereoselectivity and complete opposite selectivity with respect to alkyne insertion.
I
functionalization reactions.8−10 Until now, several directing groups such as pyridyl, pyrimidyl, anilides, imidates, and oximes have been widely employed in Co(III)-catalyzed reactions. However, the use of N-methoxyamides under redox-neutral conditions, wherein the N−O bond acts as an internal oxidant, is very rare.11 Apart from C−H functionalization, Lewis acidity of Co(III) catalyst has also been utilized via dual activation (Scheme 1). In 2015, Glorius and co-workers reported an efficient Co(III)catalyzed C−H functionalization with diazo compounds to access new class of conjugated polycyclic hydrocarbons, wherein Co(III) is believed to play a dual role as a transition-metal catalyst for C−H activation and Lewis acid to promote nucleophilic addition.12 The same group has reported Co(III)catalyzed quinazoline synthesis from aryl imidates and dioxazolones wherein cobalt is shown to perform a dual role.13a A similar kind of transformation was also reported by Ackermann and co-workers.13b Very recently, Zeng et al. reported Co(III)-catalyzed [4 + 1] cyclative capture of 2arylpyridines with aldehydes in which cobalt catalysts play a dual role as a metal catalyst and Lewis acid.14 In continuation of our interest in Cp*Co(III) catalysis,15 we postulated that the treatment of N-methoxyamides with alkynedione in the presence of Cp*Co(III) catalyst should furnish the isoquinolone via [4 + 2] annulation followed by nucleophilic addition of free N−H of the amide onto the carbonyl wherein Co(III) can act as a Lewis acid to furnish a tetracyclic indolizidine skeleton in a one-pot manner (Scheme 1). In order to validate our hypothesis, a series of experiments were conducted (see Table S1). Initially, N,4-dimethoxybenza-
ndolizidine represents one of the important structural motifs in bioactive natural products such as camptothecin, rosettacin, α-lycorane, and tylophorine (Figure 1).1 Although various
Figure 1. Representative natural products containing indolizidine scaffold.
synthetic methods have been reported to access the indolizidine skeleton,2 the development of novel synthetic methods utilizing inexpensive first-row transition-metal catalysts is highly desirable. In 2010, Fagnou et al. reported first Rh(III)-catalyzed redoxneutral C−H annulation of N-methoxy/pivaloyloxy benzamides with alkynes to furnish isoquinolones.3 After these findings, Nmethoxyamide has been utilized as a versatile directing group in number of valuable transformations and is considered as one of the important oxidizing-directing group.4 However, there are a few examples wherein an N−H group present in the product has been engaged in the further cascade-type reaction.5 In recent times, first-row transition-metal-catalyzed C−H bond functionalization has gained tremendous importance in organic synthesis.6,7 This is attributed to their low toxicity, high earth abundance, and low cost as compared to precious metals such as Rh, Ru, and Ir. Among the various first-row transition metals, Fe, Mn, Ni, and Co are widely used in C−H activation. In particular, after pioneering work from Kanai and Matsunaga Co(III) catalysis has emerged as a powerful catalytic system for various C−H © XXXX American Chemical Society
Received: March 27, 2017
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DOI: 10.1021/acs.orglett.7b00904 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Scope of Amidesa
Scheme 1. Cp*Co(III)-Catalyzed C−H Functionalization Cascade via Dual Activation
mide was treated with alkyne dione 2a in the presence of 10 mol % of [Cp*Co(CO)I2] and NaOAc (1.0 equiv) in MeOH as a solvent at 120 °C for 14 h. Unfortunately, no product was formed under these conditions. The solvent screening revealed that 2,2trifluoroethanol (TFE) was the choice of the solvent furnishing required tetracyclic indolizidine (±)-3ea in 72% yield. This may be due to lower Lewis basicity of TFE as compared to the conventional alcoholic solvents.16 The relative stereochemistry of Me and OH groups in 3aa was assigned as cis based on NOE experiments (see the Supporting Information). When the amount of NaOAc was decreased up to 50 mol %, the yield of the product was increased up to 85%. Various other additives were tested, but none of them gave better results as compared to NaOAc. The control experiments revealed that both [Cp*Co(CO)I2] and NaOAc are essential for the current C−H functionalization cascade. With the optimized conditions in hand, we next investigated the scope and generality of the reaction using different Nmethoxyamides (Scheme 2). It was found that amides having electron-donating groups furnished the products in good yields (3aa−ga). However, in case of 3g, we isolated both of the regioisomers. This is probably due to chelation of the oxygen from the dioxy ring to the cobalt to direct the C−H activation at a more hindered position. The wide range of N-methoxybenzamides containing important electrophilic and electron-withdrawing functional groups, such as F, Cl, Br, I, NO2, CF3, CN, CO2Et, Ac, and cinnamate, were well tolerated, furnishing an excellent yield of the corresponding indolizidine derivatives (3ha−qa). Moreover, meta-substituted amides and 2-naphthylamide demonstrated excellent levels of positional selectivity to furnish corresponding products as a single regioisomer (3ra−ta). However, ortho-substituted amides were not a suitable substrate (3ua−va). This can be attributed to the steric effects that hinder the formation of cobaltacycle. Gratifyingly, this protocol was further extended to amide-containing heteroarene such as thiophene (3wa). It is important to mention that the protocol was not limited to just arene C−H bonds. The acrylamide
a
Reaction conditions: 1 (0.30 mmol), 2a (1.2 equiv), [Cp*Co(CO)I2] (10 mol %), and NaOAc (50 mol %) in TFE (2.4 mL) at 120 °C for 14 h under argon atmosphere. Isolated yields are provided.
derivatives were also underwent C−H functionalization cascade via vinylic C−H bond activation (3xa−za). We subsequently investigated the scope and reactivity pattern of the alkynediones (Scheme 3). At first, electronic effects of the aryl group were tested. The aryl groups having both electrondonation and electron-withdrawing groups furnished the corresponding products in good yields (3ab−ae), although the reaction was slightly sluggish when an electron-withdrawing group was present in the aryl ring. The replacement of a Me group with Et at the C-2 position of cyclopentadienone did not have much effect on the product formation (3af−jf). Satisfyingly, six-membered alkynedione was also compatible with current catalytic conditions (3ag−jg). However, our attempts to utilize a terminal alkynedione devoid of an aryl group were unsuccessful. Finally, we were interested in employing the present C−H functionalization cascade protocol for late-stage functionalization (Scheme 4). To our delight, N-methoxyamide derived from the bioactive complex estrone also underwent a C−H functionalization cascade to produce the corresponding products having seven continuous rings.17 Next, several experiments were conducted to elucidate the mechanism of the present Co(III)-catalyzed C−H functionalizaB
DOI: 10.1021/acs.orglett.7b00904 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 3. Scope of Alkynedionesa
in product 3aa (see the Supporting Information for details). These results clearly indicate that, under the present conditions, the C−H activation step is irreversible.18 The intermolecular competition experiment between electronically different Nmethoxybenzamides revealed that the more electron-deficient arenes reacts preferentially. This observation suggests that an electrophilic C−H activation is less likely to be operative but can be rationalized in terms of a carboxylate-assisted deprotonative C−H cobaltation.19 Furthermore, higher values of kinetic isotope effect were observed in both parallel reactions and competitive reactions, indicating that C−H bond cleavage is involved in the rate-limiting step.20 Based on our mechanistic studies and precedent literature,5c,11 the plausible mechanism for the present study is depicted in Scheme 6. We proposed that Cp*Co(III)-catalyzed C−H Scheme 6. Plausible Mechanism
a
Reaction conditions: 1 (0.30 mmol), 2 (1.2 equiv), [Cp*Co(CO)I2] (10 mol %), and NaOAc (50 mol %) in TFE (2.4 mL) at 120 °C for 14 h under argon atmosphere. Isolated yields are provided.
Scheme 4. Late-Stage Functionalization of Estrone Derivative
tion cascade reaction (Scheme 5). At first, H/D exchange experiments of N-methoxybenzamide 1a were carried out to Scheme 5. Mechanistic Findings
functionalization cascade begins with the formation of catalytically active Co(III) species A from [Cp*Co(CO)I2] and NaOAc.10n,11 The catalytic active Co species A coordinates to the nitrogen atom of N-methoxybenzamide 1a which is followed by irreversible and rate-determining cobaltation to form fivemembered cobaltacycle B. The weak coordination of carbonyl oxygen of alkynedione 2a (intermediate C) to the cobalt center followed by insertion into the Co−C bond generates intermediate D. This weak coordination is responsible for the opposite regioselectivity of alkyne insertion.5c The intermediate D then undergoes reductive elimination and N−OMe bond cleavage to generate species E which on proto-demetalation furnishes isoquinolone F with concomitant release of the catalytic active cobalt species. Finally, Co(III)-assisted12−14 nucleophilic attack of amide N−H in intermediate F on to the carbonyl leads to the formation of desired indolizidine product 3aa. In summary, we have developed a Cp*Co(III)-catalyzed C−H functionalization cascade of N-methoxyamides and alkynedione for the synthesis of indolizidine scaffolds with opposite regioselectivity of alkyne insertion under redox-neutral conditions. The reaction displayed excellent functional group tolerance and is applicable for late-stage functionalization. The further exploration of Cp*Co(III) catalysis in other cascade reactions is currently underway in our laboratory.
investigate the reversibility of the C−H activation step. When 1a was treated under catalytic conditions in the absence of alkynedione with TFE/CD3OD as solvent, 7% D incorporation was observed at each ortho position as revealed by 1H NMR analysis. When the same reaction was performed in the presence of 2a; 10% D incorporation was detected in recovered starting whereas;
