Ring expansion of spirocyclopropanes with stabilized sulfonium ylides: highly diastereoselective synthesis of cyclobutanes

Abstract

A novel method was devised for regioselective ring expansion of Meldrum's acid-derived spirocyclopropanes to spirocyclobutanes with stabilized sulfonium ylides, affording 1,2-trans-disubstituted 6,8-dioxaspiro[3.5]nonane-5,9-diones in up to 87% yields without the formation of any isomers. The aforementioned reaction was also applied to the barbituric acid-derived spirocyclopropane, resulting in the formation of the corresponding cyclobutanes.

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Sulfonium ylides stabilized by electron-withdrawing groups (EWG) have been used as a versatile methylene synthon in the synthesis of a variety of carbo- and heterocyclic compounds.^1,2 As a pioneering work, Payne reported that the reaction of α,β-unsaturated diethylmalonate with EWG-stabilized sulfonium ylide 1 (EWG = CO₂Et) afforded cyclopropane in 90% yield (Scheme 1A).³ In this reaction, the Michael addition of 1 followed by S_N2-type cyclization of the carbanion (C-cyclization) proceeded with the concomitant release of the sulfide. In contrast, the reaction of the corresponding 1,3-diketone with stabilized sulfonium ylide 1 unexpectedly produced dihydrofuran in 83% yield through enolate cyclization (O-cyclization, Scheme 1A).³ The regioselectivity of these reactions may be attributed to the inherent difference between esters and ketones. Recently, we reported the ring-opening cyclization of spirocyclopropanes⁴ with EWG-stabilized sulfonium ylides 1 to afford hexahydrobenzopyranone as a single isomer via the regioselective ring-opening of cyclopropane with sulfonium ylide 1 and subsequent S_N2-type O-cyclization (Scheme 1B, eqn (1)).^4f Considering the similar reactivity of cyclopropane and carbon–carbon double bonds, we expected that the reaction of ester-derived spirocyclopropane 2 with stabilized sulfonium ylide 1 would provide spirocyclobutane 3 through C-cyclization (Scheme 1C). Because cyclobutane is a useful scaffold found in several biologically active natural products and pharmaceutically active compounds,⁵ the development of a synthetic method for cyclobutane is currently the subject of intense research.⁶ Although several instances of cyclopropane to cyclobutane ring expansion have been documented thus far,^7,8 to the best of our knowledge, there have been no examples of sulfonium ylide-mediated ring expansion (C-cyclization).⁹ Herein, we describe the ring expansion of Meldrum's acid-derived spirocyclopropanes 2 to spirocyclobutanes 3 using EWG-stabilized sulfonium ylides 1 (Scheme 1C).

Scheme 1 Reactions of various carbonyl compounds with stabilized sulfonium ylides 1 as nucleophiles.

Initially, we examined the reaction of 6,6-dimethyl-1-phenyl-5,7-dioxaspiro[2.5]octane-4,8-dione (2a)¹⁰ with dimethylsulfonium benzoylmethylide (1a) as an EWG-stabilized sulfonium ylide (Table 1). The ring expansion of 1a proceeded under the reaction conditions previously reported by our group (1.5 equiv. of 1a in refluxing CH₂Cl₂),^4f affording 1-benzoyl-7,7-dimethyl-2-phenyl-6,8-dioxaspiro[3.5]nonane-5,9-dione (3a) after 24 h in 75% yield (entry 1). Notably, no isomer formation was observed during this process. The structure of 3a including its stereochemistry was confirmed by a single-crystal X-ray diffraction analysis. This analysis revealed that the structure corresponds to that of cyclobutane with a 1,2-trans configuration (see ESI† for details). Screening of the solvents at reflux revealed that benzene and halogenated solvents, such as dichloromethane and 1,2-dichloroethane, were suitable for this reaction (entry 1 vs. entries 2–5). Finally, we found that chlorobenzene at 80 °C was the most effective and afforded 3a in 86% yield after 6 h (entry 6).

Table 1 Ring expansion of spirocyclopropane 2a with sulfonium ylide 1a

Entry	Solvent	Temp.	Time (h)	Yield^a (%)
a Isolated yield.
1	CH2Cl2	Reflux	24	75
2	EtOAc	Reflux	4.5	60
3	Benzene	Reflux	5	74
4	CH3CN	Reflux	24	59
5	ClCH2CH2Cl	Reflux	7	75
6	C6H5Cl	80 °C	6	86

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After determining the optimal conditions, we investigated the reaction of spirocyclopropane 2a using a range of sulfonium ylides 1 that are stabilized by carbonyl functional groups (Table 2). The reaction with 1.5 equiv. of p-methoxybenzoyl sulfonium ylide 1b in chlorobenzene at 80 °C afforded the corresponding spirocyclobutane 3b as the sole product after 6 h in 74% yield (entry 2). The use of m- and o-methoxybenzoyl sulfonium ylides 1c¹¹ and 1d¹² provided the corresponding products 3c and 3d in 86% and 87% yields, respectively (entries 3 and 4). The reaction with sulfonium ylide 1e bearing a p-nitro group as a strong EWG decreased the product yield, and a significantly longer reaction time was required to achieve full conversion (61% yield, 24 h, entry 5 vs. entry 1). In contrast, the reaction with p-chlorobenzoyl sulfonium ylide 1f under the optimized conditions proceeded smoothly to completion within 5 h, furnishing 3f in 83% yield (entry 6). We also investigated the suitability of an acetyl sulfonium ylide for this reaction. To this end, we used tetrahydrothiophenium acetylmethylide (1g) because of the difficulty in preparing dimethylsulfonium acetylmethylide. The reaction of 2a with 1g afforded the desired product 3g as a single isomer, albeit with a prolonged reaction time and lower yield (24 h, 36% yield, entry 7 vs. entry 1). Moreover, ethoxycarbonyl group-substituted sulfonium ylide 1h was used in the present protocol, and the corresponding cyclobutane 3h was obtained in 53% yield after 23 h (entry 8).

Table 2 Ring expansion of spirocyclopropane 2a with sulfonium ylides 1a–h

	Sulfonium ylide				Product
Entry		R^1	R^2	Time (h)		Yield^a (%)
a Isolated yield.
1	1a	C6H5	Me	6	3a	86
2	1b	p-MeOC6H4	Me	6	3b	74
3	1c	m-MeOC6H4	Me	6	3c	86
4	1d	o-MeOC6H4	Me	6	3d	87
5	1e	p-NO2C6H4	Me	24	3e	61
6	1f	p-ClC6H4	Me	5	3f	83
7	1g	Me	–(CH2)4−	24	3g	36
8	1h	EtO	Me	23	3h	53

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Next, we examined the scope of the reaction with the spirocyclopropane substrates 2 using benzoyl-substituted sulfonium ylide 1a (Table 3). Treatment of spirocyclopropanes 2b, 2c and 2d, which possess p-acetoxy-, p-methyl-, and p-bromophenyl groups on the cyclopropane, respectively, with 1a under the optimized conditions (chlorobenzene at 80 °C), afforded the corresponding products 3i, 3j, and 3k in 64%–80% yields with perfect diastereoselectivities (entries 1–3). The reaction of m-methoxyphenyl-substituted spirocyclopropane 2e for 12 h provided cyclobutane 3l in 69% yield (entry 4). Although spirocyclopropane 2f, which possesses a 2-naphthyl group, required a relatively long reaction time (48 h), 3m was obtained in a good yield (80%, entry 5). There was a concern that the use of vinyl-substituted spirocyclopropane 2g would compete with the conjugate addition, but the reaction of 2g proceeded uneventfully and afforded the desired product 3n in 68% yield (entry 6). Finally, the reaction of the simple spirocyclopropane 2h (R = H)¹³ was investigated (entry 7). A 2′,3′-nonsubstituted spirocyclopropane was found to be less reactive than an aryl-substituted one,^4e which resulted in a lower yield of product 3o (26% yield).

Table 3 Ring expansion of spirocyclopropanes 2b–h with sulfonium ylides 1a

Entry	Spirocyclopropane		Time (h)	Product
		R			Yield^a (%)
a Isolated yield.
1	2b	p-AcOC6H4	3	3i	64
2	2c	p-MeC6H4	6	3j	74
3	2d	p-BrC6H4	6	3k	80
4	2e	m-MeOC6H4	12	3l	69
5	2f	2-naphthyl	48	3m	80
6	2g	Vinyl	24	3n	68
7	2h	H	24	3o	26

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A plausible mechanism for the ring expansion of spirocyclopropane 2 with sulfonium ylide 1, stabilized by an acyl group, is shown in Scheme 2. The ring opening of spirocyclopropane 2 would proceed through the nucleophilic attack of the carbanion in 1 on the electrophilic cyclopropane carbon possessing an R¹ substituent in A. This reaction would lead to the formation of betaine intermediates B and C. S_N2-type C-cyclization of the carbanion in B would occur smoothly to afford trans-product 3 with the concomitant release of dimethyl sulfide. In contrast, the C-cyclization of C would hardly proceed owing to the severe steric repulsion between the acyl group (R²CO) and substituent R¹ in C. Consequently, intermediate C could be converted into cyclization precursor B through reversible intramolecular proton transfer via the stabilized sulfonium ylide D,^14,15 finally providing trans-isomer 3.

Scheme 2 Plausible reaction mechanism.

To demonstrate the utility of the present protocol, we examined the conversion of spirocyclobutane 3a into highly substituted non-spiro cyclobutane 4 (Scheme 3). The treatment of 3a with sulfuric acid in methanol/diethyl ether (1 : 1) at 50 °C led to a transesterification process, resulting in the formation of dimethyl ester. The reaction yielded the corresponding cyclobutane 4 in 82% yield. Since the reaction of dimethyl 2-phenylcyclopropane-1,1-dicarboxylate (5) with sulfonium ylide 1a did not proceed,^4f,16 spiro form 3a was required for the synthesis of diester 4. This ring-expansion reaction of spirocyclopropanes could be a useful method for the preparation of substituted cyclobutanes.

Scheme 3 Conversion of spirocyclobutane 3a into cyclobutane 4.

Having achieved ring expansion of ester-derived spirocyclopropanes, we further investigated the reaction of an amide-derived spirocyclopropane with an EWG-stabilized sulfonium ylide. The reaction of spirocyclopropane 6,¹⁷ derived from barbituric acid, with sulfonium ylides 1a and 1h in chlorobenzene proceeded smoothly at 50 °C to provide the corresponding spirocyclobutanes 7a and 7b in 64% and 83% yields, respectively (Scheme 4). Interestingly, unexpected products 8a and 8b, which indicated that S_N2-type O-cyclization of the enolate ion instead of the carbanion would occur, were also obtained in 8% and 9% yields, respectively. Although the results are still preliminary, the reaction of barbituric acid-derived spirocyclopropane with sulfonium ylide exhibits promise as a synthetic method of spirobarbiturate cyclobutane analogs. These compounds have potential as pharmaceutical agents.¹⁸

Scheme 4 Ring expansion of barbituric acid-derived spirocyclopropane 6 with sulfonium ylides 1a and 1h.

In conclusion, we devised a novel method for regioselective ring expansion of cyclopropanes to cyclobutanes using stabilized sulfonium ylides. Meldrum's acid-derived spirocyclobutanes with EWG-stabilized sulfonium ylides afforded the corresponding spirocyclobutanes as single diastereomers in yields of up to 87%. The present reaction provides an efficient route to highly substituted cyclobutanes. To the best of our knowledge, this is the first example of a ring expansion of cyclopropanes with sulfonium ylides. This reaction may be envisaged as a formal [3+1] cycloaddition, facilitating the construction of the four-membered ring system.¹⁹ The expansion reaction could be applied to the transformation of barbituric acid-derived spirocyclopropane into the corresponding spirocyclobutane. Ongoing efforts are being made to apply the present method to the synthesis of a variety of cyclobutane derivatives.

This research was supported, in part, by a Grant-in-Aid for Scientific Research (C) (Grant No. 21K05048) from the Ministry of Education, Culture, Sports, Science and Technology, Japan and by a Grant from Hoansha Foundation (Osaka, Japan).

Conflicts of interest

There are no conflicts to declare.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: General procedures, analytical data, and NMR spectra (PDF). CCDC 2312076 (3a). For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3cc06033k

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