One-Pot Synthesis of Strain-Release Reagents from Methyl Sulfones

Abstract

Sulfone-substituted bicyclo[1.1.0]butanes and housanes have found widespread application in organic synthesis due to their bench stability and high reactivity in strain-releasing processes in the presence of nucleophiles or radical species. Despite their increasing utility, their preparation typically requires multiple steps in low overall yield. In this work, we report an expedient and general one-pot procedure for the synthesis of 1-sulfonylbicyclo[1.1.0]butanes from readily available methyl sulfones and inexpensive epichlorohydrin via the dialkylmagnesium-mediated formation of 3-sulfonylcyclobutanol intermediates. Furthermore, the process was extended to the formation of 1-sulfonylbicyclo[2.1.0]pentane (housane) analogues when 4-chloro-1,2-epoxybutane was used as the electrophile instead of epichlorohydrin. Both procedures could be applied on a gram scale with similar efficiency and are shown to be fully stereospecific in the case of housanes when an enantiopure epoxide was employed, leading to a streamlined access to highly valuable optically active strain-release reagents.

The use of highly strained cyclic substrates in ring-expansion or ring-opening processes constitutes a powerful tool for the elaboration of complex and biologically relevant molecules.¹ In particular, “strain-release” (also known as “spring-loaded”) reagents, defined as highly strained (>50 kcal/mol) bi- or tricyclic molecules that react via cleavage of their bridging bond resulting in the release of strain,^2,3 have become increasingly prominent in recent years. Those include bicyclo[1.1.0]butanes (BCB),^2b,4 bicyclo[2.1.0]pentanes (housanes),⁵ tricyclo[1.1.1.0^1,3]pentanes (TCP or propellanes),⁶ and 1-azabicyclo[1.1.0]butanes (ABB),⁷ leading to the formation of functionalized cyclobutanes, cyclopentanes, bicyclo[1.1.1]pentanes, and azetidines, respectively, following the strain-release process. Some of these moieties are also found directly in natural products⁸ or utilized in medicinal chemistry for the introduction of bioisosteres.⁹ More specifically, sulfonyl-substituted BCB and housanes are exceptionally bench-stable and have found widespread applicability in strain-release cycloalkylation with either nucleophiles¹⁰ or radical species¹¹ as well as in formal cycloaddition,¹² where the resulting sulfonyl group serves as a handle for further derivatization (Scheme 1a, A).^13–15 Moreover, in the case of BCB, their structure can be readily diversified via sulfone-directed C–H functionalization (B).^10b,c,16,17 While their superior versatility as strain-release reagents is well established, the general access to 1-sulfonylbicyclo[1.1.0]butanes and housanes from inexpensive and readily available materials remains a challenge, typically requiring six steps and two purifications from sulfonyl chlorides in the case of BCB (Scheme 1b).^10d,e,18,19 As part of our research program directed at the elaboration and use of reagents of extreme strain such as cyclopropanones,²⁰ we discovered that these strain-release reagents could be accessed in a streamlined manner via the formation of 3-sulfonylcyclobutanol intermediates susceptible to transannular ring-closure upon activation (vide infra). Herein, we report a general procedure for the preparation of 1-sulfonyl-bicyclo[1.1.0]butanes in a single pot from readily available methyl sulfones and inexpensive epichlorohydrin (Scheme 1c). Key to the success of this transformation is the use of a commercially available dialkylmagnesium solution as a “double base” in the initial stage, as well as the careful choice of activating reagent for the 3-sulfonylcyclobutanol intermediate.

Scheme 1.

Syntheses and Applications of Sulfonyl-Substituted BCB and Housane Reagents

Through modification of the reaction conditions, a second procedure was developed allowing extension of the process to 1-sulfonylbicyclo[2.1.0]pentanes (housanes) when 4-chloro-1,2-epoxybutane was used as the electrophile instead, which is shown to be fully stereospecific and thus furnish a streamlined access to enantioenriched housanes.^10e Both one-pot procedures can be applied on a gram scale with similar efficiency and utilize minimal amounts of readily available reagents. Considering the importance of 1-sulfonylbicyclo[1.1.0]butanes and housanes as reagents in organic synthesis, the accelerated routes described herein should find widespread use in a variety of fields relying on strain-release processes for the rapid and efficient elaboration of biologically relevant molecules.

Related to our previous work involving the formation of chiral 1-sulfonylcyclopropanols as modular precursors of cyclopropanones,^20a our initial studies targeted the formation of a 2-chloromethyl-substituted sulfonylcyclopropane from a methyl sulfone and enantioenriched epichlorohydrin (eq 1).

(1)

In addition to the expected cyclopropane, the corresponding bicyclo[1.1.0]butane was observed in 24% yield via a 3-sulfonylcyclobutanol²¹ capable of transannular nucleophilic substitution upon activation with MsCl. A similar cyclobutanol intermediate was previously reported to be accessible from epichlorohydrin using n-BuLi in excess to form an α,α-dilithiated sulfone as effective nucleophile.^21a,22 To ensure the generality of the method, readily available and electron neutral phenyl methyl sulfone (1a) was selected as a model substrate for further optimization studies, leading to BCB 2a (Table 1).

Table 1.

Optimization of the One-Pot Synthesis of Bicyclobutanes

entry	base 1 (equiv)	RSO2Cl (equiv)	base 2 (equiv)	yield (%)a
1	n-BuLi (1)	MsCl (1)	n-BuLi (1)	14
2	Bu2Mg (1)	MsCl (1)	n-BuLi (1)	32
3	Bu2Mg (1)	NsClb (1)	n-BuLi (1)	<5
4	Bu2Mg (1)	PhSO2Cl (1)	n-BuLi (1)	62
5c	Bu2Mg (1)	PhSO2Cl (1)	KOt-Bu (3)	45
6c	Bu2Mg (1)	PhSO2Cl (1)	NaH (1.2)	<5
7	Bu2Mg (1)	PhSO2Cl (1.3)	n-BuLi (1.2)	77d

^aYield determined by ¹H NMR using 1,3,5-trimethoxybenzene as internal standard.

^bNsCl: 4-O₂N–C₆H₄SO₂Cl.

^cThird stage run at 0 °C to rt.

^dIsolated yield = 77%.

Applying the conditions depicted above to 1a led to a decreased yield of 14% (entry 1), along with the undesired 2-chloromethyl-substituted sulfonylcyclopropane in a 1:1 ratio.²³ In order to favor the formation of the desired sulfonylcyclobutanol intermediate, it was reasoned that at least two equivalents of base should be employed in the first stage prior to alcohol activation.²¹ Commercially available n-Bu₂Mg, acting as a “double base”, was rapidly identified as ideal for this purpose when added in stoichiometric amount (entry 2). Benzenesulfonyl chloride proved to be superior as activating agent (entries 2–4), whereas the use of n-BuLi in the final transannular S_N2 led to an increased yield compared with other bases evaluated such as KOt-Bu or NaH (entries 4–6). After slight adjustments in the reagents’ stoichiometry, the optimized conditions directly led to 2a in 77% isolated yield in one-pot from 1a (entry 7) and could be applied on a gram scale with similar efficiency (Scheme 2). The procedure is shown to be general for a wide range of methyl sulfones, which are either commercially available or readily prepared in one step by thioanisole oxidation or Cu-catalyzed cross-coupling of aryl iodides with NaSO₂Me.²³ Notably, racemic epichlorohydrin employed here as a key building block can be purchased at very low cost from most vendors ($0.04/g). In the case of brominated BCB 2j, the amount of n-BuLi used in the last stage had to be reduced to 1 equiv to minimize the formation of debrominated product formed via lithium–halogen exchange. While most bicyclo[1.1.0]butanes synthesized here could be accessed in one-pot, heterocyclic derivatives 2m and 2n and aliphatic analogues 2o and 2p required an aqueous workup after the second stage, with KOt-Bu used as an optimal base for the final transannular nucleophilic substitution.

Scheme 2. Scope of Accessible Bicyclo[1.1.0]butanes^a.

^aIsolated yields from 1a–1r on a 0.5 mmol scale. ^bIsolated yield on a 1 g scale (6.4 mmol) 1a in parentheses. ^ct-BuLi (1.2 equiv) was used in the third stage. ^dFirst and third stages were performed at −78 to −20 or 0 °C. ^e1.0 equiv of n-BuLi was used in the third stage. ^fKOt-Bu (1.5–2.5 equiv) was used in the third stage after aqueous workup. ^gTHF/HMPA (9:1) was used as solvent instead of pure THF.

Importantly, application of this procedure to substituted epichlorohydrin derivatives directly led to bicyclobutanes 2s and 2t from methyl sulfone 1a (Scheme 3). 1-Substituted epichlorohydrins, which would have also led to BCB derivatives such as 2t, were found to be incompatible under these conditions due to their poor electrophilicity and lack of regiocontrol in the initial epoxide opening step of the sequence.²³

Scheme 3. Direct Access to Substituted BCB Derivatives^a.

^aIsolated yields from 1a on a 0.5 mmol scale.

Adjustments in the reaction conditions led to extension of the method to the analogous production of sulfonyl-substituted housanes 3a–3l (Scheme 4),²³ a class of strain-release reagents previously demonstrated by Baran and co-workers as highly versatile in cyclopentylation reactions.^10d,e In this case, the addition of HMPA as a cosolvent was found to significantly improve the yield, with commercially available (n-Bu)(s-Bu)Mg used as the initial base instead of n-Bu₂Mg. Moreover, t-BuLi was employed as a base in the last stage instead of n-BuLi to avoid the formation of inseparable impurities.²³ In general, the observed yields of housane products 3a–3l were found to be slightly lower than the corresponding BCB, mostly due to incomplete reaction and competitive elimination pathways occurring on the activated 3-sulfonylcyclopentanol intermediates involved.²⁴ Racemic 4-chloro-1,2-epoxybutane used here as the electrophile can be prepared on multigram scale in two simple steps from 3-butenol.²³ Kinetic resolution using Jacobsen’s Co(III)-catalyzed hydrolytic procedure²⁵ affords access to a virtually enantiopure epoxide. Employing this chiral reagent in our one-pot procedure leads the rapid production of highly enantioenriched housanes, as demonstrated here with 3e and 3g, previously shown to constitute superior strain-release reagents in stereospecific cyclopentylation reactions (Scheme 5).^10e In order to ensure the stereospecificity of the overall process, the procedure had to be slightly modified where a shorter reaction time was employed in the second stage to minimize competitive intermolecular substitution events, leading to partial epimerization of the activated 3-sulfonylcyclopentanol intermediate.

Scheme 4. Scope of Accessible Bicyclo[2.1.0]pentanes^a.

^aIsolated yields from 1a–1h, 1k–1l, and 1q–1r on a 0.5 mmol scale. ^bIsolated yield on a 1 g scale (6.4 mmol) 1a in parentheses. ^cFirst stage was performed at −20 °C (then 0 °C, 1 h) and third stage at −78 to −20 °C. ^dn-Bu₂Mg (1 equiv) was used at −20 °C in the first stage instead of (n-Bu)(s-Bu)Mg (without HMPA).

Scheme 5. Stereospecific Synthesis of Chiral Housanes^a.

^aIsolated yields from 1e or 1g on a 0.25 mmol scale.

In summary, we report one-pot procedures for the streamlined synthesis of highly valuable 1-sulfonylbicyclo[1.1.0]butanes and housanes from readily available methyl sulfones. Both reactions can be performed on a gram scale with similar efficiency, and the use of enantiopure 4-chloro-1,2-epoxybutane is shown to afford access to highly enantioenriched housanes via a stereospecific pathway. Considering the bench stability and established versatility of sulfonyl-substituted strain-release reagents in a wide variety of processes such as cycloalkylation with nucleophiles¹⁰ or radical intermediates,¹¹ this general approach should find widespread utility in the elaboration and functionalization of biologically relevant molecules.