N-heterocyclic carbene-catalyzed rearrangements of vinyl sulfones.

NIH Public Access Author Manuscript Chem Sci. Author manuscript; available in PMC 2012 March 21. NIH-PA Author Manuscript Published in final edited form as: Chem Sci. 2011 ; 2(9): 1772–1776. doi:10.1039/C1SC00194A. N-heterocyclic carbene-catalyzed rearrangements of vinyl sulfones† Roxanne L. Atienza, Howard S. Roth, and Karl A. Scheidt Department of Chemistry, Center for Molecular Innovation and Drug Discovery, Chemistry of Life Processes Institute, Northwestern University, 2145 Sheridan Road, Evanston, IL, 60208, USA; Fax: (+1) 847-467-2184 Karl A. Scheidt: Abstract NIH-PA Author Manuscript N-heterocyclic carbenes catalyze the rearrangement of 1,1-bis(arylsulfonyl)ethylene to the corresponding trans-1,2-bis(phenylsulfonyl) under mild conditions. Tandem rearrangement/ cycloadditions have been developed to capitalize on this new process and generate highly substituted isoxazolines and additional heterocyclic compounds. Preliminary mechanistic studies support a new conjugate addition/Umpolung process involving the ejection and subsequent unusual re-addition of a sulfinate ion. NIH-PA Author Manuscript Metal free catalysis has undergone a renaissance over the last decade, leading to an explosion of efficient and stereoselective strategies for chemical synthesis.1 In the area of Lewis base-promoted reactions,2 N-heterocyclic carbene (NHC) catalysis is a rapidly growing field that employs electron lone pair-bearing heterocycles to facilitate a wide breadth of chemical transformations.3 Carbene catalysis is highly versatile and allows access to acyl anions,4 homoenolates,5 enolates,6 Cannizarro-type reductions,3c and oxidations.7 The majority of NHC catalysis currently involves the 1,2-addition of the carbene to a carbonyl-containing species which then proceeds to produce an acyl anion or homoenolate equivalent. A different mode for these nucleophilic catalysts is a conjugate addition manifold. By capitalizing on this 1,4-type reactivity, both Fu and Ye have separately reported the development of β-Umpolung-type and Morita-Baylis-Hilman reactions catalyzed by NHCs, respectively.8 This conjugate addition process provides a new direction beyond 1,2-additions. In this work, the combination of an NHC with a vinyl sulfone and nitrone results in the formation of an isoxazolidine product with an unusual transposition of a sulfone group (eqn 1). This process fundamentally differs from the previous 1,4 additions because it is neither an intramolecular alkylation8a nor a MBH reaction.8b Vinyl sulfones are useful intermediates in organic synthesis that can act as 2π participants in cycloadditions9 and as electrophiles in organometallic10 and organocatalysis.11 When we began these specific studies, the use of vinyl sulfones as substrates in NHC-catalyzed transformations had not been previously reported. In our attempts to achieve homoenolate equivalent annulations with 1,1-bis(phenylsulfonyl)ethylene (1), we discovered that the carbene derived from triazolium A promoted an unanticipated rearrangement to the trans-1,2-bis(phenylsulfonyl)ethylene in 96% yield with a t1/2 of ~6 h at 40 °C (2, eqn 2). †Electronic supplementary information (ESI) available: Experimental procedures and spectroscopic data for all new compounds. See DOI: 10.1039/c1sc00194a Correspondence to: Karl A. Scheidt, . Atienza et al. Page 2 NIH-PA Author Manuscript The isomerization of 1,1-bis(phenylsulfonyl)ethylene to date involves harsh, non-catalytic reaction conditions such as autoclave with high pressure (no isolated yield) or ammonium salts at 140 °C.12 Our survey of standard Lewis bases for this process, such as 1,4diazabicyclo[2.2.2]octane (DABCO) and triphenylphosphine, revealed there was poor and incomplete conversion when compared to the NHC catalyst generated from azolium catalyst A and sodium tert-butoxide.13 Trans-1,2-bis(arylsulfonyl)ethylene has been used in organic synthesis,14 but its preparation typically involves the use of vinyl chloride gas.15 Alternatively, the straightforward preparation of 1,1-bis(phenylsulfonyl)ethylene involves paraformaldehyde, piperidine, and acid.12b 2. Results and discussion NIH-PA Author Manuscript We viewed this unusual NHC-catalyzed generation of trans-1,2-bis(phenylsulfonyl)ethylene in situ under mild reaction conditions as an interesting opportunity to develop a two-step single flash process involving a cycloaddition step (vide infra). The initial test bed reaction we chose was the formation of the isomerization product in a one-pot process with a nitrone in a Huisgen [3 + 2] cyclization to form the isoxazolidine product.16 Our optimization studies for this NHC-catalyzed reaction began by treating the 1,1bis(phenylsulfonyl)ethylene with N-aryl nitrone and surveying various azolium salts and reaction conditions (Table 1). Of the azolium salts, triazolium A was the only catalyst which led to appreciable amounts of desired cycloadduct 4. Notably, the cycloaddition yielded a single diastereomer (as observed by 1H NMR spectroscopy).17 The reduction of catalyst loading from 20 to 10 mol% of A resulted in significant depression of yield for the two-step process (rearrangement/cycloaddition). Further experimentation revealed dichloromethane as the best solvent and sodium tert-butoxide was the optimal base, presumably since its minimal nucleophilicity did not compete with the NHC for addition to the vinyl sulfone.18 NIH-PA Author Manuscript With the optimized reaction conditions, we examined the scope of the reaction with regard to the nitrone component (Table 2). A chloride substituent in the 4 position of the N-aryl ring delivered the products in good yields, presumably due to the increased electrophilicity of the nitrone being complimentary to the cyclization step (entries 1–7). Increasing the temperature to 40 °C and adding 4 Å molecular sieves generally improved conversion and yields. Reactions with N-aryl nitrones with non-electron withdrawing groups provided moderate yields and an N-alkyl nitrone provided 86% of the desired cycloadduct (entry 13). Similar to the initial optimization reaction in Scheme 1, the isoxazolidine products were observed as a single diastereomer (1H NMR, 500 MHz). Substituted aryl sulfones are also compatible with the system (entries 14–16), but currently both sulfones are required. With these NHC conditions, mixed sulfone/carbonyl group compounds are not substrates and neither are β-substituted bis-sulfones. Since N-alkyl nitrones are productive substrates, this tandem 1,1-1,2 rearrangement/ cycloaddition with a D-ribose-based chiral auxiliary is highly selective and provides the optically active isoxazoline in 65% yield as a single diastereomer (Scheme 3, eqn 3).19 Importantly, this streamlined process is not limited to nitrones20 as the dipole coupling partner. For example, azomethine imines (such as 22) and dienes (including furan) undergo efficient reactions in [3 + 2] and [4 + 2] cycloaddition21 reactions (respectively, (...truncated)