Dimethyl Sulfoxide Mediated Elimination Reactions in 3-Aryl 2,3-Dihalopropanoates: Scope and Mechanistic Insights Wei Li,*,† Jianchang Li,† Melissa Lin,‡ Sumrit Wacharasindhu,‡ Keiko Tabei,‡ and Tarek S. Mansour‡ Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park DriVe, Cambridge, Massachusetts 02140, and Chemical and Screening Sciences, Wyeth Research, 401 North Middletown Road, Pearl RiVer, New York 10965
[email protected] ReceiVed February 1, 2007
Dimethyl sulfoxide (DMSO) efficiently causes the reductive elimination of 3-aryl 2,3-dibromopropanoates to cinnamates with good yield. With 3-phenyl 2,3-dihalopropanoates, debromination is the major pathway providing 3-phenylacrylate derivatives in high yields, whereas dehydrobromination is a competing pathway with thiophene derivatives. 1H NMR, 81Br NMR, and MS techniques indicated the formation of brominatedDMSO, MeBr, and HBr as byproducts in this transformation with no evidence for the formation of Br2. The dual role of DMSO as a nucleophile and bromine scavenger accounts for the products formed in this reaction.
Introduction Recently, we reported the synthesis of aromatic aldehydes from dihalomethylarenes via an oxygen-transfer reaction involving dialkylsulfoxides (Scheme 1).1 Unlike well-known oxidation reactions such as the Swern oxidation and its numerous variants,2-3 the oxygen-transfer reaction does not require activation of the sulfoxide and proceeds via an alkoxysulfonium intermediate in a non-oxidative manner. While oxygen-transfer reactions of sulfoxides catalyzed by metal complexes are well-established,3 the scope of these reactions has been useful mainly with phosphines and carbenes.4 In a recent work Khenkin and Neumann demonstrated that polyoxomolybdates can activate sulfoxides leading to the oxidation of alkylarenes5 and benzylic alcohols6 catalytically † ‡
Wyeth Research, Cambridge. Wyeth Research, Pearl River.
(1) Li, W.; Li, J.; DeVincentis, D.; Mansour, T. S. Tetrahedron Lett. 2004, 45, 1071. (2) (a) Tidwell, T. T. Org. React. 1990, 39, 2970. (b) Fang, X.; Bandarage, U. K.; Wange, T.; Schroeder, J. D.; Garvey, D. S. J. Org. Chem. 2001, 66, 4019. (3) Choi, M. K. W.; Toy, P. H. Tetrahedron Lett. 2003, 59, 7171. (4) (a) Kukushkin, Coord, V. Y. Chem. ReV. 1995, 139, 375. (b) Lim, B. S.; Holm, R. H. J. Am. Chem. Soc. 2004, 123, 1920. (5) Khenkin, A. M.; Neumann, R. J. Am. Chem. Soc. 2002, 124, 4198. (6) Khenkin, A. M.; Neumann, R. J. Org. Chem. 2002, 67, 7075.
SCHEME 1
via a Keggin type complex. A crystal structure of a heterobimetallic Zr-Ru complex with DMSO has been reported, indicating oxygen transfer from DMSO to a carbonyl ligand.7 Remarkably in biological systems dimethyl sulfoxide reductase is a molybdenum containing enzyme that catalyzes the oxygen atom transfer from its substrate DMSO in a two-stage reaction involving oxygen atom transfer and electron transfer.8 Expanding on our initial report that oxygen-transfer reactions involving DMSO can occur chemically without activation or the involvement of metal complexes, we further explored such reactions with 1,2-dihalo compounds. Herein, we communicate our preliminary results on this reaction which demonstrate that reductive debromination is the predominant pathway in a series (7) McAlpine, A. S.; McEwan, A. G.; Bailey, S. J. Mol. Biol. 1998, 275, 613. (8) Fabre, S.; Findeis, B.; Trosch, D. J. M.; Gade, L. H.; Scowen, I. J.; McPartlin, M. Chem. Commun. (Cambridge) 1999, 577. 10.1021/jo070217c CCC: $37.00 © 2007 American Chemical Society
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J. Org. Chem. 2007, 72, 6016-6021
Published on Web 07/12/2007
3-Aryl 2,3-Dihalopropanoate Elimination Reactions TABLE 1. Reductive Debromination of Wic-Dibromo Compounds
SCHEME 2
of substituted 2,3-dibromo-3-phenylpropanoates with dehydrobromination as the competitive reaction in some cases. Results and Discussion Our initial objective was focused on exploring the scope of the reaction of DMSO with various 1,2-dihaloethanes. To this end, we reasoned that at least one activating aryl moiety R to a halogen would be desirable since in our earlier report dihalomethylarenes were suitable substrates for reaction with DMSO. Additionally, we hypothesized further that the incorporation of an electron withdrawing group β to the aryl moiety should expand further the scope of the proposed reaction. Thus, we selected 3-phenyl-, 3-pyridyl-, and 3-thiophene-based propionic acid derivatives as useful substrates for investigation. Scheme 2 illustrates reductive elimination of various phenethyl 1,2-dibromo compounds. A diverse set of substituents at
the two carbons bearing the bromo atoms has been investigated. Representative examples in the reaction of DMSO with phenylethyl compounds as shown in Table 1 include dibenzosuberone and coumarin (entries 1 and 8 for cyclic structures), 3-phenylpropionic acids, esters and amides (entries 2-6), and (E)chalcone and phenylnitroethane (entries 7 and 9). In these reactions, reductive debromination could be easily accomplished within 1-6 h of reaction time at 75-100 °C or after longer times at room temperature (entries 8 and 9). The DL-2,3dibromo-3-phenylpropionic ester (entry 2 and 3) afforded the corresponding cinnamate in excellent yield as indicated by the large coupling constant of the vinyl protons in the 1H NMR spectrum. The trans stereochemistry was also obtained with amide (entry 6) and ketone (entry 7) derivatives in excellent yields. Carboxylic acids (entries 4 and 5) produced a mixture of trans- and cis-R,β-unsaturated acids in 5:1 and 3:1 ratio, respectively. Clearly, a broad range of functional groups (esters, acids, amides, nitro, and keto) was tolerated under the reaction conditions. We also noted that the reductive debromination is accelerated in the presence of water (∼3% in DMSO) and affords better yields and purity. The reaction has been scaled up to multigram quantities with similar outcome. It is interesting to point out that reductive debromination of the substrates in Table 1 has been the subject of many J. Org. Chem, Vol. 72, No. 16, 2007 6017
Li et al. TABLE 2. Reductive Debromination of Pyridine Wic-Dibromo Compounds
publications. For example, preparation of the cinnamates from the dibromo precursor (entry 2 of Table 1) has been frequently reported through reductive debromination under a variety of harsh reaction conditions, such as metal reducing agents,9 dissolving metal chemistry,10 or using tertiary amines under irradiation conditions.11 Clearly, this DMSO mediated debromination procedure is the most convenient and practical procedure for the preparation of these compounds. We next examined extension of the scope of reductive elimination to Vic-dibromoethylpyridine analogues (Table 2). In these cases, 2,3- and 2,5-disubstituted pyridine propanoates (entries 1, 2) gave the trans-R,β-unsaturated esters exclusively in good yield. When the ester group is replaced with another pyridine or phenyl ring (entries 5 and 6), trans-olefins are also obtained. The 4-dimethylamino moiety at the pyridine ring seemed to have adverse effect on the reaction as indicated by the low yield (entry 6, Table 2). In the case of 2,4-disubstituted pyridine or 3-substituted pyridine (entries 3 and 4), the R,βunsaturated esters were formed as the major products but were accompanied by the dehydrobromination byproducts (
