a-Halogenation of carbonyl compounds: halotrimethylsilane–nitrate salt couple as an efficient halogenating reagent system G. K. Surya Prakash ⇑ , Rehana Ismail, Jessica Garcia, Chiradeep Panja, Golam Rasul, Thomas Mathew ⇑ , George A. Olah Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, CA 90089-1661, USA article info Article history: Received 15 November 2010 Revised 3 January 2011 Accepted 10 January 2011 Available online 18 January 2011 Keywords: PTP inhibitors Direct a-halogenation Chlorotrimethylsilane Nitryl chloride Density functional theory abstract A mixture of chloro/bromotrimethylsilane and nitrate salt is found to be an effective reagent system for the a-chlorination/bromination of carbonyl compounds. The reaction occurs under mild conditions yield- ing the products in moderate to good yields. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction The conversion of C–H bonds to C–X bonds (X = F, Cl, Br and I) has a variety of applications in medicinal chemistry. The C–X bonds can alter the metabolic activity as well as bioavailability signifi- cantly. 1 a-Halogenated carbonyl compounds are important synthetic intermediates and are used as precursors for various organic transformations. 2 a-Haloacetophenone derivatives, partic- ularly the bromo analogs, have been investigated for their active participation in the inhibition of protein tyrosine phosphatases such as SHP-1 and PTP1B (Scheme 1). 3 Therefore, the development of a simple and convenient methodology for the synthesis of a-haloacetophenone derivatives is important. There are relatively few reagents known that allow direct a-halogenation of carbonyl compounds. A significant number of halogenating reagents and methods are available for the preparation of these compounds. 4–9 Most of these protocols used N-halosuccin- imides, 4a–r molecular halogen, 4h–l metal halides, 4m–s as well as re- lated or similar reagents. 5–9 Herein, we report a-chlorination/ bromination of carbonyl compounds with chloro/bromotrimeth- ylsilane–nitrate salt combination, as a source of mild chlorinating and brominating reagent. Our group has previously reported the use of ammonium nitrate and chlorotrimethylsilane with a catalytic amount of AlCl 3 as a robust nitrating reagent for the electrophilic nitration of aromatic compounds. 10 Recently, we have achieved regioselective nitration of arylboronic acids using chlorotrimethylsilane and nitrate salts. 11 ipso-Substituted nitroaromatics were obtained in high yields and purity in most of these reactions (Scheme 2). Since most nitrating agents have been shown to possess oxidizing char- acter, the oxidizing potential of the chlorotrimethylsilane–nitrate salt reagent system has also been closely examined. 12 As a result, chlorotrimethylsilane–nitrate salt system has been effectively em- ployed in smooth oxidation of sulfide to sulfones and in the direct oxidative chlorination of thiols and disulfides to the corresponding sulfonyl chlorides (Scheme 2). 13 The major advantage of this proto- col is that in most cases, products obtained need no further purifi- cation. Simple removal of the solvent from the reaction mixture provided analytically pure product in most cases. Lee et al. have used a mixture of chlorotrimethylsilane (TMSCl) and nitrate/nitrite salts for the generation of nitryl/nitrosyl chlo- ride in situ for deoximination of aldoximes/ketoximes in non- aqueous medium. 14 The chemistry of nitryl chloride (NO 2 Cl) as a reagent has been extensively investigated for nitration of aromatic and aliphatic compounds. 4,9,15 It is well known that typical nitra- tion reactions take place by electrophilic attack of NO 2 þ on the sub- strates facilitated by strong Lewis acids. Nitryl chlorides have been reported to react vigorously with ammonia to generate chloro- amine suggesting that NO 2 Cl can behave as a source of electro- philic chlorine. 16 During the oxidation of sulfides and sulfoxides, we found that the reaction of substrates carrying a-H such as methyl phenyl 0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.01.039 ⇑ Corresponding authors. Tel.: +1 213 740 5984; fax: +1 213 740 6679 (G.K.S.P.). E-mail addresses: gprakash@usc.edu (G.K. Surya Prakash), tmathew@usc.edu (T. Mathew). Tetrahedron Letters 52 (2011) 1217–1221 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet