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Stereochemical Evidence for Stabilization of a Nitrogen Cation by Neighboring Chlorine Or Bromine

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Stereochemical Evidence for Stabilization of a Nitrogen Cation by Neighboring Chlorine Or Bromine Stereochemical evidence for stabilization of a nitrogen cation by neighboring chlorine or bromine Tomohiko Ohwadaa,1, Norihiko Tania, Yuko Sakamakia, Yoji Kabasawaa, Yuko Otania, Masatoshi Kawahatab, and Kentaro Yamaguchib,1 aGraduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan; and bFaculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Kagawa 769-2193, Japan Edited by Jerrold Meinwald, Cornell University, Ithaca, NY, and approved January 25, 2013 (received for review January 8, 2013) Neighboring group participation is one of the fundamental inter- with a heteroatom-centered cation is really possible and whether actions in organic reactions and can influence the reaction rate, it influences the course of the reaction. We report an intriguing stereoselectivity, and reaction pathway through transient carbon- rearrangement reaction of oximes under Beckmann rearrange- carbon or carbon-heteroatom bond formation. The latter category ment reaction conditions in which halogen atom participation includes cyclic three- and five-membered bromonium ions, wherein results in syn-regioselectivity, in contrast to the general case of lone-pair electrons of the monovalent bromine atom stabilize a anti-selectivity. trigonal carbocation. Although similar nucleophilic interactions of The Beckmann rearrangement is the acid-catalyzed transfor- monovalent halogen atoms with non–carbon atom-centered cations mation of oximes to amides. This reaction has been well docu- have long been predicted, we know of no experimental evidence mented, extensively reviewed (6–8), and described in many of such an interaction. Here, we demonstrate a nucleophilic inter- undergraduate textbooks of organic chemistry as one of the action of neighboring monovalent halogen to stabilize an imino oldest and most familiar transformations in organic chemistry sp2 nitrogen cation. This interaction has an overwhelming impact (9). In the Beckmann rearrangement, the oxime nitrogen atom is on the reaction pathway, completely altering the migratory pref- inserted into the Coxime-Cα bond of aldehydes and ketones (Fig. erence under acid-catalyzed Beckmann rearrangement conditions. 2A). It is generally accepted that the Beckmann rearrangement In sharp contrast to the general case of anti-migration, peri-chloro– of ketoximes is stereospecific, that N-O bond cleavage occurs and peri-bromo–substituted O-tosyl oximes of 1-tetralone substruc- with simultaneous migration (e.g., in the cases of O-tosyl (Ts)- tures and their derivatives undergo syn-migration under Beck- phenyl-2-propanone oxime derivatives) (10–12), and that the mann rearrangement conditions (i.e., migration of the group on relevant C-C bond anti to the leaving group on nitrogen atom the syn side of the leaving group). The peri-chloro or peri- migrates (i.e., anti-migration) occurs to maximize antiperiplanar bromo neighboring group turned out to provide strong anchimeric electron delocalization of the C-C σ orbital to the antibonding σ* assistance for syn-migration via transient formation of a cyclic orbital of the N-O bond (Fig. 2B) (6, 7, 10–12). However, a very five-membered imino-halonium cation with dissociation of tosylic few apparent exceptions have been documented under certain acid. Thus, formation of the syn-migration products can be attrib- reaction conditions (8, 13). If a syn-migration product is uted to a reaction mechanism that is different from the conventional formed, it has been assumed that isomerization of the oxime Beckmann rearrangement mechanism. That is, the positively charged occurs before rearrangement (6–8, 13). However, such isom- imino nitrogen atom can be stabilized by, or interact with, a chloro erization of the oximes does not occur in the present case. In- or bromo group in close spatial proximity, and this interaction stead, in this article, we propose that the apparently syn- dramatically changes the reaction pathway, selectively affording Beckmann rearrangement that we observed in oximes of 1-tet- regioisomeric lactams from closely related starting materials. ralone derivatives proceeds as a consequence of strong anchi- meric assistance of the peri-chloro or peri-bromo neighboring halogen-nitrogen bonding | organic reaction mechanisms | stereochemistry group via transient formation of an imino-halonium cation (5-Br, Figs. 1B and 3). In this context, the syn-migration products are eighboring group participation is one of the fundamental derived from a reaction pathway that is distinct from the mecha- Ninteractions in organic reactions, having the potential to alter nism of the conventional Beckmann rearrangement. Our results the reaction rate, stereoselectivity, or reaction pathway through indicate that anchimeric nucleophilic monovalent halogen atom the transient formation of a carbon-carbon or carbon-heteroatom participation can potentially intervene in the interactions of bond. A bromine atom can bridge two carbon atoms to yield a positively charged imino nitrogen atoms, not only in those of cyclic three-membered bromonium ion (1a,Fig.1A)(1),wherein positively charged carbon atoms. From the viewpoint of organic lone-pair electrons of the monovalent bromine atom stabilize a synthesis, this means that a single peri-halogen atom sub- trigonal carbocationic center (1a′ or 1a″) (2). The formation of stitution may lead to an extension (or modification) of the well- halonium ions, including cyclic five-membered tetramethyleneha- established Beckmann rearrangement reaction to provide an ac- lonium ions (1b), in addition to the three-membered bromonium cess to pharmaceutically intriguing benzazepine derivatives, for ion (1a), has been confirmed under conditions in which the example (14, 15). cations are long-lived (3). Later, X-ray single-crystal structure analysis confirmed the three-membered cyclic structure of the bromonium ion (1a) generated by bromination of a sterically Author contributions: T.O. and K.Y. designed research; T.O., N.T., Y.S., Y.K., Y.O., and M.K. fi performed research; T.O., Y.O., M.K., and K.Y. analyzed data; and T.O., Y.O., and K.Y. hindered ole n, adamantylideneadamantane (4). These results wrote the paper. were examples of neighboring group participation involving nu- The authors declare no conflict of interest. cleophilic (i.e., electron-donating) monovalent halogen atoms, This article is a PNAS Direct Submission. particularly in bonding with electron-deficient carbon atoms (5). Although nucleophilic interactions of monovalent halogen atoms Data deposition: The sequences reported in this paper have been deposited in the Gen- – Bank database. For a list of accession numbers, see the SI Appendix. with non carbon atom-centered cations have long been predicted, 1To whom correspondence may be addressed. E-mail: [email protected] or to our knowledge, such an interaction has never been reported. [email protected]. Herein, we address the longstanding question of whether nucle- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. ophilic participation of monovalent halogen atoms in bonding 1073/pnas.1300381110/-/DCSupplemental. 4206–4211 | PNAS | March 12, 2013 | vol. 110 | no. 11 www.pnas.org/cgi/doi/10.1073/pnas.1300381110 Downloaded by guest on September 30, 2021 A + are essentially irreversible, and the product is formed kinetically. Br Br Br Thus, the migratory preference is determined kinetically. A high migratory selectivity was also observed upon sub- + + stitution of a bromine atom at the peri-position. The 14-bromo derivative (2e) of dehydroabietic acid ester provided only the = 1a' 1a 1a'' alkyl migration product (4e) (benzene:alkyl 0:100), whereas substitution of a bromine atom at the 12 position (2f) produced only the benzene migration product (3f) (benzene: alkyl = 100: 0) + under similar reaction conditions. Anti stereochemistry of the Br + Br + Br N-O bond of these oximes and/or oxime-O-tosylates with respect to the benzene moiety, which can minimize steric congestion, was confirmed by X-ray single-crystal structure analysis (Fig. 4A and H H H H H H SI Appendix, Table S5). This overwhelming preference for mi- H H H H H H syn 1b' 1b 1b'' gration of the alkyl group on the side of the oxime TsO group (i.e., syn-Beckmann rearrangement) is unusual. + B + Peri fi Br N Effect of -Halogen Atoms in the Simpli ed Substructure System. Br N Tetralone structure (2g) can be regarded as a simplified sub- structure of dehydroabietic acid. In the peri-fluorine–substituted tetralone oxime (2h-OH), an exceptionally large coupling con- 15 19 15 stant (J N F) between the oxime nitrogen ( N) and peri-fluorine (19F) atoms was reported (18). This is consistent with close spatial 5-Br 5-Br' proximity between the oxime nitrogen and the peri-fluorine atom, and similar proximity is expected in the cases of other peri-halogen Fig. 1. Participation of nucleophilic monovalent halogen atom. (A) Br ions atoms. In fact, X-ray single-crystal structure analysis of peri- 1a and 1b, involving transient C-Br bonding. (B) Imino-Br cation 5-Br, involving halogen–substituted oxime derivatives showed distortion of the transient N-Br bonding. peri-halogenated benzene ring and the oxime imino (C = N) bond from coplanarity to avoid van der Waals contact (SI Appendix, CHEMISTRY Results and Discussion Table S5). The parent unsubstituted tetralone O-Ts-oxime (2g) provided the benzene migration product (3g) exclusively in TFA Peri -Halogen Atom Participation in Oxime Rearrangements. In the at 20 °C (benzene:alkyl
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