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 anchimeric 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 28, 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 substructure 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 = 100:0) (Table 1). This is consistent with course of our development of potassium ion channel openers (16, the results previously reported (19). The compound with methyl fl 17), we encountered unusual regioselectivity in the tri uoroacetic substitution (2i) at the peri position also exclusively underwent acid (TFA)-catalyzed Beckmann rearrangement of oximes of benzene migration (19). However, peri-Cl substitution (2j) in- 7-oxo-dehydroabietic acid derivatives (Table 1). The parent duced alkyl migration in preference to benzene migration O-Ts-oxime of methyl 7-oxo-dehydroabietate 2a provides ex- (benzene:alkyl = 34:66). Furthermore, the peri-Br substituent clusively a benzene migration lactam 3a in TFA at 20 °C (i.e., the (2k) strongly biased the migratory preference (4k) (benzene:al- = peri nitrogen atom is inserted into the Coxime-Caromatic bond). This kyl 4:96) (Fig. 3). These results suggested that the -halogen stereoselectivity seems reasonable, because the stereochemistry atom substituent effect could be general, operating even in of the C = Nbondisanti with respect to the benzene moiety, as structurally simplified tetralone derivatives. On the other hand, confirmed by X-ray single-crystal structure analysis (Fig. 4A). fluorine atom substitution at the peri-position (2h) exclusively = On the other hand, when a chlorine atom was substituted at the induced benzene migration (benzene:alkyl 100:0). The order peri 2c of nucleophilicity of monovalent halogen atoms, deduced from position (at C14) of dehydroabietic acid ester ( ), the major < < < rearrangement reaction product in TFA at 20 °C serendipitously the basicities of halogen anions, is [F Cl Br ( I)], so that more nucleophilic halogen atoms seem to favor alkyl migration. turned out to be the alkyl migration lactam 4c [i.e., the nitrogen The stereochemistry of the C = N bond of the oximes/oxime-O- atom is inserted into the C -C bond (benzene:alkyl = oxime alkyl tosylates appears to be anti with respect to the benzene moiety in 7:93)] (Table 1). When a chlorine atom was introduced at the these peri-halogenated tetralone derivatives, based on X-ray single- aromatic 12-position (2b), i.e., at the bay region, the corre- crystal structure analysis (Fig. 4B and SI Appendix,TableS5). sponding Beckmann rearrangement reaction exclusively afforded When the corresponding anti-OH-oximes (in the absence of the the lactam product (3b) derived via benzene migration (benzene: Ts group) were subjected to reaction in TFA, no rearrangement alkyl = 100:0). Furthermore, the 12- and 14-dichloro derivative occurred at 20 °C, and the oximes were recovered. The stereo- (2d) predominantly provided the alkyl migration product (4d) chemistry of the recovered oximes was still anti, which strongly again (benzene:alkyl = 3:97). Thus, substitution of a chlorine atom suggests that the oximes, and therefore probably also the O-Ts at the peri-position leads to alkyl migration. Because the reactions oximes, do not isomerize to syn isomers in TFA at room involve dissociation of the TsOH group, these migration reactions temperature. When the leaving group was changed to mesylate (MsO), a similar preference of the migratory aptitude was observed in the cases of the unsubstituted (2g-Ms) and peri-Br (2k-Ms) cases, A B and the selectivities were comparable to those found in the OTs R R N tosylates (Table 1). N 1 1 NH OTs N H2O +TsOH + Crystallographic Data of Stable Imino-Iodonium Intermediate. In an R1 R2 H+A- R O R2 - 2 attempt to synthesize the peri-iodine–substituted tetralone oxime- (acid) A R R 1 2 O-tosylate 2-I from the corresponding anti-OH-oxime (2n-OH)by D SI Appendix Fig. 2. Beckmann rearrangement. (A) General scheme of Beckmann rear- using NaH, followed by TsCl (Fig. 4 , ), we obtained rangement. (B)Principalσ-σ* orbital interaction during migration and N-O a compound consistent with 5-I (X = I, Fig. 3), showing bonding 2 bond cleavage. between the I and sp -N atoms. The structure was confirmed by

Ohwada et al. PNAS | March 12, 2013 | vol. 110 | no. 11 | 4207 Downloaded by guest on September 28, 2021 TsOH oxime nitrogen atoms to generate 5-I.Thisideaispartially OTs X N +X N Br Br O H+ + H supported by the related formation of a carbon-nitrogen bond be- (X = Br) (CF3CO2H) N N tween various carbon nucleophiles and nitrogen of oxime bearing X= Cl, Br, I alkyl migration an O-Ts group in the presence of Brønsted acids, as reported by 2-X 5-X H+ 7-X 4-X syn-migration Narasaka et al. (22), who proposed an SN2 type reaction at the (CF3CO2H) benzene 2 ﬁ X= H, F migration Br sp nitrogen atom. Thus, we propose the involvement of a ve- anti-migration + H N X H O membered imino-halonium cation intermediate (5-Cl and 5-Br, N + N Figs. 1B and 3) (23), similar to the isolated 5-I, in the present

(X = H) 7-X' rearrangement reactions. We suggest that the peri-chlorine and 6-X 3-X peri-bromine atoms attack imine nitrogen bearing a good leaving Fig. 3. Nucleophilic monovalent halogen atom participation changes migration group (i.e., protonated O-tosylate group) in an SN2-like manner, mechanism of oximes under the Beckmann reaction conditions. OTs, O-tosyl. similarly to the reported reaction (22), with dissociation of TsOH, or attack the imino cation (5-Br′ in Fig. 1B) formed upon the preceding N-O bond cleavage, both resulting in the formation X-ray structure analysis of a single crystal prepared after partial of imino-halonium cation 5 (Fig. 3). In marked contrast to the − − replacement of Cl with BF4 using AgBF4 (one of the crystal iodine intermediate (5-I), the Cl (5-Cl) and Br intermediates − structures in a unit cell, Fig. 4D; another anion, BF4 , is omitted (5-Br) undergo alkyl migration: the nitrogen atom is inserted for clarity, SI Appendix,TableS5). A planar ﬁve-membered imino- into the alkyl C-C bond, resulting in the formation of the syn- iodonium structure involving bonding between hypervalent iodine Beckmann rearrangement products (Fig. 3). This reaction sat- − (with coordination of Cl )andsp2-N atoms was seen in 5-I (20). isﬁes the conditions that the relevant bond is located in the anti The average N-I bond length [2.063(5) Å] of 5-I is consistent with position with respect to the formally positively charged halo- those of similar hypervalent N-I(-Cl) bonding compounds prepared nium ion. These scenarios are supported by calculations, as by a different method (21). The isolated compound (5-I)didnot described in the following section. undergo Beckmann rearrangement even in TFA at 20 °C. The mechanism of formation of this intermediate is assumed to be as Computational Studies of Reaction Pathways. In density functional follows: the O-tosylate oxime (2-I, Fig. 3) was transiently generated theory calculations of substrate and transition state structures in situ, followed by bond formation between the peri-iodine and (TSs) of the migration reactions, we used experimentally real

A B

Br anti

2a 2k

OH C D I N Cl I N C C

2n-OH 90% yield Br 5-I

- (+ BF4 )

Cl N I I N

4k 5-I

Fig. 4. Crystal structures of 2a (A), 2k (B), and 4k (C), and (D) formation of 5-I and crystal structure of 5-I.

4208 | www.pnas.org/cgi/doi/10.1073/pnas.1300381110 Ohwada et al. Downloaded by guest on September 28, 2021 Table 1. Rearrangement products under Beckmann reaction conditions

Total Yield Total Yield Products (isolation yield) migration ratio Products (isolation yield) migration ratio Oxime derivatives Conditions Oxime derivatives Conditions benzene : alkyl benzene : alkyl benzene : alkyl benzene : alkyl (NMR ratio) (NMR ratio)

OTs H CH3 N CH3 O TFA N 98 % TFA 84 % 2a C, 1 hr 3i N H 2i 100 : 0 4 100 : 0 C, 1 hr 98% N H 3a H O CH3 CH3 CO Me OTs 2 CO2Me 84 % OTs H Cl O Cl Cl Cl N Cl O H 12 12 TFA N N 86 % NOE 2j + 34 : 66 83 % C, 1hr 14 (40 : 60) 2b TFA 100 : 0 3j 29% 4j 57% C, 4.5 hrs N H N H H 3b OTs OTs O 83 % Br N Br H Br O CO2Me CO2Me O H TFA N N 92 % 2k + 4 : 96 12 C, 1hr 14 14 72 % (6 : 94) 14 Cl Cl 3k 4% 4k 88% 2c TFA 7 : 93 Cl C, 3 hrs N H + O (8 : 92) OMs H H N N H N O H H O 3c H H 4c TFA N OTs CO Me 3g 72 % CO2Me CO2Me 2 67 % 2g-Ms 5 % C, 1hr 72% 100 : 0 Cl Cl Cl 12 12 14 87 % OMs Br H Br O 14 Cl Cl Br N O H 2d Cl TFA TFA N N 88 % C, 1 hr N H + O 3 : 97 + N 2k-Ms 10 : 90 H 3d N 4d(4 : 96) C, 1hr OTs H O H H CO2Me 3 % 84 % (5 : 95) CO2Me CO2Me 3k 9 % 4k 79 %

12 12 H CO H3CO 3 CHEMISTRY OCH3 14 12 14 Br TFA 97 % NOE 2e Br C, 1.5 hr O 0 :100 2l 14 TFA 95 % N N 4e N H + O H 4 C, 1 hr H H 97 % N N 92 : 8 CO Me OTs CO Me H H H H 2 2 OTs O MeO C COSY MeO2C MeO2C 2 (92 : 8) Br Br 3l87% 4l 8% J 12 12 NOE H3CO H3CO OCH3 14 TFA 87 % 12 N H 2f C, 6 hr Br 100 : 0 2m 14 TFA Br N H 3f Br 90 % H O N H + a OTs CO2Me 87 % O CO2Me C, 1 hr 20 : 80 N N H H O H H (26 : 74) OTs H MeO C OTs MeO2C MeO C H N H O 2 2 N 3m J TFA 3g 91 % 12% 4m 64% b 2g OCH [13 : 87] C, 1hr 91 % 100 : 0 + 3 (24 : 76) OTs F N H F O Br TFA N 87 % H 2h 8m 14% 3h 100 : 0 N C, 2.5 hr O 87 % O CH3 CH3

aRation of 3m and 4m. bRatio of 3m and (4m+8m).

tetralone derivatives substituted with O-mesylate (Ms) (e.g., 2g-Ms to the activation energies of related oximes (e.g., acetophenone and 2k-Ms; SI Appendix, Tables S1–S4) as a leaving group, with oxime) calculated previously (12). B hydrogen chloride as the acid in simulated HCO2H solution (12). The calculated TSs (TS-S,Fig.5 )fortheputativeattackof The TSs for the aromatic migration (TS-B) were obtained the peri-halogen atoms on the sp2 N(-OMs) group, with the MsOH (Fig. 5A) in the presence of assistance from protonation of the group leaving, involve a planar alignment of the halogen, oxime MsO group, activating it as a leaving group. Protonation can occur N and O(Ms) atoms, resembling the TSs of SN2 reactions. This in two kinds of oxygen atoms of the MsO group: an oxime oxygen process is surprisingly energetically attainable. The calculated ac- atom and a sulfone oxygen atom. Both of the calculated TSs take tivation barriers of this process [22.0 (Cl), 17.9 (Br), 15.4 (I), in a spiro structure, consisting of a benzene ring and a bisecting kcal/mol] are smaller than those of the benzene migration C = N bond, indicating involvement of electron delocalization (24–28 kcal/mol). In the case of peri-Cl, the benzene migration of the occupied aromatic π orbitals, rather than the σ orbitals can compete with the Cl-N bonding process. This is consistent (Fig. 2B), to the vacant σ*N-O bond, leading to migration with with the experimentally observed migratory preference (2j,Table1). simultaneous N-O bond cleavage (Fig. 5D) (6, 12, 24). The The magnitude of the calculated activation barriers of the sub- magnitude of the calculated activation barriers of benzene mi- stitution process is related to the nucleophilicity of the peri- gration are slightly dependent on the halogen atoms, but the values halogen atom (SI Appendix, Tables S2 and S4), i.e., in the order are within the range of 24–28 kcal/mol (SI Appendix,TablesS1and of I < Br < Cl. The orbital energy levels of the nonbonding (n) S3) despite different protonation site of the OMs (O-mesyl) group. orbital of the peri-halogen atoms of MsO-tetralone oximes in the As the halogen atom is more electronegative, the activation energy natural bond orbital basis are F (−0.397) < Cl (−0.306) < Br of the benzene migration is increased. These values are comparable (−0.278) < I(−0.243) (in atomic units). Thus, high-lying orbitals

Ohwada et al. PNAS | March 12, 2013 | vol. 110 | no. 11 | 4209 Downloaded by guest on September 28, 2021 A Benzene migration B Subsitution C Alkyl migration Br Br N N TS-B TS-A N

Br TS-S X = Br X = I

24.7 14.7 5-X 7-X 2-X 23.1 Br 23.7 17.9 15.4

Cl Br N H N Br N 7-Br 6-Br Br 5-Br (kcal/mol) reactant (2k-Ms (X=Br),2n-Ms (X=I))

3-X reaction coordinate A reaction coordinate B-C 4-X H H H D E OMs +O Ms n * O Ms n * * X N + X N N

substitution X TS-B 2-X TS-S

Fig. 5. Calculated reaction pathways for the cases of peri-Br (solid line) and peri-I (dashed line). (A) Benzene migration. (B) Substitution. (C) Alkyl migration. (D) Orbital interaction in benzene migration. (E) Orbital interactions in substitution and N-O bond cleavage.

of halogen atoms interact strongly with the oxime sp2 nitrogen different from that of the conventional Beckmann reaction atom and form stronger X—N bonding. In fact, in the TS structure involving isomerization of the oximes. of the substitution (TS-S, Fig. 5B), electron delocalization of the nonbonding (n) orbital of the peri-halogen atom (X) and vacant Kinetics of Rearrangement. Rates of disappearance of the starting 2p (π*) orbital of the imino nitrogen atom is predominant (Fig. materials, the tetralone oxime O-tosylates (2), under the Beckmann 5E), and the stabilization energies of X(n)—N(π*) bonding are rearrangement conditions were measured in TFA. The reac- fi calculated to be in the order of X = Cl (65.4) < Br (76.0) < I(81.5) tions showed rst-order kinetics with respect to the oxime peri (in kcal/mol), in terms of the natural bond orbital delocalization derivative. In the case of the -chlorine compound (2j), alkyl and benzene migrations both occurred (∼2:1), but the former was energies. These results are consistent with the features of an SN2- like reaction. From another point of view, it is reasonable that predominant. The relative rates of the reactions of the tetralone − < ∼ << more electron-donating halogen atoms can stabilize the imino derivatives at 5 °C were as follows: 2g (1.0) 2i (4.7) 2j (3.3) − − cation (Fig. 1B). Furthermore, the TSs for alkyl migration from 2k (12.7, at 20 °C, too fast to measure at 5 °C). The kinetics of these imino-halonium intermediates (5-X) were obtained (TS-A, dehydroabietic acid derivatives was also measured. In those cases, C the reaction is essentially selective, and thus the interpretation of Fig. 5 ), and the activation barriers increase in the order of − Cl (0.9) < Br (14.7) < I(23.1)(inkcal/mol)becauseofthe the kinetic data is more straightforward. The relative rates at 5°C 2b ∼ 2f << 2a << 2c < 2e disconnection of stronger X—N bonding. The peri-chlorine and were as follows: (0.05) (0.07) (1.0) (19.5) (27.9). In both cases, the trends are similar: compared with the bromine atoms can also at least partially stabilize the resulting unsubstituted case (2gj2a), the peri-Cl (2jj2c)andperi-Br (2kj2e) vinyl cation (7-X, nitrilium ion) via bending of the C—X bond atoms significantly accelerate the alkyl migration reaction, the effect (7-X′, Figs. 3 and 5), representing conventional neighboring being larger in magnitude in the latter case, whereas substitution at group participation of the halogen atom with the electron-deficient the bay region of the 12-Cl (2b) and 12-Br (2f) compounds signif- carbon atom. Benzene migration of the imino-halonium inter- icantly retarded the reactions. The reduction of the migration rates 5-X mediates ( ) can occur through recovery of anti-oxime type can be attributed to the decrease of the electron densities of the structures (like 2-X, but in which the O-Ts group is replaced with − aromatic rings resulting from substitution of the electronegative a counter anion, Cl , in the present calculation model). Benzene halogen atom. Under these circumstances, however, only benzene migration of the imino-halonium intermediates (5-X) is calcu- migration occurred in the dehydroabietic acid derivatives 2b and 2f. lated to be a higher energy process than alkyl migration, with Therefore, peri-chlorine and peri-bromine substituents provided – activation energies at 30 32 kcal/mol in the cases of Cl, Br, and significant anchimeric assistance for the alkyl migration (5). I. Thus, these calculations are consistent with the experimentally observed migratory aptitudes: (i)Theperi-Cl and peri-Br Another Natural Product System. Apart from dehydroabietic acids, atoms induced alkyl migration through nucleophilic interaction members of another family of natural products, podocarpic acid of the halogen atom with the positively charged sp2 N atom, derivatives, also contain a tetralone substructure in addition to the and the peri-Br atom is more selective for the alkyl migration; presence of a phenolic group and reverse stereochemistry of the and (ii) substitution of the peri-I atom onto the sp2 Natomis quaternary carbon atoms bearing a carboxylic acid group and very facile, but there is a high energy barrier for the alkyl mi- a methyl group (at C4). The oxime derivative of unsubstituted gration (Fig. 5). Thus, the intermediate complex 5-I is experimen- methyl O-methyl-7-oxo-podcarpate 2l predominantly afforded the tally isolated and is inert to migration. The reaction mechanism benzene migration product (benzene:alkyl = 92:8) (Table 1). The leading to the alkyl (syn-) migration, therefore, is completely peri-Br substituent in 2m was found to favor alkyl migration (4m)

4210 | www.pnas.org/cgi/doi/10.1073/pnas.1300381110 Ohwada et al. Downloaded by guest on September 28, 2021 (benzene:alkyl = 20:80, or 13:87 after adjustment for the Beck- conditions are similar to those of the Beckmann reaction. Our mann fragmentation reaction), although the benzene migration results indicate that nucleophilic halogen atoms can interact product 3m and the Beckmann-type fragmentation product 6m with and stabilize electron-deﬁcient noncarbon atoms (i.e., imino were also formed. The previous study of the Beckmann rear- nitrogen cations) in close spatial proximity by means of transient rangement of oxime derivatives of 1-phenyl-2-propanone and bonding within the reaction pathway (Fig. 1B). Such nucleophilic related compounds demonstrated that the simultaneous formation monovalent halogen atom participation appears to operate in of the Beckmann rearrangement and fragmentation reaction acid-catalyzed reactions of 1-tetralone oxime derivatives under products can be rationalized in terms of a single common TS, the Beckmann reaction conditions. This halogen-nitrogen bonding followed by dynamic reaction path bifurcation (11). Bond cleavage promotes alkyl migration that can superﬁcially be considered as in Beckmann fragmentation reactions is also known to occur in syn-migration of the relevant oximes in terms of the Beckmann an antiperiplanar fashion (10, 11). Although the reaction mech- rearrangement reaction. This participation of halogen atoms under anism of the present rearrangement reaction is different from acid-catalyzed Beckmann rearrangement conditions is expected to that of the Beckmann rearrangement, the formation of the frag- provide a method for selective synthesis of regioisomeric lactams mentation product (6m) in addition to the major alkyl migration and related amines (obtained after amide reduction) from closely reaction product (4m) also suggested the involvement of a common related starting materials. single intermediate such as 5-Br (SI Appendix,Fig.S3). Therefore, the peri-bromine atom also facilitates syn (alkyl) migration in the Materials and Methods podocarpic acid structure wherein the conformation of the em- Details concerning the synthesis and characterization of all compounds can bedded tetralone structure is different from that of dehydroabietic be found in SI Appendix, Materials and Methods. The details of kinetics can acid derivatives (SI Appendix,TableS5). be found in SI Appendix, Kinetic Measurement and Figs. S1-S3. The details of computational studies can be found in SI Appendix, Computational Methods Summary and Tables S1-S4. Details of single crystal X-ray diffraction experiments can Our present experimental results and theoretical calculations sup- be found in SI Appendix, Single-Crystal X-Ray Diffraction Experiments and port the idea that imino-halonium cations (5-X) intervene as re- Table S5. active intermediates in the unusual formation of syn-rearrangement peri – ACKNOWLEDGMENTS. We thank Drs. S. Baba and K. Miura, the Japan products of -halogen substituted 1-tetralone oxime O-tosylate Synchrotron Radiation Research Institute (JASRI) for their valuable help in derivatives under acid-catalyzed Beckmann reaction conditions.

data collection during the X-ray analysis of 3a and 4d, and the computa- CHEMISTRY These intermediates take a cyclic ﬁve-membered ring structure, tional facility for generous allotments of computer time. The synchrotron like that of the tetramethylenehalonium ion (1b). As described radiation experiment was performed at beamline BL38B1 in SPring-8, the large in this article, the conversion of the peri-halogenated oximes synchrotron radiation facility in Hyogo, Japan, with the approval of JASRI Pro- syn posals 2008B1981 and 2009B1923. The computations were performed at to -rearrangement lactam products is not truly a Beckmann the Research Center for Computational Science, Okazaki, Japan. This work rearrangement even though the starting materials and reaction was supported by the University of Tokyo and Tokushima Bunri University.

1. Roberts I, Kimball GE (1937) The halogenation of ethylenes. J Am Chem Soc 59(5):947–948. 14. López L, et al. (2010) Synthesis, 3D-QSAR, and structural modeling of benzolactam 2. Winstein S, Lucas HJ (1939) Retention of configuration in the reaction of the 3-bromo- derivatives with binding affinity for the D(2) and D(3) receptors. ChemMedChem 5(8): 2-butanols with hydrogen bromide. J Am Chem Soc 61(6):1576–1581. 1300–1317. 3. Olah GA, Westerman PW, Melby EG, Mo YK (1974) Onium ions. X. Structural study of 15. Ogawa H, et al. (1996) Orally active, nonpeptide vasopressin V-2 receptor antagonists: acyclic and cyclic halonium ions by carbon-13 nuclear magnetic resonance spectros- A novel series of 1- 4-(benzoylamino)benzoyl-2,3,4,5-tetrahydro- 1H-benzazepines copy. The question of intra- and intermolecular equilibration of halonium ions with and related compounds. JMedChem39(18):3647–3555. haloalkylcarbenium ions. J Am Chem Soc 96(11):3565–3573. 16. Cui Y-M, et al. (2010) Design, synthesis, and characterization of BK channel openers 4. Slebocka-Tilk H, Ball RG, Brown RS (1985) The question of reversible formation of based on oximation of abietane diterpene derivatives. Bioorg Med Chem 18(24): broonium ions during the course of electrophilic bromination of olefins. 2. The crystal 8642–8659. and molecular structure of the bromonium ion of adamantylideneadamantane. JAm 17. Gessner G, et al. (2012) Molecular mechanism of pharmacological activation of BK Chem Soc 107(15):4504–4508. channels. Proc Natl Acad Sci USA 109(9):3552–3557. 5. Capon B, McManus SP (1976) Neighboring Group Participation (Plenum Press, New York). 18. Mallory FB, Mallory CW (1985) Nuclear-spin-spin coupling via nonbonded interactions. 6. Donaruma LG, Heldt WZ (1960) The Beckmann rearrangement. Org React 11:1–156. 5. N-F coupling. JAmChemSoc107(17):4816–4819. 7. Gawley RE (1988) The Beckmann reactions: rearrangements, elimination-additions, 19. Lansbury PT, Mancuso NR (1965) Non-stereospecificity in the Beckmann and Schmidt fragmentations, and rearrangement-cyclizations. Org React 35:1–420. reactions. Tetrahedron Lett 6(29):2445–2450. 8. Craig D (1991) The Beckmann and related reactions. Comprehensive Organic Synthesis, 20. Ochiai M (2007) Stoichiometric and catalytic oxidations with hypervalent organo-λ3- ed Ley S (Pergamon Press, Oxford), Vol 7, pp 689–702. iodanes. Chem Rec 7(1):12–23. 9. Clayden J, Greeves N, Warren S, Wothers P (2001) Organic Chemistry (Oxford Univ 21. Niedermann K, et al. (2010) New hypervalent iodine reagents for electrophilic Press, Oxford), 969–1002. trifluoromethylation and their precursors: Synthesis, structure, and reactivity. 10. Yamamoto Y, Hasegawa H, Yamataka H (2011) Dynamic path bifurcation in the Tetrahedron 66(31):5753–5761. Beckmann reaction: Support from kinetic analyses. J Org Chem 76(11):4652–4660. 22. Kitamura M, Yoshida M, Kikuchi T, Narasaka K (2003) Synthesis of quinolones and 11. Yamataka H, Sato M, Hasegawa H, Ammal CS (2010) Dynamic path bifurcation 2H-dihydropyrroles by nucleophilic substitution at the nitrogen atom of oxime de- for the Beckmann reaction: Observation and implication. Faraday Discuss 145: rivatives. Synthesis (15):2415–2426. 327–340. 23. Ochiai M, Miyamoto K, Kaneaki T, Hayashi S, Nakanishi W (2011) Highly regioselective 12. Yamabe S, Tsuchida N, Yamazaki S (2005) Is the Beckmann rearrangement a con- amination of unactivated alkanes by hypervalent sulfonylimino-λ³-bromane. Science certed or stepwise reaction? A computational study. J Org Chem 70(26):10638–10644. 332(6028):448–451. 13. Hilmey DG, Paquette LA (2005) Promoter-dependent course of the Beckmann re- 24. Pearson DE, Cole WE (1955) The Beckmann rearrangement. 5. The rearrange- arrangement of stereoisomeric spiro[4.4]nonane-1,6-dione monoximes. Org Lett ment rates of some ortho-substituted acetophenone oximes. J Org Chem 20(4): 7(10):2067–2069. 488–493.

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