Carbanionic Rearrangements of Halomethylenecyclobutanes

Oct 6, 2010 - Zhengming Du and Karen L. Erickson. Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University, Worcester, Massachusetts ...
0 downloads 0 Views 1MB Size
Download PDF
pubs.acs.org/joc

Carbanionic Rearrangements of Halomethylenecyclobutanes. Stereochemistry of the Migrating Group Zhengming Du and Karen L. Erickson* Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University, Worcester, Massachusetts 01610, United States [email protected] Received June 22, 2010

The unusual base-induced ring-enlargement of halomethylenecyclobutanes to 1-halocyclopentenes was examined with unsymmetrical and 13C-labeled substrates to study regio- and stereochemical characteristics. Migration of a ring carbon atom (single migration) or simultaneous migration of a ring carbon atom and the halide (double migration) gives the ring-enlarged products. 13C-labeling experiments established that both rearrangements occur with retention of configuration at the migrating center. These systems are suggested as models for the Fritsch-Buttenberg-Wiechell (FBW) rearrangement.

Introduction 1,2-Shifts to carbanionic centers are relatively rare but of much theoretical interest.1 Three categories of such reactions can be defined dependent on the nature of the migration origin and the migrating group (eqs 1-3). In the Wittig (Z = O), azaWittig (Z = N), and Stevens and related rearrangements (Z = Nþ or Sþ) (eq 1),2 the migration origin is a heteroatom from which a carbon atom migrates to the adjacent carbanionic site with the heteroatom stabilizing the electron-rich intermediate or transition state. In the Grovenstein-Zimmerman rearangement (eq 2),3 no heteroatoms are involved. Migration of a (1) (a) Hunter, D. H.; Stothers, J. B.; Warnhoff, E. W. In Rearrangements in Ground and Excited States; de Mayo, P., Ed.; Academic Press: New York, 1980; Vol. 1, pp 391-470 and references cited therein. (b) Borosky, G. L. J. Org. Chem. 1998, 68, 3337–3345. (c) Campos, P. J.; Sampedro, D.; Rodriguez, M. A. Organometallics 1998, 17, 5390–5396. (2) (a) Smith, M. B.; March, J. March’s Advanced Organic Chemistry, 5th ed.; Wiley-Interscience: New York, 2001; pp 1419-1422 and references cited therein. (b) Vogel, C. Synthesis 1997, 497–511. (c) Tomooka, K. In The Chemistry of OrganolithiumCompounds; Rappoport, Z., Marek, I., Eds.; Wiley: London, 2004; Vol. 2, pp 749-828. (d) Wolfe, J. P.; Guthrie, N. J. In Name Reactions for Homologations,Part II; Li, J. J., Ed.; Wiley: Hoboken, NJ, 2009; pp 226-240. (e) Kumar, R. R.; Vanitha, K. A.; Perumal, S. In ref 2d, pp 516-530. (3) Grovenstein, E.; Singh, J.; Patil, B. B.; VanDerVeer, D. Tetrahedron 1994, 50, 5971–5998. and references cited therein. (4) (a) Eisch, J. J.; Tsai, M. R. J. Am. Chem. Soc. 1973, 95, 4065–4066. (b) Eisch, J. J.; Tsai, M. R. J. Organomet. Chem. 1982, 225, 5–23. (c) Menichetti, S.; Stirling, J. M. J. Chem. Soc., Perkin Trans. 2 1992, 741–742. (d) Anderson, D. K.; Curtis, J. M.; Sikorski, J. A. Phosphorus, Sulfur, Silicon Relat. Elem. 1995, 101, 291–293. (e) Brook, A. G.; Bassendale, A. R. In ref 1a, Vol. 2, pp 149-227. (f) Rogas, C. M. In ref 2d, pp 406-437.

DOI: 10.1021/jo101222v r 2010 American Chemical Society

Published on Web 10/06/2010

sp2- or sp-hybridized carbon atom occurs with the unsaturated nature of the migrator permitting delocalization of electron density. Migration of a heteroatom from a carbon atom to a carbanionic site (eq 3) has been observed when Z = silicon,4 sulfur,5,6 and halogen7 and suggested when Z = oxygen.5 In these cases, the migrating Z disperses the negative charge.

Whether these rearrangements occur by stepwise or concerted processes has been a matter of some debate. For first-row elements lacking low energy vacant orbitals (C, N, O, F), orbital (5) Russell, G. A.; Dedolph, D. J. Org. Chem. 1985, 50, 3878–3881. (6) (a) Shainyan, B. A.; Mirskova, A. N.; Bel’skil, V. K. J. Org. Chem. USSR (Engl. Transl.) 1986, 22, 1727–1736. (b) Shainyan, B. A. J. Phys. Org. Chem. 1993, 6, 59–63. (7) (a) Shainyan, B. A.; Mirskova, A. M. J. Org. Chem. USSR (Engl. Transl.) 1983, 19, 1201–1202. (b) Shainyan, B. A.; Mirskova, A. M.; Vitkovskii, V. Yu. J. Org. Chem. USSR (Engl. Transl.) 1985, 21, 877–884. (c) Shainyan, B. A.; Mirskova, A. M. J. Org. Chem. USSR (Engl. Transl.) 1988, 24, 224–229. (d) Shainyan, B. A. J. Org. Chem. USSR (Engl. Transl.) 1988, 24, 229–234.

J. Org. Chem. 2010, 75, 7129–7140

7129

JOC Article symmetry prohibits concerted migration in a suprafacialsuprafacial fashion and geometric constraints render an antarafacial-suprafacial process unlikely.8 On the other hand, unsaturated groups such as sp2- or sp-hybridized carbons or main group elements that can expand their octets may rearrange in a concerted manner.1 When the carbanionic site is vinylic, a carbene anion resonance form may be written:

To the extent this form contributes, one can envision an electron-deficient center within the anionic system. An adjacent atom can then migrate with its electrons to that center in a suprafacial/suprafacial manner as the rearrangement now is analogous to a 1,2-shift in a carbocation involving two electrons rather than four. In 1973, we reported9 that the base-induced ring enlargement of 1-(halomethylene)cyclobutanes to 1-halocyclopentenes (eq 4), a reaction first observed in 1965,10 may be viewed in such a manner. Deuterium-exchange studies had previously established the presence of the vinylanion in these systems.11 Similarly, Shainyan and co-workers7a,b postulated a [1,2]-sigmatropic shift of a halide in the fluorideinduced rearrangement of β,β-dihalovinyl sulfones (eq 5). In this case, the authors postulated a substantial contribution of the carbene-anion resonance form because of the stabilizing effect of the two halogen substituents.

With the halomethylenecyclobutyl systems, labeling studies12 have established that there are two competing pathways to the ring-enlarged vinyl halides as shown in Scheme 1. Route a represents a single migration of a ring carbon atom from an electron-rich site to an electron-poor site with the halide remaining attached to C-1 throughout. Alternately, a double migration (8) (a) Woodward, R. B.; Hoffmann, R. The Conservation of Orbital Symmetry; Verlag Chemie International: Deerfield Beach, 1970. (b) Fleming, I. Pericyclic Reactions; Oxford University Press: Oxford, 1999. (9) Erickson, K. L. J. Org. Chem. 1973, 38, 1463–1469. (10) Erickson, K. L.; Wolinsky, J. J. Am. Chem. Soc. 1965, 87, 1142–1143. (11) (a) Erickson, K. L.; Markstein, J.; Kim, K. J. Org. Chem. 1971, 36, 1024–1030. (b) Erickson, K. L. J. Org. Chem. 1971, 36, 1031–1036. (12) (a) Samuel, S. P.; Niu, T. Q.; Erickson, K. L. J. Am. Chem. Soc. 1989, 111, 1429–1436. (b) Du, Z.; Haglund, M. J.; Pratt, L. A.; Erickson, K. L. J. Org. Chem. 1998, 63, 8880–8887. (13) (a) Reetz, M. T. Tetrahedron 1973, 29, 2189–2194. (b) Reetz, M. T. Adv. Organomet. Chem. 1977, 16, 33–65. (c) Zou, J.-W.; Yu, C.-H. J. Phys. Chem. 2004, 108, 5649–5654. (d) Purohit, V. C.; Matla, A. S.; Romo, D. J. Am. Chem. Soc. 2008, 130, 10478–10479.

7130

J. Org. Chem. Vol. 75, No. 21, 2010

Du and Erickson SCHEME 1

(dyotropic rearrangement13) of carbon and halogen atoms occurs, either synchronously or through a carbene-halide complex, analogous to the Beckmann rearrangement14 of oximes (route b). Here, the halide dissociates but remains partially bonded or closely associated with the cyclobutyl system. Finally, the halide can also be irreversibly lost (route c) leading to wellestablished carbene chemistry.15 The present work was undertaken to determine the stereochemical fate of the migrating ring carbon in these rearrangements. Retention of configuration is demanded by each of the proposed mechanisms (single and double migration). An unsymmetrically substituted 13C-labeled halomethylenecyclobutane would define both the regiochemical preference and the stereochemical integrity of the reaction. Herein we report our attempts to synthesize a bromomethylenecyclobutane with defined different substitution on the ring carbons and a 13C-label at the exocyclic vinyl carbon. Several bromomethylenecyclobutanes were synthesized, and the regio- and stereochemistry of their ring-enlarged products were examined. Ultimately, multiple 13 C-labeling was employed to construct both isomers of an unsymmetrical system devoid of troublesome side reactions during the rearrangement process. Synthesis of Unsymmetrically Substituted 1-(Bromomethylene)cyclobutanes. 3-Ethoxy-1-(bromomethylene)cyclobutyl systems with distinguishable substitution patterns at ring carbons 2 and 4 were chosen as substrates for study. The function of the ethoxy group is to facilitate the initial cycloaddition reaction16 and provide a probe for distinguishing the stereoisomers by 13C NMR. An alkoxy group displays a γ-shielding effect on methyl groups adjacent and syn to it.17 Scheme 2 illustrates the general synthetic methods used. [2 þ 2]-Cycloaddition of the ketene,16 generated (in situ) from the corresponding acid chloride, with the appropriate vinyl ether afforded the requisite starting cyclobutanones. Conversion of these to the bromomethylenecyclobutanes was achieved by the three-step process of methylenation followed (14) (a) Yamabe, S.; Tsuchida, N.; Yamazaki, S. J. Org. Chem. 2005, 70, 10638-10644 and references cited therein. (b) Kumar, R. R.; Vanitha, K. A.; Balasubramanian, M. In ref 2d, pp 274-292. (15) (a) Jones, W. M. In Rearrangements in Ground and Excited States; de Mayo, P., Ed.; Academic Press: New York, 1980; Vol. 1, pp 95-160 and references cited therein. (b) Nickon, A. Acc. Chem. Res. 1993, 26, 84–89. and references cited therein. (16) Hyatt, J. A.; Reynolds, P. W. Org. React. 1994, 45, 159–646. (17) (a) Wehrli, F. W.; Wirthlin, T. Interpretation of Carbon-13 NMR Spectra; Heyden: London, 1978; pp 37-39. (b) Rajanbabu, T. V. J. Am. Chem. Soc. 1987, 109, 609–611. (c) Bartlett, P. A.; McLaren, K. L.; Ting, P. C. J. Am. Chem. Soc. 1988, 110, 1633–1634. (d) Gaudino, J. J.; Wilcox, C. S. J. Am. Chem. Soc. 1990, 112, 4374–4380.

JOC Article

Du and Erickson SCHEME 2

FIGURE 1. Conformations of 3,4-trans- and 3,4-cis-3-ethoxy2,4,4-trimethylmethylenecyclobutanes (8 and 9).

by bromination-dehybromination (method A) or direct bromomethylenation (method B). The latter method was only applicable to cyclobutanones with an OCH3 group in the 2-position. 3- Ethoxy-2,2,4-trimethyl Series. [2 þ 2]-Cycloaddition of dimethyl ketene with ethyl-1-propenyl ether (cis/trans mixture) gave only the 3,4-cis-cyclobutanone 6,18 but this was easily converted to the 3,4-trans-cyclobutanone 7 upon refluxing in triethylamine. Methylenation of either 6 or 7 (method A) gave only 4-trans-3-ethoxy-2,2,4-trimethyl-1-(methylene)cyclobutane (8). However, under acidic methylenation conditions,19 3,4-cisethoxy-2,2,4-trimethyl-1-(methylene)cyclobutane (9) was obtained as the major isomer (9:8 = 12:1). The isomers were inseparable chromatographically. Unfortunately, brominationdehydrobromination of either 8 or 9 gave an inseparable mixture of (Z)- and (E)-3,4-trans isomers 10 and 11 but no detectable amount of the corresponding 3,4-cis isomers.

(H-3) in the 1H NMR is also observed (3.82 vs 3.44 δ for 6 and 7 and 3.64 vs 3.14 δ for 9 and 8, respectively). Mayr and Huisgen20 first reported the shielding of H-3 in cyclobutanones by adjacent cis-methyl groups. In the 3,4-trans isomers (7 and 8) H-3 is cis to two adjacent methyl groups while in the 3,4-cis isomers (6 and 9) H-3 is cis to only one methyl group. This shielding effect may be ascribed to the conformational preferences illustrated in Figure 1. In the 3,4-trans isomers, the conformer on the left is expected to be more stable and H-3 is shielded by the double bond, while in the 3,4-cis isomers the conformer on the right predominates and H-3 is in the deshielding region of the double bond. Figure 1 also explains the large, but opposite, chemical shift difference between the C-3 carbons in the 3,4-cis and 3,4-trans isomers (δ 76.7 vs 81.5 for 6 and 7 and δ 76.8 vs 81.3 for 9 and 8, respectively). The E/Z isomers (11/10) were less readily distinguishable because of extensive overlapping in the methyl region of the 1H NMR spectrum of the inseparable mixture. The C-4 methine of the major isomer appears further upfield (δ 2.77) than that of the minor isomer (δ 2.83), suggesting that the major isomer has the Z-configuration. The vinyl hydrogen of the major isomer is also more upfield (5.73 δ) compared to that of the minor isomer (5.83 δ). These chemical shift values are in agreement with those observed for analogs whose structures were previously established.11b,12 3-Ethoxy-2-methoxy-4-methyl Series. Attempted synthesis of both cis,trans and trans,trans ring isomers of 1-(bromomethylene)-3-ethoxy-2-methoxy-4-methylcyclobutane also yielded only the trans,trans ring isomer. Ketone 12 was directly converted to the unlabeled vinyl bromides 13 and 14 (1:1 ratio) by method B and to the methylene-labeled analogues 13* and 14* via 15* by method A.

Ketones 6 and 7 and alkenes 8 and 9 were easily distinguished by the 13C chemical shift values of the C-4 secondary methyl group, which is upfield in the cis isomer (δ ∼8 in 6 and 9) relative to the trans isomers (δ 12-18 in 7, 8, 10, and 11). Additional evidence for the stereochemical assignments was provided by an NOE effect between the C-2 β-methyl (above the plane) and H-4 in 6 and between the C-2 R-methyl (below the plane) and H-4 in 7. A large chemical shift difference between the C-3 oxygen methines (18) (a) Mayr, H.; Huisgen, R. Angew. Chem., Int. Ed. 1975, 14, 499–500. (b) Dore, M.; Tesson, G.; Taboury, F. J. C. R. Congr. Natl. Soc. Savantes, Sect. Sci. 1962, 87, 449–452. (19) Takai, K.; Hotta, Y.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1978, 27, 2417–2420. (b) Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org. Chem. 994, 59, 2668–2670.

The 3,4-trans stereochemistry of 12-15 and the E/Z stereochemistry of 13 and 14 were assigned on the basis of their 1H and J. Org. Chem. Vol. 75, No. 21, 2010

7131

JOC Article 13

C chemical shift values as described for 6-11 (see the Experimental Section for δ values). The E/Z assignments were confirmed by the observation of an NOE effect between the methoxy methyl and the vinyl hydrogen in E-isomer 13 and between the C-4 methyl and the vinyl hydrogen in Z-isomer 14. 3-Ethoxy-2-methyl-2-phenyl Series. To avoid the facile isomerization at the monosubstituted R-ring carbon (with exclusive formation of the thermodynamically favored 3,4-trans isomers), the synthesis of 2,2,3-trisubstituted (bromomethylene)cyclobutanes was undertaken. Phenylmethylketene and ethylvinyl ether formed a separable mixture of 3-ethoxy-2methyl-2-phenylcyclobutanones 16 and 1720 (ratio 1.0:0.75). While direct Wittig bromomethylenation was unsuccessful, methylenation afforded high yields of 18 and 19. Bromination-dehydrobromination of 18 afforded only one isomer, tentatively identified as 1-(E)-(bromomethylene)-3-ethoxy-2methyl-2-phenylcyclobutane (20). When the crude dibromide from 18 was treated for a short period of time with base at 25 °C, rather than at reflux, the isomeric epoxides 21 and 22 (ratio 1:2) were formed. Both epoxides produced vinyl bromide 20 when treated with potassium bromide and potassium hydroxide in ethanol at reflux for 3.5 h, suggesting that they may be intermediates in the dehydrobromination reaction. We have utilized epoxide intermediates to synthesize bromomethylenecyclobutanes in previous work.12b

Although bromination of 19 afforded the dibromide, dehydrobromination with a variety of bases afforded only complex (20) Mayr, H.; Huisgen, R. Tetrahedron Lett. 1975, 1349–1352.

7132

J. Org. Chem. Vol. 75, No. 21, 2010

Du and Erickson

mixtures. Steric hindrance to approach of the base (or nucleophile) is a likely explanation for this lack of E2 (or SN2) reactivity. The stereochemistry of compounds 16 and 17 was established as follows. The C-2 methyl of 16 is shielded relative to that of 17, while the quaternary aromatic carbon of 17 is shielded compared to that of 16. In 16, both C-4 hydrogens resonate at δ 3.20; one is shielded by the phenyl ring and the other by the ethoxy group. In isomer 17, the C-4 β-hydrogen experiences shielding by both the phenyl and the ethoxy groups, while the C-4 R-hydrogen is unshielded. Additionally, the methylene and methyl protons of the ethoxy group are shielded by the phenyl in 17 compared to those protons in 16. Finally, in isomer 17, H-3 is shielded by the adjacent C-2 cismethyl group relative to H-3 in 16 where the methyl group is trans.20 The C-2 phenyl group has no effect on H-3, whether cis or trans.20 Stereochemical assignments for the methylene compounds 18 and 19 were made in an analogous fashion. The relative ring stereochemistry of vinyl bromide 20 is based on its synthesis from 18 and the 13C chemical shift value for the C-2 methyl at δ 21.0 compared to δ 20.4 for 18 and δ 27.1 for 19. Its designation as the E-isomer is reasonable from a steric perspective and from its behavior with butoxide (see below), but this stereochemistry cannot be confirmed by comparison with its (unobtainable) Z-isomer. The assignment of relative stereochemistry at the spiro junction in 21 and 22 is based on the greater chemical shift difference between the two epoxy hydrogens in 21 (δ 3.16 and 3.47) compared to 22 (δ 3.93 and 4.09). In 21, these protons are differently shielded by the adjacent cis-phenyl group, while in 22, they are more nearly equivalent and not subject to aromatic π shielding. 3-Ethoxy-2-methoxy-2,4,4-trimethyl Series. The failure to synthesize both 2,3- or 3,4-cis and -trans isomers of substituted bromomethylenecyclobutanes led us to consider the use of chemically equivalent groups distinguishable by isotopic labeling. Such a system allows an investigation of the stereochemistry of the carbanionic rearrangement without competing thermodynamic effects. Accordingly, the synthesis of the unsymmetrically labeled 1-(bromomethylene)-3-ethoxy-2-methoxy-2,4,4trimethylcyclobutanes was carried out. Methylation22 of ketone 12 with 10% enriched 13C-labeled methyl iodide gave a mixture of labeled 3-ethoxy-2-methoxy2,4,4-trimethylcyclobutanones (23a and 23b) in a ratio of 1.5:1.0. The ketones were then converted to vinyl bromides 25 and 26 (ratio of 2.3:1.0) in the usual fashion. Vinyl bromides 25 and 26 labeled only at the exocyclic carbon were also synthesized in this fashion. The stereochemistry of the ring substituents in 23-26 was assigned in the usual manner. With vinyl bromides 25 and 26, HSQC and NOESY data further verified the assigned structures. NOE interactions between the methine hydrogen at C-3 and the C-2 methoxy group as well as with the C-4 β-methyl group clearly verified the relative ring stereochemistry as shown. The E/Z stereochemistry was assigned as before on the basis of the chemical shift differences between the methyl proton resonances as a function of their proximity to the (21) Brady, W. T.; Parry, F. H.; Stockton, J. D. J. Org. Chem. 1971, 31, 1480–1489. (22) Millard, A. A.; Rathke, M. W. J. Org. Chem. 1978, 43, 1834–1835.

Du and Erickson

bromine atom.11b,12 Confirming these assignments, NOE correlations were observed between the vinyl hydrogen and both the methoxy methyl and the C-2 methyl group in 25, whereas the vinyl hydrogen of 26 displayed an NOE correlation to the C-4 β-methyl group only.

Rearrangement Reactions. Ring enlargement of the bromomethylenecyclobutanes is optimized under heterogeneous conditions. The reaction is carried out either in the absence of solvent or in a hydrocarbon solvent whose boiling point matches the desired reaction temperature. Reactive systems rearrange at 0 °C, while less reactive ones may require temperatures of 100 °C.

When the inseparable trimethylated bromomethylenecyclobutanes 10 and 11 (2.0:1.0) were treated with potassium tert-butoxide in refluxing pentane, an 81% yield of a 2.4:1.0 mixture of 3,4-trans-1-bromo-4-ethoxy-3,5,5-trimethylcyclopentene (27) and 4,5-trans-1-bromo-4-ethoxy-3,3,5-trimethylcyclopentene (28) was obtained. The two products were distinguished on the basis of the deshielding effect of the bromine on adjacent atoms. In 28, the allylic methine carbon resonates at δ 48.7 and its attached proton at δ 2.75

JOC Article compared to δ 43.7 and δ 2.56 for the same nuclei in 27. Similarly, in 27, the quaternary allylic carbon appears at δ 50.3 compared to δ 47.1 for the same carbon in 28. The trans relationship between the secondary methyl and the ethoxy group was established by its chemical shift value of δ 17.8 in 28 and δ 18.3 in 27.

Compounds 29-3112a serve as good models from which to calculate the expected δ values forthis methyl group. In these compounds, the methyl carbon resonance moves upfield when cis to an adjacent ethoxy group, as in 29 and 30, while the adjacent trans-methyl resonates approximately 7 ppm further downfield. In 31, without an ethoxy group, the methyls appear at δ 29-30. With gem-dimethyl groups, each methyl exerts a β-alkyl substituent effect, deshielding its neighboring methyl by approximately 8 ppm. Thus, with a single secondary methyl group, as in 27 and 28, the predicted chemical shift for a secondary methyl trans to an adjacent ethoxy group would be δ 18.1 (26.1-8.0) for 27 and δ 19.1 (27.1-8.0) for 28; a cis arrangement would provide chemical shift values of δ 11.1 (19.1-8.0) for 27 and δ 12.6 (20.6-8.0) for 28. The actual values of δ 17.8 and 18.3 for the secondary methyl in 27 and 28 are in good agreement with a transrelationship to the adjacent ethoxy group. The gem-dimethyl δ-values of 27 and 28 also agree with the model (see the Experimental Section for δ values). Previous work12a has established that the migration of a gem-dimethyl-bearing carbon is highly favorable. Therefore, it is reasonable to assume that 27 is the product of concerted single (and syn) migration in isomer 10, and 28 is the product of double (and anti) migration in isomer 11, both products arising from the migration of the more electron-rich ring carbon (C-2). Unfortunately, this ring carbon has no stereochemistry; therefore, nothing can be said about its stereochemical fate. If the stereogenic ring atom (C-4) did migrate, it did so with retention of configuration. It is also possible that 10 gives rise to 28, and 11 to 27, both by single (and anti) migration, but it is difficult to visualize how this could be achieved concertedly. With both starting and product isomers nonresolvable, and only one stereogenic migrating center present, we elected not to investigate this system any further. When the gem-dimethyl group of 10 and 11 was replaced by a single methoxy group, the resulting E/Z-isomers 13 and 14 were readily separable. Z-Vinyl bromide 14, labeled only at the exocyclic carbon atom, afforded 3,4-trans-4,5-trans-1bromo-4-ethoxy-3-methoxy-5-methylcyclopentene-2-13C (32) as the only product (68%) when treated with potassium tert-butoxide in refluxing pentane or at 25 °C in the absence of solvent. On the other hand, E-isomer 13 did not rearrange under these conditions and was recovered unchanged in 82% yield. At 100 °C, in the absence of solvent, 13 gave a 32% yield of 3,4-trans-1-bromo-3-ethoxy-4-methoxy-2-methylcyclopentene-1-13C (34). A 1:1 mixture (unlabeled) of 13 and 14 J. Org. Chem. Vol. 75, No. 21, 2010

7133

JOC Article at 100 °C afforded a mixture (unlabeled) of 32 (50%), 34 (18%), and recovered 13 and 14 in a 1.0:0.35 ratio.

Bromocyclopentenes 32 and 34 were identified from their 1H, C (DEPT), COSY, NOESY, and HMBC NMR spectra. The regiochemistry of 32 was assigned on the basis of a HMBC correlation between the C-5 methyl hydrogens and the vinyl carbon bearing the bromine. The chemical shift of the C-5 methyl group at δ 18.5 indicates that it is trans to the adjacent ethoxy group. The trans relationship between the ethoxy and methoxy substituents is also maintained as evidenced by a NOESY correlation between the ethoxy methine (4-H) and the OCH3 group in both 32 and 34 when the spectra are acquired in benzene-d6 for better resolution. The regiochemistry in 34 was also confirmed by HMBC correlations of the vinyl methyl hydogens with both vinyl carbons. The formation of 32 results from double migration with complete retention of stereochemistry. This apparent syn migration could be achieved via path b in Scheme 1 where a carbene-halide complex is implicated. Intermediate 33 arises from E-isomer 13 by single migration, also in a syn fashion, of the methyl-bearing ring carbon C-4. Unfortunately, 33 was not stable under the more strenuous reaction conditions required for its formation. A prototopic shift converted 33 to isomer 34, thus destroying the stereochemical integrity of the migrating carbon atom. Hence, no information regarding the stereochemistry of the single migration process was forthcoming in this system. Isomerization of the products of the type described above can be avoided with gem-disubstituted rings as in 20. This compound rearranged with potassium tert-butoxide in refluxing pentane to give an 81% yield of a 7.4:1.0:2.0 mixture of (3R*,4S*)-1bromo-4-ethoxy-3-methyl-3-phenylcyclopentene (35) (where the asterisk indicates relative stereochemistry), (4S*,5R*)-1-bromo4-ethoxy-5-methyl-5-phenylcyclopentene (36), and 1-E-1-ethoxy3-methylene-4-phenyl-1,4-pentadiene (37). Regioisomers 35 and 36 were distinguished by their NOESY spectra where a cross peak between the vinyl hydrogen and the quaternary methyl group was observed in isomer 35 but not in 36 and the bromine’s deshielding effects at the different allylic carbons. The retained cis relationship of the ethoxy and the methyl group in both isomers is evidenced by the methyls’ 13C chemical shift values. 13

The major rearrangement pathway here is likely that of anti migration of C-2 leading to the double migration product 35 with complete retention of configuration. Syn single migration 7134

J. Org. Chem. Vol. 75, No. 21, 2010

Du and Erickson

of C-4 would also give 35. Minor isomer 36 could also arise from either double or single migration. Labeling studies to distinguish the two processes were not undertaken, however. The availability of only one of the starting E/Z-isomers, as well as the serious side reaction that competes with the rearrangement, argued against pursuing this system further. Ring-opened product 37 likely arises from the allylic anion derived from 20. Isomerization of the double bond from the exocyclic to the endocyclic position makes possible a reverse conrotatory electrocyclic reaction. Dehydrobromination of the resulting allylic bromide introduces the third double bond of 37. We have observed allylic anion formation, followed by ring-opening, in previous studies when DMF was used as a solvent.9 The process is facilitated here because of the conjugation which results in the ring-opened product.

The inability to access both starting E/Z-bromomethylenecyclobutanes or both double and single migration products with any of the above systems led us to consider still other alternatives. Additionally, we wished to ensure that the stereochemistry embodied in the rearrangement products reflected that dictated by the migration mechanism rather than the more thermodynamically stable arrangement of groups. The use of selective labeling with chemically equivalent groups on the migrating carbon would achieve these objectives. Accordingly, compounds 25 and 26, readily separable by vapor-phase chromatography (VPC), were synthesized and subjected to the rearrangement reaction conditions. Chromatographically pure E-vinyl bromide 25, Z-vinyl bromide 26, or a 2.3:1.0 mixture of both (all with an a:b ratio of 1.5:1.0) reacted with potassium tert-butoxide in pentane at 036 °C to give 95-98% yields of rearranged products which were, unfortunately, inseparable chromatographically. The doublemigration product (38a/38b) accounted for 85-90% of the rearranged product mixture. The a:b ratio for both 38 and 39 was1.5:1.0, unchanged from that of the starting bromomethylenecyclobutanes, 25 and 26. Higher reaction temperatures led to a significant decrease in volatile products; at 100 °C, the combined yield of 38 and 39 dropped to 73%, and at 150 °C it was only 46%.

JOC Article

Du and Erickson

When a mixture of single-labeled 25c and 26c (ratio 1.9:1.0) was treated with potassium tert-butoxide at 100 °C, in the absence of solvent, the ratio of 38:39 increased slightly (from 5.7:1.0 at 35 °C to 7.3:1.0 at 100 °C), and significantly, minor isomer 39 now displayed labeling at both C-1 (39c) and C-2 (39d) in a relative ratio of 2.3:1.0.

SCHEME 3

The proton spectra of regioisomers 38 and 39 were essentially identical in CDCl3 except for a very slight chemical shift difference in the OCH3 groups. In C6D6, the OCH3 and the vinyl protons of the two isomers resolved. The NOESY spectrum showed that the vinyl hydrogen of the major isomer (38) correlated with protons of the OCH3 group. This fixed the position of the vinyl hydrogen on the ring carbon adjacent to that group and, by default, the bromine on the ring carbon adjacent to the gem-dimethyl group. Support for this assignment came from an analysis of the HMQC and HMBC spectra, which were used to definitively assign the three C-methyl groups. In the HMBC spectrum of the major isomer (38), the protons of both carbons of the gem-dimethyl group correlated to the bromine-bearing vinyl carbon while in the minor isomer (39) these same protons correlated to the vinyl methine carbon. Similarly, in the major isomer, the protons of the methyl group on the methoxy-bearing carbon correlated to the vinyl methine carbon while in the minor isomer these protons correlated to the brominebearing vinyl carbon. All other correlations were also consistent with the proposed structures.

migration, a fact also already established,12a then these results are explicable in terms of Scheme 3. The major rearrangement product, 38c, arises from a double migration which can be either anti (from 25c) or syn (from 26c), the latter analogous to the conversion of 14 to 32. In these cases, C-2, the methoxy-bearing ring carbon atom, migrates. Minor product 39c arises from a syn single migration, also of C-2, at lower temperatures. However, at elevated temperatures, anti double migration of C-4, the dimethyl-bearing ring carbon atom, begins to compete and isomer 39d is formed. Whether the anions, or carbenoids, of 25 and 26 are actually equilibrating remains an open question as we were unable to detect any measurable interconversion of 25 and 26 under the rearrangement reaction conditions at 35 °C (or on storage at 25 °C for several weeks). This suggests that the intermediates derived from 25/26 rearrange rapidly once formed. The reaction most closely related to the rerrangement of halomethylenecyclobutanes is the Fritsch-Buttenberg-Wiechell (FBW) rearrangement.23 First described in 1894 as the baseinduced rearrangement of 1-halo-2,2-diarylalkenes to 1,2-diarylalkynes (eq 6),24 the FBW rearrangement has since been extended to a wide variety of systems, including those with alkyl substituents on an alkylidenecarbenoid framework (eq 7).23,25 Pathway c of Scheme 1 essentially depicts the FBW rearrangement from the vinyl haloanion (a potassium alkylidenecarbenoid) through the free alkylidenecarbene to the cyclopentyne. In paths a and b of Scheme 1, however, the halovinyl anion is diverted to the 1-halocyclopentenes stereoselectively without passing through the free carbene and cylcoalkyne. Undoubtedly, ring strain plays a major role in this diversion, and an arrested FBW reaction results, i.e., rearrangement occurs, both syn and

Discussion The labeling data with compounds 25a-c and 26a-c verifies that both the double and the single migrations occur with retention of configuration of the migrating group. These results are in keeping with the proposed mechanisms outlined in Scheme 1, supporting the premise that the rearrangement reactions are concerted or very nearly so. There are two aspects to the ring enlargement of 25 and 26 that stand out: (1) the methoxy-bearing ring carbon (C-2) migrates preferentially and (2) double migration is strongly preferred. The ratio of the resultant rearranged products (38:39) is approximately the same irrespective of the stereochemistry of the starting bromomethylenecyclobutanes. Previous studies11b have shown that some minor isomerization (10-18%) of the bromomethylenecyclobutanes can occur under the rearrangement reaction conditions. If the anions derived from 25 and 26 are interconverting, and double migration is faster than single

(23) (a) Knorr, R. Chem. Rev. 2004, 104, 3795-3849 and references cited therein. (b) Jahnke, E.; Tykwinski, R. R. Chem. Commun. 2010, 46, 3235– 3249. (24) (a) Fritsch, P. Liebigs Ann. Chem. 1894, 279, 319–323. (b) Buttenberg, W. P. Liebigs Ann. Chem. 1894, 279, 324–337. (c) Wiechell, H. Liebigs Ann. Chem. 1894, 279, 337–344. (25) (a) Eisler, S.; Tykwinski, R. R. In Acetylene Chemistry. Chemistry, Biology, and Material Science; Diederich, F., Stang, P. J., Tykwinski, R. R., Eds.; Wiley-VCH: Weinheim, 2005; pp 259-302 and references cited therein. (b) Bichler, P.; Chalifoux, W. A.; Eisler, S.; Shi Shun, A. L. K.; Chernick, E. T.; Tykwinski, R. R. Org. Lett. 2009, 11, 519–522. (c) Pratt, L. M.; Nguyen, N. V.; Kwon, O. Chem. Lett. 2009, 38, 574–575.

J. Org. Chem. Vol. 75, No. 21, 2010

7135

JOC Article anti, but a haloalkene, rather than a halide-free alkyne, is the end product.

In his recent excellent review of the FBW rearrangement, Knorr23a points out that migratory aptitudes appear to depend, to some extent, on the inductive substituent constant26 of the β-substituent that does not migrate (the stationary substituent). Thus, alkoxy groups inhibit the generally facile migration of a phenyl group or a hydrogen atom. This behavior is observed with compounds 14 and 25/26 where the methoxy-substituted β-carbon inhibits the expected migration of the methyl- or gemdimethyl-substituted β-carbons such that they become the stationary groups and the methoxy-substituted carbon becomes the migrating group. The role of the potassium in these rearrangement reactions is likely to be more than that of a spectator ion. In hydrocarbon solvents, or in the absence of solvent, the potassium remains closely associated with the organic moiety as its sole source of stabilization. Here, it can initiate metal-assisted ionization (MIA)27 of the halide-carbon bond leading to rehybridization of the carbenoid carbon and generating an empty p-orbital thereon. Indeed, in their original paper27 on MIA, Walborsky and co-workers invoked such a mechanism for the anti FBW rearrangement. Although less easily visualized, the syn FBW rearrangement probably proceeds in a similar manner.23a These carbanionic rearrangements of halomethylenecyclobutanes to 1-halocyclopentenes are described by Knorr23a as reactions that are “caught in the act of FBW rearrangement.” A good deal of ambiguity remains about the mechanism of the FBW rearrangement, especially regarding the syn migration process. Hence, as suggested,23a the halomethylenecyclobutyl systems may serve as viable tools for further probing the mechanistic details of that well-known, but poorly understood, rearrangement. Experimental Section General Procedures. See the Supporting Information. Spectroscopic Data. IR spectra were run neat. 1H NMR spectra were determined at 200 MHz in CDCl3 unless otherwise noted, with TMS as the internal reference set at 0.0 ppm or residual solvent signal set at 7.24 ppm. 13C NMR spectra were recorded at 50.3 MHz in CDCl3 unless otherwise noted, with the solvent as the internal reference set at 77.0 ppm. Quantitative 13C NMR analysis of labeled compounds was carried out in the following manner: Samples were dissolved in CDCl3 containing 0.10 M chromium(III) acetoacetonate [Cr(AcAc)3]. The spectra were obtained at 150 MHz in the inverse gated broad-band decoupling mode. The integrated spectra were statistically analyzed28 to determine enrichment at the specified carbons. The average error in the measurements ranged from 2.0% to 8.1%. (26) (a) Charton, M. Prog. Phys. Org. Chem. 1981, 13, 119–251. (b) Charton, M. Prog. Phys. Org. Chem. 1987, 16, 289–315. (27) Topolski, M.; Duraisamy, M.; Rachon, J.; Gawronski, J.; Gawronska, K.; Goedken, V.; Walbortsky, H. M. J. Org. Chem. 1993, 58, 546–555. (28) Gilbert, J. C.; Blackburn, B. K. J. Org. Chem. 1986, 51, 3656–3663.

7136

J. Org. Chem. Vol. 75, No. 21, 2010

Du and Erickson Preparation of 1-Bromomethylenecyclobutanes. 3,4-cis-3Ethoxy-2,2,4-trimethylcyclobutanone (6). A solution of 20 mL of THF, 8.60 g (0.100 mol) of ethyl vinyl ether, and 10.1 g (0.100 mol) of triethylamine was cooled with an ice-water bath, and 10.6 g (0.100 mol) of isobutyryl chloride was added dropwise over 30 min. The mixture was then stirred in an 80 °C oil bath for 3 h. The volatiles were removed by short-path distillation (20 mmHg). To the remaining yellow slurry was added 100 mL of ether, and the mixture was filtered through Celite. The yellow solution was concentrated and the residue was distilled to give 14.6 g (94%) of 6: bp20 mm 80-84 °C; IR 2975, 1778, 1461, 1130 cm-1; 1H NMR δ 1.11 (3H, s, C-2 R-Me), 1.13 (3H, d, J = 8.0 Hz, C-4 Me), 1.22 (3H, t, J = 7.0 Hz, CH3CH2), 1.23 (3H, s, C-2 β-Me), 3.45 (1H, pentet, J = 8.0 Hz, H-4), 3.51 (2H, q, J = 7.0 Hz, CH3CH2), 3.82 (1H, d, J = 8.0 Hz, 3-H); 13C NMR δ 7.7 (C4 Me), 15.2 (CH3CH2), 16.0 (C-2 R- Me), 23.2 (C-2 β-Me), 54.4 (C-4), 62.1 (C-2), 66.6 (CH3CH2)), 76.7 (C-3), 218.4 (C-1). 3,4-trans-3-Ethoxy-2,2,4-trimethylcyclobutanone (7). A mixture of triethylamine (20 mL) and cis isomer 6 (8.00 g, 51.3 mmol) was refluxed for 5 h. The triethylamine was removed by fractional distillation, and 80 mL of ether was added to the residue. The solution was washed with 10% HCl, H2O, and saturated aqueous NaCl. After drying over MgSO4 and evaporation of the solvent, the residue was distilled to give 7.80 g (98%) of trans isomer 7: bp20 79-80 °C; IR 2970, 1778, 1459, 1123 cm-1; 1H NMR δ 1.17 (3H, s, C-2 β-Me), 1.19 (3H, d, J = 6.8 Hz, C-4 β-Me), 1.22 (3H, s, C-2 R-Me), 1.26 (3H, t, J = 7.0 Hz, CH3CH2), 3.29 (1H, pentet, J = 6.8 Hz, 4-H), 3.44 (1H, d, J = 6.8 Hz, 3-H), 3.53 (2H, q, J = 7.0 Hz, CH3CH2); 13C NMR δ 12.1 (C-4 β-Me), 15.3 (CH3CH2), 17.5 (C-2 R-Me), 21.7 (C-2 β-Me), 57.3 (C-4), 60.4 (C-2), 65.9 (CH3CH2), 81.5 (C-3), 215.9 (C-1). 3,4-trans-3-Ethoxy-2,2,4-trimethyl-1-(methylene)cyclobutane (8). Potassium tert-butoxide (1.25 g, 11.2 mmol) and methyltriphenylphosphonium bromide (4.00 g, 11.2 mmol) were suspended in anhydrous THF (10 mL), and the mixture was stirred at 25 °C under N2 for 2 h, during which time a yellow color developed. The cis-ketone 6 or trans-ketone 7 (1.56 g, 10.0 mmol) was added dropwise, and the reaction mixture was stirred for an additional 24 h at 25 °C under N2. The solids were removed by vacuum filtration, and the THF was removed by distillation. The residue was chromatographed on silica gel with pentane-diethyl ether (10:1) to give trans-alkene 8 (1.48 g, 96%) from either cis- or trans-ketone: IR 3067, 2958, 1670, 1458, 1120 cm-1; 1H NMR δ 1.14 (3H, s, C-2 β-Me or C-2 R-Me), 1.15 (3H, d, J = 7.1 Hz, C-4 Me), 1.16 (3H, s, C-2 β-Me or C-2 R-Me), 1.21 (3H, t, J = 7.0 Hz, CH3CH2), 2.88 (1H, m, 4-H), 3.14 (1H, d, J = 7.1 Hz, 3-H), 3.46 (2H, q, J = 7.0 Hz, CH3CH2), 4.74 (1H, d, J = 2.4 Hz, dCH), 4.76 (1H, dd, J = 2.4, 0.4 Hz, dCH); 13C NMR δ 13.5 (C-4 β-Me), 15.3 (CH3CH2), 21.9 (C-2 R-Me), 27.7 (C-2 β-Me), 40.2 (C-4), 47.8 (C-2), 65.8 (CH3CH2), 81.3 (C-3), 102.0 (dCH2), 162.2 (C-1). 3,4-cis-3-Ethoxy-2,2,4-trimethyl-1-(methylene)cyclobutane (9). A mixture of 2.9 g (44 mmol) of activated zinc powder, 25 mL of dry THF, and 1 mL (14.4 mmol) of dibromomethane was stirred under N2 in a dry ice/acetone bath at -40 °C while titanium tetrachloride (1.15 mL, 10.3 mmol) was added dropwise over 15 min. The mixture was then stirred under N2 at 5 °C for 72 h. The dark gray slurry was stirred and cooled in an ice/water bath, and 5 mL of dry CH2Cl2 was added followed by 1.54 g (10 mmol) of cis-ketone 6 dissolved in 5 mL of dry CH2Cl2 over a period of 10 min. The cooling bath was removed, and the mixture was stirred at 20 °C for 1.5 h. The mixture was diluted with 30 mL of pentane, and then a slurry of 15.0 g of NaHCO3 in 8 mL of water was added cautiously over 1 h. The clear organic solution was decanted, and the residue was washed with pentane. The pentane solution was dried over a mixture of 10 g of Na2SO4 and 2 g of NaHCO3 and then filtered through a sintered glass funnel, thoroughly washing with pentane. The solvent was removed, and the liquid residue was purified by vapor-phase chromatography (VPC) to give cis-methylenated

Du and Erickson product 9 as a clear, colorless liquid, 1.45 g (94%), with a minor amount of trans isomer 8 (9:8 = 12:1 by 1H NMR): IR 3067, 2977, 1672, 1459, 1122 cm-1; 1H NMR δ 1.11 (3H, s, C-2 β-Me or C-2 R-Me), 1.12 (3H, d, J = 6.9 Hz, C-4 Me), 1.16 (3H, s, C-2 β-Me or C-2 R-Me), 1.19 (3H, t, J = 6.9 Hz, CH3CH2), 3.14 1H, m, 4-H), 3.44 (2H, q, J = 6.9 Hz, CH3CH2), 3.64 (1H, d, J = 8.4 Hz, 3-H), 4.76 (1H, d, J = 2.6 Hz, dCH), 4.77 (1H, d, J = 2.6 Hz, dCH); 13C NMR δ 7.9 (C-4 Me), 15.1 (CH3CH2), 16.0 (C-2 R-Me), 23.2 (C-2 β-Me), 54.4 (C-4), 62.0 (C-2), 66.6 (CH3CH2), 76.8 (C-3), 104.8 (dCH2). The nonprotonated vinyl carbon was not observed. (E)- and (Z)-1-Bromomethylene-3,4-trans-3-ethoxy-2,2,4-trimethylcyclobutane (10 and 11). A solution of CH2Cl2 (30 mL) and trans-alkene 8 (1.54 g, 10.0 mmol) was cooled in an ice bath for 15 min. Br2 (1.92 g, 12.0 mmol) was added dropwise, and stirring was continued at 0 °C for 15 min. The solution was then washed with aqueous NaHSO3, 6 M HCl, water, and brine. The organic layer was dried over MgSO4 and the solvent was removed. The residue was refluxed with a solution of 2.00 g of KOH (35.7 mmol) in 20 mL of 95% ethanol for 4 h and then water was added and the mixture was extracted with pentane. The pentane extracts were washed with water and dried over MgSO4. The pentane was removed by fractional distillation and the residue was flash distilled to give 1.2 g (52%) of an E,Z-mixture of 10 and 11 (2.0:1.0, determined by 1H NMR): IR 3064, 2972, 1659, 1457, 1122 cm-1; 1H NMR δ 1.12-1.23 (m), 1.39 (s), 2.77 (m, 4-H major isomer), 2.84 (m, 4-H minor isomer) 3.21 (d, J = 6.6 Hz, 3-H)), 3.47 (q, J = 6.9 Hz, CH3CH2), 5.73 (1H, d, J = 1.9 Hz, dCHBr major isomer), 5.83 (1H, d, J = 1.9 Hz, dCHBr minor isomer); 13C NMR δ 15.7, 17.8, 18.4, 19.6, 21.0, 27.3, 28.4, 43.7 46.7, 50.3, 67.2, 93.9, 94.1). Anal. Calcd for C10H17BrO: C, 51.51; H, 7.35. Found: C, 51.79; H, 7.58. 2,3-trans-3,4-trans-3-Ethoxy-2-methoxy-4-methylcyclobutanone (12). To a mixture of 50 g (0.58 mol) of ethyl-1-propenyl ether and 13 mL (0.093 mol) of triethylamine, cooled in an icewater bath, was added dropwise over 30 min 10.0 g (0.092 mol) of 2-methoxyacetyl chloride. The mixture was then heated at an oil bath temperature of 80-85 °C for 3 h. The volatiles were removed via short-path distillation (20 mmHg). To the remaining yellow slurry was added excess ether to precipitate the triethylamine hydrochloride, and the mixture was filtered through Celite. The pale yellow filtrate was concentrated and the residue was distilled to give 10.6 g (0.067 mol, 73%) of 12: bp4 mm 65-67 °C; IR (neat) 2976, 1781, 1129 cm-1; 1H NMR δ 1.21 (3H, d, J = 7.2 Hz, C-4 Me), 1.26 (3H, t, J = 7.0 Hz, CH3CH2). 2.96 (1H, m, 4-H), 3.50 (3H, s, OMe), 3.60 (2H, q, J = 7.0 Hz, CH3CH2), 3.67 (1H, d, J = 6.7 Hz, 2-H), 4.50 (1H, dd, J = 5.3, 4.2 Hz. 3-H); 13C NMR (CDCl3) δ 11.6 (C-4 Me), 15.2 (CH3CH2), 51.8 (OMe), 58.3 (C-4), 65.8 (CH3CH2), 77.6 (C-3), 92.8 (C-2), 206.7 (C-1). Cycloaddition of methoxyketene and ethyl-1-propenyl ether afforded 12 in acceptable yields only when the vinyl ether was used as both reactant and solvent. Without the large excess of the propenyl ether, 12 was produced in low yields as part of a complex mixture or products. Tietze and co-workers29 reported a 44% yield of a mixture of 3,4-cis and trans isomers when this reaction was carried out in acetonitrile. However, their reported 1H and 13C NMR spectra are in complete agreement with ours and give no evidence for a second isomer. (E)- and (Z)-1-Bromomethylene-2,3-trans-3,4-trans-3-ethoxy2-methoxy-4-methylcyclobutane (13 and 14). A suspension of bromomethyltriphenylphosphonium bromide (0.86 g, 2.0 mmol) in dry THF (10 mL) was treated with potassium tert-butoxide (0.22 g, 2.0 mmol) under N2 at -78 °C. The mixture was stirred for 2 h at -78 °C as the yellow ylide formed. Then ketone 12 (29) Tietze, L. F.; G€ untner, C.; Gericke, K. M.; Schuberth, I.; Bunkoczi, G. Eur. J. Org. Chem. 2005, 2459–2467.

JOC Article (0.32 g, 2.0 mmol) was added dropwise. After being stirred for 1 h at -78 °C, the reaction mixture was allowed to warm to 25 °C. Water was added, and the mixture was extracted with ether. The combined ether layers were washed with water and dried over MgSO4. The ether was removed in vacuo, and the residue was subjected to VPC to give 180 mg of 13 and 170 mg of 14 (total yield 75%). Exocyclic 13C-labeled 13 and 14 were prepared from 12, again in a 1:1 ratio, via the methylene compound 15, which was subjected to a bromination-dehydrobromination sequence. (E)-1-Bromomethylene-2,3-trans-3,4-trans-3-ethoxy-2-methoxy-4-methylcyclobutane (13): IR 3065, 2976, 1666, 1123 cm-1; 1 H δ 1.23 (3H, t, J = 7.0 Hz, CH3CH2), 1.44 (3H, d, J = 7.1 Hz, C-4 Me), 2.54 (1H, d of pentets, J = 7.1, 2.8 Hz, 4-H), 3.43 (3H s, OMe), 3.47 (1H dd, J = 7.1, 5.0 Hz, 3-H), 3.56 (2H, q, J = 7.0 Hz, CH3CH2), 4.08 (1H, dd, J = 5.0, 2.0 Hz, 2-H), 6.24 (1H, dd, J = 2.8, 2.0 Hz, dCHBr); 13C δ NMR 15.4 (CH3CH2), 15.9 (CH3,C-4 Me), 40.5 (C-4), 57.0 (OMe), 64.9 (CH3CH2), 82.8 (C-3), 84.3 (C-2), 100.1 (=CHBr), 143.4 (C-1). Anal. Calcd for C9H15BrO2: C, 45.97; H, 6.43. Found: C, 45.84; H, 6.26. (Z)-1-Bromomethylene-2,3-trans-3,4-trans-3-ethoxy-2-methoxy-4-methylcyclobutane (14): IR 3074, 2976, 1665, 1123 cm-1; 1 H 1.23 (3H, t, J = 7.0 Hz, CH3CH2), 1.23 (3H, d, J = 6.8 Hz, C-4 Me), 2.40 (1H, d of pentets, J = 6.8, 2.6 Hz, 4-H), 3.53 (3H, s, OMe), 3.55 (1H dd, J = 6.8, 5.4 Hz, 3-H), 3.57 (2H, q, J = 7.0 Hz, CH3CH2), 4.18 (1H, dd, J = 5.4, 2.5 Hz, 2-H), 6.02 (1H, dd, J = 2.6, 2.5 Hz, dCHBr); 13C δ NMR 15.4 (CH3CH2), 16.4 (C-4 Me), 40.5 (C-4), 57.6 (OMe), 64.9 (CH3CH2), 82.8 (C-3), 84.4 (C-2), 98.3 (dCHBr), 140.3 (C-1). Anal. Calcd for C9H15BrO2: C, 45.97; H, 6.43. Found: C, 45.75; H, 6.75. 2,3-trans-3,4-trans-3-Ethoxy-2-methoxy-4-methyl-1-(methylene-13C)-cyclobutane (15*). Potassium tert-butoxide (2.24 g, 20.0 mmol) and methyl-13C-triphenylphosphonium iodide (10% enriched, 8.90 g, 20.0 mmol) were dissolved in 20 mL of dry THF under N2. The mixture was stirred at 25 °C for 2 h during which time the color of the solution became yellow. Ketone 12 (3.16 g, 20.0 mmol) was added dropwise, and the reaction mixture was stirred for an additional 3 h at 25 °C. The solids were removed by vacuum filtation, and the filtrate was distilled to remove the THF. The residue was extracted with pentane, and the pentane layer was washed with 50% aqueous methanol and dried over MgSO4. The solvents were removed by fractional distillation, and the residue was chromatographed on silica gel with pentane-diethyl ether (15:1) to obtain 2.90 g (18.6 mmol, 93%) of 15* as a colorless oil: IR 3078, 2976, 1688, 1124 cm-1; 1H NMR δ 1.21 (3H, d, J = 6.8 Hz, C-4 Me), 1.23 (3H, t, J = 7.1 Hz, CH3CH2), 2.42 (1H, m, 4-H), 3.38 (1H, dd, J = 6.8, 5.6 Hz, 3-H), 3.47 (3H, OMe), 3.57 (2H, q, J = 7.1 Hz, CH3CH2), 4.17 (1H, dt, J = 5.6, 2.8 Hz, 2-H), 4.95 (1H, t, J = 2.8 Hz, (dCH), 5.15 (1H, t, J = 2.8 Hz, dCH); 13C NMR δ 15.4 (CH3CH2), 16.2 (C-4 Me), 39.0 (C-4), 57.1 (OMe), 64.8 (CH3CH2), 83.6 (C-3), 84.2 (C-2), 104.6 (dCH), 148.5 (C-1). (E)-1-(Bromomethylene-13C)-2,3-trans-3,4-trans-3-ethoxy-2methoxy-4-methylcyclobutane (13*) and (Z)-1-(Bromomethylene-13C)-2,3-trans-3,4-trans-3-ethoxy-2-methoxy-4-methylcyclobutane (14*). Bromination-dehydrobromination of 15* (0.50 g, 3.2 mmol) was carried out as described for 10 and 11 to give 0.62 g (2.6 mmol, 81%) of an E- and Z-mixture of 13* and 14* (ratio 1.0:1.0). The pure vinyl bromides were separated by flash chromatography on silica gel (EtOAc/hexane = 1:4). (2R*,3S*)- and (2R*,3R*)-3-Ethoxy-2-methyl-2-phenylcyclobutanone (16 and 17). A solution of 2-phenylpropionic acid (10.0 g, 66.7 mmol) in CH2Cl2 (50 mL) was cooled in an ice bath, and SOCl2 (23.6 g, 200 mmol) was added dropwise. The mixture was stirred at 25 °C for 30 min and then refluxed for 1.5 h. Removal of the solvent gave crude 2-phenylpropionyl chloride which was used without further purification. J. Org. Chem. Vol. 75, No. 21, 2010

7137

JOC Article A solution of 4.10 g (57.0 mmol) of ethyl vinyl ether and 5.75 g (57.0 mmol) of triethylamine in 20 mL of THF was cooled in an ice bath, and 6.40 g (38.0 mmol) of 2-phenylpropionyl chloride in 10 mL of THF was added dropwise over 30 min. The mixture was stirred in an 80 °C oil bath for 3 h. The volatiles were then removed via short-path distillation (20 mmHg). To the remaining yellow slurry was added 100 mL of ether, and the mixture was filtered through Celite. The yellow solution was concentrated and the residue was subjected to VLC on silica gel with hexane/ethyl acetate (30:1) to give 5.49 g (27.0 mmol, 71%) of a mixture of trans-ketone 16 and cis-ketone 17 in a 1.0:0.75 ratio. (2R*,3S*)-3-Ethoxy-2-methyl-2-phenylcyclobutanone (16): IR 3062, 2974, 1772, 1601, 1126 cm-1; 1H δ 1.30 (3H, t, J = 7.1 Hz, CH3CH2), 1.53 (3H, s, C-2 Me), 3.20 (1H, d, J = 7.1 Hz, 4-H), 3.20 (1H, d, J = 6.8 Hz, 4-H), 3.64 (2H, q, J = 7.1 Hz, CH3CH2), 4.43 (1H, dd, J = 7.1, 6.3 Hz, 3-H), 7.34 (5H, m, ArH); 13C δ 15.2 (CH3CH2), 19.5 (C-2 Me), 50.3 (C-4), 65.8 (CH3CH2), 70.8 (C-2), 73.0 (C-3), 125.6 (2C, ArC), 126.8 (ArC), 128.7 (2C, ArC), 141.8 (ArC), 210.0 (C-1). (2R*,3R*)-3-Ethoxy-2-methyl-2-phenylcyclobutanone (17): IR 3059, 2975, 1781, 1601, 1117 cm-1; 1H δ 0.96 (3H, t, J = 7.0 Hz, CH3CH2), 1.55 (3H, C-2 Me), 3.03 (1H, dd, J = 18.0, 4.8 Hz, 4βH), 3.26 (2H, m, CH3CH2), 3.42 (1H, dd, J = 18.0, 6.9 Hz, 4R-H), 4.06 (1H, dd, J = 6.9, 4.8 Hz, 3-H), 7.27 (5H, ArH); 13C δ 14.5 (CH3CH2), 22.6 (C-2 Me), 51.1 (C-4), 65.2 (CH3CH2), 70.5 (C-2), 75.2 (C-3), 126.7 (ArC), 127.3 (2C, ArC), 127.8 (2C, ArC), 137.1 (ArC), 210.5 (C-1). (2R*,3S*)- and (2R*,3R*)-3-Ethoxy-2-methyl-1-methylene-2phenylcyclobutane (18 and 19). These isomers were prepared from 16 (88% yield) and 17 (82% yield) by means of a Wittig reaction as described for the preparation of 8. (2R*,3S*)-3-Ethoxy-2-methyl-1-methylene-2-phenylcyclobutane (18): IR 3059, 2975, 1673, 1601, 1121 cm-1; 1H δ 1.09 (3H, t, J = 7.2 Hz, CH3CH2), 1.46 (3H, s, C-2 Me), 2.70 (1H, dddd, J = 15.6, 7.1, 2.5, 2.1 Hz, 4R- or 4β-H), 2.87 (1H, dddd, J = 15.6, 7.1, 2.5, 2.1 Hz, 4R- or 4β-H), 3.31 (2H, m, CH3CH2), 4.10 (1H, dd, J = 7.7, 7.1 Hz, 3-H), 4.81 (1H, t, J = 2.5 Hz, dCH), 4.89 (1H, t, J = 2.1 Hz, dCH), 7.23 (5H, ArH); 13C δ 15.3 (CH3CH2), 20.4 (C-2 Me), 36.5 (C-4), 56.8 (C-2), 65.0 (CH3CH2), 78.9 (C-3), 106.9 (dCH2), 126.0 (3C, ArC), 128.2 (2C, ArC), 146.4 (ArC), 151.2 (C-1). (2R*,3R*)-3-Ethoxy-2-methyl-1-methylene-2-phenylcyclobutane (19): IR 3061, 2975, 1688, 1600, 1116 cm-1; 1H δ 1.00 (3H, t, J = 7.2 Hz, CH3CH2), 1.56 (3H, C-2 Me), 2.62 (dddd, J = 15.2, 7.6, 2.8, 2.1 Hz, 4β-H), 2.97 (dddd, J = 15.2, 7.2, 2.8, 1.6 Hz, 4R-H), 3.36 (2H, q, J = 7.2 Hz, CH3CH2), 3.86 (dd, J = 7.6, 7.2 Hz, 3-H), 4.99 (1H, dd, J = 2.1, 2.8 Hz, dCH), 5.12 (1H, dd, J = 1.6, 2.8 Hz, dCH), 7.34 (5H, m, ArH); 13C δ 15.0 (CH3CH2), 27.1 (C-2 Me), 38.1 (C-4), 58.0 (C-2), 64.9 (CH3CH2), 79.5 (C-3), 107.1 (dCH2), 126.1 (ArC), 127.7 (2C, ArC), 128.1 (2C, ArC), 141.8 (ArC), 150.4 (C-1). (2S*,3S*)-(E)-1-Bromomethylene-3-ethoxy-2-methyl-2-phenylcyclobutane (20). Method A. Bromination-dehydrobromination of 18 was carried out as described for 10 and 11 to give a 59% overall yield of 20. Method B. The crude dibromide (860 mg, 2.40 mmol) obtained from 18 was allowed to react with a solution of 200 mg of KOH (3.6 mmol) in 5 mL of 95% ethanol for 30 min at 25 °C. The reaction mixture was extracted with ether, and the ether extracts were washed with water and brine. After drying over MgSO4, the solvent was removed, and the residue was purified by vacuum liquid chromatography (VLC) on silica gel eluting with hexane/ethyl acetate (40:1). The pure epoxides 21 (180 mg, 0.830 mmol) and 22 (279 mg, 1.28 mmol) were obtained as colorless oils in a total yield of 88%. (3R*,4R*,5S*)-5-Ethoxy-4-methyl-4-phenyl-1-oxaspiro[2.3]hexane (21): IR 3065, 3036, 2971, 1612 cm-1; 1H δ 1.13 (3H, t, J = 7.1 Hz, CH3CH2), 1.58 (3H, s, C-4 Me), 2.51 (1H, ddd, J = 12.3, 8.1, 2.1 Hz, 6-H), 2.93 (1H, dd, J = 12.3, 7.0 Hz, 6-H), 7138

J. Org. Chem. Vol. 75, No. 21, 2010

Du and Erickson 3.16 (1H, d, J = 11.7 Hz, 2-H), 3.47 (2H, q, J = 7.1 Hz, CH3CH2), 3.48 (1H, dd, J = 11.7, 2.1 Hz, 2-H), 4.22 (1H, dd, J = 8.1, 7.0 Hz, 5-H), 7.28 (5H, m, ArH); 13C δ 15.5 (CH3CH2), 27.2 (C-4 Me), 42.8 (C-6), 45.7 (C-2), 58.1 (C-4), 64.4 (C-3), 64.9 (CH3CH2), 73.5 (C-5), 125.3 (2C, ArC), 127.1 (ArC), 128.7 (2C, ArC), 143.5 (ArC). (3S*,5S*,6R)-5-Ethoxy-6-methyl-6-phenyl-1-oxaspiro[2.3]hexane (22): IR 3062, 3035, 2968, 1610 cm-1; 1H δ 1.25 (3H, t, J = 7.0 Hz, CH3CH2), 1.49 (3H, s, C-6 Me), 2.44 (1H, dd, J = 12.7, 8.5 Hz, 4-H), 2.87 (1H, dd, J = 12.7, 6.9 Hz, 4-H), 3.61 (2H, q, J = 7.0 Hz, CH3CH2), 3.93 (1H, d, J = 11.3 Hz, 2-H), 4.09 (1H, d, J = 11.3 Hz, 2-H), 4.67 (1H, dd, J = 8.5, 6.9 Hz, 5-H), 7.31 (5H, m, ArH); 13C δ 15.0 (CH3CH2), 20.0 (C-6 Me), 41.1 (C-4), 43.7 (C-2), 58.9 (C-6), 64.7 (CH3CH2), 67.2 (C-3), 72.9 (C-5), 126.0 (2C, ArC), 126.8 (ArC), 128.4 (2C, ArC), 147.8 (ArC). A solution of epoxide 21 or 22 (100 mg, 0.460 mmol), KBr (90 mg, 0.76 mmol), KOH (26 mg, 0.46 mmol), and 95% ethanol (5 mL) was refluxed for 3.5 h. The workup was the same as that used for method A. Pure vinyl bromide 20 (65 mg, 0.23 mmol, 50%) was obtained by VLC on silica gel with hexane/ethyl acetate (20:1): IR 3080, 2973, 1668, 1603, 1121 cm-1; 1H δ 1.18 (3H, t, J = 7.0 Hz, CH3CH2), 1.56 (3H, s, C-2 Me), 2.66 (1H, ddd, J = 16.5, 6.7, 3.3 Hz, 4-H), 2.98 (1H, ddd, J = 16.5, 7.7, 2.4 Hz, 4-H), 3.42 (2H, q, J = 7.0 Hz, CH3CH2), 4.07 (1H, dd, J = 7.7, 6.7 Hz, 3-H), 5.96 (1H, dd, J = 3.3, 2.4 Hz, dCHBr), 7.17 (5H, m, ArH); 13C δ 15.8 (CH3CH2), 21.0 (C-2 Me), 37.0 (C-4), 58.0 (C-2), 65.7 (CH3CH2), 78.2 (C-3), 100.2 (dCHBr), 126.3 (2C, ArC), 127.0 (ArC), 129.0 (2C, ArC), 145.8 (ArC or C-1), 148.7 (ArC or C-1). HRMS calcd for C14H1779BrO 280.0457, found 280.0458. (2R*,3S*)-3-Ethoxy-2-methoxy-2,4,4-13C-trimethylcyclobutanone (23a and 23b). Potassium hydride (35% oil dispersion, 2.90 g, 25.2 mmol) was washed with pentane by decantation several times under a N2 atmosphere, and anhydrous THF (25 mL) was added. At 20 °C, 2.00 g (12.6 mmol) of 3-ethoxy-2methoxy-4-methylcyclobutanone (12) was added dropwise. After complete addition, stirring was continued for 5 min and then 13Clabeled iodomethane (3.60 g, 25.2 mmol, 10% enrichment) was added dropwise over 10 min. The mixture was then stirred for an additional 20 min before water (15 mL) was carefully added. The mixture was extracted with pentane, and the pentane layers were washed with water and dried over MgSO4. The solvent was removed, and the residue was purified by VLC (4% EtOAc/ petroleum ether) to give pure 23 (1.72 g, 73%). The ratio of cis-4methyl-13C labeled 23a and trans-4-methyl-13C labeled 23b was 1.51 to 1.00 as determined by 13C NMR: IR 2975, 1780, 1460, 1119 cm-1; 1H NMR δ 1.16 (3H, s, C-4 Me), 1.24 (3H, s, C-4 Me), 1.24 (3H, t, J = 6.5 Hz, CH3CH2), 1.38 (3H, s, C-2 Me), 3.37 (3H, s, OMe), 3.57 (2H, q, J = 6.5 Hz, CH3CH2), 3.82 (1H, s, 3-H); 13C δ 14.1 (C-2 or C-4 Me), 15.2 (CH3CH2), 17.3 (C-2 or C-4 Me), 22.9 (C-2 or C-4 Me), 52.5 (OMe), 56.1 (C-4), 66.7 (CH3CH2), 82.0 (C-3), 93.6 (C-2), 216.6 (C-1). Anal. Calcd for C10H18O3 (unlabeled sample): C, 64.49; H, 9.74. Found: C, 64.56; H, 9.65. (2S*,3S*)-3-Ethoxy-2-methoxy-1-13C-methylene-2,4,4-13Ctrimethylcyclobutane (24a and 24b). Methylenation of ketone 23 (3.0 g, 16 mmol) with methyl-13C-triphenylphosphonium iodide (6.5 g, 16 mmol) and KO-t-Bu (1.8 g, 16 mmol) as described for 8 gave alkene 24 in 68% yield: IR 3068, 2976, 1673, 1459, 1116 cm-1; 1H δ 1.11 (3H, s, C-4 Me), 1.20 (3H, t, J = 7.0 Hz, CH3CH2), 1.21 (3H, s, C-4 Me), 1.35 (3H, s, C-2 Me), 3.27 (3H, s, OMe), 3.51 (2H, q, J = 7.0 Hz, CH3CH2), 3.70 (1H, s, 3-H), 4.97 (1H, s, dCH), 5.04 (1H, s, dCH); 13C NMR δ 15.3 (CH3CH2), 19.5 (C-2 or C-4 Me), 21.8 (C-2 or C-4 Me), 27.9 (C-2 or C-4 Me), 41.7 (C-4), 50.9 (OMe), 66.0 (CH3CH2), 83.6 (C-2), 84.5 (C-4), 105.2 (dCH2), 158.9 (C-1). (2S*,3S*)-(E)- and (Z)-1-13C-Bromomethylene-3-ethoxy-2methoxy-2,4,4-13C-trimethylcyclobutane (25a,b and 26a,b). Bromination-dehydrobromination of alkene 24 (2.00 g, 10.9 mmol)

Du and Erickson was carried out by the procedure used for 10 and 11 to give a 2.3:1.0 mixture of E-isomer 25 and Z-isomer 26 in 42% overall yield. The isomers were separated by preparative VPC. 25: IR 3066, 2974, 1653, 1459, 1116 cm-1; 1H (600 MHz, CDCl3) δ 1.20 (3H, t, J = 7.0 Hz, CH3-CH2), 1.23 (3H, s, C-4 RMe), 1.32 (3H, s, C-2 R-Me), 1.41 (3H, s, C-4 β-Me), 3.26 (3H, s, OMe), 3.51 (2H, q, J = 7.0 Hz, CH3-CH2), 3.70 (1H, s, 3-H), 6.11 (1H, s, dCHBr); 13C (150 MHz, CDCl3, HSQC) δ 15.3 (CH3-CH2), 18.5 (C-4 R-Me), 19.8 (C-2 R-Me), 25.4 (C-4 βMe), 43.5 (C-4), 51.1 (OMe), 66.4 (CH3-CH2), 84.2 (C-3), 84.4 (C-2), 99.5 (dCHBr), 152.9 (C-1). Anal. Calcd for C11H19BrO2 (unlabeled sample): C, 50.20; H, 7.28. Found: C, 50.39; H, 7.27. 26: IR 3059, 2975, 1652, 1458, 1111 cm-1; 1H (600 MHz, CDCl3) δ 1.14 (3H, s, C-4 R-Me), 1.20 (3H, t, J = 7.0 Hz, CH3CH2), 1.24 (3H, s, C-4 β-Me), 1.47 (3H, s, C-2 R-Me), 3.34 (3H, s, OMe), 3.51 (2H, q, J = 7.0 Hz, CH3-CH2), 3.83 (1H, s, 3-H), 6.06 (1H, s, dCHBr); 13C (150 MHz, CDCl3, HSQC) δ 15.3 (CH3-CH2), 18.0 (C-2 R-Me), 21.9 (C-4 R-Me), 27.5 (C-4 β-Me), 43.8 (C-4), 51.6 (OMe), 66.4 (CH3-CH2), 82.6 (C-3), 84.4 (C-2), 99.1 (dCHBr), 153.1 (C-1). Anal. Calcd for C11H19BrO2 (10% labeled sample): C, 50.64; H, 7.23. Found: C, 50.78; H, 7.56. General Procedure for Potassium tert-Butoxide-Induced Rearrangement of Vinyl Bromides. The substrates were treated with potassium tert-butoxide in a refluxing hydrocarbon solvent, or with no solvent, at temperatures ranging from 0 to 150 °C. In all cases, chromatographically pure samples were used. All products were distilled or chromatographed with final purification achieved by preparative VPC. A typical procedure follows: Freshly sublimed potassium tert-butoxide (0.28 g, 2.5 mmol) was suspended in solvent (5 mL) in a flask equipped with a reflux condenser, a drying tube, a magnetic stirrer, a N2 inlet, and a septum cap. The system was heated to reflux, and the vinyl halide (1.0 mmol) was injected by syringe. After 30 min of reflux, water was added, and the reaction mixture was extracted with pentane. The combined pentane layers were washed with water and dried over MgSO4. The pentane was removed by fractional distillation and the residue was subjected to flash distillation under reduced pressure to give a mixture of 1-halocyclopentenes. All products were purified by preparative gas chromatography. All yields reported are isolated yields of purified products. Potassium tert-Butoxide-Induced Rearrangement of Vinyl Bromides 10 and 11 (27 and 28). A mixture of vinyl bromides 10 and 11 (500 mg, 2.1 mmol, isomeric ratio = 2.0:1.0) was treated with potassium tert-butoxide (0.40 g, 3.6 mmol) in refluxing pentane following the general procedure. An 81% yield of a mixture of 27 and 28, isomeric ratio = 2.4:1.0 was obtained. Anal. Calcd for C10H17BrO: C, 51.51; H, 7.35. Found: C, 51.62; H, 7.42 3,4-trans-1-Bromo-4-ethoxy-3,5,5-trimethylcyclopentene (27): 230 mg (46%); IR 3068, 2954, 1641 cm-1; 1H δ 0.99 (3H, s, C-5 RMe), 1.13 (3H, d, J = 7.1 Hz, C-3 Me), 1.16 (3H, s, C-5 β-Me), 1.21 (3H, t, J = 7.1 Hz, CH3-CH2), 2.56 (1H, d of pentets, J = 7.1, 2.0 Hz, 3-H), 3.25 (1H, d, J = 7.1 Hz, 4-H), 3.60 (2H, m, CH3CH2), 5.58 (1H, d, J = 2.0 Hz, 2-H); 13C δ 15.7 (CH3-CH2), 18.3 (C-3 Me), 19.5 (C-5 R-Me), 27.3 (C-5 β-Me), 43.7 (C-3), 50.3 (C-5), 67.2 (CH3-CH2), 94.0 (C-4), 131.3 (C-1), 131.7 (C-2). 4,5-trans-1-Bromo-4-ethoxy-3,3,5-trimethylcyclopentene (28): 96 mg (19%); IR 3055, 2986, 1647 cm-1; 1H NMR δ 1.00 (3H, s, C-3 R-Me, 1.15 (3H, s, C-3 β-Me), 1.17 (3H, d, J = 7.1 Hz, C-5 Me), 1.21 (3H, t, J = 7.1 Hz, CH3-CH2), 2.75 (1H, d of pentets, J = 7.1, 2.0 Hz, 5-H), 3.25 (1H, d, J = 7 Hz. 4-H), 3.61 (2H, m, CH3-CH2), 5.61 (1H, d, J = 2.0 Hz, 2-H); 13C NMR δ 15.7 (CH3CH2), 17.8 (C-5 Me), 20.9 (C-3 R-Me), 28.4 (C-3 β-Me), 47.1 (C-3), 48.7 (C-5), 67.1 (CH3-CH2), 93.9 (C-4), 123.7 (C-1), 139.3 (C-2). Potassium tert-Butoxide-Induced Rearrangement of Vinyl Bromide 14 (32). Treatment of vinyl bromide 14 (100 mg, 0.35 mmol) in pentane (36 °C), hexane (69 °C), or without solvent (25 °C) afforded 65-68 mg (65-68%) of 3,4-trans-4,5-trans-1bromo-4-ethoxy-3-methoxy-5-methyl-2-13C-cyclopentene (32):

JOC Article IR 3076, 2974, 1620, 1104 cm-1; 1H δ 1.22 (3H, t, J = 7.1 Hz, CH3-CH2), 1.24 (3H, d, J = 6.9 Hz, C-5 Me), 2.68 (1H, m, 5-H), 3.37 (3H, s, OMe), 3.59 (1H, dd, J = 5.7, 4.2 Hz, 4-H), 3.60 (2H, q, J = 7.1 Hz, CH3-CH2), 4.17 (1H, dd, J = 4.2, 1.7 Hz, 3-H), 5.98 (1H, dd, J = 1.7, 1.2 Hz, 2-H); 13C δ 15.4 (CH3-CH2), 18.5 (C-5 Me), 49.7 (C-5), 56.6 (OMe), 65.2 (CH3-CH2), 89.4 (C-4), 90.6 (C-3), 128.2 (C-2), 131.4 (C-1). Anal. Calcd for C9H15BrO2 (10% C-enriched sample): C, 46.16; H, 6.42. Found: C, 46.27; H, 6.38. Potassium tert-Butoxide-Induced Rearrangement of Vinyl Bromide 13 (34). Rearrangement of vinyl bromide 13 (100 mg, 0.35 mmol) at 100 °C without solvent gave 32 mg (32%) of 3,4trans-1-bromo-3-ethoxy-4-methoxy-2-methyl-1-13C-cyclopentene (34): IR 2976, 1665, 1103 cm-1; 1H δ 1.23 (3H, t, J = 7.0 Hz, CH3-CH2), 1.74 (3H, br s, C-2 Me), 2.50 (1H, br d, J = 16.3 Hz, 5-H), 2.98 (1H, dm, J = 16.3 Hz, 5-H), 3.36 (3H, s, OMe), 3.64 (2H, overlapping dq, J = 15.9, 7.0 Hz, CH3-CH2), 3.87 (1H, ddd, J = 7.2, 4.0, 3.1 Hz, 4-H), 4.12 (1H, br d, J = 3.1 Hz, 3-H); 13C δ 13.3 (C-2 Me), 15.5 (CH3-CH2), 43.9 (C-5), 64.9 (CH3-CH2), 84.7 (C-4), 90.0 (C-3), 118.5 (C-1), 136.5 (C-2). Anal. Calcd for C9H15BrO2 (10% 13C-enriched sample): C, 46.36; H, 6.38. Found: C, 46.71; H, 6.58. Potassium tert-Butoxide-Induced Rearrangement of Vinyl Bromide 20 (35-37). (2S*,3S*)-(E)-1-Bromomethylene-3ethoxy-2-methyl-2-phenylcyclobutane (20) (80 mg, 0.28 mmol) was stirred with potassium tert-butoxide (63 mg, 0.56 mmol) in refluxing pentane or hexane for 3 h to give a 7.4:1.0:2.0 mixture of 35, 36, and 37 as a yellow oil (65 mg, 81%). Separation by preparative TLC on silica gel with CCl4-CH2Cl2 (20:1) gave 35 (42 mg), 36 (6 mg), and 37 (5 mg). (3R*,4S*)-1-Bromo-4-ethoxy-3-methyl-3-phenylcyclopentene (35): IR 3063, 2974, 1639, 1605 cm-1; 1H δ 1.14 (3H, t, J = 6.8 Hz, CH3-CH2), 1.41 (3H, s, C-3 Me), 2.70 (1H, ddd, J = 15.7, 7.4, 2.1 Hz, 5-H), 2.89 (1H, ddd, J = 15.7, 7.4, 1.6 Hz, 5-H), 3.37 (2H, dq, J = 12.5, 6.8 Hz, CH3-CH2,), 4.06 (1H, t, J = 7.4 Hz, 4-H), 5.95 (1H, dd, J = 2.1, 1.6 Hz, 2-H), 7.32 (5H, m, ArH); 13C δ 15.4 (CH3-CH2), 19.4 (C-3 Me), 44.4 (C-5), 55.3 (C-3), 65.9 (CH3-CH2), 87.5 (C-4), 118.0 (C-1), 125.9 (ArC), 126.3 (ArC), 128.3 (ArC), 138.6 (C-2), 147.7 (ArC). Anal. Calcd for C10H17BrO: C, 51.51; H, 7.35. Found: C, 51.81; H, 7.41. (4S*,5R*)-1-Bromo-4-ethoxy-5-methyl-5-phenylcyclopentene (36): IR 3054, 2980, 1646, 1607 cm-1; 1H δ 1.08 (3H, t, J = 6.9 Hz, CH3-CH2), 1.54 (3H, s, C-5 Me), 2.32 (1H, ddd, J = 15.8, 7.1, 2.3 Hz, 3-H), 2.66 (1H, ddd, J = 15.8, 7.7, 2.6 Hz, 3-H), 3.28 (2H, dq, J = 15.0, 6.9 Hz, CH3-CH2), 4.14 (1H, dd, J = 7.7, 7.1 Hz, 4-H), 5.98 (1H, dd, J = 2.6, 2.3 Hz, 2-H), 7.32 (5H, m, ArH); 13 C δ 15.1 (CH3-CH2), 18.4 (C-5 Me), 43.5 (C-3), 61.2 (C-5), 65.3 (CH3-CH2), 89.3 (C-4), 121.5 (C-1), 126.2 (ArC), 126.8 (ArC), 128.2 (ArC), 145.5 (C-2), 158.8 (ArC). Anal. Calcd for C10H17BrO: C, 51.51; H, 7.35. Found: C, 51.86; H, 7.43. (E)-1-Ethoxy-3-methylene-4-phenyl-1,4-pentadiene (37): IR 3077, 3055, 2979, 1633, 1606 cm-1; 1H δ 1.63 (3H, t, J = 7.0 Hz, CH3-CH2), 3.70 (2H, q, J = 7.0 Hz, CH3-CH2), 4.88 (1H, d, J = 1.7 Hz), 5.08 (1H, d, J = 1.7 Hz), 5.27 (1H, d, J = 1.7 Hz), 5.47 (1H, d, J = 1.7 Hz), 5.64 (1H, d, J = 12.8 Hz), 6.33 (1H, d, J = 12.8 Hz), 7.38 (5H, m, ArH); 13C δ 14.7 (CH3-CH2), 65.3 (CH3-CH2), 106.9 (CH) 113.2 (CH2), 114.4 (CH2), 126.8 (CH), 127.5 (CH), 128.4 (CH), 139.9 (C), 145.5 (C), 148.8 (C), 150.9 (CH). This compound hydrolyzes readily to the aldehyde and then rapidly polymerizes. Potassium tert-Butoxide-Induced Rearrangement of Vinyl Bromides 25 and 26 (38 and 39). Chromatographically pure E-vinyl bromide 25 (100 mg, 0.380 mmol), Z-vinyl bromide 26 (100 mg, 0.380 mmol), or a mixture of 25 and 26 (200 mg, 0.760 mmol, in a ratio of 2.3:1.0) was treated with potassium tertbutoxide (3 equiv) in pentane at 0 °C for 6 h (98% yield), 25 °C for 2.5 h (98% yield), or at reflux (36 °C) for 2 h (95% yield). With no solvent and a reaction temperature of 100 °C, the yield dropped to 73%; at 150 °C and no solvent the yield dropped to J. Org. Chem. Vol. 75, No. 21, 2010

7139

JOC Article 46%. Preparative VPC or VLC (vacuum liquid chromatography) afforded a mixture of the rearranged products 38 and 39 in a average ratio of 6:1: IR 2973, 2928, 1618, 1462, 1118, 870 cm-1; 1H δ (CDCl3, 200 MHz) 0.99 (3H, s), 1.18 (3H, s), 1.20 (3H, t, J = 7.0 Hz), 1.24 (3H, s), 3.23 (3H, s, major isomer), 3.25 (3H, s, minor isomer), 3.65 (2H, m), 3.68 (1H, s), 5.82 (1H, s); 13 C δ (CDCl3, 50 MHz) 15.4 (CH3), 20.2 (CH3, major isomer), 20.6 (CH3, minor isomer), 21.0 (CH3, major isomer), 22.1 (CH3, minor isomer), 27.6 (CH3, major isomer), 28.6 (CH3, minor isomer), 49.6 (C), 50.7 (CH3), 66.9 (CH2, minor isomer), 67.1 (CH2, major isomer), 85.7 (CH, minor isomer), 87.8 (C), 88.9 (CH, major isomer), 124.9 (C, minor isomer), 131.6 (CH, major isomer), 135.1 (C, major isomer) 141.8 (CH, minor isomer). Anal. Calcd for C11H19BrO2 (unenriched sample): C, 50.20; H, 7.28. Found: C, 50.43; H, 7.34. (3S*,4S*)-1-Bromo-2-13C-4-ethoxy-3-methoxy-3,5,5-13C-trimethylcyclopentene (38): 1H δ (C6D6, 600 MHz) 1.16 (3H, t, J = 7.0 Hz, CH3CH2-), 1.20 (3H, s, C-5 R-Me), 1.25 (3H, s, C-5 β-Me), 1.33 (3H, s, C-3 R-Me), 3.07 (3H, s, OMe), 3.49 (m, 1H, CH3CH2-), 3.67 (m, 1H, CH3CH2-), 3.80 (1H, s, 4-H), 5.83 (1H, s, 2-H); 13C δ (C6D6, 150 MHz, HSQC) 16.1 (CH3CH2-), 20.8 (C-3 R-Me), 21.9 (C-5 R-Me), 28.3 (C-5 β-Me), 50.3 (C-5), 51.0 (OMe), 67.8 (CH3CH2-), 88.4 (C-3), 90.4 (C-4), 132.7 (C-2),

7140

J. Org. Chem. Vol. 75, No. 21, 2010

Du and Erickson 135.8 (C-1); 13C δ (CDCl3, 150 MHz) 15.4, 20.2, 21.0, 27.6, 49.6, 50.7, 67.1, 87.8, 88.9, 131.6, 135.1. (4S*,5R*)-1-Bromo-1-13C-4-ethoxy-5-methoxy-3,3,5-13C-trimethylcyclopentene (39): 1H δ (C6D6, 600 MHz) 1.16 (3H, t, J = 7.0 Hz, CH3CH2-), 1.20 (3H, s, C-3 R-Me), 1.25 (3H, s, C-3 β-Me), 1.33 (3H, s, C-5 R-Me), 3.27 (3H, s, OMe), 3.49 (m, 1H, CH3CH2-), 3.67 (m, 1H, CH3CH2-), 3.77 (1H, s, 4-H), 5.65 (1H, s, 2-H); 13C δ (C6D6, 150 MHz, HSQC) 16.2 (CH3CH2-), 21.3 (C-5 R-Me), 22.6 (C-3 R-Me), 29.0 (C-3 β-Me), 51.1 (OMe), 67.4 (CH3CH2-), 86.2 (C-4), 126.6 (C-1), 142.4 (C-2); the unenriched quaternary carbons, C-3 and C-5, were not observed in this sample; 13C δ (CDCl3, 150 MHz) 15.4, 20.6, 22.1, 28.6, 45.5, 50.6, 66.9, 85.7, 89.6, 124.9, 141.8.

Acknowledgment. We thank Guoxing Lin and Mary R. Brennan for assistance with some of the NMR data acquisition. Supporting Information Available: General experimental methods, copies of NMR spectra, and 13C label distribution tables. This material is available free of charge via the Internet at http://pubs.acs.org.