J. Org. Chem., Vol. 39, No. 15, 1974
A Bridgehead Sulfonium Salt with Nucleophiles
2153
Reactions of a Bridgehead Sulfonium Salt with Nucleophiles. The Proton Nuclear Magnetic Resonance Spectra of Hexahydro-1,l-dimethy1-3H-2,4,7-ethanylylidene-lH-cyclopenta [ c ]thiopyrilium Bromide and Its Derivativesla Pelham Wilder, Jr.,* Luis A. Feliu-Otero, and Glenn A. Diegnanlb Paul M. Gross Chemical Laboratory, Duke University, Durham, North Carolina 27706 Received January 29, 1974
On reaction with a series of nucleophiles, the bridgehead sulfonium salt hexahydro-l,l-dimethyl-3N-2,4,7ethanylylidene-1H-cyclopenta[c]thiopyriliumbromide (3) affords @-eliminationproducts in a higher proportion than substitution products. Proton nmr chemical shift assignments are presented for the salt 3, its progenitors, and its elimination and substitution products. Specifically deuterated compounds 9-12 and 14 have been prepared to assist in the nmr analysis. The anomalous downfield chemical shift of the exo methyl of 13 and the exo cyanomethyl of 16 are attributed to the proximity of the sulfur lone electron pair. In recent years in this laboratory there has been considerable interest in the synthesis and reactivity of conformationally rigid bicyclic sulfonium salts in which the sulfonium function is located a t a bridgehead position. Many examples of this type of sulfonium c o m p o ~ n d ~have -~ been found to possess biological activity as alkylating agents.6 In 1965 the synthesis of the bridgehead sulfonium salt 1 was reported.' Subsequently the study was extended8 and it was found that nucleophilic attack occurs at C-5 or C-10. No products arising from 6-elimination reactions were observed. Similar results have been reportedg for sulfonium salt 2. The synthesis of the bridgehead sul-
Scheme I
anhydride benrene
0 4
b03kH \/
\/
OH
pyridine
R R
0 5
CH,SO,CI
6,R = H
9,R = D 1
2
\/
\/
fonium compound 3 and an examination of its reactivity as an alkylating agent is the subject of the present study. The synthesis of sulfonium salt 3 is described in Scheme I. Dimethylfulvene and maleic anhydride reacted in boiling benzene to give the exo adduct 4. This adduct 7,R = H 8,R = H was hydrogenated over platinum catalyst to give 5 which, 10,R = D 11, R = D in turn, afforded exo-7-isopropylidenebicyclo[2.2.l]heptane-2,3-dimethanol (6) on reduction with LiAlH4. Reaction of the diol 6 with methanesulfonyl chloride gave the Brmethanesulfonate diester 7, and the sulfide 8 was then LUIR, prepared by a modification of the method of cylization of R Owen and PetolO using sodium sulfide nonahydrate. With R RR refluxing 48% HBr solution, the sulfide 8 afforded the cyclic bridgehead sulfonium salt 3. For the nmr analysis to be described below, the specifically deuterated sulfonium 3,R = H 13,R = H salt 12 and its several progenitors were prepared by the 12,R = D 14,R = D method in Scheme I except for the use of LiAlD4. Sulfide 14 was obtained directly from 12 by reaction with LiAlD4. tution products reveals no immediate clear-cut pattern, other than a predominance of elimination over substituResults and Discussion tion. This predominance is typical for straight- and The reactions with nucleophiles were carried out in rebranched-chain alk; h l f o n i u m salts under the conditions fluxing aqueous medium with the sodium or potassium employed, but is in contrast to results of studies in this salt of the nucleophile, with the exceptions of N-methyllaboratory for similar cyclic bridgehead sulfoniums.8.9 At aniline and LiAlH4. The product mixtures were separated the outset of these experiments it was demonstrated that by preparative glpc, and the assignment of structures was the salt 3 does not undergo unimolecular elimination; based largely upon interpretation of their nmr spectra. namely, in one experiment an aqueous solution of 3 was The product distributions for these reactions, the percentrefluxed for 48 hr without change and similar results were ages of which were determined by analytical glpc, are found for refluxing ethyl ether. summarized in Table I. The investigation of the sulfonium salt 3 as an alkylatInspection of the distribution of elimination and substiing agent presented two problems: (1) the determination
A T
-
2154
J. Org. Chem., Vol. 39, No. 15, 1974
Wilder, Felui-Otero, and Diegnan
J. Org. Chem., Vol. 39, No. 15, 1974
A Bridgehead Sulfonium Salt with Nucleophiles
Table I Product Distribution
8
3
1
15
X
%S
OAcPhNHCHa PhO LiAlH4 CN a
100
Trace5
16, Y -CN 18, Y = NU % 15
% 13 o r 1 6
0 0
0 0
53
47
0
85 40
0 10
15
2155
nucleophile and reduce (by electron release) its positive character relative to the methylene carbons. The same expectation would hold on a purely statistical basis, since product 18 may arise from two independent pathways while product 17 may arise from only one. The results tabulated in Table I bear out these predictions. On statistical grounds, one would expect to see products 8, 19, and 15 in a ratio of 1 2 6 . This would most certainly not be the case, as it is necessary to take into consideration the relative acidities and accessibilities of the various 0 protons. With alkyl onium compounds the dominating influence governing orientation in eliminations is the inductive influence (electron releasing) of any p-alkyl groups which might be present.ll Thus, the least substituted olefin is formed preferentially because the p carbon with the fewest alkyl substituents has the most acidic 0 protons. The predominance of elimination product 8 is an exception to this trend. Other studies in this laboratory have demonstrated that sulfonium salts 1 and 2 react with nucleophiles to give only substitution product^.^^^ In the initial investigation of the reaction of 1 with a variety of nucleophiles, only
50
Starting material was recovered quantitatively,
of its ability to alkylate nucleophiles of varying nucleophilicity and (2) the determination of the position of substitution during alkylation. Inherent in the cyclic sulfonium structure is the possibility for competition between substitution and elimination reactions, which could give rise to a mixture of five possible products. namely, 8, 15, 17, 18, and 19.
20
21
95%
4.574
2/1
+
& 22
50%
17
19
The symmetry of the sulfonium bromide 3 reduces the modes of ring opening in substitution to two possibilities: the positive sulfonium moiety can be displaced at the dimethyl-substituted carbon or a t either of the equivalent methylene carbons. One would expect to see only small amounts of product 17 relative to 18, as the gern-dimethyl groups would both shield the adjacent carbon sterically from a n incoming
50%
two examples were found12 in which a P-elimination occurred to form 21 and 22. The product distribution of Table I probably reflects nucleophilic strength more than any other single factor. Those cases in which substitution was observed (LiAlH4 and KCN) employed reagents of high nucleophilicity and small size. It should be noted that the LiAlH4 reaction was carried out in relatively nonsolvating, low-boiling ethyl ether, which would be expected to promote substitution. The absence of any appreciable reaction with N methylaniline, which is a good nucleophile but a poor
2156 J. Org. Chem., Vol. 39, No. 15, 1974
Wilder, Felui-Otero, and Diegnan
Table I1 Proton Chemical Shift Data for Some Norbornane Derivativesa
6, 7, 23
X
1,4
2,3 endo
Od Od OHoph OS02CH32
3.90 3.20 2.50 2.66 2.20 2.44 2.46 1.94
3.22
Compd
4 5
6 7 23
4, 5, 8, 24
H S 0 HL
3.00 1.85
2.20 1.80
13, 16
Chemical shift, gb--5,6 exoc
6 . 60e -1.66 ~ 1 . 5 5 -1.58 -1.50 -1.50 -1.50 rn
-5,6 endoc
-1.56 ~ 1 . 4 5 -1.48 -1.40 1.30 1.38 rn
~~
7
8
10
CHI
d d
d d
1.581 1.66J
3.20 4.10 0.80i 2.96!+ 3.O O k 1.52j
3.20 4.10
1,661
1.66f
1.66, 2.20k 1.64J 24 4 , 04k 1,661 13 2.90k 1.22% 2.34k 1.42" 16 CN1 2.12 I.88k m rn 3.04k 3.34 1.24" 2.4W 1.46" a The compounds are numbered as norbornane derivatives for convenience in tabulating chemical shifts. Relative to TMS (8 0.00) in CDCl,. c Assignment is indefinite and may be reversed. d Compounds 4 and 5 are anhydrides. e The 5,6 linkage is olefinic. f Isopropylidene methyl. In DMSO-de. * OH protons at 6 4.50 (2 H). OSOZCHa protons at 8 3.00 (6 H). exo-CH, protons. k See discussion. 1 C-7 proton resonance obscured by other resonances. m Resonances obscured. ngern-CH3 protons. 8
2.20 2.20 1.94
0.801
Q
base, may reflect that reagent's inability to get at the sites for substitution. The chemical shift data for a series of compounds containing the norbornane skeleton are summarized in Table
11. Acknowledgment. We wish to express our appreciation to Mr. Kurt L. Loening, Director of Nomenclature, Chemical Abstracts Service, for assistance in the naming of several of the compounds described above. The support, in part, of this research by Research Grant CA-4298 from the National Cancer Institute of the National Institutes of Health, U. S. Public Health Service, is gratefully acknowledged. Registry No.+ 51510-22-6; 3 picrate, 51703-25-4; 4, 5151023-7; exo-5, 51606-73-6; endo-5, 51606-74-7; 6, 51510-24-8; 7, 51510-25-9;8, 51510-26-0; 8 methiodide, 51606-75-8;9, 51510-27-1; 10, 61510-28-2; 11, 51703-29-8; 12, 51606-76-9; 13, 51510-29-3; 14, 51606-77-0; 15, 51510-30-6; 16, 51510-31-7; 23, 51510-32-8; 24, 51510-33-9;dimethylfulvene, 2175-91-9. Miniprint Material Available. Full-sized photocopies of the miniprinted material from this paper only or microfiche (105 X 148 mm, 24X reduction, negatives) containing all of the miniprinted and supplementary material for the papers in this issue may be obtained from the Journals Department, American Chemical Society, 1155 16th St., N.W., Washington, D. C. 20036. Remit check or money order for $4.00 for photocopy or $2.00 for microfiche,refrring to code number JOC-74-2153. References and Notes (1) (a) Taken in part from the Dissertations of L A F -0 and G A D submitted to the Graduate School of Duke University in partial fulfillment of the requirements for the Ph.D degree (1965 and 1973. respectively) The partial support of this research by a grant (CA-
4296) from the National Institutes of Health, U. S. Public Health Service, is gratefully acknowledged. (b) National Science Foundation Trainee, Duke university, 1969-1970: Allied Chemical Gorp. Predoctoral Fellow, 1971-1972. (2) V . Prelog and E. Cerkovnikov, Justus Liebigs Ann. Chem., 537, 214 (1939), (3) V . Prelog and D. Kohlbach, Ber., 7 2 , 672 (1939). (4)W. F. Cockburn and A . F. McKay, J. Amer. Chem. SOC., 76, 5703 (1954). (5) R. H. Eastman and G. Kritchevsky, J. Org. Chem., 24, 1428 (1959). (6) M. A. Stahmann, J. S. Fruton. and M. Bergmann, J. Org. Chem., 11, 704 (1946). (7) P. Wilder, Jr., and L. A. Feliu-Otero, J. Org. Chem., 30, 2560 (1965). (8)P. Wilder, Jr., L. A. Feliu-Otero, and J. M. Shepherd, Int. J. Sulfur Chem., PartA, 1, 169 (1971). (9) P. Wilder, Jr., and R. F. Gratz, J. Org. Chem., 35, 3295 (1970). (IO) L. N. Owen and A. G. Peto, J. Chem. SOC.,2363 (1955). (11) C. K. Ingold, "Structure and Mechanism in Organic Chemistry," 2nd ed, Cornell University Press, Ithaca, N. Y., 1969,pp 659-666. (12) L. A. Feliu-Otero, Ph.D. Dissertation, Duke University, 1965. (13) P. Laszlo and P. v. R. Schleyer, J , Amer. Chem. SOC.,86, 1171 (1964). (14)N. Kamezawa, K. Sakashita, and K. Hayamizu, Org. Magn. Resonance, 1, 405 (1969). (15) C.C. Price, J. Org. Chem., 38, 615 (1973). (16) E. L. Eliel and R. 0. Hutchins, J. Amer. Chem. SOC., 91, 2703 (1969). (17) H. T. Kalff and E. Havinga, R e d . Trav. Chim. Pays-Bas, 85, 467 (1966). (16) N. S. Zefirov, V. S. Blagoveshchensky, i. V. Kazimirchik, and N. S. Surova, Tetrahedron, 27, 31 1 1 (1971). (19) R. M . Silverstein and G . C. Bassler, "Spectrometric Identification of Organic Compounds," Wiley, New York, N. Y., 1967,pp 136-137. 67, (20) G. Crane, C. E. Boord, and A. L. Henne, J. Amer. Chem. SOC., 1237 (1945). (21) K. Alder and R. Ruhmann, Justus Liebigs Ann. Chem., 566, 1 (1950). (22) A. Winston, Ph.D. Dissertation, Duke University, 1955. (23) L. A . Paquette, R . E. Wingard, Jr., J. C . Phllips, G. L. Thompson, L. K. Read, and J. Clardy, J . Amer. Chem. SOC..93, 4506 (1971) (24)C . F. Culberson, Ph.D. Dissertation, Duke University, 1959.
