2442
J . Am. Chem. SOC.1987, 109, 2442-2448
8.2 Hz, 2 H), 2.356 ( s , 3 H), 2.349 ( s , 3 H); IR (Ar = p-CH,C&) (CH2C12) YC+ 1800 cm-I. In a separate experiment, heating a sample of mesylate 14b in trifluoroacetic acid for 2 h at 55 "C gave only pmethylacetophenone, 16. In a separate experiment, 8.5 mg of trifluoroacetate 15, isolated as described above, was dissolved in 0.5 mL of trifluoroacetic acid containing 0.2 M sodium trifluoroacetate in an N M R tube. The conversion of 15 top-methylacetophenone, 16, was monitored by 300-MHz N M R at 25 "C by observing the appearance of the two methyl signals of 16, which appear downfield from the methyl signals of 15. The first-order rate constant for this process is 3.05 X s-l. After completion of the reaction an authentic sample of p-methylacetophenone was added to the N M R tube to confirm its presence. Solvolysis of Mesylate 14b in Acetic Acid. A solution of 74 mg of 14b in 10 mL of HOAc containing 0.05 M NaOAc and 1% acetic anhydride was heated at 70 "C for 4 h. The mixture was then taken up into ether, the solution was washed with dilute N a O H solution and saturated NaCl solution, and the organic phase was dried over MgSO,. The solvent was removed on a rotary evaporator, leaving 46 mg of a clear oil. Analysis by 300-MHz N M R showed the presence of acetate 17 (Ar = p CH3C6H4),the elimination product 18 (Ar = p-CH,C,H,), and p methylacetophenone, 16, in a 25: 15:60 ratio, respectively. Hexane was added to the oil which was cooled in a freezer. A solid crystallized, and the hexanes were decanted leaving 10 mg of acetate 17 (Ar = p CH3C6H4):IR (Ar = p-CH,C,H,) (CH2C12)Y1760 cm-I; 'H N M R (Ar = p-CH3C6H4)(CDCI,) 6 7.71-7.62 (m, 3 H), 7.466 (t, J = 7.8 Hz, 2 H), 7.13-7.02 (AA'BB'quartet, 4 H), 2.334 ( s , 3 H), 2.277 (s, 3 H), 2.139 (s, 3 H). 18: 'H N M R (Ar =p-CH,C,H,) (CDCI,) 6 7.695 (d, 2 H), 7.526 (t, 1 H), 7.403 (t, 2 H), 7.212 (d, 2 H), 7.069 (d, 2 H), 6.596 (s, 1 H), 5.932 (s, 1 H), 2.315 (s, 3 H). p-Methylacetophenone, 16, formed in the acetolysis was identified by N M R spectral comparison with an authentic sample. Solvolysis of Mesylate 14b in Trifluoroethanol. A solution of 43 mg of 14b in 6 mL of T F E containing 40 mg of Et3N was kept at 25 "C for 7.5 h. The solvent was then removed on a rotary evaporator, and the residue was taken up into ether. The mixture was then washed with water, dilute KOH, and saturated NaCl and dried over MgSO,. The ether was removed on a rotary evaporator to give 32 mg of a mixture of ketal 19a (96%) and the elimination product 18 (4%). 19a: lH N M R (Ar = p-CH3C6H,) (CDC13) 6 7.43-7.35 (d, 2 H), 7.24-7.16 (d, 2 H), 3.90-3.66 (m, 4 H), 2.362 (s, 3 H), 1.666 (s, 3 H). Solvolysis of Bromide 35b in Formic Acid. A solution of 258 mg of 35b in 17 mL of formic acid containing 0.05 M sodium formate was heated at 55 " C for 5 h. The mixture was taken up into ether, washed
with water, dilute Na2C03,and saturated NaC1, and dried over MgSO,. The solvent was removed on a rotary evaporator, and the residue was chromatographed on 6 g of silica gel and eluted with 5% ether in hexanes. Diphenyl disulfide, 36, eluted first (41 mg) followed by p-methylacetophenone (75 mg, 70%), and finally the thiosulfonate 3725(32 mg) eluted. These products were all identified by spectral comparison with authentic samples. In a separate experiment, the reaction of 10 mg of 35b in 0.7 mL of formic acid containing 0.05 M sodium formate was monitored directly by 300-MHz N M R at 45 "C. p-Methylacetophenone, 16, was observed to form at the same rate that 35b disappeared. N o buildup of an intermediate could be observed. The two diastereomers of 35b disappeared at rates which were identical within the limits of N M R determination. Solvolysis of Bromide 35b in Trifluoroethanol. A solution of 170 mg of 35b in 8 mL of T F E containing 0.075 M 2,6-lutidine was heated for 5 h at 60 "C. The solvent was removed on a rotary evaporator, and the residue was taken up into ether, washed with water and saturated NaCI, and dried over MgSO,. N M R analysis showed the presence of ketal 19a and p-methylacetophenone, 16, along with the elimination product 38 in a 2.3:1.3:1 ratio, respectively. Also present were diphenyl disulfide, 36, and the thiosulfonate 37. The residue was chromatographed on 7 g of silica gel and eluted with 5% ether in hexanes. The initial fraction (61 mg) contained a mixture of ketal 19a and diphenyl disulfide, 36, which were identified by spectral methods and by comparison of gas chromatographic retention times with those of authentic samples. p-Methylacetophenone, 16 (32 mg, 45%), eluted next, followed by 37 (22 mg). The solvent polarity was then changed to 100% ether, and the elimination product 38 (28 mg, 22%) eluted: 'H N M R (Ar = p-CH,C,H,) (CDCI,) F 7.47-7.27 (m, 5 H), 7.09 (s, 4 H), 6.21 ( s , 1 H), 5.88 (s, 1 H), 2.31 (s, 3 HI. Solvolysis of Bromide 35b in 70% Aqueous Acetone. A solution of 144 mg of 35b in 5 mL of 70% aqueous acetone (by volume) containing 55 mg of Et,N was heated at 70 "C for 46 h and at 80 " C for 16 h. The solvent was removed on a rotary evaporator, and the residue was taken up into ether, washed with water, dilute HCI, and saturated NaCl solution, and dried over MgSO,. After solvent removal on a rotary evaporator, the residue (102 mg) was analyzed by N M R and gas chromatography, which showed p-methylacetophenone, 16, and the elimination product 38 in a 86 to 14 ratio, along with diphenyl disulfide, 36.
Acknowledgment. We thank t h e National Science Foundation and t h e donors of t h e Petroleum Research F u n d , administered by t h e American Chemical Society, for financial support of this research.
Preparation and Regiospecific Cyclization of Alkenyllithiums' William F. Bailey,* Timo T. Numi,+ Jeffrey J. Patricia, and Wei Wang Contribution from the Department of Chemistry, University of Connecticut, Storrs, Connecticut 06268. Received June 23, 1986. Revised Manuscript Received October 15. 1986
Abstract: A two-step, one-pot sequence has been developed that provides an anionic route to functionalized carbocycles containing five- or six-membered rings. Primary alkenyllithiums, which a r e prepared in excellent yield by metal-halogen interchange between the appropriate iodide and t-BuLi a t -78 O C , are stable a t low temperature. These species have been found to undergo regiospecific, and in several instances totally stereoselective, isomerization a t elevated temperature to give a five- or six-membered ring bearing a C H 2 L i moiety that m a y be functionalized with electrophiles. The more complex behavior of secondary alkenyllithiums is discussed.
T h e construction of C-C bonds is arguably t h e most important operation in organic synthesis. I t is therefore not surprising t h a t m u c h recent interest h a s focused on t h e synthetic utility2 of t h e highly regiospecific isomerization of 5-hexen- 1-yl radicals t o cyclopentylmethyl-containing product^.^ A major disadvantage of this otherwise powerful methodology is t h e fact t h a t t h e product radical is difficult to t r a p in a controlled, intermolecular reaction A conceptually simple solution to give a functionalized 'On leave from the University of Turku, Turku, Finland.
0002-7863/87/1509-2442$01.50/0
to this limitation of radical cyclizations would seem t o be provided by t h e well-established tendency of various organometallic de(1) Presented in part at the 190th National Meeting of the American Chemical Society, Chicago, IL, Sept 1985; ORGN 121. (2) Representative examples may be found in: (a) Hart, D. J. Science (Washington, D.C.) 1984, 223, 883. (b) Curran, D. P.; Rakiewicz, D. M . Tetetrahedron 1985, 19, 3943. (c) Curran, D. P.; Kuo, S.-C. J . Am. Chem. SOC.1986, 108, 1106. (d) Stork, G.; Sher, P. M. J . Am. Chem. SOC.1983, 105, 6765. (e) Tsang, R.; Fraser-Reid, B. J . Am. Chem. SOC.1986, 108, 21 16. (f) Meijs, G. F.; Beckwith, A. L. J. J . Am. Chem. SOC.1986, 108, 5890. (8) Beckwith, A. L. J.; Roberts, D. H. J . Am. Chem. SOC.1986, 108, 5893.
0 1987 American Chemical Society
J . Am. Chem. SOC.,Vol. 109, No. 8, 1987 2443
Cyclization of Alkenyllithiums rivatives of the 5-hexenyl system to cyclize to cyclopentylmethyl organometallic^.^-^ There are however two rather stringent prerequisites to the exploitation of such anionic cyclizations for the construction of functionalized carbocycles: (1) the organometallic must be produced in high yield with a minimum of side-product formation from readily available precursors; (2) the organometallic must undergo clean, rapid cyclization in a regiospecific and highly stereoselective manner. Herein we report the results of experiments designed to probe the utility of alkenyllithium cyclization as a route to functionalized carbocycles containing five- or six-membered rings. As shown below, this approach provides a synthetically useful counterpart to radicalbased strategies for the construction of carbocyclic products.
Scheme I
L1
rLi
II t-BuLi
-1
m.,
matun
I€* 6
IE+
Results and Discussion Preparation of Alkenyllithiums. Development of alkenyllithium cyclization as a viable alternative to radical-mediated methods requires that the organolithium be produced conveniently and in good yield. In the course of an ongoing investigation of the mechanism of the metal-halogen interchange reaction,lWl3we have found that such species may be easily prepared by treatment of the appropriate iodide with t-butyllithium (t-BuLi) in n-pentane-diethyl ether at -78 OC.lZ Under these conditions, as noted elsewhere,13the mechanism of the interchange reaction between a 1O RI and t-BuLi most likely involves rapid attack of the alkyllithium on the iodine atom of the substrate. Thus, addition of 2 equiv of t-BuLi in n-pentane to a -78 OC solution of 6iodo-1-hexene (1) in n-C5Hl2-Et20(3:2 by vol) results in rapid, clean interchange to produce 5-hexen-1-yllithium (2). When such reaction mixtures are quenched with an excess of anhydrous, oxygen-free methanol, 1-hexene may be isolated in virtually quantitative yield (93-99%).12 We have found, however, that the use of protio acids as quenching agents masks the fact that 5hexen- 1-yllithium (2) is generated in less than quantitative yield: 1-hexene is produced as a byproduct of the interchange reaction between 1 and t-BuLi.14 The less than quantitative yield of 2 was revealed by the results of experiments employing deuteriated reagents. Addition of 2 equiv of t-BuLi to a 0.1 M solution of 1 in n-C5HIz-Et2O(3:2 by vol) at -78 OC served to generate 2. The reaction mixture was stirred for 5 min at -78 "C and then (3) (a) Surzur, J.-M. In Reactiue Intermediates; Abramovitch, R. A., Ed.; Plenum: New York, 1982; Vol. 2, Chapter 3. (b) Beckwith, A. L. J. Tetrahedron 1981, 37, 3073. (c) Beckwith, A. L. J.; Ingold, K. U. In Rearrangements in Ground and Excited States; deMayo, P., Ed.; Academic: New York, 1980; Vol. 1, Chapter 4. (4) Termination of a radical cyclization with an iodine atom transfer has been recently reported: Curran, D. P.; Chen, M.-H.; Kim, D. J . Am. Chem.
SOC.1986, 108, 2489. (5) (a) Wardell, J. L.; Paterson, E. S . In Chemistry of the Metal-Carbon Bond; Hartley, F. R., Patai, S., Eds.; Wiley: New York, 1985; Vol. 2, Chapter 3. (b) St. Denis, J.; Dolzine, T.; Oliver, J. P. J . Am. Chem. SOC.1972, 94, 8260. (c) Drozd, V. N.; Ustynyuk, Yu. A,; Tsel'eva, M. A,; Dmitriev, L. B. J . Gen. Chem. USSR 1969, 39, 1951; Zh. Obsch. Khim. 1969, 39, 1991. (6) (a) Hill, E. A. J . Orgonomet. Chem. 1975, 91, 123. (b) Smith, M. J.; Wilson, S. E. Tetrahedron Lett. 1981, 22, 4615. (d) Cooke, M. P., Jr. J . Org. Chem. 1984, 49, 1144. (7) (a) Garst, J. F.; Hines, J. B., Jr. J . Am. Chem. SOC.1984, 106, 6443
and references therein. (b) Chamberlin, A. R.; Bloom, S . H . Tetrahedron Lett. 1986, 27, 551 and references therein. (8) (a) Ross, G. A,; Koppang, M. D.; Bartak, D. E.; Woolsey, N. F. J . Am. Chem. SOC.1985, 107,6742. (b) Koppang, M. D.; Ross, G. A,; Woolsey, N. F.; Bartak, D. E. J . Am. Chem. SOC.1986,,108, 1441. (9) Bailey, W. F.; Patricia, J. J.; DelGobbo, V. C.; Jarret, R. M.; Okarma, P. J. J. Org. Chem. 1985, 50, 1999. (10) Bailey, W. F.; Gagnier, R. P. Tetrahedron Lett. 1982, 23, 5123. ( 1 1 ) Bailey, W. F.; Gagnier, R. P.; Patricia, J. J. J . Org. Chem. 1984, 49, 2098. (12) Bailey, W. F.; Patricia, J. J.; Nurmi, T. T.;Wang, W. Tetrahedron Lett. 1986. 27. 1861. (13) Ba'iley; W. F.; Patricia, J. J.; Nurmi, T. T. Tetrahedron Lett. 1986, 27, 1865. (14) The formation of hydrocarbon formally derived from reduction of the
halide substrate appears to be a general occurrence in lithium-halogen interchange reactions that involve t-BuLi. The relevance of this observation to the mechanism of the interchange process will be discussed elsewhere (Bailey, W. F.; Patricia, J. J., unpublished results).
P
4
I
Isolated yield, b
5
E+
E
4
CH30H
H
9a
a9
CH30D
0
87
67
CO2
COZH
87
54
02
OH
7a
7a
-
quenched at -78 OC with an excess of anhydrous MeOD (>99.5% d,) to give a 95.4% yield of 1-hexene that incorporated only 91% of the available deuterium. Thus, the yield of 5-hexen-1-yllithium I
1
t-BuLi
n-CSH12/EtZO -78 'C t-BuLi-do
n-CSH,2/Et20 -78 'C
-e Me00
-78 'C
9 5 . 4 % (91% d , )
MeOH
-78 'C
94.4% ( 2 % d1)
(2) at the time of the quench was -87% (Le., 95.4% X 91%). The origin of the nondeuteriated 1-hexene formed in this experiment is suggested by the outcome of an analogous experiment involving reaction of 1 with perdeuterio t-BuLi (t-BuLi-d,). Treatment of 1 with t-BuLi-d, (>98% d9) in n-C5HI2-EtzO(3:2 by vol), followed by addition of excess MeOH, gave a 94.4% yield of 1-hexene having a d, content of 2% above natural abundance. This low but nonnegligible deuterium incorporation from t-BuLi-d, is most likely the result of an elimination reaction between 5hexen-1-yllithium (2) and the t-BuI-d, generated in the interchange to give 6-deuterio-1-hexene and CD2=C(CD3)z.14s15 The low deuterium incorporation, which presumably reflects the primary isotope effect on the elimination reaction, is consistent with the larger proportion of 1-hexene produced in the reaction of 2 with (protio) t-BuI. The significance of these observations to the matter at hand lies in the fact that alkenyllithiums generated via lithium-iodine interchange between an iodide and t-BuLi will often contain a small amount of hydrocarbon formally derived from reduction of the halide. In contrast to this clean lithium-iodine exchange, the use of the analogous bromide results in the formation of a complex mixture of productsI3 and the chloride is essentially inert when treated with t-BuLi at -78 OC.I3 The identity of the organolithium used to initiate the interchange was also found to be of importance: reaction of 1 with n-BuLi is so slow at -78 OC to be of little (15) The reaction of t-BuLi with the tert-butyl halide generated in the metal-halogen interchange is well-known. See: Corey, E. J.; Beames, D. J. J . Am. Chem. SOC.1972,94,7210. And: Seebach, D.; Neuman, H. Chem.
Ber. 1974, 107, 847. (16) Organolithiums are known to exist as aggregates whose degree of association may be affected by such factors as solvent, concentration, and temperature (Wakefield, B. J. The Chemistry of Organolithium Compounds; Pergamon: New York, 1974). For the sake of pictorial clarity, monomeric species are used in mechanistic formulations.
2444 J . Am. Chem. SOC.,Vol. 109, No. 8,1987
Bailey et al.
Table I. Cyclization of Alkenyllithiums'
entrv
precursor iodide
1
equiv TMEDA
time at room tempb,h
0
1
products, % yield'
0 -2
2
0
3
3
2
4
4
0
5
14.2
5.6
76
cb 15
6
84
15
65
2
5 6
0
4 3
(94)
d-
35 5.1
7 86.3
5.6
7
"13"'
2
3
"13^ >96
0
8d
0 '9
9dJ
10
w
I
0 0
0e 2
5.3 44.0
0
Q
7.9
