Palladium Catalysis
6333 – 6342
1
Data for 10: M.p. 40–428C; TLC: Rf =0.08; H NMR: d=5.91 (br s, 1H),
3.77 (s, 3H), 3.03 (d, J(H,H)=12.0 Hz, 1H), 2.49–2.61 (m, 1H), 2.38 (dd,
3
[1] T. Pei, R. A. Widenhoefer, J. Am. Chem. Soc. 2001, 123, 11290.
[2] H. Qian, T. Pei, R. A. Widenhoefer, Organometallics, 2004, 23, in
press.
[3] T. Pei, X. Wang, R. A. Widenhoefer, J. Am. Chem. Soc. 2003, 125,
648.
[4] C. Liu, X. Wang, T. Pei, R. A. Widenhoefer, Chem. Eur. J. 2004, 10,
DOI: 10.1002/chem.200400460.
[5] H. Qian, R. A. Widenhoefer, J. Am. Chem. Soc. 2003, 125, 2056.
[6] F. G. Bordwell, Acc. Chem. Res. 1988, 21, 456.
[7] M. Bassetti, B. Cerichelli, B. Floris, Tetrahedron 1988, 44, 2997.
[8] J. P. Guthrie, Can. J. Chem. 1979, 57, 1177.
[9] J. P. Guthrie, P. A. Cullimore, Can. J. Chem. 1979, 57, 240.
[10] Portions of this work have been communicated: a) T. Pei, R. A. Wi-
denhoefer, Chem. Commun. 2002, 650; b) X. Wang, T. Pei, X. Han,
R. A. Widenhoefer, Org. Lett. 2003, 5, 2699.
[11] a) M. Toyota, T. Wada, K. Fukumoto, M. Ihara, J. Am. Chem. Soc.
1998, 120, 4916; b) M, Toyota, A. Ilangovan, R. Okamoto, T.
Masaki, M. Arakawa, M. Ihara, Org. Lett. 2002, 4, 4293.
[12] a) A. S. Kende, B. Roth, P. J. Sanfilippo, T. J. Blacklock, J. Am.
Chem. Soc. 1982, 104, 5808; b) A. S. Kende, B. Roth, P. J. Sanfilippo,
J. Am. Chem. Soc. 1982, 104, 1784; c) A. S. Kende, D. J. Wustrow,
Tetrahedron Lett. 1985, 26, 5411; d) Y. Ito, H. Aoyama, T. Hirao, A.
Mochizuki, T. Saegusa, J. Am. Chem. Soc. 1979, 101, 494; e) Y. Ito,
H. Aoyama, T. Saegusa, J. Am. Chem. Soc. 1980, 102, 4519; f) M.
Shibasaki, T. Mase, S. Ikegami, J. Am. Chem. Soc. 1986, 108, 2090;
g) M. Toyota, T. Seishi, K. Fukumoto, Tetrahedron Lett. 1993, 34,
5947; h) M. Toyota, Y. Nishikawa, K. Motoki, N. Yoshida, K. Fuku-
moto, Tetrahedron Lett. 1993, 34, 6099; i) K. Irie, T. Isaka, Y. Iwata,
Y. Yanai, Y. Nakamura, F. Koizumi, H. Ohigashi, P. A. Wender, Y.
Satomi, H. Nishino, J. Am. Chem. Soc. 1996, 118, 10733; j) A. S.
Kende, P. J. Sanfilippo, Synth. Commun. 1983, 13, 715; k) L. E.
Torres, G. L. Larson, Tetrahedron Lett. 1986, 27, 2223; l) A. S.
Kende, B. Roth, P. J. Sanfilippo, J. Am. Chem. Soc. 1982, 104, 1784.
[13] a) K. Maeyama, N. Iwasawa, J. Am. Chem. Soc. 1998, 120, 1928;
b) N. Iwasawa, K. Maeyama, H. Kusama, Org. Lett. 2001, 3, 3871.
[14] M. Yamaguchi, A. Hayashi, M. Hirama, J. Am. Chem. Soc. 1993,
115, 3362.
[15] K.-I. Imamura, E. Yoshikawa, V. Gevorgyan, Y. Yamamoto, Tetrahe-
dron Lett. 1999, 40, 4081.
[16] In accord with this hypothesis, methyl 3-(triethylsilyloxy)-2,6-hepta-
dienoate underwent rapid desilylation in the presence of 2 without
formation of detectable amounts of cyclized product.
[17] Heating a solution of 4 in the presence of excess Me3SiCl or
Me3SiCl/CuCl2 at 558C in the absence of 2 led to no detectable cyc-
lization after 12 h.
[18] a) F. R. Hartley, Chem. Rev. 1973, 73, 163; b) H. Kurosawa, T.
Majima, N. Asada, J. Am. Chem. Soc. 1980, 102, 6996.
2
4
3
3J(H,H)=4.8, J(H,H)=18.8 Hz, 1H), 2.09 (qdd, J(H,H)=1.2, J(H,H)=
10.4, J(H,H)=18.4 Hz, 1H), 1.96 (s, 3H), 1.05 ppm (d, 3J(H,H)=6.4 Hz,
2
3H); 13C{1H} NMR: d=194.4, 170.9, 162.3, 125.6, 60.9, 52.3, 38.6, 32.8,
24.5, 20.0 ppm; IR (neat): n˜ =1742, 1667 cmꢀ1 (C=O); HRMS: m/z calcd
for C10H14O3: 182.0943 (found: 182.0954).
(E)-Methyl (5,5-dimethyldihydrofuran-2-ylidene)acetate ((E)-13):[34]
A
suspension of 11 (100 mg, 0.60 mmol), (16 mg, 0.06 mmol), CuCl2
2
(40 mg, 0.30 mmol), and Me3SiCl (0.15 mL, 1.20 mmol) in dioxane
(10 mL) was stirred at 658C for 2 h, cooled to room temperature, and
concentrated under vacuum. The resulting oily residue was subjected to
chromatography (hexanes/diethyl ether=25:1!12:1) to give (E)-13
(66 mg, 66%) as a colorless oil.
2-Phenylcyclohexanone (19): A suspension of 18 (87 mg, 0.50 mmol),
Me3SiCl (0.19 mL, 1.50 mmol), 2 (13 mg, 0.05 mmol), and CuCl2 (67 mg,
0.50 mmol) in dioxane (10 mL) was stirred at 708C for 8 h. The reaction
mixture was filtered through a plug of silica gel and eluted with diethyl
ether. The resulting solution was concentrated under vacuum and sub-
jected to chromatography (hexanes/diethyl ether=25:1!15:1) to give 19
(61 mg, 70%) as a pale yellow solid.
The remaining cyclohexanones in Tables 4 and 5 were synthesized em-
ploying a procedure analogous to that used to synthesize 19 unless noted
otherwise.
cis-2,3-Diphenylcyclohexanone (cis-23): A suspension of phenyl magnesi-
um chloride (2.0m in THF, 1.5 mL, 3.0 mmol) and CuI (32 mg,
0.17 mmol) in THF (10 mL) was stirred at 08C for 30 min and then treat-
ed with a solution of 2-phenyl-2-cyclohexenone (0.34 g, 2.0 mmol) in
THF (2 mL). The resulting suspension was stirred at room temperature
for 12 h, poured into aqueous HCl (1n), and extracted with diethyl ether.
The combined organic extracts were washed with 10% aqueous Na2S2O3
and brine, dried (MgSO4), and concentrated under vacuum. The resulting
residue was subjected to chromatography (hexanes/diethyl ether=40:1!
15:1) to give cis-23 (70 mg, 14%) as a white solid. M.p. 85–868C; TLC:
Rf =0.50; 1H NMR: d=7.20–7.12 (m, 6H), 7.03–6.99 (m, 4H), 4.05 (d,
3J(H,H)=5.6 Hz, 1H), 3.62 (m, 1H), 2.79–2.72 (m, 1H), 2.64–2.58 (m,
1H), 2.32–2.16 (m, 3H), 1.99–1.90 ppm (m, 1H); 13C{1H} NMR: d=
211.0, 141.9, 136.5, 130.0, 128.5, 128.4, 128.3, 127.0, 126.8, 61.8, 48.7, 40.8,
28.6, 24.0 ppm; IR (neat): n˜ =1708, 1679 cmꢀ1 (C=O); elemental analysis
calcd (%) for C18H18O: C 86.36, H 7.25; found: C 86.27, H 7.36.
Isomerization of cis-23 under reaction conditions: A suspension of cis-23
(58 mg, 0.23 mmol), Me3SiCl (0.12 mL, 0.94 mmol), 2 (8 mg, 0.03 mmol),
and CuCl2 (42 mg, 0.32 mmol) in dioxane (6 mL) was stirred at 708C.
After 30 min, GC analysis revealed complete (ꢁ98%) conversion to
trans-23. The reaction mixture was cooled to room temperature, filtered
through a plug of silica gel, and eluted with diethyl ether. The resulting
solution was concentrated to give trans-23 (56 mg, 97%) as a pale yellow
solid that was both chemically and isomerically pure (ꢁ95%) by
1H NMR analysis.
[19] The predominant diastereomer of 9 formed through palladium-cata-
lyzed cyclization of 8 was initially assigned incorrectly as the trans
diastereomer.[10a] This assignment was based on comparison of the
13C NMR spectrum of cis-3,5-dimethylcyclohexanone, generated
through decarboalkoxylation of 9, with the 13C NMR spectrum of
cis-3,5-dimethylcyclohexanone reported in the Sadtler handbook.[19b]
Unfortunately, the 13C NMR resonances for cis- and trans-3,5-dime-
thylcyclohexanone are transposed in this source, but are reported
correctly elsewhere.[19c,19d] The stereochemistry of cis-3,5-dimethylcy-
clohexanone can be unambiguously established by the 12.3 Hz cou-
pling between the axial a- and b-protons in the 1H NMR spectrum;
b) Sadtler Standard Carbon-13 NMR Spectra 1986, 17926c; c) K. W.
Baldry, M. J. T. Robinson, Tetrahedron 1977, 33, 1663; d) L. Bassi, B.
Joos, P. Gassmann, H.-P. Kaiser, H. Leuenberger, W. Keller-Schier-
lein, Helv. Chim. Acta 1983, 66, 92.
2-Hexylcyclohexanone (33): A suspension of 2 (13 mg, 0.05 mmol), CuCl2
(20 mg, 0.15 mmol), HCl (4 N in dioxane, 13 mL, 0.05 mmol), and 32
(91 mg, 0.50 mmol) in dioxane (6 mL) was stirred at 708C in a sealed
tube for 12 h. The resulting mixture was filtered through a short plug of
silica gel and eluted with hexanes/diethyl ether (1:1, 30 mL). The result-
ing solution was concentrated under vacuum and the residue was subject-
ed to chromatography (hexanes/diethyl ether=20:1!10:1) to give 33[35]
(70 mg, 77%) as a pale yellow oil.
The remaining cyclohexanones in Table 6 were synthesized employing a
procedure analogous to that used to synthesize 33.
[20] In a control experiment, treatment of 11 with HCl (0.5 equiv) at
758C in a sealed tube for 15 h formed a mixture of (E)-13 (54%),
11 (25%), and an unidentified isomer (11%) as determined by GC
analysis of the crude reaction mixture. We therefore rule out acid-
catalyzed conversion of 11 to (E)-13 in the cyclization of 11 cata-
lyzed by 2 in the presence of Me3SiCl and CuCl2.
[21] a) C. P. Casey, C. R. Cyr, J. A. Grant, Inorg. Chem. 1974, 13, 910;
b) J. Schwartz, J. A. Labinger, Angew. Chem. Int. Ed. 1976, 88, 402;
Angew Chem. Int. Ed. Engl. 1976, 15, 333.
Acknowledgements
The NSF (CHE-03–04994) is thanked for support of this research. R.W.
thanks the Camille and Henry Dreyfus Foundation and GlaxoSmithKline
for unrestricted financial support. We thank Dr. Peter S. White for deter-
mining the structure of trans-23.
Chem. Eur. J. 2004, 10, 6333 – 6342
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6341