Scheme 2
equiv of methyl vinyl ketone as the activated olefin 2.5 The
and converted to the corresponding ketone enolate anions
16. In the presence of a suitably disposed sulfonate leaving
group, an intramolecular alkylation takes place and cyclo-
hexane ring 17 is formed with an exocyclic electron-
withdrawing group.9 We propose that 8-endo-cycloalkylation,
with the formation of the cyclooctane ring, could also occur
if the formation of the enolate anion is performed under
kinetic conditions.10
Cycloalkylation reaction of the open chain or cyclic
sulfonate esters 15 with appropriate positions and stereo-
chemical orientation of the reacting centers is a favorable
reaction. However, when the stereochemical relations are not
suitable for intramolecular alkylation, an elimination occurs
as a side reaction to give unsaturated products.
The importance of stereochemistry in the cycloalkylation
reaction was observed in the reaction of the enolate anion
18, derived from a compound obtained by δ-alkylation of
(-)-menthyl benzenesulfenate with methyl vinyl ketone.
Possesing an equatorial leaving group, the enolate anion 18
does not undergo a substitution reaction but rather undergoes
an elimination reaction to give the unsaturated compound.11
To carry out the cycloalkylation reaction, the hydroxyl group
in the δ-alkylated product obtained from (-)-menthyl
benzenesulfenate was epimerized to the axial position (via
the p-nitrobenzoate ester).12 The enolate anion 19, derived
from the corresponding keto-methanesulfonate with an axial
leaving group, undergoes intramolecular substitution to give
the bicylic product 7. However, in addition to the bicyclic
product 7, the unsaturated compound 20 was also formed as
a product of the elimination reaction (yields of 53% and 34%,
δ-carbon radicals 13, generated by 1,5-hydrogen transfer in
the alkoxy radical 12,6 undergo intermolecular addition to
give δ-alkylated products 14 (Scheme 2).1,7 Products of the
free radical alkylation at the δ-carbon atom were isolated
and fully characterized.
The hydroxyl group in the alkylated products 14 was
converted to the corresponding toluenesulfonate or meth-
anesulfonate ester 15 by reaction with sulfonyl chlorides in
pyridine.8 In the next step, the sulfonate esters were reacted
with sodium hydride in DME under equilibrium conditions
(4) Beckwith, A. L. J.; Hay, B. P.; Williams, G. M. J. Chem. Soc., Chem.
Commun. 1989, 1202.
(5) Typical experiment: A solution of 3-cyclohexylpropyl-O-p-nitroben-
zenesulfenate ester (0.15 g; 0.51 mmol), methyl vinyl ketone (0.35 g; 5.1
mmol; 10 equiv excess), and tributyltin hydride (0.16 g; 0.55 mmol) in
benzene (40 mL) was irradiated at rt with visible light (xenon lamp 250
W, λ > 300 nm or by UV lamp) for 1 h in an argon atmosphere. After
reaction was completed, the benzene was evaporated and the residual oil
was dissolved in ether (50 mL) and washed with an aqueous NaF solution
(0.5 g in 10 mL). The ethereal solution was separated and the aqueous
solution extracted with ether (2 × 20 mL). The ethereal solutions were
dried (anhydrous Na2SO4), and by evaporation of the ether, an oily alkylation
product was obtained, which was dissolved in toluene and purified by dry
flash chromatography using petroleum ether:acetone 95:5 as eluent. 4-[(3-
Hydroxypropyl)cyclohexyl]butan-2-one was obtained as a pale yellow oil
(50 mg; 47% yield). IR (film): 3405, 1713, 1596, 1519, 1459, 1416, 1358,
1
1339, 1164, 1057, 1018, 964, 918, 852, 822 cm-1. H NMR (CDCl3, 200
MHz) δ: 0.91 (t, J ) 7.2 Hz, 2H), 1.21-1.61 (m, 14H), 1/93 (s, broad,
1H), 2.16 (s, 3H), 2.29-2.38 (m, 2H), 3.61 (t, J ) 6.4 Hz, 2H). 13C NMR
(CDCl3, 50 MHz) δ: 210.01, 63.52, 37.71, 35.58, 33.92, 3252, 30.42, 29.88,
27.67, 26.92, 26.27. 26.09, 21.41. The hydroxy ketone was converted to
the corresponding tosylate which was treated with sodium hydride in DME
to give 1-spiro[5.5]undec-2-ylethanone (8) as a colorless oil (10 mg; 77%
yield). IR (film): 1709, 1451, 1372, 1354, 1270, 1236, 1189, 1164, 964,
903, 843 cm-1. 1H NMR (CDCl3, 200 MHz) δ: 0.89-1.90 (m, 18H), 2.13
(s, 3H), 2.50 (tt, Jaa ) 12.2 Hz, Jae ) 3.4 Hz, 1H). 13C NMR (CDCl3, 50
MHz) δ: 212.84 (C), 46.68 (CH), 41.82, 38.75, 35.83 (CH2), 32.65 (C),
32.14, 28.71 (CH2), 27.93, (CH3), 26.78, 21.47. 20.67 (CH2). MS (CI): 195
(M + 1) 100%.
(6) Mihailovic, M. Lj.; Cekovic, Z. Synthesis 1970, 209. Kalvoda, J.;
Heusler, K. Synthesis 1971, 501. Barton, D. H. R. Pure and Appl. Chem.
1968, 16, 1. Majetich, G. Wheless, K. Tetrahedron (Rep. No. 375) 1995,
51, 7095. Tsunoi, S.; Ryu, I.; Okuda, T.; Tanaka, M.; Komatsu, M.; Sonoda,
N. J. Am. Chem. Soc. 1998, 120, 8692. Dorigo, A. E.; Houk, K. N. J. Org.
Chem. 1988, 53, 1650.
(8) Kabalka G. W.; Varma M.; Varma R. S. J. Org. Chem. 1986, 51,
2386. Ikeda, N.; Takahashi, M.; Uchino, T.; Ohno, K.; Tamura, Z.; Kido.
M. J. Org. Chem. 1983, 48, 4241.
(9) Caine, D. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: 1991; Vol. 3, Chapter 1 and references
therein. Caine, D. In Carbon-Carbon Bond Formation; Augustune, R. L.,
Ed.; Dekker: New York, 1979; Vol. 1, Chapter 2.
(10) House, H. O.; Sayer, T. S. B.; Zau, C.-C. J. Org. Chem. 1978, 43,
2153.
(11) Saunders, W. H., Jr.; Cockerill, A. F. Mechamisms of Elimination
Reactions; Wiley-Interscience: New York, 1973.
(7) Giese, B. Angew. Chem., Int. Ed. Engl. 1983, 22, 753; 1985, 24,
553. Giese, B. Radicals in Organic Synthesis: Formation of Carbon-
Carbon Bonds; Pergamon Press: Oxford, 1988. Curran, D. P. Synthesis
1988, 417, 489.
(12) Martin, F. S.; Dodge, A. J. Tetrahedron Lett. 1991, 26, 3017.
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