Cyclization of alkenyl radicals in 5- and 6-(π-exo)-exo-dig modes: New entry to exo-cyclic dienes

Article abstract of DOI:10.1021/ol005785s

matrix presented Radical cyclizations of alkenyl iodides in both 5- and 6-(π-exo)-exo-dig modes were effected by tributyltin hydride and AIBN to give exo-cyclic dienes fused to five- and six-membered rings in good yields.

Full text of DOI:10.1021/ol005785s

ORGANIC
LETTERS
2000
Vol. 2, No. 14
2011-2013
Cyclization of Alkenyl Radicals in 5- and
6-(π-Exo)-exo-dig Modes: New Entry to
Exo-cyclic Dienes
Chin-Kang Sha,* Zhuang-Ping Zhan, and Fu-Shing Wang
Department of Chemistry, National Tsing Hua UniVersity, Hsinchu 300,
Taiwan, Republic of China
cksha@mx.nthu.edu.tw
Received March 9, 2000
ABSTRACT
Radical cyclizations of alkenyl iodides in both 5- and 6-(π-exo)-exo-dig modes were effected by tributyltin hydride and AIBN to give exo-cyclic
dienes fused to five- and six-membered rings in good yields.
Exo-cyclic dienes are versatile and useful diene components
in Diels-Alder reactions.1 They are also characteristic
Scheme 1
substructures of vitamin D3 and its derivatives,2 e.g., 1,
Scheme 1. Among various methodologies known for syn-
thesis of exo-cyclic dienes, the palladium-catalyzed cycliza-
tion3 of enynes 2 to exo-cyclic dienes 4 and anionic
cyclization4 of haloenynes 3 to 4 are general and efficient.
Alternatively, the radical cyclizations of haloenynes 3 to 4
would be straightforward.5-7 However according to the
previous study, only 5-(π-exo)-exo-dig radical cyclization
(1) Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction,
Wiley: New York, 1990, Chapter 3.
(2) Norman, A. W. Vitamin D, The Calcium Homeostatic Steroid
Hormone; Academic Press: New York, 1979.
(3) (a) Lautens, M.; Smith, N. D.; Ostrovsky, D. J. Org. Chem. 1997,
62, 8970-8971. (b) Trost, B. M.; Tanoury, G. J.; Lautens, M.; Chan, C.;
Macpherson, D. T. J. Am. Chem. Soc. 1994, 116, 4255-4267. (c) Trost, B.
M.; Romero, D. L.; Rise, F. J. Am. Chem. Soc. 1994, 116, 4268-4278. (d)
Meyer, F. E.; Ang, K. H.; Steinig, A. G.; de Meijere, A. Synlett 1994, 191-
was facile. The corresponding 6-(π-exo)-exo-dig cyclization
193.
was reported to be unfavorable.6 To the best of our
(4) Bailey, W. F.; Wachter-Jurcsak, N. M.; Pineau, M. R.; Ovaska, T.
knowledge, there are only two cases of 6-(π-exo)-exo-dig
radical cyclization of poor yields reported in the literature.7
As an extension of our study in radical cyclization reactions,8
we have also investigated radical cyclizations of alkenyl
iodides. Contrary to the previous reports, we found that not
only 5-(π-exo)-exo-dig but also 6-(π-exo)-exo-dig radical
V.; Warren, R. R.; Lewis, C. E. J. Org. Chem. 1996, 61, 8216-8228.
(5) (a) Capella, L.; Montevecchi, P. C. Tetrahedron Lett. 1994, 35, 8445-
8448. (b) Journet, M.; Rouillard, A.; Cai, D.; Larsen, R. D. J. Org. Chem.
1997, 62, 8630-8631.
(6) Crich, D.; Fortt, S. M. Tetrahedron Lett. 1987, 28, 2895-2898.
(7) (a) Capella, L.; Montevecchi, P. C.; Navacchia, M. L. J. Org. Chem.
1995, 60, 7424-7432. (b) Caddick, S.; Shering, C. L.; Wadman, S. N. J.
Chem. Soc., Chem. Commun. 1997, 171-172.
10.1021/ol005785s CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/16/2000

cyclizations proceeded smoothly to give exo-cyclic dienes
in good yield. Herein we report our preliminary results.
Diynyl esters 11-16 were prepared by conventional
methods.9 Reaction of compounds 5, 6, 7, 9, and 10 with
n-butyllithium and methyl chloroformate gave acetylenic
methyl esters 11, 12, 13, 15, and 16. Double deprotonation
of 8 with n-butyllithium (2.2 equiv) followed by reaction
with methyl chloroformate (3 equiv) afforded diester 14.
Treatment of esters 11-16 with sodium iodide and acetic
acid at 65 °C according to Lu’s method10 gave â-iodo R,â-
unsaturated esters 17-22, Scheme 2. Radical cyclizations
exo)-exo-dig cyclizations, the exo-cyclic dienes obtained were
all in E,E configuration, Table 1.
Table 1. Radical Cyclization of â-Iodo R,â-Unsaturated Esters
Scheme 2
of â-iodo R,â-unsaturated esters 17-20 were effected by
the treatment with tributyltin hydride and AIBN to afford
exo-cyclic dienes 23-26 in 58-77% yield.11 In these 5-(π-
(8) (a) Sha, C.-K.; Shen, C.-Y.; Jean, T.-S.; Chiu, R.-T.; Tseng, W.-H.
Tetrahedron Lett. 1993, 34, 7641-7644. (b) Sha, C.-K.; Santhosh, K. C.;
Lih, S.-H. J. Org. Chem. 1998, 63, 2699-2704. (c) Sha, C.-K.; Ho, W.-Y.
J. Chem. Soc., Chem. Commun. 1998, 2709-2710. (d) Sha, C.-K.; Lee,
F.-K.; Chang, C.-J. J. Am. Chem. Soc. 1999, 121, 9875-9876.
(9) (a) Brandsma, L. PreparatiVe Acetylenic Chemistry; Elsevier: New
York, 1988; pp 97-100 and 247-288. (b) Geiger, R. E.; Lalonde, M.;
Stoller, H.; Schleich, K. HelV. Chim. Acta 1984, 67, 1274-1282. (c) Cao,
X.-P.; Chan, T.-L.; Chow, H.-F. Tetrahedron Lett. 1996, 37, 1049-1052.
(10) (a) Lu, X.; Ma, S. J. Chem. Soc., Chem. Commun. 1990, 1643-
1644. (b) Lu, X.; Ma, S. Tetrahedron Lett. 1990, 31, 7653-7656. (c) Marek,
I.; Alexakis, A.; Normant, J.-F. Tetrahedron Lett. 1991, 32, 5329-5332.
(d) Lu, X.; Ma, S. J. Org. Chem. 1992, 57, 709-713. (e) Piers, E.; Wong,
T.; Coish, P. D.; Rogers, C. Can. J. Chem. 1994, 72, 1816-1819. (f) Luo,
F.-T.; Hsieh, L.-C. J. Chin. Chem. Soc. 1994, 41, 871-873.
(11) For the first example of the â-iodo R,â-unsaturated ester radical
cyclization in 6-(π-exo)-endo-trig mode, see: Thomas, E. J.; Munt, S. P.;
Maguire, R. J. J. Chem. Soc., Perkin. Trans. 1 1998, 2853-2863.
(12) Satisfactory spectral and analytical data were obtained for all new
compounds. A typical experimental procedure for the radical cyclization
of 42 is as follows: To a solution of the 42 (100 mg, 0.26 mmol) in dry
benzene (20 mL) under reflux were added Bu3SnH (83 mg, 0.29 mmol)
and AIBN (5 mg) in dry benzene (6 mL) slowly with a syringe pump (4
h). The reaction mixture was then refluxed for 2 h. After cooling to room
temperature, the solvent was removed on a rotary evaporator. The crude
product was dissolved in Et2O (20 mL). A saturated solution of KF (10
mL) in water was added, and the mixture was stirred at room temperature
for 2 h. The organic layer was then washed with saturated NaHCO3 solution
and brine and dried (Na2SO4). Silica gel flash column chromatography
(hexane-CH2Cl2, 1:1) gave compound 49 as a mixture of E and Z isomers.
(55 mg, 82%). E and Z isomers were separated by silica gel preparative
TLC (hexane-CH2Cl2, 1:1). Data for the E isomer: colorless crystals from
a Isolated yield. b The structures of the exo-cyclic dienes were confirmed
by NOE experiments. c The ratios were determined by 1H NMR integration.
We then attempted the 6-(π-exo)-exo-dig radical cycliza-
tion with â-iodo R,â-unsaturated esters 21 and 22. Com-
pounds 21 and 22 were treated with tributyltin hydride and
AIBN by slow addition using a syringe pump. Surprisingly,
compounds 21 and 22 also underwent radical cyclization
C17H20O2 256.1463, found 256.1453. Data for the Z isomer: pale yellow
oil; 1H NMR (300 MHz, CDCl3) δ 7.20 (d, J ) 8.7 Hz, 2 H), 6.75 (d, J )
8.7 Hz, 2 H), 6.12 (d, J ) 2.0 Hz, 1 H), 5.59 (dd, appears as t, J ) 3.6 Hz,
3.6 Hz, 1 H), 4.15-3.97 (m, 2 H), 3.77 (s, 3 H), 3.68-3.58 (m, 1 H),
2.61-2.49 (m, 1 H), 2.25-2.17 (m, 1 H), 2.12-1.50 (m, 6 H); 13C NMR
(75 MHz, CDCl3) δ 20.0, 25.6, 30.0, 38.7, 55.2, 68.4, 75.3, 113.4, 123.5,
127.4, 130.0, 130.3, 134.8, 137.0, 157.8; IR (CHCl3) 2938, 1607, 1509,
1247, 1094 cm-1; MS (EI) m/z 256 (M+, 100); HRMS calcd for C17H20O2
256.1463, found 256.1464.
1
hexane; mp 105-6 °C.; H NMR (300 MHz, CDCl3) δ 7.18 (d, J ) 8.7
Hz, 2 H), 6.85 (d, J ) 8.7 Hz, 2 H), 6.48 (d, J ) 2.1 Hz, 1 H), 5.85 (dd,
appears as t, J ) 3.6 Hz, 3.6 Hz, 1 H), 4.03-3.97 (m, 2 H), 3.78 (s, 3 H),
3.53-3.43 (m, 1 H), 2.75-2.69 (m, 1 H), 2.62-2.50 (m, 1 H), 2.28-2.13
(m, 1 H), 2.11-1.99 (m, 2 H), 1.84-1.71 (m, 1 H), 1.63-1.49 (m, 2 H);
13C NMR (75 MHz, CDCl3) δ 20.3, 26.2, 29.9, 30.9, 55.3, 66.8, 75.6, 113.6,
123.0, 123.1, 130.2, 130.5, 136.5, 139.3, 158.3; IR (CHCl3) 2939, 1606,
1509, 1249, 1101 cm-1; MS (EI) m/z 256 (M+, 100); HRMS calcd for
2012
Org. Lett., Vol. 2, No. 14, 2000

smoothly to give products 27/28 and 29/30 in 68% and 76%
yields, respectively, Table 1.
Scheme 3
Encouraged by our success on 6-(π-exo)-exo-dig mode of
radical cyclization of 21 and 22, we then examined more
reactions as shown in Table 2. The required radical precur-
Table 2. 6-(π-Exo)-Exo-Dig Cyclization of Alkenyl Radicals
reaction with 3-bromo-2-iodocyclohex-1-ene gave com-
pounds 37, 38, 40-43 in 76-86% yield. Reaction of 37 with
EtMgBr and TMSCl gave compound 39 in 90% yield.
When compounds 37-43 were treated with tributyltin
hydride and AIBN, once again we found that 6-(π-exo)-exo-
dig radical cyclizations were facile, Table 2.12 In entries 1-3,
compounds 37, 38, and 39 underwent cyclization smoothly
to give exo-cyclic dienes 44, 45, and 46 in good yield. It is
noteworthy to mention that a similar cyclization in the case
of acyclic substrate was reported as totally unsuccessful by
Crich et al.6 When the triple bond was substituted with a
isopropenyl group or aromatic rings, entries 4-7, the yields
of the exo-cyclic dienes 47-50 were improved, Table 2.
In conclusion, we have developed a new alkenyl radical
cyclization methodology for the construction of exo-cyclic
dienes fused to five- and six-membered rings. Contrary to
the previous report,6 we found that 6-(π-exo)-exo-dig cy-
clizations of alkenyl radicals are highly efficient. We believe
that this methodology is potentially useful in the total
synthesis of natural products.
a Isolated yield. b The structures of the exo-cyclic dienes were confirmed
by NOE experiments, and the ratios of E and Z isomers were determined
by H NMR integration.
1
Acknowledgment. We thank the National Science Coun-
cil of the Republic of China for financial support (NSC88-
2113-m-007-025).
sors were procured as outlined in Scheme 3. Treatment of
acetylenic alcohols 31-36 with NaH in THF followed by
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