Photoinduced atom-transfer cyclization of α-iodocycloalkanones bearing an allenyl side chain

Article abstract of DOI:10.1021/ol048822e

(Chemical Equation Presented) Irradiation of α-iodocycloalkanones bearing an allenyl side chain with a sunlamp effected atom-transfer cyclization to give cyclized products in good yield. A mechanism, involving radical atom-transfer cyclization accompanied

Full text of DOI:10.1021/ol048822e

ORGANIC
LETTERS
2004
Vol. 6, No. 19
3289-3292
Photoinduced Atom-Transfer Cyclization
of r-Iodocycloalkanones Bearing an
Allenyl Side Chain
Hsien-Hsun Lin, Wen-Sheng Chang, Shun-Yuan Luo, and Chin-Kang Sha*
Department of Chemistry, National Tsing Hua UniVersity,
Hsinchu 300, Taiwan, R.O.C.
cksha@mx.nthu.edu.tw
Received June 21, 2004
ABSTRACT
Irradiation of r-iodocycloalkanones bearing an allenyl side chain with a sunlamp effected atom-transfer cyclization to give cyclized products
in good yield. A mechanism, involving radical atom-transfer cyclization accompanied by 1,5- and 1,4-hydrogen transfers, is proposed.
Halogen atom-transfer addition and cyclization mediated with
a di-tin reagent are efficient methods to form a carbon-
carbon bond.1 Although the di-tin reagent is required in only
catalytic amount, this method suffers from tedious separation
of tin-containing side products. For a reaction on a prepara-
tive scale, a tin-free condition for halogen atom-transfer
addition and cyclization is highly desirable.2 We have
demonstrated that R-carbonyl radical cyclization is an
efficient method for synthesis of both carbocyclic frame-
works and several natural products, i.e., (+)-paniculatine,
(-)-dendrobine, and (-)-5-oxosilphiperfol-6-ene.3 We also
developed tin-free conditions for this radical cyclization.4
In this Letter, we report our new results on tin-free cyclization
of R-iodocycloalkanones bearing an allenyl side chain.5
In an initial study, we found that compound 1,6 when
irradiated in the presence of (Bu3Sn)2, gave product 2 in 90%
yield, whereas irradiation of 1 without (Bu3Sn)2 afforded 2
in only 15% yield. In contrast, compound 3a,7 bearing an
allenyl side chain, cyclized under both conditions to afford
4a as a mixture of two diastereomers (1:1.1) in 81% and
78% yields, respectively (Scheme 1).
To understand the distinction of these photolytic reactions
of 1 and 3a and to explore the synthetic utility of this
photocyclization, we prepared R-iodocycloalkanones 3a-f
(1) (a) Curran, D. P.; Chen, M.-H.; Kim, D. J. Am. Chem. Soc. 1986,
108, 2489. (b) Curran, D. P.; Kim, D. Tetrahedron Lett.1986, 27, 5821. (c)
Curran, D. P.; Chang, C.-T. Tetrahedron Lett. 1987, 28, 2477. (d) Curran,
D. P.; Chang, C.-T. J. Org. Chem. 1989, 54, 3140. (e) Curran, D. P.
Synthesis 1988, 417, 489. (f) Jasperse, C. P.; Curran, D. P.; Fevig, T. L.
Chem. ReV. 1991, 91, 1237. (g) Melikyan, G. G. Synthesis 1993, 833. (h)
Iqbal, J.; Bhatia, B.; Nayyar, N. K. Chem. ReV. 1994, 94, 519. (i) Snider,
B. B. Chem. ReV. 1994, 96, 339. (j) Curran, D. P.; Potter, N. A.; Giese, B.
Stereochemistry of Radical Reactions; VCH: Weinheim, 1996. (k) Byers,
J. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-
VCH: Weinheim, 2001; Vol. 1, Chapter 1.5. (l) Gansauer, A.; Bluhm, H.
Chem. ReV. 2000, 100, 2771. (m) Yorimitsu, H.; Shinokubo, H.; Matsubara,
S.; Oshima, K. J. Org. Chem. 2001, 66, 7776. (n) Li, C.; Wang, J. J. Org.
Chem. 2002, 67, 1271.
(2) (a) Devin, P.; Fensterbank, L.; Malacria, M. Tetrahedron Lett. 1999,
40, 5511. (b) Kim, S.; Song, H.-J.; Choi, T.-L.; Yoon, J.-Y. Angew. Chem.,
Int. Ed. 2001, 40, 2524. (c) Ollivier, C.; Bark, T.; Renaud, P. Synthesis
2000, 1598. (d) Kim, S.; Song, H.-J. Synlett 2002, 2110. (e) Ouvry, G.;
Zard, S. Z. Chem. Commun. 2003, 778. (f) Vaillard, S. E.; Postigo, A.;
Rossi, R. A. J. Org. Chem. 2004, 69, 2037.
(3) (a) Sha, C.-K.; Jean, T.-S.; Wang, D.-C. Tetrahedron Lett. 1990, 31,
3745. (b) Sha, C.-K.; Chiu, R.-T.; Yang, C.-F.; Yao, N.-T.; Tseng, W.-H.;
Liao, F.-L.; Wang, S.-L. J. Am. Chem. Soc. 1997, 119, 4130. (c) Sha, C.-
K.; Santhosh, K. C.; Lih, S.-H. J. Org. Chem. 1998, 63, 2699. (d) Sha,
C.-K.; Ho, W.-Y. Chem. Commun. 1998, 2709. (e) Sha, C.-K.; Lee, F.-K.;
Chang, C.-J. J. Am. Chem. Soc. 1999, 121, 9875.
(4) Sha, C.-K.; Santhosh, K. C.; Tseng, C.-T.; Lin, C.-T. Chem. Commun.
1998, 397.
(5) For radical cyclization of allenes, see: (a) Crandall, J. K.; Ayers, T.
A. Tetrahedron Lett. 1991, 32, 3659. (b) Macro-Contelles, J.; Balme, G.;
Bouyssi, D.; Destabel, C.; Henriet-Bernard, C. D.; Grimaldi, J.; Hatem, J.
M. J. Org. Chem. 1997, 62, 1202. (c) Villar, F.; Renaud, P. Tetrahedron
Lett. 1998, 39, 8655.
(6) Compound 1 was prepared from 5a using a sequence of reactions as
shown in Scheme 2. 5-Iodo-1-pentyne was used as alkylating agent.
(7) Preparation of 3a is shown in Scheme 2. The experimental procedures
are in Supporting Information.
10.1021/ol048822e CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/21/2004

Scheme 1
Table 1. Photoinduced Atom-Transfer Cyclization of
2-Substituted R-Iodocycloalkanones
and investigated this reaction systematically. Cycloalkanones
5a-c were thus converted to N,N-dimethylhydrazones 6a-
c. Deprotonation of 6a-c with n-BuLi followed by alkylation
with 6-iodo-hexa-1,2-diene or 7-iodo-hepta-1,2-diene and
hydrolysis gave 7a-f.8 Treatment of cycloalkanones 7a-f
with trimethylsilyl iodide/hexamethyldisilazane followed by
m-CPBA/NaI9 afforded R-iodocycloalkanones 3a-f (Scheme
2).
Scheme 2
a Reaction condition: hν, PhH. b Reaction condition: hν, PhH, (Bu3Sn)2.
experiments to be Z. The reason of selective formation of Z
side product was unclear. Compounds 8b-d were unstable
and could not be separated by silica gel column chromatog-
raphy. By comparison of their 1H NMR spectra with that of
8a, compounds 8b-d were assigned as Z isomers.
Photolysis of 3a-c, in the presence of (Bu3Sn)2, effected
5-exo-cyclizations (entries 1-3) in comparable yields. In
contrast, photolysis to effect 6-exo-cyclizations of 3d-f in
the presence of (Bu3Sn)2 gave cyclized products 4d-f
(entries 4-6) in only trace proportions.
Furthermore, 3-substituted R-iodocycloalkanones 11a,b
were prepared from cycloalkenones 9a,b. Iodination of
enones 9a,b according to Johnson’s method gave iodo-
cycloalkenones 10a,b.10 1,4-Addition of the cuprate reagent,
generated from 5-iodo-penta-1,2-diene/t-BuLi/CuCN, to 10a,b
gave R-iodocycloalkanones 11a,b (Scheme 3).
Irradiation of R-iodocycloalkanones 3a-f in benzene
solution with a sunlamp afforded cyclized products as a
mixture of two diastereomers 4a-f with some side products
8a-d (Table 1). 5-exo-Cyclizations (entries 1-3) gave
products 4a-c in 78-82% yield and side products 8a-c in
2-9%. 6-exo-Cyclizations (entries 4-6) afforded products
4d-f in smaller yield (15-45%). In entry 4, 8d was obtained
in 7% yield. Compound 8a was separated. The stereochem-
istry of the double bond in 8a was determined with NOE
Scheme 3
(8) Johnson, E. P.; Chen, G.-P.; Fales, K. R.; Lenk, B. E.; Szendroi, R.
J.; Wang, X.-J.; Carlson, J. A. J. Org. Chem. 1995, 60, 6595.
(9) Sha, C.-K.; Young, J.-J.; Jean, T.-S. J. Org. Chem. 1987, 52, 3919.
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Org. Lett., Vol. 6, No. 19, 2004

R-Iodocycloalkanone 14 was synthesized from 4,4-di-
methyl-2-cyclohexene-1-one 12 via conjugate addition of the
cuprate reagent, generated from 5-iodo-penta-1,2-diene/t-
BuLi/CuCN, trapping the enolate with TMSCl, and then
treatment with NaI/m-CPBA (Scheme 4).
Table 2. Photoinduced Atom-Transfer Cyclization of
3-Substituted R-Iodocycloalkanones
Scheme 4
R-Iodocycloalkanone 18 was prepared from 3-ethoxy-2-
cyclohexene-1-one 15. 1,2-Addition of the lithium reagent,
generated from 5-iodo-penta-1,2-diene and t-BuLi, to 15
followed by hydrolysis gave 16. Conjugate addition of
lithium dimethylcuprate to 16 followed by trapping the
enolate with TMSCl and iodination with NaI/m-CPBA
yielded 18 (Scheme 5).
isomer, and its stereochemistry was not determined. Com-
pounds 19b, 21, and 23 were formed as a mixture of two
diastereomers. Compound 23 was unstable. The minor
Scheme 5
Scheme 6
Irradiation of R-iodocycloalkanones 11a, 11b, 14, and 18
in benzene solution with a sunlamp afforded major products
19a, 19b, 21, and 23 and minor products 20a, 20b, 22, and
24 (Table 2).
Di-tin-mediated photolysis of 11a, 11b, 14, and 18 gave
similar results. Compound 19a was obtained as a single
(10) Johnson, C. R.; Adems, J. P.; Branu, M. P.; Senanayake, C. B. W.;
Wovkulich, P. M.; Uskokovic´, M. R. Tetrahedron Lett. 1992, 33, 917.
Org. Lett., Vol. 6, No. 19, 2004
3291

product 20a was separated. The stereochemistry of the double
bond in 20a was also determined with NOE experiments to
be Z. By comparison of their H NMR spectra with that of
20a, compounds 20b, 22, and 24 were also assigned as the
Z isomers.
To rationalize the formation of the two products in these
reactions, we propose a free radical atom-transfer mechanism
as shown in Scheme 6. Irradiation of 3a in the absence of
di-tin gives radical 25. Radical 25 undergoes cyclization to
give vinyl radical 26. Abstraction of an iodine atom from
starting material 3a by radical 26 affords product 4a and
regenerates 25. Radical 26 can also undergo 1,5-hydrogen
transfer to yield radical 27 and/or 28.11 Subsequent 1,5-
hydrogen or 1,4-hydrogen transfer12 in radical 27 and/or 28
produces radical 29. Abstraction of an iodine atom from 3a
by radical 29 delivers side product 8a.
In conclusion, we have demonstrated that iodine atom-
transfer cyclization of R-iodocycloalkanones can be effected
by irradiation with a sunlamp without use of a di-tin reagent.
A mechanism, involving radical atom-transfer cyclization
accompanied by 1,5- and 1,4-hydrogen transfers, is proposed.
Further study to understand the different results obtained in
the photolysis of 3d-f, with or without di-tin and the
application of this reaction for the total synthesis of natural
products are under current investigation.
1
Acknowledgment. We thank the National Science Coun-
cil of the Republic of China for financial support through a
grant (NSC92-2113-M-007-055).
Supporting Information Available: Full details of
experimental procedures, spectral data for all new com-
pounds, and the NOE experiments for determining stereo-
chemistry of the double bond in 8a and 20a. This material
is available free of charge via the Internet at http://pubs.acs.org.
(11) Sha, C.-K.; Ho, W.-Y.; Mohanakrishnan, A. K.; Lin, C.-L.; Chu,
SS.-Y. C. R. Acad. Sci., Ser. IIc: Chim. 2001, 4, 439.
(12) Journet, M.; Malacria, M. Tetrahedron Lett. 1992, 39, 1893.
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