Yanada et al.
TABLE 1. Ra d ica l Cycliza tion of Iod oa lk yn e 1a
1b in 71% yield under condition B. Atom-transfer radical
cyclization and reductive radical cyclization reactions
were achieved for the first time by only controlling the
quantities of In and I2.
Next, we examined radical cyclizations to various
aliphatic iodoalkynes (2-9) under conditions A and B.
As can be seen from Table 2, iodoalkynes 2 and 4-611
predominantly gave atom-transfer cyclization products
2a , 4a , 5a , and 6a 11,12 under conditions A and gave
reductive cylization products 2b, 4b,13 5b,14 and 6b15
under conditions B (runs 1 and 3-5). Even under
conditions A, the use of substrates 3 and 7 bearing an
electron-delocalizing phenyl group on the sp carbon
resulted in smooth reductive radical cyclization reactions
to produce compounds 3b16 and 7b (runs 2 and 6). In
general, it is thought that the reduction of vinyl radical
intermediates (Scheme 1, D) to a vinyl-indium compound
(E) is slower than the addition of iodine from compound
1 to give atom-transfer cyclization products (1a and 1b)
under conditions A. On the other hand, vinylic radicals
bearing phenyl groups (electrophilic radicals) might
result in subsequent rapid electron transfer to produce
a reductive radical cyclization product even under condi-
tion A. The atom-transfer cyclization or reductive cy-
clization may be realized by a subtle balance of reaction
rates. We tried this reductive cyclization as an approach
to synthesis of bicyclic sugars via radical cyclization (runs
7 and 8). Bicyclic sugars are interesting compounds
because of their utility as building blocks for synthesis
of natural products and because of their biological activi-
ties.17 The sugar iodides 8 and 9 were prepared from
glucal and galactal with propargyl alcohol in the presence
of N-iodosuccinimide in CH3CN.18 Cyclization reactions
with indium were carried out under conditions B using
compounds 8 and 9.19 The reductive cyclization products
8b and 9b were obtained in 74 and 75% yields, respec-
tively.
yield (%)
In
I2
time
(h)
run condition (equiv) (equiv)
1a 1b 1c total
1
2
3
4
1
1
0.1
2
0.0
0.5
0.05
1.0
17
5
32
17
46
76
69
0
4
4
8
0
5
3
3
55
83
80
85
A
B
85
a
Conditions A: 1 (2 mmol), In (2 mmol), I2 (1 mmol), MeOH (4
mL). Conditions B: 1 (2 mmol), In (4 mmol), I2 (2 mmol), MeOH
(4 mL).
Atom -Tr a n sfer Cycliza tion s a n d Red u ctive Cy-
cliza tion s of Iod oa lk yn es. We first investigated cy-
clization reactions of iodoalkyne 1 under various condi-
tions. The results are summarized in Table 1. Iodoalkyne
1 was treated with In (1 equiv) in MeOH at room
temperature to give 5-exo cyclized atom-transfer products
1a (Z) and 1b (E) in 50% yield (Z:E ) 11.5:1, run 1). The
Z-selectivity is in agreement with results reported by
Curran et al.9 They analyzed the formation of (Z)- and
(E)-vinyl iodides with the aid of a Curtin-Hammett
kinetic scheme. In the case of compound 1, high stereo-
selectivity was observed and the cis-fused products 1a -c
were obtained as shown by NMR spectroscopy (1H-1H
NOESY and NOE spectra). Trans-fused products and
6-endo cyclization products were not observed. It is well-
known that In reacts with I2 in aromatic solvent under
reflux to produce In1+, In2+, and In3+ 10
. I2 (0.5 equiv) was
therefore added to In (1 equiv) in MeOH (condition A).
The reaction proceeded smoothly to yield atom-transfer
products 1a and 1b in 80% yield within 5 h (19:1, run
2). This atom-transfer-type reaction could be initiated by
a catalytic amount of In and I2. The reaction using In
(0.1 equiv) and I2 (0.05 equiv) gave the expected iodo-
olefins in 77% yield (1a :1b ) 8.6:1, run 3), but the
reaction took a long time.
Intermolecular coupling reactions of alkyl iodide with
electron-deficient olefins are well-known. To confirm the
presence of radical intermediate D (Scheme 1), we
investigated In-mediated cyclization of 1 in the presence
of electron-deficient olefins such as R,â-unsaturated
Next, we used an excess amount of In. In (2 equiv) and
I2 (1 equiv) (condition B) gave only a reductive 5-exo
cyclization product 1c in 85% yield (run 4). Compound
1c was also obtained from atom-transfer products 1a and
(11) Haaima, G.; Hanton, L. R.; Lynch, M.-J .; Mawson, S. D.;
Routledge, A.; Weavers, R. T. Tetrahedron 1994, 50, 2161-2174.
(12) Haaima, G.; Lynch, M.-J .; Routledge, A.; Weavers, R. T.
Tetrahedron 1993, 49, 4229-4252.
(13) Okuma, K.; Kamahori, Y.; Tsubakihara, K.; Yoshihara, K.;
Tanaka, Y.; Shioji, K. J . Org. Chem. 2002, 67, 7355-7360.
(14) Trost, B. M.; Marrs, C. M. J . Am. Chem. Soc. 1993, 115, 6636-
6645.
(15) Haaima, G.; Lynch, M.-J .; Routledge, A.; Weavers, R. T.
Tetrahedron 1991, 47, 5203-5214.
(16) Torii, S.; Inokuchi, T.; Yukawa, T. J . Org. Chem. 1985, 50,
5875-5877.
(17) Recently, bicyclic sugars have been prepared extensively with
Bu3SnH. (a) Ferrier, R. J .; Petersen, P. M. Tetrahedron 1990, 46, 1-11.
(b) De Mesmaeker, A.; Hoffman, P.; Winkler, T.; Waldner, Synlett 1990,
201-204. (c) Moufid, N.; Chapleur, Y.; Mayon, P. J . Chem. Soc., Perkin
Trans. 1 1992, 991-998. (d) Lesueur, C.; Nouguier, R.; Bertrand, M.
P.; Hoffmann, P.; De Masmaeker, Tetrahedron 1994, 50, 5369-5380.
(e) Mayer, S.; Prandi, J .; Bamhaoud, T.; Bakkas, S.; Guillou, O.
Tetrahedron 1998, 54, 8753-8770. (f) Yamazaki, O.; Yamaguchi, K.;
Yokoyama, M.; Togo, H. J . Org. Chem. 2000, 65, 5440-5442.
(18) R-Isomers 8 and 9 were obtained predominantly (8: 75% yield,
R: â ) 13:1; 9: 74% yield, R: â ) 14:1). (a) Audin, C.; Lancelin, J .-M.;
Beau, J .-M. Tetrahedron Lett. 1988, 29, 3691-3694. (b) De Mesmaeker,
A.; Hoffmann, P.; Ernst, B. Tetrahedron Lett. 1989, 30, 57-60.
(19) Cyclization products 8b and 9b were probably deacetylated by
InXn(OMe)3-n. Thus, reacetylation with acetic anhydride and (dim-
ethylamino)pyridine in THF was done.
(6) (a) Nakajima, M.; Takahashi, H.; Sasaki, M.; Kobayashi, Y.;
Ohno, Y.; Usami, M. Teratog., Carcinog., Mutagen. 2000, 20, 219-
227. (b) Nakajima, M.; Sasaki, M.; Kobayashi, Y.; Ohno, Y.; Usami,
M. Teratog., Carcinog., Mutagen. 1999, 19, 205-209.
(7) (a) Yorimitsu, H.; Nakamura, T.; Shinokubo, H.; Oshima, K. J .
Org. Chem. 1998, 63, 8604-8605. (b) Chakraborty, A.; Marek, I. Chem.
Commun. 1999, 2375-2376. (c) Yorimitsu, H.; Nakamura, T.; Shi-
nokubo, H.; Oshima, K.; Omoto, K.; Fujimoto, H. J . Am. Chem. Soc.
2000, 122, 11041-11047.
(8) Atom-transfer cyclization reactions with Bu3SnH have been
reported. (a) Curran, D. P.; Chen, M.-H.; Kim, D. J . Am. Chem. Soc.
1986, 108, 2489-2490. (b) Curran, D. P.; Chen, M.-H.; Kim, D. J . Am.
Chem. Soc. 1989, 111, 6265-6276.
(9) Curran, D. P.; Chen, M.-H.; Kim, D. J . Am. Chem. Soc. 1989,
111, 6265-6276.
(10) (a) Freeland, B. H.; Tuck, D. G. Inorg. Chem. 1976, 15, 475-
476. In reacts with I2 in a refluxing aromatic solvent to form InI3. A
solution of InI3 reacts with excess In under reflux with gradual
precipitation of pure, highly crystalline InI2. On treatment of InI2 with
diethyl ether or other Lewis bases, the insoluble InI is precipitated
and the corresponding InI3-Lewis base adduct is formed. (b) Marshall,
J . A.; Grant, C. M. J . Org. Chem. 1999, 64, 8214-8219.
2418 J . Org. Chem., Vol. 69, No. 7, 2004