The scope and limitations of 1,3-stannyl shift-promoted intramolecular cyclizations of α-stannyl radicals with a formyl group

Article abstract of DOI:10.1021/jo052176v

α-Tributylstannyl radicals can be generated from the corresponding bromides or xanthates. These radicals undergo efficient intramolecular 1,5-cyclizations with a formyl group. The resulting β-stannyl alkoxy radicals proceed through a 1,3-stannyl shift fro

Full text of DOI:10.1021/jo052176v

The Scope and Limitations of 1,3-Stannyl Shift-Promoted
Intramolecular Cyclizations of r-Stannyl Radicals with a Formyl
Group
Shau-Hua Ueng, Ming-Jen Chen, Shu-Fang Chu, Yar-Fang Shao, Gang-Ting Fan,
Sheng-Yueh Chang, and Yeun-Min Tsai*
Department of Chemistry, National Taiwan UniVersity, Taipei, Taiwan 106, Republic of China
ymtsai@ntu.edu.tw
ReceiVed October 19, 2005
R-Tributylstannyl radicals can be generated from the corresponding bromides or xanthates. These radicals
undergo efficient intramolecular 1,5-cyclizations with a formyl group. The resulting â-stannyl alkoxy
radicals proceed through a 1,3-stannyl shift from carbon to oxygen to afford â-stannyloxy radicals. This
novel rearrangement is most likely irreversible and serves as a driving force to promote the cyclizations.
Although the cyclization rates can be accelerated when the formyl group carries R-dimethyl substituents,
unfortunately â-scission of the alkoxy radicals becomes competitive with the 1,3-stannyl shift. The
â-stannyloxy radicals can be employed in further cyclizations to obtain tandem cyclization products.
SCHEME 1
Introduction
Radical reactions have emerged as useful synthetic tools in
recent years.1 Among the radical reactions, the 5-hexenyl radical
cyclization system is widely received as an important avenue
to construct five-membered ring skeletons. In contrast, although
the 4-formylbutyl and 5-formylpentyl radicals (Scheme 1) can
also undergo cyclizations to construct cyclopentane and cyclo-
hexane rings2 with rates (k1 ) 8.7 × 105 s-1, k2 ) 1.0 × 106
s-1 at 80 °C)2a comparable to those of the 5-exo cyclization of
5-hexenyl radical (kexo ) 1.3 × 106 s-1 at 80 °C),3 ring openings
of the cyclized cyclopentyloxy and cyclohexyloxy radicals
proceed with a much faster pace (k-1 ) 4.7 × 108 s-1, k-2
)
1.1 × 107 s-1 at 80 °C).2a,b However, the cyclizations can be
irreversible in highly substituted systems4 and quite efficient
when assisted by the gem-dialkyl effect.5,6 Nonetheless, the
inherent reversible property still renders the carbonyl radical
cyclizations a less attractive possibility, so far as the cyclization
is concerned.7
To cope with this problem, there were several methods
developed to trap the cyclized alkoxy radical irreversibly so
that the reaction could be driven toward cyclization. Thus, Batey
(3) Chatgilialoglu, C.; Ingold, K. U.; Scaiano, J. C. J. Am. Chem. Soc.
1981, 103, 7739-7742.
(4) (a) Tsang, R.; Fraser-Reid, B. J. Am. Chem. Soc. 1986, 108, 2116-
2117. (b) Tsang, R.; Fraser-Reid, B. J. Am. Chem. Soc. 1986, 108, 8102-
8104. (c) Tsang, R.; Dickson, J. K., Jr.; Pak, H.; Walton, R.; Fraser-Reid,
B. J. Am. Chem. Soc. 1987, 109, 3484-3486. (d) Fraser-Reid, B.; Vite, G.
D.; Yeung, B.-W. A.; Tsang, R. Tetrahedron Lett. 1988, 29, 1645-1648.
(e) Dickson, J. K., Jr.; Tsang, R.; Llera, J. M.; Fraser-Reid, B. J. Org. Chem.
1989, 54, 5350-5356. (f) Walton, R.; Fraser-Reid, B. J. Am. Chem. Soc.
1991, 113, 5791-5799. (g) Knapp, S.; Gibson, F. S.; Choe, Y. H.
Tetrahedron Lett. 1990, 31, 5397-5400. (h) Knapp, S.; Gibson, F. S. J.
Org. Chem. 1992, 57, 4802-4809.
* Corresponding author. Telephone: 886-2-3366-1651. Fax: 886-2-2363-
6359.
(1) (a) Fossey, J.; Lefort, D.; Sorba, J. Free Radicals in Organic
Chemistry; John Wiley & Sons: New York, 1995. (b) Giese, B.; Kopping,
B.; Go¨bel, T.; Dickhaut, J.; Thoma, G.; Kulicke, K. J.; Trach, F. Org. React.
1996, 48, 301-856. (c) Radicals in Organic Synthesis; Renaud, P., Sibi,
M. P., Eds.; Wiley-VCH: Weinheim, 2001.
(2) (a) Beckwith, A. L. J.; Hay, B. P. J. Am. Chem. Soc. 1989, 111,
230-234. (b) Beckwith, A. L. J.; Hay, B. P. J. Am. Chem. Soc. 1989, 111,
2674-2681. (c) Beckwith, A. L. J.; Raner, K. D. J. Org. Chem. 1992, 57,
4954-4962.
(5) Batey, R. A.; MacKay, D. B. Tetrahedron Lett. 1998, 39, 7267-
7270.
10.1021/jo052176v CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/12/2006
1502
J. Org. Chem. 2006, 71, 1502-1512

Intramolecular Cyclizations of R-Stannyl Radicals
SCHEME 2
SCHEME 3
and MacKay successfully employed phenylsilane to selectively
transfer hydrogen atom to the oxygen radical instead of the
carbon radical.5 Triethylborane was found to be able to improve
the efficiency of the carbonyl radical cyclizations.8 The ability
of triethylborane to trap the intermediate alkoxy radical probably
plays an important role.8b Kim and Oh reported that triphen-
ylphosphine was able to trap the cyclized alkoxy radicals and
subsequently lose triphenylphosphine oxide to afford five- and
six-membered ring radicals.9 In an intramolecular pinacol
coupling of 1,5- and 1,6-dicarbonyl compounds using tributyltin
hydride (Scheme 2), Hays and Fu found that a tributyltin moiety
served as an intramolecular trap of the alkoxy radical through
a fast SN2 pathway and releasing a butyl radical.10
SCHEME 4
In the case of acylgermanes11 and thio- and seleno-esters12
(Scheme 3), the cyclized alkoxy radicals were reported to
undergo â-scissions to afford cyclic ketones. In contrast, the
cyclized alkoxy radical intermediates in acylsilanes13,14 were
found to proceed irreversibly through a radical-Brook rear-
rangement15,16 to generate silyloxy-substituted cyclic radicals.
Interestingly, the acylsilane system is formally an equivalent
of the 4-formylbutyl and 5-formylpentyl radical cyclizations.
A few years ago, we reported the cyclization of R-stannyl
bromide 1 (Scheme 4) using tributyltin hydride to give cyclo-
pentanol.17 This process involves the generation of R-stannyl
radical 4.15e,19-22 Subsequent hydrogen atom abstraction of
radical 4 from tributyltin hydride and destannylation give
cyclopentanol. A bond energy difference of 19 kcal/mol between
the stronger O-Sn bond (∼84 kcal/mol)23 and weaker C-Sn
(13) (a) Tsai, Y.-M.; Cherng, C.-D. Tetrahedron Lett. 1991, 32, 3515-
3518. (b) Tsai, Y.-M.; Tang, K.-H.; Jiaang, W.-T. Tetrahedron Lett. 1993,
34, 1303-1306. (c) Curran, D. P.; Jiaang, W.-T.; Palovich, M.; Tsai, Y.-
M. Synlett 1993, 403-404. (d) Tsai, Y.-M.; Chang, S.-Y. J. Chem. Soc.,
Chem. Commun. 1995, 981-982. (e) Chuang, T.-H.; Fang, J.-M.; Jiaang,
W.-T.; Tsai, Y.-M. J. Org. Chem. 1996, 61, 1794-1805. (f) Tsai, Y.-M.;
Tang, K.-H.; Jiaang, W.-T. Tetrahedron Lett. 1996, 37, 7767-7770. (g)
Tsai, Y.-M.; Nieh, H.-C.; Pan, J.-S.; Hsiao, D.-D. J. Chem. Soc., Chem.
Commun. 1996, 2469-2470. (h) Chang, S.-Y.; Jiaang, W.-T.; Cherng, C.-
D.; Tang, K.-H.; Huang, C.-H.; Tsai, Y.-M. J. Org. Chem. 1997, 62, 9089-
9098. (i) Jiaang, W.-T.; Lin, H.-C.; Tang, K.-H.; Chang, L.-B.; Tsai, Y.-
M. J. Org. Chem. 1999, 64, 618-628. (j) Huang, C.-H.; Chang, S.-Y.;
Wang, N.-S.; Tsai, Y.-M. J. Org. Chem. 2001, 66, 8983-8991. (k) Tang,
K.-H.; Liao, F.-Y.; Tsai, Y.-M. Tetrahedron 2005, 61, 2037-2045.
(14) For recent reviews about acylsilanes, see: (a) Ricci, A.; Degl’Innocenti,
A. Synthesis 1989, 647-660. (b) Page, P. C. B.; Klair, S. S.; Rosenthal, S.
Chem. Soc. ReV. 1990, 19, 147-195. (c) Cirillo, P. F.; Panek, J. S. Org.
Prep. Proced. Int. 1992, 24, 553-582. (d) Page, P. C. B.; McKenzie, M.
J.; Klair, S. S.; Rosenthal, S. In The chemistry of organic silicon compounds;
Rappoport, Z., Apeloig, Y., Eds.; John Wiley & Sons: New York, 1998;
Vol. 2, Chapter 27, pp 1599-1665. (e) Bonini, B. F.; Comes-Franchini,
M.; Fochi, M.; Mazzanti, G.; Ricci, A. J. Organomet. Chem. 1998, 567,
181-189.
radical 2 that cyclizes to afford â-stannyl alkoxy radical 3.18
A
key 1,3-stannyl shift occurs to generate â-stannyloxy-substituted
(6) For the gem-dialkyl effect, see: (a) Beckwith, A. L. J.; Lawrence,
T. J. Chem. Soc., Perkin Trans. 2 1979, 1535-1539. (b) Capon, B.;
McManus, S. P. Neighboring Group Participation; Plenum: New York,
1976; Vol. 1, pp 58-75. (c) Kirby, A. J. AdV. Phys. Org. Chem. 1980, 17,
183-278.
(7) For the application of radical cyclizations of carbonyl group in ring
expansion reactions, see: (a) Dowd, P.; Zhang, W. Chem. ReV. 1993, 93,
2091-2115. (b) Yet, L. Tetrahedron 1999, 55, 9349-9403. (c) Zhang, W.
In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-
VCH: Weinheim, 2001; Vol. 2, pp 234-245. (d) Zhang, W. Curr. Org.
Chem. 2002, 6, 1015-1029.
(8) (a) Clive, D. L. J.; Postema, M. H. D. J. Chem. Soc., Chem. Commun.
1993, 429-430. (b) Devin, P.; Fensterbank, L.; Malacria, M. Tetrahedron
Lett. 1998, 39, 833-836. (c) Devin, P.; Fensterbank, L.; Malacria, M.
Tetrahedron Lett. 1999, 40, 5511-5514. (d) Chareyron, M.; Devin, P.;
Fensterbank, L.; Malacria, M. Synlett 2000, 83-85. (e) Yoshimitsu, T.;
Tsunoda, M.; Nagaoka, H. J. Chem. Soc., Chem. Commun. 1999, 1745-
1746. (f) Yoshimitsu, T.; Arano, Y.; Nagaoka, H. J. Org. Chem. 2003, 68,
625-627. (g) Yoshimitsu, T.; Makino, T.; Nagaoka, H. J. Org. Chem. 2003,
68, 7548-7550. (h) Yoshimitsu, T.; Arano, Y.; Nagaoka, H. J. Org. Chem.
2005, 70, 2342-2345. (i) Yoshimitsu, T.; Arano, Y.; Nagaoka, H. J. Am.
Chem. Soc. 2005, 127, 11610-11611.
(15) (a) Dalton, J. C.; Bourque, R. A. J. Am. Chem. Soc. 1981, 103,
699-700. (b) Harris, J. M.; MacInnes, I.; Walton, J. C.; Maillard, B. J.
Organomet. Chem. 1991, 403, C25-C28. (c) Tsai, Y.-M.; Ke, B.-W. J.
Chin. Chem. Soc. (Taipei) 1993, 40, 641-642. (d) Robertson, J.; Burrows,
J. N. Tetrahedron Lett. 1994, 35, 3777-3780. (e) Schiesser, C. H.; Styles,
M. L. J. Chem. Soc., Perkin Trans. 2 1997, 2335-2340. (f) Paredes, M.
D.; Alonso, R. Tetrahedron Lett. 1999, 40, 3973-3976. (g) Paredes, M.
D.; Alonso, R. J. Org. Chem. 2000, 65, 2292-2304.
(16) For a recent review about Brook rearrangement, see: Moser, W.
H. Tetrahedron 2001, 57, 2065-2084.
(9) Kim, S.; Oh, D. H. Synlett 1998, 525-527.
(10) (a) Hays, D. S.; Fu, G. C. J. Am. Chem. Soc. 1995, 117, 7283-
7284. (b) Hays, D. S.; Fu, G. C. J. Org. Chem. 1998, 63, 6375-6381.
(11) (a) Curran, D. P.; Liu, H. J. Org. Chem. 1991, 56, 3463-3465. (b)
Curran, D. P.; Palovich, M. Synlett 1992, 631-632. (c) Curran, D. P.;
Diederichsen, U.; Palovich, M. J. Am. Chem. Soc. 1997, 119, 4797-4804.
(d) Diederichsen, U.; Curran, D. P. J. Organomet. Chem. 1997, 531, 9-12.
(12) (a) Kim, S.; Jon, S. Y. J. Chem. Soc., Chem. Commun. 1996, 1335-
1336. (b) Kim, S.; Jon, S. Y. J. Chem. Soc., Chem. Commun. 1998, 815-
816. (c) Kim, S.; Jon, S. Y. Tetrahedron Lett. 1998, 39, 7317-7320.
(17) Chang, S.-Y.; Shao, Y.-F.; Chu, S.-F.; Fan, G.-T.; Tsai, Y.-M. Org.
Lett. 1999, 1, 945-948.
(18) For a novel 1,3-cyclization of R-stannyl radical to carbonyl in ring
expansion reactions, see: Nishida, A.; Takahashi, H.; Takeda, H.; Takada,
N.; Yonemitsu, O. J. Am. Chem. Soc. 1990, 112, 902-904.
(19) For homolytic stannyl group transfers from carbon to oxygen, see:
(a) Kim, S.; Lee, S.; Koh, J. S. J. Am. Chem. Soc. 1991, 113, 5106-5107.
(b) Kim, S.; Lim, K. M. J. Chem. Soc., Chem. Commun. 1993, 1152-
1153. (c) Kim, S.; Lim, K. M. Tetrahedron Lett. 1993, 34, 4851-4854.
J. Org. Chem, Vol. 71, No. 4, 2006 1503

Ueng et al.
SCHEME 5 a
SCHEME 6
a Reagents and conditions: (i) HS(CH2)3SH, BF3‚OEt2, CH2Cl2, 0 °C
(81% for 5); (ii) (a) Bu3SnH, LDA, (b) Ph3P, CBr4, (c) CAN, CH3CN/
H2O, -15 °C (56% for 1 and 42% for 8); (iii) TsOH, H2O/THF, 65 °C
(84% for 7); (iv) HO(CH2)2OH, TsOH, PhH, 80 °C (69% for 10); (v) (a)
O3, NaHCO3 (7 equiv), CH2Cl2, (b) Et3N (2 equiv) (80% for 11); (vi) (a)
Bu3SnH, LDA, THF, -78 °C, (b) CS2, -78 °C, (c) MeI, -78 °C to rt
(67% for 12); (vii) TsOH (1 equiv), HCHO (3 equiv), THF/H2O, 60 °C
(90% for 13).
methods. The required aldehyde 7 was derived from the
hydrolysis of 1,3-dioxolane 6.27
The radical cyclization reactions were performed by slow
addition of a benzene solution of tributyltin hydride and a
catalytic amount of azobisisobutyronitrile (AIBN) to a refluxing
benzene solution of the bromo aldehyde. For the reaction of
bromo aldehyde 1 with tributyltin hydride (Scheme 6), we were
never able to isolate the expected cyclopentyl tributyltin ether
(14). Instead, we could isolate the destannylated product cyclo-
pentanol. However, due to the volatility of cyclopentanol, the
isolation yield was low. As shown in Scheme 6, we decided to
trap the intermediate stannyl ether 14 by directly adding excess
benzoyl chloride (5 equiv), triethylamine (4 equiv), and tetra-
butylammonium fluoride (1 equiv) to the reaction mixture after
the cyclization, and the resulting mixture was heated to 80 °C
for 12 h. Benzoate 15 was isolated in a 57% yield along with
12% of the uncyclized straight reduction product 16 (12%). A
trace amount of benzoate 17 was also detected. This material
is most likely coming from benzoylation of alcohol 18 that is
derived from further reduction of aldehyde 16 by tributyltin
hydride.28
To demonstrate that the cyclization occurs through a 1,3-
stannyl shift (Scheme 4), we treated bromo aldehyde 1 with
allyltributyltin (4 equiv) to trap the â-stannyloxy radical
intermediate 4.29 This reaction was initiated with a catalytic
amount of hexabutylditin (0.2 equiv) and irradiated with long
wavelength UV lamps at room temperature. Although the
intermolecular radical trapping process is sluggish, we were able
to isolate 35% of trans-2-allylcyclopentanol (19).30 A trace
amount of allyl ketone 20 was also obtained. The formation of
20 reflects the presence of a small fraction of acyl radical 21
coming from 1,5-hydrogen abstraction of R-stannyl radical 2.2b
However, this experiment suggests that the predominant mode
bond (∼65 kcal/mol)23 presumably serves as the driving force
for the key rearrangement that makes this carbonyl cyclization
a success. Now, we wish to report our full investigation in this
direction.
Results and Discussion
The Model System. Our initial study was carried out using
R-bromostannanes 1 and 8 (Scheme 5). Bromide 1 was prepared
from glutaric dialdehyde by first protecting one formyl group
as 1,3-dithiane to give the monoaldehyde 5 (81%). Aldehyde 5
was then treated with tributyltin lithium,24 and the resulting
R-stannyl alcohol obtained was converted to the corresponding
bromide with carbon tetrabromide and triphenylphosphine.25
Because of the presence of the nucleophilic sulfur atoms in the
dithiane moiety at the other end, this bromide is not stable and
should be used as soon as possible in the next step. Subsequent
hydrolysis of the dithiane with ceric ammonium nitrate (CAN)
in wet acetonitrile26 afforded bromoaldehyde 1 in a 56% overall
yield from aldehyde 5. The homologous bromo aldehyde 8 was
synthesized from aldehyde 7 in a 42% yield using similar
(20) For homolytic stannyl group transfers from oxygen to oxygen, see:
(a) Alberti, A.; Hudson, A. Chem. Phys. Lett. 1977, 48, 331-333. (b) Barker,
P. J.; Davies, A. G.; Hawari, J. A.-A.; Tse, M.-W. J. Chem. Soc., Perkin
Trans. 2 1980, 1488-1496. (c) Davies, A. G.; Tse, M.-W. J. Organomet.
Chem. 1978, 155, 25-30. (d) Kim, S.; Koh, J. S. J. Chem. Soc., Chem.
Commun. 1992, 1377-1378. (e) Kim, S.; Do, J. Y.; Lim, K. M. J. Chem.
Soc., Perkin Trans. 1 1994, 2517-2518. (f) Kim, S.; Do, J. Y.; Lim, K. M.
Chem. Lett. 1996, 669-670.
(21) For homolytic stannyl group transfers involving nitrogen radicals,
see: Kim, S.; Jung, M. S.; Cho, C. H.; Schiesser, C. H. Tetrahedron Lett.
2001, 42, 943-945.
(26) (a) Ho, T.-L.; Ho, H. C.; Wong, C. M. J. Chem. Soc., Chem.
Commun. 1972, 791-791. (b) Ho, H. C.; Ho, T.-L.; Wong, C. M. Can. J.
Chem. 1972, 50, 2718-2721.
(22) For theoretical studies about homolytic stannyl group translocations,
see: (a) Kim, S.; Horvat, S. M.; Schiesser, C. H. Aust. J. Chem. 2002, 55,
753-755. (b) Matsubara, H.; Schiesser, C. H. J. Org. Chem. 2003, 68,
9299-9309.
(23) Jackson, R. A. J. Organomet. Chem. 1979, 166, 17-19.
(24) Still, W. C. J. Am. Chem. Soc. 1978, 100, 1481-1487.
(25) Torisawa, Y.; Shibasaki, M.; Ikegami, S. Tetrahedron Lett. 1981,
22, 2397-2400.
(27) Grigg, R.; Markandu, J.; Surendrakumar, S.; Thornton-Pett, M.;
Warnock, W. J. Tetrahedron 1992, 48, 10399-10422.
(28) Ingold, K. U.; Lusztyk, J.; Scaiano, J. C. J. Am. Chem. Soc. 1984,
106, 343-348.
(29) Rosenstein, I. In Radicals in Organic Synthesis; Renaud, P., Sibi,
M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1, pp 50-71.
(30) Curran, D. P.; Liu, H. J. Chem. Soc., Perkin Trans. 1 1994, 1377-
1393.
1504 J. Org. Chem., Vol. 71, No. 4, 2006

Intramolecular Cyclizations of R-Stannyl Radicals
SCHEME 7
SCHEME 8
SCHEME 9
of reaction of radical 2 is the cyclization followed by a 1,3-
stannyl shift to give â-stannyloxy radical 4.
The reaction of bromo aldehyde 8 with tributyltin hydride
(Scheme 7) gave 27% of cyclohexanol as determined by gas
chromatographic analysis of the reaction mixture using decane
1
as internal standard. The H NMR spectrum (in CDCl3) of the
crude cyclization mixture exhibits a broad singlet at δ 3.56
(O-CH of cyclohexanol) overlapped with a triplet at δ 3.62
(O-CH2 of alcohol 23). Intensive chromatographic separation
afforded straight reduction product 22 (29%) and over-reduction
product 23 (9%). When bromo aldehyde 8 was treated with 2
equiv of allyltributyltin, we isolated 10% of the alcohol 2431
and 50% of aldehyde 25. A small amount of the trans-isomer
amine workup36 gave aldehyde 11 in an 80% yield. Note that
the use of sodium bicarbonate in the ozonolysis reaction in
dichloromethane is essential to ensure a good yield. Aldehyde
11 was then treated with tributyltin lithium,24 and the resulting
alkoxide was trapped with carbon disulfide and methyl iodide
in sequence to generate the xanthate 12 (67%). The dioxolane
in 12 was then removed under acidic condition in the presence
of excess paraformaldehyde in wet THF to afford xanthate
aldehyde 13 (90%).
The cyclization of xanthate aldehyde 13 (Scheme 8) gave a
48% GC yield of alcohol 27,37 using decane as internal standard,
and 7% yield of straight reduction product 29. In addition, we
also isolated dithiocarbonate 28 in 9% yield. This product
presumably comes from the addition of the radical intermediate
30 to the sulfur atom of the thiocarbonyl group in xanthate 13
followed by a â-scission of the O-C bond.34 Comparing this
result to the cyclization of bromide 1 (Scheme 6), the cyclization
of xanthate 13 was only improved slightly based on the
cyclization/reduction product ratio (vide infra).
Tandem Cyclizations Terminated with an Olefin. With our
initial success in the model studies, we decided to investigate
the radical system 31 (Scheme 9). A 1,5-cyclization of radical
31 to the formyl group would produce alkoxy radical 32. This
process would be followed by a 1,3-stannyl shift to afford radical
33, which could cyclize with the olefin to give the bicyclic
radical 34. However, when radical 31 adds to the olefin first,
the process would lead to the monocyclic radical 35. Taking
the ratio of products derived from radicals 34 and 35 would
give us useful information about the relative rates of the two
cyclizations of radical 31.
1
of alcohol 2432 with a characteristic H NMR signal (CDCl3)
at δ 3.25 (td, J ) 9.7, 4.6 Hz) was also observed in the crude
product but not isolated. Aldehyde 25 is apparently derived from
the trapping of R-carbonyl radical 26 by the allylstannane.
Radical 26 in turn comes from a 1,5-hydrogen abstraction of
the R-stannyl radical generated from bromo aldehyde 8.2c The
lower yield of cyclohexanol for the cyclization of aldehyde 8
and the formation of a large amount of aldehyde 25 in the
trapping experiment indicate that the 1,5-hydrogen transfer is a
serious competing process of the 1,6-cyclization reaction.
In the 5-hexenyl radical system, the gem-dialkyl effect is
known to be able to accelerate the cyclization for at least 10-
fold.6a The gem-dimethyl substitution is also often found in
many triquinane natural products.33 Therefore, we prepared
xanthate 13 with gem-dimethyl substituents at the R position
of the carbonyl group for our radical cyclization study.34 The
reason that we did not employ the corresponding bromide is
due to the synthetic difficulties that we had by using the same
approach as the synthesis of bromide 1; the gem-dimethyl
substituents severely destabilize the dithiane bromide synthetic
intermediate, and the overall yield is too low. As shown in
Scheme 5, the xanthate synthesis started from the protection of
aldehyde 935 with ethylene glycol to afford dioxolane 10 (69%).
Ozonolysis of the terminal olefin in 10 followed by a triethyl-
(31) Speziale´, V.; Armat, M.; Lattes, A. Heterocycl. Chem. 1976, 13,
349-3
(32) Hegedus, L. S.; McKearin, J. M. J. Am. Chem. Soc. 1982, 104,
2444-2451.
(33) Mehta, G.; Srikrishna, A. Chem. ReV. 1997, 97, 671-719.
(34) Zard, S. Z. Radicals in Organic Synthesis; Renaud, P., Sibi, M. P.,
Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1, pp 90-108.
(35) House, H. O.; Liang, W. C.; Weeks, P. D. J. Org. Chem. 1974, 39,
3102-3107.
To prepare suitable substrates to generate radical 31, we
started by the reaction of aldehyde 5 with cyclohexylamine
(Scheme 10). The resulting imine was then alkylated with
(36) Hon, Y.-S.; Lin, S.-W.; Lu, L.; Chen, Y.-J. Tetrahedron 1995, 51,
5019-5034.
(37) Kopecky, K. R.; Levine, C. Can. J. Chem. 1981, 59, 3273-3279.
J. Org. Chem, Vol. 71, No. 4, 2006 1505

Ueng et al.
SCHEME 10 a
TABLE 1. Radical Cyclizations of Xanthate 38 with Tributyltin
Hydride (TBTH)
product yield (%)
entry methoda,b (equiv) 53a,cc 53b 54 55 56
TBTH
CdO/
CdC
1
2
3
A
B
B
1.3
1.3
2.6
29
32
34
4
33
5
0.87
0.73
0.80
5d 51
9e 23 31
a Method A: A benzene solution of tributyltin hydride and AIBN
(5-15 mol %) was added over 4 h to a refluxing benzene solution of the
substrate (0.1 M). The resulting mixture was heated at the same temperature
for 2 h. Method B: Tributyltin hydride was added in one portion to a
refluxing benzene solution of the substrate and AIBN (15 mol %). The
resulting mixture was heated at the same temperature for 4 h. b The final
concentration relative to the substrate was 0.05 M. c 53a/53c ) 85/15. This
ratio was extrapolated from the GC ratio of the corresponding benzoates.
d 54a/54b ) 76/24. e 54a/54b ) 87/13.
Bicyclic alcohols 53a-c are tandem cyclization products
derived from radical addition to the carbonyl group first. Alcohol
53b was isolated in 4% yield. The stereochemistry of 53b was
determined by comparing its benzoate derivative with the
spectroscopic data reported by Nagai, Lazor, and Wilcox.38 The
major bicyclic alcohol 53a was isolated as a mixture with
another stereoisomer in a combined yield of 29%. This mixture
was converted to the benzoate, and the ratio of the two benzoates
determined by gas chromatography is 85/15. The major benzoate
was identified by comparison to the reported spectroscopic data;
however, the minor isomer does not correspond to any of the
three stereoisomers reported by Nagai, Lazor, and Wilcox.38
We therefore speculate that this benzoate not reported by Nagai
et al. might be derived from alcohol 53c with the hydroxyl and
methyl groups at the exo-face.
To probe the reversibility of the carbonyl cyclization step,
we performed the reaction by adding tributyltin hydride (1.3
equiv) in one portion to the xanthate 38 in refluxing benzene
(entry 2). By mixing tributyltin hydride with the substrate in
this fashion, it provides a high local tributyltin hydride
concentration so that trapping the radical intermediates could
be easier. If the carbonyl cyclization is reversible, we may be
able to trap the alkoxy radical 32 and isolate more carbonyl
addition products this way.4f
As shown in entry 2, we obtained 32% of a bicyclic alcohol
mixture of 53a and 53c, and 51% of aldehyde 55. We also
isolated 5% of a monocyclic alcohol mixture consisting of 54a13i
and 54b in a ratio of 76/24 (54a/54b) as determined by 1H NMR
integration of the olefinic protons. Although the isomers are
not separable, the presence of 54b is apparent by observing a
multiplet at δ 5.32-5.42, typical for a vicinal disubstituted
olefin, in the 1H NMR spectrum (CDCl3). The cis/trans isomer
ratio of these 3-substituted cyclopentanols could not be deter-
mined.
a Reagents and conditions: (i) cyclohexylamine, K2CO3, PhH, rt; (ii)
LDA, THF, -78 °C, Br(CH2)2CHdCH2 for 36 and 50, 2-(2-bromoethyl)-
1,3-dithiane for 40; (iii) 1 N HCl; (iv) Bu3SnH, LDA, THF, -78 °C; (v)
CS2, -78 °C followed by MeI, -78 °C to rt; (vi) MeI, acetone/H2O, reflux;
(vii) NaH, DMF followed by I(CH2)3CCTMS; (viii) NaCN, DMF, 120 °C;
(ix) LAH, THF, 0 °C; (x) Swern oxid.; (xi) TsOH (1 equiv), HCHO (3
equiv), THF/H2O, 60 °C.
4-bromobutene followed by hydrolysis to afford aldehyde 36
(62%). According to the methods described above, we prepared
xanthate 38 from aldehyde 36 through xanthate 37.
As shown in Table 1 (entry 1), slow addition of a benzene
solution of tributyltin hydride and a catalytic amount of AIBN
to a refluxing benzene solution of 38 gave a total of 33% yield
of bicyclic alcohols 53a-c. In addition to these alcohols, we
also isolated aldehyde 55 (33%) and alcohol 56 (5%). These
latter two products are derived from direct olefin cyclization of
the R-stannyl radical and appear to be mixtures of stereoisomers,
and we did not determine the stereochemistry. Alcohol 56
presumably comes from further reduction of the formyl group
in 55 by the excess tributyltin hydride.28
(38) Nagai, M.; Lazor, J.; Wilcox, C. S. J. Org. Chem. 1990, 55, 3440-
3442.
1506 J. Org. Chem., Vol. 71, No. 4, 2006

Intramolecular Cyclizations of R-Stannyl Radicals
SCHEME 11
The presence of these two monocyclic alcohols indicates that
with a higher local concentration of tributyltin hydride we could
trap the intermediate â-stannyloxy-substituted radical 33. The
surprising isomerization of the olefin observed in 54 is presum-
ably due to the allylic hydrogen abstraction of the terminal olefin
by some unidentified radical species. The ratio of CdO addition
products 53 and 54 versus direct CdC addition product 55 is
0.73. By doubling the amount of tributyltin hydride to 2.6 equiv
(entry 3), the isolation yield of the monocyclic alcohol mixture
of 54 (9%; 54a/54b ) 5/1) almost doubled. We also obtained
an appreciable amount of an over-reduction product 56 (31%).
Apparently, the trapping of radical 33 becomes more efficient
with higher concentration of tributyltin hydride. However, the
overall ratio of CdO/CdC addition products ((53 + 54)/(55 +
56)) is 0.80. This value is not significantly different from that
of the reaction with 1.3 equiv of tributyltin hydride (entry 2).
In fact, in the two experiments with direct mixing of the
substrate with tributyltin hydride (entries 2, 3), the CdO/CdC
addition product ratios are slightly lower than that of the
experiment with slow addition of tributyltin hydride (entry 1).
We believe that these differences are within experimental errors.
As shown in entries 2 and 3 of Table 1, we were not able to
trap the alkoxy radical 32 by having high local concentration
of tributyltin hydride. This phenomenon indicates that the 1,3-
stannyl shift must be so fast that intermolecular trapping of the
alkoxy radical by high concentration of tributyltin hydride is
not possible. In addition, although â-stannyloxy radical 33 can
be trapped, the more efficient trapping of this radical does not
significantly increase the ratio of CdO/CdC addition products.
The cyclization of radical 31 with the olefin to give radical 35
belongs to the 5-hexenyl radical cyclization system and is
presumably an irreversible process.39 Therefore, the 1,3-stannyl
shift is more likely an irreversible process.
SCHEME 12
These results also reveal that the apparent rate of formation
of â-stannyloxy radical 33 is similar to the rate of 5-exo
cyclization of R-stannyl radical with the olefin. Therefore, either
by choosing a slower olefin cyclization system or by finding
ways to accelerate the carbonyl addition rate may direct the
reaction to the tandem cyclization pathway.
The stereoselectivity of the tandem cyclization products 53
can be explained by adopting a pseudo-chair transition state
31A with all of the substituents at the equatorial position as
shown in Scheme 11.40,41 This approach constructs the 1,3-trans
relationship in alkoxy radical 32A. The oxy radical and the
tributylstannyl group have a cis-relationship; therefore, a facile
stannyl shift occurs to give radical trans-33. Further cyclization
of trans-33 proceeds with a well-known endo-selectivity41 and
gives the major isomer 53a and the minor isomer 53c.
The other isomer 53b presumably comes from the pseudo-
chair transition state 31B in which the butenyl group occupies
the axial position. The cyclization of 31B gives alkoxy radical
32B with a 1,3-cis relationship of the substituents. 1,3-Stannyl
shift of 32B gives radical cis-33 that cyclizes to afford bicyclic
alcohol 53b. It is interesting to find that with a high local
concentration of tributyltin hydride, bicyclic alcohol 53b was
not found (entries 3, 4). This is an indication that the cyclization
of radical cis-33 is slower due to the steric effect. The steric
effect also explains the exo-selectivity for the cyclization of
cis-33.
Tandem Cyclizations Terminated with a Triple Bond. As
mentioned above, to increase the extent of tandem cyclizations,
we need a slower cyclization system such that the cyclization
of the carbonyl group can outmatch. It is known that 5-hexynyl
radical undergoes 5-exo cyclization with a slower rate than
5-hexenyl radical.39 We therefore synthesized alkyne xanthate
42 from aldehyde 3942 (Scheme 10) using methodology similar
to that of the preparation of xanthates 38.
The cyclization of xanthate 42 with tributyltin hydride
(Scheme 12) gave bicyclic alcohols 57a (32%), 57b (17%), 57c
(13%), and 57d (6%) in addition to 10% of monocyclic alcohol
58. The bicyclic alcohols 57 are tandem cyclization products,
and the monocyclic alcohol 58 comes from direct addition of
the R-stannyl radical to the triple bond. Indeed, the ratio of
57/58 is increased to 6.8 by comparison to the cyclization of
xanthate 38.
(39) Beckwith, A. L. J. Tetrahedron 1981, 37, 3073-3100.
(40) (a) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron Lett. 1985,
26, 373-376. (b) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985,
41, 3925-3941. (c) Spellmeyer, D. C.; Houk, K. N. J. Org. Chem. 1987,
52, 959-974. For a review, see: Schiesser, C. H.; Skidmore, M. A. In
Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH:
Weinheim, 2001; Vol. 1, pp 337-359.
(41) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of radical
Reactions; VCH: Weinheim, 1996; Chapter 2, pp 23-115.
(42) Louw, J. van der; Baan, J. L. van der; Kanter, F. J. J. de; Bickelhaupt,
F.; Klumpp, G. W. Tetrahedron 1992, 48, 6087-6104.
J. Org. Chem, Vol. 71, No. 4, 2006 1507

Ueng et al.
TABLE 2. Radical Cyclizations of Xanthate 52
SCHEME 13
product yield (%)
TBTH
CdO/
entry methoda (equiv) 61 62 63 64ac 64b 65 66c CdC
1
2
3
4
Ab
Bb
Bb
C
1.3
1.3
5.2
41d
32d
31d
5
21
11 20
5
5
5
13
13
14
4
16
14
9
17e 16
14
a Methods A and B: Same as in Table 1. Method C: A benzene solution
(0.05 M) of xanthate 52 was mixed with 4 equiv of triethylborane (1 M in
hexane) and then purged with dry air (75 mL/mol of 52). The reaction
mixture was stirred at rt for 4 h. b The final concentration relative to 52
was 0.05 M. c Aldehydes 64a and 66 were not separable by SiO2 column
equiv) to 52 (entry 1), we isolated bicyclic alcohols 61 (41%)
and 62 (5%). Alcohol 62 comes from the bicyclic radical 70
(Scheme 13) through addition of 70 to the sulfur atom of the
thiocarbonyl moiety of xanthates.
1
chromatography, and the yields were based on H NMR integrations. For
the purpose of identification, an authentic sample of 64a was obtained by
oxidation of alcohol 64b. d 61a/61b ) 8/1. e Only 61a.
The bicyclic alcohol 61 is an 8/1 mixture of two isomers.
The major isomer 61a was separated by silica gel column
chromatography. However, a pure sample of the minor isomer
61b could only be obtained through preparative gas chroma-
tography. The stereochemical assignments of the bicyclic
alcohols 61a,b are based on the NOESY experiments. This
stereochemical result is also in accord with the prediction based
on the transition state model shown in Scheme 11. By analogy,
we assume that bicyclic alcohol 62 has the same stereochemistry
as the major alcohol isomer 61a. This is supported by observing
the same 13C NMR chemical shifts (in CDCl3) of C(2) at δ
80.7 for these two compounds.
Interestingly, we also obtained 21% of aldehyde 64a con-
taminated with 5% of aldehyde 66 derived from direct cycliza-
tion of R-stannyl radical 67 (Scheme 13) to the olefin.
Cyclization of radical 67 to the carbonyl group generates alkoxy
radical 68. The formation of 64a indicates that the alkoxy radical
68 not only undergoes 1,3-stannyl shift to give â-stannyloxy
radical 69 but also proceeds through a â-scission47 to give the
tertiary radical 71. The formation of a tertiary radical apparently
facilitates the â-scission process. This tertiary radical cyclizes
further to the olefin and affords radical 72. The R-stannyl
aldehyde moiety is known to equilibrate with the corresponding
tin enolate and destannylates easily;48,49 therefore, radical 72
eventually leads to the final product aldehyde 64a. The
combined yields of 61, 62, and 64a are 67% and reflect the
fraction of carbonyl cyclization of radical 67. This value (67%)
The stereochemical relationships of the four isomeric alcohols
57 were determined by NOE experiments and 13C NMR
spectroscopy.43 The monocyclic alcohol 58 is a mixture of
several stereoisomers, and we did not determine their structures
rigorously.
As shown in Scheme 10, we also prepared xanthate 49 from
malonate 43.13i Alkylation of 43 with 5-iodo-1-trimethylsilyl-
1-pentyne44 gave malonate 44 (73%). Heating of 44 with sodium
cyanide in DMF yielded the monoester 45 (64%).45 The ester
was reduced with LAH to give alcohol 46 (98%) and then
oxidized via Swern oxidation to afford aldehyde 47 (89%).46
The conversion of aldehyde 47 to xanthate 49 was accomplished
according to the same protocol described above.
With an even slower 6-heptynyl radical cyclization system39
present in xanthate 49, the cyclization of 49 (Scheme 12) gave
only monocyclic alcohol 59 in 58% yield as a mixture of
cis/trans isomers (1/5.7). We also isolated 15% of uncyclized
reduction product 60a and the over-reduction product alcohol
60b (13%).
Tandem Cyclizations with gem-Dimethyl Substituents. As
mentioned earlier, for the cyclization of xanthate 13, the
acceleration effect of the geminal dimethyl groups at the
R-position of the carbonyl is only modest. To examine this
system more closely, we also synthesized xanthate 52 (Scheme
10) from aldehyde 11 using the same approach described above.
The radical cyclization studies of 52 are shown in Table 2.
Under the condition of slow addition of tributyltin hydride (1.3
(47) For reviews, see: (a) Sua´rez, E. In Radicals in Organic Synthesis;
Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2, pp
440-454. (b) Hartung, J.; Gottwald, T.; Sˇpehar, K. Synthesis 2002, 1469-
1498.
(48) Pereyre, M.; Quintard, J.-P.; Rahm, A. Tin in Organic Synthesis;
Butterworth: London, 1987; Chapter 12, p 286.
(43) Whitesell, J. K.; Matthews, R. S. J. Org. Chem. 1977, 42, 3878-
3882.
(44) Mukai, C.; Nomura, I.; Kitagaki, S. J. Org. Chem. 2003, 68, 1376-
1385.
(45) McMurry, J. E. Org. React. 1976, 24, 187-224.
(46) (a) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978,
43, 2480-2482. (b) Mancuso, A. J.; Swern, D. Synthesis 1981, 165-185.
(49) Dang, H.-S.; Roberts, B. P. J. Chem. Soc., Perkin Trans. 1 1996,
769-775.
1508 J. Org. Chem., Vol. 71, No. 4, 2006

Intramolecular Cyclizations of R-Stannyl Radicals
divided by the yield of aldehyde 66 (5%) gives a CdO/CdC
addition products ratio of 13. As compared to the cyclization
of xanthate 38 (Table 1), the extent of carbonyl addition of
xanthate 52 has increased appreciably. However, although the
gem-dimethyl substituents at the R-position of the carbonyl
group can accelerate the carbonyl cyclization, due to the
competing â-scission, this structural modification does not help
us to obtain more bicyclic alcohols.
Recall that the cyclization of xanthate 13 gives alcohol
products 27 and 28 with combined yields of only 57% (Scheme
8). Re-examining this cyclization, we prepared an authentic
sample of 5-methylhexanal50 and found the presence of this
aldehyde in the crude product. 5-Methylhexanal is the product
derived from â-scission of the cyclized alkoxy radical. Direct
analysis of the reaction aliquot by GC and 1H NMR analysis of
the crude product all indicate that the ratio of alcohol 27 relative
to 5-methylhexanal is about 3/1.
the overall ratios of the CdO/CdC addition products stay at
similar values for the three experiments in entries 1-3, and we
are not able to trap the intermediate alkoxy radical 68 by
tributyltin hydride. The ratio of products derived from 1,3-
stannyl shift of alkoxy radical 68 relative to the products from
â-scission of 68 remains at an approximately constant value of
2. The trapping of â-stannyloxy radical 69 under high local
concentration of tributyltin hydride does not significantly change
the CdO/CdC addition products ratios nor the partitions
between 1,3-stannyl shift and â-scission of alkoxy radical 68.
Therefore, it is likely that 1,3-stannyl shift and â-scission of
radical 68 are irreversible processes. The 6-exo cyclization of
radical 71 must be very fast because we could not find the
product from direct trapping of this tertiary radical by tributyltin
hydride.
Summary
We also carried out the reaction by stirring a benzene solution
of xanthate 52 with 4 equiv of triethylborane in the presence of
air51 at room temperature, hoping to perform a group transfer
type of cyclization (Table 2, entry 4). Ethyl radical generated
from this initiation method could add to the sulfur atom of the
carbonyl group in xanthate 52 and subsequently release R-stan-
nyl radical 67. Indeed, we were able to isolate 16% of alcohol
62; however, surprisingly we still obtained 17% of alcohol 61.52
In this experiment, we also isolated 14% of aldehyde 65 derived
from radical 72. This aldehyde is a 5/1 mixture of two isomers,
and we did not determine the stereochemistry. Aldehyde 66 is
eliminated under this condition. This is because triethylborane
is known to be able to promote radical cyclizations of carbonyl
compounds.8 The ratio of (61 + 62)/65 ) 2.4 represents the
partition between 1,3-tin transfer and â-scission, respectively,
and is about the same as the reaction carried out with tributyltin
hydride at 80 °C (entry 1; (61 + 62)/64a ) 2.2).
To study the effect of the concentration of tributyltin hydride,
we performed the reaction by directly mixing xanthate 52 with
tributyltin hydride and heating at 80 °C in benzene (entries 2,
3). This method using 1.3 equiv of tributyltin hydride (entry 2)
gave 32% of an alcohol mixture of 61a and 61b (61a/61b )
8/1). Under this condition, we could isolate 11% of monocyclic
alcohol 63 derived from trapping of the â-tributylstannyloxy-
substituted radical 69 by tributyltin hydride. Interestingly,
alcohol 63 is approximately a 1/1 mixture of cis and trans
isomers. Presumably, the cis radical 69 cyclizes slower than
the trans isomer and is trapped easier by tributyltin hydride,
whereas most of the trans radical 69 cyclizes to give the tandem
cylization products 61. The aldehyde 64a was obtained in 20%
in addition to 5% of aldehyde 66. Because of the more efficient
trapping of radicals 70 and 72 by the higher local concentration
of tributyltin hydride in this reaction condition, the dithiocar-
bonates 62 and 65 were not formed; however, further reduction
of aldehyde 64a by tributyltin hydride occurred and gave 4%
of alcohol 64b.
In summary, intramolecular cyclization of R-tributylstannyl
radical with formyl group proceeds quite successfully for five-
membered ring formation. The intermediate â-tributylstannyl
alkoxy radical undergoes a facile 1,3-stannyl shift and generates
a â-tributylstannyloxy-substituted carbon radical. This 1,3-
stannyl shift is likely to be irreversible and drives the cyclization
to completion. This special feature allows us to construct tandem
cyclization systems to afford the bicyclo[3.3.0]octan-2-ol skel-
eton. gem-Dimethyl substituents carried at the R-position of the
formyl group can enhance the cyclization rate; however,
â-scission of the cyclized alkoxy radical giving a tertiary radical
becomes a serious competing process.
Experimental Section
General. For details, see the Supporting Information.
5-Bromo-5-(tributylstannyl)pentanal (1). To a solution of 0.46
mL (3.3 mmol) of diisopropylamine in 3 mL of dry THF cooled in
an ice-water bath was added dropwise 2.2 mL (3.3 mmol) of a
1.5 M solution of butyllithium in hexane. The reaction mixture was
stirred at the same temperature for 10 min followed by the addition
of 0.89 mL (3.3 mmol) of tributyltin hydride over 10 min. The
resulting solution was stirred at 0 °C for another 30 min and then
cooled in a dry ice-acetone bath. To this cooled solution was added
over a period of 1 h a solution of 567 mg (2.98 mmol) of aldehyde
5 in 3 mL of dry THF. The resulting mixture was stirred at the
same temperature for 1 h and then poured into a mixture of ether
(100 mL) and saturated ammonium chloride solution (50 mL). The
organic layer was washed with brine (50 mL), dried (MgSO4), and
concentrated in vacuo. To a solution of the residue and 2.0 g (6.0
mmol) of carbon tetrabromide in 6 mL of dichloromethane cooled
in an ice-water bath was added dropwise a solution of 1.6 g (6.0
mmol) of triphenylphosphine in 6 mL of dichloromethane. The
reaction mixture was stirred at room temperature for another 1 h,
poured into 20 mL of a mixture of hexane/ethyl acetate (9/1),
filtered through a short silica gel column, and then concentrated in
vacuo. The residue was mixed with 108 mg of sodium bicarbonate,
130 mg of Celite, 3 mL of dichloromethane, and 2 mL of
acetonitrile, and then cooled at -15 °C. To this cooled mixture
was added over 10 min a solution of 4.93 g (9.0 mmol) of ceric
ammonium nitrate in 25 mL of acetonitrile/water (9/1). The resulting
mixture was stirred at the same temperature for another 10 min,
filtered, and the filtrate was partitioned between ether (100 mL)
and water (50 mL). The organic layer was washed with brine (50
mL), dried (MgSO4), and concentrated in vacuo. The residue was
chromatographed over silica gel (eluted with hexane/ethyl acetate,
98/2) to give 762 mg (56%) of 1 as a pale yellow oil: IR (neat)
When we used a large excess of tributyltin hydride (5.2 equiv;
entry 3), the monocyclic alcohol 63 slightly increased to 14%.
The yield of over-reduction product 64b also increased (16%)
with diminished amount of aldehyde 64a (9%). Once again,
(50) Oscarsson, K.; Poliakov, A.; Oscarson, S.; Danielson, U. H.;
Hallberg, A.; Samuelsson, B. Bioorg. Med. Chem. 2003, 11, 2955-2964.
(51) Yorimitsu, H.; Oshima, K. In Radicals in Organic Synthesis; Renaud,
P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1, pp 11-27.
(52) Spiegel, D. A.; Wiberg, K. B.; Schacherer, L. N.; Medeiros, M. R.;
Wood, J. L. J. Am. Chem. Soc. 2005, 127, 12513-12515.
1
1718 cm-1; H NMR (200 MHz) δ 0.80-1.17 (m, 15H), 1.18-
J. Org. Chem, Vol. 71, No. 4, 2006 1509

Ueng et al.
1.82 (m, 14H), 1.82-2.12 (m, 2H), 2.32-2.56 (m, 2H), 3.58 (dd,
J ) 8.3, 5.5 Hz, 1H), 9.74 (br s, 1H); 13C NMR (75 MHz) δ 9.9
(t, J ) 1.8 Hz, 1H), 9.74 (t, J ) 2.0 Hz, 1H); 13C NMR (CDCl3,
100 MHz) δ 21.7 (q), 29.3 (t), 36.6 (s), 39.1 (t), 65.2 (t), 109.6 (d),
202.9 (d); HRMS calcd for C9H15O3 (M - H) m/z 171.1021, found
171.1039.
(JC-Sn ) 310 Hz), 13.6, 22.4, 27.3 (JC-Sn ) 60 Hz), 28.9 (JC-Sn
)
20 Hz), 36.8, 38.6, 42.8, 202.0. Anal. Calcd for C17H35BrOSn: C,
44.97; H, 7.77. Found: C, 45.37; H, 8.11.
O-[1-Tributylstannanyl-4-methyl-4-(2,5-dioxolanyl)]pentyl S-
Methyl Dithiocarbonate (12). To a solution of 2.70 mL (19.5
mmol) of diisopropylamine in 18 mL of dry THF cooled in an
ice-water bath was added over 15 min 12.2 mL (19.5 mmol) of a
1.6 M solution of butyllithium in hexane. The reaction mixture was
stirred at the same temperature for 15 min followed by the addition
of 5.20 mL (19.5 mmol) of tributyltin hydride over 5 min. The
resulting solution was stirred at 0 °C for another 30 min and then
cooled in a dry ice-acetone bath. To this cooled solution was added
over a period of 30 min a solution of 3.04 g (17.7 mmol) of
aldehyde 11 in 18 mL of dry THF. The resulting mixture was stirred
at the same temperature for 1.5 h followed by the addition of 1.2
mL (19.5 mmol) of carbon disulfide over 1 min and then slowly
warmed to room temperature over 1.5 h. The reaction mixture was
cooled again to -78 °C followed by the addition of 1.65 mL (26.6
mmol) of methyl iodide over 1 min and then stirred for another 45
min. The cold bath was removed, and the resulting mixture was
stirred for 45 min at room temperature and then partitioned between
300 mL of ether and 100 mL of water. The organic layer was
washed in sequence with water (100 mL) and brine (100 mL), dried
(MgSO4), and concentrated in vacuo. The residue was chromato-
graphed over silica gel (eluted with hexane/ethyl acetate, 95/5) to
give 6.55 g (67%) of 12 as a yellow oil: 1H NMR (CDCl3, 400
MHz) δ 0.79-0.99 (m overlapped with a t at 0.87, J ) 7.3 Hz,
and a s at 0.89, 21H), 1.20-1.36 (m overlapped with a sextet at
1.28, J ) 7.3 Hz, 7H), 1.36-1.54 (m, 7H), 1.86-1.95 (m, 1H),
2.01-2.12 (m, 1H), 2.51 (s, 3H), 3.78-3.93 (m, 4H), 4.51 (s, 1H),
5.70 (dd, J ) 8.9, 5.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ
10.3 (t), 13.7 (q), 18.6 (q), 21.5 (q), 21.7 (q), 27.4 (t), 28.6 (t),
29.0 (t), 35.2 (t), 36.9 (s), 65.2 (t), 85.5 (d), 109.8 (d), 213.4 (s).
Anal. Calcd for C23H46O3S2Sn: C, 49.91; H, 8.38. Found: C, 49.70;
H, 8.31.
4-(2,6-Dithiacyclohexyl)butanal (5). A 50% glutaric dialdehyde
aqueous solution (27 mL, 149 mmol) was extracted with chloroform
(25 mL × 3). To the combined chloroform extracts was added 3.10
mL of 1,3-propanedithiol (30.9 mmol). The resulting solution was
cooled in an ice-water bath followed by the addition of 1.30 mL
(10.3 mmol) of boron trifluoride diethyl etherate over a period of
2 min. The reaction mixture was then stirred at 60-70 °C for 5 h
and then washed with water (100 mL × 3). The organic layer was
dried (MgSO4) and concentrated in vacuo. The residual oil was
chromatographed over silica gel (eluted with hexane/ethyl acetate,
9/1) to give 4.77 g (81%) of 5 as a pale yellow oil: IR (neat) 1713
1
cm-1; H NMR (CDCl3, 200 MHz) δ 1.55-1.85 (m, 5H), 1.86-
2.07 (m, 1H), 2.34 (t, J ) 7.0 Hz, 2H), 2.60-2.88 (m, 4H), 3.90
(t, J ) 7.0 Hz, 2H), 9.62 (t, J ) 1.5 Hz, 1H); 13C NMR (CDCl3,
75 MHz) δ 18.9, 25.5, 29.9, 34.3, 42.8, 47.6, 201.4; HRMS calcd
for C8H14S2O m/z 190.0643, found 190.0644.
5-(2,6-Dithiacyclohexyl)pentanal (7). A mixture of 2.31 g (9.31
mmol) of 1,3-dioxolane 6,27 17 mg (0.09 mmol) of p-toluenesulfonic
acid monohydrate, 10 mL of THF, and 5 mL of water was stirred
at 65-70 °C overnight and then carefully poured into 50 mL of a
saturated sodium carbonate solution. The resulting mixture was
extracted with dichloromethane (75 mL × 2). The combined organic
layers were dried (MgSO4) and concentrated in vacuo. The residue
was chromatographed over silica gel (eluted with hexane/ethyl
acetate, 9/1) to give 1.6 g (84%) of 7 as a pale yellow oil: IR
1
(neat) 1713 cm-1; H NMR (CDCl3, 200 MHz) δ 1.41-1.95 (m,
7H), 2.00-2.20 (m, 1H), 2.41 (td, J ) 8.6, 1.5 Hz, 2H), 2.65-
2.95 (m, 4H), 4.00 (t, J ) 6.9 Hz, 2H), 9.72 (t, J ) 1.5 Hz, 1H);
13C NMR (CDCl3, 50 MHz) δ 21.6, 25.9, 26.1, 30.4, 35.1, 43.5,
47.2, 202.1. Anal. Calcd for C9H16OS2: C, 52.91; H, 7.83. Found:
C, 52.65; H, 7.87.
O-[(1-Τributylstannyl-4,4-dimethyl-5-oxo)-pentyl] S-Methyl
Dithiocarbonate (13). A mixture of 1.00 g (1.80 mmol) of acetal
12, 0.160 g (5.40 mmol) of paraformaldehyde, and 0.310 g (1.63
mmol) of p-toluenesulfonic acid monohydrate in 9 mL of THF/
H2O (4/1) was heated at 60 °C overnight and then partitioned
between ether (100 mL) and a 0.5 M solution of sodium hydroxide
(50 mL). The organic layer was washed in sequence with water
(50 mL) and brine (50 mL), dried (MgSO4), and concentrated in
vacuo. The residue was chromatographed over silica gel (eluted
with hexane/ethyl acetate, 95/5) to give 0.83 g (90%) of 13 as a
2-(1,1-Dimethyl-4-pentenyl)-1,3-dioxolane (10). A mixture of
2.32 g (18.4 mmol) of aldehyde 9,35 1.54 mL (27.6 mmol) of
ethylene glycol, 0.32 g (1.68 mmol) of p-toluenesulfonic acid
monohydrate, and 29 mL of benzene was heated under reflux for
4 h using a Dean-Stark apparatus to trap the water. The resulting
mixture was partitioned between 100 mL of ether and 50 mL of a
1 N sodium hydroxide solution. The organic layer was washed in
sequence with water (50 mL) and brine (50 mL), dried (MgSO4),
and concentrated in vacuo. The residue was chromatographed over
silica gel (eluted with hexane/ethyl acetate, 95/5) to give 2.17 g
(69%) of 10 as a pale yellow liquid: IR (neat) 1643 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 0.88 (s, 6H), 1.33-1.42 (m, 2H), 2.04 (dtt,
J ) 10.7, 6.5, 1.4 Hz, 2H), 3.78-3.94 (m, 4H), 4.53 (s, 1H), 4.89
(ddt, J ) 10.2, 2.0, 1.4 Hz, 1H), 4.98 (dq, J ) 17.1, 1.4 Hz, 1H),
5.72-5.87 (ddt, J ) 17.1, 10.2, 6.5 Hz, 1H); 13C NMR (CDCl3,
100 MHz) δ 21.4 (q), 28.1 (t), 36.8 (t), 37.0 (s), 65.2 (t), 109.9 (d),
113.9 (t), 139.6 (d); HRMS calcd for C10H18O2 m/z 170.1307, found
170.1297.
1
yellow oil: IR (neat) 1731 cm-1; H NMR (CDCl3, 400 MHz) δ
0.77-0.99 (m overlapped with a t at 0.87, J ) 7.3 Hz, 15H), 1.05
(s, 6H), 1.28 (sextet, J ) 7.3 Hz, 6H), 1.37-1.51 (m, 7H), 1.61
(td, J ) 13.5, 4.5 Hz, 1H), 1.77 (tt, J ) 12.2, 4.5 Hz, 1H), 1.98
(m, 1H), 2.52 (s, 3H), 5.71 (dd, J ) 9.7, 4.5 Hz, 1H), 9.43 (s, 1H);
13C NMR (CDCl3, 100 MHz) δ 10.3 (t, Jc-sn ) 321.2, 307.4 Hz),
13.6 (q), 18.8 (q), 21.3 (q), 27.4 (t, Jc-sn ) 56.8 Hz), 29.0 (t, Jc-sn
) 20.0 Hz), 35.2 (t), 45.6 (s), 84.4 (d), 205.7 (d), 213.8 (s). Anal.
Calcd for C21H42O2S2Sn: C, 49.51; H, 8.31. Found: C, 49.20; H,
8.13.
Radical Cyclization of Bromide 1 Followed by Benzoyla-
tion: 5-(Tributylstannyl)pentanal (16). To a solution of 342 mg
(0.75 mmol) of bromide 1 in 3 mL of benzene heated at 80 °C was
added over 4 h a solution of 0.24 mL (0.9 mmol) of tributyltin
hydride and 6 mg (0.04 mmol) of AIBN in 4.5 mL of benzene.
The reaction mixture was stirred for another 1 h followed by the
addition of 0.44 mL (3.75 mmol) of benzoyl chloride, 0.43 mL
(3.0 mmol) of triethylamine, and 0.75 mL (0.75 mmol) of a 1 N
tetrabutylammonium fluoride solution in THF. The resulting mixture
was stirred under reflux for 12 h and then partitioned between ether
(100 mL) and saturated ammonium chloride solution (100 mL).
The organic layer was washed with brine (50 mL), dried (MgSO4),
and concentrated in vacuo. To the residue was added a few drops
4-Methyl-4-(2,5-dioxolanyl)pentanal (11). A stream of ozone
gas was passed into a mixture of 1.05 mL (5.90 mmol) of olefin
10 and 3.50 g (41.3 mmol) of sodium bicarbonate in 30 mL of
dichloromethane cooled in a dry ice-acetone bath. After 20 min,
the reaction mixture was purged with nitrogen for another 20 min
at the same temperature followed by the addition of 1.60 mL (11.8
mmol) of triethylamine in one portion. The resulting mixture was
slowly warmed to room temperature over a period of 2 h and then
partitioned between 100 mL of ether and 50 mL of water. The
organic layer was washed in sequence with water (50 mL) and brine
(50 mL), dried (MgSO4), and concentrated in vacuo. The residue
was chromatographed over silica gel (eluted with hexane/ethyl
acetate, 8/2) to give 0.82 g (80%) of 11 as a colorless liquid: IR
1
(neat) 1727 cm-1; H NMR (CDCl3, 400 MHz) δ 0.89 (s, 6H),
1.59-1.69 (m, 2H), 2.40-2.50 (m, 2H), 3.78-3.93 (m, 4H), 4.50
1510 J. Org. Chem., Vol. 71, No. 4, 2006

Intramolecular Cyclizations of R-Stannyl Radicals
of triethylamine, and then it was chromatographed over silica gel
(eluted with hexane/ethyl acetate) to give 84 mg (57%) of cylopentyl
benzoate (15) and 41 mg (12%) of 16 as a colorless liquid: IR
was partitioned between ether (150 mL) and water (100 mL). The
organic layer was washed with brine (50 mL), dried (MgSO4), and
concentrated in vacuo. The residue was chromatographed over silica
gel (eluted in gradient with hexane/ethyl acetate) to give 1.512 g
1
(neat) 1718 cm-1; H NMR (300 MHz) δ 0.65-1.00 (m, 17H),
1
1.20-1.75 (m, 16H), 2.41 (td, J ) 7.2, 1.9 Hz, 2H), 9.74 (t, J )
1.9 Hz, 1H); 13C NMR (75 MHz) δ 8.5 (t; JC-Sn ) 310 Hz), 8.7 (t;
JC-Sn ) 310 Hz), 13.6 (q), 26.8 (t), 27.4 (t; JC-Sn ) 60 Hz), 28.2
(t), 29.2 (t; JC-Sn ) 20 Hz), 43.5 (t), 202.9 (d); HRMS calcd for
C17H35O118Sn (M+ - H) m/z 373.1704, found m/z 373.1706.
The Reaction of Bromide 1 with Allyltributyltin: 8-Tribu-
tylstannyl-1-octen-4-one (20). A solution of 290 mg (0.64 mmol)
of bromide 1, 0.803 mL (2.62 mmol) of allyltributyltin, and 65 µL
(0.13 mmol) of hexabutylditin in 1.2 mL of benzene was irradiated
under argon for 12 h with 3500 Å lamps. The resulting solution
was concentrated in vacuo. The residue was chromatographed over
silica gel (eluted in gradient with hexane/ethyl acetate) several times
to obtain 29 mg (36%) of trans-2-(2-propenyl)cyclopentanol (19)30
and 6.8 mg (3%) of 20 as a pale yellow oil: IR (neat) 1705, 1633
cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.66-0.95 (m, 17H), 1.19-
1.61 (m, 16H), 2.43 (t, J ) 7.0 Hz, 2H), 3.15 (d, J ) 7.0 Hz), 5.11
(d, J ) 17.0 Hz, 1H), 5.16 (d, J ) 10.1 Hz, 1H), 5.91 (ddt, J )
17.0, 10.1, 7.0 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 8.6, 8.7,
13.7, 26.7, 27.4, 28.4, 29.2, 42.0, 47.7, 118.7, 130.8, 209.0; HRMS
calcd for C16H31O120Sn m/z 359.1397, found 359.1417.
(62%) of 36 as a pale yellow oil: IR (neat) 1716, 1633 cm-1; H
NMR (CDCl3, 300 MHz) δ 1.45-1.95 (m, 7H), 1.95-2.15 (m,
3H), 2.25-2.35 (m, 1H), 2.75-2.90 (m, 4H), 3.99 (t, J ) 6.5 Hz,
1H), 4.94-5.04 (m, 2H), 5.73 (ddt, J ) 16.9, 10.2, 6.7 Hz, 1H),
9.56 (t, J ) 2.5 Hz, 1H); 13C NMR (CDCl3, 50 MHz) δ 25.0, 25.3,
27.1, 29.6, 30.4, 32.1, 46.6, 50.0, 115.0, 137.0, 203.5; HRMS calcd
for C12H20OS2 m/z 244.0956, found 244.0970.
O-[1-(Tributylstannyl)-2-(2-formylethyl)-5-hexenyl] S-Methyl
Dithiocarbonate (38). A mixture of 453 mg (0.72 mmol) of 37,
304 mg (3.62 mmol) of sodium bicarbonate, 0.67 mL (10.9 mmol)
of methyl iodide, 2 mL of acetone, and 0.2 mL of water was stirred
under reflux for 16 h and then poured into ether (30 mL) and water
(30 mL). The aqueous phase was extracted with 30 mL of ether.
The combined organic layers were washed with brine (30 mL),
dried (MgSO4), and concentrated in vacuo. The residue was
chromatographed over silica gel (eluted with hexane/ethyl acetate,
92/8) to give 0.27 g (70%) of 38 as a yellow oil: a 1:1 mixture of
two diatereomers. IR (neat) 1718, 1633 cm-1; 1H NMR (300 MHz)
δ 0.82-1.12 (m overlapped with t, J ) 7.7 Hz, at 0.87, 15H), 1.28
(sixtet, J ) 7.2 Hz, 6H), 1.39-1.98 (m, 10H), 1.98-2.34 (m, 3H),
2.37-2.64 (m overlapped with a s at 2.52, 5H), 4.91-5.10 (m,
2H), 5.67-5.86 (m, 1H), 5.96 (d, J ) 5.9 Hz, 0.5H, OCH of one
isomer), 6.04 (d, J ) 4.1 Hz, 0.5H, OCH of another isomer), 9.71-
9.80 (two overlapped t, J ) 1.5 Hz, at 9.75 and 9.76, 1H). Anal.
Calcd for C23H44O2S2Sn: C, 51.60; H, 8.28. Found: C, 51.21; H,
8.30.
General Procedure for Radical Cyclizations. Radical Cy-
clization of Bromide 8: 6-(Tributylstannyl)hexanal (22) and
6-(Tributylstannyl)hexanol (23). To a solution of 553 mg (1.18
mmol) of bromide 8 in 12 mL of benzene heated at 80 °C was
added over 6 h a solution of 0.35 mL (1.3 mmol) of tributyltin
hydride and 12 mg (0.07 mmol) of AIBN in 12 mL of benzene.
The reaction mixture was stirred for another 1 h and then directly
analyzed by GC (10% SE-30 on Chromosorb W, 3 m × 3.3 mm,
column temperature ) 80 °C, flow rate ) 25 mL/min) using nonane
as an internal standard (tR ) 10.18 min). We observed the formation
of 27% of cyclohexanol (tR ) 8.50 min). The reaction mixture was
then concentrated in vacuo followed by the addition of a few drops
of triethylamine and then chromatographed over silica gel (eluted
in gradient with hexane/ethyl acetate) to give 131 mg (29%) of 22
and 42 mg (9%) of 23 as pale yellow oils. 22: IR (neat) 1720
cm-1; 1H NMR (300 MHz) δ 0.65-0.90 (m, 17H), 1.20-1.69 (m
overlapped with a quintet, J ) 7.5 Hz, at 1.61, 18H), 2.38 (t, J )
Dimethyl 2-(5-Trimethylsilyl-4-pentynyl)-2-[2-(2,6-dithiocy-
clohexyl)ethyl]propanedioate (44). To a mixture of 518 mg (17.3
mmol) of sodium hydride (80% dispersed in mineral oil) in 17 mL
of dry DMF cooled in an ice-water bath was added over 15 min
a solution of 4.00 g (14.4 mmol) of diester 4313i in 28 mL of dry
DMF. The resulting mixture was stirred at 0 °C for another 30
min followed by the addition of 5.23 g (19.7 mmol) of 5-iodo-1-
trimethylsilylpentyne.44 The reaction mixture was stirred at room
temperature for 12 h and then partitioned between ether (200 mL)
and water (200 mL). The organic layer was washed with brine (100
mL), dried (MgSO4), and concentrated in vacuo. The residue was
chromatographed over silica gel (eluted with hexane/ethyl acetate,
85/15) to give 4.37 g (73%) of 44 as a pale yellow oil: IR (neat)
7.4 Hz, 2H), 9.73 (br s, 1H); 13C NMR (75 MHz) δ 8.6 (t; JC-Sn
)
310 Hz), 8.7 (t; JC-Sn ) 310 Hz), 13.7 (q), 21.6 (t), 26.7 (t), 27.4
(t; JC-Sn ) 60 Hz), 29.2 (t; JC-Sn ) 20 Hz), 33.9 (t; JC-Sn ) 60
Hz), 43.9 (t), 202.8 (d); HRMS calcd for C18H37O120Sn (M+ - H)
1
2173, 1728 cm-1; H NMR (CDCl3, 300 MHz) δ 0.10 (s, 9H),
1.25-1.48 (m, 2H), 1.53-1.69 (m, 2H), 1.71-1.99 (m, 3H), 1.99-
2.27 (m overlapped with a t, J ) 7.1 Hz, at 2.18, 5H), 2.71-2.91
(m, 4H, SCH2), 3.68 (s, 6H), 3.94 (t, J ) 6.8 Hz); 13C NMR (CDCl3,
75 MHz) δ 0.1 (q), 20.0 (t), 23.5 (t), 25.8 (t), 29.8 (t), 30.2 (t),
31.8 (t), 47.2 (d), 52.4 (q), 57.0 (s), 85.0 (s), 106.3 (s), 171.5 (s).
Anal. Calcd for C19H32O4S2Si: C, 54.77; H, 7.74. Found: C, 54.52;
H, 7.66.
m/z 389.1866, found m/z 389.1862. 23: IR (neat) 3354 (br) cm-1
;
1H NMR (300 MHz) δ 0.66-0.91 (m, 17H), 1.20-1.60 (m, 20H),
1.70 (s, 1H), 3.62 (t, J ) 6.6 Hz, 2H); 13C NMR (75 MHz) δ 8.7
(JC-Sn ) 310 Hz), 8.9 (JC-Sn ) 310 Hz), 13.7, 25.3, 26.9, 27.3
(JC-Sn ) 60 Hz), 29.2 (JC-Sn ) 20 Hz), 32.8, 34.2 (J ) 60 Hz),
63.1; HRMS calcd for C18H39O120Sn (M+ - H) m/z 391.2023, found
m/z 391.2031.
Methyl 2-[2-(2,6-Dithiocyclohexyl)ethyl]-7-trimethylsilyl-6-
heptynoate (45). A mixture of 4.37 g (10.5 mmol) of 44 and 617
mg (12.6 mmol) of sodium cyanide in 10 mL of DMF was heated
at 120 °C for 16 h and then partitioned between ether (200 mL)
and water (200 mL). The organic layer was washed with brine (100
mL), dried (MgSO4), and concentrated in vacuo. The residue was
chromatographed over silica gel (eluted with hexane/ethyl acetate,
95/5) to give 2.39 g (64%) of 45 as a pale yellow oil: IR (neat)
2-(2,6-Dithiacyclohexyl)ethyl-5-hexenal (36). A solution of 1.9
g (10 mmol) of aldehyde 5 in 10 mL of benzene was added over
10 min to a mixture of 2.3 mL (20 mmol) of cyclohexylamine and
690 mg (5.0 mmol) of sodium carbonate in 7 mL of benzene. The
resulting mixture was stirred at room temperature for 1 h, filtered,
and then concentrated in vacuo to give the crude imine. To another
solution of 1.4 mL (10 mmol) of diisopropylamine in 10 mL of
dry THF cooled in an ice-water bath was added over 10 min a
solution of 1.6 M butyllithium in hexane (6.3 mL, 10 mmol). The
resulting mixture was stirred at the same temperature for another
30 min followed by the addition of a solution of the crude imine
in 10 mL of dry THF over a period of 20 min. The reaction mixture
was stirred at 0 °C for 1 h and then cooled in a dry ice-acetone
bath. To this cooled solution was added dropwise 1.32 mL (13
mmol) of 4-bromo-1-butene. The resulting mixture was slowly
warmed to room temperature, stirred for another 4 h, and then
poured into 20 mL of a 1 N HCl solution. The resulting mixture
1
2173, 1732 cm-1; H NMR (CDCl3, 300 MHz) δ 0.05 (s, 9H),
1.32-1.86 (m, 9H), 1.96-2.09 (m, 1H), 2.12 (t, J ) 6.7 Hz, 2H),
2.23-2.38 (m, 1H), 2.64-2.85 (m, 4H), 3.59 (s, 3H), 3.87-3.98
(m, 1H); 13C NMR (CDCl3, 75 MHz) δ 0.0 (q), 19.5 (t), 25.8 (t),
26.0 (t), 29.0 (t), 30.1 (t), 31.0 (t), 32.9 (t), 44.4 (d), 47.0 (d), 51.4
(q), 84.7 (s), 106.5 (s), 175.6 (s). Anal. Calcd for C17H30O2S2Si:
C, 56.94; H, 8.43. Found: C, 56.83; H, 8.19.
7-Trimethylsilyl-2-[2-(2,6-dithiacyclohexyl)ethyl]-6-heptyn-1-
ol (46). To a mixture of 380 mg (10 mmol) of LAH in 10 mL of
dry THF cooled in an ice-water bath was added over 10 min a
J. Org. Chem, Vol. 71, No. 4, 2006 1511

Ueng et al.
solution of 2.39 g (6.68 mmol) of 45 in 7 mL of dry THF. The
reaction mixture was stirred at the same temperature for 1 h, diluted
with 15 mL of ether, followed by sequential addition of 0.4 mL of
water, 0.4 mL of a 15% sodium hydroxide solution, and 0.8 mL of
water. The resulting mixture was stirred at room temperature for
30 min, filtered, dried (MgSO4), and concentrated in vacuo to give
2.18 g (98%) of 46 as a colorless liquid: IR (neat) 3414 (br), 2172
cm-1; 1H NMR (CDCl3, 200 MHz) δ 0.12 (s, 9H), 1.32-1.69 (m,
8H), 1.71-1.92 (m, 3H), 2.03-2.27 (m overlapped with a t, J )
7.0 Hz, 3H), 2.75-2.92 (m, 4H), 3.53 (d, J ) 4.4 Hz, 2H), 4.00 (t,
J ) 6.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 0.2 (q), 20.1 (t),
25.8 (t), 26.0 (t), 27.8 (t), 29.8 (t), 30.4 (t), 32.7 (t), 39.8 (d), 47.8
(d), 65.2 (t), 84.7 (s), 107.2 (s); HRMS calcd for C16H30OS2Si
330.1507, found 330.1509.
to room temperature over 30 min, and then filtered over a short
pad of silica gel. The filtrate was concentrated in vacuo, and the
residue was chromatographed over silica gel (eluted with hexane/
ethyl acetate, 9/1) to give 1.93 g (89%) of 47 as a colorless oil: IR
1
(neat) 2173, 1724 cm-1; H NMR (CDCl3, 300 MHz) δ 0.11 (s,
9H), 1.39-1.91 (m overlapped with a t, J ) 5.9 Hz, at 1.73, 9H),
2.01-2.14 (m, 1H), 2.16-2.33 (m overlapped with a t, J ) 6.7
Hz, at 2.21, 3H), 2.85-2.94 (m, 4H), 3.99 (t, J ) 6.5 Hz,
1H), 9.55 (d, J ) 2.9 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 0.1
(q), 19.8 (t), 25.6 (t), 25.7 (t), 25.8 (t), 27.5 (t), 30.3 (t), 32.7 (t),
47.2 (d), 50.9 (d), 85.2 (s), 106.3 (s), 204.1 (d). Anal. Calcd for
C16H28OS2Si: C, 58.51; H, 8.60. Found: C, 58.30; H, 8.26.
Acknowledgment. Financial support by the National Science
7-Trimethylsilyl-2-[2-(2,6-dithiacyclohexyl)ethyl]-6-heptyn-1-
al (47). To a solution of 0.80 mL (9.24 mmol) of oxalyl chloride
in 18 mL of dichloromethane cooled in a dry ice-acetone bath
was added over 5 min a solution of 1.40 mL (18.5 mmol) of dry
DMSO in 5 mL of dichloromethane. The resulting solution was
stirred at the same temperature for 5 min followed by the addition
of a solution of 2.18 g (6.61 mmol) of 46 in 7 mL of dichlo-
romethane over a period of 5 min. The reaction mixture was stirred
at the same temperature for 30 min followed by the addition of
5.50 mL (4.00 mmol) of triethylamine over 5 min, slowly warmed
Council of the Republic of China is gratefully acknowledged.
Supporting Information Available: Compound characterization
data of 8, 25, 27-29, 37, 40-42, 48-53, and 55-66. 1H/13C NMR
spectra of all new compounds, and NOESY spectra of 61a and
61b. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO052176V
1512 J. Org. Chem., Vol. 71, No. 4, 2006