Diastereoselective synthesis of polysubstituted tetrahydropyrans and thiacyclohexanes via indium trichloride mediated cyclizations

Article abstract of DOI:10.1021/jo001136i

Polysubstituted tetrahydropyrans and thiacyclohexanes were synthesized in high yields with excellent diastereoselectivities via indium trichloride mediated cyclizations between homoallyl alcohols and mercaptans with aldehydes. In the case of tetrahydropyran products, the stereochemistry of the product was found to be directly correlated with the geometry of the homoallyl alcohols; whereas the cross-cyclization of aldehydes with trans-homoallyl alcohols generated (up-down-up) 2,3,4-trisubstituted tetrahydropyran products exclusively, the reaction of aldehydes with cis-homoallyl alcohols provided mainly (up-up-up) 2,3,4-trisubstituted products. When a trisubstituted homoallyl alcohol was used, its cross-cyclization with aldehydes generated (up-down-up-down-up) pentasubstituted tetrahydropyran derivatives with simultaneous controlling of five stereogenic centers. On the other hand, a cyclization-decyclization equilibrium was observed in the formation of thiacyclohexanes. The reaction of both cis- and trans-homoallyl mercaptans with aldehydes provided the same major diastereomers.

Full text of DOI:10.1021/jo001136i

J . Org. Chem. 2001, 66, 739-747
739
Dia ster eoselective Syn th esis of P olysu bstitu ted Tetr a h yd r op yr a n s
a n d Th ia cycloh exa n es via In d iu m Tr ich lor id e Med ia ted
Cycliza tion s1
Xiao-Fan Yang, J oel T. Mague, and Chao-J un Li*
Department of Chemistry, Tulane University, New Orleans, Louisiana 70118
cjli@tulane.edu
Received J uly 26, 2000
Polysubstituted tetrahydropyrans and thiacyclohexanes were synthesized in high yields with
excellent diastereoselectivities via indium trichloride mediated cyclizations between homoallyl
alcohols and mercaptans with aldehydes. In the case of tetrahydropyran products, the stereochem-
istry of the product was found to be directly correlated with the geometry of the homoallyl alcohols;
whereas the cross-cyclization of aldehydes with trans-homoallyl alcohols generated (up-down-up)
2,3,4-trisubstituted tetrahydropyran products exclusively, the reaction of aldehydes with cis-
homoallyl alcohols provided mainly (up-up-up) 2,3,4-trisubstituted products. When a trisubstituted
homoallyl alcohol was used, its cross-cyclization with aldehydes generated (up-down-up-down-up)
pentasubstituted tetrahydropyran derivatives with simultaneous controlling of five stereogenic
centers. On the other hand, a cyclization-decyclization equilibrium was observed in the formation
of thiacyclohexanes. The reaction of both cis- and trans-homoallyl mercaptans with aldehydes
provided the same major diastereomers.
In tr od u ction
many others. Thiacyclohexanes, sometimes called thio-
tetrahydropyrans, are less frequently encountered in
nature. Some thiacyclohexane derivatives are found in
petroleum oil.12 Thiacyclohexane rings also play a key
role in the biological activities of a number of phar-
maceutical agents such as cephalosporins and dithia-
thromboxane A2.13 Recently, there has been an increasing
interest in developing sulfur analogues of oligosaccha-
rides as potential enzyme inhibitors.14 In addition, thia-
cyclohexane derivatives can be transformed into a variety
of structures through simple reactions such as hydro-
genolysis, oxidation, and olefination.15
The condensation of olefins with aldehydes under
strongly acidic conditions, known as the Prins reaction,
was discovered in 1899 to give a mixture of compounds.16
Major products of classical Prins reactions are normally
1,3-dioxanes, 1,3-glycols, unsaturated alcohols, and al-
cohols derived from hydration of the olefins, as well as
products obtained from acid-catalyzed polymerization of
the olefin. In the late 1960s, Stapp briefly examined the
direct synthesis of tetrahydropyran derivatives via the
Prins reaction.17 Recently, there has been an increasing
Six-membered saturated oxygen and sulfur hetero-
cycles are structural features of a variety of biologically
important natural products such as polyether antibiotics,
marine toxins, pheromones, and pharmaceutical agents.2
Tetrahydropyran is also the structural core of most
carbohydrates, as well as their oligomers and polymers,
which are the most abundant biological molecules on
earth and play several crucial roles in living organisms.3
Considerable efforts have been made toward the synthe-
sis of tetrahydropyran type compounds.4 Some examples
are via hetero-Diels-Alder reactions,5 oxiranyl anions,6
carbonyl ylides,7 Claisen rearrangements,8 ring opening
of epoxides,9 iodocyclizations,10 olefin-metathesis,11 and
(1) Taken in part from the M.S. thesis of Xiao-Fan Yang, Tulane
University, 2000.
(2) Reviews: Wesley, J . W. Annu. Rep. Med. Chem. 1975, 10, 246.
Pressman, B. C. Annu. Rev. Biochem. 1976, 45, 501. Bhagwat, S. S.;
Hamann, P. R.; Still, W. C.; Buntiny, S.; Fitzpatrick, F. A. Nature 1985,
315, 511. Ohuchida, S.; Hamanaka, N.; Hayashi, M. Tetrahedron 1983,
39, 4203. Kale, V. N.; Clive, D. L. J . J . Org. Chem. 1984, 49, 1554.
(3) Horton, H. R.; Moran, L. A.; Ochs, R. S.; Rawn, J . D.; Scrimgeour,
K. G. Principles of Biochemistry, 2nd ed.; Prentice Hall: Upper Saddle
River, NJ , 1996.
(4) For a review, see: Boivin, T. L. B. Tetrahedron 1987, 43, 3309.
(5) For a review, see; Tietze, L. F.; Kettschau, G.; Gewert, J . A.;
Schuffenhauer, A. Curr. Org. Chem. 1998, 2, 19. Schmidt, R. R. Acc.
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(6) Mori, Y. Chem. Eur. J . 1997, 3, 849.
(7) Padwa, A. Acc. Chem. Res. 1991, 24, 22.
(12) Gal’pern, G. D. Int. J . Sulfur Chem. B 1971, 6, 115.
(13) Woodward, R. B.; Heusler, K.; Gosteli, J .; Naegeli, P.; Oppolzer,
W.; Ramage, R.; Ranganathan, S.; Vorbruggen, H. J . Am. Chem. Soc.
1966, 88, 852. Casy, G.; Lane, S.; Taylor, R. J . K. J . Chem. Soc., Perkin
Trans. 1 1986, 1397. Ohuchida, S.; Hamanaka, N.; Hagashi, M.
Tetrahedron Lett. 1983, 39, 4273.
(8) Ziegler, F. E. Acc. Chem. Res. 1977, 10, 227.
(9) For an example, see: Nicolaou, K. C.; Prasad, C. V. C.; Somers,
C. K. J . Am. Chem. Soc. 1989, 111, 5330.
(10) For a review, see; Bartlett. P. A. In Asymmetric Synthesis;
Morrison, J . D., Ed.; Academic Press: New York, 1984; Vol. 3, Part B,
Chapter 6.
(11) For examples of cycloether formations, see: Rutjes, F. P. J . T.;
Kooistra, T. M.; Hiemstra, H.; Schoemaker, H. E. Synlett 1998, 192.
Clark, J . S.; Hamelin, O.; Hufton, R. Tetrahedron Lett. 1998, 39, 8321
(14) Mehta, S.; Andrews, J . S.; J ohnston, B. D.; Svensson, B.; Pinto,
B. M. J . Am. Chem. Soc. 1995, 117, 9783.
(15) Block, E. Reactions of Organosulfur Compounds; Academic
Press: New York, 1978. Woodward, R. B.; Logusch, E.; Nambiar, K.
P.; Sakan, K.; Ward, D. E.; Au-Yeung, B. W.; Balaram, P.; Browne,
L. J .; Card, P. J .; Chen, C. H. J . Am. Chem. Soc. 1981, 103, 3210.
(16) Arundale, E.; Mikesaka, L. A. Chem. Rev. 1952, 51, 505. Kovacs,
O.; Kovari, I. Magy. Kem. Foly. 1964, 70, 223. Adams, D. R.; Bhatnagar,
S. P. Synthesis 1977, 661. Snider, B. B. In Comprehensive Organic
Synthesis; Trost, B. M., Ed., Pergamon Press: Oxford, 1991; Vol. 2,
pp 527-561.
and refs therein. For
a review, see: Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413.
10.1021/jo001136i CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/12/2001

740 J . Org. Chem., Vol. 66, No. 3, 2001
Yang et al.
F igu r e 2.
Sch em e 1
F igu r e 1.
interest in using Prins-cyclization to generate tetra-
hydropyran derivatives in a stereocontrolled manner,
with potential applications to the synthesis of polyether
antibiotics and other complex natural products that
contain tetrahydropyran backbones. A large number of
papers have been published on this type of cyclization
during the past decade.18 A variety of Lewis acids have
been used to mediate such a cyclization. In most cases,
the cyclization products are either 2,6-disubstituted
dihydropyran or 2,4,6-trisubstituted tetrahydropyran
derivatives. Some methodologies start with the forma-
tion of a stable acetal compound whereas others involve
direct condensation of a homoallylic alcohol with alde-
hyde through a hemiacetal intermediate. The most
striking feature of tetrahydropyran derivatives in natural
products is the attachment of multiple substituents with
well-defined stereochemistry. We envisioned that an
efficient method toward the stereocontrolled formation
of poly-substituted tetrahydropyran and thiacyclohexane
derivatives is through the Prins-type cyclization of
substituted homoallyl alcohols and mercaptans with
aldehydes (Figure 1).19 Herein, we describe our results
of investigation on this subject by using indium chloride
as a mild mediator.
the formation of tetrahydropyran derivatives as the major
products selectively and tetrahydrofuran derivatives as
the minor products due to their stability difference.21
Most homoallyl alcohols used in our research are
commercially available and trans-3-nonen-1-ol 2b was
readily prepared from 1-heptyne (1) via hydroalumina-
tion followed by reaction with ethylene oxide (eq 1).22
When trans-3-hexen-1-ol (2a ) was stirred with benzal-
dehyde (3a ) and indium trichloride in methylene chloride
at ambient temperature, an immediate color change was
observed. Disappearance of the starting material was
then detected by TLC after 3 h of stirring. After a usual
workup, an unsymmetrical 2,3,4-trisubstituted tetra-
hydropyran 4a was generated in high yield with an
exclusive up-down-up (>99:1) diastereoselectivity as
estimated by 1H NMR analysis of the crude reaction
mixture. After purification, the stereochemistry was
further confirmed by DQF-COSY NMR analyses, ex-
amination of the coupling constants (Figure 2), and
comparison with related compounds reported in the
literature. A variety of other aromatic aldehydes (entries
1-5) were also examined, providing high yield and
diastereoselectivity in each case (eq 2) (Table 1). Chang-
ing the homoallyl alcohol to trans-3-nonen-1-ol (2b) did
Resu lts a n d Discu ssion s
2,3,4-Tr isu bstitu ted Tetr a h yd r op yr a n s. Although
2,4,6-trisubstituted tetrahydropyrans were readily syn-
thesized with high diastereoselectivities through a num-
ber of Prins-cyclizations, extension of the method to tetra-
or pentasubstituted derivatives has not been reported.19
With internal olefins the regioselectivity becomes crucial
when the double bond attacks the oxonium ion interme-
diate: tetrahydropyran derivatives will be formed with
the attack from the terminal carbon of the olefin moiety
whereas attack from the other end of the double bond
generates the tetrahydrofuran products (Scheme 1).20
Unlike most strong Lewis acid catalysts (such as TiCl4,
SnCl4) developed for Prins-cyclization, a milder Lewis
acid like InCl3 was envisioned to be effective in promoting
(17) Stapp, P. R. J . Org. Chem. 1969, 34, 479.
(18) For some examples with other Lewis acids for Prins-type
cyclizations, see: Bratz, M.; Bullock, W. H.; Overman, L. E.; Takemoto,
T. J . Am. Chem. Soc. 1995, 117, 5958. Rychnovsky, S. D.; Hu, Y.;
Ellsworth, B. Tetrahedron Lett. 1998, 39, 7271. Semeyn, C.; Blaauw,
R. H.; Hiemstra, H.; Speckamp, W. N. J . Org. Chem. 1997, 62, 3426.
Nishizaw, M.; Shigaraki, T.; Takao, H.; Imagawa, H.; Sugihara, T.
Tetrahedron Lett. 1999, 40, 1153. Cloninger, M. J .; Overman, L. E. J .
Am. Chem. Soc. 1999, 121, 1092. Wei, Z. Y.; Li, J . S.; Wang, D.; Chan,
T. H. Tetrahedron Lett. 1987, 28, 3441. Wei, Z. Y.; Wang, D.; Li, J . S.;
Chan, T. H. J . Org. Chem. 1989, 54, 5768. Coppi, L.; Ricci, A.; Taddi,
M. J . Org. Chem. 1988, 53, 911; Marko, I. E.; Dobbs, A. P.; Scheirmann,
V.; Chelle, F.; Bayston, D. J . Tetrahedron Lett. 1997, 38, 2899. Brown,
M. J .; Harrison, T.; Herrinton, P. M.; Hopkins, M. H.; Hutchinson, K.
D.; Mishra, P.; Suginome, M.; Iwanami, T.; Ito, Y. J . Org. Chem. 1998,
63, 6096.
not affect the stereoselectivity but decreased the yield
slightly, possibly due to an increase of steric hindrance
in the transition state for the ring-closing step. Cycliza-
tion of the alcohols with aliphatic aldehydes (entries 6-8)
(21) Yang, J .; Viswanathan, G. S.; Li, C. J . Tetrahedron Lett. 1999,
40, 1627. Viswanathan, G. S.; Yang, J .; Li, C. J . Org. Lett. 1999, 1,
993. For reviews on synthetic applications of indium and indium
reagents, see: Cintas, P. Synlett 1995, 1087. Hashmi, A. S. K. J . Prakt.
Chem., Chem. Zeit. 1998, 340, 84. Paquette, L. A. In Green Chemis-
try: Frontiers in Benign Chemical Syntheses and Processes; Anastas,
P. A.; Williamson, T. C., Eds.; Oxford University Press: Cary, NC, 1998.
Li, C. J .; Chan, T. H. Tetrahedron 1999, 55, 11149. Ranu, B. C. Eur.
J . Org. Chem. 2000, 2347.
(19) For a preliminary communication on the thiacyclohexane study,
see: Yang, X. F.; Li, C. J . Tetrahedron Lett. 2000, 41, 1321; see also:
Rychnovsky, S. D.; Thomas, C. R. Org. Lett. 2000, 2, 1217.
(20) Overman, L. E. J . Am. Chem. Soc. 1991, 113, 5365.
(22) Negishi, E.; Baba, S.; King, A. O. J . Chem. Soc. Chem. Commun.
1976, 17.

Indium Trichloride Mediated Cyclizations
J . Org. Chem., Vol. 66, No. 3, 2001 741
Ta ble 1. Ster eoselective F or m a tion of 2,3,4-Tr isu bstitu ted Tetr a h yd r op yr a n s fr om tr a n s-Hom oa llyl Alcoh olsa
a
All reaction were carried out with the general procedure. Yields were Isolated ones after column chromatography.
gave the same high diastereoselectivity; however, the
yields decreased as the length of aliphatic chain in-
creased, also possibly due to the steric effect.
the tetrahydropyran derivatives were assigned via careful
examinations of coupling constants of the two distinct
pair of signals at ca. 4.0 ppm. The structure of the
tetrahydrofuran products was determined by DQF-
COSY NMR analysis and the cis configuration was
assigned by comparison with NMR data of similar
compounds reported in the literature (Figure 3).23
To study the effect of the olefin geometry on the
product formation, cis-homoallyl alcohols were also
examined. The condensation between cis-3-hexen-1-ol
(5a ) and benzaldehyde was carried out under the same
reaction conditions as with the trans homoallyl alcohols.
In this case, no color change was observed and dis-
appearance of the starting material was detected by TLC
after 10 h of vigorous stirring at room temperature.
Unlike the cyclization of trans homoallyl alcohols, the
formation of two cyclic ether compounds 6 and 7 were
observed, with (up,up,up)-2,3,4-trisubstituted tetrahydro-
pyran derivative 6 as the major product and cis-2,3-
disubstituted tetrahydrofuran derivative 7 as the minor
one (eq 3). The combined overall yield was less than the
cyclization with the corresponding trans homoallyl alco-
hols. Replacing benzaldehyde with acetaldehyde, the
cyclization generated an all cis tetrahydropyran product
in moderate yield whereas aldehydes with longer ali-
phatic chains gave rise to a mixture of inseparable
products in low overall yields. Changing the alcohol to
cis-3-nonen-1-ol (5b) gave the two products as a 1:1
mixture of the tetrahydropyran and tetrahydrofuran
derivatives. However, the overall yield was not signifi-
cantly affected (Table 2). The relative configurations of
The formation of tetrahydrofuran derivatives sug-
gested that a different transition-state might be involved
in the cyclization of cis homoallyl alcohols as compared
to the cyclization of trans homoallyl alcohols in which
no such products were detected. A possible explanation
is that in the case of trans homoallyl alcohol, the inter-
mediate 8a undergoes cyclization via the usual chair
transition-state 8b in which all the substituents are
equatorial; whereas in the case of cis homoallyl alcohols,
(23) Dana, G.; Touboul, E.; Convert, O.; Pascal, Y. L. Tetrahedron
1988, 44, 429.

742 J . Org. Chem., Vol. 66, No. 3, 2001
Yang et al.
Ta ble 2. Ster eoselective F or m a tion of 2,3,4-tr isu bstitu ted Tetr a h yd r op yr a n s fr om cis Hom oa llyl Alcoh olsa
a
All reactions were carried out with the general procedure. Yields were Isolated ones after column chromatography.
F igu r e 3.
the disfavored pseudo 1,3-diaxial interaction in 8c leads
to a mixture of carbocations 8d and 8e. Subsequently,
nucleophilic attack of 8d by the chloride ion gave the
more stable tetrahydropyran products whereas attack of
8e produced tetrahydrofuran derivatives (Scheme 2).
Dia ster eoselective Syn th esis of P en ta su bstitu ted
Tetr a h yd r op yr a n s. To study the formation of penta-
substituted tetrahydropyran derivatives, commercially
available cyclohexene oxide was converted into trans-2-
(1-hepten-1-yl)cyclohexanol (9) in high yield by a method
Sch em e 2

Indium Trichloride Mediated Cyclizations
J . Org. Chem., Vol. 66, No. 3, 2001 743
Sch em e 3
aldehydes gave rise to a mixture of at least three
cyclization products 13, 15, and 16 (as was shown by GC/
of Alexakis and J achiet (Scheme 3).24 Condensations of
9 with both benzaldehyde and hexanal were carried out
under the same standard reaction conditions. The reac-
tions generated a pentasubstituted tetrahydropyran de-
rivative 10a and 10b (essentially as a single product in
both cases) in which five stereogenic centers (up-down-
up-down-up) were controlled (Scheme 4). X-ray crystal
analysis of 10a confirmed the stereochemistry of this
compound, in which all five substituents on the tetra-
hydropyran ring occupy equatorial positions.25
F or m a tion of Tr isu bstitu ted Th ia cycloh exa n es.
Indium trichloride mediated cross-coupling between homo-
allyl mercaptans and aldehydes was also investigated.
The homoallyl mercaptans such as 12 were readily
synthesized by reacting the corresponding homoallyl
alcohols (such as compound 11) with thioacetic acid via
a modification of the Mitsunobu protocol26 followed by
lithium aluminum hydride (LAH) reduction (eq 4). At-
tempts to synthesize the thiols by using the Lawesson’s
reagent27 were not successful. The stirring of phenyl
homoallyl mercaptan 12 with benzaldehyde and indium
chloride in methylene chloride led to the smooth forma-
tion of 2,4,6-trisubstituted thiacyclohexanes 13a and 13b
(97%) as a 8:1 mixture of diastereomers (eq 5). However,
reaction of this thiol with other substituted aromatic
MS analysis of the reaction mixture). A plausible expla-
nation of this scrambling is the existence of equilibrium
between different kinds of carbocation intermediates 17,
18, and 19 during the course of reaction (Scheme 5). On
the other hand, the reaction of an aliphatic homoallyl
mercaptan 20 (when a cis isomer 20a was used) with
aldehydes generated unsymmetrical 2,3,4-trisubstituted
thiacyclohexanes 21 and 22 in high yield with good
diastereoselectivity together with a trace amount of
thiacyclohexene derivative 23 (eq 6). The diastereoselec-
tivity remains nearly the same in all cases at ca. 7:1
Sch em e 4
Sch em e 5

744 J . Org. Chem., Vol. 66, No. 3, 2001
Yang et al.
F igu r e 4.
Ta ble 3. Dia ster eoselective Syn th esis of
Ta ble 4. Dia ster eoselective Syn th esis of
Th ia cycloh exa n es via cis-3-Non en e-1-th iol (20a )a
Th ia cycloh exa n es via w ith tr a n s-3-Non en e-1-th iol (20b)a
a
Yields are (total) isolated ones (after column chromatogra-
a
phy on silica gel) for both diastereomers. Ratios of diastereomers
were measured with GC/MS or 1H NMR on the crude reaction
mixtures.
Yields are (total) isolated ones (after column chromatography
on silica gel) for both diastereomers. Ratios of diastereomers were
measured with GC/MS or 1H NMR on the crude reaction mixtures.
tion, the corresponding trans-isomer mercaptan 20b was
also prepared by the previous method and was reacted
with the aldehydes used earlier and indium trichloride
under the same reaction conditions. Interestingly, reac-
tions of both cis and trans mercaptans generated the
major cyclized product 21 with the same configuration
but different selectivity. Whereas the use of the cis-
mercaptan gave rise to a mixture of up-up-up and up-
down-up thiacyclohexane derivatives 21 and 22 with the
latter as the predominant product, the reaction of the
trans mercaptan generated a up-down-up thiacyclohex-
ane derivative 21 exclusively (Table 4). Therefore, unlike
the alcohol cyclization, stereoselective formation of the
more stable up-down-up isomer took place regardless of
the geometry of the starting mercaptan. The results
would suggest that, with the use of the trans-mercaptan,
the stereospecificity associated with the product forma-
tion was most likely due to the formation of a chair-
transition-state 24 in the ring closure process which
generated carbocation 25 and leading to product 21a ;
whereas, in the case of the cis-mercaptan, an isomeriza-
tion of the less stable carbocation intermediate 26 to the
more stable carbocation 25 might have occurred (possibly
via a decyclization to give 27 followed by recyclization)
favoring the up-down-up isomers (Table 3). The relative
configurations of the diastereomers were assigned via the
coupling constants of the two distinct pairs of peaks at
ca. 4.0 ppm as shown in Figure 4.
To investigate the effect of cis-trans conformations of
the mercaptan on the diastereoselectivity of the cycliza-
(24) Alexakis, A.; J achiet, D. Tetrahedron 1989, 45, 6179.
(25) See Supporting Information for ORTEP Figure of 4a and tables
of X-ray crystallographic data.
(26) Mitsunobu, O. Synthesis 1981, 1.
(27) Nishio, T. J . Chem. Soc., Perkin Trans. 1 1993, 1113.

Indium Trichloride Mediated Cyclizations
J . Org. Chem., Vol. 66, No. 3, 2001 745
Sch em e 6
(CDCl3, 100 MHz, ppm): δ ) 140.0, 128.6, 128.4, 127.4, 83.7,
67.3, 60.3, 50.8, 37.8, 20.5, 9.0. Anal. Calcd for C13H17OCl: C,
69.48; H, 7.62. Found: C, 69.62; H, 7.66.
which also led to the formation of the more stable up-
down-up product 21a (Scheme 6). Alternatively, a boat-
transition-state 28 might be involved in the cyclization
of the cis-isomer, generating the same major product as
in the case of the trans-isomer. The scope and mechanism
of the reaction, as well as the biological activities of the
thiacyclohexane derivatives are under investigation.
In conclusion, indium chloride mediated Prins-type
cyclization provided a convenient method in generating
polysubstituted tetrahydropyrans and thiacyclohexanes
in high yields with excellent stereochemical control.
Further investigation would include a more detailed
mechanistic study and possible applications of this
methodology to natural product synthesis.
4-Ch lor o-3-eth yl-2-p h en yltetr a h yd r op yr a n (u p-u p-u p)
(6a ): IR (neat, cm-1): 2961, 2848, 1450, 1264, 1151, 1115,
1
1073, 1001, 764, 743, 702; H NMR (CDCl3, 400 MHz, ppm):
δ ) 7.24-7.38 (m, 5H), 4.53 (s, 1H), 4.44 (dt, J ) 12.5, 4.2 Hz,
1H), 4.18 (dd, J ) 5.1, 11.7 Hz, 1H), 3.59 (dt, 2.6, 12.1 Hz,
1H), 2.01-2.14 (m, 2H), 1.85-1.92 (m, 1H), 1.42-1.60 (m, 2H),
0.38 (t, J ) 7.5 Hz, 3H); 13C NMR (CDCl3, 100 MHz, ppm): δ
) 140.4, 128.1, 127.0, 125.2, 81.3, 67.7, 62.3, 49.8, 32.0, 15.7,
15.3. Anal. Calcd for C13H17OCl: C, 69.48; H, 7.62. Found: C,
69.53; H, 7.60.
cis-3-(1-Ch lor op r op yl)-2-p h en yltetr a h yd r ofu r a n (7a ):
1
IR (neat, cm-1): 2969, 2875, 1454, 1066, 751, 699; H NMR
(CDCl3, 400 MHz, ppm): δ ) 7.26-7.40 (m, 5H), 5.23 (d,
J ) 7.3 Hz, 1H), 4.34 (dt, J ) 1.8, 8.4 Hz, 1H), 4.02 (ddd, J )
7.0, 8.8, 10.3 Hz, 1H), 3.22 (dt, J ) 2.7, 9.2 Hz, 1H), 2.91
(ddt, J ) 9.5, 11.4, 7.1 Hz, 1H), 2.03-2.21 (m, 1H), 1.86-1.98
(m, 1H), 1.71-1.80 (m, 1H), 1.54-1.67 (m, 1H), 0.94 (t,
J ) 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz, ppm): δ )
140.1, 128.0, 127.5, 127.3, 82.6, 68.5, 64.6, 52.0, 29.5, 28.1,
10.3.Anal. Calcd for C13H17OCl: C, 69.48; H, 7.62. Found: C,
69.58; H, 7.58.
4-Ch lor o-3-eth yl-2-(m -flu or op h en yl)tetr a h yd r op yr a n
(u p-d own -u p) (4b): IR (neat, cm-1): 2969, 2857, 1593, 1450,
1266, 1138, 1092, 790, 698; 1H NMR (CDCl3, 400 MHz, ppm):
δ ) 7.30-7.37 (m, 1H), 6.99-7.17 (m, 3H), 4.04-4.16 (m, 3H),
3.57 (dt, 1H, J ) 2.9, 12.1 Hz, 1H), 2.15-2.30 (m, 2H), 1.89
(ddt, J ) 2.9, 4.8, 10.6 Hz, 1H), 1.58-1.70 (m, 1H), 1.17-1.29
(m, 1H), 0.74 (t, J ) 7.5 Hz, 3H); 13C NMR (CDCl3, 100 MHz,
ppm): δ ) 164.1, 161.7, 142.6, 142.5, 130.1, 130.0, 123.1, 123.1,
115.4, 115.1, 114.4, 114.2, 82.9, 82.9, 67.3, 60.0, 50.9, 37.6, 20.4,
9.0. Anal. Calcd for C13H16OClF: C, 64.33; H, 6.64. Found: C,
64.56; H, 6.69.
4-Ch lor o-3-eth yl-2-(m -flu or op h en yl)tetr a h yd r op yr a n
(u p-u p-u p) (6b): IR (neat, cm-1): 2966, 2849, 1592, 1445,
1277, 1251, 1114, 1078, 770, 693; 1H NMR (CDCl3, 400 MHz,
ppm): δ ) 7.25-7.34 (m, 1H), 7.04-7.12 (m, 2H), 6.91-6.98
(m, 1H), 4.51 (s, H), 4.41 (dt, J ) 12.5, 4.4 Hz, 1H), 4.17 (ddd,
J ) 1.5, 5.1, 6.6 Hz, 1H), 3.58 (dt, J ) 2.7, 12.5 Hz, 1H), 1.99-
2.12 (m, 2H), 1.84-1.92 (m, 1H), 1.38-1.60 (m, 2H), 0.41 (t, J
) 7.5 Hz, 3H); 13C NMR (CDCl3, 100 MHz, ppm): δ ) 164.2,
161.7, 143.2, 143.1, 129.6, 129.5, 120.9, 120.9, 113.9, 113.7,
112.6, 112.4, 80.6, 67.6, 61.9, 49.6, 31.8, 15.7, 15.3. Anal. Calcd
for C13H16OClF: C, 64.33; H, 6.64. Found: C, 64.42; H, 6.56.
4-Ch lor o-3-eth yl-2-(m -ch lor op h en yl)tetr a h yd r op yr a n
(u p-d own -u p) (4c): IR (neat, cm-1): 2964, 2851, 1575, 1437,
1206, 1139, 1088, 775, 699; 1H NMR (CDCl3, 400 MHz, ppm):
δ ) 7.21-7.40 (m, 4H), 4.04-4.13 (m, 3H), 3.56 (dt, J ) 2.6,
12.1 Hz, 1H), 2.14-2.30 (m, 2H), 1.90 (ddt, J ) 2.9, 4.8, 10.6
Exp er im en ta l Section
Commercially available reagents were used without further
purification. Methylene chloride was dried with 4 Å molecular
sieves overnight, and tetrahydrofuran was distilled over metal
sodium and benzophenone prior to use. All other solvents were
used as purchased. NMR spectra were recorded on GE Omega
400 MHz FT-NMR Spectrometer. Advanced NMR structural
analyses such as DQF-COSY, TOCSY, and ROESY were
provided by Tulane University Coordinated Instrumental
Facilities (CIF). IR spectra were obtained with Perkin-Elmer
RX I FT-IR Spectrometer and GC-MS analysis was performed
with Hewlett-Packard 5890 Series II Gas Chromatography and
Hewlett-Packard 5989A Mass Spectrometer. Thin-layer chro-
matography (TLC) was carried out on glass supported plates
and compounds were visualized by cerium molybdate, potas-
sium permanganate, or UV light. Elemental analysis was also
performed at CIF.
A Gen er a l P r oced u r e for th e Cycliza tion of Hom oa llyl
Alcoh ols w ith Ald eh yd es. To a slurry of indium trichloride
(332 mg, 1.5 mmol) and benzaldehyde (106 mg, 1 mmol) in 15
mL methylene chloride (which was predried with 4 Å molec-
ular sieves overnight) was added trans-3-hexen-1-ol (200 mg,
2 mmol) dropwise. After 3 h (10 h for cis-homoallyl alcohol) of
stirring at room temperature, the reaction mixture was
concentrated in vacuo. Flash chromatography of the crude
mixture over silica gel (eluting with hexane/ethyl acetate )
350:1) gave 190 mg (85%) of 4-chloro-3-ethyl-2-phenyltetra-
hydropyran (up-down-up isomer).
4-Ch lor o-3-eth yl-2-p h en yltetr a h yd r op yr a n (u p-d own -
u p) (4a ): IR(neat, cm-1): 2964, 2851, 1457, 1088, 755, 699;
1H NMR (CDCl3, 400 MHz, ppm): δ ) 7.30-7.41 (m, 5H),
4.07-4.16 (m, 3H), 3.59 (dt, J ) 3.3, 11.8 Hz, 1H), 2.17-2.32
(m, 2H), 1.96 (ddt, J ) 2.9, 4.8, 10.6 Hz, 1H), 1.60-1.69 (m,
1H), 1.18-1.30 (m, 1H), 0.73 (t, J ) 7.5 Hz, 3H); 13C NMR

746 J . Org. Chem., Vol. 66, No. 3, 2001
Yang et al.
Hz, 1H), 1.59-1.70 (m, 1H), 1.16-1.28 (m, 1H), 0.74 (t, J )
7.5 Hz, 3H); 13C NMR (CDCl3, 100 MHz, ppm): δ ) 142.1,
134.5, 129.8, 128.5, 127.5, 125.6, 82.9, 67.3, 59.9, 50.7, 37.6,
20.4, 9.0. Anal. Calcd for C13H16OCl2: C, 60.25; H, 6.22.
Found: C, 60.49; H, 6.24.
2.01-2.12 (m, 2H), 1.84-1.92 (m, 1H), 1.40-1.48 (m, 2H),
0.78-1.09 (m, 5H), 0.66 (t, J ) 7.0 Hz, 3H), 0.31-0.46 (m, 1H);
13C NMR (CDCl3, 100 MHz, ppm): δ ) 140.4, 128.1, 127.0,
125.2, 81.5, 67.7, 62.2, 47.8, 32.0, 31.7, 30.0, 22.4, 22.1, 13.9.
Anal. Calcd for C16H23OCl: C, 72.03; H, 8.69. Found: C, 72.07;
H, 8.73.
cis-3-(1-Ch lor oh exyl)-2-ph en yltetr ah ydr ofu r an (7e): IR
(neat, cm-1): 2957, 2931, 2869, 1455, 1094, 1058, 753, 702;
1H NMR (CDCl3, 400 MHz, ppm): δ ) 7.26-7.40 (m, 5H), 5.22
(d, J ) 7.3 Hz, 1H), 4.33 (dt, J ) 2.2, 8.4 Hz, 1H), 4.02 (ddd,
J ) 7.0, 8.4, 9.9 Hz, 1H), 3.30 (dt, J ) 2.9, 8.8 Hz, 1H), 2.92
(ddt, J ) 9.2, 11.0, 8.0 Hz, 1H), 2.04-2.13 (m, 1H), 1.89-2.01
(m, 1H), 1.44-1.70 (m, 3H), 1.07-1.30 (m, 5H), 0.85 (t, J )
7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz, ppm): δ ) 140.0,
128.0, 127.5, 127.2, 82.6, 68.4, 63.3, 52.2, 36.2, 31.2, 28.1, 25.5,
22.5, 14.0. Anal. Calcd for C16H23OCl: C, 72.03; H, 8.69.
Found: C, 71.99; H, 8.67.
4-Ch lor o-3-eth yl-2-(m -ch lor op h en yl)tetr a h yd r op yr a n
(u p-u p-u p ) (6c): IR (neat, cm-1): 2964, 2849, 1575, 1150,
1
1113, 1076, 767, 688; H NMR (CDCl3, 400 MHz, ppm): δ )
7.16-7.38 (m, 4H), 4.48 (s, 1H), 4.40 (dt, J ) 12.5, 4.2 Hz,
1H), 4.16 (ddd, J ) 1.5, 5.1, 6.6 Hz, 1H), 3.56 (dt, J ) 2.6,
12.1 Hz, 1H), 1.99-2.11 (m, 2H), 1.84-1.91 (m, 1H), 1.49-
1.61 (m, 1H), 1.37-1.49 (m, 1H), 0.42 (t, J ) 7.7 Hz, 3H);
13C NMR (CDCl3, 100 MHz, ppm): δ ) 142.6, 134.3, 129.4,
127.2, 125.6, 123.5, 80.6, 67.6, 61.9, 49.5, 31.8, 15.7, 15.4.
Anal. Calcd for C13H16OCl2: C, 60.25; H, 6.22. Found: C, 60.14;
H, 6.14.
cis-3-(1-Ch lor op r op yl)-2-(m -ch lor op h en yl)tetr a h yd r o-
fu r a n (7c): IR (neat, cm-1): 2969, 2878, 1574, 1204, 1071,
787, 683; 1H NMR (CDCl3, 400 MHz, ppm): δ ) 7.25-7.36
(m, 4H), 5.20 (d, J ) 7.3 Hz, 1H), 4.34 (dt, J ) 1.8, 8.8 Hz,
1H), 4.01 (ddd, J ) 6.2, 8.4, 10.3 Hz, 1H), 3.20 (dt, J ) 1.9,
9.2 Hz, 1H), 2.91 (ddt, J ) 9.5, 11.4, 7.3 Hz, 1H), 2.03-2.11
(m, 1H), 1.82-1.94 (m, 1H), 1.71-1.82 (m, 1H), 1.55-1.68 (m,
1H), 0.97 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz,
ppm): δ ) 142.4, 134.0, 129.2, 127.7, 127.4, 125.7, 82.0, 68.7,
64.2, 52.1, 29.6, 28.2, 10.2. Anal. Calcd for C13H16OCl2: C,
60.25; H, 6.22. Found: C, 60.28; H, 6.25.
4-Ch lor o-3-eth yl-2-m eth yltetr a h yd r op yr a n (u p-d own -
u p) (4f): IR (neat, cm-1): 2964, 2848, 1464, 1379, 1152, 1097,
775;1H NMR (CDCl3, 400 MHz, ppm): δ ) 3.19-4.00 (m, 2H),
3.42 (dt, J ) 2.2, 12.1 Hz, 1H), 3.30 (dq, J ) 9.5, 6.2 Hz, 1H),
2.15-2.18 (m, 1H), 2.03 (dq, J ) 4.8, 12.1 Hz, 1H), 1.73-1.85
(m, 1H), 1.44-1.64 (m, 2H), 1.26 (d, J ) 6.2 Hz, 3H), 0.88 (t,
J ) 7.7 Hz, 3H); 13C NMR (CDCl3, 100 MHz, ppm): δ ) 76.2,
66.8, 60.3, 51.5, 37.8, 20.6, 19.7, 8.9. Anal. Calcd for C8H15
OCl: C, 59.07; H, 9.29. Found: C, 59.14; H, 9.23.
-
4-Ch lor o-3-eth yl-2-m eth yltetr a h yd r op yr a n (u p-u p-u p)
(6f): IR (neat, cm-1): 2966, 2847, 1465, 1268, 1107, 1081, 765,
557;1H NMR (CDCl3, 400 MHz, ppm): δ ) 4.22 (dt, J ) 11.4,
4.4 Hz, 1H), 3.95 (ddd, J ) 2.6, 4.8, 11.7 Hz, 1H), 3.55 (dq, J
) 2.2, 6.6 Hz, 1H), 3.44 (dt, J ) 2.9, 11.0 Hz, 1H), 1.93 (ddt,
J ) 4.8, 13.2, 11.4 Hz, 1H), 1.77-1.84 (m, 1H), 1.52-1.68 (m,
3H), 1.24 (d, J ) 6.6 Hz, 3H), 1.01 (t, J ) 7.7 Hz, 3H); 13C
NMR (CDCl3, 100 MHz, ppm): δ ) 76.1, 66.1, 62.0, 48.2, 32.3,
18.7, 16.5, 15.9. Anal. Calcd for C8H15OCl: C, 59.07; H, 9.29.
Found: C, 59.25; H, 9.33.
4-Ch lor o-3-eth yl-2-p en tyltetr a h yd r op yr a n (u p-d own -
u p) (4g): IR (neat, cm-1): 2959, 2853, 1459, 1379, 1152, 1097,
775; 1H NMR (CDCl3, 400 MHz, ppm): δ ) 3.91-4.00 (m, 1H),
3.37 (dt, J ) 2.2, 12.1 Hz, 1H), 3.11-3.18 (m, 1H), 2.10-2.17
(m, 1H), 2.01 (dq, J ) 4.8, 12.1 Hz, 1H), 1.72-1.84 (m, 1H),
1.18-1.70 (m, 10H), 0.89 (t, J ) 7.0 Hz, 3H), 0.87 (t, J ) 7.7
Hz, 3H); 13C NMR (CDCl3, 100 MHz, ppm): δ ) 79.7, 66.8,
60.7, 49.4, 37.9, 33.0, 31.9, 24.9, 22.7, 20.5, 14.1, 9.0. Anal.
Calcd for C12H23OCl: C, 65.88; H, 10.60. Found: C, 65.93; H,
10.65.
4-Ch lor o-3-eth yl-2-(m -br om op h en yl)tetr a h yd r op yr a n
(u p-d own -u p) (4d ): IR (neat, cm-1): 2965, 2853, 1571, 1207,
1
1141, 1090, 777, 695; H NMR (CDCl3, 400 MHz, ppm): δ )
7.53 (s, 1H), 7.44-7.49 (m, 1H), 7.21-7.30 (m, 2H), 4.04-4.13
(m, 3H), 3.56 (dt, J ) 2.6, 12.1 Hz, 1H), 2.14-2.30 (m, 2H),
1.90 (ddt, J ) 3.3, 4.8, 10.6 Hz, 1H), 1.59-1.71 (m, 1H), 1.17-
1.28 (m, 1H), 0.74 (t, J ) 7.5 Hz, 3H); 13C NMR (CDCl3, 100
MHz, ppm): δ ) 142.3, 131.4, 130.4, 130.1, 126.1, 122.7, 82.8,
67.3, 59.8, 50.7, 37.6, 20.4, 9.0. Anal. Calcd for C13H16OClBr:
C, 51.43; H, 5.31. Found: C, 51.40; H, 5.33.
4-Ch lor o-3-eth yl-2-(m -br om op h en yl)tetr a h yd r op yr a n
(u p-u p-u p) (6d ): IR (neat, cm-1): 2964, 2852, 1568, 1153,
1
1117, 1071, 769, 703; H NMR (CDCl3, 400 MHz, ppm): δ )
7.52 (s, 1H), 7.40 (dt, J ) 7.0, 2.0 Hz, 1H), 7.18-7.25 (m, 2H),
4.48 (s, 1H), 4.39 (dt, J ) 12.1, 4.2 Hz, 1H), 4.16 (ddd, J ) 1.5,
5.1, 6.6 Hz, 1H), 3.56 (dt, J ) 2.6, 12.1 Hz, 1H), 1.99-2.15 (m,
2H), 1.84-1.91 (m, 1H), 1.49-1.61 (m, 1H), 1.36-1.49 (m, 1H),
0.43 (t, J ) 7.5 Hz, 3H); 13C NMR (CDCl3, 100 MHz, ppm): δ
) 142.8, 130.1, 129.7, 128.5, 123.9, 122.5, 80.5, 67.6, 61.8, 49.5,
31.8, 15.7, 15.4. Anal. Calcd for C13H16OClBr: C, 51.43; H,
5.31. Found: C, 51.49; H, 5.29.
4-Ch lor o-3-eth yl-2-(9-d ecen -1-yl)tetr a h yd r op yr a n (u p-
d own -u p) (4h ): IR (neat, cm-1): 2929, 2853, 1640, 1464, 1152,
1097, 991, 911, 775; 1H NMR (CDCl3, 400 MHz): δ ) 5.82 (ddt,
J ) 10.3, 16.9, 6.6 Hz, 1H), 4.96-5.03 (m, 1H), 4.93 (ddt, J )
2.2, 10.3, 1.1 Hz, 1H), 3.92-4.00 (m, 2H), 3.37 (dt, J ) 2.2,
12.1 Hz, 1H), 3.11-3.18 (m, 1H), 2.10-2.17 (m, 1H), 1.95-
cis-3-(1-Ch lor op r op yl)-2-(m -br om op h en yl)tetr a h yd r o-
fu r a n (7d ): IR (neat, cm-1): 2970, 2876, 1561, 1457, 1068,
783, 664; 1H NMR (CDCl3, 400 MHz, ppm): δ ) 7.19-7.52
(m, 4H), 5.19 (d, J ) 7.3 Hz, 1H), 4.34 (dt, J ) 1.8, 8.4 Hz,
1H), 3.81 (ddd, J ) 6.6, 8.4, 10.3 Hz, 1H), 3.20 (dt, J ) 2.9,
9.2 Hz, 1H), 2.91 (ddt, J ) 9.9, 12.7, 7.0 Hz, 1H), 2.03-2.11
(m, 1H), 1.81-1.93 (m, 1H), 1.71-1.81 (m, 1H), 1.55-1.68 (m,
1H), 0.97 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz,
ppm): δ ) 142.7, 130.7, 130.3, 129.5, 126.2, 122.3, 82.0, 68.7,
64.2, 52.1, 29.6, 28.2, 10.2. Anal. Calcd for C13H16OClBr: C,
51.43; H, 5.31. Found: C, 51.37; H, 5.27.
2.08 (m, 3H), 1.20-1.84 (m, 17H), 0.87 (t, J ) 7.3 Hz, 3H); 13
C
NMR (CDCl3, 100 MHz, ppm): δ ) 139.2, 114.1, 79.7, 66.8,
60.7, 49.4, 37.9, 33.8, 33.1, 29.7, 29.6, 29.5, 29.1, 28.9, 25.2,
20.5, 9.0. Anal. Calcd for C17H31OCl: C, 71.17; H, 10.89.
Found: C, 71.09; H, 10.84.
Tr a n s-fu sed 4-ch lor o-3-p en tyl-2-p h en ylocta h yd r oben -
zop yr a n (10a ): IR (film, cm-1): 2935, 2853, 1452, 1095, 756,
697, 532; 1H NMR (CDCl3, 400 MHz, ppm): δ ) 7.28-7.39
(m, 5H), 4.22 (d, J ) 10.3 Hz, 1H), 3.76 (t, J ) 10.8 Hz, 1H),
3.17 (dt, J ) 4.0, 10.3 Hz, 1H), 2.31-2.39 (m, 1H), 1.96-2.06
(m, 2H), 1.72-1.86 (m, 2H), 1.61-1.72 (m, 1H), 0.90-1.56 (m,
12H), 0.79 (t, J ) 7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz,
ppm): δ ) 140.3, 128.5, 128.2, 127.5, 83.7, 80.7, 68.1, 50.7,
50.6, 32.4, 32.1, 28.9, 28.2, 25.3, 24.8, 24.5, 22.3, 14.0. The
structure was confirmed by X-ray analysis.
4-Ch lor o-3-p en tyl-2-ph en yltetr a h yd r op yr a n (u p-d own -
u p) (4e): IR (neat, cm-1): 2954, 2928, 2857, 1455, 1138, 1087,
754, 698; 1H NMR (CDCl3, 400 MHz, ppm): δ ) 7.30-7.40
(m, 5H), 4.02-4.15 (m, 3H), 3.58 (dt, J ) 3.3, 11.7 Hz, 1H),
2.15-2.30 (m, 2H), 1.94 (ddt, J ) 2.6, 4.8, 10.6 Hz, 1H), 1.44-
1.55 (m, 1H), 0.95-1.25 (m, 7H), 0.79 (t, J ) 7.1 Hz, 3H); 13
C
NMR (CDCl3, 100 MHz, ppm): δ ) 140.1, 128.5, 128.3, 127.4,
84.3, 67.4, 61.3, 50.4, 37.8, 32.0, 28.0, 24.6, 22.3, 13.9; IR (neat,
cm-1): 2954, 2928, 2857, 1455, 1138, 1087, 754, 698. Anal.
Calcd for C16H23OCl: C, 72.03; H, 8.69. Found: C, 72.14; H,
8.77.
Tr a n s-fu sed
4-ch lor o-2,3-d ip en t yloct a h yd r ob en zo-
p yr a n (10b): IR (film, cm-1): 2937, 2864, 1457, 1374, 1099,
751, 611; 1H NMR (CDCl3, 400 MHz, ppm): δ ) 3.61 (t,
J ) 10.6 Hz, 1H), 3.20 (dt, J ) 2.4, 9.1 Hz, 1H), 2.93 (dt, J )
4.0, 10.1 Hz, 1H), 2.22-2.30 (m, 1H), 1.91-1.98 (m, 1H),
1.12-1.84 (m, 23H), 0.81-0.95 (m, 7H); 13C NMR (CDCl3,
100 MHz, ppm): δ ) 80.2, 79.7, 68.7, 50.7, 49.4, 33.1, 32.5,
32.4, 31.9, 29.0, 28.4, 25.3, 25.1, 24.9, 24.7, 22.7, 22.5, 14.1,
4-Ch lor o-3-p en t yl-2-p h en ylt et r a h yd r op yr a n (u p -u p -
u p) (6e): IR (neat, cm-1): 2957, 2931, 2853, 1450, 1151, 1125,
1
1084, 743, 702; H NMR (CDCl3, 400 MHz, ppm): δ ) 7.22-
7.37 (m, 5H), 4.52 (s, 1H), 4.43 (dt, J ) 12.5, 4.4 Hz, 1H), 4.18
(ddd, J ) 1.5, 5.1, 6.6 Hz, 1H), 3.59 (dt, J ) 2.6, 12.5 Hz, 1H),

Indium Trichloride Mediated Cyclizations
J . Org. Chem., Vol. 66, No. 3, 2001 747
14.1. Anal. Calcd for C19H35ClO: C, 72.46; H, 11.20. Found:
C, 72.54; H, 11.25.
63.5, 51.1, 50.7, 39.5, 32.0, 29.9, 29.5, 23.4, 22.3, 14.0. Anal.
Calcd for C16H23SCl: C, 67.94; H, 8.19. Found: C, 67.90; H,
8.22.
A Gen er a l P r oced u r e for Syn t h esis of H om oa llyl
Mer ca p ta n s.26 Diethyl azodicarboxylate (8.33 g, 40 mmol) was
added to an efficiently stirred solution of triphenyl phosphine
(10.50 g, 40 mmol) in 100 mL of tetrahydrofuran at 0 °C. The
mixture was stirred at 0 °C for 30 min. A solution of cis-3-
nonen-1-ol (2.85 g, 20 mmol) and thioacetic acid (3.04 g, 40
mmol) in 50 mL of tetrahydrofuran was added dropwise over
10 min, and the mixture was stirred for 1 h at 0 °C and 1 h at
ambient temperature. A clear yellowish solution was formed.
The solution was concentrated, and the residue was purified
by flash chromatography over silica gel (eluting with hexane/
methylene chloride ) 5:2) to gave 3.4 g (85%) of the desired
thioacetate. The thioacetate (3.02 g, 15 mmol) was then
dissolved in 25 mL of anhydrous tetrahydrofuran and added
dropwise to a suspension of lithium aluminum hydride (0.57
g, 4 equiv) in 15 mL of anhydrous ether under a nitrogen
atmosphere. The reaction mixture was stirred at ambient
temperature for 30 min, and the excess lithium aluminum
hydride was destroyed by careful addition of 10 mL of 1 N aq
HCl. The ether layer was separated and dried over magnesium
sulfate. Evaporation of the solvent gave 2.35 g (100%) of cis-
3-nonene-1-thiol (20a ) as a colorless oil, which was used
directly without further purification.
2,6-Diph en yl-4-ch lor oth iacycloh exan e (u p-u p-u p) (22a):
1
IR (cm-1, neat): 2931, 1401, 1262, 695; H NMR (CDCl3, 400
MHz, ppm): δ ) 7.24-7.39 (m, 10H), 4.12 (dd, J ) 2.4, 12.0
Hz, 2H), 4.05 (tt, J ) 4.0, 11.6 Hz, 1H), 2.68-2.76 (m, 2H),
2.30 (q, J ) 12.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz, ppm):
δ ) 140.1, 128.8, 127.9, 127.4, 58.4, 48.3, 44.6. Anal. Calcd
for C17H17SCl: C, 70.69; H, 5.93. Found: C, 70.62; H, 5.92.
4-Ch lor o-3-p en tyl-2-(p-flu or op h en yl)th ia cycloh exa n e
(u p-d own -u p) (21b): IR (neat, cm-1) 2951, 2929, 2858, 1507,
1228, 832, 797, 529; 1H NMR (CDCl3, 400 MHz, ppm): δ )
7.27-7.33 (m, 2H), 6.99-7.06 (m, 2H), 3.91 (dt, J ) 3.3, 11.4
Hz, 1H), 3.81 (d, J ) 11.0 Hz, 1H), 2.81-2.92 (m, 1H), 2.59-
2.69 (m, 2H), 2.18-2.33 (m, 2H), 1.63-1.74 (m, 1H), 0.95-
1.26 (m, 7H), 0.80 (t, J ) 7.6 Hz, 3H); 13C NMR (CDCl3, 100
MHz, ppm): δ ) 163.3, 160.9, 135.7, 135.7, 129.6, 129.5, 115.7,
115.5, 63.3, 51.2, 49.9, 39.4, 32.0, 29.9, 29.5, 23.4, 22.3, 13.9.
Anal. Calcd for C16H22SClF: C, 63.87; H, 7.37. Found: C,
63.81; H, 7.40.
4-Ch lor o-3-p en tyl-2-(p-ch lor op h en yl)th ia cycloh exa n e
(u p-d own -u p) (21c): IR (neat, cm-1): 2950, 2926, 2857, 1489,
1
1093, 1015, 815, 741; H NMR (CDCl3, 400 MHz, ppm): δ )
7.24-7.32 (m, 4H), 3.90 (dt, J ) 3.2, 11.7 Hz, 1H), 3.79 (d, J
) 11.0 Hz, 1H), 2.82-2.92 (m, 1H), 2.61-2.68 (m, 2H), 2.18-
2.33 (m, 2H), 1.64-1.75 (m, 1H), 0.97-1.24 (m, 7H), 0.80 (t, J
) 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz, ppm): δ ) 138.4,
133.4, 129.3, 128.9, 63.1, 51.0, 49.9, 39.4, 32.0, 29.9, 29.5, 23.3,
22.3, 13.9. Anal. Calcd for C16H22SCl2: C, 60.56; H, 6.99;
Found: C, 60.62; H, 6.96.
1-P h en yl-3-bu ten e-1-th iol (12): FTIR (film): 3045, 2903,
1
2574, 897, 691 cm-1; H NMR (CDCl3, 400 MHz, ppm): δ )
7.22-7.38(m, 5H), 5.67-5.79(m, 1H), 5.06-5.17 (m, 2H), 4.08
(ddd, J ) 4.8, 6.4, 7.5 Hz, 1H), 2.60-2.80 (m, 2H), 2.06 (d, J
) 4.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz, ppm): δ ) 143.9,
135.3, 128.7, 127.3, 127.1, 117.8, 44.1, 43.8. The thiol was used
directly upon preparation.
4-Ch lor o-3-p en tyl-2-(p-br om op h en yl)th ia cycloh exa n e
cis-3-Non en e-1-th iol (20a ): FTIR (film): 2989, 2940, 2553,
(u p-d own -u p) (21d ): IR (neat cm-1): 2951, 2928, 2859, 1490,
1
1
695 cm-1; H NMR (CDCl3, 400 MHz, ppm): δ ) 5.46-5.56
1073, 1010, 816, 736; H NMR (CDCl3, 400 MHz, ppm): δ )
(m, 1H), 5.30-5.40 (m, 1H), 2.55 (q, J ) 7.2 Hz, 2H), 2.30 (q,
J ) 7.1 Hz, 2H), 2.00 (q, J ) 7.2 Hz, 2H), 1.20-1.45 (m, 7H),
0.88 (t, J ) 6.8 Hz, 3H);13C NMR (CDCl3, 100 MHz, ppm): δ
) 133.3, 127.2, 36.9, 32.5, 31.4, 29.2, 24.7, 22.6, 14.1. The thiol
was used directly upon preparation.
tr a n s-3-Non en e-1-th iol (20b): FTIR (film): 2995, 2937,
2564, 679 cm-1; 1H NMR (CDCl3, 400 MHz, ppm): δ ) 5.45-
5.55 (m, 1H), 5.30-5.39 (m, 1H), 2.54 (q, J ) 7.2 Hz, 2H), 2.30
(q, J ) 7.0 Hz, 2H), 1.99 (q, J ) 7.0 Hz, 2H), 1.22-1.44 (m,
7H), 0.88 (t, J ) 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz,
ppm): δ ) 133.3, 127.2, 36.9, 32.5, 31.4, 29.1, 24.7, 22.5, 14.1.
The thiol was used directly upon preparation.
A Gen er a l P r oced u r e for th e Cycliza tion of cis- a n d
tr a n s-3-Non en e-1-th iol a n d Ald eh yd es. Indium trichloride
(265 mg, 1.2 mmol) was added to a mixture of benzaldehyde
(212 mg, 2.0 mmol) and trans-3-nonene-1-thiol (158 mg, 1.0
mmol) in 15 mL of methylene chloride which was predried with
4 Å molecular sieves overnight. After being stirred at room
temperature for 10 h (same as cis- homoallyl thiol), the mixture
was concentrated. Flash chromatography of the crude reaction
mixture over silica gel (eluting with pure hexane) gave 220
mg (yield, 75%) of 4-chloro-3-pentyl-2-phenylthiacyclohexane
as a colorless oil.
7.44-7.49 (m, 2H), 7.18-7.23 (m, 2H), 3.90 (dt, J ) 3.3, 11.3
Hz, 1H), 3.78 (d, J ) 11.0 Hz, 1H), 2.82-2.92 (m, 1H), 2.60-
2.68 (m, 2H), 2.18-2.33 (m, 2H), 1.64-1.75 (m, 1H), 0.98-
1.25 (m, 7H), 0.80 (t, J ) 7.2 Hz, 3H);13C NMR (CDCl3, 100
MHz, ppm): δ ) 139.0, 131.9, 129.7, 121.5, 63.1, 50.9, 50.0,
39.4, 32.0, 29.9, 29.5, 23.3, 22.3, 13.9. Anal. Calcd for C16H22
SClBr: C, 53.12; H, 6.13. Found: C, 53.07; H, 6.11.
-
4-Ch lor o-3-p en t yl-2-(p -et h ylp h en yl)t h ia cycloh exa n e
(u p-d own -u p) (21e): IR (neat, cm-1): 2956, 2931, 2867, 1511,
1
1456, 821, 756; H NMR (CDCl3, 400 MHz, ppm): δ ) 7.21-
7.26 (m, 2H), 7.13-7.18 (m, 2H), 3.92 (dt, J ) 3.3, 11.4 Hz,
1H), 3.80 (d, J ) 10.6 Hz, 1H), 2.82-2.92 (m, 1H), 2.60-2.69
(m, 4H), 2.22-2.34 (m, 2H), 1.63-1.73 (m, 1H), 1.24 (t, J )
7.6 Hz, 3H), 1.00-1.28 (m, 7H), 0.79 (t, J ) 7.3 Hz, 3H); 13C
NMR (CDCl3, 100 MHz, ppm): δ ) 143.7, 137.0, 128.1, 127.9,
63.6, 51.2, 50.4, 39.5, 32.0, 29.9, 29.5, 28.5, 23.4, 22.3, 15.4,
13.9. Anal. Calcd for C18H27SCl: C, 69.53; H, 8.75. Found: C,
69.58; H, 8.72.
Registr a tion n u m ber s (supplied by author): trans-3-
nonen-1-ol [10339-61-4]; cis-3-nonen-1-ol [10340-23-5]; trans-
2-(E,1-heptenyl)cyclohexanol [127128-25-0].
Ack n ow led gm en t . We are grateful to NSF
(Early CAREER Award program) for partial support
of this research. X.F.Y. thanks Tulane’s Center of
Bioenvironmental Research (DoD) for a CBR Research
Scholarship. We thank Dr. K. Maskos for help on NOE
experiments.
2,6-Dip h en yl-4-ch lor oth ia cycloh exa n e (u p-d own -u p)
1
(13a ): IR (cm-1, neat): 2931, 1490, 1451, 762, 695; H NMR
(CDCl3, 400 MHz, ppm): δ ) 7.23-7.41 (m, 10H), 4.89 (p, J )
3.6 Hz, 1H,), 4.65 (dd, J ) 3.2, 11.6 Hz, 2H), 2.38-2.54 (m,
4H); 13C NMR (CDCl3, 100 MHz, ppm): δ ) 140.6, 128.7, 127.7,
127.7, 59.6, 42.2, 41.0. Anal. Calcd for C17H17SCl: C, 70.69;
H, 5.93. Found: C, 70.77; H, 5.96.
4-Ch lor o-3-p en tyl-2-p h en ylth ia cycloh exa n e (u p-d own -
u p) (21a ): IR (neat, cm-1): 2953, 2927, 2861, 1455, 733, 692;
1H NMR (CDCl3, 400 MHz, ppm): δ ) 7.26-7.37 (m, 5H), 3.93
(dt, J ) 3.3, 11.4 Hz, 1H), 3.82 (d, J ) 11.0 Hz, 1H), 2.83-
2.93 (m, 1H), 2.62-2.70 (m, 2H), 2.24-2.35 (m, 2H), 1.65-
Su p p or tin g In for m a tion Ava ila ble: X-ray data for com-
pound 10a and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1.75 (m, 1H), 0.98-1.35 (m, 7H), 0.79 (t, J ) 7.3 Hz, 3H); 13
C
NMR (CDCl3, 100 MHz, ppm): δ ) 139.9, 128.7, 128.0, 127.8,
J O001136I