Cyclopentene Synthesis from 1,3-dienes via base-induced ring contraction of 3,6-dihydro-2H-thiopyrans: Studies on diastereoselection and mechanism

Article abstract of DOI:10.1021/jo960537o

An investigation of the scope and mechanism of a new synthesis of cyclopentenes from 3,6-dihydro-2H-thiopyrans is described. Alkyl halides substituted with an electron-withdrawing group in the α-position were reacted with sodium thiosulfate, yielding the corresponding Bunte salts, which could be transformed to reactive thiocarbonyl compounds by elimination of the elements of bisulfite with mild base treatment. In situ trapping by 1,3-dienes afforded in good yields a variety of 3,6-dihydro-2H-thiopyrans substituted with electron-withdrawing groups at the 2-position. Exposure of these cycloadducts to strong base at low temperature effected a novel ring contraction, affording 2-(methylthio)-3-cyclopentenes after quenching with methyl iodide. The level of diastereoselectivity exhibited during the generation of these cyclopentenes was found to be dependent on the nature of the electron-withdrawing group at the 2-position of the dihydrothiopyran as well as the substitution pattern originally present in the diene component. In some cases, reducing the temperature during the ring contraction resulted in the isolation of good yields of vinyl cyclopropanes of high isomeric purity. With one substrate, highly diastereoselective rearrangement of a vinyl cyclopropane to a cyclopentene was unambiguously demonstrated, suggesting that this might be a key feature of the overall ring contraction mechanism.

Full text of DOI:10.1021/jo960537o

J . Org. Chem. 1996, 61, 4725-4738
4725
Cyclop en ten e Syn th esis fr om 1,3-Dien es via Ba se-In d u ced Rin g
Con tr a ction of 3,6-Dih yd r o-2H-th iop yr a n s: Stu d ies on
Dia ster eoselection a n d Mech a n ism
Scott D. Larsen,*,† Peter V. Fisher,† Brian E. Libby,1 Randy M. J ensen,†
Stephen A. Mizsak,‡ and William Watt‡
Discovery Chemistry, and Structural, Analytical and Medicinal Chemistry, Pharmacia & Upjohn, Inc.,
Kalamazoo, Michigan 49001
Warren R. Ronk and Scott T. Hill
Department of Chemistry, Alma College, Alma, Michigan 48801
Received March 20, 1996X
An investigation of the scope and mechanism of a new synthesis of cyclopentenes from 3,6-dihydro-
2H-thiopyrans is described. Alkyl halides substituted with an electron-withdrawing group in the
R-position were reacted with sodium thiosulfate, yielding the corresponding Bunte salts, which
could be transformed to reactive thiocarbonyl compounds by elimination of the elements of bisulfite
with mild base treatment. In situ trapping by 1,3-dienes afforded in good yields a variety of 3,6-
dihydro-2H-thiopyrans substituted with electron-withdrawing groups at the 2-position. Exposure
of these cycloadducts to strong base at low temperature effected a novel ring contraction, affording
2-(methylthio)-3-cyclopentenes after quenching with methyl iodide. The level of diastereoselectivity
exhibited during the generation of these cyclopentenes was found to be dependent on the nature of
the electron-withdrawing group at the 2-position of the dihydrothiopyran as well as the substitution
pattern originally present in the diene component. In some cases, reducing the temperature during
the ring contraction resulted in the isolation of good yields of vinyl cyclopropanes of high isomeric
purity. With one substrate, highly diastereoselective rearrangement of a vinyl cyclopropane to a
cyclopentene was unambiguously demonstrated, suggesting that this might be a key feature of the
overall ring contraction mechanism.
Sch em e 1
In tr od u ction
The ubiquity with which cyclopentanoid rings are
encountered in natural products continues to foster
interest in stereoselective methods for their generation.2
One strategy which has received relatively little attention
is the transformation of 1,3-dienes to cyclopentenes.2e,3
This approach is particularly appealing, considering the
ready availability of conjugated dienes and the potential
for translating diene geometry into product stereochem-
istry in a manner analogous to the enormously successful
Diels-Alder reaction. In principle, this construction
could be achieved directly by a [4 + 1] cycloaddition of a
carbene to a 1,3-diene, ideally in a completely stereospe-
cific fashion (Scheme 1). In practice, however, the desired
outcome is typically foiled by the well-known propensity
for carbenes to add exclusively to only one of the olefins,
yielding vinyl cyclopropanes.3f Conversion to the target
Sch em e 2
cyclopentenes then requires a rearrangement step by one
of several possible means: direct thermolysis, chemical
catalysis, or anionic acceleration (Scheme 1).3,4
A number of years ago, we were intrigued by the
possibility of converting 3,6-dihydro-2H-thiopyrans, readily
available by the hetero-Diels-Alder cycloaddition of
thiocarbonyl compounds with 1,3-dienes,5 into cyclo-
pentenes (Scheme 2). The potential lability of the two
carbon-sulfur bonds within the six-membered ring sug-
gested that a net extrusion of sulfur might be feasible,
resulting in an overall ring contraction to cyclopentenes.
† Discovery Chemistry.
‡ Structural, Analytical, and Medicinal Chemistry.
X Abstract published in Advance ACS Abstracts, J une 15, 1996.
(1) Undergraduate research participant from Kalamazoo College,
Kalamazoo, MI.
(2) (a) Ramaiah, M. Synthesis 1984, 529. (b) Paquette, L. A. Top.
Curr. Chem. 1984, 119, 1. (c) Hudlicky, T.; Price, J . D. Chem. Rev.
1989, 89, 1467. (d) Ejiri, S.; Yamago, S.; Nakamura, E. J . Am. Chem.
Soc. 1992, 114, 8707 and references cited therein. (e) Padwa, A.;
Filipkowski, M. A.; Meske, M.; Murphree, S. S.; Watterson, S. H.; Ni,
Z. J . Org. Chem. 1994, 59, 588 and references cited therein.
(3) (a) Corey, E. J .; Walinsky, S. W. J . Am. Chem. Soc. 1972, 94,
8932. (b) Negishi, E.-I.; Brown, H. C. Synthesis 1974, 77. (c) Hudlicky,
T.; Kosyck, F. J .; Kutchan, T. M.; Sheth, J . P. J . Org. Chem. 1980, 45,
5020. (d) Danheiser, R. L.; Martinez-Davila, D.; Auchus, R. J .;
Kadonaga, J . T. J . Am. Chem. Soc. 1981, 103, 2443. (e) Danheiser, R.
L.; Bronson, J . J .; Okano, K. J . Am. Chem. Soc. 1985, 107, 4579. (f)
J enneskens, L. W.; de Wolf, W. H.; Bickelhaupt, F. Angew. Chem., Int.
Ed. 1985, 24, 585. (g) Xiong, H.; Rieke, R. D. J . Am. Chem. Soc. 1992,
114, 4415. (h) Shono, T.; Ishifune, M.; Kinugasa, H.; Kashimura, S. J .
Org. Chem. 1992, 57, 5561.
The inspiration to employ base to effect this transfor-
mation was provided by ample literature precedent for
(4) (a) Hudlicky, T.; Kutchan, T. M.; Naqvi, S. M. Org. React. 1985,
33, 247. (b) Kulinkovich, O. G. Russ. Chem. Rev. 1993, 62, 839.
(5) (a) Weinreb, S. M.; Staib, R. R. Tetrahedron 1982, 38, 3087. (b)
Metzner, P. Synthesis 1992, 1185. (c) Bryce, M. R.; Becher, J .; Falt-
Hansen, B. In Advances in Heterocyclic Chemistry; Academic Press:
New York, 1992; Vol. 55, p 1.
S0022-3263(96)00537-3 CCC: $12.00 © 1996 American Chemical Society

4726 J . Org. Chem., Vol. 61, No. 14, 1996
Larsen et al.
Sch em e 3
Sch em e 4
the contraction of six-membered heterocycles to five-
membered heterocycles under various basic conditions.6
Two examples are illustrated in eqs 16b and 2.6d Presum-
ably these reactions entail initial allylic proton abstrac-
tion from the carbon adjacent to one of the heteroatoms
with concomitant E2 elimination of the other heteroatom,
thereby cleaving the heteroatom-heteroatom bond. The
resulting carbon-heteroatom double bond is then at-
tacked intramolecularly by the eliminated heteroatom,
giving rise to the observed products.
systematic investigation of the diastereoselectivity of the
rearrangement was undertaken, in particular its depen-
dence on the steric and electronic nature of the C-2
substitution. In addition, we describe experiments de-
signed to provide insight into the mechanism of this
interesting ring contraction.
Resu lts a n d Discu ssion
Syn t h esis of 3,6-Dih yd r o-2H -t h iop yr a n s. The
preparation of dihydrothiopyrans with varying substitu-
tion at C-2 was primarily achieved via hetero-Diels-
Alder reaction of various thiocarbonyls with 2,3-dimeth-
ylbutadiene. This particular diene was chosen for its
relatively high level of reactivity and the fact that the
corresponding cycloadducts would lack chirality at C-3,
greatly facilitating the determination of diastereomer
ratios of the final cyclopentenes.
Thiocarbonyl generation and hetero-Diels-Alder reac-
tion were effected by a modification of the Kirby protocol8
which we had employed in our earlier work.7 Various
halides 4 were reacted with sodium thiosulfate in aque-
ous ethanol until conversion to the corresponding Bunte
salts 5 was complete, as indicated by TLC analysis
(Scheme 4). No attempt was made to isolate the indi-
vidual Bunte salts. Rather, the crude reaction mixtures
were simply diluted with diene and then subjected to slow
addition of triethylamine, resulting in smooth thioketone
6 production and subsequent cycloaddition to afford 3,6-
dihydro-2H-thiopyrans 7.9,10 Results are summarized in
Table 1. The unoptimized yields varied quite dramati-
cally depending on the halide substrate employed, but
any dearth in efficiency was compensated for by the ease
with which each reaction could be performed on multi-
gram scale.
It seemed plausible that a similar outcome might be
expected upon exposure of 3,6-dihydro-2H-thiopyrans to
strong base, provided that the 2-position was fully
substituted to block deprotonation at that site, and at
least one of the 2-substituents was a suitable carbanion-
stabilizing group. In fact, as reported by us in an earlier
communication,7 this approach was successfully applied
to a series of diethyl 3,6-dihydro-2H-thiopyran-2,2-dicar-
boxylates, affording diethyl 2-(methylthio)-3-cyclopen-
tene-1,1-dicarboxylates in excellent yields and with good
diastereoselectivity following quenching with methyl
iodide. A representative example is presented in Scheme
3, wherein 2-methyl-1,3-pentadiene (1) is converted in a
stereoselective fashion to the cis-cyclopentene 3 (16:1 cis:
trans) via the dihydrothiopyran 2.7 This was, to the best
of our knowledge, the first reported example of this type
of ring contraction to involve the apparent intermediacy
of a carbanion.
In some cases this procedure failed to give useful
amounts of the desired cycloadducts (entries 2, 13), so
alternative preparations had to be devised. Carboxamide
7m was prepared from ester 7a by sequential saponifica-
tion, acid chloride formation, and addition of dimethyl-
The following report details studies aimed at expand-
ing the scope of this methodology by the utilization of
alternate potential carbanion-stabilizing groups at C-2
of the 3,6-dihydro-2H-thiopyran cycloadducts. In those
cases where C-2 was unsymmetrically substituted, a
(8) (a) Kirby, G. W.; Lochead, A. W. J . Chem. Soc., Chem. Commun.
1983, 1325. (b) Kirby, G. W.; Lochead, A. W.; Sheldrake, G. N. J . Chem.
Soc., Chem. Commun. 1984, 922, 1469. (c) Kirby, G. W.; McGregor,
W. M. J . Chem. Soc., Perkin Trans. 1 1990, 3175.
(9) For closely related thioketone generations and [4 + 2] cycload-
ditions see: (a) Abelman, M. M. Tetrahedron Lett. 1991, 32, 7389. (b)
Pinto, I. L.; Buckle, D. R.; Rami, H. K.; Smith, D. G. Tetrahedron Lett.
1992, 33, 7597. (c) Capozzi, G.; Menichetti, S.; Nativi, C.; Rosi, A.
Tetrahedron 1992, 48, 9023.
(6) (a) Firl, J .; Kresze, G. Chem. Ber. 1966, 99, 3695. (b) Kayama,
Y.; Oda, M.; Kitahara, Y. Chem. Lett. 1974, 345. (c) Consonni, P.;
Favara, D.; Omodei-Sale, A.; Bartolini, G.; Ricci, A. J . Chem. Soc.,
Perkin Trans.
2 1983, 967. (d) Forrest, A. K.; Schmidt, R. R.
Tetrahedron Lett. 1984, 25, 1769. (e) J ager, U.; Sundermeyer, W. Chem.
Ber. 1986, 119, 3405. (f) Bell, S. I.; Parvez, M.; Weinreb, S. M. J . Org.
Chem. 1991, 56, 373. (g) Desai, M. C.; Doty, J . L.; Stephens, L. M.;
Brighty, K. E. Tetrahedron Lett. 1993, 34, 961.
(10) There are now numerous methods to generate thiocarbonyl
compounds. For a recent review see: McGregor, W. M.; Sherrington,
D. C. Chem. Soc. Rev. 1993, 22, 199.
(7) Larsen, S. D. J . Am. Chem. Soc. 1988, 110, 5932.

Cyclopentene Synthesis from 1,3-Dienes
J . Org. Chem., Vol. 61, No. 14, 1996 4727
Ta ble 1. Syn th esis of Dih yd r oth iop yr a n s 7 (Sch em e 4)
Sch em e 5
reactant
product
yield (%)
entry
G1
CO2Et
G2
X
no.
1
2
CH3
i-Pr
CH3
Ph
Br
Br
Br
Br
Br
Br
Cl
Br
Br
Cl
Br
Br
Br
7a
7b
7c
7d
7e
7f
7g
7h
7i
75
15
48
86
63
30
35
68
12
77
50
66
0
CO2Et
ficient. Diastereomer assignments were made based on
one of the following criteria: (1) single crystal x-ray
analysis; (2) NOE analysis; or (3) analogy of the proton
spectrum with one or more of the compounds assigned
by X-ray or NOE.13 A key distinguishing feature of the
proton NMR spectra of these cyclopentenes is the chemi-
cal shift of the C-2 methine proton adjacent to the
methylthio group. In the major diastereomer 11 this
proton consistently appears 0.5-0.8 ppm downfield from
the corresponding methine proton within the minor
isomer 12. This is likely a manifestation of the “syn-
upfield rule” whereby protons syn to a vicinal substituent
are shielded relative to the corresponding anti protons.14
This effect has been noted to be particularly large when
the vicinal substituent is methyl, and an opposite effect
has been noted with vicinal carboxyl groups. It is thus
entirely consistent that diastereomer 12, in which the
methine proton is syn to the methyl group and anti to
the carboxyl group, should be characterized by the
substantially upfield signal of its methine proton.
3
4
5
6
CO2t-Bu
CO2Et
-CO2CH2CH2-
PhCO
p-F-PhCO
p-CF3-PhCO
p-MeO-PhCO
PhCO
CH3
CH3
CH3
CH3
Ph
7
8a
9a
10
11
12
13
7j
7k
7l
CN
CH3
9-fluorenylidene
CONMe2 CH3
7m
a
Bromide prepared as in ref 21.
amine (Scheme 5). The hindered ester 7b was most
efficiently obtained by direct alkylation11 of the known
cycloadduct 9 with isopropyl iodide (eq 3).
The influence (or lack thereof) of the steric and
electronic attributes of groups G1 and G2 on the stereo-
chemical outcome of the rearrangement is evident from
the results summarized in the Table. Entries 1-3
illustrate that the steric nature alone of either the alkyl
group or the ester group at C-2 of the dihydrothiopyran
had little effect on the product diastereomer ratio.
However, replacing the C-2 alkyl group with either a
phenyl group or a methylthio group drastically reduced
the diastereoselectivity of the rearrangement, although
the major isomers in each case retained the same relative
stereochemistry (entries 4 and 5). Surprisingly, replace-
ment of the methyl group of 7f with a phenyl group (7j,
entry 12) effected a large increase in diastereoselectivity
and in the opposite direction. In this case, 12j was the
A small set of dihydrothiopyrans derived from other
dienes was also created in order to evaluate the effect of
diene substitution on the diastereoselectivity of the final
ring contraction (Table 2). In each of these cases, ethyl
2-bromopropionate was employed as the thiocarbonyl
precursor, yielding the corresponding ethyl 2-methyl-3,6-
dihydro-2H-thiopyran-2-carboxylates 10. Disappoint-
ingly, the level of regioselectivity in these hetero-Diels-
Alder reactions was less than what we had observed with
diethyl thioxomalonate.7 Furthermore, cycloaddition of
2-methyl-1,3-pentadiene (entry 4) proceeded without
significant endo selectivity, giving the major product 10f
as a 1:1 mixture of diastereomers. This was not of
immediate concern, however, since it was anticipated
that stereochemical integrity at C-2 would be lost in the
ensuing rearrangement anyway.
Ba se-in d u ced Rin g Con tr a ction s of 3,6-Dih yd r o-
2H-th iop yr a n s to Cyclop en ten es. In our previous
communication we described the ring contraction of
dihydrothiopyran 7a .7 Exposure of 7a to lithium diiso-
propylamide (LDA)/hexamethylphosphoramide (HMPA)12
in THF at -78 °C followed by warming to 0 °C and
quenching with methyl iodide afforded cyclopentenes 11a
and 12a in 87% yield as an 8:1 mixture of diastereomers,
respectively (Table 3, entry 1). The above protocol was
used effectively in most of the examples illustrated in
Table 3. In some cases, the alternate base, potassium
bis(trimethylsilyl)amide (KBA), proved to be more ef-
only product detected in the crude reaction mixture.13
A
significant amplification of the diastereoselectivity was
also observed with the rigid spirolactone 7e (entry 6),
which rearranged almost exclusively to trans-spirolactone
11e. Entries 8-11 summarize experiments designed to
examine what impact the electron-withdrawing ability
of G1 might have independent of steric factors. In these
cases, it was necessary to employ KBA as base to achieve
uniformly good yields. Although this resulted in signifi-
cant erosion of the diastereoselectivity in the rearrange-
ment of dihydrothiopyran 7f (entry 7 vs 8), it was
nevertheless sufficient to illustrate the complete lack of
(13) ORTEP diagrams for structures 12j, 12m , and 21 and NOE
analyses of structures 11a , 11d , 12d , 12f, 13b, 13c, 14b, 14c, 18m ,
19, and 20 are provided in the supporting information. The full X-ray
data will also be included in a separate manuscript: Watt, W.; Fisher,
P. V.; Larsen, S. D. Acta Cryst. Sect. B 1996, submitted for publication.
The author has deposited atomic coordinates for these structures with
the Cambridge Crystallographic Data Centre. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
(11) Kirby, G. W.; Mahajan, M. P.; Rahman, M. S. J . Chem. Soc.,
Perkin Trans. 1 1991, 2033.
(12) HMPA is now considered to be a highly dangerous carcinogen!
We have recently observed that N,N′-dimethyl-N,N′-propyleneurea
(DMPU) may be substituted for HMPA in several of the reactions
described herein with little or no loss of stereoselectivity. Mukho-
padhyay, T.; Seebach, D. Helv. Chim. Acta 1982, 65, 385.
(14) Anteunis, M.; Danneels, D. Org. Magn. Reson. 1975, 7, 345.

4728 J . Org. Chem., Vol. 61, No. 14, 1996
Ta ble 2. Syn th esis of Dih yd r oth iop yr a n s 10
Larsen et al.
Ta ble 3. Rin g Con tr a ction of Dih yd r oth iop yr a n s 7
entry in Table 3 indicates that the scope of this meth-
odology could not be expanded to include the use of
nitriles as the carbanion-stabilizing group.
Table 4 summarizes the disappointing results obtained
upon rearrangement of the variously substituted ethyl
2-methyl-3,6-dihydro-2H-thiopyran-2-carboxylates 10 from
Table 2. The totally unsubstituted dihydrothiopyran 10a
(entry 1) underwent ring contraction in a less diastereo-
selective fashion than did the corresponding 4,5-dimethyl
analog 7a (Table 3). Also, introduction of two methyl
groups at C-3 of the dihydrothiopyran (10d , entry 3)
completely abolished the diastereoselectivity of the ring
contraction. The results within entry 2 are intriguing
and may provide insight into the mechanism of the
rearrangement. When the inseparable mixture of iso-
prene cycloadducts 10b and 10c was subjected to base,
the individual regioisomers underwent ring contraction
with differing levels of diastereoselectivity. The 4-methyl
isomer 10c was clearly more selective in its transforma-
tion to the trans cyclopentene diastereomer than was the
5-methyl isomer 10b.15 The 3,5-dimethyl isomer 10f was
completely nonselective during the ring contraction,
affording a nearly statistical mixture of all four possible
diastereomeric cyclopentenes 13f (entry 4). This last
product(s)
reactant
G1
CO2Et
7b CO2Et
7c CO2t-Bu
condi-
yield
ratiob (%)
entry no.
G2 tionsa
no.
1
2
7a
CH3
i-Pr
CH3
Ph
A
A
A
A
A
A
A
B
B
B
B
A
A
11a /12a 8:1
11b/12b 8.5:1
87
84
95
93
61
3
4
5
6
7
8
9
10
11
12
13
11c/12c
8:1
7d CO2Et
11d /12d 2:1
11w /12w 2:1
7w c CO2Et
SMe
7e
7f
7f
-CO2CH2CH2-
PhCO
PhCO
11e
>15:1 71
CH3
CH3
CH3
11f/12f
11f/12f
10:1
63
75
69
72
83
2.5:1
7g p-F-PhCO
7h p-CF3-PhCO CH3
11g/12g 2.5:1
11h /12h 2.5:1
7i
7j
p-MeO-PhCO CH3
PhCO
11i/12i
2.5:1
Ph
CH3
12j
<1:20 93
7k CN
0
a
Condition A: LDA/HMPA, -78 °C f 0 °C; B: KBA/18-crown-
6, -78 °C f 0 °C. Ratio of 11:12 determined by 1H NMR
integration of signals in crude product mixtures. c Prepared as in
reference 20.
b
(15) Regioisomer assignments for the mixture of isomers were made
based on NOE analysis (see supporting information). Diastereomer
assignments were made based on the relative chemical shifts of the
C-2 methine protons (vide supra).
effect which the para substituent on the aromatic ring
had on the outcome of the rearrangement. The final

Cyclopentene Synthesis from 1,3-Dienes
J . Org. Chem., Vol. 61, No. 14, 1996 4729
Ta ble 4. Rin g Con tr a ction a of Dih yd r oth iop yr a n s 10
result was particularly disappointing in light of the high
degree of diastereoselectivity observed previously during
the rearrangement of the related dihydrothiopyran ma-
lonate 2 (Scheme 3).
Ba se-in d u ced Rin g Con tr a ction s of 3,6-Dih yd r o-
2H-th iop yr a n s to Vin yl Cyclop r op a n es. In 1970,
Biellmann first reported the rearrangement of 4,5-
dimethyl-2,2-diphenyl-3,6-dihydro-2H-thiopyran (15) to
vinyl cyclopropane 16 following deprotonation with n-
butyllithium at low temperature and subsequent quench-
ing with methyl iodide (eq 4).16
cyclopentene 17, suggesting that no equilibration of vinyl
cyclopropane to five-membered ring was occurring. A
dramatically different result was seen with the closely-
related fluorenyl dihydrothiopyran 7l17 (eq 6), which
rearranged entirely to cyclopentene 11l under our condi-
tions at or below 0 °C. It is tempting to speculate that
the greater carbanion-stabilizing ability of the fluorenyl
substitution at C-2 of 7l relative to the simple diphenyl
substitution of 15 was responsible for the complete
conversion to five-membered ring product.
Three-membered ring product was also observed when
the base-induced rearrangement of ester 7a was carried
out without warming above -45 °C, whereupon vinyl
cyclopropane 18a was the major product along with a 3:1
mixture of cyclopentenes 11a and 12a (Table 5, entry 1).7
Under otherwise identical conditions, warming to 0 °C
prior to the methyl iodide quench gave exclusively an 8:1
mixture of cyclopentenes 11a and 12a (entry 2), suggest-
ing that here a vinyl cyclopropane might be an interme-
diate in the formation of the cyclopentenes. Of particular
interest was the observation that the mixture of diaster-
eomeric cyclopentenes became enriched in the proportion
of 11a (from 3:1 to 8:1) when the reaction was warmed
until no more cyclopropane was obtained. A shift to
cyclopentene products with enhanced diastereoselectivity
upon warming was also noted with the dihydrothiopyran
When we subjected Biellmann’s substrate 15 to our
LDA/HMPA protocol, we obtained a mixture of three- and
five-membered rings, 16 and 17 (eq 5). Rather surpris-
ingly, allowing our reaction to stir for prolonged periods
at room temperature did not increase the proportion of
(16) (a) Biellmann, J . F.; Ducep, J . B. Tetrahedron Lett. 1970, 2899.
(b) Biellmann, J . F.; Ducep, J . B.; Vicens, J . J . Tetrahedron 1976, 32,
1801. For related work see: (c) Reglier, M.; J ulia, S. A. Tetrahedron
Lett. 1983, 24, 2387. (d) Reglier, M.; J ulia, S. A. Tetrahedron Lett. 1985,
26, 2319.
(17) Middleton, W. J . J . Org. Chem. 1965, 30, 1390.

4730 J . Org. Chem., Vol. 61, No. 14, 1996
Larsen et al.
Ta ble 5. Con ver sion of Dih yd r oth iop yr a n s 7 to
Cyclop r op a n es 18 or Cyclop en ten es 11 a n d 12
Sch em e 6
product(s)
reactant
yield
ratio (%)
entry
G1
no.
conditionsa
nos.
1
2
3
4
CO2Et
CO2Et
7a -45 °C, 10 min 18a /11a /12a
7/3/1
0/8/1
64
87
7a 0 °C, 30 min 18a /11a /12a
CONMe2 7m 0 °C, 30 min
CONMe2 7m 25 °C, 24 h
18m /11m /12m 12/1/3 81
18m /11m /12m 1/14/3 88
we designed an experiment to prove that the rearrange-
ment in question was plausible. When the low temper-
a
Reaction conditions prior to MeI quench.
carboxamide 7m (Table 5, entries 3 and 4). It is very
interesting to note here that the vinyl cyclopropanes 18
in each case were isolated as a single diastereomer and
olefin isomer.13
ature rearrangement protocol was carried out on dihy-
drothiopyran ester 7a followed by quenching with benzoyl
chloride instead of methyl iodide, benzoate 21 was
isolated in 80% yield as a single isomer (Scheme 6). The
relative configuration was unambiguously established by
single crystal X-ray analysis.13 It was anticipated that
exposure of 21 to lithium dialkylamide base under
conditions approximating that of the standard rearrange-
ment protocol would result in cleavage of the thioester
and subsequent release of lithio vinyl cyclopropane 22.
In the event, lithium diethylamide/HMPA addition at
-78 °C followed by warming to 0 °C and quenching with
methyl iodide provided cyclopentene 11a in good yield
and with excellent diastereoselectivity (Scheme 6). The
high isomeric purity of the cyclopentene product obtained
in this experiment is consistent with the isomeric enrich-
ment seen in the previous experiments (Table 5) following
the disappearance of vinyl cyclopropane.
One of the entries in Table 3 which displayed poor
diastereoselectivity (entry 4) was examined further to
determine if vinyl cyclopropane intermediate(s) could be
identified. The temperature at which methyl iodide
quenching was performed was steadily reduced until
starting material began to be recovered (at -78 °C). At
no point was vinyl cyclopropane ever detected, and the
product cyclopentene was isolated as an unchanging 2:1
mixture of diastereomers, suggesting that this particular
example might not proceed via a vinyl cyclopropane,
perhaps accounting for the poor diastereoselectivity.
The evidence that vinyl cyclopropanes were equilibrat-
ing to cyclopentenes raised the question of whether the
product cyclopentenes themselves might be capable of
equilibrating, resulting in thermodynamic diastereomeric
mixtures rather than kinetic ones. To address this
question, mercaptans 23 and 24 were prepared by
It is clear from the data presented in Table 5 that the
rate at which the apparent vinyl cyclopropane to cyclo-
pentene rearrangement occurs is dependent on the
nature of the electron-withdrawing group G1. Carbox-
amide 7m afforded almost exclusively vinyl cyclopropane
products under the same conditions (0 °C, 30 min) that
ester 7a was converted entirely to cyclopentenes (entries
2 and 3). Complete conversion of carboxamide 7m to
cyclopentenes required 24 h at 25 °C! We have also
observed that the degree of methyl substitution on the
dihydrothiopyran affects this rate. The simple dihy-
drothiopyran 10a , bearing no methyl groups on the olefin,
rearranged only to vinyl cyclopropanes 19 and 20 when
the temperature was maintained at 0 °C (eq 7). The
closely related 4,5-dimethyldihydrothiopyran 7a , as men-
tioned above, gave entirely cyclopentenes under these
conditions. Warming 10a to 25 °C was required for
complete conversion to cyclopentenes (Table 4, entry 1),
suggesting that methyl substitution somehow facilitates
this vinyl cyclopropane to cyclopentene rearrangement.
Mech a n istic Stu d ies. The results in Table 5 strongly
suggested that the major diastereomeric cyclopentenes
were arising largely via the stereoselective rearrange-
ment of vinyl cyclopropanes. To support this mechanism,

Cyclopentene Synthesis from 1,3-Dienes
J . Org. Chem., Vol. 61, No. 14, 1996 4731
Sch em e 7
Sch em e 8
groups at C-2 (eq 8). Subjecting 29 to our standard
conditions resulted only in recovery of unchanged start-
ing material, suggesting that a concerted E2-like elimi-
nation of a carbanionic C-2 center might be a required
first step in the rearrangement process.
Unfortunately, it is simply not possible to propose a
mechanism for this novel base-induced rearrangement
of 3,6-dihydro-2H-thiopyrans to vinyl cyclopropanes and
cyclopentenes which accounts for all of the observations
of this study. The data accumulated to this point,
however, support a process which entails the following:
(1) generation of an intermediate carbanion at C-2 of the
dihydrothiopyran; (2) formation of a vinyl cyclopropane
intermediate with at least some of the substrates; and
(3) the rearrangement of a vinyl cyclopropane to a
cyclopentene at low temperature. One plausible se-
quence is presented in Scheme 9 for the rearrangement
of dihydrothiopyran 7a since most of our data was
gathered for this particular substrate. Proton abstraction
at C-6 could be accompanied by rapid E2-elimination of
a stabilized carbanion, cleaving the C-2-sulfur bond and
forming a reactive thioaldehyde. This unstable inter-
mediate would be expected to undergo a rapid intramo-
lecular thioaldol condensation via either 1,2 or 1,4-
addition of the incipient enolate to the thioaldehyde. To
account for the formation of benzoate 21 (Scheme 6), the
enolate would have to attack the thioaldehyde by a 1,4-
addition via the conformer 30, in which the unsaturated
thioaldehyde remains in conjugation with the olefin in
the cisoid conformation. Direct 1,2-addition to give
cyclopentenes 32 would also be possible, particularly after
rotation of the thiocarbonyl out of planarity with the
olefin. The high degree of diastereoselectivity observed
in the conversion of 21 to 11a (Scheme 6) suggests a
concerted anionic-accelerated [1,3]sigmatropic rearrange-
ment of vinyl cyclopropane 31 to cyclopentene 32a .
Although the stereochemical outcome is opposite to what
one would expect from a thermally allowed rearrange-
ment,19 anion-accelerated vinylcyclopropane rearrange-
quenching the rearrangement of 7a with ammonium
chloride (Scheme 7). Resubmitting either a 4:1 mixture
of 23:24 or pure 23 to the rearrangement conditions
followed by quenching with methyl iodide gave, respec-
tively, a 4:1 mixture of methylthio cyclopentenes 11a :
12a or only 11a , establishing that equilibration of the
intermediate lithio mercaptides 25 by a retro aldol-like
process was not occurring.
One other key mechanistic question was addressed in
this study. It had been assumed that the initial event
following deprotonation of the dihydrothiopyrans R to the
sulfur was an E2-like elimination of a stabilized carban-
ion, evidence for which would be the loss of stereochem-
ical integrity at the C-2 carbon. To establish that this
was occurring, dihydrothiopyran 9 was condensed with
acetaldehyde under standard aldol conditions to afford
a 1:1 mixture of alcohols 26 (Scheme 8). Separation of
the alcohols by flash chromatography followed by protec-
tion of the hydroxyl with TMSCl provided a single
diastereomeric silyl ether 27. If the relative stereochem-
istry between the two chiral centers of 27 were preserved
during the ensuing base-induced rearrangement, only
two possible diastereomeric cyclopentenes could be formed.
In the event, subjecting 27 to the standard rearrange-
ment conditions afforded cyclopentene 28 as a mixture
of all four possible diastereomers, indicating that the ring
contraction proceeded at least in part with stereochemical
scrambling at C-2 of the dihydrothiopyran, thereby
providing evidence for intermediate carbanion formation
at that carbon.
One final piece of evidence supporting the necessity
for generating a carbanion at C-2 of the dihydrothiopyran
was provided by an attempted rearrangement of dihy-
drothiopyran 29,18 which lacks any carbanion-stabilizing
(20) Vedejs, E.; Arnost, M. J .; Dolphin, J . M.; Eustache, J . J . Org.
Chem. 1980, 45, 2601.
(21) Prepared by the method of Kajigaeshi, S.; Kakinami, T.;
Okamoto, T.; Fujiisaki, S. Bull. Chem. Soc. 1987, 60, 1159. We found
chloroform to be superior to the reported solvent, dichloromethane,
for these preparations.
(18) Degl’Innocenti, A.; Capperucci, A.; Mordini, A.; Reginato, G.;
Ricci, A.; Cerreta, F. Tetrahedron Lett. 1993, 34, 873.
(19) Baldwin, J . E.; Bonacorsi, S., J r. J . Org. Chem. 1994, 59, 7401.

4732 J . Org. Chem., Vol. 61, No. 14, 1996
Larsen et al.
Sch em e 9
base in the ensuing step.7 Secondly, the degree of
diastereoselectivity in the ring contraction with dihy-
drothiopyrans bearing unsymmetrical substitution at C-2
is substrate-dependent, particularly with regard to the
alkyl substitution pattern present in the original diene
component. This is in contrast to the malonate sub-
strates bearing symmetrical substitution at C-2 (e.g. 2),
which rearrange with a high degree of diastereoselectiv-
ity.7
With some dihydrothiopyran substrates, reducing the
temperature of the base-induced ring contraction resulted
in the isolation of vinyl cyclopropanes of high isomeric
purity and in good yields, suggesting that vinyl cyclo-
propanes might be intermediates in the formation of
cyclopentenes. With one substrate (7a ), we demonstrated
unambiguously that such a rearrangement is possible
and proceeds with high diastereoselectivity.
The synthetic utility of the cyclopentenes generated
during the course of this work remains to be explored,
as does the obvious potential for this methodology to be
developed into a diastereoselective synthesis of cyclopro-
panes from 1,3-dienes. Research toward these ends is
ongoing and will be reported in due course.
Exp er im en ta l Section
Melting points were determined on a capillary apparatus
and are uncorrected. 1H NMR spectra were recorded at 300
MHz in CDCl3 with TMS as internal standard unless otherwise
noted and are reported as ppm. 13C NMR spectra were
recorded at 75 MHz in the same solvent. IR spectra were
recorded either as neat liquids (film) or as mineral oil mulls
(mull). Electron impact (EI) mass spectra were obtained with
an ionization voltage of 70 eV. Data are reported in the form
m/z (relative intensity). In some cases, high resolution mass
spectral (HRMS) data are reported for the m/ z of the parent
ion, using EI or fast atom bombardment (FAB). All moisture-
sensitive reactions were conducted under a nitrogen atmo-
sphere in oven- or flame-dried glassware. Unless specified,
all commercially available solvents and reagents were used
without further purification. THF was Aldrich “anhydrous”,
packaged in Sure-Seal bottles. Solvent removal was by rotary
evaporator operating at house vacuum (20-40 Torr). Flash
chromatography was accomplished with EM Science silica
(230-400 mesh ASTM).
2H-Th iop yr a n -2,2-d ica r boxylic Acid , 3,6-Dih yd r o-3,5-
d im eth yl-, Dieth yl Ester (2). A mixture of diethyl chloro-
malonate (11.3 mL, 70 mmol) and sodium thiosulfate pen-
tahydrate (21.7 g, 87.5 mmol) in absolute ethanol (70 mL) was
stirred at 48 °C for 19 h. The yellow mixture was diluted with
toluene (140 mL) before the addition of calcium chloride
dihydrate (15.4 g, 105 mmol) and trans-2-methyl-1,3-penta-
diene (4.93 g, 60.0 mmol). While stirring at room temp, a
solution of triethylamine (9.8 mL, 70 mmol) in toluene (35 mL)
was added via syringe pump at a rate of 8.4 mL/h. The thick
mixture was stirred an additional 1.5 h following addition. The
mixture was diluted with ether (200 mL) and washed with
saturated aqueous NaHCO3. The organic phase was dried over
magnesium sulfate and concentrated in vacuo, leaving a pale
yellow oil (19.7 g). NMR analysis indicated a 12:1 mixture of
regioisomers had been formed with 2 as the major isomer.
Flash chromatography (20% ether/hexane) provided pure 2
along with its minor regioisomer (15.47 g, 94%) as a colorless
oil which solidified on standing. Regioisomerically pure 2
could be obtained by recrystallization from hexane (colorless
prisms, mp 46-48 °C). 1H NMR 5.50 (m, 1 H), 4.25 (m, 4 H),
3.07, 2.78 (ABq, J ) 17 Hz, 2 H), 3.00 (m, 1 H), 1.72 (bs, 3 H),
1.28 (t, J ) 7 Hz, 3 H), 1.26 (t, J ) 7 Hz, 3 H), 1.06 (d, J ) 7
Hz, 3 H); IR (film) 1733, 1247, 1207, 1044 cm-1; EI MS 272
(M+, 60), 183 (91), 125 (100). Anal. Calcd for C13H20O4S: C,
57.33; H, 7.40; S, 11.77. Found: C, 57.04; H, 7.27; S, 11.73.
3-Cyclop en ten e-1,1-d ica r boxylic Acid , 3,5-Dim eth yl-2-
(m eth ylth io)-, Dieth yl Ester (3). A solution of 2 (5.00 g,
ments have previously been reported that occur by “non-
allowed” pathways.3d
The results presented in Table 5 imply that following
the formation of 30 there is competitive 1,4 and 1,2-
addition to the thioaldehyde, the former being highly
diastereoselective and the latter much less so. The
initially formed mixture of cyclopentenes 32, formed by
relatively nonselective 1,2-addition, is then enriched in
the major diastereomer as the reaction is warmed and
31 rearranges diastereoselectively to 32a . An obvious
question is: why should the 1,4-addition to form vinyl
cyclopropane be so much more diastereoselective than the
direct 1,2-addition? At this point, we can only speculate
that 1,4-addition is more sterically demanding due to the
requirement that the thioaldehyde be planar (conjugated)
with the olefin. 1,2-Addition, on the other hand, can
occur to the thioaldehyde even after it has rotated out of
plane with the olefin.
Con clu sion s
With this work, we have established a general synthe-
sis of usefully functionalized cyclopentenes from 1,3-
dienes and alkyl halides bearing at least one carbanion-
stabilizing group bound to the same carbon as the
halogen. The two-step protocol proceeds in most cases
in overall good to excellent yields and is readily executed
on a multigram scale. We have delineated two limita-
tions to the scope. First, the regioselectivity of the initial
hetero Diels-Alder reaction is not impressive; however,
this does not present a liability when the minor regioi-
someric cycloadduct possesses substitution at C-6 (e.g.
10g in Table 2), since this prevents reaction with strong

Cyclopentene Synthesis from 1,3-Dienes
J . Org. Chem., Vol. 61, No. 14, 1996 4733
18.4 mmol) in THF (95 mL) was cooled to -64 °C before the
addition via syringe drive (2.5 mL/min) of a solution of KBA
(0.5 M in toluene, 62 mL, 31 mmol). The pale yellow solution
was stirred at -64 °C for 7 h before the addition of methyl
iodide (5.7 mL, 92 mmol). Stirring was continued for 1 h before
the solution was allowed to warm to room temp. The reaction
was then diluted with ether (250 mL) and washed successively
with saturated aqueous NaHCO3 and water. The organic layer
was dried over magnesium sulfate and concentrated in vacuo,
leaving a yellow oil (6.3 g). NMR analysis indicated that a
16:1 mixture of diastereomers had been formed. Flash chro-
matography (17% ether/hexane) provided pure 3, still as a
mixture of diastereomers, as a colorless oil (3.91 g, 74%). 1H
NMR Major diastereomer: 5.24 (bs, 1 H), 4.22 (m, 4 H), 4.09
(bs, 1 H), 3.16 (m, 1 H), 2.22 (s, 3 H), 1.82 (bs, 3 H), 1.29 (t, J
) 7 Hz, 3 H), 1.27 (t, J ) 7 Hz, 3 H), 1.26 (d, J ) 6 Hz, 3 H);
minor diastereomer: 5.22 (bs, 1 H), 4.1-4.4 (m, 4 H), 4.05 (bs,
1 H), 3.57 (m, 1 H), 1.90 (s, 3 H), 1.80 (bs, 3 H), 1.29 (t, J ) 7
Hz, 3 H), 1.25 (t, J ) 7 Hz, 3 H), 1.02 (d, J ) 7 Hz, 3 H);
remaining data is for the mixture: IR (film) 1732, 1253, 1214,
1205 cm-1; EI MS 286 (M+, 100), 225 (90), 165 (86). Anal.
Calcd for C14H22O4S: C, 58.72; H, 7.74. Found: C, 59.08; H,
7.94.
2H-Th iop yr a n -2-ca r boxylic Acid , 3,6-Dih yd r o-2,4,5-tr i-
m eth yl-, Eth yl Ester (7a ). Gen er a l P r oced u r e. A mixture
of ethyl 2-bromopropionate (13.0 mL, 100 mmol) and sodium
thiosulfate pentahydrate (37.2 g, 150 mmol) in absolute
ethanol (100 mL) was stirred at 60-65 °C for 17 h (or until
starting halide was consumed, as determined by TLC analy-
sis). The mixture was diluted with toluene (230 mL) before
the addition of calcium chloride dihydrate (24 g, 160 mmol)
and 2,3-dimethylbutadiene (30 mL, 260 mmol). While stirring
at 60-65 °C, a solution of triethylamine (18 mL, 130 mmol)
in toluene (17 mL) was added via syringe pump at a rate of
5.1 mL/h. After addition was complete, the mixture was
stirred an additional 1 h at the same temperature before
cooling. The mixture was diluted with ether (300 mL) and
washed with saturated aqueous NaHCO3. Drying of the
organic phase with MgSO4 and concentration in vacuo afforded
a yellow oil. Flash chromatography (7% ether/hexane) gave
pure product (16 g, 75%) as a pale yellow oil. 1H NMR 4.17
(m, 2 H), 3.24, 2.93 (ABq, J ) 16 Hz, 2 H), 2.63, 2.23 (ABq, J
) 16 Hz, 2 H), 1.71 (s, 3 H), 1.69 (s, 3 H), 1.51 (s, 3 H), 1.26 (t,
J ) 7 Hz, 3 H); IR (film)1727 (s), 1233 (s), 1217 (s), 1161 (s)
cm-1; EI MS 214 (M+, 59), 141 (91), 139 (99). Anal. Calcd for
C11H18O2S: C, 61.65; H, 8.46. Found: C, 62.04; H, 8.46.
HRMS: Calcd: 214.1027. Found: 214.1017.
2H -Th iop yr a n -2-ca r b oxylic Acid , 3,6-Dih yd r o-4,5-d i-
m eth yl-2-(1′-m eth yleth yl)-, Eth yl Ester (7b) by Meth od
of Equ a tion 3. To a cooled solution (-10 °C) of 9 (2 0 g, 10
mmol) and HMPA (2.6 mL, 15 mmol) in THF (100 mL) was
added LDA (22 mL, 20 mmol, 0.9 M in cyclohexane). The
solution was stirred at -10 °C over a period of 0.5 h followed
by addition of 2-iodopropane (5.0 mL, 50 mmol) and allowed
to gradually warm to room temperature over a period of 2 h.
The reaction mixture was diluted with diethyl ether (100 mL)
and saturated sodium bicarbonate (80 mL) with stirring over
a period of 5 min. The organic portion was washed with water
(2 × 25 mL), dried (MgSO4), and concentrated to give a red
oil. Purification via column chromatography (10% Et2O/
hexanes) afforded 1.9 g (79%) of 7b as a colorless oil. IR (film)
2973, 1725 cm-1; 1H NMR 4.27-4.09 (m, 2H), 3.22-2.85 (ABq,
J ) 17 Hz, 2H), 2.52, 2.33 (ABq, J ) 17 Hz, 2H), 2.19 (heptet,
J ) 7 Hz, 1H), 1.70 (s, 6H), 1.25 (t, J ) 6 Hz, 3H), 1.04 (d, J
) 7 Hz, 3H), 1.01 (d, J ) 7 Hz, 3H); 13C NMR 172.9, 126.5,
121.9, 60.8, 36.9, 34.8, 30.4, 20.2, 18.9, 18.0, 17.8, 17.4, 14.0;
HRMS calcd for C13H22O2S 242.1340; found 242.1355.
2H -Th iop yr a n -2-ca r b oxylic Acid , 3,6-Dih yd r o-4,5-d i-
m eth yl-2-p h en yl-, Eth yl Ester (7d ). By the method de-
scribed for 7a : Purification via flash chromatography (10%
Et2O/hexanes) afforded 7d (86%) as a white solid: mp ) 44-
1
45 °C; IR (mull) 3028, 2927, 1728 cm-1; H NMR 7.52-7.45
(m, 2H), 7.34-7.22 (m, 3H), 4.24-4.07 (m, 2H), 3.13, 2.81
(ABq, J ) 16 Hz, 2H), 2.98, 2.83 (ABq, J ) 17 Hz, 2H), 1.75
(s, 3H), 1.68 (s, 3H), 1.18 (t, J ) 7 Hz, 3H); 13C NMR 172.0,
139.8, 128.0, 127.2, 126.3, 125.8, 122.9, 61.5, 55.0, 40.8, 31.2,
20.1, 18.8, 13.7. Anal. Calcd for C16H20O2S: C, 69.53; H, 7.29.
Found: C, 69.34; H, 7.36.
2-Oxa-6-th iaspir o[4.5]dec-8-en -1-on e, 8,9-Dim eth yl- (7e).
By the method described for 7a : Flash chromatography (20%
ethyl acetate/hexane) gave the product as a yellow oil (63%)
which solidified on standing. Recrystallization from aqueous
ethanol afforded white needles (5.83 g, mp 55-56 °C). 1H
NMR 4.3-4.5 (m, 2 H), 3.40 (d, AB, J ) 15 Hz, 1 H), 2.90 (d,
AB, J ) 15 Hz, 1 H), 2.2-2.45 (m, 4 H), 1.78 (s, 3 H), 1.72 (s,
3 H); IR (mull) 3003, 1754 (s), 1184 (s) cm-1; MS (EI) 198 (M+,
99), 165 (38), 151 (56). Anal. Calcd for C10H14O2S: C, 60.58;
H, 7.12. Found: C, 60.39; H, 7.26.
Meth a n on e, 3,6-Dih yd r o-2,4,5-tr im eth yl-2H-th iop yr a n -
2-yl-, P h en yl- (7f). By the method described for 7a : Flash
chromatography (8% ether/hexane) yielded 7f as a yellow oil
(30% yield). 1H NMR 1.67 (s, 3H), 1.71 (s, 3H), 1.76 (s, 3H),
2.19, 2.74 (ABq, 2H, J ) 17 Hz), 2.85, 3.05 (ABq, 2H, J ) 17
Hz); IR (mull) 1665, 1455, 1446, 1244, 1162 cm-1; MS (EI) 246
(M+, 9) 141 (100). Anal. Calcd for C15H18OS: C, 73.13; H,
7.36; S, 13.01. Found: C, 71.86; H, 7.37; S, 14.89.
Meth a n on e, 3,6-Dih yd r o-2,4,5-tr im eth yl-2H-th iop yr a n -
2-yl-, 4-F lu or op h en yl- (7g). By the method described for
7a : Purification via flash chromatography (8% Et2O/hexanes)
afforded 7g (35%) as an oil. IR (mull) 3076, 2914, 1672, 1598
1
cm-1
; H NMR 8.3-8.2 (m, 2H), 7.06 (t, J ) 8 Hz, 2H), 3.02,
2.84 (ABq, J ) 17 Hz, 2H), 2.72, 2.17 (ABq, J ) 17 Hz, 2H),
1.75 (s, 3H), 1.69 (s, 3H), 1.64 (s, 3H); 13C NMR 198.2, 164.7
(d, J F ) 252 Hz), 132.2 (d, J F ) 9 Hz), 131.8, 127.1, 120.8,
114.70 (d, J F ) 21 Hz), 50.1, 42.8, 30.8, 26.4, 20.0, 18.9. Anal.
Calcd for C15H17OSF: C, 68.15; H, 6.48. Found: C, 67.85; H,
6.51.
Meth an on e, (3,6-Dih ydr o-2,4,5-tr im eth yl-2H-th iopyr an -
2-yl)-, 4-(Tr iflu or om eth yl)p h en yl- (7h ). By the method
described for 7a : Purification via flash chromatography (10%
Et2O/hexanes) afforded 7h (68%) as a white solid: mp ) 40-
1
41 °C; IR (mull) 3005, 2925, 1676 cm-1; H NMR 8.23 (d, J )
8 Hz, 2H), 7.65 (d, J ) 8 Hz, 2H), 3.02, 2.84 (ABq, J ) 17 Hz,
2H), 2.70, 2.19 (ABq, J ) 17 Hz, 2H), 1.75 (s, 3H), 1.71 (s,
3H), 1.62 (s, 3H); 13C NMR 199.2, 139.3, 132.9 (q, J F ) 32 Hz),
129.5, 126.9, 124.8, 123.5 (q, J F ) 270 Hz), 120.9, 50.2, 42.3,
30.7, 26.1, 20.0, 18.9. Anal. Calcd for C16H17OSF3: C, 61.13;
H, 5.45. Found: C, 61.17; H, 5.59.
Meth a n on e, 3,6-Dih yd r o-2,4,5-tr im eth yl-2H-th iop yr a n -
2-yl-, (4-Meth oxyp h en yl)- (7i). By the method described for
7a : Purification via flash chromatography (10% Et2O/hexanes)
afforded 7i (12%) as a white solid: mp ) 64-65 °C; IR (mull)
3007, 2927, 1658, 1601 cm-1 1H NMR 8.29-8.24 (m, 2H),
;
6.91-6.85 (m, 2H), 3.86 (s, 3H), 3.03, 2.84 (ABq, J ) 17 Hz,
2H), 2.76, 2.15 (ABq, J ) 17 Hz, 2H), 1.76 (s, 3H), 1.69 (s,
3H), 1.67 (s, 3H); 13C NMR 198.2, 162.6, 132.2, 128.0, 127.4,
121.0, 113.0, 55.3, 50.4, 43.2, 31.1, 26.8, 20.2, 19.0. Anal. Calcd
for C16H20O2S: C, 69.53; H, 7.29. Found: C, 69.19; H, 7.29.
Met h a n on e, 3,6-Dih yd r o-4,5-d im et h yl-2-p h en yl-2H -
th iop yr a n -2-yl-, P h en yl- (7j). By the method described for
7a : Purification via flash chromatography (10% Et2O/hexanes)
afforded 7j (77%) as a white solid: mp ) 92-93 °C; IR (mull)
2912, 1673, 1597 cm-1; 1H NMR 7.70-7.66 (m, 2H), 7.49-7.19
(m, 8H), 3.03, 2.86 (ABq, J ) 16 Hz, 2H), 2.94, 2.51 (ABq, J )
16 Hz, 2H), 1.75 (s, 3H), 1.70 (s, 3H); 13C NMR 196.4, 141.8,
134.8, 132.0, 130.1, 128.9, 127.6, 127.5, 126.2, 122.1, 60.2, 44.4,
2H-Th iop yr a n -2-ca r boxylic Acid , 3,6-Dih yd r o-2,4,5-tr i-
m eth yl-, 1′,1-Dim eth yl Ester (7c). By the method described
for 7a : Purification via flash chromatography (10% ether/
hexanes) afforded 7c (48%) as a pale yellow oil: IR (film) 2978,
30.9, 19.9, 19.0, one carbon not seen. Anal. Calcd for C20H20
OS: C, 77.92; H, 6.49. Found: C, 77.98; H, 6.43.
-
1723 cm-1
;
1H NMR 3.24, 2.91 (ABq, J ) 17 Hz, 2H), 2.56,
2H -Th iop yr a n -2-ca r b on it r ile, 3,6-Dih yd r o-2,4,5-t r i-
m eth yl- (7k ). By the method described for 7a : Flash chro-
matography (10% ether/hexane) provided 7k (50%) as a light
yellow mobile liquid. 1H NMR 3.69 and 2.96 (ABq, 2H, J )
17 Hz), 2.46 and 2.36 (ABq, 2H, J ) 17 Hz), 1.78 (s, 3H), 1.70
2.20 (ABq, J ) 17 Hz, 2H), 1.71 (s, 3H), 1.69 (s, 3H), 1.48 (s,
3H), 1.44 (s, 9H); 13C NMR 172.8, 125.9, 121.5, 80.7, 46.6, 42.2,
30.9, 27.6, 25.2, 20.2, 18.9; HRMS calcd for C13H22O2S 242.1340;
found 242.1328.

4734 J . Org. Chem., Vol. 61, No. 14, 1996
Larsen et al.
(s, 3H), 1.67 (s, 3H); IR (film) 2230, 1449, 1416, 1381 cm-1; EI
MS 167 (M+, 100), 82 (72), 67 (39); HRMS calcd for C9H13NS
167.0769; found 167.0774.
was diluted with toluene (280 mL) followed by addition of
calcium chloride dihydrate (31 g, 210 mmol) and 2-methyl-
1,3-butadiene (56 mL, 560 mmol). To the resulting mixture
was added triethylamine (24 mL, 175 mmol) dissolved in
toluene (26 mL) at a rate of 5.4 mL/h via syringe pump. After
addition was complete the reaction mixture was allowed to stir
at 60 °C over a period of 6 h, cooled to room temperature, and
then diluted with diethyl ether (300 mL) and saturated sodium
bicarbonate (200 mL). The organic portion was washed with
saturated sodium bicarbonate, dried (MgSO4), and concen-
trated to give a pale yellow oil. Purification via flash chro-
matography (10% Et2O/hexanes) afforded 19 g (68%) of 10b:
10c as a 3:2 mixture of regioisomers (colorless oil). Analytical
data was obtained on the inseparable mixture. IR (neat) 3043,
2979, 1725 cm-1; 1H NMR (10b) 5.52-5.50 (m, 1H), 4.18 (q, J
) 7 Hz, 2H), 3.25, 2.91 (ABq, J ) 16 Hz, 2H), 2.73, 2.26 (ABq
of multiplets, J ) 17 Hz, 2H), 1.74 (s, 3H), 1.52 (s, 3H), 1.26
(t, J ) 7 Hz, 3H); (10c) 5.58-5.56 (m, 1H), 4.18 (q, J ) 7 Hz,
2H), 3.31, 3.06 (ABq of multiplets, J ) 16 Hz, 2H), 2.60, 2.18
(ABq, J ) 17 Hz, 2H), 1.74 (s, 3H), 1.54 (s, 3H), 1.26 (t, J ) 7
Hz, 3H); 13C NMR 173.8, 173.0, 134.1, 129.5, 120.9, 116.2, 61.2,
46.0, 45.0, 40.5, 36.4, 29.5, 26.1, 25.5, 25.2, 24.6, 23.9, 14.0;
HRMS calcd for C10H16O2S 200.0871; found 200.0874.
2H-Th iop yr a n -2-ca r boxylic Acid , 3,6-Dih yd r o-2,3,3,5-
tetr a m eth yl-, Eth yl Ester (10d ). Ethyl bromoproprionate
(3.3 mL, 26 mmol) and sodium thiosulfate pentahydrate (8 g,
32 mmol) were stirred in ethanol (95%, 30 mL) at 60 °C for 18
h. The reaction mixture was diluted with toluene (45 mL)
followed by addition of calcium chloride dihydrate (6 g, 39
mmol) and 2,4-dimethyl-1,3-pentadiene (5.0 g, 52 mmol). To
the resulting mixture was added triethylamine (4.5 mL, 32
mmol) dissolved in toluene (35 mL) at a rate of 1.67 mL/h via
syringe. After addition was complete the reaction mixture was
allowed to stir at 60 °C over a period of 1 h, cooled to room
temperature, and diluted with diethyl ether (100 mL) and
saturated sodium bicarbonate (75 mL). The organic portion
was washed with saturated sodium bicarbonate, dried (Mg-
SO4), and concentrated to give an orange oil. Purification via
repeated flash chromatography (10% Et2O/hexanes) afforded
0.87 g (15%) of 10d and 10e as a 4:1 mixture of regioisomers.
Analytical data was obtained with the mixture. IR (neat)
2973, 1724 cm-1; 1H NMR (10d ) 5.13 (q, J ) 1 Hz, 1H), 4.22-
4.08 (m, 2H), 3.12, 2.92 (ABq, J ) 17 Hz, 2H), 1.74 (d, J ) 1
Hz, 3H), 1.49 (s, 3H), 1.27 (t, J ) 7 Hz, 3H), 1.13 (s, 3H), 1.07
(s, 3H); (10e) 5.30 (m, 1H), 4.22-4.08 (m, 2H), 2.63, 2.08 (ABq,
J ) 17 Hz, 2H), 1.77 (bs, 3H), 1.51 (s, 3H), 1.31 (s, 3H), 1.28
(s, 3H), 1.27 (t, J ) 7 Hz); HRMS calcd for C12H20O2S 228.1184;
found 228.1189.
2-(9-F lu or e n ylid e n e )-3,6-d ih yd r o-2H -4,5-d im e t h yl-
th iop yr a n (7l). By the method described for 7a : Recrystal-
lization from 95% ethanol yielded 66% yield of product. An
analytical sample was obtained by recrystallization from
hexane (mp 122-124 °C, lit.17 125 °C). 1H NMR 1.81 (s, 3H),
2.00 (bs, 3H), 2.68 (bs, 2H), 3.47 (bs, 2H), 7.30-7.52 (m, 6H),
7.76-7.81 (dm, J ) 5.0 Hz, 2H); IR (mull) 1446, 732 cm-1
;
MS (EI) 278, (M+, 24), 196 (100). Anal. Calcd for C19H18S:
C, 81.97; H, 6.52; S, 11.52. Found: C, 82.20; H, 6.59; S, 11.73.
2H-Th iop yr a n -2-ca r boxa m id e, 3,6-Dih yd r o-N,N,2,4,5-
p en ta m eth yl- (7m ). To an ice cold solution of 8 (1.0 g, 5.4
mmol) in methylene dichloride (30 mL) and dimethylforma-
mide (42 mL, 0.5 mmol) was added oxalyl chloride (1.4 mL,
16.0 mmol) via syringe. The resulting solution was stirred at
0 °C over a period of 0.75 h before the addition of excess
dimethylamine (3.0 mL, 29 mmol) via cannula and continued
stirring over a period of 1 h. The reaction mixture was diluted
with diethyl ether (50 mL) and washed with water, and the
organic portion was dried (MgSO4) and concentrated to give
1.13 g of an oily solid. Purification via flash chromatography
(1:1 Et2O/hexanes) afforded 960 mg (83%) of 7m as a white
1
solid: mp ) 41 °C; IR (mull) 2909, 1627 cm-1; H NMR 3.18
(br s, 3H), 3.12 (br s, 3H), 2.90, 2.10 (ABq, J ) 16 Hz, 2H),
2.85 (1/2 of an ABq, J ) 18 Hz, 1H, second half obscured),
1.73 (s, 3H), 1.71 (s, 3H), 1.53 (s, 3H); 13C NMR 172.5, 128.2,
121.0, 46.2, 45.0, 38.9 (br), 31.5, 25.0, 20.2, 19.0. Anal. Calcd
for C11H19ONS: C, 61.93; H, 8.98; N, 6.56. Found: C, 61.83;
H, 9.00; N, 6.53.
2H-Th iop yr a n -2-ca r boxylic Acid , 3,6-Dih yd r o-2,4,5-tr i-
m eth yl- (8). To 7a (5 g, 23 mmol) in ethanol (95%, 200 mL)
was added 8 M potassium hydroxide (12 mL, 92 mmol), and
the reaction mixture was stirred at ambient temperature over
a period of 17 h. The milky white solution was concentrated
by rotary evaporation, diluted with water (30 mL), and
neutralized with concentrated hydrochloric acid. The aqueous
solution was saturated with solid sodium chloride and ex-
tracted with hot ethyl acetate (4 × 150 mL). The organic
portion was dried (MgSO4) and concentrated to give 4.4 g
(100%) of 8 as a white solid. An analytical sample could be
obtained by recrystallizing from hexanes/diethyl ether: mp )
90-92 °C; IR (mull) 2924, 1700, 1414 cm-1; 1H NMR 6.17 (br
s, 1H), 3.29, 2.92 (ABq, J ) 17 Hz, 2H), 2.63, 2.23 (ABq, J )
17 Hz, 2H), 1.72 (s, 3H), 1.69 (s, 3H), 1.54 (s, 3H); 13C NMR
179.5, 125.9, 121.9, 46.2, 41.7, 30.9, 25.6, 20.1, 19.0; HRMS
calcd for C9H14O2S 186.0714; found 186.0724.
2H-Th iop yr a n -2-ca r boxylic a cid , 3,6-Dih yd r o-, Eth yl
Ester (10a ). Ethyl bromoproprionate (9.1 mL, 70 mmol) and
sodium thiosulfate pentahydrate (22 g, 88 mmol) were stirred
in ethanol (95%, 70 mL) at 60 °C for 24 h. The solution was
cooled to -78 °C followed by addition of toluene (140 mL),
calcium chloride dihydrate (15 g, 102 mmol), 1,3-butadiene (42
mL, 924 mmol), and triethylamine (10 mL, 72 mmol). The
resulting reaction mixture was placed in a Parr bomb and
heated to 100 °C over a period of 2 h and then cooled to 40 °C
over a period of 18 h. The reaction mixture was cooled to room
temperature followed by dilution with diethyl ether (300 mL)
and saturated sodium bicarbonate (200 mL). The organic
portion was washed with saturated sodium bicarbonate, dried
(MgSO4) and concentrated to give 13 g of a pale yellow oil.
Purification via flash chromatography (10% Et2O/hexanes)
afforded 4.3 g (33%) of 10a as a colorless oil: IR (film) 3025,
2H-Th iop yr a n -2-ca r boxylic Acid , 3,6-Dih yd r o-2,3,5-tr i-
m eth yl-, Eth yl Ester (10f). Ethyl bromoproprionate (9.0 mL,
70 mmol) and sodium thiosulfate pentahydrate (22 g, 88 mmol)
were stirred in ethanol (95%, 70 mL) at 60 °C for 18 h. The
reaction mixture was diluted with toluene (140 mL) followed
by addition of calcium chloride dihydrate (15 g, 105 mmol) and
2-methyl-1,3-pentadiene (5.0 g, 61 mmol). To the resulting
mixture was added triethylamine (10 mL, 70 mmol) dissolved
in toluene (35 mL) at a rate of 8.4 mL/h via syringe pump.
After addition was complete the reaction mixture was allowed
to stir at 60 °C over a period of 1 h and cooled to room
temperature followed by dilution with diethyl ether (200 mL)
and saturated sodium bicarbonate (150 mL). The organic
portion was washed with saturated sodium bicarbonate, dried
(MgSO4), and concentrated to give 13 g of an orange oil. NMR
analysis indicated that a 9:1 mixture of 10f:10g had been
formed, each as a 1:1 mixture of diastereomers. Purification
via flash chromatography (10% Et2O/hexanes) afforded 8.4 g
(65%) of 10f:10g, as a colorless oil, unchanged in isomer ratios.
Analytical data was obtained on the mixture (data reported
1
2979, 1725 cm-1; H NMR 5.90-5.78 (m, 2H), 4.19 (q, J ) 7
Hz, 2H), 3.35, 3.07 (ABq of multiplets, J ) 16 Hz, 2H), 2.78,
2.28 (ABq of multiplets J ) 16 Hz, 2H), 1.53 (s, 3H), 1.27 (t,
J ) 7 Hz, 3H); 13C NMR 173.7, 126.7, 122.4, 61.4, 45.2, 35.7,
25.8, 25.5, 14.1; HRMS calcd for C9H14O2S 186.0714; found
186.0723.
2H -Th iop yr a n -2-ca r b oxylic Acid , 3,6-Dih yd r o-2,5-d i-
m eth yl-, Eth yl Ester (10b) a n d 2H-Th iop yr a n -2-ca r boxy-
lic Acid , 3,6-Dih yd r o-2,4-d im eth yl-, Eth yl Ester (10c).
Ethyl bromoproprionate (18 mL, 140 mmol) and sodium
thiosulfate pentahydrate (43 g, 175 mmol) were stirred in
ethanol (95%, 140 mL) at 60 °C for 17 h. The reaction mixture
only for 10f diastereomers). IR (neat) 3037, 2976, 1727 cm-1
;
1H NMR 5.40-5.37 (m, 1H), 5.35-5.32 (m, 1H), 4.25-4.11 (m,
4H, both isomers), 3.17, 2.91 (ABq, J ) 17 Hz, 2H), 3.07, 3.00
(ABq of multiplets, J ) 17 Hz, 2H), 2.90 (bm, 1H), 2.46-2.39
(m, 1H), 1.75 (s, 3H), 1.68 (s, 3H), 1.56 (s, 3H), 1.39 (s, 3H),
1.33-1.20 (m, 6H, both isomers), 1.04 (d, J ) 7 Hz, 3H), 1.03
(d, J ) 7 Hz, 3H); 13C NMR 174.2, 173.1, 128.9, 128.4, 127.9,
126.6, 61.4, 61.0, 50.2, 49.4, 39.1, 36.5, 29.5, 29.4, 24.4, 23.9,

Cyclopentene Synthesis from 1,3-Dienes
J . Org. Chem., Vol. 61, No. 14, 1996 4735
20.7, 17.7, 16.9, 14.1; HRMS calcd for C11H18O2S 214.1027;
found 214.1030.
61.6, 61.3, 60.2, 38.8, 35.3, 18.6, 17.7, 17.0, 14.0, 13.3, 11.5;
HRMS calcd for C14H24O2S 256.1497; found 256.1501.
3-Cyclop en ten e-1-ca r boxylic Acid , 1,3,4-Tr im eth yl-2-
(m eth ylth io)-, 1,1-Dim eth yleth yl Ester (11c/12c). By the
method outlined for the preparation of 11b/12b: Purification
via flash chromatography (5% Et2O/hexanes) afforded 95% of
11c:12c as an 8:1 diastereomeric mixture. Analytical data was
obtained on the mixture. IR (film) 2976, 1724 cm-1; 1H NMR
(11c) 3.95 (s, 1H), 2.75, 2.07 (ABq, J ) 16 Hz, 2H), 1.94 (s,
3H) 1.68 (s, 3H), 1.64 (s, 3H), 1.43 (s, 9H), 1.38 (s, 3H); (12c)
3.15 (s, 1H), 3.03, 1.87 (ABq, J ) 16 Hz, 2H), 1.83 (s, 3H),
1.50 (s, 9H), 1.29 (s, 3H), vinyl methyls obscured; 13C NMR
(11c) 176.9, 132.8, 129.5, 80.1, 64.1, 52.6, 48.2, 27.9, 21.6, 13.9,
13.8, 12.5. Anal. Calcd for C14H24O2S: C, 65.58; H, 9.43.
Found: C, 65.97; H, 9.31.
3-Cyclop en ten e-1-ca r boxylic Acid , 1,3,4-Tr im eth yl-2-
(m eth ylth io)-, Eth yl Ester (11a /12a ). LDA (bis THF com-
plex, 1.05 M in hexane, 11.6 mL, 12.1 mmol) was added over
10 min to a -78 °C solution of sulfide 7a (2.00 g, 9.33 mmol)
and HMPA (2.1 mL, 12 mmol) in THF (50 mL) under nitrogen.
The bright yellow solution was then stirred at that temp for 1
h and then allowed to warm to 0 °C for 30 min. Neat methyl
iodide (2.9 mL, 47 mmol) was added, and the reaction was
stirred for another 30 min at 0 °C. The reaction was diluted
with ether (50 mL) and washed successively with saturated
aqueous NaHCO3 and water. The organic phase was dried
over magnesium sulfate and concentrated in vacuo, affording
an amber oil (2.26 g). NMR analysis indicated an 8:1 mixture
of 11a :12a had formed. Flash chromatography (10% ether/
hexane) provided the product as a mixture of diastereomers
(1.85 g, 87%). A pure sample of 11a could be obtained by
HPLC (Whatman M9 silica, 1% ether/hexane, 3.5 mL/min).
1H NMR (11a ) 4.13 (q, J ) 7 Hz, 2 H), 4.00 (bs, 1 H), 2.81,
2.11 (ABq, J ) 16 Hz, 2 H), 1.94 (s, 3 H), 1.68 (s, 3 H), 1.64 (s,
3 H), 1.42 (s, 3 H), 1.24 (t, J ) 7 Hz, 3 H); (12a ) 4.20 (q, J )
7 Hz, 2 H), 3.21 (bs, 1 H), 3.12, 1.90 (ABq, J ) 16 Hz, 2 H),
1.81 (s, 3 H), 1.69 (s, 3 H), 1.66 (s, 3 H), 1.57 (s, 3 H), 1.30 (t,
J ) 7 Hz, 3 H); remaining data is for the mixture: IR (film)
1728 (s), 1446, 1177 (s), 1097 (s); MS (EI) 228 (M+, 25), 107
(99). Anal. Calcd for C12H20O2S: C, 63.12; H, 8.83; S, 14.04.
Found: C, 62.66; H, 8.79; S, 13.54; HRMS calcd 228.1184;
found 228.1184.
3-Cyclop en t en e-1-ca r b oxylic Acid , 3,4-Dim et h yl-2-
(m eth ylth io)-1-p h en yl-, Eth yl Ester (11d /12d ). By the
method outlined for the preparation of 11b/12b: Purification
via flash chromatography (8% Et2O/hexanes) afforded 11d :12d
(93%) as a colorless oil and a 2:1 mixture of diastereomers.
Analytical data was obtained on the mixture. IR (film) 3024,
1728, 1601 cm-1; 1H NMR (400 MHz) (11d ) 7.39-7.37 (m, 2H),
7.32-7.28 (m, 2H), 7.24-7.20 (m, 1H), 4.42 (s, 1H), 4.12-3.94
(m, 2H), 3.06, 2.95 (ABq, J ) 16 Hz, 2H), 1.76 (s, 3H), 1.74 (s,
3H), 1.49 (s, 3H), 1.10 (t, J ) 7 Hz, 3H); (12d ) 7.26-7.15 (m,
5H), 4.21-4.10 (m, 2H), 3.94 (s, 1H), 3.45, 2.24 (ABq, J ) 16
Hz, 2H), 1.94 (s, 3H), 1.78 (s, 3H), 1.59 (s, 3H), 1.19 (t, J ) 7
Hz, 3H); HRMS calcd for C17H22O2S 290.1340; found 290.1341.
2-Oxa sp ir o[4.4]n on -7-en -1-on e, 7,8-Dim eth yl-6-(m eth -
ylth io)- (11e). By the method outlined for the preparation
of 11b/12b: Purification via flash chromatography (10% Et2O/
hexanes) afforded 11e (71%) as a 15:1 diastereomeric mixture
(the minor isomer was tentatively assigned and was not
resolved). The major isomer 11e was recrystallized from
pentanes (-20 °C) to afford 170 mg (67%) of white needles
(mp ) 55-56 °C). IR (mull) 2918, 1754, cm-1; 1H NMR 4.35-
4.22 (m, 2H), 3.81 (s, 1H), 2.88 (ddd, J ) 13, 7, 6 Hz, 1H),
2.65, 2.28 (ABq, J ) 17 Hz, 2H), 2.17 (ddd, J ) 13, 7, 6 Hz,
1H), 1.82 (s, 3H), 1.72 (s, 6H); 13C NMR 181.3, 131.9, 128.9,
65.9, 61.9, 49.6, 47.5, 33.5, 13.7, 12.4, 11.7. Anal. Calcd for
C11H16O2S: C, 62.23; H, 7.59. Found: C, 62.05; H, 7.58.
Meth a n on e, P h en yl-, 1,3,4-Tr im eth yl-2-(m eth ylth io)-
3-cyclop en ten -1-yl- (11f/12f). By the method outlined for
the preparation of 11b/12b: Flash chromatography (8% ether/
hexane) yielded 11f:12f as a very pale yellow oil (63% yield),
which was a 10:1 mixture of diastereomers. 1H NMR (11f)
1.62 (s, 3H), 1.68 (s, 6H), 1.95 (s, 3H), 2.22, 3.18 (ABq, 2H, J
) 16 Hz), 4.25 (s, 1H), 7.39-7,53 (m, 3H), 7.83-7.86 (m, 2H);
(12f) 1.42 (s, 3H), 1.70 (s, 3H), 1.65-1.72 (m, 6H), 1.90, 3.41
(ABq, J ) 16 Hz, 2H), 3.69 (s, 1H), 7.4-7.55 (m, 3H), 7.85 (m,
2H); IR (film) 1674, 1447, 973, 713, 697; MS(EI) 260 (M+, 2),
105 (100); HRMS calcd for C16H20OS 260.1235; found 260.1228.
Meth a n on e, 4-F lu or op h en yl-, 1,3,4-Tr im eth yl-2-(m e-
th ylth io)-3-cyclop en ten -1-yl- (11g/12g). 7g (290 mg, 1.1
mmol) was dissolved in THF (10 mL). 18-Crown-6 (580 mg,
2.2 mmol) was added, and the solution was cooled to -78 °C.
To the stirring solution was added KBA (4.4 mL, 2.2 mmol,
0.5 M in toluene) via syringe, and the reaction mixture was
stirred at -78 °C over a period of 0.5 h. The solution was
warmed to 0 °C and stirred over a period of 0.5 h followed by
addition of iodomethane (340 mL, 5.5 mmol) via syringe. The
solution was stirred for an additional 10 min followed by
partitioning between ether and saturated aqueous sodium
bicarbonate. The organic portion was washed with water,
dried (MgSO4), and filtered. Purification via preparative layer
chromatography (silica gel, 1 mm thickness, 33% Et2O/hex-
anes) afforded 212 mg (69%) of 11g:12g as a 5:2 diastereomeric
mixture. Analytical data was obtained on the mixture. IR
3-Cyclop en ten e-1-ca r boxylic Acid , 1,3,4-Tr im eth yl-2-
(m eth ylth io)-, Eth yl Ester (11a , by Rea r r a n gem en t of
Cyclop r op a n e 19). Cyclopropane 19 (350 mg, 1.1 mmol) was
dissolved in THF (5 mL). HMPA (250 µL, 1.4 mmol) was
added via syringe, and the solution was cooled to -78 °C. To
the stirring solution was added lithium diethylamide (2.3 mL,
1.4 mmol, 0.6 M in THF, generated from diethylamine (1.05
mL, 10 mmol) and n-BuLi (6.25 mL, 10 mmol, 1.6 M in
hexanes) at -78 °C) via syringe, and the reaction mixture was
stirred at -78 °C over a period of 0.5 h. The solution was
warmed to 0 °C and stirred over a period of 0.25 h followed by
addition of iodomethane (340 mL, 5.5 mmol) via syringe. The
solution was stirred for an additional 10 min followed by
partitioning between diethyl ether (100 mL) and saturated
sodium bicarbonate (10 mL). The organic portion was dried
(MgSO4) and filtered over a plug of silica gel (7 g), rinsing with
diethyl ether. NMR analysis indicated that 11a :12a were
present in a 16:1 ratio. Flash chromatography (10% Et2O/
hexanes) afforded 198 mg (79%) of 11a :12a as a 16:1 mixture
of diastereomers.
3-Cyclop en ten e-1-ca r boxylic Acid , 3,4-Dim eth yl-1-(1′-
m eth yleth yl)-2-(m eth ylth io)-, Eth yl Ester (11b/12b). Gen -
er a l P r oced u r e for Rin g Con tr a ction to Cyclop en ten es.
7b (970 mg, 4.0 mmol) was dissolved in THF (40 mL). HMPA
(0.90 mL, 5.2 mmol) was added via syringe, and the solution
was cooled to -78 °C. To the stirring solution was added
LDA‚THF (6.0 mL, 5.2 mmol, 0.9 M in cyclohexane) via
syringe, and the reaction mixture was stirred at -78 °C over
a period of 0.5 h. The solution was warmed to 0 °C and stirred
over a period of 0.5 h before the addition of iodomethane (1.24
mL, 20.0 mmol) via syringe. The solution was stirred for an
additional 10 min before partitioning between diethyl ether
(80 mL) and saturated sodium bicarbonate (20 mL). The
organic portion was washed with water, dried (MgSO4), and
filtered. Purification via flash chromatography (10% Et2O/
hexanes) afforded 864 mg (84%) of 11b:12b as a 17:2 mixture
of diastereomers. Analytical data was obtained on the mix-
ture. IR (neat) 2973, 1721, 1445 cm-1 1H NMR (11b) 4.3-
;
1
(film) 3073, 2917, 1673, 1599 cm-1; H NMR (11g) 7.95-787
4.0 (m, 3H), 2.81, 2.04 (ABq, J ) 15 Hz, 2H), 2.31 (heptet, J )
7 Hz, 1H) 1.83 (s, 3H), 1.68-1.62 (m, 6H), 1.24 (t, J ) 7 Hz,
3H), 0.98 (d, J ) 7 Hz, 3H), 0.92 (d, J ) 7 Hz, 3H); (12b) 4.3-
4.0 (m, 2H), 3.27 (br s, 1H), 2.96, 1.99 (ABq, J ) 17 Hz, 2H),
2.22 (heptet, J ) 7 Hz, 1H), 1.80 (s, 3H), 1.59 (br s, 6H), 1.26
(t, J ) 7 Hz, 3H), 0.84 (d, J ) 7 Hz, 3H), 0.68 (d, J ) 7 Hz,
3H); 13C NMR (11b) 175.1, 133.6, 130.4, 63.8, 61.3, 61.2, 45.0,
32.3, 19.7, 18.6, 14.2 13.7, 12.4, 12.2; (12b) 174.4, 134.0, 126.9,
(m, 2H), 7.12-7.03 (m, 2H), 4.21 (s, 1H), 3.19, 2.22 (ABq, J )
16 Hz, 2H), 1.94 (s, 3H), 1.68 (s, 6H), 1.60 (s, 3H); (12g) 7.95-
7.87 (m, 2H), 7.12-7.03 (m, 2H), 3.66 (s, 1H), 3.42, 1.89 (ABq,
J ) 17 Hz, 2H), 1.76 (s, 3H), 1.71 (s, 3H), 1.66 (s, 3H), 1.41 (s,
3H); 13C NMR (mixture) 202.1, 200.6, 164.7 (d, J F ) 252 Hz),
164.4 (d, J F ) 251 Hz), 133.6, 133.2, 132.9, 132.0 (d, J F ) 9
Hz), 131.8 (d, J F ) 9 Hz), 131.3, 130.0, 128.5, 125.5, 115.2 (d,

4736 J . Org. Chem., Vol. 61, No. 14, 1996
Larsen et al.
J F ) 21 Hz), 114.9 (d, J F ) 21 Hz), 63.6, 62.8, 58.8, 56.2, 49.4,
48.3, 28.7, 23.7, 13.8, 13.2, 12.6, 11.7, 10.7. Anal. Calcd for
C16H19OSF: C, 69.03; H, 6.88. Found: C, 68.99; H, 6.92.
Met h a n on e, 4-(Tr iflu or om et h yl)p h en yl-, 1,3,4-Tr i-
m eth yl-2-(m eth ylth io)-3-cyclop en ten -1-yl- (11h /12h ). By
the method described for the preparation of 11g/12g: Purifica-
tion via flash chromatography (10% Et2O/hexanes) afforded
11h :12h (72%) as a 5:2 diastereomeric mixture. Analytical
data was obtained on the mixture. IR (film) 3068, 2976, 1682
cm-1; 1H NMR (11h ) 7.91 (d, J ) 8 Hz, 2H), 7.69 (d, J ) 8 Hz,
2H), 4.17 (s, 1H), 3.11, 2.24 (ABq, J ) 17 Hz, 2H), 1.95 (s,
3H), 1.69 (s, 6H), 1.60 (s, 3H); (12h ) 7.95 (d, J ) 8 Hz, 2H),
7.69 (d, J ) 8 Hz, 2H), 3.67 (s, 1H), 3.42, 1.83 (ABq, J ) 16
Hz, 2H), 1.77 (s, 3H), 1.72 (s, 3H), 1.70 (s, 3H), 1.40 (s, 3H);
13C NMR (11h ) 203.8, 138.9, 132.9, 129.6, 129.4, 129.1, 125.3,
125.2, 63.5, 56.6, 49.2, 23.3, 13.9, 13.5, 12.6; (12h ) 201.3, 140.3,
133.1, 129.6, 125.5, 125.0, 124.9, 62.6, 56.4, 47.9, 28.2, 13.6,
11.5, 10.5 (one carbon resonance not seen). Anal. Calcd for
C17H19OSF3: C, 62.18; H, 5.83. Found: C, 62.01; H, 5.97.
Meth a n on e, 4-Meth oxyp h en yl-, 1,3,4-Tr im eth yl-2-(m e-
th ylth io)-3-cyclop en ten -1-yl- (11i/12i). By the method
described for the preparation of 11g/12g: Flash chromatog-
raphy (10% ether/hexane) afforded a pure mixture of the two
diastereomers (5:2 11i:12i) (83%) as a pale yellow oil. 1H NMR
(11i) 7.91 (d, 2H, J ) 9 Hz), 6.90 (d, 2H, J ) 9 Hz), 4.26 (bs,
1H), 3.84 (s, 3H), 3.24 and 2.19 (ABq, 2H, J ) 15 Hz), 1.94 (s,
3H), 1.69 (s, 3H), 1.65 (s, 3H), 1.61 (s, 3H); (12i) 7.78 (d, 2H,
J ) 9 Hz), 6.91 (d, 2H, J ) 9 Hz), 3.84 (s, 3H), 3.67 (bs, 1H),
3.42 and 1.89 (ABq, 2H, J ) 16 Hz), 1.75 (s, 3H), 1.72 (s, 3H),
1.69 (s, 3H), 1.43 (s, 3H); Remaining data is for the mixture:
IR (film) 1666 (s), 1602 (s), 1258 (s), 1169 (s); MS (EI) 290 (M+,
3), 135 (99). HRMS (EI) calcd for C17H22O2S 290.1340; found
290.1349.
133.6, 126.1, 37.3, 35.4, 31.3, 30.5, 26.1, 22.2, 19.5, 19.1, 17.6.
Anal. Calcd for C12H21ONS: C, 63.39; H, 9.31; N, 6.16.
Found: C, 63.66; H, 9.34; N, 6.33.
11m /12m a n d 18m (by Con d ition s of Ta ble 5, En tr y 3).
7m (680 mg, 3.2 mmol) was dissolved in THF (30 mL). HMPA
(0.730 mL, 4.2 mmol) was added via syringe, and the solution
was cooled to -78 °C. To the stirring solution was added
LDA‚THF (4.6 mL, 4.2 mmol, 0.9 M in cyclohexane) via
syringe, and the reaction mixture was stirred at -78 °C over
a period of 0.5 h. The solution was warmed to 0 °C temper-
ature and stirred over a period of 0.5 h followed by addition of
iodomethane (1.0 mL, 16.0 mmol) via syringe. The solution
was stirred for an additional 10 min followed by partitioning
with diethyl ether (200 mL) and saturated sodium bicarbonate
(20 mL). The organic portion was washed with water, and
the aqueous layer was extracted with ethyl acetate. The
combined organic portions were dried (MgSO4) and filtered to
give a brown oil. Purification via flash chromatography (1:1
Et2O/hexanes) afforded 154 mg (21%) of 11m :12m as a 1:3
mixture of diastereomers and 437 mg (60%) of 18m as a
crystalline solid. Recrystallization of 11m :12m from ether/
hexanes afforded analytically pure 12m , mp ) 101-102 °C,
suitable for single crystal X-ray diffraction analysis.
3-Cyclopen ten e-1-car boxylic Acid, 1,2-Bis(m eth ylth io)-
3,4-d im eth yl- (11w /12w ). By the method outlined for the
preparation of 11b/12b: Purification via flash chromatography
(10% Et2O/hexanes) afforded 11w :12w (61%) as a 2:1 mixture
of diastereomers (oil). Analytical data was obtained on the
1
mixture. IR (film) 2919, 1722 cm-1; H NMR (11w ) 4.20 (s,
1H), 4.20 (q, J ) 7 Hz, 2H), 3.17, 2.38 (ABq, J ) 15 Hz, 2H),
2.10 (s, 3H), 1.95 (s, 3H), 1.69 (s, 6H), 1.28 (t, J ) 7 Hz, 3H);
(12w ) 4.30-4.16 (m, 2H), 3.49 (s, 1H), 3.23, 2.21 (ABq, J ) 20
Hz, 2H), 2.18 (s, 3H), 1.92 (s, 3H), 1.71 (s, 6H), 1.35 (t, J ) 7
Hz, 3H); HRMS calcd for C12H20O2S2 260.0905; found 260.0902.
Meth a n on e, P h en yl-, 1,3,4-Tr im eth yl-1-p h en yl-2-(m e-
th ylth io)-3-cyclop en ten -1-yl- (12j). By the method outlined
for the preparation of 11b/12b: Purification via flash chro-
matography (10% Et2O/hexanes) afforded 12j (93%) as a >20:1
mixture of diastereomers. Recrystallization from pentanes
afforded analytically pure 12j (mp ) 112 °C). IR (mull) 3052,
3023, 1670, 1595 cm-1; 1H NMR 7.65-7.60 (m, 2H), 7.36-7.08
(m, 8H), 4.24 (s, 1H), 3.78, 2.11 (ABq, J ) 17 Hz, 2H), 1.86 (s,
3H), 1.66 (s, 3H), 1.65 (s, 3H); 13C NMR 197.6, 146.6, 137.1,
132.7, 131.6, 129.8, 128.8, 128.0, 127.2, 126.5, 125.5, 66.3, 60.3,
50.5, 13.9, 11.7, 11.6. Anal. Calcd for C21H22OS: C, 78.22;
H, 6.88. Found: C, 78.37; H, 7.07.
Sp ir o[3-cyclop en ten e-1,9′-[9H]flu or en e], 3,4-Dim eth yl-
2-(m eth ylth io)- (11l). By the method outlined for the prepa-
ration of 11b/12b: Flash chromatography (2% ether/hexane)
yielded 11l (79%) as a pale yellow oil. 1H NMR 1.45 (s, 3H),
1.82 (s, 3H), 1.89 (s, 3H), 2.57, 2.98 (ABq, J ) 16 Hz, 2H),
3.70 (s, 1H), 7.21-7.45 (m, 5H), 7.67-7.71 (m, 2H), 7.83 (d, J
) 7 Hz, 1H); IR (film) 2914, 1448, 738 cm-1; MS (EI) 292 (M+,
14), 245 (100); HRMS calcd for C20H20S 292.1276; found
292.1286.
3-Cyclopen ten e-1-car boxam ide, N,N,1,3,4-P en tam eth yl-
2-(m eth ylth io)- (11m /12m ) a n d Cyclop r op a n eca r boxa m -
id e,
N,N,1,2-Tet r a m et h yl-2-[1-m et h yl-2-(m et h ylt h io)-
eth en yl]- (18m ) (by Con d ition s of Ta ble 5, En tr y 4). 7m
(435 mg, 2.0 mmol) was dissolved in THF (15 mL). HMPA
(0.460 mL, 2.6 mmol) was added via syringe, and the solution
was cooled to -78 °C. To the stirring solution was added
LDA‚THF (1.2 mL, 1.4 mmol, 1.2 M in cyclohexane) via
syringe, and the reaction mixture was stirred at -78 °C over
a period of 0.5 h. The solution was warmed to ambient
temperature and stirred over a period of 24 h followed by
addition of iodomethane (0.620 mL, 10.0 mmol) via syringe.
The solution was stirred for an additional 10 min followed by
partitioning between diethyl ether (100 mL) and saturated
sodium bicarbonate (30 mL). The organic portion was washed
with water, dried (MgSO4), and filtered to give a brown oil.
Analysis of the crude reaction mixture by 1H NMR (300 MHz)
showed a 14:3:1 ratio of 11m :12m :18m , respectively. Purifica-
tion via flash chromatography (1:1 ether/hexanes then 100%
ether) afforded 375 mg (82%) of 11m :12m as a 5:1 mixture of
diastereomers (colorless oil) and 27 mg (6%) of 18m (white
solid). Analytical data was obtained on the mixture of 11m :
12m . IR (neat) 2917, 1632 cm-1; 1H NMR (11m ) 3.95 (s, 1H),
3.20, 2.06 (ABq, J ) 17 Hz, 2H), 2.94 (s, 6H), 1.90 (s, 3H),
1.67 (s, 6H), 1.46 (s, 3H); (12m ) 3.36, 1.94 (ABq, J ) 17 Hz,
2H), 3.27 (s, 1H), 3.01 (brs, 6H), 1.74 (s, 3H), 1.72 (s, 3H), 1.66
(s, 3H), 1.36 (s, 3H); 13C NMR (11m ) 176.3, 133.2, 128.5, 63.8,
54.6, 50.5, 38.0 (br, 2C), 22.6, 13.9, 12.9, 12.6; (12m ) 174.8,
133.4, 125.3, 63.0, 54.7, 51.0, 38.7, 37.2, 27.0, 13.8, 12.0, 9.9.
Anal. Calcd for C12H21ONS: C, 63.39; H, 9.31; N, 6.16.
Found: C, 63.47; H, 9.31; N, 5.98. (18m ) mp ) 58-60 °C; IR
(mull) 3003, 2921, 1625, 1592 cm-1; 1H NMR 5.70 (s, 1H), 3.18
(s, 3H), 2.94 (s, 3H), 2.24, (s, 3H), 1.87 (s, 3H), 1.28 (s, 3H),
1.15, 1.05 (ABq, J ) 5 Hz, 2H), 1.06 (s, 3H); 13C NMR 173.1,
3-Cyclop en ten e-1-ca r boxylic Acid , 1-Meth yl-2-(m eth -
ylth io)-, Eth yl Ester (13a /14a ). 10a (625 mg, 3.4 mmol) was
dissolved in THF (15 mL). HMPA (0.760 mL, 4.4 mmol) was
added via syringe and the solution was cooled to -78 °C. To
the stirring solution was added LDA‚THF (3.8 mL, 4.4 mmol,
1.1 M in cyclohexane) via syringe, and the reaction mixture
was stirred at -78 °C over a period of 0.5 h. The solution
was warmed to ambient temperature and stirred over a period
of 2 h followed by addition of iodomethane (1.0 mL, 17.0 mmol)
via syringe. The solution was stirred for an additional 10 min
and then partitioned between diethyl ether (100 mL) and
saturated sodium bicarbonate (10 mL). The organic portion
was dried (MgSO4) and concentrated. Purification via flash
chromatography (10% Et2O/hexanes) afforded 290 mg (43%)
of 13a :14a as a 3:1 mixture of diastereomers and 32 mg (5%)
of 19:20 as an 8:1 mixture of isomers. Analytical data was
obtained on the mixture. IR (film) 3063, 2980, 1727, 1611
1
cm-1; H NMR (13a ) 5.80-5.74 (m, 1H), 5.70-5.62 (m, 1H),
4.24 (d, J ) 3 Hz, 1H), 4.15 (q, J ) 7 Hz, 2H), 2.97, 2.22 (ABq
of multiplets, J ) 17 Hz, 2H), 2.06 (s, 3H), 1.42 (s, 3H), 1.24
(t, J ) 7 Hz, 1H); (14a ) 5.85-5.80 (m, 1H), 5.55-5.51 (m, 1H),
4.26-4.14 (m, 2H, obscured), 3.48 (br s, 1H), 3.15, 2.09 (ABq
of multiplets, J ) 17 Hz, 2H), 1.95 (s, 3H), 1.37 (s, 3H), 1.31
(t, J ) 7 Hz, 3H); 13C NMR (13a ) 177.2, 130.7, 130.2, 60.8,
58.5, 52.7, 43.8, 21.3, 14.6, 14.0; (14a ) 174.6, 130.4, 127.8, 60.6,
59.7, 54.4, 41.8, 26.4, 14.1, 12.8; FAB HRMS calcd for
C10H16O2S (M - 1) 199.0792; found 199.0796.
3-Cyclop en t en e-1-ca r b oxylic Acid , 1,3-Dim et h yl-2-
(m eth ylth io)- (13b/14b) a n d 3-Cyclop en ten e-1-ca r boxylic
Acid , 1,4-Dim eth yl-2-(m eth ylth io)- (13c/14c). To a -78 °C

Cyclopentene Synthesis from 1,3-Dienes
J . Org. Chem., Vol. 61, No. 14, 1996 4737
solution of 10b and 10c (3:2, 2.11 g, 9.8 mmol) and DMPU
(12 mL) in THF (100 mL) was added dropwise LDA‚THF (12
mL, 1.1 M, 12.7 mmol). The solution was stirred at -78 °C
for 30 min and then allowed to come to room temperature for
2 h. Methyl iodide (3.1 mL, 50 mmol) was added. After 30
min, the reaction was partitioned between ether and saturated
aqueous sodium bicarbonate, and the organic phase was
washed with water, dried over sodium sulfate, and concen-
trated. NMR analysis of the crude mixture indicated that the
four possible isomers 13b:14b:13c:14c were present in a ratio
of 14:7:13:2, respectively. Flash chromatography (10% ether/
hexane) provided the same mixture of isomers free of other
impurities (1.74 g, 82%) as a colorless oil. Isomer assignments
were based on NOE analysis (see supporting information) and
on the relative chemical shifts of the methine protons adjacent
to the methylthio group (vide supra). Analytical data was
obtained on the mixture. IR (film) 3048, 2979, 2930, 1728,
Hz); 13f′′: 4.10 (bs, 1H), 2.98 (m, 1H), 2.09 (s, 3H), 0.98 (d,
3H, J ) 7 Hz); 13f′′′: 4.18 (bs, 1H), 2.50 (m, 1H), 2.04 (s, 3H),
0.90 (d, 3H, J ) 7 Hz); remaining data is for the mixture of
13f′-13f′′′. IR (film) 2975 (s), 1727 (s), 1240 (s), 1218 (s), 1114
(s); MS (EI) 228 (M+, 20), 107 (99); HRMS (EI) calcd for
C12H20O2S 228.1184; found 228.1181. The minor isomer (13f′′′)
was tentatively assigned as 1,2-trans-1,5-cis based on the
chemical shifts of the two methine protons relative to the other
isomers (vide supra).
Cyclopr opan e, 1,1-Diph en yl-2-m eth yl-2-[2-(m eth ylth io)-
1-(m eth yl)eth en yl]- (16) a n d Cyclop en ten e, 1,2-Dim eth yl-
3-(m eth ylth io)-4,4-d ip h en yl- (17). To a -78 °C solution of
1516b (690 mg, 2.46 mmol) and HMPA (0.549 mL, 3.16 mmol)
in dry THF (14 mL) was added LDA (1.03 M in hexane, 3.02
mL, 3.16 mmol) dropwise. The deep wine-red reaction was
stirred at -78 °C for 1 h and then warmed to 25 °C for 30
min. Methyl iodide (0.23 mL, 3.7 mmol) was added, and the
solution was stirred for 10 min before partitioning between
ether and saturated aqueous sodium bicarbonate. The organic
phase was washed with water, dried over magnesium sulfate,
and concentrated to a viscous yellow oil (0.69 g). Flash
chromatography (2% ether/hexane) provided pure 16 (149 mg),
a mixture of 16 and 17 (356 mg), and pure 17 (63 mg). The
total yield was 78%. The proton NMR spectrum of 16 agreed
with that reported in the literature.16b Analysis of cyclopen-
tene 17: 1H NMR 7.1-7.3 (m, 10H), 4.19 (bs, 1H), 3.37, 2.55
(ABq, J ) 15 Hz, 2H), 1.87 (bs, 3H), 1.68 (bs, 3H), 1.59 (s,
3H); 13C NMR (multiplicity) 150.6 (s), 145.9 (s), 132.1 (s), 131.1
(s), 128.9, 127.7, 127.4, 127.2, 125.9, 125.5 (all d), 65.4 (d), 58.4
(s), 50.0 (t), 14.0, 13.6, 12.3 (all q); IR (film) 2919, 1493, 1443,
696 cm-1; HRMS calcd for C20H22S 294.1442; found 294.1455.
Cyclop r op a n eca r boxylic Acid , 2-[2-(m eth ylth io)-1-m e-
th yleth en yl]-, 1,2-Dim eth yl-, Eth yl Ester (18a ). To a -78
°C solution of 7a (4.50 g, 21.0 mmol) and HMPA (4.7 mL, 27
mmol) in THF (125 mL) was added LDA bis(THF) (1.06 M in
hexane, 26 mL, 27 mmol) via syringe drive over about 10 min.
The brown solution was stirred at that temperature for 1 h
and then at -45 °C for 10 min before quenching with methyl
iodide (6.5 mL, 105 mmol). The reaction was stirred at -45
°C for 15 min and then warmed to room temperature. After
dilution with ether (250 mL), the solution was washed with
saturated aqueous NaHCO3 and then water. Drying of the
organic phase over MgSO4 and concentration in vacuo left an
amber oil (5 g). NMR analysis indicated a 7:3:1 mixture of
18a :11a :12a . Flash chromatography (3:1 chloroform:hexane)
provided the mixture free from other impurities (3.07 g, 64%)
but could not separate the components. An analytical sample
of 18a was obtained by HPLC (Waters Prep 500A, 60%
methylene chloride/hexane). 1H NMR 5.71 (bs, 1H), 4.16 (q,
2H, J ) 7 Hz), 2.23 (s, 3H), 1.76 (s, 3H), 1.39 (half of ABq, 1H,
J ) 5 Hz), 1.2-1.3 (half of ABq, 1H, obscured), 1.274 (s, 3H),
1.269 (t, 3H, J ) 7 Hz), 1.25 (s, 3H); 13C NMR (multiplicity)
173.8 (s), 134.1 (s), 125.1 (d), 60.3 (t), 33.1 (s), 30.0 (s), 25.6
(t), 22.2 (q), 17.8 (q), 17.5 (q), 17.2 (q), 14.3 (q); IR (film) 1720,
1440, 1290, 1220, 1170, 1140-1; EI MS 228 (M+, 7), 107 (100);
HRMS calcd for C12H20O2S 228.1184; found 228.1174.
1655 cm-1
;
1H NMR (13b) 5.41 (bs, 1H), 4.14 (q, J ) 7 Hz,
2H), 3.99 (s, 1H), 2.87, 2.09 (ABq of multiplets, J ) 17 Hz,
2H), 1.96 (s, 3H), 1.78 (s, 3H), 1.42 (s, 3H), 1.24 (t, J ) 7 Hz,
1H); (14c) 5.17 (bs, 1H), 4.25-4.10 (2H, obscured), 3.44 (s, 1H),
3.10 (half of ABq, 1H, other half obscured), 1.96 (s, 3H), 1.75
(bs, 3H), 1.38 (s, 3H), 1.25 (t, 3H, obscured); (13c) 5.26 (bm,
1H), 4.20 (bs, 1H), 4.15 (q, 2H, obscured), 2.86, 2.16 (ABq, J )
17 Hz, 2H), 2.06 (s, 3H), 1.72 (bs, 3H), 1.41 (s, 3H), 1.25 (t, J
) 7 Hz, 3H); (14b) 5.46 (s, 1H), 4.25-4.17 (m, 2H, obscured),
3.17 (s, 1H), 3.05, 2.00, (ABq of multiplets, J ) 17 Hz, 2H),
1.85 (s, 3H), 1.76 (bs, 3H), 1.36 (s, 3H), 1.31 (t, J ) 7 Hz, 3H);
HRMS calcd for C11H18O2S 214.1027; found 214.1039.
3-Cyclopen ten e-1-car boxylic Acid, 1,3,5,5-Tetr am eth yl-
2-(m eth ylth io)-, Eth yl Ester (13d /14d ). A mixture of 10d
and 10e (4:1, 353 mg, 1.5 mmol) was dissolved in THF (10
mL). HMPA (0.350 mL, 2.0 mmol) was added via syringe, and
the solution was cooled to -78 °C. To the stirring solution
was added LDA‚THF (1.75 mL, 2.0 mmol, 1.1 M in cyclohex-
ane) via syringe, and the reaction mixture was stirred at -78
°C over a period of 0.5 h. The solution was warmed to 0 °C
and stirred over a period of 0.5 h followed by addition of
iodomethane (470 mL, 7.5 mmol) via syringe. The solution
was stirred for an additional 10 min followed by partitioning
between diethyl ether (50 mL) and saturated sodium bicarbon-
ate (10 mL). The organic portion was dried (MgSO4), filtered
over a plug of silica gel (7 g, rinsing with diethyl ether), and
concentrated. Purification via flash chromatography (10%
Et2O/hexanes) afforded 284 mg (78%) of 13d :14d as a 1:1
mixture of diastereomers (colorless oil). Analytical data was
obtained on the mixture. IR (film) 2975, 1725 cm-1; 1H NMR
(both isomers) 5.87 (s, 1H), 5.77 (s, 1H), 5.09 (bs, 1H), 4.31
(bs, 1H), 4.21-4.10 (m, 4H, both isomers), 2.16 (s, 3H), 1.90
(bs, 3H), 1.82-1.77 (bs, 6H, both isomers), 1.67 (bs, 3H), 1.52
(s, 6H, both isomers), 1.31-1.24 (m, 9H, both isomers), 1.08
(s, 3H), 0.89 (s, 3H). Anal. Calcd for C13H22O2S: C, 64.42; H,
9.15. Found: C, 64.06; H, 9.11.
3-Cyclop en ten e-1-ca r boxylic Acid , 1,3,5-Tr im eth yl-2-
(m eth ylth io)-, Eth yl Ester (13f/13f′/13f′′/13f′′′). To a -78
°C solution of ester 10f (1:1 mixture of diastereomers, 1.00 g,
4.66 mmol) in dry THF (25 mL) and HMPA (1.0 mL, 6.1 mmol)
was added LDA (mono THF, 1.3 M in cyclohexane, 4.6 mL,
6.1 mmol) dropwise. The solution was stirred at -78 °C for
30 min and then at 0 °C for 30 min. The reaction was
quenched by the addition of methyl iodide (1.45 mL, 23 mmol)
and then stirred another 30 min at 0 °C. The reaction was
partitioned between saturated NaHCO3 and ether, and the
organic layer was washed with water and then dried over
MgSO4. Concentration in vacuo provided an orange oil (1.18
g) which was an approximately 2:2:2:1 mixture of cyclopentene
diastereomers (minor isomer: 13f′′′) in combination with a
mixture of vinyl cyclopropanes (about 2:1 five-membered ring:
three-membered ring). Flash chromatography (5% ether/
hexane) provided a mixture of three of the cyclopentene
diastereomers (13f′-13f′′′) (0.52 g, 49%) along with the fourth
diastereomer 13f as a mixture with vinyl cyclopropanes (63
mg, 6%), all as colorless oils. Analyses were performed on the
mixture. 1H NMR (CDCl3) (significant peaks only): 13f: 3.25
(bs, 1H), 2.58 (m, 1H), 2.20 (s, 3H), 1.03 (d, 3H, J ) 7 Hz);
13f′: 3.37 (m, 1H), 3.17 (bs), 1.90 (s, 3H), 0.96 (d, 3H, J ) 7
Cyclop r op a n eca r b oxylic Acid , 2-[2-(Met h ylt h io)-
eth en yl]-1-m eth yl-, Eth yl Ester (19/20). 10a (308 mg, 1.66
mmol) was dissolved in THF (10 mL). HMPA (0.375 mL, 2.2
mmol) was added via syringe, and the solution was cooled to
-78 °C. To the stirring solution was added (LDA‚THF, 1.7
mL, 2.2 mmol, 1.3 M in cyclohexane) via syringe, and the
reaction mixture was stirred at -78 °C over a period of 0.5 h.
The solution was warmed to 0 °C and stirred over a period of
0.5 h followed by addition of iodomethane (0.52 mL, 8.3 mmol)
via syringe. The solution was stirred for an additional 10 min
before partitioning between diethyl ether (100 mL) and
saturated sodium bicarbonate (10 mL). The organic portion
was dried (MgSO4), filtered over a plug of Celite with diethyl
ether, and concentrated. Purification via preparative layer
chromatography (silica gel, 1 mm, 10% Et2O/hexanes) afforded
269 mg (81%) of 19:20 as an 7:1 mixture of diastereomers along
with ca. 5% of 13a :14a (1:2) (colorless oil). Analytical data
was obtained on the mixture. IR (film) 3082, 2981, 1718, 1604
1
cm-1; H NMR (19) 6.08 (d, J ) 9 Hz, 1H), 5.21 (t, J ) 9 Hz,
1H), 4.15 (q, J ) 6 Hz, 2H), 2.30 (s, 3H), 2.25 (br t, J ) 9 Hz,

4738 J . Org. Chem., Vol. 61, No. 14, 1996
Larsen et al.
1H), 1.65 (dd, J ) 9, 4 Hz, 1H), 1.27 (s, 3H), 1.25 (t, J ) 7 Hz,
3H), 0.71 (dd, J ) 6.5, 4 Hz, 1H); (20) (apparent peaks only)
5.94 (d, J ) 9 Hz, 1H), 5.50 (t, J ) 9 Hz, 1H), 2.29 (s, 3H),
1.90 (br m, 1H), 1.47 (m, 1H), 1.07 (dd, J ) 9, 4 Hz, 1H). Anal.
Calcd for C10H16O2S: C, 59.96; H, 8.05. Found: C, 59.64; H,
8.07.
1H), 3.13, 2.97 (ABq, J ) 17 Hz, 2H), 2.78 (d, J ) 7 Hz, 1H),
2.56, 2.32 (ABq, J ) 17 Hz, 2H), 1.72 (s, 6H), 1.30-1.23 (m,
6H); 13C NMR (26, high Rf) 173.0, 127.3, 123.6, 71.0, 61.5, 58.4,
34.6, 30.8, 20.4, 19.0, 17.9, 14.1; (26, low Rf) 172.4, 126.1, 122.9,
71.4, 61.4, 57.4, 36.8, 30.3, 20.2, 19.0, 18.4, 14.1.
2H -Th iop yr a n -2-ca r b oxylic Acid , 3,6-Dih yd r o-4,5-d i-
m eth yl-2-[1-[(tr im eth ylsilyl)oxy]eth yl]-, Eth yl Ester (27).
To a -78 °C solution of 26 (high Rf) (717 mg, 2.9 mmol) in
THF (15 mL) was added LDA‚THF (2.9 mL, 3.2 mmol, 1.1 M
in cyclohexane). The reaction mixture was allowed to stir at
-78 °C over a period of 0.5 h followed by addition of trimeth-
ylsilyl chloride (1.1 mL, 6.3 mmol) via syringe. The reaction
mixture was warmed to 0 °C and stirred over a period of 10
min before being partitioned between diethyl ether (100 mL)
and saturated sodium bicarbonate (20 mL). The organic
portion was dried (MgSO4) and concentrated to give 2.0 g of a
yellow oil. Purification via flash chromatography (10% Et2O/
hexanes) afforded 900 mg (96%) of 27 as a single diastereomer
(colorless oil). IR (film) 2980, 1728 cm-1; 1H NMR 4.12-3.94
(m, 3H), 3.03, 2.74 (ABq, J ) 16 Hz, 2H), 2.37, 2.32 (ABq, J )
16 Hz, 2H), 1.59 (s, 3H), 1.56 (s, 3H), 1.12 (t, J ) 7 Hz, 3H),
1.07 (d, J ) 6 Hz, 3H), 0.00 (s, 9H); 13C NMR 172.0, 126.7,
122.2, 71.6, 60.8, 57.5, 34.6, 30.7, 20.1, 19.2, 16.8, 13.9, 0.0;
FAB HRMS calcd for C15H28O3SSi (M + 1) 317.1607; found
317.1602.
Cyclop r op a n eca r boxylic Acid , 2-[2-(Ben zoylth io)-1-
m eth yleth en yl]-, 1,2-Dim eth yl-, Eth yl Ester (21). To a
-78 °C solution of 7a (1.25 g, 5.8 mmol) in THF (45 mL) and
HMPA (1.3 mL, 7.6 mmol) was added LDA‚THF (5.1 mL, 7.6
mmol, 1.5 M in cyclohexane) via syringe. The reaction mixture
was stirred over a period of 0.5 h at -78 °C and then warmed
to -45 °C and stirred over a period of 40 min. This was
followed by addition of benzoyl chloride (3.5 mL, 30.0 mmol)
via syringe. The solution was stirred for an additional 0.5 h
and then poured into diethyl ether (50 mL) and saturated
sodium bicarbonate (20 mL). The organic portion was washed
with water, dried (MgSO4), and filtered. Purification via flash
chromatography (10% Et2O/hexanes) afforded 1.61 g (86%) of
21 contaminated with a small amount (approximately 10%)
of cyclopentenes as a 1:1 mixture of diastereomers. Analyti-
cally pure 21 suitable for single crystal X-ray diffraction
analysis could be obtained via fractional recrystallization from
pentanes (-30 °C) then ethanol/water (3:1, -20 °C). mp )
42-43 °C; IR (mull) 3035, 2929, 1720, 1672, 1595 cm-1 1H
;
NMR 8.00-7.97 (m, 2H), 7.62-7.56 (m, 1H), 7.50-7.44 (m,
2H), 6.72 (s, 1H), 4.22-4.13 (m, 2H), 2.04 (s, 3H), 1.48 (br s,
1H), 1.33-1.25 m, 9H), 0.99 (br s, 1H). Anal. Calcd for
C18H22O3S: C, 67.89; H, 6.96; S, 10.07. Found: C, 67.91; H,
6.95; S, 10.10.
3-Cyclop en t en e-1-ca r b oxylic Acid , 3,4-Dim et h yl-2-
(m eth ylth io)-1-[1-[(tr im eth ylsilyl)oxy]eth yl]-, Eth yl Es-
ter (28). 27 (single high Rf diastereomer, 70 mg, 0.2 mmol)
was dissolved in THF (2 mL), and DMPU (0.240 mL) was
added. The solution was cooled to -78 °C before the addition
of LDA‚THF (0.220 mL, 0.3 mmol, 1.3 M in cyclohexane) via
syringe, and the reaction mixture was stirred at -78 °C over
a period of 0.5 h. The solution was warmed to 0 °C and stirred
over a period of 0.5 h before the addition of iodomethane (68
mL, 1.1 mmol) via syringe. The solution was stirred for an
additional 10 min and then poured into diethyl ether (25 mL)
and saturated sodium bicarbonate (10 mL). The organic
portion was dried (MgSO4) and concentrated to give a yellow
oil. Purification via preparative layer chromatography (silica
gel, 1 mm thickness, 75 g, 10% Et2O/hexanes) gave 43 mg
(59%) of 28 as a 20:10:7:1 mixture of diastereomers (28:28′:
28′′:28′′′), determined by NMR integration of the methine
protons R to the sulfur. Analytical data was obtained on the
mixture. IR (film) 2974, 1733, 1722 cm-1; 1H NMR (diagnostic
signals only) (28) 4.47 (q, J ) 6 Hz, 1H), 3.95 (bs, 1H), 2.58,
2.03 (ABq, J ) 16 Hz), 1.83 (s, 3H), 1.58 (bs, 3H), 1.53 (bs,
3H); (28′) 4.19 (q, J ) 6 Hz, 1H), 3.80 (bs, 1H), 2.75, 2.05 (ABq,
J ) 16 Hz), 1.74 (s, 3H); (28′′) 3.34 (bs, 1H), 2.81, 2.20 (ABq,
J ) 16 Hz, 2H), 1.73 (s, 3H), 1.00 (d, J ) 6 Hz); (28′′′) 4.25 (q,
1H, J ) 6 Hz), 3.00 (bs, 1H), 0.78 (d, J ) 6 Hz, 3H). Anal.
Calcd for C16H30O3SSi: C, 58.14; H, 9.15. Found: C, 58.34;
H, 9.05.
Cyclop en ten e-1-ca r boxylic Acid , 2-Mer ca p to-1,3,4-tr i-
m eth yl-, Eth yl Ester (23/24). To a -78 °C solution of 7a
(1.0 g, 4.7 mmol) dissolved in THF (50 mL) and HMPA (1.0
mL, 6.1 mmol) was added LDA‚THF (5.5 mL, 6.1 mmol). The
reaction mixture was allowed to stir at -78 °C over a period
of 0.5 h and then warmed to 0 °C and stirred over for 0.5 h
before partitioning between diethyl ether (100 mL) and
saturated ammonium chloride (50 mL). The organic portion
was washed with water, dried (MgSO4), filtered over a plug of
silica gel with ether, and concentrated to give an orange oil.
Purification via flash chromatography (10% Et2O/hexanes)
afforded 0.48 g (48%) of 23:24 as a 6:1 mixture of diastereomers
and ca. 5% of unreacted 7a (colorless oil). A pure sample of
23 could be obtained by repeat chromatography. IR (film)
1
2933, 2914, 2564, 1728 cm-1; H NMR (23) 4.19 (br d, J ) 9
Hz, 1H), 4.13 (q, J ) 7 Hz, 2H), 2.80, 2.22 (ABq, J ) 16 Hz,
2H), 1.69 (s, 3H), 1.62 (s, 3H), 1.38 (s, 3H), 1.24 (t, J ) 7 Hz,
3H), 1.22 (d, J ) 9 Hz, 1H); (24) (apparent peaks only) 4.19
(q, J ) 7 Hz, 2H), 3.42 (br d, J ) 8 Hz, 1H), 3.18, 1.92 (ABq,
J ) 16 Hz, 2H), 1.63 (s, 3H), 1.62 (s, 3H), 1.48 (d, J ) 8 Hz,
1H); HRMS calcd for C11H18O2S 214.1027; found 214.1039.
2H -Th iop yr a n -2-ca r b oxylic Acid , 3,6-Dih yd r o-4,5-d i-
m eth yl-2-(1-h yd r oxyeth yl)-, Eth yl Ester (26). To a -78
°C solution of 911 (1.27 g, 6.3 mmol) in THF (40 mL) was added
LDA‚THF (6.3 mL, 8.2 mmol, 1.3 M in cyclohexane). The
reaction mixture was allowed to stir at -78 °C over a period
of 0.5 h followed by addition of excess acetaldehyde (3.5 mL,
63 mmol) via cannula. The reaction mixture was allowed to
Ack n ow led gm en t. We are indebted to Barbara S.
Holroyd for her assistance in the preparation of the
schemes and tables for this manuscript. We also wish
to thank the personnel of Structural, Analytical and
Medicinal Chemistry for elemental analyses, mass
spectra, and IR data.
stir at -78 °C over
a period of 10 min before directly
partitioning between diethyl ether (100 mL) and saturated
sodium bicarbonate (50 mL). The organic portion was dried
(MgSO4) and concentrated to give 2.5 g of a yellow oil.
Purification via flash chromatography (1:1 Et2O/hexanes)
afforded 1.48 g (96%) of 26 as a 1:1 mixture of diastereomers.
Analytical data obtained on the mixture: IR (film) 3486, 2932,
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 7a , 7b, 7c, 7k , 8, 10a , 10b/10c, 10d /10e, 10f, 11a ,
11b/12b, 11d /12d , 11f, 11i/12i, 11l, 11w /12w , 13a /14a , 13b/
13c, 14b/14c, 13f, 17, 18a , 23, 27; NOE analyses of compounds
11a , 11d /12d , 12f, 18m , 13b/14b, 13c/14c, 19/20; ORTEP
diagrams13 of compounds 12j, 12m , 21 (31 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
2910, 1727 cm-1
. Anal. Calcd for C12H20O3S: C, 58.98; H,
8.25. Found: C, 58.72; H, 8.33. The individual diastereomers
could be separated via iterative column chromatography using
silica gel and eluting with 1:1 Et2O/hexanes. 1H NMR (26,
high Rf) 4.28-4.12 (m, 2H), 4.04 (quintet, J ) 6 Hz, 1H), 3.14,
2.98 (ABq, J ) 16 Hz, 2H), 2.77 (d, J ) 6 Hz, 1H), 2.56, 2.48
(ABq, J ) 16Hz, 2H), 1.76 (s, 3H), 1.73 (s, 3H), 1.32-1.23 (m,
6H); (26, low Rf) 4.28-4.16 (m, 2H), 3.94 (quintet, J ) 7 Hz,
J O960537O