A new method for the preparation of 2-thio substituted furans by methylsulfanylation of γ-dithiane carbonyl compounds

Article abstract of DOI:10.1021/jo010986a

Several related methods for the preparation of differentially substituted 2-thiofurans are described. The general procedure involves the formation of a thionium ion from a γ-dithianyl substituted carbonyl compound followed by cyclization of this reactive intermediate onto the tethered carbonyl group. Two methods for thionium ion generation were explored. One of these involved an acid-catalyzed reaction of β-ketenedithioacetals, prepared from the condensation of 2,2-bis(methylsulfanyl)acetaldehyde with a variety of ketones. Cyclization followed by loss of methane thiol gave 2-thiofurans 17, 18 and 23, 24 in 70-90% yield. Attempts to prepare 5-heteroatom substituted 2-thiofurans from the corresponding β-ketenedithioacetal amides or esters were unsuccessful, leading to 1,2-thio rearranged products. A more successful route involved the reaction of β-acetoxy-γ-thianyl carbonyl compounds with dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF). Treatment of the dithiane with this reagent resulted in the smooth generation of a thionium ion. Cyclization followed by loss of acetic acid afforded thiofurans 17, 18, 23, 47-49, 51, and 61-64 in 40-100% yield. The N-butenyl substituted thioamido furan furnished a rearranged hexahydropyrroloquinolin-2-one in high yield when heated at 110 °C.

Full text of DOI:10.1021/jo010986a

J . Org. Chem. 2002, 67, 1595-1606
1595
A New Meth od for th e P r ep a r a tion of 2-Th io Su bstitu ted F u r a n s
by Meth ylsu lfa n yla tion of γ-Dith ia n e Ca r bon yl Com p ou n d s
Albert Padwa,* Cheryl K. Eidell, J ohn D. Ginn, and Michael S. McClure
Department of Chemistry, Emory University, Atlanta, Georgia 30322
chemap@emory.edu
Received October 9, 2001
Several related methods for the preparation of differentially substituted 2-thiofurans are described.
The general procedure involves the formation of a thionium ion from a γ-dithianyl substituted
carbonyl compound followed by cyclization of this reactive intermediate onto the tethered carbonyl
group. Two methods for thionium ion generation were explored. One of these involved an acid-
catalyzed reaction of â-ketenedithioacetals, prepared from the condensation of 2,2-bis(methylsul-
fanyl)acetaldehyde with a variety of ketones. Cyclization followed by loss of methane thiol gave
2-thiofurans 17, 18 and 23, 24 in 70-90% yield. Attempts to prepare 5-heteroatom substituted
2-thiofurans from the corresponding â-ketenedithioacetal amides or esters were unsuccessful, leading
to 1,2-thio rearranged products. A more successful route involved the reaction of â-acetoxy-γ-thianyl
carbonyl compounds with dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF). Treatment
of the dithiane with this reagent resulted in the smooth generation of a thionium ion. Cyclization
followed by loss of acetic acid afforded thiofurans 17, 18, 23, 47-49, 51, and 61-64 in 40-100%
yield. The N-butenyl substituted thioamido furan furnished a rearranged hexahydropyrroloquinolin-
2-one in high yield when heated at 110 °C.
The synthesis of variously substituted furans continues
to be of considerable interest1-3 due to the presence of
this heteroaromatic nucleus in commercially important
pharmaceuticals,4 fragrances, and dyes.5 Furans are also
common substructures in numerous naturally occurring
biologically active compounds.6,7 These heteroaromatics
also serve as useful intermediates for the synthesis of
aromatic, acyclic, and cyclic molecules.8 Accordingly,
many strategies have been developed for the preparation
of substituted furans.9 2-Alkylthio furans are particu-
larly attractive intermediates that have found usage in
organic synthesis. They undergo a variety of reactions
including addition/elimination,10 nickel-catalyzed Grig-
nard coupling,11 Michael addition,12 ortho-metalation,13
and acid hydrolysis to butenolides,14 as well as [4 +
2]-cycloaddition chemistry.15 Although a number of syn-
thetic procedures are available for their formation,13,16
most of the existing methods often require harsh condi-
tions and are frequently based on the use of a preexisting
furan ring. Examples include the addition/elimination of
thiols,17 sulfanylation of ortho-metalated anions,18 meta-
lation of disulfides,13 and alkylation of furan thiolates.19
Our own interest in this area stems from the facility with
which 2-alkylthio-5-amino substituted furans undergo
Diels-Alder cycloaddition chemistry and the potential
use of the resulting oxabicyclic adducts for alkaloid
synthesis (Scheme 1).20 Although this methodology al-
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10.1021/jo010986a CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/07/2002

1596 J . Org. Chem., Vol. 67, No. 5, 2002
Padwa et al.
Sch em e 1
Sch em e 3
aromatization of the dihydrofuran by loss of sulfide,
thereby avoiding the need for a subsequent oxidation
step. Ketene dithioacetals are well-known to generate
thionium ions under acidic conditions and have been
trapped with tethered nucleophiles to give polycyclic
products.25-28 Indeed, our early work showed that the
acid-catalyzed reaction of â-oxo ketene thioacetals 13 and
14 gave furans 17 and 18 in 70% and 83% yield,
respectively.22 This reaction presumably proceeds by a
protonation-cyclization-elimination sequence as out-
lined in Scheme 3. The starting ketene dithioacetals were
prepared by an aldol condensation of ketones 8 and 9
with bis(methylsulfanyl)acetaldehyde29 (10) followed by
dehydration with mesyl chloride and triethylamine.
Interestingly, when the related cyclic aldol condensa-
tion products 19 and 20 were subjected to identical
elimination conditions, the expected ketene dithioacetals
were not isolated, but rather the rearranged trans-
dithiosubstituted dihydrofurans 21 and 22 were formed
in 66% and 94% yield, respectively. Conversion to the
corresponding furanyl systems was readily achieved in
87% and 89% by heating a sample of the appropriate
dihydrofuran with a trace of camphorsulfonic acid at 110
°C. The formation of the rearranged dihydrofuran can
be envisioned to proceed via an episulfonium ion inter-
mediate (i.e., 25) formed by [1,2]-SR participation fol-
lowed by enolization and subsequent ring opening (Scheme
4). Episulfonium ions are well-recognized reactive inter-
mediates that have been postulated many times in the
literature to rationalize the stereoselectivity observed
upon treating 1,2-thio alcohols with acid.30 A preferred
5-endo cyclization (rather than 4-exo) by the enol oxygen
atom on the three-membered cationic intermediate nicely
accounts for the observed products. The observed trans-
relationship of the methylthio groups in the final product
is seemingly related to thermodynamic issues. It is not
at all clear, however, why these cyclic â-hydroxy ketones
(i.e., 19 and 20) prefer to give dihydrofurans rather than
eliminate water, as was encountered with the acyclic
Sch em e 2
lowed for the facile and rapid access to the erythrinane
skeleton,21 there were limitations in the synthesis of the
starting thio-amidofuran system that prompted us to
explore alternate methods of preparing these useful
heterocycles. Consequently, we decided to develop a
general method for the preparation of 2-thio substituted
furans with the intention of using these substrates as
reactive dienes for alkaloid synthesis. In an earlier report
we described some preliminary results in this area,22 and
in this paper we expand on our initial findings.
Resu lts a n d Discu ssion
2-Alkylthio substituted furans have been prepared
from the acid-catalyzed cyclization of ketones onto vinyl
sulfides.23,24 A drawback to this procedure is that after
the thionium ion is trapped by the neighboring carbonyl
oxygen to furnish a dihydrofuran, a subsequent oxidation
step is necessary in order to produce the thiofuran ring
system (i.e., 6). In the absence of an oxidant, elimination
of the thiol group would normally occur leading to the
formation of a simple furan 7 (Scheme 2).
We reasoned that the use of a ketene dithioacetal
would allow for both the facile formation and subsequent
cyclization of a thionium ion and also permit rapid
(25) Kolb, M. Synthesis 1990, 171.
(26) Anderson, N.; Yamamoto, Y.; Denniston, A. Tetrahedron Lett.
1975, 4547.
(20) Ginn, J . D.; Lynch, S. M.; Padwa, A. Tetrahedron Lett. 2000,
41, 9387. Padwa, A.; Brodney, M. A.; Lynch, S. M. J . Org. Chem. 2001,
66, 1716.
(21) Padwa, A.; Rudiger, H.; Kappe, C. O.; Reger, T. S. J . Org. Chem.
1998, 63, 1144. Kappe, C. O.; Padwa, A. J . Org. Chem. 1996, 61, 6166.
(22) Padwa, A.; Ginn, J . D.; McClure, M. S. Org. Lett. 1999, 1, 1559.
(23) Hiroi, K.; Sato, H.; Chen, L.; Kotsuji, K. Chem. Pharm. Bull.
1987, 35, 1413.
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(28) Rigby, J .; Koitus, A.; Kramer, J . Tetrahedron Lett. 1983, 24,
2939. Rigby, J .; Koitus, A. Tetrahedron Lett. 1987, 28, 4943.
(29) Nakane, M.; Hutchinson, C. J . Org. Chem. 1978, 43, 3922.
(30) Nicolaou, K. C.; Ladduwahetty, T.; Randall, J . L.; Chucholowski,
A. J . Am. Chem. Soc. 1986, 108, 2466. McIntyre, S.; Warren, S.
Tetrahedron Lett. 1990, 31, 3457. Sansbury, F. H.; Warren, S.
Tetrahedron Lett. 1992, 33, 539.
(24) Kano, S.; Tanaka, Y.; Hibino, S.; Shibuya, S. J . Chem. Soc.,
Chem. Commun. 1979, 238.

Preparation of 2-Thio Substituted Furans
J . Org. Chem., Vol. 67, No. 5, 2002 1597
Sch em e 4
Sch em e 7
Sch em e 8
Sch em e 5
35 involves an acid-induced 1,3-hydrogen shift of 29 to
give 34, which is followed by conjugate addition of the
neighboring methylthio group onto the activated π-bond.
Once formed, episulfonium ion 35 can undergo a subse-
quent ring opening in the opposite direction to produce
thionium ion 36, which undergoes deprotonation and
double bond isomerization to give 33. A related set of
reactions also takes place when 33 is subjected to the
acidic conditions, eventually giving thioketene acetal 29
as the minor product (20%) from the equilibrating
mixture.
Sch em e 6
systems (i.e., 11 and 12). The closer proximity of the enol
oxygen atom to the episulfonium ion may play an
important role here. Restricted rotation about the bond
between the R-carbon and the carbonyl group could create
an environment wherein the enol oxygen atom is properly
oriented to facilitate the cyclization reaction.
Related rearrangements occurred with the amido
substituted ketene thioacetals 30 and 31 (Scheme 8).
Thus, heating a sample of pyrrolidinone 30 with cam-
phorsulfonic acid in toluene at 120 °C afforded the
rearranged thio-conjugated lactam 38 in 83% yield.
Similarly, the acid-catalyzed reaction of the homologous
piperidinone 31 furnished 39 as the major reaction
product (40%), together with lesser quantities (22%) of
40 derived by a 1,3-hydrogen shift from 39. Presumably
these products are formed in a fashion analogous to that
described above with the lactone system (see Scheme 7).
The difference in the acid-catalyzed behavior of 29-31
from that encountered with ketene thioacetals 13 and
14 may be related to the lower concentration of the enol
tautomer of the lactone and/or lactam, thereby permitting
methylthio group migration to compete with cyclization.
The series of steps shown in Scheme 7, although
credible in retrospect, was totally unexpected. Our in-
ability to prepare the furanyl systems 32 from the acid-
catalyzed reaction of the thioketene acetals 29-31 led
us to consider some alternate ways to synthesize these
compounds. It was known that treatment of thioketals
with dimethyl(methylthio)sulfonium tetrafluoroborate
(DMTSF)31 causes the carbon-sulfur bond to become
labile upon methylthiolation.32,33 The initially formed
Encouraged by the facility with which the above ketene
dithioacetals cyclized to give 2-alkylthio substituted
furans, we next investigated the related reaction using
substrates derived from the aldol condensation of lactones
and lactams with aldehyde 10 (Scheme 5). With these
systems, dehydration proceeded smoothly to give ketene
dithioacetals 29-31. However, when 29-31 were sub-
jected to the acid-catalyzed conditions employed earlier,
none of the desired furan (i.e., 32) could be detected.
Instead, products arising from a 1,2-methylthio shift were
isolated. For example, subjection of 29 to the aforemen-
tioned acidic conditions gave the rearranged thio-
conjugated lactone 33 in 80% yield together with unre-
acted starting material (Scheme 6). Interestingly, when
33 was subjected to the same acidic conditions, thioketene
acetal 29 was formed in 20% yield in addition to
recovered 33. We believe that the interconversion of 29
and 33 occurs via the transient episulfonium ion 35
(Scheme 7). The critical step leading to the formation of

1598 J . Org. Chem., Vol. 67, No. 5, 2002
Padwa et al.
Sch em e 9
Sch em e 12
Sch em e 10
first documented by Helmkamp and co-workers in their
work on the preparation of DMTSF and its addition to
alkenes and alkynes.36 These reactions, and related
studies by Meerwein,37 indicate that reagents such as
DMTSF may be regarded as sulfanyl derivatives and can
function as a potential source of alkylsulfanyl ions.31,38
It was known from earlier work in the literature that
carbon-sulfur bonds of sulfides become labile on alkyl-
sulfanylation and that the sulfonium ions so formed are
highly reactive intermediates that seldom can be iso-
lated.32 It follows, therefore, that the conversion of 44-
46 (or 50) to 47-49 (or 51) upon treatment with DMTSF
proceeds by the pathway outlined in Scheme 12. Meth-
ylthiolation of one of the methylthio groups with DMTSF
first produces an alkylthiosulfonium salt that easily
dissociates to generate thionium ion 52 and methyl
disulfide. Attack of the amido carbonyl oxygen onto the
cationic center produces dihydrofuran 53 as a transient
intermediate that readily loses acetic acid to furnish the
observed thio substituted furan 47.
Simple 2-alkylamino substituted furans such as 47 are
extremely susceptible toward hydrolysis and are difficult
to work with. However, the presence of an electron-
withdrawing group on the nitrogen atom (i.e., tosyl,
acetyl) stabilizes the furan ring and allows for the ready
isolation of substrates suitable for cycloaddition studies
(vide infra). Since we were particularly interested in
using N-acylamido furans containing olefinic tethers as
substrates for alkaloid synthesis, we required an easy
method for their preparation. The facility with which the
DMTSF-induced reaction of the acetoxy substituted thio-
acetal 44 gave furan 47 prompted us to investigate a
related approach toward various N-acylamido substituted
furans. After some experimentation, we found that these
systems can be prepared by the mixed aldol reaction of
the N-trimethylsilyl protected δ-valerolactam42 (or ꢀ-ca-
prolactam) with bis(methylsulfanyl)acetaldehyde 10.
Sch em e 11
alkylthiosulfonium ion easily dissociates to produce a
thionium ion and methyl disulfide.34,35 We reasoned that
by converting the hydroxyl group present in the lactone
and lactam derived aldol products to the corresponding
acetates, it should be possible to promote cyclization of
the lactone/lactam carbonyl group onto the resulting
thionium ion formed from the DMTSF-induced reaction.
Once the dihydrofuran ring has been forged, elimination
of acetic acid should proceed readily to furnish the desired
cyclic alkoxy and/or amido substituted furans. Indeed,
this two step protocol worked extremely well for acetates
41-43, resulting in the formation of thiofurans 17, 18,
and 23 in high yield (Scheme 9). Moreover, we found that
this protocol could also be successfully executed with
N-substituted lactams 44-46, giving rise to the corre-
sponding cyclic aminofurans 47-49 in 98%, 87%, and
78% yield, respectively (Scheme 10).
A representative example of a 2-oxo-5-thiofuran that
was prepared using this method is outlined in Scheme
11. Thus, the aldol product 26 derived from δ-valero-
lactone and aldehyde 10 was acetylated in high yield
using acetic anhydride. When the resulting acetate 50
was treated with DMSTF and NEt3, the cyclic 2-oxo-5-
thiofuran 51 was obtained in 40% yield. Although un-
stable to silica gel chromatography, furan 51 could be
purified by filtration through basic alumina and was
stable for prolonged periods when stored at -10 °C.
The ease with which the S-S bond of (dimethylthio)-
sulfonium salts are cleaved by nucleophilic reagents was
(35) Gra`cia, J .; Casamitjana, N.; Bonjoch, J .; Bosch, J . J . Org. Chem.
1994, 59, 3939.
(36) Helmkamp, G. K.; Pettitt, D. J . J . Org. Chem. 1963, 28, 2932.
Helmkamp, G. K.; Olsen, B. A.; Pettitt, D. J . J . Org. Chem. 1965, 30,
676. Helmkamp, G. K.; Cassey, H. N.; Olsen, B. A.; Pettitt, D. J . J .
Org. Chem. 1965, 30, 933. Helmkamp, G. K.; Olsen, B. A.; Kaskinen,
J . R. J . Org. Chem. 1965, 30, 1623. Helmkamp, G. K.; Owsley, D. C.;
Barnes, W. M.; Cassey, H. N. J . Am. Chem. Soc. 1968, 90, 1635.
(37) Meerwein, H.; Zenner, K. F.; Gipp, R. J ustus Liebigs Ann.
Chem. 1965, 688, 67.
(31) Kice, J .; Favstritsky, N. J . Am. Chem. Soc. 1969, 91, 1751.
(32) Smallcombe, S.; Caserio, M. J . Am. Chem. Soc. 1971, 93, 5826.
Kim, J .; Pau, J .; Caserio, M. J . Org. Chem. 1979, 44, 1544.
(33) Trost, B.; Murayama, E. J . Am. Chem. Soc. 1981, 103, 6529.
Trost, B.; Sato, T. J . Am. Chem. Soc. 1985, 107, 719.
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(38) Benesch, R. E.; Benesch, R. J . Am. Chem. Soc. 1958, 80, 1666.

Preparation of 2-Thio Substituted Furans
J . Org. Chem., Vol. 67, No. 5, 2002 1599
Sch em e 13
Sch em e 14
Sch em e 15
Quenching the reaction with acetic anhydride followed
by aqueous workup provided the expected aldol product
(i.e., 54 or 55) in high yield as a mixture of diastereomers
(Scheme 13). The cyclic lactams were acylated with acetic
anhydride or an acid chloride using powdered 4Å molec-
ular sieves as a neutral acid scavenger to provide the
corresponding imides 57-60 in high yield. Subsequent
treatment with DMTSF afforded the desired N-acylamido
furans 61-63 in yields ranging from 55% to 70%.
Compounds 56 and 60 are prepared from 1,1-bis(meth-
ylsulfanyl)butan-2-one instead of bis(methylsulfanyl)-
acetaldehyde (10). With this system the tertiary alcohol
does not need to be acylated for the subsequent trans-
formation to furan 64.
An unexpected acyl rearrangement was encountered
when N-pivaloyl-N-methylacetamide (65) was employed
as the starting amide. With this system, the initially
formed crossed-aldol intermediate 66 underwent a rapid
N-O acyl transfer reaction to provide the secondary
amide 67 upon aqueous workup. Further reaction of 67
with pivaloyl chloride afforded imide 68 in 80% yield,
which on treatment with DMTSF furnished the acyclic
amido thiofuran 69 in 61% yield (Scheme 14).
was whether the cyclic amido thiofuran system would
undergo an intramolecular Diels-Alder reaction, since
this step was critical for our planned alkaloid syntheses.
We therefore initiated a simple model study and discov-
ered that the thermolysis of the N-butenyl substituted
thioamido furan 62 furnished the rearranged hexahydro-
pyrroloquinolin-2-one 72 as the only isolable product in
92% yield as a 3:2 mixture of diastereomers after silica
gel chromatography (Scheme 15). Demethylthioation
occurred smoothly when a sample of 72 was subjected to
Raney-nickel reduction in 95% ethanol, producing 73 in
85% yield. The initially formed oxo-bridged cycloadduct
70 could not be isolated as it readily underwent ring
opening to produce the transient N-acyl iminium ion 71.
A subsequent 1,2-methylthio shift afforded the observed
product. The stage is now set for us to explore the
synthetic use of these thiofurans in [4 + 2]-cycloaddition
chemistry, and we will report our findings at a later date.
In summary, we have described a mild method for the
preparation of differentially substituted 2-alkylthio sub-
With a satisfactory method for the synthesis of the
cycloaddition precursors in place, we became interested
in evaluating the facility with which these thiofuranyl
systems would react. At the outset, our principal concern
(39) Barbero, M.; Cadamuro, S.; Degani, I.; Dughera, S.; Fochi, R.
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Chem. 1990, 55, 2682.

1600 J . Org. Chem., Vol. 67, No. 5, 2002
Padwa et al.
133.1, 136.0, 136.3, and 196.9. Anal. Calcd for C12H14OS2: C,
60.49; H, 5.93. Found: C, 60.24; H, 5.87.
stituted furans from readily available starting materials.
This method should be useful for the preparation of a
wide assortment of thio substituted furans containing
acid-sensitive functional groups. Application of this
methodology toward the construction of more complex
alkaloids is currently in progress in our laboratory.
2-Meth ylsu lfa n yl-5-p h en ylfu r a n (17). To a sample of 0.3
g (1.1 mmol) of 13 in toluene (11 mL) was added a catalytic
amount of camphorsulfonic acid. The reaction mixture was
heated to reflux for 6 h and was then cooled to room temper-
ature. The solvent was removed under reduced pressure, and
the residue was purified by flash silica gel chromatography to
give 0.15 g (72%) of 17 as a colorless oil: IR (neat) 1496, 1474,
1019, and 756 cm-1; 1H NMR (CDCl3, 300 MHz) δ 2.50 (s, 3H),
6.54 (d, 1H, J ) 3.4 Hz), 6.65 (d, 1H, J ) 3.4 Hz), 7.29 (m,
1H), 7.41 (m, 2H), and 7.71 (m, 2H); 13C NMR (CDCl3, 75 MHz)
δ 19.2, 106.5, 116.4, 123.6, 127.5, 128.6, 130.3, 146.7, and
155.9. Anal. Calcd for C11H10OS: C, 69.46; H, 5.30. Found: C,
69.28; H, 5.24.
4-Meth yl-6,6-bis(m eth ylsu lfa n yl)h ex-5-en -3-on e (14).
To a solution of 1.8 mL (13 mmol) of diisopropylamine in THF
(26 mL) at -40 °C was added n-butyllithium (5.6 mL of a 2.5
M solution in hexane). The reaction mixture was stirred at
this temperature for 40 min and was then cooled to -78 °C.
To this solution was added dropwise 1.2 mL (12 mmol) of
3-pentanone (9). The solution was stirred at -78 °C for 40 min,
and to this solution was added 1.4 g (10 mmol) of 2,2-bis-
(methylsulfanyl)acetaldehyde (10) dissolved in THF (10 mL).
The reaction mixture was stirred for 1 h and was quenched
with a saturated aqueous NH4Cl solution. The organic layer
was separated, and the aqueous layer was extracted with ethyl
acetate. The combined organic phase was dried over anhydrous
MgSO4. The solvent was removed under reduced pressure, and
the residue was purified by flash silica gel chromatography to
give 1.9 g (81%) of 5-hydroxy-4-methyl-6,6-bis(methylsulfanyl)-
hexan-3-one (12), which consisted of a 1:1 inseparable mixture
of diastereomers. The mixture was used in the next step
without further purification.
To a solution of 0.8 g (3.5 mmol) of the above alcohol in
toluene (18 mL) was added 0.7 mL (5 mmol) of Et3N followed
by 0.3 mL (4 mmol) of mesyl chloride. The reaction mixture
was stirred at 0 °C for 1 h, and to this solution was added 2.5
mL (9 mmol) of additional Et3N. The mixture was warmed to
room temperature for 30 min and was then heated at reflux
for 6 h. The reaction mixture was cooled to room temperature,
poured into ether, and washed with a saturated aqueous
NaHCO3 solution. The organic layer was dried over anhydrous
MgSO4, the solvent was removed under reduced pressure, and
the residue was purified by flash silica gel chromatography to
give 0.5 g (70%) of 14 as a colorless oil: IR (neat) 2968, 1709,
1446, and 848 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.98 (t, 3H,
J ) 7.1 Hz), 1.19 (d, 3H, J ) 7.0 Hz), 2.20 (s, 3H), 2.28 (s,
3H), 2.33-2.60 (m, 2H), 3.39 (q, 1H, J ) 7.0 Hz), and 6.16 (s,
1H); 13C NMR (CDCl3, 75 MHz) δ 7.96, 15.7, 15.9, 17.1, 33.6,
53.1, 129.5, 133.4, and 210.1; HRMS calcd for C9H16OS2
204.0643, found 204.0651.
2-Eth yl-3-m eth yl-5-(m eth ylsu lfa n yl)fu r a n (18). To a 0.6
g (3 mmol) sample of 14 in toluene (30 mL) was added a
catalytic amount of camphorsulfonic acid. The reaction mixture
was heated to reflux for 36 h then cooled to room temperature.
The solvent was removed under reduced pressure, and the
crude residue was purified by flash silica gel chromatography
to give 0.3 g (56%) of 18 as a colorless oil: IR (neat) 2919,
1432, 1190, and 1069 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.20
(t, 3H, J ) 7.6 Hz), 1.93 (s, 3H), 2.36 (s, 3H), 2.58 (q, 2H, J )
7.6 Hz), and 6.23 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 9.55,
12.8, 19.3, 19.6, 114.8, 118.0, 143.0, and 155.1. Anal. Calcd
for C8H12OS: C, 61.51; H, 7.75. Found: C, 61.42; H, 7.59.
2-(1-H y d r o x y -2,2-b is (m e t h y ls u lfa n y l)e t h y l)c y c lo -
h exa n on e (19). To a solution of 1.6 mL (11 mmol) of
diisopropylamine in THF (20 mL) at -40 °C was added
n-butyllithium (5 mL of a 2.5 M solution in hexane). The
reaction mixture was stirred at this temperature for 40 min
and was then cooled to -78 °C. To this mixture was added
dropwise 1.1 mL (10 mmol) of cyclohexanone. The solution was
stirred at -78 °C for 40 min, and 1.3 g (9 mmol) of 2,2-bis-
(methylsulfanyl)acetaldehyde (10) dissolved in THF (10 mL)
was added. The solution was stirred for 1 h and was then
quenched with a saturated aqueous NH4Cl solution. The
Exp er im en ta l Section
Melting points are uncorrected. Mass spectra were deter-
mined at an ionizing voltage of 70 eV. Unless otherwise noted,
all reactions were performed in flame-dried glassware under
an atmosphere of dry argon. Solutions were evaporated under
reduced pressure with a rotary evaporator, and the residue
was chromatographed on a silica gel column using a 5% ethyl
acetate/hexane mixture as the eluent unless specified other-
wise. All solids were recrystallized from 3% ethyl acetate/
hexane for analytical data.
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-Su bsti-
tu ted Th iofu r a n s Usin g DMTSF . To a sample of the
appropriate thioacetal using either CH2Cl2 or CH3CN (0.2 M)
as the solvent at -40 °C was added 1 equiv of DMTSF. The
mixture was stirred at -40 °C for 30 min and then warmed
to 0 °C. After 4 h of stirring at 0 °C, 5 equiv of Et3N was added.
The mixture was diluted with diethyl ether and poured into a
saturated aqueous NaHCO3 solution. The organic phase was
separated, and the aqueous phase was washed with ether. The
organic layer was dried over anhydrous K2CO3, the solvent
was removed under reduced pressure, and the residue was
subjected to silica gel chromatography.
3-H yd r oxy-4,4-b is(m et h ylsu lfa n yl)-1-p h en ylb u t a n -1-
on e (11). To a cooled solution of 1.3 mL (9.1 mmol) of
diisopropylamine at -40 °C in THF (18 mL) was added
n-butyllithium (4.0 mL of a 2.5 M solution in hexane). The
reaction mixture was stirred at this temperature for 40 min
and then cooled to -78 °C. To this solution was added dropwise
1.0 mL (8 mmol) of acetophenone (8). The reaction mixture
was stirred at -78 °C for 40 min, and to this solution was
added 1.0 g (7.5 mmol) of 2,2-bis(methylsulfanyl)acetaldehyde
(10)39 dissolved in THF (8 mL). The reaction mixture was
stirred for 1 h at -78 °C and was quenched with a saturated
NH4Cl solution. The organic layer was separated, and the
aqueous layer was extracted with ethyl acetate. The organic
phase was combined and dried over anhydrous MgSO4. The
solvent was removed under reduced pressure, and the residue
was purified by flash silica gel chromatography to give 1.6 g
(84%) of 11 as a colorless oil: IR (neat) 3467, 1674, 1211, and
1040 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.14 (s, 3H), 2.18 (s,
3H), 3.32 (dd, 1H, J ) 17.4 and 8.0 Hz), 3.47 (d, 1H, J ) 3.2
Hz), 3.48 (dd, 1H, J ) 17.4 and 3.6 Hz), 3.80 (d, 1H, J ) 6.0
Hz), 4.44 (m, 1H), 7.42 (dd, 2H, J ) 8.2 and 7.8 Hz), 7.53 (t,
1H, J ) 8.2 Hz), and 7.93 (d, 2H, J ) 7.8 Hz); 13C NMR (100
MHz, CDCl3) δ 13.6, 14.4, 42.3, 60.5, 69.2, 128.0, 128.4, 133.3,
136.5, and 199.1; HRMS calcd for C12H16O2S2 256.0592, found
256.0587.
4,4-Bis(m et h ylsu lfa n yl)-1-p h en ylb u t -3-en -1-on e (13).
To a solution containing 0.9 g (3.6 mmol) of alcohol 11 in
toluene (18 mL) at 0 °C was added 0.8 mL (5.4 mmol) of Et3N
and 0.3 mL (4 mmol) of mesyl chloride. The reaction mixture
was stirred at 0 °C for 1 h, and to this solution was added 2.5
mL (9 mmol) of additional Et3N. The mixture was warmed to
room temperature for 30 min and was then heated at reflux
for 6 h. The reaction mixture was cooled to room temperature,
poured into ether, and washed with a saturated aqueous
sodium bicarbonate solution. The organic layer was dried over
anhydrous MgSO4, and the solvent was removed under
reduced pressure. The crude oil was purified by flash silica
gel chromatography to give 0.65 g (76%) of 13 as a colorless
oil: IR (neat) 1681, 1595, 1332, and 1204 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 2.33 (s, 3H), 2.34 (s, 3H), 4.10 (d, 2H, J )
6.6 Hz), 6.13 (t, 1H, J ) 6.6 Hz), 7.48 (dd, 2H, J ) 8.2 and 7.6
Hz), 7.58 (t, 1H, J ) 7.6 Hz), and 8.00 (d, 2H, J ) 8.2 Hz); 13
C
NMR (CDCl3, 75 MHz) δ 16.8, 17.0, 40.2, 124.2, 128.1, 128.5,

Preparation of 2-Thio Substituted Furans
J . Org. Chem., Vol. 67, No. 5, 2002 1601
organic layer was separated, and the aqueous layer was
extracted with ethyl acetate. The combined organic phase was
dried over anhydrous MgSO4. The solvent was removed under
reduced pressure, and the residue was purified by flash silica
gel chromatography to give 1.6 g (74%) of 19 as a white solid:
mp 75-76.5 °C; IR (neat) 3504, 1697, and 1125 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 1.59-1.78 (m, 3H), 1.91 (m, 1H), 2.08 (m,
2H), 2.16 (s, 3H), 2.17 (s, 3H), 2.19-2.44 (m, 2H), 2.95 (m, 1H),
3.56 (d, 1H, J ) 4.8 Hz), 3.86 (d, 1H, J ) 5.6 Hz), and 3.90 (m,
1H); 13C NMR (CDCl3, 100 MHz) δ 13.2, 14.0, 24.8, 27.5, 30.9,
42.8, 53.3, 57.9, 75.0, and 214.6. Anal. Calcd for C10H18O2S2:
C, 51.27; H, 7.75. Found: C, 51.04; H, 7.52.
layer was dried over anhydrous MgSO4, the solvent was
removed under reduced pressure, and the residue was purified
by flash silica gel chromatography to give 0.4 g (94%) of 22 as
a white solid: mp 86-87 °C; IR (neat) 2919, 1674, 1417, and
1
905 cm-1; H NMR (CDCl3, 400 MHz) δ 2.02 (s, 3H), 2.32 (s,
3H), 2.47 (m, 2H), 2.99 (t, 2H, J ) 7.9 Hz), 3.87 (dt, 1H, J )
3.5 and 1.3 Hz), 5.74 (d, 1H, J ) 3.5 Hz), 7.20 (m, 3H), and
7.33 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 11.1, 13.5, 20.0,
28.4, 56.8, 93.6, 107.7, 120.9, 126.3, 127.2, 127.4, 128.1, 136.4,
150.7. Anal. Calcd for C14H16OS2: C, 63.62; H, 6.11. Found:
C, 63.55; H, 5.89.
2-Met h ylsu lfa n yl-4,5-t et r a h yd r on a p h t h o[1,2-b]fu r a n
(24). To a 0.3 g (1.2 mmol) sample of 22 in toluene (25 mL)
was added a catalytic amount of camphorsulfonic acid. The
mixture was heated at reflux for 6 h and was then cooled to
room temperature. The solvent was removed under reduced
pressure, and the residue was purified by flash silica gel
chromatography to give 0.23 g (89%) of 24 as a colorless oil:
tr a n s-2,3-Bis(m eth ylsu lfan yl)-2,3,4,5,6,7-h exah ydr oben -
zofu r a n (21). To a sample of 19 in toluene (14 mL) at 0 °C
was added 0.6 mL (4 mmol) of Et3N followed by 0.2 mL (3
mmol) of mesyl chloride. The mixture was stirred at 0 °C for
1 h, and 1.0 mL (7 mmol) of additional Et3N was added. The
solution was warmed to room temperature for 30 min and was
then heated to reflux for 6 h. The mixture was cooled to room
temperature, poured into ether, and washed with a saturated
aqueous NaHCO3 solution. The organic layer was dried over
anhydrous MgSO4, the solvent was removed under reduced
pressure, and the residue was purified by flash silica gel
chromatography to give 0.4 g (66%) of 21 as a colorless oil: IR
1
IR (neat) 2919, 1773, 1674, and 1040 cm-1; H NMR (CDCl3,
300 MHz) δ 2.46 (s, 3H), 2.70 (t, 2H, J ) 7.6 Hz), 2.95 (t, 2H,
J ) 7.6 Hz), 6.40 (s, 1H), 7.12-7.26 (m, 3H), and 7.49 (d, 1H,
J ) 7.6 Hz); 13C NMR (CDCl3, 75 MHz) δ 19.5, 20.9, 29.0,
115.6, 119.3, 120.6, 126.5, 126.6, 127.5, 127.8, 134.4, 146.5,
and 152.0. Anal. Calcd for C13H12OS: C, 72.20; H, 5.60.
Found: C, 72.14; H, 5.51.
1
(neat) 2925, 1704, 1195, and 916 cm-1; H NMR (CDCl3, 400
MHz) δ 1.59-1.76 (m, 4H), 1.95 (s, 3H), 1.97-2.20 (m, 4H),
2.23 (s, 3H), 3.63 (bs, 1H), 5.46 (d, 1H, J ) 3.2 Hz); 13C NMR
(CDCl3, 75 MHz) δ 11.0, 13.6, 21.2, 22.5, 22.6, 23.1, 57.0, 92.5,
105.4, 152.9. Anal. Calcd for C10H16OS2: C, 55.54; H, 7.46.
Found: C, 55.36; H, 7.25.
3-(1-H yd r oxy-2,2-b is(m e t h ylsu lfa n yl)e t h yl)t e t r a h y-
d r op yr a n -2-on e (26). To a 1.5 mL (11 mmol) solution of
diisopropylamine in THF (22 mL) at -40 °C was added
n-butyllithium (5 mL of a 2.5 M solution in hexane). The
reaction mixture was stirred at this temperature for 40 min
and was then cooled to -78 °C. To this solution was added
1.0 g (10 mmol) of δ-valerolactone. The solution was stirred
at -78 °C for 40 min, and 1.2 g (9.0 mmol) of 2,2-bis-
(methylsulfanyl)acetaldehyde (10) dissolved in THF (9 mL)
was added. The reaction mixture was stirred for 1 h and was
quenched with a saturated aqueous NH4Cl solution. The
organic layer was separated, and the aqueous layer was
extracted with ethyl acetate. The combined organic phase was
dried over anhydrous MgSO4, the solvent was removed under
reduced pressure, and the residue was purified by silica gel
chromatography to give 1.5 g (71%) of 26 as a colorless oil: IR
(neat) 3483, 1718, 1390, and 1084 cm-1; 1H NMR (CDCl3, 400
MHz) δ 1.77 (m, 1H), 1.90 (m, 2H), 2.02 (m, 1H), 2.11 (s, 3H),
2.14 (s, 3H), 3.10 (ddd, 1H, J ) 12.4, 8.0 and 4.8 Hz), 3.70 (d,
1H, J ) 3.2 Hz), 3.83 (m, 1H), 4.02 (d, 1H, J ) 7.2 Hz), and
4.31 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 12.2, 13.9, 21.9,
22.3, 42.8, 58.0, 68.6, 74.3, and 173.0; HRMS calcd for
C9H16O3S2 236.0541, found 236.0540.
2-Met h ylsu lfa n yl-4,5,6,7-t et r a h yd r ob en zofu r a n (23).
To a sample of 0.8 g (2.7 mmol) of 21 in toluene (90 mL) was
added a catalytic amount of camphorsulfonic acid. The mixture
was heated at reflux for 6 h and was then cooled to room
temperature. The solvent was removed under reduced pres-
sure, and the crude residue was purified by silica gel chroma-
tography to give 0.4 g (87%) of 23 as a colorless oil: IR (neat)
2932, 1495, and 1118 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.70
(m, 2H), 1.81 (m, 2H), 2.36 (s, 3H), 2.35-2.39 (m, 2H), 2.55-
2.59 (m, 2H), and 6.26 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ
19.7, 21.9, 22.9 (2), 23.3, 116.3, 118.7, 144.1, and 153.7. Anal.
Calcd for C9H12OS: C, 64.26; H, 7.20. Found: C, 64.13; H, 7.09.
2-(1-Hydr oxy-2,2-bis(m eth ylsu lfan yl)eth yl)-3,4-dih ydr o-
2H-n a p h th a len -1-on e (20). To a solution of 1.1 mL (7.5
mmol) of diisopropylamine in THF (14 mL) at -40 °C was
added n-butyllithium (3.3 mL of a 2.5 M solution in hexane).
The reaction mixture was stirred at this temperature for 40
min and was then cooled to -78 °C. To this solution was added
0.9 mL (6.8 mmol) of R-tetralone. The solution was stirred at
-78 °C for 40 min, and 0.8 g (6.2 mmol) of 2,2-bis(methylsul-
fanyl)acetaldehyde (10) dissolved in THF (7 mL) was added.
The mixture was stirred for 1 h and was quenched with a
saturated aqueous NH4Cl solution. The organic layer was
separated, and the aqueous layer was extracted with ethyl
acetate. The combined organic phase was dried over anhydrous
MgSO4. The solvent was removed under reduced pressure, and
the residue was purified by silica gel chromatography to give
1.0 g (58%) of 20 as a colorless oil: IR (neat) 3495, 2919, 1674,
1595, 1453, and 1289 cm-1; 1H NMR (CDCl3, 400 MHz) δ 2.17
(s, 3H), 2.19 (s, 3H), 2.14-2.56 (m, 2H), 2.91 (d, 1H, J ) 2.8
Hz), 3.02-3.13 (m, 3H), 3.89 (d, 1H, J ) 9.0 Hz), 4.49 (ddd,
1H, J ) 9.0, 3.2, and 2.8 Hz), 7.23 (m, 2H), 7.47 (dt, 1H, J )
7.3 and 1.5 Hz), and 8.03 (dd, 1H, J ) 7.8 and 1.5 Hz); 13C
NMR (CDCl3, 100 MHz) δ 12.1, 13.8, 22.3, 28.8, 49.9, 59.1,
69.5, 126.5, 127.3, 128.5, 132.6, 133.4, 143.9, and 198.4; HRMS
calcd for C14H18O2S2 282.0748, found 282.0746.
3-(2,2-Bis(m et h ylsu lfa n yl)vin yl)t et r a h yd r op yr a n -2-
on e (29). To a 0.7 g (3 mmol) sample of 26 in toluene (14 mL)
at 0 °C was added 0.6 mL (4.3 mmol) of Et3N followed by 0.25
mL (3 mmol) of mesyl chloride. The reaction mixture was
stirred at 0 °C for 1 h, and 1.0 mL (7.2 mmol) of additional
Et3N was added. The mixture was warmed to room temper-
ature for 30 min and then heated at reflux for 6 h. The reaction
mixture was cooled to room temperature, poured into ether,
and washed with a saturated aqueous NaHCO3 solution. The
organic layer was dried over anhydrous MgSO4, the solvent
was removed under reduced pressure, and the residue was
purified by flash silica gel chromatography to give 0.4 g (62%)
of 29 as a colorless oil: IR (neat) 2925, 1725, 1628, and 1139
1
cm-1; H NMR (CDCl3, 400 MHz) δ 1.85-2.14 (m, 4H), 2.28
(s, 3H), 2.32 (s, 3H), 3.44 (dd, 1H, J ) 10.4 and 7.2 Hz), 4.36
(dd, 1H, J ) 7.2 and 5.2 Hz), and 6.43 (s, 1H); 13C NMR (CDCl3,
100 MHz) δ 16.2, 16.8, 21.9, 26.0, 50.5, 69.6, 127.8, 138.7, and
170.9; HRMS calcd for C9H14O2S2 218.0435, found 218.0428.
3-(1,2-Bis(m eth ylsu lfan yl)eth yliden e)tetr ah ydr opyr an -
2-on e (33). To a 0.3 g (1.4 mmol) sample of 29 in toluene (20
mL) was added a catalytic amount of camphorsulfonic acid.
The reaction mixture was heated at reflux for 3 h, cooled to
room temperature, poured into ether, and washed with a
saturated aqueous NaHCO3 solution. The organic layer was
separated and dried over anhydrous MgSO4. The solvent was
removed under reduced pressure, and the residue was purified
by silica gel chromatography to give 0.25 g (80%) of 33 as a
tr a n s-2,3-Bis(m eth ylsu lfa n yl)-2,3,4,5-tetr a h yd r on a p h -
th o[1,2-b]fu r a n (22). To a solution of 0.5 g (1.7 mmol) of 20
in toluene (9 mL) at 0 °C was added 0.4 mL (2.6 mmol) of Et3N
followed by 0.15 mL (1.9 mmol) of mesyl chloride. The reaction
mixture was stirred at 0 °C for 1 h, and 0.6 mL (4.3 mmol) of
additional Et3N was added. The mixture was warmed to room
temperature for 30 min and then heated to reflux for 6 h. The
solution was cooled to room temperature, poured into ether,
and washed with a saturated solution of NaHCO3. The organic

1602 J . Org. Chem., Vol. 67, No. 5, 2002
Padwa et al.
colorless oil: IR (neat) 2918, 1683, 1544, and 1111 cm-1; H
NMR (CDCl3, 400 MHz) δ 1.93 (m, 2H), 2.11 (s, 3H), 2.48 (S,
3H), 2.52 (t, 2H, J ) 7.2 Hz), 4.11 (s, 2H), and 4.18 (t, 2H, J
) 5.2 Hz); 13C NMR (CDCl3, 100 MHz) δ 13.9, 14.5, 22.7, 26.8,
31.3, 67.6, 119.2, 154.3, and 164.6; HRMS calcd for C9H14O2S2
218.0435, found 218.0431.
3.63 (d, 1H, J ) 9.6 Hz), and 4.32 (dd, 1H, J ) 9.6 and 2.8
Hz); 13C NMR (100 MHz, CDCl3) δ 11.3, 13.3, 19.8, 22.0, 35.0,
1
44.0, 49.7, 58.7, 70.5, and 170.7. Anal. Calcd for C10H19
-
NO2S2: C, 48.18; H, 7.69; N, 5.62. Found: C, 48.13; H, 7.48;
N, 5.47.
3-(2,2-Bis(m eth ylsu lfa n yl)vin yl)-1-m eth yl-p ip er id in -2-
on e (31). To a 3.8 g (15 mmol) sample of 28 in toluene (70
mL) at 0 °C was added 3 mL (23 mmol) of Et3N followed by
1.3 mL (17 mmol) of mesyl chloride. The reaction mixture was
stirred at 0 °C for 2 h, and 5.3 mL (38 mmol) of additional
Et3N was added. The mixture was warmed to room temper-
ature for 2 h and was then heated at reflux for 6 h. The
solution was cooled to room temperature and was poured into
ether. The organic phase was washed with 10% NaOH,
followed by brine, and then dried over anhydrous MgSO4. Silica
gel chromatography provided 2.7 g (78%) of 31 as a colorless
3-(2,2-Bis(m eth ylsu lfa n yl)vin yl)-1-m eth yl-p yr r olid in -
2-on e (30). To a solution of 1.6 mL (11 mmol) of diisopropyl-
amine in THF (22 mL) at -40 °C was added n-butyllithium
(5 mL of a 2.5 M solution in hexane). The reaction mixture
was stirred at this temperature for 40 min and was then cooled
to -78 °C. To this solution was added 1.0 g (10 mmol) of
N-methylpyrrolidinone. The solution was stirred at -78 °C for
40 min, and 1.2 g (9.1 mmol) of 2,2-bis(methylsulfanyl)-
acetaldehyde (10) dissolved in THF (9 mL) was added. The
reaction mixture was stirred for 1 h and was quenched with a
saturated aqueous NH4Cl solution. The organic layer was
separated, and the aqueous layer was extracted with ethyl
acetate. The combined organic phase was dried over anhydrous
MgSO4, the solvent was removed under reduced pressure, and
the residue was purified by flash silica gel chromatography to
give 1.3 g (61%) of 3-[(1-hydroxy-2,2-bis(methylsulfanyl)ethyl)]-
1-methylpyrrolidin-2-one (27) as a 1:1 inseparable mixture of
diastereomers, which was used directly in the next step
without further purification.
oil: IR (neat) 2919, 1638, 1496, and 1047 cm-1 1H NMR
;
(CDCl3, 400 MHz) δ 1.70-1.78 (m, 1H), 1.80-1.90 (m, 2H),
1.99-2.07 (m, 1H), 2.23 (s, 3H), 2.29 (s, 3H), 2.93 (s, 3H), 3.19-
3.27 (m, 2H), 3.32-3.38 (m, 1H), and 6.24 (s, 1H); 13C NMR
(CDCl3, 100 MHz) δ 15.9, 16.8, 20.9, 27.4, 35.0, 50.0, 51.0,
130.2, 136.1, and 169.2; HRMS calcd for C10H17NOS2 231.0752,
found 231.0751.
3-(1,2-Bis(m eth ylsu lfa n yl)eth ylid en e)-1-m eth yl-p ip er i-
d in -2-on e (39). To a 0.7 g (3.2 mmol) sample of 31 in toluene
(30 mL) was added a catalytic amount of camphorsulfonic acid.
The reaction mixture was heated at reflux for 24 h and then
cooled to room temperature. The solvent was removed under
reduced pressure, and the crude residue was purified by flash
silica gel chromatography to give 0.07 g (10%) of recovered
starting material and 0.3 g (41%) of a clear oil whose structure
was assigned as 39 on the basis of its spectral properties: IR
(neat) 3395, 1617, 1553, and 1190 cm-1; 1H NMR (CDCl3, 400
MHz) δ 1.87 (m, 2H), 2.14 (s, 3H), 2.42 (s, 3H), 2.61 (t, 2H, J
) 6.4 Hz), 2.98 (s, 3H), 3.30 (t, 2H, J ) 5.6 Hz), and 4.27 (s,
2H); 13C NMR (CDCl3, 100 MHz) δ 14.3, 14.7, 23.0, 28.5, 31.8,
To a 1.3 g (5.6 mmol) sample of the above alcohol in toluene
(28 mL) at 0 °C was added 1.2 mL (8 mmol) of Et3N followed
by 0.5 mL (6 mmol) of mesyl chloride. The mixture was stirred
at 0 °C for 1 h, and 1.9 mL (14 mmol) of additional Et3N was
added. The mixture was warmed to room temperature for 30
min and then heated at reflux for 6 h. The solution was cooled
to room temperature, poured into ether, and washed with a
saturated solution of NaHCO3. The organic layer was dried
over anhydrous MgSO4, the solvent was removed under
reduced pressure, and the residue was purified by flash silica
gel chromatography to give 0.8 g (65%) of 30 as a colorless oil:
1
IR (neat) 2919, 1688, 1282, and 1097 cm-1; H NMR (CDCl3,
35.4, 49.6, 125.5, 145.1, and 164.4; HRMS calcd for C10H17
NOS2 231.0752, found 231.0748.
-
300 MHz) δ 2.02-2.22 (m, 2H), 2.25 (s, 3H), 2.32 (s, 3H), 2.86
(s, 3H), 3.25-3.45 (m, 3H), and 6.45 (s, 1H); 13C NMR (CDCl3,
75 MHz) δ 16.1, 16.9, 24.9, 30.1, 47.6, 50.9, 128.3, 137.5, and
173.2; HRMS calcd for C9H15NOS2 217.0595, found 217.0595.
3-(1,2-Bis(m eth ylsu lfa n yl)eth ylid en e)-1-m eth ylp yr r o-
lid in -2-on e (38). To a solution of 0.6 g (2.7 mmol) of 30 in
toluene (30 mL) was added a catalytic amount of camphor-
sulfonic acid. The reaction mixture was heated at reflux for
16 h and cooled to room temperature. The solvent was removed
under reduced pressure, and the residue was purified by flash
silica gel chromatography to give 0.5 g (83%) of 38 as a white
solid: mp 78-79 °C; IR (neat) 2919, 1666, 1425, and 1076
3-(1,2-Bis(m eth ylsu lfa n yl)vin yl)-1-m eth yl-p ip er id in -2-
on e (40). The minor fraction that was isolated from the
chromatography column contained 0.16 g (22%) of a colorless
oil whose structure was assigned as 40 on the basis of its
spectral properties: IR (neat) 2919, 1638, 1432, and 1197 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 1.83 (m, 1H), 1.98 (m, 3H), 2.28
(s, 3H), 2.29 (s, 3H), 2.95 (s, 3H), 3.26 (m, 1H), 3.41 (dt, 1H, J
) 11.6 and 4.0 Hz), 3.73 (dd, 1H, J ) 10.0 and 6.8 Hz), and
5.85 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 16.8, 17.9, 22.5,
27.2, 35.1, 47.2, 50.1, 122.4, 136.5, and 168.4; HRMS calcd for
C
10H17NOS2 231.0752, found 231.0756.
1
cm-1; H NMR (CDCl3, 300 MHz) δ 1.97 (s, 3H), 2.31 (s, 3H),
Acet ic Acid 1-(Bis(m et h ylsu lfa n yl)m et h yl)-3-oxo-3-
2.57 (t, 2H, J ) 6.6 Hz), 2.76 (s, 3H), 3.26 (t, 2H, J ) 6.6 Hz),
p h en yl-p r op yl Ester (41). To a 0.7 g (2.5 mmol) sample of
alcohol 11 in CH2Cl2 (5 mL) at 0 °C were added 0.6 mL (7.6
mmol) of pyridine, 0.03 g (0.25 mmol) of DMAP, and 0.5 mL
(5 mmol) of acetic anhydride. The mixture was stirred at 0 °C
for 2 h, warmed to room temperature for 10 min, and poured
into a saturated aqueous NaHCO3 solution. The organic phase
was separated, and the aqueous layer was extracted with
CH2Cl2. The combined organic layer was washed with brine
and dried over anhydrous MgSO4. The solvent was removed
under reduced pressure, and the crude residue was purified
by flash silica gel chromatography to give 0.7 g (96%) of 41 as
a colorless oil: IR (neat) 2904, 1736, 1225, and 1026 cm-1; 1H
NMR (CDCl3, 400 MHz) δ 2.05 (s, 3H), 2.21 (s, 3H), 2.23 (s,
3H), 3.46 (dd, 1H, J ) 17.5 and 7.3 Hz), 3.61 (dd, 1H, J ) 17.5
and 5.1 Hz), 4.02 (d, 1H, J ) 4.4 Hz), 5.75 (ddd, 1H, J ) 7.3,
5.1 and 4.4 Hz), 7.47 (t, 2H, J ) 8.3 Hz), 7.58 (t, 1H, J ) 7.9
Hz), and 7.96 (d, 2H, J ) 7.3 Hz); 13C NMR (CDCl3, 100 MHz)
δ 14.7, 15.0, 21.0, 39.9, 57.4, 71.3, 128.1, 128.7, 133.4, 136.6,
170.1, and 196.5; HRMS calcd for C14H18O3S2 298.0697, found
298.0695. Treatment of this acetate with DMTSF and NEt3
gave furan 17 in 93% yield.
and 4.18 (s, 2H); 13C NMR (CDCl3, 75 MHz) δ 13.0, 14.0, 25.0,
27.9, 29.8, 45.4, 124.7, 140.9, and 166.2. Anal. Calcd for C9H15
-
NOS2: C, 49.74; H, 6.96; N, 6.44. Found: C, 49.89; H, 7.08;
N, 6.49.
3-(1-Hydr oxy-2,2-bis(m eth ylsu lfan yl)eth yl)-1-m eth ylpi-
p er id in -2-on e (28). To a 11 mL (77 mmol) solution of
diisopropylamine in THF (150 mL) at -40 °C was added
n-butyllithium (34 mL of a 2.5 M solution in hexane). The
reaction mixture was stirred at this temperature for 40 min
and was then cooled to -78 °C. To this solution was added 8
mL (70 mmol) of N-methylpiperidone. The solution was stirred
at -78 °C for 40 min, and 8.6 g (63 mmol) of 2,2-bis-
(methylsulfanyl)acetaldehyde (10) in THF (130 mL) was added.
The reaction mixture was stirred for 1 h and was quenched
with a saturated aqueous NH4Cl solution. The organic layer
was separated, and the aqueous layer was extracted with ethyl
acetate. The combined organic phase was dried over anhydrous
MgSO4, the solvent was removed under reduced pressure, and
the residue was purified by flash silica gel chromatography to
give 11.4 g (73%) of 28 as a 1.7:1 mixture of diastereomers.
The major diastereomer was crystallized from ethyl acetate:
Acetic Acid 1-(Bis(m eth ylsu lfa n yl)m eth yl)-2-m eth yl-
3-oxo-p en tyl Ester (42). To a 0.9 g (4.0 mmol) sample of
alcohol 12 in CH2Cl2 (8 mL) at 0 °C were added 1 mL (12 mmol)
of pyridine, 0.05 g (0.4 mmol) of DMAP, and 0.8 mL (8 mmol)
1
mp 90-91 °C; IR (neat) 3388, 1617, 1197, and 1083 cm-1; H
NMR (400 MHz, CDCl3) δ 1.75-1.91 (m, 4H), 2.07 (s, 3H), 2.10
(s, 3H), 2.75 (m, 1H), 2.90 (s, 3H), 3.28 (m, 1H), 3.31 (m, 1H),

Preparation of 2-Thio Substituted Furans
J . Org. Chem., Vol. 67, No. 5, 2002 1603
of acetic anhydride. The reaction mixture was stirred at 0 °C
for 2 h, warmed to room temperature for 10 min, and poured
into a saturated aqueous NaHCO3 solution. The organic phase
was separated, and the aqueous layer was extracted with
CH2Cl2. The combined organic layer was washed with brine
and dried over anhydrous MgSO4. The solvent was removed
under reduced pressure, and the residue was purified by flash
silica gel chromatography to give 1.0 g (93%) of the syn
3.03 (m, 2H), and 6.31 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
20.4, 21.3, 22.8, 38.3, 51.9, 96.5, 119.8, 135.6, and 157.6; HRMS
calcd for C9H13NOS 183.0718, found 183.0718.
3-(1-Hyd r oxy-2,2-bis(m eth ylsu lfa n yl)eth yl-1-(tolu en e-
4-su lfon yl)-p ip er id in -2-on e. To a 1.2 mL (8.7 mmol) solution
of diisopropylamine in THF (40 mL) at -40 °C was added
n-butyllithium (3.6 mL of a 2.5 M solution in hexane). The
mixture was stirred at this temperature for 40 min and then
cooled to -78 °C. To this solution was added a 2.0 g (8 mmol)
sample of N-(p-toluenesulfonyl)-δ-valerolactam40 in hot toluene
(20 mL). The solution was stirred at -78 °C for 40 min, and
1.0 g (7.5 mmol) of 2,2-bis(methylsulfanyl)acetaldehyde (10)
dissolved in THF (8 mL) was added. The mixture was stirred
for 1 h and quenched with a saturated aqueous NH4Cl solution.
The organic layer was separated, and the aqueous layer was
extracted with ethyl acetate. The combined organic phase was
dried over anhydrous MgSO4. The solvent was removed under
reduced pressure, and the residue was purified by flash silica
gel chromatography to give 2.2 g (76%) of the above titled
compound as a colorless oil: IR (neat) 3509, 1688, 1168, and
1
diastereomer of 42: IR (neat) 2969, 1709, and 1218 cm-1; H
NMR (CDCl3, 400 MHz) δ 1.03 (t, 3H, J ) 7.3 Hz), 1.14 (d,
3H, J ) 7.0 Hz), 2.05 (s, 3H), 2.14 (s, 3H), 2.17 (s, 3H), 2.42-
2.61 (m, 2H), 3.23 (dq, J ) 7.3 and 7.0 Hz), 3.83 (d, 1H, J )
5.2 Hz), and 5.37 (dd, 1H, J ) 7.3 and 5.2 Hz); 13C NMR
(CDCl3, 100 MHz) δ 7.60, 13.6, 13.8, 14.6, 20.7, 35.2, 47.7, 56.2,
74.6, 169.8, and 211.4; HRMS calcd for C9H16OS2 264.0854,
found 264.0852. Treatment of this acetate with DMTSF and
NEt3 gave furan 18 in 91% yield.
Acetic Acid 2,2-Bis(m eth ylsu lfa n yl)-1-(2-oxo-cycloh ex-
yl) Eth yl Ester (43). To a 0.8 g (3.4 mmol) sample of 19 in
CH2Cl2 (7 mL) at 0 °C were added 0.8 mL (10 mmol) of
pyridine, 0.04 g (0.3 mmol) of DMAP, and 0.6 mL (6.8 mmol)
of acetic anhydride. The reaction mixture was stirred at 0 °C
for 2 h, warmed to room temperature for 10 min, and poured
into a saturated aqueous NaHCO3 solution. The organic phase
was separated, and the aqueous layer was extracted with
CH2Cl2. The combined organic layer was washed with brine
and dried over anhydrous MgSO4. The solvent was removed
under reduced pressure, and the residue was purified by flash
silica gel chromatography to give 0.9 g (90%) of 43 as a color-
1
1083 cm-1; H NMR (CDCl3, 400 MHz) δ 1.65 (m, 1H), 1.76-
1.90 (m, 2H), 1.91-2.10 (m, 1H), 2.00 (s, 3H), 2.08 (s, 3H), 2.43
(s, 3H), 2.96 (m, 1H), 3.42 (s, 1H), 3.76-3.92 (m, 3H), 4.10 (m,
1H), 7.29 (d, 2H, J ) 7.9 Hz), and 7.86 (d, 2H, J ) 7.9 Hz); 13
C
NMR (CDCl3, 100 MHz) δ 12.2, 13.6, 21.6, 22.6, 23.4, 46.4,
46.5, 58.4, 74.0, 128.6, 128.7, 129.3, 144.7, and 171.5; HRMS
calcd for C16H23NO4S3 389.0789, found 389.0788.
Acetic Acid 2,2-Bis(m eth ylsu lfan yl)-1-[2-oxo-1-(tolu en e-
4-su lfon yl)-p ip er id in -3-yl] Eth yl Ester (45). To a 3.9 g (10
mmol) sample of the above compound in CH2Cl2 (20 mL) at 0
°C were added 2.4 mL (30 mmol) of pyridine, 0.12 g (1.0 mmol)
of DMAP, and 1.9 mL (20 mmol) of acetic anhydride. The
reaction mixture was stirred at 0 °C for 2 h, warmed to room
temperature for 10 min, and poured into a saturated aqueous
NaHCO3 solution. The organic phase was separated, and the
aqueous layer was extracted with CH2Cl2. The combined
organic layer was washed with brine and dried over anhydrous
MgSO4. The solvent was removed under reduced pressure, and
the residue was crystallized to give 3.6 g (84%) of 45 as a white
solid: mp 140-141.5 °C; IR (neat) 2919, 1745, 1225, and 1161
cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.57-1.73 (m, 1H), 1.74-
1.82 (m, 1H), 1.79 (s, 3H), 1.94-1.97 (m, 1H), 1.99 (s, 3H), 2.00
(s, 3H), 2.04-2.10 (m, 1H), 2.42 (s, 3H), 2.96 (ddd, 1H, J )
11.7, 6.7 and 2.5 Hz), 3.63 (dt, 1H, J ) 12.1 and 3.8 Hz), 3.97
(d, 1H, J ) 10.2 Hz), 4.21 (m, 1H), 5.31 (dd, 1H, J ) 10.2 and
2.5 Hz), 7.28 (d, 2H, J ) 8.3 Hz), and 7.87 (d, 2H, J ) 8.3 Hz);
13C NMR (CDCl3, 100 MHz) δ 12.0, 13.1, 20.8, 21.6, 22.8, 23.0,
46.0, 46.7, 55.5, 73.2, 128.8, 129.1, 136.1, 144.5, 168.1, and
169.7. Anal. Calcd for C18H25NO5S3: C, 50.09; H, 5.84; N, 3.25.
Found: C, 50.05; H, 5.89; N, 3.25.
N-(Tolu en e-4-su lfon yl)-2-m eth ylsu lfan yl-4,5,6,7-tetr ah y-
d r ofu r o[2,3-b]-p yr id in e (48). To a 0.05 g (0.1 mmol) sample
of 45 in CH2Cl2 (5 mL) at -40 °C was added 0.03 g (0.1 mmol)
of DMTSF. Following the general procedure, flash silica gel
chromatography of the reaction mixture gave 0.04 g (98%) of
48 as a colorless oil: IR (neat) 2926, 1624, and 1190 cm-1; 1H
NMR (CDCl3, 400 MHz) δ 1.42 (m, 2H), 2.20 (t, 2H, J ) 6.4
Hz), 2.37 (s, 3H), 2.38 (s, 3H), 3.68 (m, 2H), 6.23 (s, 1H), 7.23
(d, 2H, J ) 8.4 Hz), and 7.61 (d, 2H, J ) 8.4 Hz); 13C NMR
(CDCl3, 100 MHz) δ 19.6, 19.8, 20.6, 21.6, 47.9, 107.4, 116.5,
127.5, 129.7, 135.2, 142.4, 144.2, and 144.8; HRMS calcd for
1
less oil: IR (neat) 2933, 1752, 1425, and 1012 cm-1; H NMR
(CDCl3, 400 MHz) δ 1.55 (m, 1H), 1.67 (m, 2H), 1.87 (m, 1H),
2.01 (m, 2H), 2.05 (s, 3H), 2.10 (s, 3H), 2.11 (s, 3H), 2.21-2.41
(m, 2H), 3.00 (m, 1H), 4.15 (d, 1H, J ) 7.3 Hz), 5.23 (dd, 1H,
J ) 7.3 and 5.4 Hz); 13C NMR (CDCl3, 100 MHz) δ 12.9, 14.1,
20.9, 24.6, 27.2, 30.5, 42.4, 51.7, 56.1, 72.3, 170.3, 209.4; HRMS
calcd for C10H16OS2 276.0854, found 276.0854. Treatment of
this acetate with DMTSF and NEt3 gave furan 23 in 96% yield.
Acetic Acid 1-(1-Meth yl-2-oxop ip er id in -3-yl)-2,2-bis-
(m eth ylsu lfa n yl) Eth yl Ester (44). To a solution containing
2.7 mL (19 mmol) of diisopropylamine in THF (60 mL) cooled
to -40 °C was added n-butyllithium (12 mL of a 1.5 M solution
in hexane). After 1 h of stirring, the reaction was cooled to
-75 °C, and 2 g (18 mmol) of 1-methyl-2-piperidone was added
as a THF solution (10 mL). The temperature was raised to
-40 °C, and the reaction was stirred for 30 min. The temper-
ature was lowered to -75 °C, and 2.5 g (18 mmol) of 2,2-bis-
(methylsulfanyl)acetaldehyde (10) in 20 mL of THF was added
dropwise. The mixture was stirred for an additional 30 min,
and 2.5 mL (26 mmol) of acetic anhydride was added. The
solution was slowly warmed to room temperature overnight,
poured into a saturated aqueous NaHCO3 solution, and
extracted with CH2Cl2. The solvent was removed under
reduced pressure, and flash silica gel chromatography of the
residue afforded 3.5 g (69%) of 44 as a yellow oil that consisted
of a 1:1 mixture of diastereomers: IR (neat) 2920, 1743, 1498,
1
and 1035 cm-1; H NMR (400 MHz, CDCl3) (major diastere-
omer) δ 1.60-2.00 (m, 4H), 2.06 (s, 3H), 2.16 (s, 3H), 2.17 (s,
3H), 2.91 (s, 3H), 3.01-3.08 (m, 1H), 3.21-3.47 (m, 2H), 4.16
(d, 1H, J ) 6.8 Hz), and 5.68 (t, 1H, J ) 6.2 Hz); (minor
diastereomer) δ 1.60-2.00 (m, 4H), 2.08 (s, 3H), 2.10 (s, 3H),
2.16 (s, 3H), 2.90 (s, 3H), 3.01-3.08 (m, 1H), 3.21-3.47 (m,
2H), 4.61 (d, 1H, J ) 10.0 Hz), and 5.19 (dd, 1H, J ) 10.0 and
2.4 Hz); 13C NMR (100 MHz, CDCl3) (major diastereomer) δ
13.8, 14.4, 21.0, 22.2, 22.4, 35.2, 43.4, 50.0, 57.7, 72.9, 169.7,
and 170.0; (minor diastereomer) δ 12.7, 13.7, 21.3, 22.5, 25.7,
35.0, 43.0, 49.9, 57.2, 74.6, 168.8, and 170.6; HRMS calcd for
C
15H17NO3S2 323.0650, found 323.0655.
Acetic Acid 1-[1-(2,2-Dim eth yl-pr opion yl)-2-oxo-azepan -
3-yl]-2,2-bis(m eth ylsu lfa n yl) Eth yl Ester (46). To a cooled
solution of 1.5 mL (11 mmol) of diisopropylamine at -40 °C
in THF (20 mL) was added n-butyllithium (7.2 mL of a 1.5 M
solution in hexane). The mixture was stirred at -40 °C for 30
min and was then cooled to -78 °C. To this solution was added
dropwise a solution of 2.0 g (10 mmol) of acetic acid 1-(2,2-
dimethyl-propionyl)-azepan-2-one41 in THF (10 mL). The
mixture was warmed to -40 °C and was stirred at this
temperature for 30 min before cooling to -78 °C. To this
solution was added 1.5 g (11 mmol) of 2,2-bis(methylsulfanyl)-
acetaldehyde (10) in 30 mL of THF. The solution was stirred
for 30 min before the addition of 1.4 mL (15 mmol) of acetic
C
12H21NO3S2 244.1007, found 244.1019.
N-Meth yl-2-m eth ylsu lfa n yl-4,5,6,7-tetr a h yd r ofu r o[2,3-
b]p yr id in e (47). To a solution containing 0.1 g (0.3 mmol) of
44 in CH2Cl2 (2.5 mL) was added 0.07 g (0.4 mmol) of DMTSF
in one portion at -40 °C. Following the general procedure,
silica gel chromatography of the crude reaction mixture gave
0.05 g (87%) of 47 as a yellow oil: IR (neat) 2919, 1623, 1408,
1
and 1045 cm-1; H NMR (400 MHz, CDCl3) δ 1.85-1.93 (m,
2H), 2.30 (s, 3H), 2.37 (t, 2H, J ) 8.4 Hz), 2.82 (s, 3H), 2.99-

1604 J . Org. Chem., Vol. 67, No. 5, 2002
Padwa et al.
anhydride. The mixture was warmed to room temperature,
stirred for 12 h, poured into a saturated aqueous Na2CO3
solution, and extracted with ethyl acetate. The organic phase
was washed with water and brine. After drying over anhydrous
MgSO4, the solvent was removed under reduced pressure, and
the residue was purified by recrystallization from hexane/ether
to give 2.7 g (72%) of 46 as a white solid: mp 115-116 °C; IR
solvent was removed under reduced pressure, and the residue
was purified by flash silica gel chromatography to provide 6.9
g (70%) of 54 as a 1:1 mixture of diastereomers: IR (neat) 3299,
1742, 1661, and 1231 cm-1 1H NMR (400 MHz, CDCl3)
;
(diastereomer A) δ 1.62 (m, 1H), 1.73 (m, 1H), 1.92 (m, 2H),
2.08 (s, 3H), 2.10 (s, 3H), 2.18 (s, 3H), 3.09 (ddd, 1H, J ) 10.8,
6.0, and 2.4 Hz), 3.25 (m, 2H), 4.58 (d, 1H, J ) 10 Hz), 5.19
(dd, 1H, J ) 10 and 2.4 Hz), and 6.13 (s, 1H); (diastereomer
B) δ 1.71 (m, 2H), 1.96 (m, 2H), 2.08 (s, 3H), 2.16 (s, 3H), 2.18
(s, 3H), 3.05 (m, 1H), 3.29 (m, 2H), 4.06 (d, 1H, J ) 7.6 Hz),
and 5.69 (dd, 1H, J ) 7.6 and 4.8 Hz), and 5.83 (s, 1H); 13C
NMR (100 MHz, CDCl3) (diastereomer A) δ 12.9, 13.6, 21.3,
22.3, 25.2, 42.3, 42.8, 56.9, 74.3, 170.7, and 171.0; (diastere-
omer B) δ 13.4, 14.2, 21.0, 21.7, 22.0, 31.2, 43.2, 57.2, 72.3,
169.9, and 171.7; HRMS calcd for C11H19NO3S2 277.0806, found
277.0804.
Acetic Acid 1-(1-Acetyl-2-oxo-p ip er id in -3-yl)-2,2-bis-
(m eth ylsu lfa n yl) Eth yl Ester (57). To a 1.0 g (3.8 mmol)
sample of 54 dissolved in CH2Cl2 (20 mL) were added 4 g of
oven-dried 4 Å powdered molecular sieves and 0.4 mL (5.6
mmol) of acetyl chloride. The mixture was stirred at room
temperature for 15 h and was filtered through a plug of silica
with ether. The organic layer was washed with a saturated
aqueous NaHCO3 solution and dried over anhydrous MgSO4,
and the solvent was removed under reduced pressure. The
residue was purified by flash silica gel chromatography to
provide 1.0 g (80%) of 57 as a 1:1 mixture of diastereomers:
IR (neat) 2919, 1751, 1695, and 1160 cm-1; 1H NMR (400 MHz,
CDCl3) (diastereomer A) δ 1.68-1.84 (m, 2H), 1.88-2.02 (m,
1H), 2.02-2.10 (m, 1H), 2.07 (s, 3H), 2.14 (s, 3H), 2.19 (s, 3H),
2.48 (s, 3H), 3.25 (ddd, 1H, J ) 11.2, 7.0, and 4.2 Hz), 3.66-
3.79 (m, 2H), 3.89 (d, 1H, J ) 8 Hz), and 5.69 (dd, 1H, J ) 8.0
and 4.4 Hz); (diastereomer B) δ 1.60-1.78 (m, 2H), 1.93-2.09
(m, 2H), 2.10 (s, 3H), 2.11 (s, 3H), 2.14 (s, 3H), 2.50 (s, 3H),
3.16 (ddd, J ) 11.2, 6.4, and 3.2 Hz), 3.58 (ddd, 1H, J ) 13.6,
and 9.6, and 4.4 Hz), 3.82-3.88 (m, 1H), 4.21 (d, 1H, J ) 9.6
Hz), and 5.40 (dd, 1H, J ) 9.6 and 3.2 Hz); 13C NMR (100 MHz,
CDCl3) (diastereomer A) δ 13.2, 13.9, 21.0, 21.1, 21.7, 27.8,
43.4, 46.0, 56.8, 72.2, 169.8, 173.7, and 173.7; (diastereomer
B) 12.9, 13.6, 21.2, 21.9, 23.8, 27.9, 43.8, 46.63, 56.4, 73.6,
170.3, 172.4, and 174.0; HRMS calcd for C13H21NO4S2 319.0912,
found 319.0913.
1
(film) 2923, 1748, 1705, and 1219 cm-1; H NMR (400 MHz,
CDCl3) δ 1.28 (s, 9H), 1.60-1.65 (m, 3H), 1.79-1.82 (m, 1H),
1.87-1.93 (m, 2H), 2.09 (s, 3H), 2.14 (s, 3H), 2.14 (s, 3H), 3.33-
3.42 (m, 2H), 3.74-3.79 (m, 1H), 4.21 (d, 1H, J ) 6.8 Hz), and
5.38 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 12.9, 14.6, 21.2,
27.1, 28.1, 28.6, 44.4, 47.1, 47.2, 56.5, 73.6, 170.7, 175.7, and
191.4. Anal. Calcd for C17H29NO4S2: C, 54.37; H, 7.78; N, 3.37.
Found: C, 54.43; H, 7.73; N, 3.83.
N-(2-Meth ylsu lfan yl-4,5,6,7-tetr ah ydr ofu r o[2,3-b]azepin -
2,2-d im eth yl P r op ion a m id e (49). To a sample of 1.0 g (2.7
mmol) of 46 in CH2Cl2 (10 mL) at -40 °C was added 0.7 g (3.5
mmol) of DMTSF. Following the general procedure, flash silica
gel chromatography of the reaction mixture gave 0.6 g (78%)
of 49 as a white solid: mp 60-62 °C; IR (neat) 2986, 1661,
1628, and 1162 cm-1 1H NMR (300 MHz, CDCl3) δ 1.12 (s,
;
9H), 1.58-1.61 (m, 2H), 1.76-1.84 (m, 2H), 2.35-2.39 (m, 2H),
2.39 (s, 3H), 3.61 (bs, 2H), and 6.31 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 19.8, 24.8, 25.8, 28.1, 29.9, 30.7, 40.9, 48.1,
117.9, 118.7, 141.2, and 178.3. Anal. Calcd for C14H21NO2S:
C, 62.89; H, 7.92; N, 5.24. Found: C, 62.77; H, 7.75; N, 5.19.
Acetic Acid 2,2-Bis(m eth ylsu lfa n yl)-1-(2-oxo-tetr a h y-
d r op yr a n -3-yl) Eth yl Ester (50). To a cooled solution of 1.2
g (5.2 mmol) of 26 in CH2Cl2 (10 mL) at 0 °C was added 0.06
g (0.5 mmol) of DMAP, 0.5 mL (5.6 mmol) of pyridine, and 0.5
mL (5.3 mmol) of acetic anhydride. The reaction was slowly
warmed to room temperature and was stirred for 4 h before
the reaction mixture was poured into a saturated aqueous
NaHCO3 solution. The organic phase was separated, and the
aqueous phase was extracted with CH2Cl2. The combined
organic layer was washed with water and then brine. After
drying over anhydrous MgSO4, the solvent was removed under
reduced pressure, and the residue was purified by flash silica
gel chromatography to provide 1.3 g (87%) of 50 as a colorless
oil: IR (neat) 2958, 1748, 1437, and 1229 cm-1; 1H NMR (400
MHz, CDCl3) δ 1.66-1.76 (m, 1H), 1.87-1.95 (m, 2H), 2.05-
2.11 (m, 1H), 2.11 (s, 3H), 2.13 (s, 3H), 2.16 (s, 3H), 3.27 (ddd,
1H, J ) 11.6, 7.2, and 2.8 Hz), 4.25-4.31 (m, 1H), 4.36 (d, 1H,
J ) 9.2 Hz), 4.34-4.38 (m, 1H), and 5.26 (dd, 1H, J ) 9.6 and
3.2 Hz); 13C NMR (100 MHz, CDCl3) δ 13.1, 13.5, 21.2, 22.6,
23.2, 42.4, 56.4, 69.1, 73.5, 169.8, and 170.5; HRMS calcd for
N -(2-Me t h ylsu lfa n yl-5,6-d ih yd r o-4H -fu r o[2,3-b]p y-
r id in e)a ceta m id e (61). To a sample of 0.2 g (0.6 mmol) of
57 in CH2Cl2 (3 mL) cooled to -40 °C was added 0.12 g (0.6
mmol) of DMTSF. Following the general procedure, flash silica
gel chromatography of the crude reaction mixture gave 0.08 g
(64%) of 61 as a yellow oil: IR (neat) 2995, 1676, 1431, and
1379 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.87 (m, 2H), 2.35 (s,
3H), 2.42 (s, 3H), 2.43 (t, 2H, J ) 6.4 Hz), 3.80 (m, 2H), and
6.35 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 20.1, 20.6, 23.1,
24.5, 42.9, 104.9, 117.8, 140.8, 146.5, and 168.2; HRMS calcd
for C10H13NO2S 211.0667, found 211.0662.
C
11H18O4S2 278.0646, found 278.0645.
2-Meth ylsu lfa n yl-5,6-d ih yd r o-4H-fu r o[2,3-b]p yr a n (51).
To a solution of 0.2 g (0.7 mmol) of 50 in CH2Cl2 (1.5 mL) cooled
to -40 °C was added 0.16 g (0.8 mmol) of DMTSF. Following
the general procedure, chromatography of the crude reaction
through a plug of basic alumina gave 0.05 g (40%) of 51 as a
colorless oil: IR (neat) 2991, 1638, 1517, and 978 cm-1 1H
;
Acetic Acid 1-(1-Bu t-3-en oyl-2-oxo-p ip er id in -3-yl)-2,2-
bis(m eth ylsu lfa n yl) Eth yl Ester (58). To a 2.1 g (7.6 mmol)
sample of 54 dissolved in CH2Cl2 (40 mL) was added 7.6 g of
oven-dried 4 Å powdered molecular sieves followed by 1.3 g
(13 mmol) of but-3-enoyl chloride.43 The reaction was stirred
at 25 °C for 15 h then filtered through a silica gel column and
washed with ether. The organic phase was washed with a
saturated aqueous NaHCO3 solution and dried over anhydrous
MgSO4. The solvent was removed under reduced pressure, and
the crude mixture was subjected to flash silica gel chroma-
tography to give 2.5 g (94%) of the titled compound as a yellow
oil that contained a 1:1 mixture of diastereomers. For analyti-
cal purposes, the diastereomers were separated by HPLC: IR
NMR (300 MHz, CDCl3) δ 1.90-1.98 (m, 2H), 2.31 (s, 3H), 2.39
(t, 2H, J ) 6.2 Hz), 4.25-4.28 (m, 2H), and 6.33 (s, 1H); 13C
NMR (75 MHz, CDCl3) δ 18.9, 21.0, 23.2, 69.8, 92.1, 119.1,
135.0, and 158.3. Anal. Calcd for C8H10O2S: C, 56.46; H, 5.93.
Found: C, 56.31, H, 5.87.
Acetic Acid 2,2-Bis(m eth ylsu lfa n yl)-1-(2-oxo-p ip er i-
d in -3-yl) Eth yl Ester (54). To 5.0 mL (36 mmol) diisopropyl-
amine in THF (100 mL) cooled to 0 °C was added n-butyl-
lithium (24 mL of a 1.5 M solution in hexane). The mixture
was stirred at 0 °C for 30 min, and then 6.1 g (36 mmol) of
N-trimethylsilyl δ-valerolactam42 dissolved in THF (50 mL)
was added. The reaction mixture was stirred at 0 °C for 30
min and then cooled to -78 °C. A solution of 5.0 g (37 mmol)
of 2,2-bis(methylsulfanyl)acetaldehyde (10) dissolved in THF
(50 mL) was added over a 3 h period. After the addition was
complete, 5.0 mL (53 mmol) of acetic anhydride was added,
and the mixture was slowly warmed to room temperature and
stirred for 12 h. The solution was poured into a saturated
aqueous NaHCO3 solution, and the organic phase was sepa-
rated. The aqueous phase was washed with ethyl acetate, and
the organic layer was dried over anhydrous MgSO4. The
1
(neat) 1751, 1689, 1425, and 1238 cm-1; H NMR (400 MHz,
CDCl3) δ (diastereomer A) 1.68-1.85 (m, 2H), 1.92-1.98 (m,
1H), 2.03-2.10 (m, 1H), 2.08 (s, 3H), 2.15 (s, 3H), 2.20 (s, 3H),
3.23-3.30 (m, 1H), 3.66 (dd, 2H, J ) 0.8 and 6.8 Hz), 3.72-
3.77 (m, 2H), 3.90 (d, 1H, J ) 8.0 Hz), 5.10-5.16 (m, 2H), 5.70
(dd, 1H, J ) 4.2 and 8.0 Hz), and 5.94-6.04 (m, 1H));
(43) Knapp, S.; Levorse, A. J . Org. Chem. 1988, 53, 4006.

Preparation of 2-Thio Substituted Furans
J . Org. Chem., Vol. 67, No. 5, 2002 1605
(diastereomer B) δ 1.60-1.80 (m, 2H), 1.94-2.07 (m, 2H), 2.11
(s, 3H), 2.21 (s, 3H), 2.14 (s, 3H), 3.15 (m, 1H), 3.57-3.64 (m,
1H), 3.66-3.69 (m, 2H), 3.82-3.89 (m, 1H), 4.22 (d, 1H, J )
9.6 Hz), 5.11-5.17 (m, 2H), 5.40 (dd, 1H, J ) 9.6 and 3.2 Hz),
and 5.97-6.07 (m, 1H); 13C NMR (100 MHz, CDCl3) (diaste-
reomer A) δ 13.2, 14.0, 21.0, 21.7, 43.6, 44.2, 46.0, 56.8, 72.1,
118.4, 131.4, 169.8, 173.7, and 174.8; (diastereomer B) δ 12.9,
13.6, 21.2, 21.9, 23.7, 43.9, 44.3, 46.3, 56.4, 73.6, 118.3, 131.6,
170.3, 172.4, and 175.1; HRMS calcd for C15H23NO4S2Li [M +
Li]+ 352.1229, found 352.1232.
4.71-4.77 (m, 1H), 5.37 (dd, 1H, J ) 7.0 and 6.0 Hz, major
diastereomer), and 5.64 (dd, 1H, J ) 7.6 and 4.4 Hz, minor
diastereomer); 13C NMR (100 MHz, CDCl3) δ 12.7, 14.3, 14.6,
15.1, 21.0, 21.2, 26.6, 27.3, 27.7, 27.7, 27.9, 27.9, 42.2, 42.2,
48.2, 48.4, 56.5, 57.1, 73.7, 73.7, 170.4, 170.8, 173.3, 173.4,
176.2, and 177.1; HRMS calcd for C14H23NO4S2Li [M + Li]
340.1229. Found: 340.1221.
N -(2-Me t h ylsu lfa n yl-4,5,6,7-t e t r a h yd r ofu r o[2,3-b]-
a zep in e)a ceta m id e (63). To a 0.5 g (1.5 mmol) sample of 59
in CH3CN (15 mL) was added 0.3 g (1.5 mmol) of DMTSF in
one portion at -40 °C. Following the general procedure, flash
silica gel chromatography of the reaction mixture gave 0.2 g
(55%) of 63 as a yellow oil: IR (neat) 1686, 1442, 1378, and
N-(2-Met h ylsu lfa n yl-5,6-d ih yd r o-4H -fu r o[2,3-b]p yr i-
d in e)-bu t-3-en a m id e (62). To a 0.6 g (1.9 mmol) sample of
58 in CH2Cl2 (10 mL) was added 0.5 g (2.4 mmol) of DMTSF
in one portion at -40 °C. Following the general procedure,
flash silica gel chromatography of the crude reaction mixture
gave 0.3 g (68%) of 62 as a clear oil: IR (neat) 1673, 1624,
1510, and 1368 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.85-1.91
(m, 2H), 2.44 (t, 2H, J ) 6.4 Hz), 3.55 (d, 2H, J ) 7.2 Hz),
3.80-3.83 (m, 2H), 5.14-5.20 (m, 2H), 6.94-6.05 (m, 1H), and
6.36 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 20.2, 20.6, 23.1,
41.0, 43.1, 105.3, 117.8, 118.3, 131.5, 141.0, 146.2, and 169.0;
HRMS calcd for C12H15NO2S 237.0823, found 237.0815.
Acetic Acid 2,2-Bis(m eth ylsu lfa n yl)-1-(2-oxo-a zep a n -
3-yl) Eth yl Ester (55). To 5.3 mL (38 mmol) of diisopropyl-
amine in THF (100 mL) cooled to 0 °C was added n-butyl-
lithium (38 mmol, 30 mL of a 1.25 M solution in hexane). The
mixture was stirred at 0 °C for 30 min. To this solution was
added 8.0 g (38 mmol) of 1-trimethylsilanyl-azepan-2-one42
dissolved in THF (50 mL). The reaction mixture was stirred
at 0 °C for 30 min and then cooled to -78 °C. A solution of 5.2
g (38 mmol) of 2,2-bis(methylsulfanyl)acetaldehyde (10) dis-
solved in THF (50 mL) was added dropwise. After addition of
the aldehyde, 5.2 mL (55 mmol) of acetic anhydride was added,
and the mixture was slowly warmed to room temperature and
stirred for 12 h. The reaction mixture was poured into a
saturated aqueous solution of NaHCO3, and the organic phase
was separated. The aqueous phase was washed with EtOAc,
and the combined organic layers were dried over anhydrous
MgSO4. The solvent was removed under reduced pressure, and
the residue was purified by flash silica gel chromatography to
provide 8.8 g (80%) of 55 as a yellow oil consisting of a 4:1
mixture of diastereomers: IR (neat) 1743, 1666, 1434, and
1
1203 cm-1; H NMR (400 MHz, CDCl3) δ 1.59-1.64 (m, 2H),
1.77-1.82 (m, 2H), 2.38 (s, 3H), 2.39-2.42 (m, 2H), 3.62-3.65
(m, 2H), and 6.29 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 19.5,
22.8, 24.7, 25.9, 30.5, 45.6, 117.3, 118.3, 142.2, 148.9, and
171.0; HRMS calcd for C11H15NO2S 225.0823, found 225.0823.
3-[1-(Bis(m et h ylsu lfa n yl)m et h yl)-1-h yd r oxy-p r op yl]-
a zep a n -2-on e (56). To 9.8 mL (70 mmol) of diisopropylamine
in THF (150 mL) cooled to 0 °C was added n-butyllithium (46
mL of a 1.5 M solution in hexane). The reaction mixture was
stirred at 0 °C for 30 min and then 13 g (70 mmol) of
1-trimethylsilanyl-azepan-2-one42 dissolved in THF (100 mL)
was added dropwise over 30 min. The solution was stirred at
0 °C for an additional 30 min and then cooled to -78 °C. To
this mixture was added 11.4 g (70 mmol) of 1,1-bis(methyl-
sulfanyl)-butan-2-one44 in 100 mL of THF. After the addition
was complete, the mixture was stirred for an additional 30
min before being poured into saturated aqueous NH4Cl solu-
tion. The organic phase was separated, and the aqueous phase
was washed with ethyl acetate. The combined organic layer
was dried over anhydrous MgSO4, and the solvent was
removed under reduced pressure. The residue was purified by
flash silica gel chromatography to give 13 g (65%) of 56 as a
light yellow oil that contained a 1.5:1 inseparable mixture of
diastereomers: IR (neat) 1708, 1644, 1476, and 1434 cm-1; 1H
NMR (400 MHz, CDCl3) δ 0.86 (t, 3H, J ) 7.6 Hz, major
diastereomer), 0.87 (t, 3H, J ) 7.8 Hz, minor diastereomer),
1.34-2.10 (m, 8H), 2.14 (s, 3H), 2.18 (s, 3H, minor diastere-
omer), 2.19 (s, 3H, minor diastereomer), 2.20 (s, 3H, major
diastereomer), 2.93-2.96 (m, 1H, minor diastereomer), 3.09-
3.15 (m, 1H), 3.23-3.26 (m, 1H, major diastereomer), 3.27-
3.38 (m, 1H), 3.91 (s, 1H, minor diastereomer), 4.10 (d, 1H, J
) 1.6 Hz, major diastereomer), 5.01 (s, 1H, major diastere-
omer), 5.10 (s, 1H, minor diastereomer), and 6.75 (t, 1H, J )
6.0 Hz); 13C NMR (100 MHz, CDCl3) δ 8.8, 9.6, 17.0, 17.5, 17.7,
18.2, 24.1, 24.8, 27.8, 28.3, 28.4, 28.5, 28.8, 30.2, 41.6, 41.7,
45.8, 46.9, 64.8, 65.9, 79.4, 80.5, 180.7, and 181.2. Anal. Calcd
for C12H23NO2S2: C, 47.63; H, 6.90; N, 5.02. Found: C, 47.56;
H, 6.94; N, 5.13.
1
1236 cm-1; H NMR (400 MHz, CDCl3) (major diastereomer)
δ 1.42-1.83 (m, 5H), 1.96-2.08 (m, 1H), 2.21 (s, 6H), 2.15 (s,
3H), 3.10-3.35 (m, 3H), 4.39 (d, 1H, J ) 10.4 Hz), 5.32 (dd,
1H, J ) 10.0 and 7.2 Hz), and 5.84 (t, 1H, J ) 8.0 Hz); (minor
diastereomer) δ 1.36-1.48 (m, 2H), 1.53-1.64 (m, 1H), 1.67-
1.71 (m, 1H), 1.79-1.84 (m, 1H), 1.98-2.03 (m, 1H), 2.12 (s,
3H), 2.17 (s, 3H), 2.18 (s, 3H), 3.15-3.21 (m, 2H), 3.32-3.40
(m, 1H), 4.20 (d, 1H, J ) 3.2 Hz), 5.65 (dd, 1H, J ) 9.2 and
2.8 Hz), and 6.04 (t, 1H, J ) 6.0 Hz); 13C NMR (100 MHz,
CDCl3) (major diastereomer) δ 12.8, 14.5, 21.3, 27.0, 29.2, 29.3,
42.4, 45.5, 56.5, 73.7, 171.1, and 176.4; (minor diastereomer)
δ 14.8, 15.4, 21.0, 25.9, 29.3, 29.4, 42.2, 45.5, 57.2, 73.6, 170.6,
and 177.4. Anal. Calcd for C12H21NO3S2: C, 49.46; H, 7.26; N,
4.81. Found: C, 49.31; H, 7.22; N, 4.73.
Acetic Acid 1-(1-Acetyl-2-oxo-a zep a n -3-yl)-2,2-bis-
(m eth ylsu lfa n yl) Eth yl Ester (59). To a 1.0 g (3.5 mmol)
sample of 55 in CH2Cl2 (20 mL) were added 3.5 g of oven dried
4 Å powdered molecular sieves and 0.4 mL (5.2 mmol) of acetyl
chloride. The mixture was stirred at room temperature for 15
h, followed by filtration through a plug of silica with ether.
The organic layer was washed with a saturated aqueous
NaHCO3 solution and dried over anhydrous MgSO4, and the
solvent was removed under reduced pressure. The residue was
purified by flash silica gel chromatography to give 0.9 g (75%)
of 59 as a yellow oil that contained a 4:1 mixture of diaster-
eomers: IR (neat) 1747, 1699, 1395, and 1115 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.36-1.56 (m, 2H), 1.60-1.69 (m, 1H),
1.84-1.95 (m, 3H) 2.12 (s, 3H, major diastereomer), 2.13 (s,
3H), 2.15 (s, 3H, major diastereomer), 2.17 (s, 3H, minor
diastereomer), 2.19 (s, 3H, minor diastereomer), 2.48 (s, 3H,
minor diastereomer), 2.49 (s, 3H, major diastereomer), 3.13-
3.23 (m, 1H), 3.44-3.52 (m, 1H), 4.04 (d, 1H, J ) 4.4 Hz, minor
diasteromer), 4.19 (d, 1H, J ) 7.0 Hz, major diastereomer),
1-Acetyl-3-[1-(bis(m eth ylsu lfa n yl)m eth yl)-1-h yd r oxy-
p r op yl]-a zep a n -2-on e (60). To a 2.0 g (7.3 mmol) sample of
the above alcohol in CH2Cl2 (40 mL) was added 7 g of oven-
dried 4 Å powdered molecular sieves and 0.8 mL (11 mmol) of
acetyl chloride. The mixture was stirred at room temperature
for 15 h, followed by filtration through a plug of silica with
ether. The organic layer was washed with a saturated aqueous
NaHCO3 solution and dried over anhydrous MgSO4, and the
solvent was removed under reduced pressure. The residue was
purified by flash silica gel chromatography to give 1.5 g (64%)
of 60 as a colorless oil that contained a 1.5:1 inseparable
mixture of diastereomers: IR (neat) 1702, 1462, 1396, and
1
1189 cm-1; H NMR (400 MHz, CDCl3) δ 0.91 (t, 3H, J ) 7.6
Hz, major diastereomer), 0.96 (t, 3H, J ) 7.6 Hz, minor
diastereomer), 1.48-2.17 (m, 8H), 2.18 (s, 3H, major diaste-
reomer), 2.23 (s, 3H, minor diastereomer), 2.25 (s, 3H, minor
diastereomer), 2.27 (s, 3H, major diastereomer), 2.46 (s, 3H,
minor diastereomer), 2.50 (s, 3H, major diastereomer), 3.18-
3.31 (m, 1H), 3.37-3.41 (m, 1H, minor diastereomer), 3.42 (dd,
1H, J ) 9.4 and 3.4 Hz, major diastereomer), 3.78 (s, 1H, minor
(44) Solladie, G.; Boeffel, D.; Maignan, J . Tetrahedron 1996, 52,
2065.

1606 J . Org. Chem., Vol. 67, No. 5, 2002
Padwa et al.
diastereomer), 4.01 (s, 1H, minor diastereomer), 4.06 (d, 1H,
J ) 1.2 Hz, major diastereomer), 4.30 (s, 1H, major diastere-
omer), and 4.71 (dt, 1H, J ) 15.2 and 4.4 Hz); 13C NMR (100
MHz, CDCl3) δ 8.9, 9.9, 16.9, 17.1, 17.8, 18.0, 25.1, 25.5, 26.6,
27.0, 27.2, 27.3, 27.8, 28.0, 28.2, 30.2, 41.9, 42.1, 48.7, 51.0,
65.1, 65.8, 80.0, 81.4, 173.4, 179.8, and 180.8; HRMS calcd for
C14H23NO2S2 [M - H2O] 301.1170, found 301.1176.
9H), 1.27 (s, 9H), 2.11 (s, 3H), 2.12 (s, 3H), 2.83 (dd, 1H, J )
21.6 and 9.6 Hz), 3.08 (s, 3H), 3.19 (dd, 1H, J ) 22.4 and 7.2
Hz), 3.89 (d, 1H, J ) 5.6 Hz), and 5.46-5.52 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 14.3, 14.9, 27.1, 28.2, 32.6, 38.8, 39.2, 42.5,
57.6, 71.7, 172.7, 177.4, and 185.2; HRMS calcd for C17H31
NO4S2 377.1694, found 377.1693.
-
2,2-(N-Tr im eth yl-N-(5-m eth ylsu lfa n ylfu r a n -2-yl)-p r o-
p ion a m id e (69). To a solution containing 1.0 g (2.7 mmol) of
68 in CH3CN (14 mL) was added 0.6 g (2.9 mmol) of DMTSF
in one portion at -40 °C. Following the general procedure,
flash silica gel chromatography of the reaction mixture gave
0.4 g (59%) of 69 as a pale yellow oil: IR (neat) 1665, 1608,
N-(3-E t h yl-2-m et h ylsu lfa n yl-4,5,6,7-t et r a h yd r ofu r o-
[2,3-b]a zep in e)-a ceta m id e (64). To a solution of 0.3 g (1.0
mmol) of 60 in CH2Cl2 (5 mL) cooled to -40 °C was added 0.2
g (1.0 mmol) of DMTSF. Following the general procedure, flash
silica gel chromatography of the reaction mixture provided 0.15
g (56%) of 64 as a yellow oil: IR (neat) 1687, 1634, and 1377
1332, and 1101 cm-1 1H NMR (400 MHz, CDCl3) δ 1.06 (s,
;
1
cm-1; H NMR (400 MHz, CDCl3) δ 1.09 (t, 3H, J ) 7.6 Hz),
9H), 2.39 (s, 3H), 3.15 (s, 3H), 6.07 (d, 1H, J ) 3.2 Hz), and
6.41 (d, 1H, J ) 3.2 Hz); 13C NMR (100 MHz, CDCl3) δ 19.3,
28.6, 39.6, 40.8, 107.0, 115.9, 144.6, 151.6, and 179.2; HRMS
calcd for C11H17NO2S 227.0980, found 227.0978.
1.60-1.66 (m, 2H), 1.78-1.84 (m, 2H), 2.07 (s, 3H), 2.31 (s,
3H), 2.37-2.40 (m, 2H), 2.46 (q, 2H, J ) 7.6 Hz), and 3.63-
3.66 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 15.6, 18.1, 20.1,
22.8, 23.0, 25.8, 30.5, 45.5, 116.6, 133.4, 137.9, 148.6, and
171.0; HRMS calcd for C13H19NO2S 253.1136, found 253.1143.
7-Meth ylsu lfan yl-5,6,9,9a-tetr ah ydr o-1H,4H,7H-pyr r olo-
[3,2,1-ij]qu in olin e-2,8-d ion e (72). A 0.7 g (3.0 mmol) sample
of 62 dissolved in toluene (15 mL) was heated at reflux for 1
2,2-Dim eth ylpr opion ic Acid 1-Meth ylcar bam oylm eth yl-
2,2-bis(m eth ylsu lfa n yl) Eth yl Ester (67). To a solution
containing 0.5 mL (3.5 mmol) of diisopropylamine in THF (11
mL) cooled to 0 °C was added n-butyllithium (2.3 mL of a 1.5
M solution in hexane). After stirring for 1 h, the mixture was
cooled to -40 °C, 0.5 g (3.2 mmol) of N-methyl-pivalylacet-
amide (65)45 in 2 mL of THF was added, and the mixture was
stirred for 1 h. The temperature was lowered to -75 °C, and
0.4 g (3.3 mmol) of 2,2-bis(methylsulfanyl)acetaldehyde (10)
was added dropwise as a THF solution (4 mL). The reaction
mixture was stirred for an additional 30 min and was
quenched by the addition of a saturated aqueous NH4Cl
solution. The solution was slowly warmed to room temperature
and extracted with CH2Cl2. The organic layer was dried over
MgSO4, and the solvent was removed under reduced pressure.
Silica gel column chromatography of the crude residue afforded
0.5 g (49%) of 67 as a yellow oil: IR (neat) 1731, 1649, 1562,
and 1152 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.20 (s, 9H), 2.20
(d, 6H, J ) 8.8 Hz), 2.59 (dd, 1H, J ) 14.6 and 7.4 Hz), 2.79
(d, 3H, J ) 4.8 Hz), 2.86 (dd, 1H, J ) 14.6 and 5.4 Hz), 4.00
h
at 110 °C. The reaction mixture was cooled to room
temperature, and the solvent was removed under reduced
pressure. The crude residue was purified by flash silica gel
chromatography to provide 0.6 g (92%) of 72 as a yellow oil
that consisted of a 1.4:1 mixture of diatereomers: IR (neat)
1716, 1682, 1420, and 1197 cm-1; 1H NMR (400 MHz, CDCl3)
δ 1.84-1.94 (m, 4H), 1.99-2.07 (m, 2H), 2.10 (s, 3H), 2.12 (s,
3H), 2.16-2.32 (m, 4H), 2.32-2.47 (m, 1H), 2.58-2.60 (m, 1H),
2.67 (dd, 1H, J ) 16.4 and 8.4 Hz), 2.76 (dd, 1H, J ) 17.2 and
10 Hz), 3.02-3.08 (m, 3H), 3.35-3.46 (m, 5H), and 3.59-3.69
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 15.9, 16.1, 21.1, 21.2,
22.8, 23.6, 29.3, 34.0, 37.1, 37.2, 38.8, 39.1, 39.5, 42.1, 52.9,
54.0, 102.4, 103.7, 138.3, 140.7, 173.2, 173.3, 201.2, and 201.4;
HRMS calcd for C12H15NO2S 237.0823, found 237.0819.
5,6,9,9a-Tetr ah ydr o-1H,4H,7H-pyr r olo[3,2,1-ij]qu in olin e-
2,8-d ion e (73). To a 0.1 g (0.4 mmol) sample of 72 dissolved
in EtOH (2 mL) was added an excess of Raney nickel. The
reaction mixture was stirred at room temperature for 15 h and
then filtered through a pad of Celite, which was subsequently
washed with EtOAc. The solvent was removed under reduced
pressure, and the crude residue was purified by flash silica
gel chromatography to provide 0.04 g (42%) of 73 as a clear
oil: IR (film) 1687, 1602, 1411, and 1362 cm-1; 1H NMR (400
MHz, CDCl3) δ 1.80-2.10 (m, 4H), 2.26 (dd, 1H, J ) 16.8 and
8.8 Hz), 2.38 (dd, 1H, J ) 14.6 and 12.6 Hz), 2.71-2.86 (m,
3H), 2.93-3.00 (m, 1H), 3.07-3.16 (m, 1H), 3.31-3.37 (m, 1H),
and 3.75-3.80 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 21.1,
24.8, 31.5, 37.3, 38.8, 42.1, 45.1, 103.4, 135.7, 173.1, and 208.3;
HRMS calcd for C11H13NO2 191.0946, found 191.0947.
(d, 1H, J ) 4.8 Hz), 5.42-5.46 (m, 1H), and 5.62 (brs, 1H); 13
C
NMR (100 MHz, CDCl3) δ 14.6, 15.1, 26.5, 27.2, 38.6, 39.1,
57.7, 72.1, 169.9, and 177.8; HRMS calcd for C12H23NO3S2
293.1119, found 293.1118.
2,2-Dim eth ylp r op ion ic Acid 1-(Bis(m eth ylsu lfa n yl-
m eth yl)-3-[(2,2-d im eth ylp r op ion yl)-m eth yla m in o]-3-oxo-
p r op yl Ester (68). To a solution containing 1.0 g (3.4 mmol)
of 67 in CH2Cl2 (17 mL) was added 0.8 mL (6.5 mmol) of
trimethylacetyl chloride followed by 3.4 g of powdered molec-
ular sieves. After stirring at room temperature for 12 h, the
suspension was filtered through a pad of silica gel and washed
several times with ether. The filtrate was washed with a
saturated aqueous NaHCO3 solution, dried over MgSO4, and
concentrated under reduced pressure. The crude reaction
mixture was subjected to flash silica gel chromatography to
give 1.0 g (80%) of 68 as a yellow oil: IR (neat) 1808, 1690,
Ack n ow led gm en t. We gratefully acknowledge the
National Institutes of Health (GM59384 and GM60003)
for generous support of this work.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for new compounds lacking elemental analyses. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1475, and 1060 cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.12 (s,
(45) Bon, E.; Bigg, D.; Bertrand, G. J . Org. Chem. 1994, 59, 4035.
J O010986A