Bis(alkylthio)carbenes as novel reagents for organic synthesis

Article abstract of DOI:10.1016/S0040-4020(00)00855-3

Bis(alkylthio)carbenes have been shown to be a useful class of reactive intermediates for applications to organic synthesis. Substituted hydroindolones, isatins and hydroquinolones can be prepared by the addition of these carbenes to vinyl isocyanates. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00855-3

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 10101±10111
Bis(alkylthio)carbenes as Novel Reagents for Organic Synthesis
*
James H. Rigby, Stephane Laurent, Weitong Dong and M. Diana Danca
Department of Chemistry, Wayne State University, Detroit, MI 48202-3489, USA
Received 5 August 1999; accepted 3 February 2000
AbstractÐBis(alkylthio)carbenes have been shown to be a useful class of reactive intermediates for applications to organic synthesis.
Substituted hydroindolones, isatins and hydroquinolones can be prepared by the addition of these carbenes to vinyl isocyanates. q 2000
Elsevier Science Ltd. All rights reserved.
Vinyl isocyanates are versatile functions that can undergo
ef®cient reaction with a wide variety of nucleophilic
addends to deliver a range of product structures.1 Pyridones
of various types can be assembled using enamines,2a
benzynes2b and ester enolates as reaction partners with
isocyanates. Furthermore, pyrrolidone structures can be
accessed by reaction with various 1,1-dipolar equivalents
such as alkyl isocyanides3a and dimethoxycarbene3b
(Scheme 1).
The products of these novel transformations are rich in
functionality and, consequently, are well-suited to various
synthetically useful post-cycloaddition manipulations.
Approaches into the basic ring systems of a number of
alkaloid targets have been achieved in this fashion, as
have several total synthetic efforts. Entries into the
erythrina,4a galanthan,4a camptothecin4b and stemona4c
systems and total syntheses of several amaryllidaceae5a,b
and narciclasine5c alkaloids have been accomplished
Scheme 1.
Keywords: carbenes; cycloadditions; isocyanates.
* Corresponding author. Fax: 1313-577-1377; e-mail: jhr@chem.wayne.edu
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00855-3

10102
J. H. Rigby et al. / Tetrahedron 56 (2000) 10101±10111
Scheme 2.
employing vinyl isocyanate cyclization technology as the
key strategy-level transformation.
somewhat elusive. After considerable experimentation, the
sequences outlined in Scheme 2 were found to provide
suitable quantities of various dithiocarbene precursors.
Thus, N0-isopropylidenehydrazinecarbothioic acid S-propyl
ester was prepared by sequential treatment of excess
1-propanethiol with CDI, hydrazine and acetone. Exposure
of this material to Pb(OAc)4 afforded the corresponding
mixed O,S-oxadiazoline, paralleling previous work.7a
Exchange of the acetoxy substituent for a second propylthio
group was achieved only under precisely controlled con-
ditions employing 5 equiv. of PrSH in the presence of a
catalytic amount of TsOH´H2O at 08C. This provided the
crucial, thermally labile carbene precursor 1 in excellent
yield. A closely related process was developed to make
various cyclic species (2±4) as well (Scheme 2).
ꢀ1†
With a number of carbene precursors in hand, attention
turned to exploring the reactions of these species with
vinyl isocyanates. In most instances in situ conversion of
the corresponding acyl azide into the reactive isocyanate
followed by addition of 1 was the most convenient pro-
cedure. Thus, heating precursor 1 (2.5 equiv.) in the
presence of the isocyanate derived from acyl azide 5 in
re¯uxing benzene afforded the expected 2:1 adduct 6 in
excellent yield. This result closely parallels our previous
observations in the corresponding dimethoxy carbene
series.3b The insertion of the second equivalent of carbene
at the enamide nitrogen is interesting and probably involves
initial deprotonation of the relatively acidic amide proton
followed by re-addition of the resultant dithioxonium ion, a
Recently, bis(alkylthio)carbenes have been added to the list
of nucleophilic carbenes that are useful 1,1-dipole equiva-
lents in reactions with vinyl isocyanates, often displaying
reactivity that is somewhat different than other carbenes
studied to date.6 An extensive examination of these
interesting reactive intermediates has been conducted in
our laboratory, and a generalized reaction scheme is
shown in Eq. (1).
Key to the success of this endeavor was the accessibility of
the requisite dithiooxadiazoline (1) as the precursor to the
carbene. While the corresponding dialkoxy-substituted
heterocycles were readily available using the procedures
of Warkentin,7,8 the dithio species initially proved to be

J. H. Rigby et al. / Tetrahedron 56 (2000) 10101±10111
10103
process not without relevant precedent.9 Additional
examples of typical reactions in this series are shown in
Eqs. (3)±(5).
ꢀ6†
ꢀ2†
ꢀ3†
ꢀ7†
ꢀ8†
ꢀ4†
ꢀ5†
ꢀ9†
Cyclic dithiocarbenes were also reacted with various vinyl
isocyanates to give, in most cases, products paralleling those
shown above. The exception was when oxadiazoline 2 was
heated with the isocyanate derived from acyl azide 5. In this
instance no adducts of any kind could be isolated, a result
which was fully anticipated based on the well-known frag-
mentation of ®ve-membered cyclic carbenes of this general
type (Fig. 1).10 Based on these observations, our attention
was refocused on the six- and seven-membered cyclic
dithiocarbenes.
ꢀ10†
The corresponding six- and seven-membered dithiocarbenes
behaved well and provided the expected 2:1 adducts in good
yields (Eqs. (6)±(11)).
ꢀ11†
A
noteworthy feature of several of the adducts
described above came to light when it was observed
that rapid equilibration of the enamide double bond to
Figure 1. Fragmentation of dithiolane carbenes.

10104
J. H. Rigby et al. / Tetrahedron 56 (2000) 10101±10111
the ring-fusion position occurred while obtaining 1H
NMR spectra in CDCl3 that was not pre-treated with
basic alumina. Interestingly, a similar bond migration
was not observed in the dioxo-series, even under more
forcing conditions. This difference in behavior may stem
from slight conformational dissimilarities in the two series.
Examples of this process are shown in the following
equations.
yield of the reaction with 4-tri¯uoromethylphenyl
isocyanate (Eq. (18)).
ꢀ14†
ꢀ12†
ꢀ15†
ꢀ13†
ꢀ16†
ꢀ17†
ꢀ18†
In addition to exhibiting a reaction pro®le that, by and large,
parallels that of the dioxycarbenes, bis(alkylthio)carbenes
also undergo several transformations that the oxygen
species do not. Notable among these reactions is a [411]
addition to aryl isocyanates to produce highly substituted
isatins, a pathway that is in dramatic contrast to the course
of reaction between dimethoxycarbene and phenyl iso-
cyanate, which is known to give hydantoin products via
an alternative 2:1 route.11 This contrasting behavior is
summarized in Scheme 3.
To the best of our knowledge only one other example of a
[411] cycloaddition between an aryl isocyanate and a
nucleophilic carbene has been observed.8b In the present
case, heating phenyl isocyanate with excess bis(n-
propylthio)oxadiazoline (1) in re¯uxing benzene afforded
the 2:1 adduct 18 in serviceable yields.
The reaction is, for the most part, general in scope, and in
most instances the reaction can be carried out directly on the
corresponding acyl azide precursor. Naphthalene and
electron-rich aryl isocyanates provide adducts in reasonable
yields, particularly when performed in MeCN as solvent
(Eqs. (15)±(17)). However, electron de®cient systems are
much less effective substrates as evidenced by the inferior
Yet another remarkable reaction of bis(alkylthio)carbenes
with vinyl isocyanates that ®nds no equivalent in the dioxo
series is the novel 2:1 addition process depicted in Scheme
4. In this case, a substituted hydropyridone is produced
when a very large excess of oxadiazoline is rapidly decom-
posed in the presence of an isocyanate partner.
Scheme 3.

J. H. Rigby et al. / Tetrahedron 56 (2000) 10101±10111
10105
A second possibility involves the addition of carbene to the
carbonyl group of the initially formed acylimine 27
followed by ring expansion in a pinacol-like process. Efforts
to test this hypothesis experimentally have not been success-
ful, so it cannot be excluded as a viable alternative at this
point in time.
Scheme 4.
Thus, heating a large excess of 1 with cyclohexenyl
isocyanate yields the 2:1 adduct 23 in good yield. It is note-
worthy that no insertion of the carbene into the enamide NH
bond has occurred. Furthermore, the reaction appears to be
as general in scope as the `normal' addition process
described above. Typical examples of these transformations
are given in Eqs. (19)±(21).
ꢀ23†
Finally, a simple double addition pathway can be con-
sidered. The keys to the workability of this route would
be that the rate for the second carbene addition must be
competitive with ring closure of the initially formed 1:1
adduct, and that the acylimine 28 has a longer lifetime
than the unreacted carbene.14 Again no experimental
evidence in support of this pathway has been identi®ed,
although further work in this direction is currently underway
in our laboratory.
ꢀ19†
ꢀ20†
ꢀ21†
ꢀ24†
In summary, the reactions of bis(alkylthio)carbenes offer
numerous synthetic opportunities that are often unique and
afford considerable opportunities for application to organic
synthesis. Utilization of this methodology in several natural
product syntheses is currently being pursued in our
laboratory.
Mechanistically, this is a very intriguing reaction and three
plausible pathways can be envisioned. It is possible that
with the high concentration of carbene that prevails in
these reactions an addition of two carbene units occur to
produce dimer 26 which then undergoes a [412] cyclo-
addition across the vinyl isocyanate to give the observed
products. This pathway is consistent with the absence of
NH insertion and each step is well-presented in other
contexts.12,13 This pathway was tested by intentionally
dimerizing the dithiocarbene to give 26 and then heating
this species with the isocyanate under standard conditions
in an attempt to produce 23. However, none of this product
was obtained, thus discounting this pathway.
Experimental15
N0-Isopropylidene-hydrazinecarbothioic acid S-propyl
ester
To a solution of 1,10-carbonyldiimidazole (6 g, 37.0 mmol)
in CH2Cl2 (60 mL) was added 1-propanethiol (6.2 g,
81.4 mmol) at room temperature, the reaction mixture was
stirred for 24 h. Hydrazine monohydrate (2.8 g, 55.5 mmol)
was then added and stirring was continued for an additional
48 h at room temperature. At this time, acetone (30 mL) was
ꢀ22†

10106
J. H. Rigby et al. / Tetrahedron 56 (2000) 10101±10111
added and the reaction mixture was stirred for 20 min. The
solvent was removed in vacuo and water (30 mL) was added
to the residue. The aqueous layer was extracted with CH2Cl2
(3£30 mL), the combined organic layers were dried
(MgSO4) and the solvent was removed in vacuo. The
residue was chromatographed (4:1 Hexanes/EtOAc) to
give product (6 g, 93%) as a white solid: mpˆ74±758C
(3.82 mL, 90%, 41.0 mmol) at 08C under N2, the reaction
was stirred for 24 h at ambient temperature. Hydrazine
monohydrate (2.80 g, 55.5 mmol) was then added and stir-
ring was continued for an additional 72 h at room tempera-
ture. Then, acetone (30 mL) was added and the reaction
mixture was stirred overnight. The solvent was removed
in vacuo and the oily residue was chromatographed (3:1
Hexanes/EtOAc) to give the desired product (5.54 g, 78%)
1
(Hexanes/EtOAc); H NMR (CDCl3, 300 MHz) d 9.20 (br
1
s, 1H, 2.83 (t, Jˆ7.2 Hz, 2H), 2.02 (s, 3H), 1.88 (s, 3H), 1.63
(m, 2H), 0.98 (t, Jˆ7.5 Hz, 3H); 13C NMR (CDCl3,
75 MHz) d 172.3, 150.7, 30.7, 25.4, 23.3, 16.6, 13.4; IR
(CDCl3) n 3182, 1632 cm21; mass spectrum (EI) m/e (rel.
int.) 174 (M1, 86.8), 99 (93.9), 43 (100); HRMS calcd for
C7H14N2OS 174.08267, found 174.0825; Anal. calcd for
C7H14N2OS: C, 48.25; H, 8.10; N, 16.09; Found: C, 48.34;
H, 7.99; N, 16.21.
as a white solid: mpˆ111±1138C (Hexanes/EtOAc); H
NMR (CDCl3, 400 MHz) d 9.36 (br s 1H), 3.07 (t,
Jˆ7.4 Hz, 2H), 2.79±2.70 (m, 2H), 2.03 (s, 3H), 1.90 (s,
3H), 1.63 (t, Jˆ8.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d
171.2, 151.1, 32.9, 25.2, 25.1, 16.6; IR (neat) n 3180, 3063,
1672, 1328, 1218 cm21; mass spectrum (EI) (rel. int.) 192
(M1, 4.1 (133 (32.2), 99 (100); HRMS calcd for
C6H12N2OS2 192.0391, found 192.0392.
2,2-Bis(propylthio)-5,5-dimethyl-D3-1,3,4-oxadiazoline
(1). To a stirred solution of N0-isopropylidene-hydrazine-
carbothioic acid S-propyl ester (3 g, 17.2 mmol) in CH2Cl2
(80 mL) at 08C, was added dropwise a solution of Pb(OAc)4
(9.2 g, 20.7 mmol, Aldrich) in CH2Cl2 (20 mL). When the
addition was complete, the yellow solution was stirred 3 h at
08C. The lead precipitate was ®ltered through Celite 521 and
the ®lter cake was washed with CH2Cl2 (3£20 mL). The
organic layer was washed with cold aqueous NaHCO3
solution (5% in weight, 100 mL), cold brine (50 mL) and
dried over anhydrous MgSO4. The yellow organic layer was
®ltered through Celite 521 and the solvent was removed in
vacuo to afford the nearly pure 2-acetoxy-5,5-dimethyl-2-
propylthio-D3-1,3,4-oxadiazoline (quantitative) as a bright
N-(1-Aza-2-methylprop-1-enyl)(30-sulfanylpropylthio)-
carboxamide
To
a
solution of 1,10-carbonyldiimidazole (6.00 g,
37.0 mmol) in CH2Cl2 (60 mL) was added 1,3-propane-
dithiol (4.64 mL, 46.4 mmol) at 08C under N2, and the
reaction was stirred for 24 h at ambient temperature. Hydra-
zine monohydrate (2.80 g, 55.5 mmol) was then added and
stirring was continued for an additional 72 h at room
temperature. Acetone (30 mL) was then added and the
reaction mixture was stirred overnight. The solvent was
removed in vacuo and the oily reside was chromatographed
(3:1 hexanes/EtOAc) to give the desired product (6.35 g,
84%) as a white solid: mpˆ56±588C (hexanes/EtOAc);
1H NMR (CDCl3, 400 MHz) d 8.90 (br s, 1H), 2.98 (t,
Jˆ6.8 Hz, 2H), 2.68±2.58 (m, 2H), 2.03 (s, 3H), 1.94
(quin, Jˆ6.8 Hz, 2H), 1.88 (s, 2H), 1.39 (t, Jˆ8.2 Hz,
1H); 13C NMR (CDCl3, 100 MHz) d 171.7, 151.1, 34.0,
27.1, 25.4, 23.4, 16.7; IR (neat) n 3180, 3050, 2910,
1660, 1320, 1210 cm21; mass spectrum (EI) m/e (rel. int.)
99 (100); mass spectrum (CI) m/e (rel. int.) 207 (M111,
68), 99 (100); HRMS calcd for C7H14N2OS2 206.0548,
found 206.0507.
1
yellow oil. H NMR (CDCl3, 500 MHz) d 2.93 (m, 2H),
2.13 (s, 3H), 1.73 (m, 2H), 1.66 (s, 3H), 1.56 (s, 3H), 1.01
(t, Jˆ7.5 Hz, 3H). The oxadiazoline was used directly in the
next step without further puri®cation.
To a cold solution (08C) of 2-acetoxy-5,5-dimethyl-2-
propylthio-D3-1,3,4-oxadiazoline (4 g, 17.2 mmol) in
CH2Cl2 (30 mL) was added 1-propanethiol (6.56 g,
86.2 mmol) and TsOH´H2O (33 mg, 0.17 mmol). The
yellow solution was stirred at 08C until the starting material
was gone (approximately 2 h). When the reaction was
complete, the solvent was removed in vacuo at 08C, and
the residue was chromatographed (20:1 Hexanes/EtOAc)
using a jacketed column cooled to 08C. The desired product
eluted ®rst and was collected in a 500 mL round bottom
¯ask kept at 08C. The solvent was removed in vacuo at
08C and the residue was dried under high vacuum (1 h,
0.3 mmHg, 08C) to give 2,2-bis(propylthio)-5,5-dimethyl-
D3-1,3,4-oxadiazoline 1 (3.9 g, 91%) as a pale yellow oil:
1H NMR (CDCl3, 300 MHz) d 2.63 (dt, Jˆ8.4 Hz, Jˆ
1.8 Hz, 4H), 1.61 (m, 4H), 1.57 (s, 6H), 0.94 (t, Jˆ7.2 Hz,
6H); 13C NMR (CDCl3, 75 MHz) d 12.8.8, 123.4, 33.4,
24.2, 22.9, 13.5. IR (neat) n 2957, 1449, 1365, 1224,
1048, 822 cm21. Note: The compound is not stable at
room temperature, it was stored for weeks as a 1 M solution
in hexanes in the freezer (258C).
N-(1-Aza-2-methylprop-1-enyl)(40-sulfanylbutylthio)-
carboxamide
To
a
solution of 1,10-carbonyldiimidazole (6.00 g,
37.0 mmol) in CH2Cl2 (60 mL) was added 1,4-butanedithiol
(5.34 mL, 90%, 40.7 mmol) at 08C under N2, the reaction
was stirred for 24 h at ambient temperature. Hydrazine
monohydrate (2.80 g, 55.5 mmol) was then added and stir-
ring was continued for an additional 72 h at room tempera-
ture. Acetone (30 mL) was then added and the reaction
mixture was stirred overnight. The solvent was removed
in vacuo and the oily residue was chromatographed (3:1
hexanes/EtOAc) to give the desired product (6.10 g, 75%)
as a white solid. Mpˆ61.5±638C (hexanes/EtOAc); 1H
NMR (CDCl3, 400 MHz) d 9.37 (br s, 1H), 2.90±2.81 (m,
2H), 2.52 (q, Jˆ6.8 Hz, 2H), 2.02 (s, 3H), 1.88 (s, 3H),
1.77±1.65 (m, 4H), 1.34 (t, Jˆ8.0 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) d 171.9, 151.0, 32.9, 28.7, 28.0, 25.4,
24.1, 16.7; IR (neat) 3180, 3063, 2931, 1663, 1312,
1235 cm21; mass spectrum (EI) m/e (rel. int.) 187
(M12SH, 2.4), 132 (10.8), 99 (100), 72 (54.3); HRMS
calcd for C8H15N2OS (M2SH) 187.0805, found 187.0905.
N-(1-Aza-2-methylprop-1-enyl)(20-sulfanylethylthio)-
carboxamide
To
a
solution of 1,10-carbonyldiimidazole (6.00 g,
37.0 mmol) in CH2Cl2 (60 mL) was added 1,2-ethanedithiol

J. H. Rigby et al. / Tetrahedron 56 (2000) 10101±10111
10107
8,9-Diaza-7,7-dimethyl-6-oxa-1,4-dithiaspiro[4,4]non-8-
ene (2). To a stirred solution of Pb(OAc)4 (5.97 g, 95%,
12.7 mmol) in CH2Cl2 (35 mL) at 08C under N2, was
added dropwise a solution of N-(1-aza-2-methylprop-1-
enyl) (2-sulfanylethylthio)carboxamide (2.22 g, 11.6 mmol)
in CH2Cl2 (35 mL). When the addition was completed, the
yellow solution was stirred 1 h at 08C, then another 545 mg
(1.16 mmol) of Pb(OAc)4 was added. After 30 min, the lead
precipitate was ®ltered by vacuum ®ltration and the ®lter
cake was washed with CH2Cl2 (3£20 mL). The organic
layer was washed with cold sat. NaHCO3, cold brine and
dried over Na2SO4. The yellow solution was ®ltered through
a cotton plug and the solvent was removed in vacuo. The
residue was chromatographed (4:1 hexanes/EtOAc to 3:1
hexanes/EtOAc) to give 1.5 g (52%) of 5,5-dimethyl-2-
(20-sulfanylethylthio)-1,3,4-oxadiazolin-2-yl acetate as a
propylthio)-1,3,4-oxadiazolin-2-yl acetate (2.8 g, 10.6 mmol)
in CH2Cl2 (80 mL) was added TsOH´H2O (280 mg,
1.06 mmol). The yellow solution was stirred at 08C until
the starting material was gone (approximately 2 h). When
the reaction was complete, the solvent was removed in
vacuo at 08C, and the residue was chromatographed (20:1
hexanes/EtOAc) using a jacketed column cooled at 08C. The
fraction with the desired product was collected and the
solvent was removed in vacuo at 08C. The residue was
dried under high vacuum (4 h, 0.3 mmHg, 08C) to give
3,4-diaza-2,2-dimethyl-1-oxa-6,10-dithiaspiro[4.5]dec-3-ene
1
(1.23 g, 57%) as a pale yellow solid: H NMR (CDCl3,
400 MHz) d 3.60±3.50 (m, 2H), 2.98±288 (m, 2H), 2.25±
2.15 (m, 1H), 2.05±1.93 (m, 1H), 1.52 (s, 6H); 13C NMR
(CDCl3, 100 MHz) d 124.4, 120.1, 30.8, 2437, 23.6; IR
(neat) 2960, 2921, 1421, 1366, 1228, 1082 cm21. Note:
This compound is not stable at room temperature, it could
be stored in the freezer for months.
1
1
yellow oil (.95% purity by H NMR): H NMR (CDCl3,
400 MHz) d 3.32±3.23 (m, 1H), 3.22±3.13 (m, 1H), 3.11±
3.01 (m, 1H), 2.99±2.98 (m, 1H), 2.11 (s, 3H), 1.62 (s, 3H),
1.59 (s, 1H), 1.51 (s, 3H); IR (neat) 2989, 2930, 1780, 1368,
3,4-Diaza-2,2-dimethyl-1-oxa-6,11-dithiaspiro[4.6]un-
dec-3-ene (4). To a stirred solution of Pb(OAc)4 (10.3 g,
95%, 22.0 mmol) in CH2Cl2 (60 mL) at 08C under N2, was
added dropwise a solution of N-(1-aza-2-methylprop-1-
enyl)(4-sulfanylbutylthio)carboxamide (4.40 g, 20.0 mmol)
in CH2Cl2 (60 mL). When the addition was completed, the
yellow solution was stirred 1 h at 08C, then another 940 mg
(2.00 mmol) of Pb(OAc)4 was added. After 30 min, the lead
precipitate was ®ltered out by vacuum ®ltration and the ®lter
cake was washed with CH2Cl2 (3£20 mL). The organic
layer was washed with cold saturated NaHCO3 solution,
cold brine and dried over anhydrous Na2SO4. The yellow
solution was ®ltered through a cotton plug and the solvent
was removed in vacuo. The residue was chromatographed
(4:1 hexanes/EtOAc to 3:1 hexanes/EtOAc) to give 1.87 g
(34%) of 5,5-dimethyl-2-(40-sulfanylbutylthio)-1,3,4-oxa-
1202 cm21
.
To a cold solution (08C) of 5,5-dimethyl-2-(20-sulfanyl-
ethylthio)-1,3,4-oxadiazolin-2-yl acetate (1.5 g 6.0 mmol)
in CH2Cl2 (30 mL) was added TsOH´H2O (115 mg,
0.60 mmol). The yellow solution was stirred at 08C until
the starting material was gone (approximately 2 h). When
the reaction was complete, the solvent was removed in
vacuo at 08C, and the residue was chromatographed (20:1
hexanes/EtOAc) using a jacketed column cooled at 08C. The
fraction with the desired product was collected and the
solvent was removed in vacuo at 08C. The residue was
dried under high vacuum (4 h, 0.3 mmHg, 08C) to give
8,9-diaza-7,7-dimethyl-6-oxa-1,4-dithiaspiro[4.4]non-8-ene
(593 mg, 52%) as a white solid with a trace of TsOH´H2O
1
1
inside. H NMR (CDCl3, 400 MHz) d 3.62±3.52 (m, 4H),
diazolin-2-yl acetate as a yellow oil (.95% purity by H
NMR). H NMR (CDCl3, 400 MHz) d 3.07±2.98 (m, 1H),
1.49 (s, 6H); 13C NMR (CDCl3, 100 MHz) d 138.5, 122.3,
1
40.7, 23.7; IR (neat) 2982, 2931, 1369, 1058, 824 cm21
Note: This compound is not stable at room temperature,
but it could be stored in the freezer for months.
.
2.97±2.88 (m, 1H), 2.74±2.65 (m, 2H), 2.13 (s, 3H), 1.86±
1.76 (m, 4H), 1.66 (s, 3H), 1.63 (s, 1H), 1.55 (s, 3H): IR
(neat) 2988, 2938, 1779, 1367, 1212 cm21
.
3,4-Diaza-2,2-dimethyl-1-oxz-6,10-dithiaspiro[4.5]dec-
3-ene (3). To a stirred solution of Pb(OAc)4 (16.40 g, 95%,
34.9 mmol) in CH2Cl2 (100 mL) at 08C under N2, was added
dropwise a solution of N-(1-aza-2-methylprop-1-enyl)(3-
sulfanylpropylthio)carboxamide (6.54 g, 31.7 mmol) in
CH2Cl2 (100 mL). When the addition was completed, the
yellow solution was stirred 1 h at 08C, then another 1.49 g
(3.17 mmol) of Pb(OAc)4 was added. After 30 min, the lead
precipitate was ®ltered out by vacuum ®ltration and the ®lter
cake was washed with CH2Cl2 (3£20 mL). The organic
layer was washed with cold sat. NaHCO3, cold brine and
dried over Na2SO4. The yellow solution was ®ltered through
a cotton plug and the solvent was removed in vacuo. The
residue was chromatographed (3:1 hexanes/EtOAc) to give
2.95 g (35%) of 5,5-dimethyl-2-(30-sulfanylpropylthio)-
1,3,4-oxadiazolin-2-yl acetate as a yellow oil (.95% purity
by 1H NMR): 1H NMR (CDCl3, 400 MHz) d 3.13±2.98 (m,
2H), 2.80±2.74 (m, 2H), 2.13 (s, 3H), 2.19±2.06 (m, 2H),
1.65 (s, 3H), 1.62 (s, 1H), 1.54 (s, 3H): IR (neat) 2988, 2940,
To a cold solution (08C) of 5,5-dimethyl-2-(40-sulfanyl-
butylthio)-1,3,4-oxadiazolin-2yl acetate (3.0 g, 10.8 mmol)
in CH2Cl2 (100 mL) was added TsOH´H2O (280 mg,
1.06 mmol). The yellow solution was stirred at 08C until
the starting material was gone (approximately 2 h). When
the reaction was complete, the solvent was removed in
vacuo at 08C, and the residue was chromatographed (20:1
hexanes/EtOAc) using a jacketed column cooled at 08C. The
fraction with the desired product was collected and the
solvent was removed in vacuo at 08C. The residue was
dried under high vacuum (4 h, 0.3 mmHg, 08C) to give
3,4-diaza-2,2,-dimethlo-1-oxa-6,11-dithiaspiro[4.6]undec-
3-ene (1.49 g, 60%) as a colorless oil. Due to the
coexistence of several conformers of the 7-membered ring
at room temperature, the peaks of each conformer could be
observed by both 1H NMR and 13C NMR. 1H NMR (CDCl3,
400 MHz) d 3.21±2.61 (br m, 5H), 2.13 (s, small peak for
±CH3), 2.05 (br s, for ±CH3), 1.97±1.62 (br m, 3H), 1.56 (s,
for ±CH3), 1.50 (s, for ±CH3), 1.26 (s, small peak for
±CH3), 1.24 (s, small peak for ±CH3); 13C NMR (CDCl3,
100 MHz) d 132.9, 129.1, 124.3, 123.6, 38.6, 31.9, 31.5
(small), 30.8, 30.6 (medium), 30.3 (small), 27.3, 27.0,
1779, 1367, 1212 cm21
.
To a cold solution (08C) of 5,5-dimethyl-1-(30-sulfanyl-

10108
J. H. Rigby et al. / Tetrahedron 56 (2000) 10101±10111
24.6, 24.3, 21.7; IR (neat 2918, 1667, 1229, 1048 cm21
Note: This compound is not stable at room temperature,
but it could be stored in the freezer for months.
.
(M1, 1.9), 408 (100), 333 (28.2); HRMS calcd for
C24H37NOS4 (M1) 483.17579, found 483.1757.
5,6-Bis-(tert-butyl-dimethyl-silanyloxy)-1-bis(propyl-
thio)methyl-3,3-bis(propylthio-1,3,3a,4,5,6-hexahydro-
indol-2-one (8). From the acyl azide (155 mg, 0.38 mmol)
and the oxadiazoline 1 (830 mL, 0.83 mmol) was obtained
after ¯ash chromatography (40:1 hexanes/EtOAc12%
Et3N) indolone 8 (226 mg, 85%) as a colorless oil. The
product consisted of a 1:1 mixture of inseparable dia-
General procedure for the preparation of acyl azides
To a solution of the a,b-unsaturated carboxylic acid, the
preparations of which have been described elsewhere,2a in
benzene (0.2 M) is added Et3N (1.0 equiv.) and after 10 min
of stirring, diphenylphosphorzaeidate DPPA (1.0 equiv.) is
slowly added. The resulting reaction mixture is stirred for an
additional 40 min at which time the solvent is removed in
vacuo. The crude mixture is puri®ed by ¯ash chromato-
graphy (10:1 hexanes/Et2O) to afford the pure acyl azide.
1
stereomers. H NMR (CDCl3, 500 MHz) d 6.46 (s, 1H),
6.37 (s, 1H), 5.71 (s, 2H), 4.37 (m, 1H), 4.05 (m, 1H),
3.93 (m, 1H), 3.77 (m, 1H), 3.37 (m, 1H), 3.25 (m, 1H0,
3.00±2.30 (m, 16H), 2.12 (t, Jˆ11.0 Hz, 1H), 1.96 (m, 2H),
1.82 (m, 1H), 1.68±1.50 (m, 16H), 1.11±0.82 (m, 60H),
0.14±0.08 (m, 24H); 13C NMR (CDCl3, 125 MHz) d
171.4, 170.8, 135.3, 133.8, 108.4, 105.4, 74.6, 74.4, 70.7,
68.8, 61.2, 60.70, 57.9, 57.6, 46.9, 41.3, 35.2, 35.0, 34.8,
34.5, 34.4, 32.3, 32.0, 31.9, 31.9, 31.4, 26.0, 25.9, 25.9,
25.7, 25.6, 25.1, 22.6, 22.5, 22.4, 22.3, 22.2, 22.1, 22.0,
17.9, 17.8, 13.7, 13.6, 13.5, 13.3, 13.2, 23.9, 24.1, 24.2,
24.5, 24.6, 24.7, 24.8, 24.9; IR (neat) n 2950, 1717,
1675, 1245, 1083, 829 cm21; mass spectrum (EI) m/e (rel.
int.) 632 (M2C3H7S, 51.5), 556 (49.6), 469 (20.2), 163
(100); HRMS calcd for C33H65NO3S4Si2 (M2C3H7S)
632.31173, found 632.3120.
General procedure for the [411] cycloaddition of vinyl
isocyanates with bis-(alkylthio)carbenes
The appropriate acyl azide (1 equiv.) was dissolved in dry
benzene (concentrationˆ0.2 M) and re¯uxed for 45 min to
afford the corresponding isocyanate. To the re¯uxing
mixture was added the oxadiazoline 1 (about 2.5 equiv.,
1 M solution in hexanes kept at 2788C prior to addition)
over a period of 45 min via syringe. After the addition was
complete, the reaction mixture was re¯uxed for another
30 min at which point the pale yellow solution was allowed
to cool to room temperature. The solvent was removed in
vacuo and the residue was chromatographed (hexanes/
EtOAc12% Et3N) to give the pure products. CDCl3 was
passed through basic alumina (ICN Biomedicals) before
obtaining NMR of all compounds described below.
1-Bis(propylthio)methyl-3,3-bis(propylthio)-5,5-ethylene-
dioxy-3a-methyl-1,3,3a,4,5,6-hexahydro-indol-2-one (9).
From the acyl azide (269 mg, 1.20 mmol) and the oxadiazo-
line 1 (3 mL, 3.00 mmol) was obtained after ¯ash chromato-
graphy (20:1 hexanes/EtOAc) indolone 9 (293 mg, 47%) as
a colorless oil. 1H NMR (CDCl3, 500 MHz) d 6.39 (s, 1H),
5.68 (t, Jˆ4 Hz, 1H), 4.03 (m, 2H), 3.96 (m, 1H), 3.90 (m,
1H), 2.87 (m, 1H), 2.69 (m, 2H), 2.60±2.45 (m, 7H), 2.41
(d, Jˆ13 Hz, 1H), 1.70±1.55 (m, 9H), 1.48 (s, 3H), 1.03 (t,
Jˆ7.5 Hz, 3H), 0.97 (m, 9H); 13C NMR (CDCl3, 125 MHz)
d 170.6, 137.4, 107.6, 102.5, 71.7, 64.6, 63.7, 58.1, 49.0,
38.1, 35.1, 34.7, 34.6, 32.7, 31.0, 25.8, 22.5, 22.5, 22.3,
21.8, 13.8, 13.8, 13.7, 13.3; IR (neat) 2957, 1710,
1675 cm21, mass spectrum (EI) m/e (rel. int.) 519 (M1,
1.1), 444 (100), 369 (21.7), 163 (70.4); HRMS calcd for
C24H41NO3S4 (M1) 519.19692, found 519.1974.
1-Bis(propylthio)methyl-3,3-bis(propylthio)-1,3,3a,4,5,6-
hexahydro-indol-2-one (6). From the acyl azide 5 (72 mg,
0.48 mmol) and the oxadiazoline 1 (1.20 mL, 1.20 mmol)
was obtained, after ¯ash chromatography (30:1 hexanes/
EtOAc12% Et3N), indolone 6 (186 mg, 86%) as a colorless
oil. 1H NMR (CDCl3, 500 MHz) d 6.42 (s, 1H), 5.72 (s, 1H),
3.06 (m, 1H), 2.90 (m, 1H), 2.64±2.47 (m, 7H), 2.23 (m,
2H), 1.96 (m, 2H), 1.76±1.53 (m, 10H), 1.01±0.94 (m,
12H): 13C NMR (CDCl3, 125 MHz) d 171.0, 133.5, 106.6,
62.6, 58.6, 48.2, 36.1, 35.5, 32.9, 32.6, 24.2, 23.4, 23.4,
23.3, 23.1, 23.0, 22.4, 14.5, 14.5, 14.1, 14.1; IR (neat) n
2914, 1710, 1675, 1449, 1365 cm21; mass spectrum (EI)
m/e (rel. int.) 372 (M2C3H7S, 100), 297 (21); HRMS
calcd for C21H37NOS4 (M2C3H7S) 372.14895, found
372.1487; Anal. calcd for C21H37NOS4: C, 56.35; H, 8.34;
N, 3.13; found: C, 56.58; H, 8.22; N, 2.94.
7-(1,3-Dithian-2-yl)spiro[1,3-dithiane-2,30-3,40,50,60,3a0-
pentahydroindole]-8-one (10). From the acyl azide
(30 mg, 0.2 mmol) in 4.0 mL of benzene and oxadiazoline
3 (1.0 mL, 0.5 mmol) was obtained 59 mg (82%) of the
desired product as a colorless oil after ¯ash chromatography
(5:1 hexanes/EtOAc12% NEt3). 1H NMR (CDCl3,
400 MHz) d 6.48 (s, 1H), 5.81±5.75 (m, 1H), 4.11 (dt,
J1ˆ13.2 Hz, J2ˆ2.8 Hz, 1H), 3.44±3.33 (m, 1H), 3.17±
3.03 (m, 2H), 3.02±2.92 (m, 2H), 2.69±2.53 (m, 3H),
2.28±2.06 (m, 4H), 1.98±1.64 (m, 5H), 1.61±1.45 (m,
1H); 13C NMR (CDCl3, 100 MHz) d 170.8, 133.4, 104.8,
56.9, 50.4, 45.7, 32.5, 32.4, 27.2, 26.4, 25.2, 24.8, 23.2,
1-Bis(propylthio)methyl-3,3-bis(propylthio)-5-methyl-
ene-4-phenyl-pyrrolidin-2-one (7). From the acyl azide
(88 mg, 0.47 mmol) and the oxadiazoline 1 (1.20 mL,
1.20 mmol) was obtained, after ¯ash chromatography
(40:1 hexanes/EtOAc12% Et3N), pyrrolidinone
7
(210 mg, 92%) as a colorless oil. 1H NMR (CDCl3,
500 MHz) d 7.42±7.34 (m, 5H), 6.61 (s, 1H), 5.33 (s,
1H), 4.48 (s, 1H), 4.28 (s, 1H), 2.75±2.55 (m, 6H), 2.43
(t, Jˆ7.5 Hz, 2H), 1.74±1.61 (m, 6H), 1.36 (1, Jˆ7.5 Hz,
2H), 1.01 (m, 9H), 0.82 (t, Jˆ7.5 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) d 170.1, 140.8, 135.1, 130.7, 128.1,
127.8, 95.2, 62.8, 58.4, 56.4, 35.2, 35.1, 32.9, 32.0, 22.7,
22.6, 22.1, 22.0, 13.8, 13.4, 13.4; IR (neat) n 2957, 1710,
1639, 1315 cm21; mass spectrum (EI) m/e (rel. int.) 483
22.2, 21.5; IR (neat)
n 2917, 1718, 1682, 1377,
1311 cm21; mass spectrum (EI) m/e (rel. int.) 359 (M1,
4.3) 240 (76.4), 119 (100); HRMS calcd for C15H21NOS4
359.0506, found 359.0506.
6-(1,3-Dithian-2-yl)-3a-methyldispiro[1,3-dioxolane-2,
50,30,40,5,60,3a0-pentahydroinole-30,200-1,3-dithiane]-7-

J. H. Rigby et al. / Tetrahedron 56 (2000) 10101±10111
10109
one (11). From the acyl azide (46 mg, 0.2 mmol) in 4.0 mL
of benzene and 3 (1.0 mL, 0.5 mmol) was obtained 45 mg
(52%) of the desired produce as a colorless oil after ¯ash
chromatography (3.5:1 hexanes/EtOAc12% NEt3): 1H
NMR (CDCl3, 400 MHz) d 6.48 (s, 1H), 5.70 (t,
Jˆ4.0 Hz, 1H), 4.07±3.86 (m, 5H), 3.28±3.18 (m, 1H),
3.15±2.92 (m, 4H), 2.74±2.43 (m, 4H), 2.34 (d,
Jˆ5.6 Hz, 1H), 2.18±2.07 (m, 2H), 1.86±1.72 (m, 3H),
1.40 (s, 3H); 13C NMR (CDCl3, 100 MHz) d 170.3, 137.6,
107.5, 102.1, 64.4, 63.7, 58.1, 56.8, 46.5, 35.7, 34.8, 32.3,
32.1, 27.2, 26.6, 25.1, 24.6, 22.9; IR (neat) n 2964, 2929,
2896, 1723, 1687 cm21; mass spectrum (EI) m/e (rel. int.)
431 (M1, 7.2), 312 (47.4), 119 (100); HRMS calcd for
C18H25NO3S4 431.0717, found 431.0712.
2.65 (m, 8H), 2.30±1.68 (m, 8H); 13C NMR (CDCl3,
100 MHz) d 172.5, 140.9, 134.5, 130.9, 130.0, 128.1,
128.0, 127.8, 94.8, 62.6, 59.1, 57.0, 39.2, 39.1, 33.3, 33.1,
31.7, 31.1, 29.9, 28.9, 28.2, 28.0, 27.7, 27.4; IR (neat) n
2918, 1712, 1650, 1326 cm21; mass spectrum (EI) m/e (rel.
int.) 423 (M1, 17.8), 289 (21.0), 132 (100), 120 (84.7), 87
(51.7); HRMS calcd for C20H24NOS4 423.0819, found
423.0817.
2-Aza-2-(1,3-dithiepan-2-yl)-4-methyl-3-methylene-6,11-
dithiaspiro[4.6]undecan-1-one (15). From the acyl azide
(31 mg, 0.25 mmol) in 5.0 mL of benzene and 4 (1.0 mL,
0.5 mmol) was obtained 41 mg (50%) of the desired product
as a colorless oil after ¯ash chromatography (15:1 hexanes/
EtOAc12% NEt3). Due to the coexistence of several
conformers of the two 7-membered rings at room tempera-
ture, the peaks of each conformer could be observed by both
1H NMR and 13C NMR: 1H NMR (CDCl3, 400 MHz) d 6.47
(s, 1H), 5.20 (s, 0.5H), 5.06 (t, Jˆ2.2 Hz, 1H), 4.91 (d, 0.5H,
Jˆ2.8 Hz), 4.52 (t, Jˆ2.2 Hz, 1H), 3.34±3.07 (m, 1H),
3.01±2.58 (m, 8H), 2.22±1.71 (m, 8H), 1.34 (d,
Jˆ6.8 Hz, 3H), 1.29 (d, 0.5H, Jˆ6.4 Hz); 13C NMR
(CDCl3, 100 MHz) d 172.6, 143.1, 91.9, 61.7, 58.8, 45.6,
39.3, 39.1, 33.1 32.9, 31.8, 31.6, 31.5, 30.4, 30.0, 29.7, 28.9,
28.2, 27.7, 27.4, 27.3, 27.2; IR (neat) 2923, 2850, 1713,
1649, 1326, 1213 cm21; mass spectrum (EI) m/e (rel. int.)
361 (M1, 55.6) 228 (53.3), 133 (100), 87 (50.2); HRMS
calcd for C15H23NOS4 361.0663, found 361.0661.
2-Aza-2-(1,3-dithian-2-yl)-3-methyl-4-phenyl-6,10-di-
thiaspiro[4.5]decan-1-one (12). From the acyl azide
(38 mg, 0.2 mmol) in 4.0 mL of benzene and 3 (1.0 mL,
0.5 mmol) was obtained 67 mg (85%) of the desired product
as a colorless oil after ¯ash chromatography (5:1 hexanes/
1
EtOAc12% NEt3). H NMR (CDCl3, 400 MHz) d 7.38±
7.29 (m, 5H), 6.67 (s, 1H), 5.47 (t, Jˆ2.2 Hz, 1H), 4.42 (t,
Jˆ2.2 Hz, 1H), 3.97 (t, Jˆ1.8 Hz, 1H), 3.82 (dt,
J1ˆ13.4 Hz, J2ˆ2.4 Hz, 1H), 3.66 (dt, J1ˆ13.4 Hz,
J2ˆ2.4 Hz, 1), 3.23±3.10 (m, 2H), 3.08±2.96 (m, 2H),
2.60 (td, J1ˆ14.0 Hz, J2ˆ3.4 Hz, 1H), 2.51 (td,
J1ˆ14.0 Hz, J2ˆ3.4 Hz, 1H), 2.21±2.06 (m, 2H), 1.91±
1.69 (m, 2H); 13C NMR (CDCl3, 100 MHz) d 170.4,
141.9, 134.6, 130.1, 128.4, 128.0, 94.1, 57.1, 55.6, 50.7,
32.5, 32.4, 27.9, 27.1, 25.1, 24.0; IR (neat) n 2918, 1710,
1645, 1354, 1210 cm21; mass spectrum (EI) m/e (rel. int.)
395 (M1, 7.7) 276 (86.6), 119 (100); HRMS calcd for
C18H21NOS4 395.0506, found 395.0505.
7-(1,3-Dithian-2-yl)spiro[1,3-dithiane-2,30-3,40,50,60,70-
pentahydroindole]-8-one (16). At room temperature, a
total of 54 mg (0.15 mmol) of 10 was dissolved into
0.5 mL of CDCl3 (obtained from Cambridge Isotope
Laboratories, Inc.; directly used without passing through
basic alumina) in a NMR tube. The reaction turned out to
2-Aza-2-(1,3-dithian-2-yl)-4-methyl-3-methylene-6,10-
dithiaspiro[4.5]decan-1-one (13). From the acyl azide
(25 mg, 0.2 mmol) in 4.0 mL of benzene and 3 (1.0 mL,
0.5 mmol) was obtained 52 mg (78%) of the desired product
as a colorless oil after ¯ash chromatography (7:1 hexanes/
1
be a slow process and monitored by H NMR. After 2 d at
room temperature, the ratio between the desired product and
the starting material was 13.5:1. This ratio had been the
same even after 7 d: H NMR (CDCl3, 400 MHz) d 6.45
1
1
EtOAc12% NEt3). H NMR (CDCl3, 400 MHz) d 6.53 (s,
(s, 1H), 3.90 (dt, J1ˆ13.6 Hz, J2ˆ2.4 Hz, 2H), 3.08 (dt,
J1ˆ13.6 Hz, J2ˆ2.4 Hz, 2H), 2.96 (td, J1ˆ13.6 Hz,
J2ˆ3.6 Hz, 2H), 2.76±2.68 (m, 2H), 2.54 (td, J1ˆ13.6 Hz,
1H), 5.30 (t, Jˆ2.4 Hz, 1H), 4.46 (t, Jˆ2.4 Hz, 1H), 3.99
(dt, J1ˆ13.4 Hz, J2ˆ2.4 Hz, 1H), 3.54±3.43 (m, 1H), 3.17±
3.04 (m, 2H), 3.04±2.92 (m, 2H), 2.82±2.73 (m, 1H), 2.69±
2.54 (m, 2H), 2.28±2.06 (m, 2H), 1.92±1.74 (m, 2H), 1.31
(d, Jˆ7.2 Hz, 3H): 13C NMR (CDCl3, 100 MHz) d 170.9,
143.7, 91.2, 56.9, 50.9, 43.7, 32.5, 32.4, 27.3, 26.3, 25.1,
J2ˆ3.6 Hz, 2H), 2.25±2.05 (m, 4H), 1.98±1.64 (m, 6H); 13
C
NMR (CDCl3, 100 MHz) d 175.8, 138.2, 114.4, 55.7, 49.1,
32.8, 24.9, 24.2, 230, 22.2, 21.9, 19.8. After the solvent was
removed, a total of 54 mg (93% of the desired product based
on the ratio) of an inseparable mixture was obtained as a
24.6, 11.6; IR (neat) n 2910, 1710, 1680, 1340, 1300 cm21
;
mass spectrum (EI) m/e (rel. int.) 333 (M1, 5.7), 214 (99.5),
119 (100); HRMS calcd for C13H19NOS4 333.0350, found
333.0350.
pale yellow oil. IR (neat) n 2933, 1705, 1668, 1315 cm21
;
mass spectrum (EI) m/e (rel. int.) 359 (M1, 8.0), 240 (50.6),
119 (100); HRMS calcd for C15H21NOS4 359.0506, found
359.0506.
2-Aza-2-(1,3-diethiepan-2-yl)-3-methylene-4-phenyl-6,11-
dithiaspiro[4.6]undecan-1-one (14). From the acyl azide
(38 mg, 0.2 mmol) in 4.0 mL of benzene and oxadiazoline 4
(1.0 mL, 0.5 mmol) was obtained 47 mg (56%) of the
desired product as a colorless oil after ¯ash chromatography
(10:1 hexanes/EtOAc12% NEt3). Due to the coexistence of
several conformers of the two 7-membered rings at room
temperature, the peaks of each conformer could be observed
by both 1H NMR and 13C NMR: 1H NMR (CDCl3,
400 MHz) d 7.48±7.30 (m, 5H), 6.58 (br s, 1H), 5.19 (s,
1H), 5.15 (br s, 0.5H), 4.47 (t, Jˆ2.0 Hz, 1H), 4.42 (m,
0.5H), 4.17 (t, Jˆ2.0 Hz, 1H), 3.35±3.26 (m, 1H), 2.93±
2-Aza-2-(1,3-dithian-2-yl)-3-methyl-4-phenyl-6,10-di-
thiaspiro[4.5]dec-3-en-1-one (17). At room temperature,
60 mg (0.15 mmol) of 12 was dissolved in 0.5 mL of
CDCl3 (obtained from Cambridge Isotope Laboratories,
Inc.; directly used without passing through basic alumina)
in a NMR tube: 1H NMR demonstrated that the reaction was
1
complete. H NMR (CDCl3, 400 MHz) d 7.44±7.30 (m,
5H), 6.59 (s, 1H), 3.95 (dt, J1ˆ13.6 Hz, J2ˆ2.4 Hz, 2H),
3.17±3.08 (m, 2H), 3.00 (td, J1ˆ14.0 Hz, J2ˆ3.8 Hz, 2H),
2.51 (td, J1ˆ14.0 Hz, J2ˆ3.8 Hz, 2H), 2.33 (s, 3H), 2.18±
2.10 (m, 2H), 1.91±1.74 (m, 2H); 13C NMR (CDCl3,

10110
J. H. Rigby et al. / Tetrahedron 56 (2000) 10101±10111
100 MHz) d 174.9, 138.3, 131.7, 130.5, 128.0, 127.8, 117.4,
56.0, 50.6, 32.8, 25.0, 24.8, 23.8, 12.9. After the solvent was
removed, a total of 60 mg (100%) of the desired product was
obtained as a pale yellow oil. IR (neat) 2939, 2889, 1701,
1344 cm21; mass spectrum (EI) m/e (rel. int.) 395 (M1, 9.1),
276 (19.9), 119 (100); HRMS calcd for C18H21NOS4
395.0506, found 395.0511.
163 (100), 121 (12), 79 (6); HRMS for C22H33NO3S4 calcd
487.1343, found 487.1340.
6-Dimethylamino-1-[bis(propylthio)methyl]-3,3-bis-
(propylthio)indolin-2-one (21). 3-Dimethylaminobenzoyl-
azide (0.12 g, 0.63 mmol) in CH3CN (6 mL) gave 0.233 g
(70%) of product: 1H NMR (500 MHz, CDCl3) d 0.89±0.94
(m, 12H), 1.48±1.53 (m, 4H), 1.58±1.66 (m, 4H), 2.41±
2.47 (m, 2H), 2.55±2.66 (m, 6H), 3.02 (s, 6H), 6.43±6.44
(d, 1H, Jˆ8.5 Hz), 6.64 (s, 1H), 6.98 (s, 1H), 7.25±7.27 (d,
1H, Jˆ9.0 Hz); 13C NMR (125 MHz, CDCl3) d 13.6, 13.8,
22.6, 22.9, 32.6, 35.1, 40.8, 56.7, 57.5, 98.5, 107.0, 115.3,
124.9, 139.1, 151.4, 174.9; IR (NaCl) n 2961, 1713, 1619,
1511, 1376, 1116 cm21; mass spectrum m/e (rel. int.) 411
(49), 293 (20), 249 (100), 223 (14), 163 (15), 121 (6), 76 (3);
HRMS for C20H31N2OS3 (M2C3H7S) calcd 411.1599,
found 411.1499; Anal. for C23H38N2OS4 calcd C 56.77; H,
7.88; N, 5.76; found C, 56.95; H, 7.75; N 5.68.
General procedure for the [411] cycloaddition between
aryl isocyanates and bis(alkylthio)carbenes
To a two-necked round bottom ¯ask equipped with a re¯ux
condenser, is added the pure acyl azide in a CH3CN solution
(0.1 M) and re¯uxed for 0.5±1.0 h until the corresponding
isocyanate is formed (monitored by IR). To this solution is
added oxadiazoline 1 in a THF solution (1.0 M) in 0.200 mL
portions every 10 min. The resulting solution is re¯uxed for
16 h at which time the solvent is removed under vacuum.
Flash chromatography (hexanes/Et2O) of the mixture
affords the pure adduct.
1-[Bis(propylthio)methyl]-3,3-bis(propylthio)-5-(tri-
¯uoromethyl)indolin-2-one (22). 4-Tri¯uoromethyl-
benzene-1-isocyanate (0.15 g, 0.8 mmol) in acetonitrile
1
1-[Bis(propylthio)methyl]-3,3-bis(propylthio)indolin-2-
one (18). Phenyl isocyanate (0.1 g, 0.87 mol) in acetonitrile
(8 mL) afforded 0.156 g (42%) of product: 1H NMR
(500 MHz, CDCl3) d 0.97±1.00 (m, 12H), 1.58±1.62 (m,
4H), 1.65±1.67 (m, 4H), 2.54 (m, 2H), 2.68±2.71 (m, 2H),
2.81±2.86 (m, 2H), 7.11±7.34 (m, 6H); 13C NMR
(125 MHz, CDCl3) d 14.2, 14.7, 21.7, 22.8, 23.3, 32.2,
35.4, 58.8, 115.4, 124.0, 129.2, 129.7, 130.1, 139.9, 165.4;
(8 mL) gave 0.054 (13%) of product: H NMR (500 MHz,
CDCl3) d 0.92±1.02 (m, 12H), 1.51±1.57 (m, 4H), 1.59±
1.67 (m, 4H), 2.43±2.47 (m, 2H), 2.54±2.60 (m, 2H), 2.63±
2.72 (m, 4H), 6.64 (s, 1H), 7.61±7.63 (d, 1H, Jˆ10 Hz),
7.69±7.71 (d, 1H, Jˆ10 Hz); 13C NMR (125 MHz,
CDCl3) d 14.0, 14.2, 14.5, 22.5, 22.9, 23.3, 30.4, 33.4,
34.3, 35.6, 58.3, 114.6, 119.7, 122.1, 127.3; IR (NaCl)
2963, 2873, 1721, 1620, 1327, 1165; mass spectrum m/e
(relative intensity) 436 (47), 350 (30), 232 (17), 163 (54),
57 (21), 43 (100); HRMS for C19H24F3NOS3 (M±C3H7S)
calcd 436.1051, found 436.1053.
IR (NaCl) n 2960, 2871, 1728, 1639, 1463, 1273 cm21
;
mass spectrum m/e (rel. int.) 368 (20), 293 (9), 194 (14),
163 (63), 119 (100), 91 (40), 43 (58); HRMS for
C18H26NOS3 (M12C3H7S) calcd 368.1171, found
368.1182.
General procedure for the double cycloaddition of
bis(propylthio)carbenes with vinyl isocyanates
1-[Bis(propylthio)methyl]-3,3-bis(propylthio)benz[g]in-
dolin-2-one (19). 1-Naphthyloylazide (0.11 g, 0.56 mmol)
A round bottom ¯ask (100 mL) was ®tted with a long
condenser. The appropriate acyl azide (1 equiv.) was
dissolved in dry benzene (concentrationˆ0.5 M) and
re¯uxed for 45 min (oil bath temperature 958C) to give
the corresponding isocyanate. The oxadiazoline
(10 equiv.) was dissolved in hexanes (concentration
ˆ6.0 M) at room temperature and added as fast as possible
to the re¯uxing solution of isocyanate via syringe through
the condenser (CAUTION: VERY EXOTHERMIC
REACTION). The reaction was re¯uxed for 30 min after
which time a light orange solution was obtained. The
reaction mixture was allowed to cool to room temperature
and the solvent was removed in vacuo. The residue was
chromatographed (hexanes/EtOAc12% Et3N) to give the
pure products.
1
in CH3CN (6 mL) yielded 0.193 g (70%) of product: H
NMR (300 MHz, CDCl3) d 0.87±0.96 (m, 12H), 1.43±
1.56 (m, 4H), 1.61±1.71 (m, 4H), 2.54±2.75 (m, 8H), 7.13
(s, 1H), 7.48±7.60 (m, 2H), 7.62±7.64 (m, 2H), 7.72±7.75
(d, 1H), 7.83±7.86 (d, 1H), 8.89±8.92 (d, 1H); 13C NMR
(75 MHz, CDCl3) d 13.6, 13.8, 22.5, 23.1, 32.4, 63.1, 56.3,
59.6, 120.9, 121.4, 125.5, 125.7, 125.9, 126.6, 127.6, 129.1,
135.6, 136.0, 176.1; IR (NaCl) n 2930, 1709, 1393, 1298,
1039 cm21; mass spectrum m/e (rel. int.) 493 (2), 330 (26),
256 (8), 163 (100), 121 (10), 43 (19); HRMS for
C25H35NOS4 calcd 493.1602, found 493.1601; Anal. for
C25H35NOS4 calcd C, 61.83; H, 7.15; N, 2.85; found C,
61.57; H, 7.14; N, 2.94.
5-[Bis(propylthio)methyl]-7,7-bis(propylthio)-5H-1,3-
dioxolano[4,5-f]indolin-2-one (20). Piperonyloylazide
(0.19 g, 1 mmol) in acetonitrile (10 mL) gave 0.281 g
1-Bis(propylthio)methyl-3,3,4,4-tetrakis(propylthio)-
3,4,4a,5,6,7-hexahydro-1H-quinolin-2-one (23). From the
acyl azide (210 mg, 1.39 mmol) and the oxadiazoline 1
(3.40 g, 13.9 mmol) was obtained after ¯ash chromato-
graphy (20:1 hexanes/EtOAc12% Et3N) quinolinone 23
(290 mg, 47%) as a pale yellow solid: mpˆ87±898C
1
(58%) of product: H NMR (500 MHz, CDCl3) d 0.92±
0.95 (m, 12H), 1.50±1.55 (m, 4H), 1.58±1.66 (m, 4H),
2.42±2.46 (m, 2H), 2.54±2.58 (m, 2H), 2.61±2.66 (m,
4H), 5.99 (s, 2H), 6.62 (s, 1H), 6.96 (s, 1H), 7.23 (s, 1H);
13C NMR (125 MHz, CDCl3) d 14.1, 14.3, 23.0, 23.3, 32.9,
35.5, 58.1, 97.9, 102.2, 105.9, 121.5, 132.8, 144.8, 148.8,
1
(hexanes/EtOAc); H NMR (CDCl3, 500 MHz) d 7.70 (s,
1H, exchangeable with D2O), 4.88 (d, Jˆ3.0 Hz, 1H), 3.75
(m, 1H), 2.92 (m, 6H), 2.76 (m, 1H), 2.62 (m, 1H), 2.35 (m,
1H), 2.14 (m, 2H), 1.90 (m, 2H), 1.72±1.50 (m, 9H), 1.00 (t,
174.9; IR (NaCl) n 2962, 1712, 1471, 1156, 1038 cm21
;
mass spectrum m/e (rel. int.) 412 (25), 337 (15), 224 (13),

J. H. Rigby et al. / Tetrahedron 56 (2000) 10101±10111
10111
Jˆ7.5 Hz, 9H), 0.95 (t, Jˆ7.5 Hz, 3H); 13C NMR (CDCl3,
References
125 MHz) d 170.6, 136.4, 98.6, 79.1, 68.9, 46.1, 35.4, 35.4,
35.4, 34.6, 25.9, 23.2, 22.3, 22.2, 22.1, 22.1, 22.1, 14.0,
14.0, 14.0, 13.7; IR (CDCl3) n 3224, 2943, 1689,
1449 cm21; mass spectrum (EI) m/e (rel. int.) 372
(M2C3H7S, 10) 236 (100); HRMS calcd for C21H37NOS4
(M2C3H7S) 372.14895, found 372.1493; Anal. calcd for
C21H37NOS4: C, 56.35; H, 8.34; N, 3.13; found: C, 56.12;
H, 8.24; N, 3.21.
1. Rigby, J. H. Synlett 2000, 1.
2. (a) Rigby, J. H.; Balasubramanian, N. J. Org. Chem. 1989, 54,
224. (b) Rigby, J. H.; Holsworth, D. D.; James, K. J. Org. Chem.
1989, 54, 4019. (c) Rigby, J. H.; Qabar, M. J. Org. Chem. 1989, 54,
5852.
3. (a) Rigby, J. H.; Qabar, M. N. J. Am. Chem. Soc. 1991, 113,
8975. (b) Rigby, J. H.; Cavezza, A.; Ahmed, G. J. Am. Chem. Soc.
1996, 118, 12848.
6-Methylene-5-phenyl-3,3,4,4-tetrakis(propylthio)-
piperidin-2-one (24). From the acyl azide (190 mg,
1.01 mmol) and the oxadiazoline 1 (2.52 g, 10.10 mmol)
was obtained after ¯ash chromatography (20:1 hexanes/
EtOAc12% Et3N) piperidinone 24 (244 mg, 50%) as a
4. (a) Rigby, J. H.; Hughes, R. C.; Heeg, M. J. J. Am. Chem. Soc.
1995, 117, 7834. (b) Rigby, J. H.; Danca, D. M. Tetrahedron Lett.
1997, 38, 4969. (c) Rigby, J. H.; Laurent, S.; Cavezza, A.; Heeg,
M. J. J. Org. Chem. 1998, 63, 5587.
5. (a) Rigby, J. H.; Mateo, M. E. Tetrahedron 1996, 52, 10569.
(b) Rigby, J. H.; Cavezza, A.; Heeg, M. J. J. Am. Chem. Soc. 1998,
120, 3664. (c) Rigby, J. H.; Mateo, M. E. J. Am. Chem. Soc. 1997,
119, 12655.
1
pale yellow oil: H NMR (CDCl3, 500 MHz) d 8.35 (s,
1H, exchangeable with D2O), 7.64 (m, 2H), 7.27 (m, 3H),
5.28 (t, Jˆ2.5 Hz, 1H), 4.50 (t, Jˆ2.5 Hz, 1H), 3.91 (t,
Jˆ2.5 Hz, 1H), 2.87 (m, 3H), 2.71 (m, 4H), 2.40 (m, 1H),
1.58 (m, 6H), 1.35 (m, 1H), 1.25 (m, 1H), 0.98 (t, Jˆ7.0 Hz,
9H), 0.83 (t, Jˆ7 Hz, 3H); 13C NMR (CDCl3, 125 MHz) d
170.0, 146.2, 138.4, 127.1, 126.9, 126.9, 87.8, 80.4, 71.8,
55.5, 35.5, 35.5, 35.5, 35.3, 22.2, 22.2, 22.1, 22.1, 14.0,
14.0, 14.0, 13.6; IR (®lm) n 3232, 2922, 1689, 1450,
1337, 1273, 1224 cm21; mass spectrum (CI) m/e (rel. int.)
408 (M2C3H7S, 28.4), 334 (18.7), 248 (14), 237 (100);
HRMS calcd for C24H37NOS4 (M2C3H7S) 408.14895,
found 408.1488.
6. (a) Rigby, J. H.; Laurent, S. J. Org. Chem. 1999, 64, 1766.
(b) Rigby, J. H.; Danca, M. D. Tetrahedron Lett. 1999, 40, 6891.
7. (a) Couture, P.; Terlous, J. K.; Warkentin, J. J. Am. Chem. Soc.
1996, 118, 4214. (b) Pole, D. L.; Sharma, P. K.; Warkentin, J. Can.
J. Chem. 1996, 74, 1335.
8. For related sulfur-containing carbenes, see: (a) Warkentin, J. In
Advances in Carbene Chemistry; Brinker, U., Ed., JAI: 1998; Vol.
2, p 263. (b) Er, H.-T.; Pole, D. L.; Warkentin, J. Can. J. Chem.
1996, 74, 1480.
9. (a) Kirmse, W. In Adv. in Carbene Chemistry, Brinker, U. H.,
Ed.; JAI; 1994; Vol. 1, p 1. (b) Moss, R. A.; Shen, S.; Wiostowski,
M. Tetrahedron Lett. 1988, 29, 6417. (c) Kirmse, W. Justus Liebigs
Ann. Chem. 1963, 666, 9.
6,6-Ethylenedioxy-3,3,4,4-tetrakis(propylthio)-3,4,4a,5,
6,7-hexahydro-1H-quinolin-2-one (25). From the acyl
azide (300 mg, 1.43 mmol) and the oxadiazoline 1 (3.56 g,
14.30 mmol) was obtained after ¯ash chromatography (4:1
hexanes/EtOAc12% Et3N) quinolinone 25 (326 mg, 45%)
as a pale yellow solid: mpˆ128±1298C (CH3CN); 1H NMR
(CDCl3, 500 MHz) d 8.17 (s, 1H, exchangeable with D2O),
4.83 (m, 1H), 4.12±3.93 (m, 5H), 2.89 (t, Jˆ7.0 Hz, 6H),
2.73 (m, 1H), 2.58 (m, 1H), 2.51±2.43 (m, 2H), 2.30 (m,
1H), 2.09 (t, Jˆ12.0 Hz, 1H), 1.63±1.55 (m, 6H), 1.52±1.47
(m, 2H), 0.98 (t, Jˆ7.5 Hz, 9H), 0.92 (t, Jˆ7.5 Hz, 3H); 13C
NMR (CDCl3, 125 MHz) d 171.3, 136.1, 108.5, 95.3, 78.7,
69.0, 64.4, 64.3, 44.5, 35.3, 35.3, 35.3, 34.6, 34.5, 34.3,
22.2, 22.1, 22.1, 22.1, 13.6, 13.9, 13.9, 13.7; IR (CDCl3)
3251, 2948, 1694, 1454, 1088 cm21; mass spectrum (FAB)
m/e (rel. int.) 538 (M1H, 1), 430 (100), 354 (27.6); HRMS
calcd for C23H39NO3S4 (M2C3H7S) 430.15443, found
430.1542; Anal. calcd for C23H39NO3S4: C, 54.63; H,
7.78; N, 2.77; found: C, 54.90; H, 7.78; N, 2.80.
10. Corey, E. J.; Carey, F. A.; Winter, R. A. F. J. Am. Chem. Soc.
1965, 87, 934.
11. (a) Hoffmann, R. W.; Steinbach, K.; Dittrich, B. Chem. Ber.
1973, 106, 2174. (b) Kassam, K.; Pole, D. L.; El-Saidi, M.;
Warkentin, J. J. Am. Chem. Soc. 1994, 116, 1161.
12. Dimerization of nucleophilic carbenes is a well-known
process: Nakayama, J. Synthesis 1975, 168.
13. Numerous electron rich alkenes undergo [412] cyclization
with vinyl isocyanates: (a) Fuks, R. Tetrahedron 1970, 26, 2161.
(b) Rigby, J. H.; Burkhardt, F. J. J. Org. Chem. 1986, 51, 1374.
14. Calculations (SYBYL force ®eld) performed on Spartan SGI
(copyright 1991-95, Wave Functions, Inc.) suggest that 28 is only
0.2 kcal/mol less stable than 23, thus adding some credence to this
pathway. We thank Ms. Sylvie Bosio for performing these
calculations.
15. For general experimental details, see: Rigby, J. H.; Qabar, M.;
Ahmed, G.; Hughes, R. C. Tetrahedron 1993, 49, 10219.
Acknowledgements
We wish to thank the National Science Foundation for their
generous support of this investigation.