Reactions of dimethoxycarbene with carbon-sulfur double bonds

Article abstract of DOI:10.1002/poc.857

Unlike electrophilic carbenes, which react at sulfur to produce thiocarbonyl ylide intermediates, dimethoxycarbene (DMC), generated by thermolysis of an oxadiazoline at 110°C in benzene in a sealed tube, reacts at carbon, possibly to generate a zwitterionic intermediate, or at both carbon and sulfur in a concerted process that generates a thiirane. In case of the strained 2,2,4,4-tetramethylcyclobutane-1,3-dithione (2), an assumed zwitterion undergoes ring expansion. In analogous reactions, unstrained thiones afford thiiranes, possibly by ring closure of the postulated intermediates or by concerted addition. Desulfurization of thiiranes, which occurs spontaneously in some instances, results in the formation of ketene acetals, many of which hydrolyze during workup. O-Alkyl thioesters and xanthates react to afford products via insertion of the DMC into C_sp2-O or C_sp2-S bonds, respectively. Copyright

Full text of DOI:10.1002/poc.857

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2005; 18: 86–89
Published online 21 September 2004 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/poc.857
Review Commentary
Reactions of dimethoxycarbene with carbon–sulfur
double bondsy
Malgorzata Dawid,1 Darren L. Reid,1§ John Warkentin1* and Grzegorz Mloston2
z
1Department of Chemistry, McMaster University, Hamilton, Ontario L8S 4M1, Canada
2Department of Organic and Applied Chemistry, Section of Heteroorganic Compounds, University of Lo´ dz, Lo´ dz, Poland
Received 3 November 2003; revised 1 February 2004; accepted 5 March 2004
ABSTRACT: Unlike electrophilic carbenes, which react at sulfur to produce thiocarbonyl ylide intermediates,
dimethoxycarbene (DMC), generated by thermolysis of an oxadiazoline at 110 ꢀC in benzene in a sealed tube, reacts
at carbon, possibly to generate a zwitterionic intermediate, or at both carbon and sulfur in a concerted process that
generates a thiirane. In case of the strained 2,2,4,4-tetramethylcyclobutane-1,3-dithione (2), an assumed zwitterion
undergoes ring expansion. In analogous reactions, unstrained thiones afford thiiranes, possibly by ring closure of
the postulated intermediates or by concerted addition. Desulfurization of thiiranes, which occurs spontaneously in
some instances, results in the formation of ketene acetals, many of which hydrolyze during workup. O-Alkyl
thioesters and xanthates react to afford products via insertion of the DMC into Csp2 —O or Csp2 —S bonds,
respectively. Copyright # 2004 John Wiley & Sons, Ltd.
KEYWORDS: dimethoxycarbene; ketene acetals; oxadiazoline; reactive intermediates; thiiranes; thiocarbonyl compounds
INTRODUCTION
seems to explain many of the observed products (the fact
that the postulate is convenient for the explanation of
diverse reaction paths does not mean that it is right, of
course). On the other hand, thiocarbonyl groups are
known to undergo carbophilic and/or thiophilic reac-
tions3 with other nucleophilic agents and, in the case of
DMC, both reaction courses could compete. This mini-
review covers our groups’s research on the chemistry of
DMC with thiocarbonyl compounds and the limited
research of some others.
Although there are numerous publications concerning
reactions of electrophiliic carbenes and carbenoids with
thiocarbonyl groups (see, for example, Ref. 1), there are
fewer concerning reactions of nucleophilic carbenes with
analogous compounds (see, for example, Ref. 2). Elec-
—
trophilic carbenes add to sulfur of C S compounds to
—
generate thiocarbonyl ylides,1 whereas nucleophilic car-
—
benes add to carbon of C S, either in concert with
—
addition at S or to form a dipolar intermediate. A dipolar
intermediate has been demonstrated for the case of
diaminocarbenes and CS2 only2c (Scheme 1), and it
seems reasonable to postulate an analogous intermediate
for reactions of dimethoxycarbene (DMC) with thiocar-
bonyl compounds, particularly because such a postulate
RESULTS AND DISCUSSION
2,2,4,4-Tetramethyl-1,3-cyclobutanedithione
Reaction of dimethoxycarbene (DMC, 1) with the cyclo-
butanedithione 2 resulted in two major products, 6 [1H
NMR (300 MHz, CDCl3): ꢀ 1.37 (s, 6H), 1.49 (s, 6H),
3.33 (s, 6H).13 C NMR (75 MHz, CDCl3): ꢀ 24.1, 33.6,
50.6, 64.5, 70.3, 198.6, 259.1, 272.0. MS (HR): m/z calcd
for C11H18O2S2 246.0748; found 246.0749] and 7 [1H
NMR (300 MHz, CDCl3): ꢀ 1.26 (s, 6H), 1.48 (s, 3H),
1.54 (s, 3H), 3.35 (s, 3H), 3.40 (s, 3H), 3.55 (s, 3H), 3.69
(s, 3H). 13C NMR (75 MHz, CDCl3): ꢀ 24.8, 27.9, 29.1,
32.4, 50.6, 52.5, 55.6, 60.2, 66.4, 108.4, 109.4, 278.5. MS
(EI): m/z 320 (Mþ)], formed by primary ring expansion of
*Correspondence to: J. Warkentin, Department of Chemistry,
McMaster University, Hamilton, Ontario L8S 4M1, Canada.
E-mail: warkent@mcmaster.ca
ySelected article presented at the Seventh Latin American Conference
on Physical Organic Chemistry (CLAFQO-7), 21–26 September 2003,
´
Florianopolis, Brazil.
zPresent address: Torcan Chemicals, Aurora, Ontario L4G 3H4,
Canada.
§Present address: Analytical Research and Development, Pfizer Inc.,
2800 Plymouth Road, Ann Arbor, Michigan 48105, USA.
Contract/grant sponsor: Natural Sciences and Engineering Research
Council of Canada; Contract/grant number: 1110.
Contract/grant sponsor: Polish State Committee for Scientific Re-
search; Contract/grant number: 4 T09A 046 25.
Copyright # 2004 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 86–89

REACTIONS OF DIMETHOXYCARBENE WITH C—S DOUBLE BONDS
87
Scheme 4. Thiirane formation from reaction of DMC with
adamantanethione
Scheme 1. Reaction of stable diaminocarbenes with carbon
disulfide
Along with the zwitterionic intermediate from the
reaction of a diaminocarbene with carbon disulfide,
presented in Scheme 1, there is a report by Hoffmann
et al.,4 who postulated a similar structure 8 for an
intermediate formed initially from DMC and phenyl
isothiocyanate. Hoffmann’s group trapped DMC with
aryl isocyanates and aryl isothiocyanates to give 5,5-
dimethoxyhydantoins and 5,5-dimethoxydithiohydan-
toins, respectively. The short-lived dipolar intermediate
was trapped efficiently with another molecule of phenyl
isothiocyanate to yield the imidazolidine-2,5-dithione (9)
shown in Scheme 3.4 Nair et al. have also invoked a
dipolar intermediate, from the reaction of dimethoxycar-
bene with dimethyl acetylenedicarboxylate, which adds
to carbonyl compounds.5
2 (Scheme 2).2b The expected thiirane 5 was not found in
the reaction mixture. Products 6 and 7 can be accounted
for in terms of intermediate 3 (or an analogous transition
state) that does not have the correct geometry for facile
formation of thiirane 5 but does have the correct geome-
try for ring expansion to 6.
Ring-expansion product 6 could be formed most ra-
pidly, because of relief of ring strain, either from an
intermediate such as 3 or a transition state analogous to it.
—
Compound 6, with non-equivalent C S groups, reacts
—
regioselectively with 1, at the C S moiety flanked by
—
—
the methoxy substituents. We attribute the enhanced
reactivity of that group (the isomeric thiirane was not
found) to the polar effect of those methoxy groups. Two
ꢁ-methoxy groups (as in 2,2-dimethoxycyclopentanone)
raise the carbonyl stretching frequency above that of
cyclopentanone, by about 15 cmꢁ1. A through-space
interaction of a methoxy group with the incoming car-
Dimethoxythiiranes have been isolated in a few
cases,2a most notably from reaction of 1 with adaman-
tanthione6 to afford 10 (Scheme 4).
Diarylthiones
bene unit, that becomes positively charged as it bonds to
2a,b
—
carbon of C S, cannot be ruled out.
Presumably
Reactions of aromatic thiones with DMC did not lead to
isolable dimethoxythiiranes. Thus 4,40-dimethoxythio-
benzophenone (M. Dawid, G. Mloston and J. Warkentin,
unpublished observation) gave the known7 methyl ester
—
addition to 6 involves an intermediate (or transition state)
similar to 3 but, in the absence of strain, further ring
expansion is slowed.
Scheme 2. Reaction of dimethoxycarbene with a cyclobutanedithione
Scheme 3. Dipolar intermediate from reaction of DMC with phenyl isothiocyanate
Copyright # 2004 John Wiley & Sons, Ltd. J. Phys. Org. Chem. 2005; 18: 86–89

88
M. DAWID ET AL.
Scheme 5. Reaction of DMC with 4,40-dimethoxythiobenzophenone
of 2,2-bis(4,40-dimethoxyphenyl)ethanoic acid (13) in
54% yield. Scheme 5 illustrates a possible sequence,
involving desulfurization of thiirane 11 and subsequent
hydrolysis of ketene acetal 12. Those intermediates might
be isolable under some conditions.
Methyl dithiobenzoate
Methyl dithiobenzoate (19) gave 22 [1H NMR
(300 MHz, CDCl3): ꢀ 2.08 (s, 3H), 3.74 (s, 3H), 4.52
(s, 1H), 7.26–7.46 (m, 5H). 13C NMR (125 MHz,
CDCl3): ꢀ 14.9, 52.6, 53.4, 128.1, 128.4, 128.6, 135.7,
171.1, MS (HR): m/z calcd for C10H12O2S 196.0558;
found 196.0545] in 22% yield and 18 in 28% yield
(Scheme 7).2b Again, it is plausible to think of 22 as a
final product arising via 20 and 21. Some support for the
proposed mechanism came from the isolation of an
impure sample of a material thought to be 21 {1H
NMR (200 MHz, CDCl3): ꢀ 1.98 (s, 3H), 3.52 (s, 3H),
3.77 (s, 3H), 7.18–7.47 (m, 5H). 13C NMR (75 MHz,
CD3Cl): ꢀ 17.0, 57.5, 97.5, 126.4, 128.1, 129.7, 136.9,
159.2. MS (EI): m/z (%) 210 ([M ꢁ S]þ, 70), 195 (100),
167 (32), 135 (15), 121 (85), 105 (58), 91 (12), 77 (55)},
which after chromatographic workup was transformed
into 22. The precursor of 18 is pictured as structure 24.
Neither 23 nor 24 was found.
O-Methyl thiobenzoate
O-Methyl thiobenzoate (14) reacted with 2 equiv. of 1
to afford the known8 18 in 84% yield (Scheme 6), and
we propose 15–17 as intermediates in this cascade
conversion.2a
Compound 17 could not be isolated in completely pure
form but its structure was unambigously confirmed by
means of spectroscopic data [1H NMR (300 MHz,
CDCl3): ꢀ 3.23 (s, 3H); 3.34 (s, 9H), 3.68 (s, 3H),
7.26–7.32 (m, 3H), 7.53–7.57 (m, 2H). 13C NMR
(125 MHz, CDCl3): ꢀ 51.4, 56.0, 57.9, 108.1, 113.1,
127.1, 127.4, 130.6, 137.0]. Attempts to purify it by
further chromatography led to partial or complete hydro-
lysis to 18.
It is not clear what the features are that lead to
desulfurization, or what species remove the thiirane
Scheme 6. Reaction of DMC with O-methyl thiobenzoate
Scheme 7. Reaction of DMC with dimethyl dithiobenzoate
Copyright # 2004 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 86–89

REACTIONS OF DIMETHOXYCARBENE WITH C—S DOUBLE BONDS
89
further, to isolate and characterize some of the postulated
intermediates.
Acknowledgments
Scheme 8. Reaction of DMC with dimethyl xanthate
M. D., D. L. R. and J. W. thank the Natural Sciences and
Engineering Research Council of Canada for financial
support (Grant No. 1110). G. M. acknowledges support
by the Polish State Committee for Scientific Research
(Grant No. 4 T09A 046 25).
sulfur. Moreover, there are additional minor products that
might have mechanistic significance.
Dimethyl xanthate
Initial attack of 1 on dimethyl xanthate (25) is pictured in
terms of 26, in which the choice for migration is between
a methoxy and a methylthio group (Scheme 8). One
would expect the latter to migrate to afford the product
that was isolated (27) [1H NMR (200 MHz, C6D6): ꢀ 1.87
(s, 3H), 3.15 (s, 6H), 3.69 (s, 3H). 13C NMR (50.3 MHz,
C6D6): ꢀ 13.4, 50.9, 58.8, 111.5, 211.6], given the weaker
C—S bond and the greater polarizability of sulfur com-
pared with oxygen.2a
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CONCLUSION
The reactions of thiocarbonyl compounds with nucleo-
philic carbenes are in their infancy, as indicated by the
above early review. However, there is no doubt that their
interesting diversity leaves much scope for investigation
of mechanisms, by both experimental and computational
approaches. It will be particularly important to try,
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Copyright # 2004 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 86–89