S-alkyl chlorothioformates from xanthates

Article abstract of DOI:10.1055/s-2007-983756

Reaction of S-alkyl O-ethyl xanthates (S-alkyl O-ethyl dithiocarbonates) with catalytic Vilsmeier reagent generated in situ from N-formylmorpholine (morpholine-4-carbaldehyde) gives S-alkyl chlorothioformates in good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983756

SHORT PAPER
2097
S-Alkyl Chlorothioformates from Xanthates
S
-Alkyl Chlorothio
l
forma
t
e
esfrom
X
a
x
nthates andra M. Gade, Christopher J. Abelt*
Department of Chemistry, College of William and Mary, Williamsburg, VA 23187, USA
Fax +1(757)2212715; E-mail: cjabel@wm.edu
Received 16 March 2007
incomplete conversion because of the undesired side reac-
tion of 7 with oxalyl chloride to give chloro-substituted
derivative 9. A separate NMR spectroscopic experiment
showed that treating 7 (in CD3CN) independently with
threefold excess oxalyl chloride gave 2 and 9 in a ratio of
88:12. Most of the yields of 8 were around 80% for a
representative range of alkyl group types (Table 1). The
reaction of the S-tert-butyl xanthate gave the lowest yield.
The product 8e decomposed slowly to tert-butyl chloride
under the reaction conditions and the yield dropped to
20% over 24 hours. The reported yield was for a three-
hour reaction.
Abstract: Reaction of S-alkyl O-ethyl xanthates (S-alkyl O-ethyl
dithiocarbonates) with catalytic Vilsmeier reagent generated in situ
from N-formylmorpholine (morpholine-4-carbaldehyde) gives S-
alkyl chlorothioformates in good yields.
Key words: halogenation, desulfurization, Vilsmeier reagent, chlo-
rothioformates, dithiocarbonates
S-Alkyl chlorothioformates are useful intermediates for
the preparation of thioesters,1–4 thiocarbamates,5,6 and
thiocarbonates.7–9 The typical preparation of S-alkyl chlo-
rothioformates involves the reaction of a thiol with phos-
gene.10,11 This method suffers from two problems,
namely, the thiol and the phosgene. While triphosgene is
a reasonable substitute for phosgene,1 working with thiols
is problematic. Not only do they produce a stench, but
they also undergo oxidation to form disulfides. If the thiol
precursor must be prepared as well, then the overall prep-
aration of the S-alkyl chlorothioformate will likely in-
volve three steps. Thiols usually are prepared by first
alkylating a sulfur nucleophile, such as thioacetate, then
releasing the thiol in a deprotection step.12 Xanthate salts
are also good sulfur nucleophiles.13 The desired alkane-
thiol is generated by reaction of the S-alkylated xanthate
with a base, such as 2-aminoethanol.14 In this paper, we
describe a preparation of S-alkyl chlorothioformates that
circumvents the generation of the corresponding thiol.
O
O
N
Cl
H
S
+S
–
+
N
Cl
O
S
R
+
O
S
R
Cl
H
1
2
3
O
N
O
+
N
–
Cl
H
Cl
+
Cl
S
H
S
O
S
R
S
R
O
S-Alkyl chlorothioformates 815–17 were prepared by the re-
action of the corresponding S-alkyl O-ethyl xanthates 1
with catalytic Vilsmeier reagent 2, generated in situ from
N-formylmorpholine (Scheme 1 and Table 1). O-Ethyl
xanthates were used simply for convenience and because
of the commercial availability of potassium ethyl xan-
thate. The choice of reagent 2 was to minimize the reac-
tion time and to assist in the isolation of
chlorothioformates 8 from the product mixture of 8 and 7
in the extraction and washing steps. This Vilsmeier re-
agent is known to be more reactive than the more common
N,N-dimethylchloromethaniminium chloride derived
from N,N-dimethylformamide.18,19 Acetonitrile was cho-
sen as the solvent in order to maximize the solubility of 2.
Oxalyl chloride (50% excess relative to 1) was used to re-
generate 2 from N-thioformylmorpholine (7). The reac-
tion required one-third equivalent of N-formyl-
morpholine. Using less that this amount sometimes gave
6
5
4
O
N
O
(ClCO)2
O
2
+
+
R
N
Cl
S
S
H
S
Cl
9
7
8
Scheme 1 Proposed mechanism for the preparation of S-alkyl chlo-
rothioformates
The proposed mechanism for the transformation is indi-
cated in Scheme 1. The Vilsmeier reagent 2 was necessary
for the reaction to go to completion rapidly (ca. 3 h). Other
common chlorinating agents [e.g. SOCl2, (ClCO)2,
POCl3, and PCl5] either gave no reaction or much slower
conversion. In fact, only phosphorus pentachloride (PCl5)
gave greater than 10% conversion over one day, and its
conversion was still incomplete (ca. 75%) after 18 hours.
Indeed, Zard and Tournier have reported the generation of
a chloride from an alcohol using PCl5 without affecting an
adjacent xanthate.20 Sulfuryl chloride (SO2Cl2) is known
SYNTHESIS 2007, No. 14, pp 2097–2099
x
x.
x
x
.
2
0
0
7
Advanced online publication: 03.07.2007
DOI: 10.1055/s-2007-983756; Art ID: M01907SS
© Georg Thieme Verlag Stuttgart · New York

2098
A. M. Gade, C. J. Abelt
SHORT PAPER
Xanthates 1a–c and 1f,g were prepared by the standard method of
nucleophilic substitution of the appropriate alkyl bromide with po-
tassium ethyl xanthate.13,25–27 Two equivalents of iodocyclohexane
were used for the preparation of 1d.28 Zinc xanthate was used for the
preparation of 1e.29–31 All xanthates were purified by vacuum distil-
lation and checked by GC/MS before use. NMR spectroscopy was
performed on a Varian VX-400 spectrometer, with TMS as an inter-
nal standard.
to react with xanthates to give the net addition of chlorine
(Cl2) across the thiocarbonyl group.21,22 To see if the pres-
ence of any of the proposed intermediates 3, 5, or 6 could
be detected, the reaction was conducted in NMR spectro-
scopic tubes using a slight stoichiometric excess of 2. Oth-
er than the reactants and final products, only ethyl
chloride (4) was observed. In contrast, the adduct of a pri-
mary O-alkyl xanthate anion and 2 could be observed by
NMR spectroscopy.23 This adduct is isomeric with 6, but
it has a thiocarbonyl instead of a carbonyl group. We
speculate that the greater reactivity of the carbonyl group
in 6 prevented its buildup to detectable quantities.
S-Alkyl Chlorothioformates 8; General Procedure
Oxalyl chloride (4.77 g, 37.5 mmol) was added dropwise with stir-
ring to a solution of morpholine-4-carbaldehyde (0.96 g, 8.3 mmol)
in MeCN (25 mL) cooled in an ice bath. The mixture was stirred for
an additional 15 min before adding S-alkyl O-ethyl dithiocarbonate
1 (25 mmol). The ice bath was removed, and the mixture was stirred
for at least 6 h over which time it became very dark. The mixture
was then extracted with PE (3 × 150 mL). The combined organic ex-
tracts were washed with ice-water (2 × 150 mL), dried (Na2SO4),
filtered, and concentrated in vacuo. The S-alkyl chlorothioformates
were distilled under reduced pressure (see Table 1). The purity of
the distilled products was greater than 98% by GC/MS.
We attribute the success of this transformation to the fac-
ile initial electrophilic attack. While the reaction between
a neutral xanthate and a neutral chlorinating agent goes
slowly at best, the positively charged Vilsmeier reagent is
a strong enough electrophile to react with the weakly nu-
cleophilic xanthate. The first proposed intermediate 3 is a
triheteroatom-substituted carbocation. A similar cation is
formed when xanthates react with a sulfenyl chloride.
These cations are reported to suffer nucleophilic attack by
chloride ion resulting in cleavage of the carbon–oxygen
bond and generation of a carbonyl group and an alkyl
chloride.5,24 Cleavage of the carbon–sulfur bond is not ob-
served. Likewise, in the reaction of 1 with 2 the carbon–
oxygen bond is cleaved in overwhelming preference to the
carbon–sulfur bond. The only exception was in the reac-
tion of 1e. Analysis of the crude reaction product from 1e
showed that the formation of O-ethyl chlorothioformate
was 0.9% relative to 8e. All of the other xanthates gave
undetectable amounts of this side product (Table 1). In the
reaction of 1a with PCl5, this side product was much more
pronounced (6% relative to 8a).
8a
1H NMR (400 MHz, CDCl3): d = 2.95 (t, J = 7.3 Hz, 2 H), 1.66 (tt,
J = 7.7, 7.3 Hz, 2 H), 1.42 (tq, J = 7.7, 7.3 Hz, 2 H), 0.94 (t, J = 7.3
Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 166.10, 33.89, 30.95, 21.91,
13.66.
8b
1H NMR (400 MHz, CDCl3): d = 2.96 (t, J = 7.7 Hz, 2 H), 1.66
(nonet, J = 6.6 Hz, 1 H), 1.56 (dt, J = 7.7, 6.6 Hz, 2 H), 0.93 (d, J =
6.6 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 166.09, 37.65, 32.32, 27.60,
22.29.
8c
1H NMR (400 MHz, CDCl3): d = 3.49 (sext, J = 6.9 Hz, 1 H), 1.67
(dq, J = 7.4, 6.9 Hz, 2 H), 1.38 (d, J = 6.9 Hz, 3 H), 1.00 (t, J = 7.4
Hz, 3 H).
In conclusion, S-alkyl chlorothioformates can be prepared
directly from xanthates without having to prepare and iso-
late the corresponding thiol.
Table 1 Preparation of S-Alkyl Chlorothioformates from Xanthates
Compound
R
Yield (%)
Formation of EtO(CS)Cl Bp (°C/14 mmHg)
Lit. bp (°C/mmHg)
Ref.
relative to 8 (%)
8a
Bu
75
80
80
93
55b
64
76
<0.1
<0.1
<0.1
<0.1
0.9
66–67
76–77
76–78 (18)
85 (22)
15,16
17
8b
isopentyl
s-Bu
Cy
8c
57–58
89–90 (60)
17
a
8d
104–106
48–49
16
8e
t-Bu
All
50 (16)
17
8f
<0.1
<0.1
45–47
60–61 (91)
65–70 (0.001)
16,17
16,17
8g
Bn
130–134c,d
a Not reported.
b After 3 h and 97% conversion.
c Slightly decomposes at these temperatures.
d Bp 57–60 °C/0.3 mmHg.
Synthesis 2007, No. 14, 2097–2099 © Thieme Stuttgart · New York

SHORT PAPER
S-Alkyl Chlorothioformates from Xanthates
2099
13C NMR (100 MHz, CDCl3): d = 165.47, 46.78, 28.99, 20.24,
11.49.
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1H NMR (400 MHz, CDCl3): d = 1.50 (s, 9 H).
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8f
1H NMR (400 MHz, CDCl3): d = 5.84 (ddt, J = 16.8, 10.0, 7.0 Hz,
1 H), 5.32 (d, J = 16.8 Hz, 1 H), 5.23 (d, J = 10.0 Hz, 1 H), 3.59 (d,
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1H NMR (400 MHz, CDCl3): d = 7.35–7.27 (m, 5 H), 4.15 (s, 2 H).
13C NMR (100 MHz, CDCl3): d = 165.65, 134.83, 129.09, 129.07,
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Acknowledgment
J. Synthesis 2006, 4118.
Acknowledgment is made to the Donors of The Petroleum Research
Fund, administered by the American Chemical Society, for support
of this research.
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Synthesis 2007, No. 14, 2097–2099 © Thieme Stuttgart · New York