Synthesis of racemic and enantiopure 2-alkylsulfinyl dithioacetates and thioacetamides

Article abstract of DOI:10.1055/s-1999-3447

New 2-alkylsulfinyl dithioacetates and thioacetamides have been prepared. The asymmetric synthesis of (R)-2-(cyclohexylsulfinyl)-N,N- dimethylthioacetamide from previously unreported (S)-diacetone-D-glucose cyclohexanesulfinate was achieved in excellent y

Full text of DOI:10.1055/s-1999-3447

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Carole Alayrac,* Stéphanie Nowaczyk, Margareth Lemarié, Patrick Metzner*
Laboratoire de Chimie Moléculaire et Thio-organique (UMR CNRS n° 6507), ISMRA-Université, 6 boulevard du Maréchal Juin, F-14050
Caen, France
Fax +33(2)31452877; E-mail: alayrac@ismra.fr
5HFHLYHGꢀꢁꢀ6HSWHPEHUꢀꢂꢁꢁꢃꢄꢀUHYLVHGꢀꢅꢀ1RYHPEHUꢀꢂꢁꢁꢃ
bident nucleophiles, they may react through the carbon
$EVWUDFWꢅ New 2-alkylsulfinyl dithioacetates and thioacetamides
atom (with ketones or aldehydes) or through the sulfur
atom (with alkyl halides) depending on the electrophile;
and (3) the attack of a nucleophile on the thiocarbonyl
have been prepared. The asymmetric synthesis of (5)-2-(cyclohex-
ylsulfinyl)-1,1-dimethylthioacetamide from previously unreported
(6)-diacetone-D-glucose cyclohexanesulfinate was achieved in ex-
cellent yield (91%) and enantiomeric excess (98%). Methyl (5)-2- function may be carbophilic or thiophilic, opening up a
(cyclohexylsulfinyl)dithioacetate (98% ee) was obtained from
chiral cyclohexyl methyl sulfoxide (99% ee).
range of possible transformations.
We report herein the preparation of new a-alkylsulfinyl
.H\ꢂZRUGVꢅꢂsulfoxide, thioamide, dithioester, asymmetric synthe-
dithioesters and thioamides in racemic and enantiopure
sis, chiral sulfinate
forms. Three retrosynthetic schemes were envisaged for
such a synthesis (Scheme 1). Pathway D consists of the re-
action of a sulfinyl anion with a thiocarbonyl compound.
Chiral sulfoxides play a key role as versatile tools in
The few examples of 2-sulfinyl dithioesters described in
asymmetric synthesis.1 For example, highly stereoselec-
tive aldol-type condensations2,3 as well as carbonyl reduc-
tion reactions,4,5 Diels–Alder reactions,6,7 Pummerer
reactions8,9 and very recently Heck reactions10 have been
reported. The two main strategies to prepare optically
pure sulfoxides are: (1) the Andersen synthesis11,12 which
involves the nucleophilic substitution of chiral sulfinate
esters by Grignard reagents and proceeds with inversion
of configuration at sulfur; and (2) the enantioselective ox-
idation of prochiral sulfides with chiral reagents (the mod-
ified Sharpless reagent developed by Kagan13,14 and
Modena15,16 or the Davis chiral oxaziridine17and related
procedures18) or with chiral catalysts19,20 which proceeds
efficiently with aromatic prochiral sulfides. The Andersen
synthesis requires a chiral sulfinate, the most popular re-
agent is menthyl (6)-Sꢆtoluenesulfinate which is readily
prepared on a large scale2 and is also commercially avail-
able. It is, therefore, not surprising that most of the report-
ed examples of asymmetric syntheses involve aromatic
sulfoxides. However the search for efficient and general
protocols giving access to chiral dialkyl sulfoxides is very
active.21,48
the literature were prepared according to this route.24,26,27
Pathway E corresponds to the reaction of a sulfinate with
an enethiolate. Such a reaction is not known with
dithioester enolates, but has been successfully applied to
the preparation of (5)-1,1-dimethyl-2-(S-tolylsulfi-
nyl)thioacetamide by Cinquini and co-workers.25 Pathway
F involves the oxidation of a sulfide bearing a thiocarbon-
yl function. Some problems of chemoselectivity may be
encountered as thiocarbonyls are very sensitive towards
oxidizing agents.29,30 However Aloup et al. reported the
selective oxidation of a sulfide bearing dithioester and py-
ridyl moieties by using MCPBA as oxidant.24 Another
drawback of this approach is the difficulty of achieving
enantioselective oxidation of dialkyl sulfides. In the
present study, we did not consider pathway F further.
In connection with our work on the stereocontrolled thio-
Claisen rearrangement mediated by a sulfinyl group,22 we
were interested in the preparation of thiocarbonyl com-
pounds bearing a chiral alkylsulfinyl moiety. A few exam-
ples of these compounds have been described in the
literature.23–27
The great synthetic interest in thiocarbonyl molecules
stems from several unique features28 when compared to
their oxygen analogues: (1) under kinetic conditions,
deprotonation leads preferentially to the enethiolates of
FLV geometry which are configurationally stable and pos-
sess good thermal stability; (2) enethiolates are soft, am-
We first examined the route outlined by pathway D. Typi-
cally, dithioesters can be prepared by the addition of a
Grignard reagent to carbon disulfide in THF and the sub-
sequent alkylation of the resulting dithioacid magnesium
salt.31,32 The analogous reaction with alkyllithiums usual-
Synthesis 1999, No. 4, 669–675 ISSN 0039-7881 © Thieme Stuttgart · New York

ꢀꢆꢇ
C. Alayrac et al.
3$3(5
ly (though not always) is low yielding.33 It is thought that
this is due to the disproportionation reaction of the dithio-
acid lithium salt into the corresponding enedithiolate and
dithioacid.34
Synthesis of Racemic Dithioesters and Thioamides
En-
try
R1
mp
(°C)
Yield
(%)
mp
(°C)
Yield
(%)
1
2
3
4
5
Me
Pr
–
–
43
38
123
37
67
74
52
72
82
62
69
57
91
95
95
–
Recently, Barton and co-workers reported an efficient
preparation of 2-sulfonyl dithioesters based on the care-
fully controlled addition of only 1 equivalent of methyl io-
dide to a dilithium salt intermediate.35 We attempted to
apply this method to the synthesis of dithioester ꢃG start-
ing from WHUW-butyl methyl sulfoxide ꢈꢉGꢊꢂ(Scheme 2); in
this case, the reaction was unselective. We identified as
major byproducts the corresponding ketene dithioacetal
and dimethyl trithiocarbonate which is the alkylation
product of CS32– resulting from the addition of butyllithi-
um to carbon disulfide.
C6H11
Bu
1-ada-
mantyl
Ph
113
ꢃH
–
–
6
–
30
–
Deprotonation of sulfoxides ꢉD±I by 1 equivalent of me-
thyllithium in THF at –40 °C and subsequent addition of
0.5 equivalents of compound ꢋ led to the dithioesters ꢃD±
I which were deprotonated in situ by the remaining 0.5
equivalents of sulfinyl anions. This deprotonation is un-
avoidable due to the relatively high acidity of the protons
of the methylene group. Protonation by ammonium chlo-
ride of the intermediate enethiolates gave dithioesters ꢃD±
I with yields ranging from 30 to 74% (Table 1). The low-
est yields (entries 1 and 6) reflect the very low stability of
dithioesters ꢃD and ꢃI which decompose at room temper-
ature. However, dithioesters ꢃE±H can be stored for sever-
al months at –30°C as crystalline solids.
Many methods for the synthesis of thioamides exist and
have been reviewed;36,37 the reaction of an amide with
phosphorus pentasulfide or Lawesson’s reagent is the
most commonly employed process.38–40 As we had several
dithioesters to hand, aminolysis appeared to be the most
direct route to the required thioamides. The thioacylation
of amines is much faster with dithiocarboxylates than with
2-alkyl thiocarboxylates and esters.41 Dithioesters are
known to be very useful thioacylating reagents in endothi-
opeptide synthesis.42–44
To circumvent these problems we chose to use dimethyl
trithiocarbonate instead of carbon disulfide by analogy
with the work of Yokoyama et al.26,27 They isolated the
moderately stable dithioester ꢃD as a red oil in 71% yield
by reaction of the dimsyl anion with dimethyl trithiocar-
bonate. The same method, applied to the preparation of
dithioester ꢃG from the sulfinyl anion of WHUW-butyl methyl
sulfoxide, was low yielding. We, thus investigated other
trithiocarbonates as well as dithiocarbamates. No reaction
was observed with methylimidazoledithiocarboxylate.
The best results were obtained with aromatic trithiocarb-
onates and in particular one bearing a good leaving group,
namely, 4-fluorophenyl methyl trithiocarbonate ꢈꢋꢊ
(Scheme 3).
Thioamides ꢌD±G were readily obtained by aminolysis of
dithioesters ꢃD±G using 2 M dimethylamine in THF
(Scheme 3). The reaction proceeded smoothly at room
temperature (Table 1). All thioamides ꢌ are stable, crystal-
line solids.
It should be mentioned that our attempts to prepare the 2-
sulfinyl thioamides YLD the addition of a sulfinyl anion to
various dithiocarbamates failed. Indeed, dithiocarbamates
are much less electrophilic than trithiocarbonates because
of the greater electronegativity of the nitrogen atom com-
pared to the sulfur atom.
By analogy with our previous studies in the racemic se-
ries, we first examined the synthesis of enantiopure
dithioester ꢃF via path D. The preparation of the chiral sul-
foxide ꢉF by enzymatic oxidation of the corresponding
sulfide has recently been published,45 but it has not been
optimized for preparative scale synthesis. As mentioned
above, the enantioselective chemical oxidation of
prochiral sulfides is not as efficient with dialkyl substrates
Synthesis 1999, No. 4, 669–675 ISSN 0039-7881 © Thieme Stuttgart · New York

3$3(5
Synthesis of Racemic and Enantiopure 2-Alkylsulfinyl Dithioacetates and Thioacetamides
Synthesis of Enantiopure Thioamide from Chiral
ꢀꢆꢉ
as with aromatic sulfides. The enantioselective synthesis
of dialkyl sulfoxides from chiral sulfinates or 1-sulfi-
nyloxazolidinones via Andersen-type syntheses has been
reported.46,47 Recently Alcudia et al. have published the
preparation of enantiopure sulfoxides from diacetone-D-
glucose (DAG) sulfinates.48,49 The method is very attrac-
tive: (1) the synthesis of DAG sulfinates is highly diaste-
reoselective; (2) it leads to either diastereomer by merely
changing the nature of the base (1,1-diisopropylethy-
lamine and pyridine give sulfinates of (6)- and (5)-config-
uration respectively); (3) dialkyl sulfoxides (3 examples)
are obtained with high enantioselectivity; and (4) the
chiral auxiliary is inexpensive (glucose). Thus we applied
the Alcudia method to prepare the previously unreported
DAG cyclohexanesulfinate ꢀꢂ(Scheme 4). The reaction of
racemic cyclohexanesulfinyl chloride ꢈꢍꢊ50 with DAG and
1,1-diisopropylethylamine quantitatively led to sulfinate
Sulfinate
En-
try
Equiv
Base
Temp
(°C)
Time
Yield
(%)
ee
(%)
1
2
3
4
5
0.5
0.5
0.5
0.5
0.5
BuLi
BuLi
BuLi
LDA
NaH-
MDS
NaH-
MDS
KH-
–78
–40
0
0
–40
1 h
2 h
3 h
3.5 h
2 h
–
–
28
59
82
70
78
46
40
92
6
7
0.25
0.25
–78
–78
30 min
30 min
91
70
98
14
MDS
ꢀ with (6) configuration at sulfur, the diastereomeric ex- Enantiopure thioamide ꢌF was obtained quantitatively by
1
cess was 86%, based on H NMR analysis of the crude aminolysis of ꢃF without any significant loss of enan-
product. Recrystallization from ethyl acetate/petroleum tiopurity. The enantiomeric excess (96% ee) was mea-
ether (1:4) afforded enantiopure (6)-sulfinate ꢀ in 70% sured by 1H NMR in the presence of (6)-
yield. The absolute configuration of ꢀ was confirmed by methoxyphenylacetic acid.
X-ray crystallography,51 and this is the first direct assign-
ment of the stereochemistry of a chiral DAG sulfinate.
Previous assignments of analogous DAG sulfinates were
We also examined path E (Scheme 1) as a more straight-
forward route to the required thioamides from compound
ꢀ. The reaction between chiral sulfinates and magnesium
made indirectly by their transformation into known sul-
ester enolates is reported to be enantioselective.2,53 How-
foxides. Reaction of (6)-sulfinate ꢀ with methylmagne-
ever epimerization is observed when lithium ketone eno-
sium iodide led to cyclohexyl methyl (5)-sulfoxide ꢈꢉFꢊ
with 65% yield after purification by medium pressure
chromatography. The enantiomeric excess was greater
than 99% (chiral HPLC, Daicel OB column). It was then
converted into dithioester ꢃFꢂin 71% yield according to the
procedure followed in the racemic series. Retention of
lates are used.54 This problem can be circumvented by
their transformation into a-lithio 1,1-dimethylhydra-
zones.54,55 In the thiocarbonyl series, only one example is
described in the literature (by the group of Cinquini): (5)-
1,1-dimethyl-(S-tolylsulfinyl)thioacetamide which can
be obtained from menthyl (6)-S-toluenesulfinate in 60%
yield and 98% ee.25 Recently Alcudia reported that the re-
action of potassium methyl 2-pyridyl ketone enolate with
DAG methanesulfinate proceeded in 70% yield and 33%
ee.56 We studied the reactivity of sulfinate ꢀ with 1,1-
dimethylthioacetamide enolate. With lithium bases (BuLi,
LDA), the reaction was very slow at low temperature and
poorly stereoselective (Table 2, entries 2–4). Careful anal-
ysis of the crude product (Table 2, entry 4) by TLC and 1H
NMR revealed the formation of some (5)-sulfinate ꢀꢂ(that
is with the configuration opposite to that of the starting
material). We believe that there is competitive attack of
the DAG alcoholate, which is produced in situ, on chiral
sulfinate ꢀ and this results in the loss of diastereopurity of
the sulfinate; some precedence for this can be found in the
literature.57
1
enantiopurity (98% ee) was observed by H NMR in the
presence of a chiral shift reagent: addition of (6)-methox-
yphenylacetic acid (3 equiv) into the NMR tube induced a
split (0.03 ppm) of the SMe signal.52
We decided to change the counterion from lithium to so-
dium; the increased ionic nature should boost the reactiv-
ity of the enethiolate and, indeed, it proved to be much
more reactive. The reaction was carried out with 0.25
equivalents of ꢀ and was complete after 30 minutes at
–78 °C resulting in thioamide ꢌF in 91% isolated yield
with 98% ee (Scheme 5). Under the same experimental
conditions, thioamide ꢌD was obtained from DAG meth-
anesulfinate ꢆ48 in 57% yield and 80% ee. Moreover, anal-
1
ysis by H NMR of the mixture of ꢌD or ꢌF with (6)-a-
Synthesis 1999, No. 4, 669–675 ISSN 0039-7881 © Thieme Stuttgart · New York

ꢀꢆꢃ
C. Alayrac et al.
3$3(5
methoxyphenylacetic acid in CDCl3 after several days at asymmetric version of the thio-Claisen rearrangement is
room temperature revealed no change in enantiomeric ex- underway.
cess. Thus these compounds appear to be configurational-
ly stable.
Compounds ꢉE±F,H,60,61 ꢋ,62 and ꢆ48 were prepared according to the
literature. All solvents were purified and dried by standard methods.
ꢃꢄ6XOILQ\Oꢂ'LWKLRDFHWDWHVꢂꢃD±Iꢎꢂ*HQHUDOꢂ3URFHGXUH
To a solution of methyl sulfoxide ꢉD±I (14.4 mmol) in THF (60 mL)
was added dropwise at –40 °C 1.6 M MeLi in Et2O (9.0 mL, 14.4
mmol, 1 equiv). The mixture was stirred for 40 min at –20 °C then
cooled to –40 °C and a solution of methyl 4-fluorophenyl trithiocar-
bonate ꢈꢋꢊ (1.57 g, 7.2 mmol, 0.5 equiv) in THF (6 mL) was added.
The mixture was stirred 1.5 h at –20 °C then allowed to warm up to
0 °C. The mixture was worked up by addition of sat. aq NH4Cl (20
mL) followed by extraction with CH2Cl2 (3 x 30 mL). The com-
bined organic layers were washed with brine, dried (MgSO4) then
concentrated to dryness. Purification of the residue by column chro-
matography (silica gel, petroleum ether/EtOAc 1:1) afforded the
By contrast the same reaction does not work well with
dithioesters ꢃD±I.
dithioester enolates. We attempted the reaction of sodium
methyl dithioacetate enolate with sulfinate ꢀ (Scheme 5).
We were able to isolate a 39% yield of dithioester ꢃFꢂwhen
the reaction was carried out at –40 °C. All of the sulfinate
was consumed. Side reactions probably account for the
low yield. For example, sulfinylation of the sulfur atom
0HWK\Oꢂꢈ5ꢀ6ꢊꢄꢃꢄꢈ0HWK\OVXOILQ\OꢊHWKDQHGLWKLRDWHꢂꢈꢃDꢊ ꢂ
Orange oil; yield: 37%.
1H NMR (CDCl3, 250 MHz): d = 2.70 (s, 6 H, CH3SO + SCH3), 4.35
and 4.47 (AB, -AB = 12.4 Hz, 2 H, CH2).
13C NMR (CDCl3, 62 MHz): d = 21.1 (SCH3), 38.7 (CH3SO), 73.5
(CH2), 221.3 (C=S).
due to the ambident nucleophilic character of enethiolates
(as mentioned before)28,58 would lead to an unstable, un-
0HWK\Oꢂꢈ5ꢀ6ꢊꢄꢃꢄꢈ,VRSURS\OVXOILQ\OꢊHWKDQHGLWKLRDWHꢂꢈꢃEꢊ
Orange oil; yield: 67%.
saturated thiosulfinate. At –78 °C the reaction rate of side
reactions is presumably reduced, thus resulting in the re- 1H NMR (CDCl3, 250 MHz): d = 1.34 (d, - = 6.9 Hz, 3 H, CH3), 1.36
(d, - = 6.9 Hz, 3 H, CH3), 2.70 (s, 3 H, SCH3), 2.97 (sept, - = 6.9
Hz, 1 H, CH), 4.31 (s, 2 H, CH2).
13C NMR (CDCl3, 62 MHz): d = 13.6 (CH3), 16.9 (CH3), 21.0
(SCH3), 50.0 (CH), 68.9 (CH2CS), 222.7 (C=S).
covery of unreacted sulfinate. However, the conversion
into dithioester ꢃF was then also slower and the isolated
yield was only 30%. Additionally, the isolated compound
ꢃF was racemic. As in the case of the lithium thioamide
enolate the racemization of the sulfinate can be invoked to
IR (NaCl): n = 2964, 2922, 2348, 1458, 1418, 1386, 1366, 1222,
1184, 1134, 1058, 1026, 970, 836 cm–1.
1
explain this result. Analysis of the crude product by H
MS (EI): Pꢇ] (%) = 196 (M+, 5), 106 (6), 105 (5), 91 (12), 75 (41),
73 (41), 61 (100), 59 (39), 58 (71), 48 (9), 47 (23), 45 (43), 43 (78),
41 (80).
NMR revealed that the diastereomeric excess of the re-
maining sulfinate had changed from 100% to 90%. How-
ever another process that is worthy of consideration
especially in view of the ambident nucleophilic character
of enethiolates is the 6-sulfinylation of the enethiolate and
subsequent sulfinyl exchange with another enethiolate
unit via a SN2 process.54
Anal. calcd for C6H12OS3: C, 36.70; H, 6.16; O, 8.15; S, 48.99.
Found: C, 36.47; H, 6.24; O, 8.42; S, 48.79.
0HWK\Oꢂꢈ5ꢀ6ꢊꢄꢃꢄꢈ&\FORKH[\OVXOILQ\OꢊHWKDQHGLWKLRDWHꢂꢈꢃFꢊ
Orange crystals; yield: 74%; mp 43 °C.
1H NMR (CDCl3, 250 MHz): d = 1.18–2.15 (m, 10 H, CH2), 2.70 (s,
3 H, SCH3), 2.75 (tt, - = 3.6, 11.5 Hz, 1 H, CH), 4.32 and 4.37 (AB,
The results above demonstrate the different reactivity of
dithioester and thioamide enolates towards DAG sulfi-
nates. The former seems to react through the sulfur atom
while the latter reacts through the carbon atom.59 Access
to enantiopure a-sulfinyl dithioesters from reaction of the
sulfinyl anion of the corresponding chiral methyl sulfox-
ide could be achieved while the analogous thioamide
could not be obtained by this scheme. Pathways D and E
(Scheme 1) are then complementary in allowing access to
enantiopure a-sulfinyl dithioesters and thioamides.
-AB = 12.5 Hz, 2 H, CH2CS).
13C NMR (CDCl3, 62 MHz): d = 21.1 (SCH3), 24.0, 25.2, 25.5, 25.6,
26.9 (5 CH2), 58.5 (CH), 68.8 (CH2CS), 222.8 (C=S).
IR (NaCl): n = 3424, 2930, 2852, 1648, 1448, 1414, 1264, 1202,
1124, 1054, 970, 730 cm–1.
MS (EI): Pꢇ] (%) = 236 (M+, 0.8), 106 (18), 91 (14), 84 (12), 83
(15), 81 (7), 73 (32), 61 (59), 59 (31), 58 (67), 55 (96), 48 (11), 47
(28), 45 (42), 43 (33), 41 (100).
Anal. calcd for C9H16OS3: C, 45.76; H, 6.83; S, 40.64. Found: C,
45.80; H, 6.86; S, 40.39.
In summary a large range of new thiocarbonyl compounds
bearing a racemic alkylsulfinyl group were synthesized.
We were able to prepare enantiopure alkylsulfinyl com-
pounds in both the thioamide and dithioester series fol-
lowing different strategies. We developed an asymmetric
synthesis of 2-(cyclohexylsulfinyl)-1,1-dimethylthioace-
tamide with excellent yield and enantiomeric excess. Use
of the enantiopure titled molecules as substrates for a new
0HWK\Oꢂꢈ5ꢀ6ꢊꢄꢃꢄꢈWHUWꢄ%XW\OVXOILQ\OꢊHWKDQHGLWKLRDWHꢂꢈꢃGꢊ
Orange crystals; yield: 52%; mp 38 °C.
1H NMR (CDCl3, 250 MHz): d = 1.33 (s, 9 H, CH3), 2.71 (s, 3 H,
SCH3), 4.09 and 4.18 (AB, -AB = 12.1 Hz, 2 H, CH2CS).
13C NMR (CDCl3, 62 MHz): d = 21.1 (SCH3), 23.1 (CH3), 55.2
[&(CH3)3], 68.2 (CH2CS), 224.5 (C=S).
Synthesis 1999, No. 4, 669–675 ISSN 0039-7881 © Thieme Stuttgart · New York

3$3(5
Synthesis of Racemic and Enantiopure 2-Alkylsulfinyl Dithioacetates and Thioacetamides
ꢀꢆꢌ
IR (NaCl): n = 2972, 2960, 2920, 2864, 1472, 1462, 1440, 1416,
MS (EI): Pꢇ] (%) = 193 (M+, 18), 189 (10), 149 (19), 70 (84), 58
(32), 44 (100).
1404, 1394, 1368, 1228, 1178, 1130, 1052, 974, 838, 668, 652 cm–1.
MS (EI): Pꢇ] (%) = 210 (M+, 6), 154 (16), 153 (24), 152 (100), 73
HRMS: found 193.0663, C7H15ONS2 (M+ ) requires 193.0595.
(9), 61 (18), 57 (97), 41 (21).
HRMS: found 210.0195, C7H14OS3 (M+ ) requires 210.0207.
ꢈ5ꢀ6ꢊꢄꢃꢄꢈ&\FORKH[\OVXOILQ\Oꢊꢄ1ꢏ1ꢄGLPHWK\OHWKDQHWKLRDPLGHꢂ
ꢈꢌFꢊ
White crystals; yield: 95%; mp 69 °C.
0HWK\Oꢂꢈ5ꢀ6ꢊꢄꢃꢄꢈꢉꢄ$GDPDQW\OVXOILQ\OꢊHWKDQHGLWKLRDWHꢂꢈꢃHꢊ
Orange crystals; yield: 72%; mp 123 °C.
1H NMR (CDCl3, 250 MHz): d = 1.71–1.98 (m, 12 H), 2.22 (m, 3
H), 2.71 (s, 3 H), 4.16 and 4.20 (AB, -AB = 12.1 Hz, 2 H).
13C NMR (CDCl3, 62 MHz): d = 21.1 (SCH3), 28.8 (CH), 35.4
(CH2), 36.3 (CH2), 57.6 (CSO), 66.5 (CH2CS), 225.0 (C=S).
IR (KBr): n = 2904, 2850, 1058, 1030, 970 cm–1.
MS (EI): Pꢇ] (%) = 289 (MH+, 3), 288 (M+, 4), 135 (99), 93 (100),
1H NMR (CDCl3, 250 MHz): d = 1.18–2.17 (m, 10 H, CH2), 3.05
(tt, - = 3.6, 11.5 Hz, 1 H, CH), 3.48 (s, 3 H, NCH3), 3.52 (s, 3 H,
NCH3), 4.22 and 4.31 (AB, -AB = 12.9 Hz, 2 H, CH2).
13C NMR (CDCl3, 62 MHz): d = 24.0, 25.2, 25.52, 25.54, 26.9
(5 CH2), 43.4 (NCH3), 45.0 (NCH3), 58.6 (CH), 61.2 (CH2), 191.5
(C=S).
IR (KBr): n = 2930, 2876, 2852, 1520, 1442, 1392, 1278, 1148,
1116, 1024, 894, 866, 670 cm–1.
MS (EI): Pꢇ] (%) = 233 (M+, 9), 228 (18), 216 (27), 211 (31), 151
(11), 150 (34), 149 (70), 102 (28), 70 (100), 58 (36), 56 (16), 55
(61), 45 (13), 44 (90), 43 (39), 42 (34).
79 (99), 48 (23).
Anal. calcd for C13H20OS3: C, 54.12; H, 6.99; S, 33.34. Found: C,
53.92; H, 6.91; S, 33.43.
HRMS: found 233.0913, C10H19NOS2 (M+) requires 233.0908.
0HWK\Oꢂꢈ5ꢀ6ꢊꢄꢃꢄꢈ3KHQ\OVXOILQ\OꢊHWKDQHGLWKLRDWHꢂꢈꢃIꢊ
Orange oil; yield: 30%.
Anal. calcd for C10H19NOS2: C, 51.46; H, 8.21; N, 6.00; O, 6.86; S,
27.47. Found: C, 51.62; H, 8.34; N, 6.29; O, 6.88; S, 27.33.
1H NMR (CDCl3, 250 MHz): d = 2.60 (s, 3 H, SCH3), 4.30 and 4.54
(AB, -AB = 12.1 Hz, 2 H, CH2CS), 7.50–7.55 (m, 3 H, aromatic H),
7.64–7.69 (m, 2 H, RUWKR aromatic H).
13C NMR (CDCl3, 62 MHz): d = 20.9 (SCH3), 77.4 (CH2), 124.5,
129.4, 131.9 (aromatic C), 142.8 (quaternary aromatic C), 221.1
(C=S).
ꢈ5ꢀ6ꢊꢄꢃꢄꢈWHUWꢄ%XW\OVXOILQ\Oꢊꢄ1ꢏ1ꢄGLPHWK\OHWKDQHWKLRDPLGHꢂꢈꢌGꢊ
White needles; yield: 95%; mp 113 °C.
1H NMR (CDCl3, 250 MHz): d = 1.34 (s, 9 H, CH3), 3.50 (s, 3 H,
NCH3), 3.55 (s, 3 H, NCH3), 4.01 and 4.19 (AB, -AB = 12.0 Hz, 2
H, CH2).
13C NMR (CDCl3, 62 MHz): d = 23.0 (CH3), 43.5 (NCH3), 45.4
(NCH3), 55.1 [&(CH3)3], 60.5 (CH2), 193.0 (C=S).
ꢃꢄ6XOILQ\Oꢂ7KLRDFHWDPLGHVꢂꢌD±Gꢎꢂ*HQHUDOꢂ3URFHGXUHꢂIRUꢂWKHꢂ
$PLQRO\VLVꢂRIꢂ'LWKLRDFHWDWHVꢂꢃD±G
To a solution of dithioester ꢃD±G (3 mmol) in THF (5 mL) was add-
ed dropwise at r.t. 2 M HNMe2 in THF (7.5 mL, 15 mmol, 5 equiv).
The mixture was stirred for 15–20 min then concentrated to dryness.
Purification of the residue by column chromatography (silica gel,
EtOAc) afforded the thioamides ꢌD±G. An analytically pure sample
was obtained by recrystallization from EtOAc/pentane.
IR (KBr): n = 2988, 1530, 1464, 1424, 1386, 1364, 1278, 1214,
1174, 1138, 1078, 1042, 926, 838, 698, 530 cm–1.
MS (EI): Pꢇ] (%) = 207 (M+, 28), 202 (27), 151 (12), 150 (100), 149
(39), 69 (14), 58 (47), 57 (59), 56 (18), 44 (10), 43 (10), 41 (10).
HRMS: found 207.0753, C8H17NOS2 (M+) requires 207.0752.
Anal. calcd for C8H17NOS2: C, 46.34; H, 8.26; N, 6.76; O, 7.72; S,
30.92. Found: C, 46.04; H, 8.25; N, 6.78; O, 7.53; S, 30.97.
ꢈ5ꢀ6ꢊꢄ1ꢏ1ꢄ'LPHWK\OꢄꢃꢄꢈPHWK\OVXOILQ\OꢊHWKDQHWKLRDPLGHꢂꢈꢌDꢊ
Pale yellow crystals; yield: 57%; mp 82 °C.
1H NMR (CDCl3, 250 MHz): d = 2.86 (s, 3 H, CH3SO), 3.46 (s, 3
H, NCH3), 3.51 (s, 3 H, NCH3), 4.27 and 4.33 (AB, -AB = 13.3 Hz,
2 H, CH2).
13C NMR (CDCl3, 62 MHz): d = 39.5 (CH3SO), 43.2 (NCH3), 44.8
(NCH3), 65.9 (CH2), 190.3 (C=S).
ꢉꢏꢃꢅꢍꢏꢀꢄ'Lꢄ2ꢄLVRSURS\OLGHQHꢄaꢄ ꢄJOXFRIXUDQRV\Oꢂꢈ6ꢊꢄ&\FORKH[ꢄ
DQHVXOILQDWHꢂꢈꢀꢊ
Cyclohexanesulfinyl chloride ꢍ was prepared according to the liter-
ature.50 It was obtained in 91% yield after distillation [bp 65–66 °C/
0.075 Torr (lit. 63 bp 62–64 °C/0.07 Torr)].
Cyclohexanesulfinate ꢀ was prepared according to the method de-
scribed by Alcudia et al.48,49 To a cooled (–40 °C) solution of freshly
distilled ꢍ (25 g, 0.15 mol, 1.5 equiv) in anhyd THF (80 mL) was
added dropwise and with vigorous stirring a mixture of diacetone-
D-glucose (26.03 g, 0.10 mol, 1 equiv) and iPr2EtN (20.9 mL, 15.5
g, 0.12 mol, 1.2 equiv) in anhyd THF (80 mL). The mixture was
stirred at –40 °C for 2 h and then quenched with water (100 mL).
The aqueous layer was extracted with CH2Cl2 (3 x 100 mL). The
combined organic extracts were successively washed with 5% aq
HCl (100 mL), 2% aq NaHCO3 (100 mL) and brine (100 mL) then
dried (Na2SO4) and concentrated to dryness to afford the crude sul-
finate (39 g) as a white solid. The diastereomeric ratio was deter-
IR (NaCl): n = 3418, 2932, 1520, 1418, 1394, 1278, 1088, 1032
cm–1.
MS (EI): Pꢇ] (%) = 165 (M+, 63), 150 (26), 149 (14), 70 (10), 59
(46), 58 (38), 44 (100), 42 (46).
Anal. calcd for C5H11NOS2: C, 36.34; H, 6.71; N, 8.48; O, 9.68; S,
38.79. Found: C, 36.45; H, 6.46; N, 8.35; O, 9.88; S, 38.69.
ꢈ5ꢀ6ꢊꢄꢃꢄꢈ,VRSURS\OVXOILQ\Oꢊꢄ1ꢏ1ꢄGLPHWK\OHWKDQHWKLRDPLGHꢂꢈꢌEꢊ
Pale yellow crystals; yield: 91%; mp 62 °C.
1H NMR (CDCl3, 250 MHz): d = 1.36 (d, - = 6.9 Hz, 3 H, CH3), 1.37
(d, - = 6.9 Hz, 3 H, CH3), 3.27 (sept, - = 6.9 Hz, 1 H, CH), 3.48 (s,
3 H, NCH3), 3.52 (s, 3 H, NCH3), 4.21 and 4.24 (AB, -AB = 12.9 Hz,
2 H, CH2).
1
mined by H NMR analysis: (5)/(6) 7:93. This ratio was similar
when the reaction was performed at –78 °C. Compound ꢀ was iso-
lated as white needles (27.3 g, 70% yield) by crystallization from
EtOAc/petroleum ether 1:4. mp 114 °C; [a]D22 –60 (F = 4, acetone).
1H NMR (CDCl3, 250 MHz): d = 1.32, 1.35, 1.44 and 1.52 [4 s, 12
H, OC(CH3)2O], 1.20–2.05 (m, 10 H, CH2), 2.62 (m, 1 H, CHSO),
3.96–4.15 (m, 2 H, H-6), 4.26–4.35 (m, 2 H, H-4 and H-5), 4.59 (d,
- = 3.6 Hz, 1H, H-2), 4.72 (d, - = 2.1 Hz, 1H, H-3), 5.90 (d, - = 3.6
Hz, 1H, H-1).
13C NMR (CDCl3, 62 MHz): d = 13.8 (CH3), 16.7 (CH3), 43.4
(NCH3), 45.0 (NCH3), 50.2 (CH), 61.4 (CH2), 191.3 (C=S).
IR (NaCl): n = 3444, 2966, 1530, 1392, 1280, 1084, 1048, 1022
cm–1.
Synthesis 1999, No. 4, 669–675 ISSN 0039-7881 © Thieme Stuttgart · New York

ꢀꢆꢋ
C. Alayrac et al.
3$3(5
13C NMR (CDCl3, 62 MHz): d = 24.4, 24.6, 25.1 and 25.21 (4 CH2),
25.25 [1 OC(&H3)2O], 25.6 (1 CH2), 26.3, 26.7 and 26.8 [3
OC(&H3)2O], 64.1 (CHSO), 66.7 (C-6), 72.6 (C-5), 79.9 (C-3), 80.5
(C-4), 83.6 (C-2), 105.0 (C-1), 109.2 and 112.5 [2 O&(CH3)2O].
MS (CI, isobutane): Pꢇ] (%) = 391 (MH+, 100), 333 (23), 261 (32),
131 (13), 89 (12).
ꢌF was obtained as white crystals by recrystallization (EtOAc/pen-
tane) (100% ee); mp 86 °C; [a]D22 + 80 (F =1.1, acetone).
Anal. calcd for C10H19NOS2: C, 51.46; H, 8.21; N, 6.00; O, 6.86; S,
27.47. Found: C, 51.65; H, 8.08; N, 6.02; O, 6.72; S, 27.38.
It was also obtained by aminolysis of (5)-dithioester ꢃF according
to the general procedure described for racemic thioamides ꢌD±G in
a quantitative yield and 96% ee.
HRMS: found 391.1802, C18H31O7S (MH+) requires 391.1790;
Anal. calcd for C18H30O7S: C, 55.36; H, 7.74; O, 28.68; S, 8.21.
Found: C, 55.24; H, 7.73; O, 28.75; S, 8.25.
ꢈ6ꢊꢁ1ꢏ1ꢄ'LPHWK\OꢄꢃꢄꢈPHWK\OVXOILQ\OꢊHWKDQHWKLRDPLGHꢂꢈꢌDꢊ
ꢌD was prepared according to the method described for ꢌF, starting
from (6)-DAG methanesulfinate ꢆ,48 in a 57% yield after purifica-
tion by column chromatography (silica gel, EtOAc/MeOH 98:2).
The enantiopurity (80% ee) was measured by 1H NMR by addition
of (6)-a-methoxyphenylacetic acid (3 equiv). The same enantio-
meric ratio was found for the crude and purified products; mp 56–
59 °C; [a]D22 +50 (F =1.1, acetone).
&\FORKH[\Oꢂ0HWK\Oꢂꢈ5ꢊꢄ6XOIR[LGHꢂꢈꢉFꢊ
A solution of MeMgI [prepared from MeI (0.64 mL, 10.27 mmol,
1.5 equiv), magnesium (0.27 g, 11.31 mmol, 1.65 equiv) and Et2O
(11 mL)] was added dropwise to a solution of ꢀ (2.67 g, 6.85 mmol,
1 equiv) in anhyd toluene (135 mL) at 0 °C. After the addition, the
mixture was stirred for 4 h at 0 °C and then quenched by addition of
sat. aq sodium bisulfate (50 mL). The aqueous phase was extracted
with CH2Cl2 (3 x 30mL). The organic phase was dried (MgSO4), fil-
tered and concentrated to dryness. The residue was dissolved in
MeCN (20 mL) then water (7.5 mL) and TFA (0.36 mL, 0.0047
mmol) were added. The mixture was stirred for 4 h at r.t., then neu-
tralized by addition of powdered NaHCO3 (3 g) and a small amount
of water (5 mL) and extracted with CH2Cl2 (3 x 30mL). The organic
layer was washed with water (20mL) then dried (MgSO4), filtered
and concentrated to dryness to afford a brown oil (1.36 g). Purifica-
tion by medium pressure chromatography (CH2Cl2/EtOAc/MeOH
1:1:0.1) gave 0.65 g (65% yield) of ꢉF as a yellow oil. Its enantiopu-
rity (ee>99%) was measured by HPLC on a Chiralcel OB Daicel
HRMS: found 165.0272, C5H11NOS2 (M+) requires 165.0282.
$FNQRZOHGJHPHQW
We thank CNRS and the Region of Normandy for a fellowship to S.
Nowaczyk. We also thank Dr. Vincent Reboul for optimizing the
preparation of 1,2:5,6-di-2-isopropylidene-a-D-glucofuranosyl
(S)-cyclohexanesulfinateꢂꢈꢀꢊ.
5HIHUHQFHV
21
(1) Preparation and synthetic applications of this class of
compounds have been recently reviewed:
column (hexane/iPrOH 9:1, l = 214.8 nm); [a]D –56 (F = 1,
CHCl3).
Page, P. C. B.ꢀ2UJDQRVXOIXUꢀ&KHPLVWU\ꢀ²ꢀ6\QWKHWLFꢀDQGꢀ
6WHUHRFKHPLFDOꢀ$VSHFWV; Academic Press: London, 1998; Vol.
2.
0HWK\Oꢂꢈ5ꢊꢄꢃꢄꢈ&\FORKH[\OVXOILQ\OꢊHWKDQHGLWKLRDWHꢂꢈꢃFꢊ
The general procedure described for the preparation of racemic 2-
sulfinyl dithioesters ꢃ was followed with enantiopure sulfoxide ꢉF
as starting material. However we observed that the reaction of the
sulfinyl anion on 4-fluorophenyl methyl trithiocarbonate could be
carried out at higher temperature (between –10 °C and –5 °C instead
of –20 °C) with a significant gain of time (30 min instead of 1.5 h).
ꢃF was isolated with a 71% yield after purification by column chro-
matography (silica gel, petroleum ether/EtOAc 1:1). Its enantiopu-
rity (98% ee) was measured by 1H NMR by addition of 3
equivalents of (6)-a-methoxyphenylacetic acid (chiral shift re-
agent); mp 77 °C; [a]D23 + 313 (F = 1, acetone).
Mikolajczyk, M.; Drabowicz, J.; Kielbasinski, P. &KLUDOꢀ
6XOIXUꢀ5HDJHQWVꢀꢈ$SSOLFDWLRQVꢀLQꢀ$V\PPHWULFꢀDQGꢀ
6WHUHRVHOHFWLYHꢀ6\QWKHVLVꢉ, CRC: Boca Raton, 1997.
Walker, A. J. 7HWUDKHGURQꢊꢀ$V\PPHWU\ ꢉꢁꢁꢃ, ꢋ, 961.
(2) Mioskowski, C.; Solladié, G. 7HWUDKHGURQꢀꢉꢁꢐꢇ, ꢋꢌ, 227.
(3) Solladié, G. 6\QWKHVLV ꢉꢁꢐꢉ, 185.
(4) Carreno, M. C. &KHPꢍꢀ5HYꢍ ꢉꢁꢁꢍ, ꢁꢎ, 1717.
(5) Solladié, G.; Carreno, M. C. 2UJDQRVXOIXUꢀ&KHPLVWU\ꢀ²ꢀ
6\QWKHWLFꢀ$VSHFWV; Page, P. C. B., Ed.; Academic Press:
London, 1995; Vol. 1, pp 1.
(6) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Giannetto, P.
7HWUDKHGURQꢊꢀ$V\PPHWU\ ꢉꢁꢁꢆ, ꢃ, 1339.
(7) Garcia Ruano, J. L.; Carretero, J. C.; Carreno, M. C.; Martin
Cabrejas, L. M.; Urbano, A. 3XUHꢀ$SSOꢍꢀ&KHPꢍ ꢉꢁꢁꢀ, ꢌꢃ, 925.
(8) Kita, Y.; Shibata, N.; Yoshida, N.; Fujita, S. -ꢍꢀ&KHPꢍꢀ6RFꢍꢏꢀ
3HUNLQꢀ7UDQVꢍꢀꢂ ꢉꢁꢁꢋ, 3335.
Anal. calcd for C9H16OS3: C, 45.76; H, 6.83; O, 6.78; S, 40.64.
Found: C, 45.74; H, 6.98; O, 6.73; S, 40.88.
ꢈ5ꢊꢄꢃꢄꢈ&\FORKH[\OVXOILQ\Oꢊꢄ1ꢏ1ꢄGLPHWK\OHWKDQHWKLRDPLGHꢂꢈꢌFꢊ
To a cooled (–78 °C) solution of thioacetamide (1.41 g, 13.7 mmol,
1 equiv) in anhyd THF (17 mL) was added dropwise a 2 M NaH-
MDS in THF (6.9 mL, 13.7 mmol, 1 equiv). The mixture was stirred
at –78 °C for 1 h then a solution of ꢀ (1.34 g, 3.4 mmol, 0.25 equiv)
in anhyd THF (17 mL) was added dropwise. The reaction was mon-
itored by TLC. It was complete after 30 min and quenched by addi-
tion of a H2O/THF (1:4) mixture at –78 °C. The mixture was
worked up by addition of dil. aq H2SO4 solution (10 mL), followed
by extraction with CH2Cl2 (3 x 15 mL). The combined organic lay-
ers were washed with brine, dried (MgSO4) and then concentrated
to dryness. Only one enantiomer could be detected by analysis of
(9) Kita, Y.; Shibata, N. 6\QOHWW ꢉꢁꢁꢀ, 289.
(10) Buezo, N. D.; Alonso, I.; Carretero, J. C. -ꢍꢀ$Pꢍꢀ&KHPꢍꢀ6RFꢍ
ꢉꢁꢁꢐ, ꢂꢅꢐ, 7129.
(11) Andersen, K. K.; Gaffield, W.; Papnikolaou, N. E.; Foley, J.
W.; Perkins, R. I. -ꢍꢀ$Pꢍꢀ&KHPꢍꢀ6RFꢍ ꢉꢁꢀꢋ, ꢃꢌ, 5637.
(12) Solladié, G. 3HUVSHFWLYHVꢀLQꢀWKHꢀ2UJDQLFꢀ&KHPLVWU\ꢀRIꢀ6XOIXUꢀ
ꢈ6WXGLHVꢀLQꢀ2UJDQLFꢀ&KHPLVWU\ꢀꢆꢀ3DUWꢀꢅꢃꢉ; Zwanenburg, B.,
Klunder, A. J. H., Eds.; Elsevier: Amsterdam, 1987; pp 293.
(13) Kagan, H. B.; Rebière, F. 6\QOHWW ꢉꢁꢁꢇ, 643.
(14) Pitchen, P.; Dunach, E.; Deshmukh, M. N.; Kagan, H. B. -ꢍꢀ
$Pꢍꢀ&KHPꢍꢀ6RFꢍ ꢉꢁꢐꢋ, ꢂꢐꢌ, 8188.
1
the H NMR spectrum of the mixture of the residue and 3 equiva-
lents of (6)-a-methoxyphenylacetic acid (chiral shift reagent). Puri-
fication by column chromatography (silica gel, EtOAc) afforded
0.73 g (91% yield) of the (5)-enantiomer of ꢌF (98% ee) as a white
solid; mp 82 °C. Its enantiopurity was measured by 1H NMR by ad-
dition of (6)-a-methoxyphenylacetic acid (3 equiv).
(15) Bortolini, O.; Di Furia, F.; Licini, G.; Modena, G.; Rossi, M.
7HWUDKHGURQꢀ/HWWꢍ ꢉꢁꢐꢀ, ꢅꢑ, 6257.
(16) Di Furia, F.; Modena, G.; Seraglia, R. 6\QWKHVLV ꢉꢁꢐꢋ, 325.
(17) Davis, F. A.; Reddy, R. T.; Han, W.; Carroll, P. J. -ꢍꢀ$Pꢍꢀ
&KHPꢍꢀ6RFꢍ ꢉꢁꢁꢃ, ꢂꢂꢒ, 1428.
Synthesis 1999, No. 4, 669–675 ISSN 0039-7881 © Thieme Stuttgart · New York

3$3(5
Synthesis of Racemic and Enantiopure 2-Alkylsulfinyl Dithioacetates and Thioacetamides
ꢀꢆꢍ
(18) Page, P. C. B.; Heer, J. P.; Bethell, D.; Collington, E. W.;
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(19) Bolm, C.; Bienewald, F. $QJHZꢍꢀ&KHPꢍꢏꢀ,QWꢍꢀ(Gꢍꢀ(QJOꢍ ꢉꢁꢁꢍ,
ꢋꢒ, 2640.
(20) Brunel, J.-M.; Kagan, H. B. %XOOꢍꢀ6RFꢍꢀ&KLPꢍꢀ)Uꢍ ꢉꢁꢁꢀ, ꢂꢋꢋ,
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&KHPꢍꢀ6RFꢍꢏꢀ3HUNLQꢀ7UDQVꢍꢀꢂ ꢉꢁꢐꢋ, 785.
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$Pꢍꢀ&KHPꢍꢀ6RFꢍ ꢉꢁꢁꢐ, ꢂꢅꢐ, 8011.
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Synthesis 1999, No. 4, 669–675 ISSN 0039-7881 © Thieme Stuttgart · New York