Synthesis of ω-aminodithioesters

Article abstract of DOI:10.1055/s-2006-942452

ω-Aminodithioester derivatives were obtained from thionolactams by reaction with an alkyl triflate followed by thiolysis with hydrogen sulfide. The presence of an electron-withdrawing group was required on the N1 position (p-nitrophenyl or benzoyl) to favor the ring opening of γ-, δ- and ε-thionolactams. In the case of β-thionolactam, activation was provided by a CF₂ motif in C3 position. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942452

PAPER
2327
Synthesis of w-Aminodithioesters
Synthesis of
w
i
-Amin
m
Unité de Chimie Organique et Médicinale, Université catholique de Louvain, Bâtiment Lavoisier, Place Louis Pasteur 1,
1348 Louvain-la-Neuve, Belgium
Fax +32(10)474168; E-mail: Marchand@chim.ucl.ac.be
Received 13 December 2005; revised 6 March 2006
X
X
X
X
Abstract: w-Aminodithioester derivatives were obtained from
thionolactams by reaction with an alkyl triflate followed by thioly-
sis with hydrogen sulfide. The presence of an electron-withdrawing
group was required on the N1 position (p-nitrophenyl or benzoyl) to
favor the ring opening of g-, d- and e-thionolactams. In the case of
b-thionolactam, activation was provided by a CF2 motif in C3 posi-
tion
F
18F
NPht
S
NPht
F
SR
1a, X = H
1b, X = F
NPht = Phthalimido protecting group
Scheme 1
Key words: dithioesters, thionolactams, thioamidinium salts, thio-
Pinner reaction
with ethanethiol. The same strategy could be applied for
the synthesis of 1b, but with lower yields.19 In fact, the
preparation of a-perfluorinated dithioesters was scarcely
Dithioesters have attracted considerable attention in re- described in the previous literature and required particular
cent years as versatile tools for organic synthesis.1–5 Meth- methods.22–25
ods of dithioester preparation have been known for a long
Just having in hand a practical synthesis of 3,3-difluoro-1-
time.6 Generally, organometallic compounds or carban-
benzhydrylazetidin-2-one (2),26,27 we decided to examine
the possibility of using the corresponding azetidin-2-
thione 3 as precursor of 1b. Our plan was to transform the
b-thionolactam into 2-thioalkyl-azetidinium salt 4 by se-
ions are treated with carbon disulfide followed by addition
of an alkyl halide,7–9 or reacted with aryl trithiocarbon-
ates,10 or alkyl dithiocarbonyl chlorides.11 Another gener-
al approach was based on a Pinner-like reaction:8 thiolysis
lective S-alkylation; the subsequent thiolysis with hydro-
with hydrogen sulfide of in situ-generated thiolimi-
gen sulfide should create the dithioester function by
nucleophilic addition on the C2 position followed by C2–
doesters produced dithioesters.12–17
In the course of a program dedicated to the 18F-radiolabel- N1 ring opening.
ing of perfluorinated amine derivatives (to be incorporat-
ed in nitroimidazolic markers of hypoxia), we became
The precursor 3 was readily obtained by treatment of aze-
tidinone 2 with Lawesson’s reagent (Scheme 2). Reaction
of 3 with methyl triflate quantitatively furnished the salt 4,
interested in dithioester compounds 1a,b (Scheme 1) as
precursors of [18F]CF3 and [18F]C2F5 motifs by an oxida-
within 30 minutes at room temperature, in dichlo-
tive fluorodesulfurization reaction using 1,3-dibromo-
romethane solution (control by 1H NMR). Then a stream
5,5-dimethylhydantoin (DBH) and [18F]HF·pyridine.18,19
of hydrogen sulfide was bubbled into the solution of 4; the
We had already prepared 1a (X = H; R = Et);20 the key dithioester 5a was formed in about 80% yield, the side-
step for the dithioester formation was the nucleophilic product being the thiolester 5b due to some competitive
substitution of a thioacyl-N-phthalimide intermediate21 hydrolysis. After chromatographic purification, com-
F
F
F
F
F
F
F
3
H
4
F
i
ii
iii
Ph
N
S
–OTf
Ph
N1
2
N
N+
Ph
80%
97%
100%
Ph
Ph
Ph
Y
O
S
S
Ph
Ph
5a, Y = S
(5b, Y = O)
2
3
4
O
F
H2N+
F
F
F
iv
85%
Cl–
v, vi
S
N
S
ref 19, 26
S
6
S
O
1b
Scheme 2 Reagents and conditions: (i) Lawesson’s reagent, THF, reflux, 3 h; (ii) MeOTf, CH2Cl2, 20 °C, 30 min.; (iii) H2S/DMF, 15 min;
(iv) a) DDQ, toluene, 1 h; b) 0.1 N HCl, 15 min; (v) PYBOP, 2-carboxymethyl benzoic acid; (vi) cat. p-TsOH.
SYNTHESIS 2006, No. 14, pp 2327–2334
x
x.
x
x
.
2
0
0
6
Advanced online publication: 28.06.2006
DOI: 10.1055/s-2006-942452; Art ID: P19305SS
© Georg Thieme Verlag Stuttgart · New York

2328
S. Lacroix et al.
PAPER
pound 5a was N-deprotected by dehydrogenation with
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) fol-
lowed by acidic hydrolysis of the resulting benzophenone-
imine.28 Methyl 3-amino-2,2-difluoropropanedithioate
(6) was isolated in 85% yield as the hydrochloride salt and
fully characterized (see experimental). The phthalimido
derivative 1b was prepared in two steps as usual.19,26
ii
i
(1)
(2)
N
N
NH
Ph
Ph
11%
65%
O
S
O
Ph
Ph
9
8
R = Me: 10
R = CH2Ph: 11
R = 4-O2NC6H4: 12
ii
O
S
N
R
N
83–97%
R
Our synthesis of b-aminodithioester 6 represents the first
application of the Pinner reaction with hydrogen sulfide to
a b-thionolactam precursor. The recent interest of poly-
mer chemists in functional dithioesters29,30 for their ability
to control RAFT31,32 (Reversible Addition–Fragmentation
chain Transfer) radical polymerization, prompted us to
explore further the scope of thionolactams as precursors
of w-aminodithioesters via the intermediate salts 7
(Scheme 3).
n
n
n
Ph
ii
iii
70–80%
(3)
N
N
N
H
H
75–88%
O
O
S
S
n = 0 :
n = 1 :
n = 2 :
n = 3 :
(13)
15
17
(14)
16
18
20
19
Scheme 4 Reagents and conditions: (i) KOH, Ph2CHBr, benzene
(see note); (ii) Lawesson’s reagent, THF, reflux; (iii) Benzoyl chlo-
ride, pyridine, CH2Cl2.
X–
n
N+
S
R1
R1
N
H
n
g-thionolactams 10 and 11, irrespective of the alkylating
agent used (methyl or ethyl triflate, benzyl bromide, ben-
zhydryl bromide; Table 1, entries 3–7). The formation of
the intermediate salts was proven by 1H and/or 13C NMR
analysis of the crude reaction mixtures. Treatment with
hydrogen sulfide in pyridine or with NaHS gave 10 and 11
again (Scheme 5).
SR2
S
R2
7
n
n
N
N
H
R1
O
S
n = 0–3
X–
Scheme 3
n
n
NaHS
N+
N
Alk
Alk
The tested thionolactams were prepared according to
Scheme 4. The commercially available b-lactam was N-
alkylated with benzhydryl bromide and reacted with
Lawesson’s reagent to furnish 1-benzhydrylazetidin-2-
thione (9) (Equation 1 in Scheme 4). The commercially
available N-alkyl and N-aryl pyrrolidin-2-ones (g-lac-
tams) could be directly transformed into pyrrolidin-2-
thiones 10–12 with Lawesson’s reagent (Equation 2 in
Scheme 4). For the preparation of 1-benzoyl thionolac-
tams, the corresponding b- to e-lactams were first treated
with Lawesson’s reagent (13, 15, 17, 19), then N-acylated
with benzoyl chloride (Equation 3 in Scheme 4); the g-, d-
and e-thionolactams (16, 18, 20) were recovered in good
yields but not the b-thionolactam 14 due to extensive po-
lymerization during the thionation step.
SR
HS
SR
n
N
Alk
Alk
S
N
H
n
S
9–11
SR
Scheme 5
At this stage, we speculated that an electron-withdrawing
group on the N1 position should enhance the ability of the
C2–N1 bond to cleave during the decomposition of the
tetrahedral intermediate. This was first verified with the
N-p-nitrophenyl precursor 12 (Table 1, entry 8;
Scheme 6). S-Methylation was performed with methyl tri-
flate in dichloromethane, followed by thiolysis with hy-
drogen sulfide in DMF during 15 minutes. After work-up,
three products were identified: the g-aminodithioester 21a
(major product), the g-aminothiolester 21b (minor prod-
uct) and the g-lactam 24 (very minor product). By careful-
ly controlling the experimental conditions (to avoid
moisture), we could determine that the side compounds
21b and 24 arose from competitive hydrolysis. Moreover,
21b was the precursor of 24 (intramolecular cyclization
by standing at temperature 25 °C). During the chromato-
graphic purification of 21a on silica gel column, we ob-
served extensive cyclization of 21b into 24 and partial
cyclization of 21a into the starting material 12.
We started the study with the N-benzhydryl b-thionolac-
tam 9, and tried to apply the protocol successfully devel-
oped for the corresponding bisfluorinated precursor 3.
The 2-thiomethylazetidinium salt (Scheme 5; R = Me, n =
0, X = OTf) could be obtained by treatment with methyl
triflate [1H NMR: d = 2.79 ppm (CH3S)], but this salt was
unreactive towards hydrogen sulfide, even in polar sol-
vents. With the more nucleophilic sodium hydrosulfide
(NaHS), reaction occurred but the tetrahedral intermedi-
ate decomposed with expulsion of methylthiolate instead
of C2–N1 ring cleavage. Thus b-thionolactam 9 was re-
covered (Table 1, entry 2). The same disappointing results
were observed in the case of N-methyl and N-benzyl
Synthesis 2006, No. 14, 2327–2334 © Thieme Stuttgart · New York

PAPER
Synthesis of w-Aminodithioesters
2329
X–
R1
SiO2
H2S/DMF
(H2O)
N+
Y
R1
N
R1
N
or
∆
H
SR2
SR2
R1 = 4-O2NC6H4
Y
Y = S/O; R2 = Me: 21a/b
Y = S/O; R2 = Et: 22a/b
Y = S/O; R2 = CH2Ph: 23a/b
Y = S: 12
Y = O: 24
Scheme 6
However, a pure sample of 21a was obtained, without lactam (16) was treated with methyl triflate and then with
chromatography, by taking extra care to avoid moisture hydrogen sulfide in DMF to furnish the g-amino-
during the thiolysis (< 5% of 21b were present, as deter- dithioester 25a as main product; this was stable and did
mined by 1H NMR). The dithioester 22a (R2 = Et; Table 1, not cyclize under purification conditions (Table 1, entry
entry 9 and Scheme 6) was similarly prepared by using 11 and Scheme 7). The same protocol allowed us to obtain
ethyl triflate as alkylating agent, and with the same prob- d- and e-aminodithioesters 26a and 27a from the corre-
lems due to the occurrence of side-products 22b, 24, and sponding N-benzoylthionolactams 18 and 20 (Table 1, en-
12. The synthesis of the benzyl dithioester 23a made use tries 12 and 13, Scheme 7). We tried to apply the benzyl
of benzyl bromide and silver triflate for the alkylation step bromide/silver triflate strategy to 16 (in situ formation of
(R2 = CH2Ph; Table 1, entry 10 and Scheme 6), the proto- benzyl triflate), but we only recovered g-thionolactam 15.
col for thiolysis being identical to 21a and 22a. Unfortu- N-Deprotection most probably occurred through Lewis
nately, although 23a was identified by 13C NMR and mass acid catalysis by the silver salt.
spectrometry of the crude reaction mixture, we were not
able to isolate an analytical sample.
O
H2S/
X–
Y
DMF
n
With these examples, we proved the validity of the strate-
gy outlined in Scheme 3, but the method was handicapped
by the recyclization of the target compounds into starting
materials under purification conditions. Accordingly, we
considered further the N-benzoyl motif as activating
group for the thiolysis step and protecting group for mask-
ing the amine nucleophilicity. Thus N-benzoyl-g-thiono-
N
O
N+
n
H
SMe
(H2O)
Ph
SMe
n = 1; Y = S/O: 25a/b
n = 2; Y = S/O: 26a/b
n = 3; Y = S/O: 27a/b
Scheme 7
Table 1 Reactions of Thionolactams
Entry
Starting material Intermediate salt
R1
Products with H2S (or NaHS)
R2
X
1
2
3
CHPh2
CHPh2
Me
Me
OTf
OTf
OTf
Br
5a + 5b (80:20) (Scheme 2)
9
Me
No reaction (or 9) (Scheme 5)
No reaction (or 10) (Scheme 5)
No reaction (or 10) (Scheme 5)
No reaction (or 10) (Scheme 5)
No reaction (or 11) (Scheme 5)
No reaction (or 11) (Scheme 5)
21a + 21b (95:5) (Scheme 6)
22a + 22b (95:5) (Scheme 6)
23a + 23b + 24 (25:25:50) (Scheme 6)
25a + 25b (80:20) (Scheme 7)
26a + 26b (80:20) (Scheme 7)
27a + 27b(80:20) (Scheme 7)
3
10
10
10
11
11
12
12
12
16
18
20
Et
4
Me
CH2Ph
CHPh2
Me
5
Me
Br
6
CH2Ph
CH2Ph
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
COPh
OTf
Br
7
CH2Ph
Me
8
OTf
OTf
OTf
OTf
OTf
OTf
9
Et
10
11
12
13
CH2Ph
Me
COPh
Me
COPh
Me
Synthesis 2006, No. 14, 2327–2334 © Thieme Stuttgart · New York

2330
S. Lacroix et al.
PAPER
Bruker AC 250 spectrometer at 75 MHz. References for the NMR
spectra were CDCl3 for 1H and 13C NMR and CFCl3 for 19F NMR.
Multiplicities are indicated as follows: (br) s: (broad) singlet; d:
doublet; t: triplet; q: quadruplet; qt: quintuplet; m: multiplet; dt:
doubled triplet. NMR attributions were made at 125 MHz by using
correlations spectroscopies (COSY, HMBC). Mass spectra were
obtained on a Finnigan-MAT TSQ-70 instrument at 70 eV (chemi-
cal ionization mode). Microanalyses were performed at the Christo-
pher Ingold Laboratories, University College, London, UK. HRMS
were recorded at the University of Mons, Belgium (Prof. R. Flam-
mang). TLC analyses were carried out on silica gel 60 plates F254
(Merck, 0.1 mm thickness); visualization was effected with UV
light and/or iodine. Column chromatography (under medium pres-
sure) was carried out with Merck silica gel 60 of 230–240 mesh
ASTM.
Finally, we found that the in situ production of benzyl tri-
flate could be bypassed and that the S-benzyl iminium in-
termediate was also accessible from the lactam precursor
treated with triflic anhydride followed by benzyl thiol.
This alternative protocol has been illustrated with the
preparation of benzyl-4-(p-nitrophenyl)aminobutane-
dithioate (23a) in 80% yield from 24 (Scheme 8). We also
found that compound 23a could be protected against in-
tramolecular cyclization by direct treatment with trifluo-
roacetic anhydride to yield the trifluoroacetamide 28.
In conclusion, we have disclosed a novel and practical
route for preparing w-amino dithioesters, protected as N-
benzoyl or N-p-nitrophenyl and trifluoroacetyl deriva-
tives, starting from g-, d-, and e-lactams. The key interme-
diate was a S-alkyl thioamidinium triflate, which suffers
thiolysis with ring opening. b-Lactam could not be used in
this strategy because the starting material (14, see
Scheme 4) was not readily available. On the other hand,
a,a¢-difluoro-b-thionolactam (3) represents a particular
case where ring opening did not require the presence of a
N1-electronwithdrawing group.
Synthesis of Thionolactams from Lactams; General Procedure
Lawesson’s reagent (1.2 equiv) was added to a THF solution (5 mL/
mmol) of the amide (1 equiv). The stirred mixture was then brought
to reflux overnight (unless specified below). After evaporation of
the solvent under vacuum, the resulting oil was submitted to column
chromatography.
1-Benzhydryl-3,3-difluoroazetidin-2-thione (3)
b-Thionolactam 3 was obtained from azetidinone 2 (1.8 g, 6.6
mmol, 1 equiv) after 3 h of reflux, according to the general proce-
dure. Column chromatography (SiO2; hexane–EtOAc, 7:3; Rf =
0.95) afforded 3 (1.9 g; 97% yield) as a pale yellow solid. Analytical
sample was obtained by recrystallization from i-PrOH; mp 76–78
°C.
Ph
S
N+
OTf
N+
i
ii
–OTf
–OTf
24
crude
crude
IR (NaCl): 1593, 1273, 1198 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.16–7.41 (m, 10 Harom), 6.73 (s,
NO2
NO2
1 H, Ph2CH), 4.11 (t, 3JHF = 6.3 Hz, 2 H, CH2CF2).
S
H
N
2
13C NMR (125 MHz, CDCl3): d = 192.4 (t, JCF = 31 Hz, C=S),
iii
80%
S
Ph
1
136.0, 129.3, 128.8, 128.2, 112.3 (t, JCF = 282 Hz, CF2), 61.4
23a
(CHPh2), 61.2 (t, 2JCF = 31 Hz).
O2N
75%
19F NMR (282 MHz, CDCl3): d = –111.53 (t, 2JCF = 31 Hz).
iv
MS (CI+, CH4N2O): m/z (%) = 292.1 (1) [M + 2 + H]+, 290.0 (20)
O
CF3
[M + H]+, 167.0 (100) [CHPh2 + H+].
S
N
HRMS: m/z calcd for C16H13NSF2: 289.07364; found: 289.07368
S
Ph
Anal. Calcd for C16H13NSF2: C, 66.42; H, 4.53; N, 4.84. Found: C,
66.43; H, 4.50; N, 4.84.
28
O2N
Scheme 8 Reagents and conditions: (i) Tf2O, 30 min; (ii) benzyl-
thiol, 2,6-di-tert-butylpyridine, 30 min; (iii) H2S/DMF, 15 min; (iv)
Et3N, (CF3CO)2O, 2 h.
1-Benzhydrylazetidin-2-thione (9)
To a stirred solution of azetidin-2-one (200 mg, 2.8 mmol, 1 equiv)
in benzene (25 mL; caution: see note) were successively added at
r.t., benzhydryl bromide (1.25 g, 4.6 mmol, 2 equiv), powdered
KOH (190 mg, 3.4 mmol, 1.2 equiv), and 18-crown-6 (897 mg, 3.4
mmol, 1.2 equiv). After 4 h of stirring, the reaction mixture was fil-
tered and the solvent was evaporated under vacuum. After column
chromatography (hexane–EtOAc, 8:2; Rf = 0.85), 8 (60 mg, 0.3
mmol; 11% yield) was recovered as a white solid.
The novel compounds prepared in this article were char-
acterized by the usual spectroscopies, but 13C NMR was
the most indicative method. The C=X chemical shifts of
thionolactams, dithioesters and thiolesters are 202–209
ppm (NC=S), 236–240 ppm (SC=S) and 198–200 ppm
(SC=O), respectively, for the non-fluorinated compounds. IR (NaCl): 1738 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.25 (m, 10 Harom), 6.16 (s, 1 H,
The presence of a CF2 motif in a position provokes a
shielding effect: 192 ppm (NC=S of 3), 225 ppm (SC=S
of 5a) and 193 ppm (OC=S of 5b)
Ph2CH), 3.16 (t, 3J = 4 Hz, 2 H), 2.91 (t, 3J = 4 Hz, 2 H).
N-Benzhydrylazetidinone (8; 120 mg, 0.5 mmol, 1 equiv) was treat-
ed according to the general procedure. Column chromatography
(SiO2; hexane–EtOAc, 7:3, Rf = 0.85) afforded 9 (82 mg; 65%
yield) as a pale yellow solid.
1H NMR (300 MHz, CDCl3): d = 7.19–7.38 (m, 10 Harom), 6.66 (s,
1 H, Ph2CH), 3.75 (t, 3J = 3.6 Hz, 2 H, CH2N), 3.06 (t, 3J = 3.6 Hz,
2 H, CH2C=S).
Melting points were determined with an electrothermal microscope
and are uncorrected. IR spectra were taken with a Bio-Rad FTS 135
1
instrument and were calibrated with polystyrene. The H and 19F
NMR spectra were recorded on a Varian Gemini 300 spectrometer
(300 MHz for 1H, and 282 MHz for 19F). 13C NMR spectra were re-
corded on a Bruker Avance 500 spectrometer at 125 MHz and on a
Synthesis 2006, No. 14, 2327–2334 © Thieme Stuttgart · New York

PAPER
Synthesis of w-Aminodithioesters
2331
13C NMR (75 MHz, CDCl3): d = 207.7 (C=S), 133.4, 130.0, 128.9,
128.4, 61.3 (CHPh2), 46.8 (CN), 39.5 (CC=S).
13C NMR (75 MHz, CDCl3): d = 205.6 (C=S), 49.9 (CN), 43.6
(CC=S), 23.0 (CCC).
MS (CI+, CH4N2O): m/z (%) = 255 (4) [M + 2 + H]+, 253 (30) [M +
MS (CI+, CH4N2O): m/z (%) = 103.99 (4) [M + 2 + H]+, 101.99
H]+, 167.0 (100) [CHPh2 + H+].
(100) [M + H]+.
Anal. Calcd for C4H7NS: C, 47.49; H, 6.97; N, 13.84; S, 31.69.
Found: C, 47.87; H, 7.15; N, 13.87; S, 31.81.
N-Methyl Pyrrolidin-2-thione (10)33
Compound 10 was obtained from N-methyl pyrrolidin-2-one (1 g,
11 mmol) according to the general procedure. Column chromatog-
raphy (SiO2; hexane–EtOAc, 5:5; Rf = 0.5) afforded 10 (1.06 g; 84%
yield) as a yellow oil.
Piperidin-2-thione (d-Thiovalerolactam) (17)34
Compound 17 was obtained from piperidin-2-one (2 g, 20 mmol)
according to the general procedure. Column chromatography (SiO2;
hexane–EtOAc, 5:5; Rf = 0.45) afforded 17 (4.5 g; 75% yield) as a
white powder. Recrystallization from i-PrOH produced analytically
pure white needles; mp 110–113 °C.
1H NMR (300 MHz, CDCl3): d = 3.75 (t, J = 8 Hz, 2 H, CH2N),
3
3
3.27 (s, 3 H, NCH3), 3.05 (t, J = 8 Hz, 2 H, CH2C=S), 2.08 (qt,
3J = 8 Hz, 2 H, CCH2C).
13C NMR (125 MHz, CDCl3): d = 201.1 (C=S), 59.6 (NCH3), 56.9
(CH2N), 44.5 (CC=S), 19.3 (CCC).
IR (NaCl): 3186, 1561, 1261, 1111 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.90 (br s, 1 H, NH), 3.35 (dt,
MS (CI+, CH4N2O): m/z (%) = 255 (4) [M + 2 + H]+, 253 (30) [M +
3JHCH = 6.2 Hz, 2 H, CH2N), 2.89 (t, J = 6.3 Hz, 2 H, CH2C=S),
3
H]+, 167.0 (100) [CHPh2 + H+].
1.79–1.84 (m, 2 H, NCCH2C), 1.74–1.77 (m, 2 H, CCH2CC=S).
13C NMR (125 MHz, CDCl3): d = 202.9 (C=S), 44.9 (CN), 39.2
(CC=S), 20.9 (CCN), 20.3 (CCC=S).
N-Benzyl Pyrrolidin-2-thione (11)34
Compound 11 was obtained from N-benzyl pyrrolidin-2-one (1 g, 6
mmol) according to the general procedure. Column chromatogra-
phy (SiO2; hexane–EtOAc, 7:3; Rf = 0.65) afforded 11 (910 mg;
83% yield) as a pale yellow oil.
MS (CI+, CH4N2O): m/z (%) = 117.9 (4) [M + 2 + H]+, 116.1 (100)
[M + H]+.
Anal. Calcd for C5H9NS: C, 52.13; H, 7.87; N, 12.16. Found: C,
51.96; H, 7.91; N, 11.96.
IR (NaCl): 1509, 1265 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.27–7.34 (m, 5 Harom), 4.99 (s, 2
H, CH2Ph), 3.59 (t, 3J = 7.4 Hz, 2 H, CH2N), 3.11 (t, 3J = 7.4 Hz, 2
H, CH2N), 2.02 (qt, 3J = 7.4 Hz, 2 H, CCH2C).
13C NMR (75 MHz, CDCl3): d = 201.9 (C=S), 135.3, 129.0, 128.5,
128.2, 54.2, 51.7, 45.1, 19.6.
Azepan-2-thione (e-Thiocaprolactam) (19)37
Compound 19 was obtained from e-caprolactam (2.5 g, 22 mmol)
according to the general procedure. Column chromatography (SiO2;
hexane–EtOAc, 5:5; Rf = 0.45) afforded 19 (2.32 g; 88% yield) as a
white powder. Recrystallization from i-PrOH produced analytically
pure white needles; mp 113–115 °C.
MS (CI+, CH4N2O): m/z (%) = 194.0 (5) [M + 2 + H]+, 192.0 (100)
[M + H]+, 90.9 (100) [CH2Ph+].
IR (NaCl): 3185, 1563, 1262, 1116 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.50 (br s, 1 H, NH), 3.37–3.42
(m, 2 H, CH2N), 2.99–3.27 (m, 2 H, CH2C=S), 1.66–1.81 (m, 2 H,
NCCH2C), 1.74–1.77 (m, 6 H, CCH2CH2CH2C).
13C NMR (125 MHz, CDCl3): d = 210.4 (C=S), 47.2 (CN), 44.95
(CC=S), 30.4 (CCN), 28.1 (CCC=S), 24.5 (CCCCC).
1-(4-Nitrophenyl)pyrrolidin-2-thione (12)35
Compound 12 was obtained from 1-(4¢-nitrophenyl)pyrrolidine-2-
one (2 g, 10 mmol) after 24 h of reflux, according to the general pro-
cedure. Column chromatography (SiO2; hexane–EtOAc, 7:3; Rf =
0.2) afforded 12 (2.09 g; 97% yield) as a yellow powder. Recrystal-
lization from i-PrOH produced yellow needles for elemental analy-
sis; mp 148–150 °C.
MS (CI+, CH4N2O): m/z (%) = 131 (4) [M + 2]+, 129 (100) [M]+.
HRMS (EI): m/z calcd for C6H11NS: 129.06083; found: 129.06122.
IR (NaCl): 1597, 1266, 1145 cm–1.
Anal. Calcd for C6H11NS: C, 55.77; H, 8.58; N, 10.84. Found: C,
55.76; H, 8.69; N, 10.72.
1H NMR (500 MHz, CDCl3): d = 8.30–8.32 (m, 2 Harom, CHCNO2),
7.88–7.90 (m, 2 Harom, CHCN), 4.21 (t, 3JCH = 7.3 Hz, 2 H, CH2N),
3.26 (t, 3JCH = 7.8 Hz, 2 H, CH2C=S), 2.28 (qt, 3JCH = 7.8 Hz, 2 H,
CCH2C).
13C NMR (125 MHz, CDCl3): d = 204.5 (C=S), 145.9 (CHN), 145.8
(CHN), 124.9 (CHCN), 124.6 (CHCNO2), 58.0 (CH2N), 47.0
(CH2C=S), 20.9 (CCH2C).
Synthesis of N-Benzoylthionolactams; General Procedure
To a CH2Cl2 solution (3 mL/mmol) of the NH-thionolactam (1
equiv) were successively added benzoyl chloride (1.1 equiv) and
pyridine (1.1 equiv). The mixture was stirred at r.t. overnight. The
reaction mixture was then washed with 0.1 N HCl solution (3 × 30
mL). The organic phase was dried over MgSO4. After evaporation,
the residue was submitted to column chromatography on silica gel.
MS (APCI+): m/z (%) = 225.7 (4) [M + 2 + H]+, 223.7 (100) [M +
H]+.
Anal. Calcd for C10H10N2O2S: C, 54.04; H, 4.53; N, 12.60; S, 14.43.
Found: C, 53.69; H, 4.50; N, 12.42; S, 14.59.
N-Benzoylpyrrolidin-2-thione (16)
Compound 16 was obtained from thionolactam 15 (1 g, 10 mmol)
according to the general procedure. After chromatography (cyclo-
hexane–EtOAc, 7:3; Rf = 0.7), 16 was recovered as an orange oil
(1.43 g; 70% yield).
Pyrrolidin-2-thione (15)36
Compound 15 was obtained from pyrrolidin-2-one (5 g, 58 mmol)
according to the general procedure. After column chromatography
(SiO2; hexane–EtOAc, 4:6; Rf = 0.4) 15 (4.5 g; 77% yield) was ob-
tained as a white powder. Recrystallization from i-PrOH produced
analytically pure white needles; mp 120–122 °C.
IR (NaCl): 1711, 1599, 1191 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.27–7.72 (m, 5 Harom), 4.19 (t,
3J = 7.1 Hz, 2 H, CH2N), 3.15 (t, 3J = 7.7 Hz, 2 H, CH2C=S), 2.23
(qt, 3J = 7.5 Hz, 2 H, CCH2C).
13C NMR (75 MHz, CDCl3): d = 208.8 (C=S), 172.7 (PhC=O),
133.9, 132.8, 129.5, 128.5, 54.2 (CN), 48.4 (CC=S), 27.1 (CCN),
20.9 (CCC=S).
IR (NaCl): 3158 1540, 1294, 1115 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.10 (br s, 1 H, NH), 3.67 (t, 3J =
7.2 Hz, 2 H, CH2N), 2.92 (t, 3J = 7.2 Hz, 2 H, CH2C=S), 2.26 (qt,
3J = 7.2 Hz, 2 H, CCH2C).
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MS (CI+, CH4N2O): m/z (%) = 208.0 (4) [M + 2 + H]+, 206.0 (100)
1H NMR (300 MHz, CDCl3): d = 7.20–7.42 (m, 10 Harom), 4.97 (s,
1 H, Ph2CH), 3.36 (t, 3JHF = 13.5 Hz, 2 H, CH2CF2), 2.68 (s, 3 H,
SCH3).
[M + H]+, 105.1 [PhCO]+.
HRMS (EI+): m/z calcd for C11H11NOS: 205.0561; found:
205.0563.
2
13C NMR (125 MHz, CDCl3): d = 225.35 (t, JCF = 27 Hz, C=S),
1
143.23, 128.68, 127.47, 127.43, 121.49 (t, JCF = 252 Hz, CF2),
N-Benzoylpiperidin-2-thione (18)
66.55 (CHPh2), 52.32 (t, 2JCF = 27 Hz, CH2CF2), 19.51 (SCH3).
19F NMR (282 MHz, CDCl3): d = –96.41 (t, J = 14 Hz).
Compound 18 was obtained from thionolactam 17 (0.9 g, 8 mmol)
according to the general procedure. After chromatography (hexane–
EtOAc, 6:4; Rf = 0.6), 18 was recovered as an orange oil (1.22 g;
70% yield).
MS (APCI+): m/z (%) = 338 (3) [M + H]+, 167.0 (100) [CHPh2 +
H+].
IR (NaCl): 1715, 1597, 1241, 1152 cm–1.
Anal. Calcd for C17H17NS2F2: C, 60.51; H, 5.68; N, 4.15. Found: C,
60.38; H, 6.01; N, 3.93.
1H NMR (300 MHz, CDCl3): d = 7.46–7.86 (m, 5 Harom), 3.72 (t,
3J = 6.3 Hz, 2 H, CH2N), 3.06 (t, 3J = 6.3 Hz, 2 H, CH2C=S), 2.04–
2.12 (m, 2 H, NCCH2C), 1.91–1.99 (m, 2 H, CCH2CC=S).
13C NMR (75 MHz, CDCl3): d = 205.2 (C=S), 175.4 (PhC=O),
133.7, 132.2, 129.7, 129.2, 49.05 (CN), 42.4 (CC=S), 21.9 (CCN),
21.1 (CCC=S).
Methyl 4-[(4¢-Nitrophenyl)amino]butanedithioate (21a)
Compound 21a was obtained from thionolactam 12 (300 mg, 1.4
mmol) according to the general procedure. The reaction mixture
was stirred for 15 min after methyl triflate (320 mL, 2.8 mmol) ad-
dition and for 15 min after DMF–H2S addition. The crude 21a (340
mg, 1.3 mmol; 95% yield) was obtained as an orange powder. Re-
crystallization from i-PrOH–acetone (95:5) afforded an analytical
sample; mp 72–74 °C.
MS (APCI+): m/z (%) = 222.1 (5) [M + 2 + H]+, 220.1 (100) [M +
H]+, 105.1 (6) [PhCO]+.
Anal. Calcd for C12H13NOS: C, 65.72; H, 5.97; N, 6.39; S, 14.62.
Found: C, 66.09; H, 6.50; N, 5.96; S, 14.29.
IR (NaCl): 3368, 1600, 1275, 1112 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.08–8.11 (d, 2 Harom, CHCNO2),
6.52–6.55 (d, 2 Harom, CHCN), 3.31 (t, 3JCH = 6.6 Hz, 2 H, CH2N),
3.15 (t, 3JCH = 6.6 Hz, 2 H, CH2C=S), 2.66 (s, 3 H, SCH3), 2.23 (qt,
3JCH = 6.6 Hz, 2 H, CCH2C).
13C NMR (125 MHz, CDCl3): d = 238.1 (C=S), 153.3 (CHNH),
138.1 (CHNO2), 126.6 (CHCNO2), 111.17 (CHCNH), 48.79
(CH2C=S), 42.3 (CH2N), 29.85 (SCH3), 20.86 (CCH2C).
N-Benzoylazepan-2-thione (20)
Compound 20 was obtained from thionocaprolactam 19 (0.95 g, 7.4
mmol) according to the general procedure. After chromatography
(hexane–EtOAc, 6:4; Rf = 0.6), 20 was recovered as a yellow pow-
der (1.38 g; 80% yield); mp 87–88 °C.
IR (NaCl): 1709, 1597, 1258, 1192 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.45–7.89 (m, 5 Harom), 3.9 (m, 2
H, CH2N), 3.23 (m, 2 H, CH2C=S), 1.91 (m, 6 H).
MS (APCI+): m/z (%) = 273.01 (8) [M + 2 + H]+, 271.01 (60) [M +
H]+, 223.01 (100) [M – CH3SH]+.
13C NMR (125 MHz, CDCl3): d = 211.4 (C=S), 175.9 (C=O), 133.4,
132.8, 129.7, 129.1, 51.85 (CN), 48.4 (CC=S), 29.9 (CCN), 28.2
(CCC=S), 25.3 (CCCCC).
Anal. Calcd for C11H14N2O2S2: C, 48.87; H, 5.22; N, 10.36; S,
23.72. Found: C, 49.21; H, 5.43; N, 10.12; S, 23.79.
Ethyl 4-[(4¢-Nitrophenyl)amino]butanedithioate (22a)
Compound 22a was obtained from thionolactam 12 (200 mg, 0.9
mmol) according to the general procedure. The reaction mixture
was stirred for 15 min after ethyl triflate addition (235 mL, 1.8
mmol) and for 15 min after DMF–H2S addition. Crude 22a (240
mg, 0.8 mmol; 95% yield) were obtained as an orange powder. Re-
crystallization from i-PrOH–acetone (95:5) afforded an analytical
sample; mp 78–80 °C.
MS (IC+, CH4N2O): m/z (%) = 236.1 (6) [M + 2 + H]+, 234.1 (100)
[M + H]+.
HRMS (EI+): m/z calcd for C13H15NOS: 233.0874; found:
233.0869.
Synthesis of Dithioesters from Thionolactams; General Proce-
dure
To a solution of thionolactam (1 equiv, in flame-dried glassware,
under Ar) in anhyd CH2Cl2 (3 mL/mmol), was added methyl (or eth-
yl) triflate (2 equiv) at r.t. The mixture was stirred for 15–30 min
(see particular cases below). Afterwards a H2S-sat. anhyd DMF so-
lution was added (5 mL/mmol). Care should be taken to avoid mois-
ture. After 15 min or more (see particular cases below), the mixture
was diluted with Et2O (20 mL) and washed 3–4 times with brine.
The Et2O phase was dried (MgSO4) and evaporated under vacuum.
The crude product could be purified by column chromatography if
necessary (see below).
IR (NaCl): 3346, 1603, 1273, 1108 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.06–8.11 (d, 2 Harom, CHCNO2),
6.50–6.54 (d, 2 Harom, CHCN), 4.55 (br s, 1 H, NH), 3.30 (t, 3JCH
=
7.1 Hz, 2 H, CH2N), 3.22 (q, 3JCH = 7.1 Hz, 2 H, SCH2CH3), 3.14 (t,
3JCH = 7.4 Hz, 2 H, CH2C=S), 2.15 (qt, 3JCH = 7.1 Hz, 2 H, CCH2C),
1.31 (t, 3JCH = 7.4 Hz, 3 H, SCH2CH3).
13C NMR (125 MHz, CDCl3): d = 237.4 (C=S), 153.3 (CHNH),
138.1 (CHNO2), 126.6 (CHCNO2), 111.16 (CHCNH), 48.8
(CH2C=S), 42.3 (CH2N), 29.85 (SCH2), 29.7 (CCH2C), 12.28
(CH2CH3).
Methyl 3-(Benzhydrylamino)-2,2-difluoropropanedithioate
(5a)
MS (APCI+,): m/z (%) = 273.01 (8) [M + 2 + H]+, 271.01 (60) [M +
H]+, 223.01 (100) [M – CH3SH]+.
Compound 5a was obtained from b-thionolactam 3 (580 mg, 2
mmol) according to the general procedure. The mixture was stirred
for 30 min after methyl triflate (450 mL, 4mmol) addition and for 15
min after DMF–H2S addition. After chromatography on silica gel
(cyclohexane–EtOAc, 5:5; Rf = 0.5), 5a was recovered as an orange
oil (540 mg; 80% yield).
Anal. Calcd for C12H16N2O2S2: C, 50.68; H, 5.67; N, 9.85; S, 22.55.
Found: C, 50.40; H, 5.67; N, 9.74; S, 22.76.
Methyl 4-(Benzoylamino)butanedithioate (25a)
Compound 25a was obtained from thionolactam 16 (225 mg, 1.1
mmol) according to the general procedure. The reaction mixture
was stirred for 30 min after methyl triflate (248 mL, 2.2 mmol) ad-
dition and for 6 h after DMF–H2S addition [addition of anhyd pyri-
dine (1 mL) reduced this time to 20 min). After chromatography on
IR (NaCl): 3338, 1203, 1099 cm–1.
Synthesis 2006, No. 14, 2327–2334 © Thieme Stuttgart · New York

PAPER
Synthesis of w-Aminodithioesters
2333
silica gel (hexane–EtOAc, 7:3; Rf = 0.5), 25a was recovered as an
orange oil (178 mg; 64% yield).
IR (NaCl): 3308, 1634, 1539, 1308, 1163 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.78–7.75 (m, 2 Harom), 7.48–7.38
(m, 3 Harom), 6.45 (br s, 1 H, NH), 3.5 (qdt, 3J = 6.6 Hz, 2 H, CH2N),
2.62 (s, 3 H, SCH3), 3.13 (t, 3J = 7.2 Hz, 2 H, CH2C=S), 2.17 (qt,
3J = 6.6 Hz, 2 H, CCH2C).
13C NMR (125 MHz, CDCl3): d = 236.7 (C=S), 167.7 (C=O),
133.3, 131.6, 126.6, 127.1, 48.9 (CC=S), 39.9 (CN), 30.6 (CCC),
20.18 (SC).
1H NMR (300 MHz, CDCl3): d = 8.05–8.09 (d, 2 Harom, CHCNO2),
7.29 (br s, 5 Harom), 6.47–6.51 (d, 2 Harom, CHCN), 4.47 (s, 2 H,
SCH2Ph), 3.28 (q, 3JCH = 8.0 Hz, 2 H, CH2N), 3.13 (t, 3JCH = 8.0 Hz,
2 H, CH2C=S), 2.24 (qt, 3JCH = 7.7 Hz, 2 H, CCH2C).
13C NMR (125 MHz, CDCl3): d = 236.6 (C=S), 153.6 (CHNH),
138.3 (CHNO2), 131.3, 124.0, 125.9 (CHCNO2), 122.8 119.5,
111.2 (CHCNH), 48.7 (CH2N), 41.1 (CH2C=S), 29.9 (SCH2Ph),
17.8 (CCH2C).
MS (APCI): m/z (%) = 349 (9) [M + 2 + H]+, 348 (18) [M + 1 + H]+,
347 (100) [M + H]+.
MS (APCI+): m/z (%) = 258 (1) [M + 4 + H]+, 256.0 (9) [M + 2 +
Benzyl 4-[2,2,2-Trifluoro-N-(4-nitrophenyl)acetamido]butane-
dithioate (28)
H]+, 254.0 (100) [M + H]+, 105.1 (95) [PhCO]+.
Compound 23b (crude mixture) was dissolved in anhyd CH2Cl2 (10
mL) and Et3N (83 mL, 0.6 mmol, 1 equiv) followed by addition of
trifluoroacetic anhydride (85 mL, 0.6 mmol, 1 equiv). The mixture
was then stirred at 25 °C for 2 h. The solvent was then evaporated
under vacuum. After column chromatography on silica gel (hex-
ane–EtOAc, 5:5; Rf = 0.5), 28 (198 mg, 0.45 mmol; 75% yield) was
recovered as a yellow oil.
1H NMR (300 MHz, CDCl3): d = 8.15–8.18 (d, 2 Harom, CHCNO2),
7.40–7.42 (d, 2 Harom, CHCN), 7.21 (br s, 5 Harom), 4.43 (s, 2 H,
SCH2Ph), 3.93 (t, 3JCH = 7.6 Hz, 2 H, CH2N), 3.05 (t, 3JCH = 8.0 Hz,
2 H, CH2C=S), 2.18 (qt, 3JCH = 7.7 Hz, 2 H, CCH2C).
Methyl 5-(Benzoylamino)pentanedithioate (26a)
Compound 26a was obtained from thionolactam 18 (150 mg, 0.7
mmol) according to the general procedure. The reaction mixture
was stirred for 30 min after methyl triflate (160 mL, 1.4 mmol) ad-
dition and for 6 h after DMF–H2S addition [addition of anhyd pyri-
dine (1 mL) reduced this time to 20 min]. After chromatography on
silica gel (hexane–EtOAc, 6:4; Rf = 0.6), 26a was recovered as an
orange oil (125 mg; 67% yield).
IR (NaCl): 3315, 1638, 1540, 1161 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.79–7.70 (m, 2 Harom), 7.49–7.40
3
13C NMR (125 MHz, CDCl3): d = 235.8 (C=S), 157.3 (C=O), 150.3
(CHNH), 137.3 (CHNO2), 131.2, 124.1, 125.7 (CHCNO2), 122.6,
119.4, 113.9 (CF3), 111.2 (CHCNH), 42.6 (CH2N), 40.9 (CH2C=S),
29.8 (SCH2Ph), 18.6 (CCH2C).
(m, 3 Harom), 6.18 (br s, 1 H, NH), 3.48 (qdt, J = 7.2 Hz, 2 H,
3
CH2N), 3.09 (t, J = 7.5 Hz, 2 H, CH2C=S), 2.62 (s, 3 H, SCH3),
1.90–2.02 (m, 2 H, NCCH2), 1.63–1.75 (m, 2 H, CH2CC=S).
13C NMR (125 MHz, CDCl3): d = 239.4 (C=S), 167.7 (C=O), 133.1,
131.5, 128.7, 126.9, 51.1(CC=S), 39.7 (CN), 28.6 (CCN), 28.3
(CCC=S), 20.18 (SC).
MS (ESI): m/z (%) = 443 (3) [M + 2 – H], 441 (18) [M – H], 317
(100) [M – SCH2Ph].
MS (APCI+): m/z (%) = 272 (1) [M +4 + H]+, 270 (21) [M + 2 + H]+,
HRMS (ESI): m/z calcd for C19H17O3NS2F3·Na: 465.0530; found:
465.0538.
268 (100) [M + H]+, 106 [PhCO]+.
Methyl 6-(Benzoylamino)hexanedithioate (27a)
Methyl 3-Amino-2,2-difluoropropanedithioate Hydrochloride
(6)
Compound 27a was obtained from thionolactam 20 (100 mg, 0.4
mmol) according to the general procedure. The reaction mixture
was stirred for 30 min after methyl triflate (91 mL, 0.8 mmol) addi-
tion and for 6 h after DMF–H2S addition [addition of anhyd pyri-
dine (1 mL) reduced this time to 20 min]. After chromatography on
silica gel (hexane–EtOAc, 5:5; Rf = 0.45), 27a was recovered as an
orange oil (92 mg; 82% yield).
Compound 5a (450 mg, 1.3 mmol, 1 equiv) and DDQ (2,3-dichloro-
5,6-dicyanoquinone; 295 mg, 1.3 mmol, 1 equiv) were successively
added to a suspension of crushed 4 Å molecular sieve in anhyd tol-
uene (5 mL/mmol). The reaction medium was then protected from
light and brought to 60 °C for 1 h. After filtration on a short pad of
basic alumina (washed with toluene), the solvent was evaporated
under vacuum. The oil obtained was taken back in Et2O (10 mL)
and 0.1 N HCl (10 mL) was subsequently added. The biphasic mix-
ture was then stirred for 8 h. To prevent formation of a,a-difluoro-
b-alanine (by hydrolysis of the dithioester moiety), the aqueous
phase should be collected every 2 h. ‘Fresh’ 0.1 N HCl (10 mL) was
added and the operation was repeated until no imine intermediate
could be detected in the Et2O phase [1H NMR: d = 7.12–7.60 (m, 10
IR (NaCl): 3337, 1647, 1273, 1108 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.67–7.69 (m, 2 Harom), 7.19–7.44
3
(m, 3 Harom), 6.06 (br s, 1 H, NH), 3.39 (qdt, J = 7.0 Hz, 2 H,
CH2N), 2.99 (t, 3J = 7.4 Hz, 2 H, CH2C=S), 2.54 (s, 3 H, SCH3), 1.84
3
3
(qt, J = 7.4 Hz, 2 H, CH2CC=S), 1.59 (qt, J = 7.4 Hz, 2 H,
NCCH2), 1.38 (qt, 3J = 7.5 Hz, 2 H, CCCH2CC).
13C NMR (125 MHz, CDCl3): d = 239.8 (C=S), 167.7 (C=O), 134.9,
131.5, 128.7, 127.0, 51.6 (CC=S), 40.0 (CN), 30.8 (CCC=S), 29.5
(CCN), 26.1 (CCCCC), 20.1 (SC).
3
Harom), 4.11 (t, JCF = 13 Hz, 2 H, CH2CF2), 2.69 (s, 3 H, SCH3)].
Meanwhile, the aqueous phases were mixed and concentrated under
vacuum. Compound 6 (228 mg, 1.1 mmol, 85% yield) was recov-
ered as an orange powder.
1H NMR (250 MHz, D2O): d = 3.91 (t, 3JHF = 40 Hz, 2 H, CH2CF2),
2.71 (s, 3 H, SCH3).
MS (APCI+): m/z (%) = 286 (1) [M + 4 + H]+, 284 (10) [M + 2 +
H]+, 282 (100) [M + H]+, 106 (25) [PhCO]+.
Synthesis of Dithioester from Lactam (23a) (Scheme 8)
13C NMR (125 MHz, D2O): d = 221.4 (t, 2JCF = 25 Hz, C=S), 118.34
To a solution of lactam 24 (200 mg, 1 mmol, 1 equiv, in flame-dried
glassware, under Ar) in anhyd CH2Cl2 (3 mL/mmol) was added tri-
flic anhydride (170 mL, 1 equiv) dropwise at 0 °C. The ice bath was
removed after completion of the addition. After 30 min at r.t., 2,6-
di-t-butylpyridine (224 mL, 1 equiv) was added, followed by drop-
wise addition of benzyl thiol (120 mL, 1 equiv). The stirring was
maintained for 30 min before DMF–H2S addition (5 mL). After 15
min, the mixture was diluted with Et2O (20 mL) and washed 3–4
times with brine. The Et2O phase was dried (MgSO4) and evaporat-
ed under vacuum to give crude 23a (190 mg, 55% yield).
1
2
(t, JCF = 251 Hz, CF2), 44.29 (t, JCF = 25 Hz, CH2CF2), 19.9
(SCH3).
19F NMR (282 MHz, D2O): d = –99.31 ppm.
MS (ESI): m/z (%) = 173.9 (9) [M + 2 – Cl]+, 171.9 (100) [M – Cl]+.
HRMS (ESI): m/z calcd for C4H8NS2F2: 172.0062; found:
172.0066.
Synthesis 2006, No. 14, 2327–2334 © Thieme Stuttgart · New York

2334
S. Lacroix et al.
PAPER
Note on use of benzene: Benzene is a known carcinogen, and suit-
able protective equipment should be used. We have tried to use tol-
uene instead, but no reaction occurred.
(16) Hartke, K.; Barrmeyer, S. J. Prakt. Chem. 1996, 338, 251.
(17) Neugebauer, W.; Pinet, E.; Kim, M.; Carey, P. R. Can. J.
Chem. 1996, 74, 341.
(18) Josse, O.; Labar, D.; Georges, B.; Gregoire, V.; Marchand-
Brynaert, J. Bioorg. Med. Chem. 2001, 9, 665.
(19) Cheguillaume, A.; Gillart, J.; Labar, D.; Gregoire, V.;
Marchand-Brynaert, J. Bioorg. Med. Chem. 2005, 13, 1357.
(20) Josse, O.; Labar, D.; Marchand-Brynaert, J. Synthesis 1999,
404.
Acknowledgment
This work was supported by FNRS, FRIA and the Walloon Govern-
ment (contract No 11-4656). J.-M. B. is a senior research associate
of FNRS and S.L. was granted by FRIA. We would like to thank Dr
D. Chapon for the analysis of NMR spectra.
(21) Brain, C. T.; Hallett, A.; Ko, S. Y. J. Org. Chem. 1997, 62,
3808.
(22) Babadzhanova, L. A.; Kirij, N. V.; Yagupolskii, Y. L. J.
Fluorine Chem. 2004, 125, 1095.
(23) Laduron, F.; Nyns, C.; Janousek, Z.; Viehe, H. G. J. Prakt.
Chem. 1997, 339, 697.
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