Alkylation of SH-heterocycles with diethyl phosphite using tetrachloroethylene as an efficient solvent

Article abstract of DOI:10.1002/hc.20729

Treatment of mercapto-heterocyclic compounds with diethyl phosphite in the presence of 4-dimethylaminopyridine (DMAP) in tetrachloroethylene has given the S-ethylated product in good yields and high chemoselectivity. This procedure is compatible with a wide range of SH-compounds such as 1,3,4-oxadiazole-2-thiol, 1,3,4-thiadiazole-2-thiol, benzo[d]thiazole-2-thiol, and substituted benzenethiol. Copyright

Full text of DOI:10.1002/hc.20729

Heteroatom Chemistry
Volume 22, Number 5, 2011
Alkylation of SH-Heterocycles with Diethyl
Phosphite Using Tetrachloroethylene as an
Efficient Solvent
Zheng-Jun Quan, Rong-Guo Ren, Yu-Xia Da, Zhang Zhang,
and Xi-Cun Wang
Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education, China,
Gansu Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering,
Northwest Normal University, Lanzhou, Gansu 730070, People’s Republic of China
Received 9 November 2010; revised 14 January 2011
thesis of organophosphonate derivatives, which are
ABSTRACT: Treatment of mercapto-heterocyclic
an important class of biologically active compounds
compounds with diethyl phosphite in the presence
[1]. A large number of useful transformations have
of 4-dimethylaminopyridine (DMAP) in tetra-
been achieved during the past decades, in which
chloroethylene has given the S-ethylated product
dialkyl phosphites were used as standard nucle-
in good yields and high chemoselectivity. This
ophilic species for the construction of C P bonds,
procedure is compatible with a wide range of SH-
in which various compounds can act as the ac-
compounds such as 1,3,4-oxadiazole-2-thiol, 1,3,4-
ceptor, such as imines (ketimines) [2], carbonyl
thiadiazole-2-thiol, benzo[d]thiazole-2-thiol, and
groups [3], α, β-unsaturated carbonyl compounds
ꢀ
C
substituted benzenethiol. 2011 Wiley Periodicals, Inc.
[4], nitroalkenes [5], and so on. Recently, some
new catalyst systems have also been developed to
fully promote the use of dialkyl phosphites in dif-
Heteroatom Chem 22:653–658, 2011; View this article
online at wileyonlinelibrary.com. DOI 10.1002/hc.20729
ferent ways (Fig. 1). Among these efficient proto-
cols toward the use of dialkyl phosphite derivatives,
INTRODUCTION
cleavage of the P H bond was inevitably involved
homolytic cleavage [6] as the source of P-centered
radicals under radical-initiated or heterolytic cleav-
age conditions [7]. Besides, there are few reports
showing that dialkyl phosphites could also partici-
pate in the construction of C N and C O bonds, in-
volving the cleavage of the C O bond [8]. Generally,
the reaction was performed at a high temperature
(100–169◦C) in the presence of catalytic amounts
of acid. Although few publications have reported S-
alkylation of SH compounds by trialkylphosphites
[9], we have not observed any S-alkylation using di-
alkyl phosphites. This efficient approach to alkyla-
tion of nitrogen heterocycles and etherification of al-
cohols was largely ignored in the later decades, and
Dialkyl phosphites, as a kind of useful phosphorus-
containing reagents, are widely applied to the syn-
Correspondence to: Zheng-Jun Quan; e-mail: quanzhengjun@
hotmail.com; Xi-Cun Wang; e-mail: wangxicun@nwnu.edu.cn.
Contract grant sponsor: National Natural Science Foundation
of China.
Contract grant number: 20902073.
Contract grant sponsor: Natural Science Foundation of Gansu
Province.
Contract grant number: 096RJZA116.
Contract grant sponsor: Scientific and Technological
Innovation Engineering Program of Northwest Normal
University.
Contract grant number: nwnu-kjcxgc-03-64.
2011 Wiley Periodicals, Inc.
c
ꢀ
653

654 Quan et al.
instead of pyridine, both the product yield and the
selectivity were reduced (entries 2–4, Table 1). In
the presence of DMAP, however, both the yield and
the selectivity of 2-(ethylthio)-1,3,4-thiadiazole (2a)
were improved (entry 5, Table 1). Thus, when 20
mol% of DMAP was used as a catalyst, a similar re-
action proceeded smoothly to produce S-ethylated
products as major products, with high regioselec-
tivity. On the basis of the catalyst and the reactivity,
the reaction conditions shown in run 5 were the opti-
mal conditions for the present thioethylation. Thus,
we decided to use 2 equiv of diethyl phosphite in
TCE at 110◦C using DMAP as catalyst as the optimal
reaction conditions for the preparation of S-ethyl
products.
With these results, we then explored the scope
and generality of this alkylation reaction (entries 6–
12, Table 1). First, we changed the phenyl group
1a to 2-chlorophenyl (1b) and 4-methylphenyl (1c),
and the reaction occurred smoothly, affording the
desired products in good yields and regioselectivi-
ties. Treatment of benzo[d]thiazole-2-thiol 1d and
5-(benzofuran-2-yl)-1,3,4-oxadiazole-2-thiol 1e with
diethyl phosphite also led to the S-ethyl products 2d
and 2e, with formation of N-ethyl products 3d and
3e, respectively (entries 8 and 9). Interestingly, all
reactions gave S-ethylated products 2 as the major
products.
These promising results then encouraged us
to investigate the possible reaction of thiophe-
nols with diethyl phosphite. Interestingly, when 4-
methylbenzenethiol (1f) was treated with diethyl
phosphite in tetrachloroethylene at 110◦C, O,O-
diethyl S-(4-methylphenyl)phosphorothioate (2f)
was obtained with good yield (86%; entry 10,
Table 1). However, when 4-aminobenzenethiol (1g)
was used as a substrate, 4-(ethylthio)-N-(1,2,2-
trichlorovinyl)aniline (2g) was isolated with 76%
yield (entry 11, Table 1). In this reaction, substi-
tution occurred both on the amino and mercapto
groups by attacking on tetrachloroethylene and di-
ethyl phosphite, respectively. As expected, only the
S-ethylated product 4-(ethylthio)aniline (2h) was ob-
tained in moderate yield when the reaction was per-
formed in toluene at 110◦C (entry 12, Table 1). Ef-
forts to widen the scope of this reagent, improvement
in the synthesis and scale-up, and its continued in-
tegration into diversity-oriented synthetic protocols
are underway.
FIGURE 1 Reactions of dialkyl phosphite.
therefore the scope and limitation of dialkyl phos-
phites as an alternative alkylation agent is still limit-
edly explored.
The thioether linkage is present in numerous
bioactive, natural and pharmaceutical agents. A few
methods are proposed for the preparation of C S
bonds. Most of the existing methods for the syn-
thesis of thioethers require the use of functional-
ized substrates such as α-halocarbonyl compounds
[10], alkyl orthoformates [11], substrates that con-
tain acidic C H bonds [12], α, β-unsaturated car-
bonyl compounds [13], or allylic acetates/carbonates
[14]. More recently, Robertson and Wu [15] reported
that the allylic thioethers were prepared in one step
by the addition of an exogenous alkoxide to the cor-
responding allylic phosphorothioate ester.
Considering that the skeletons of 1,3,
4-thiadiazole and 1,3,4-oxadiazole are active
medicinal agents for the treatment of many dis-
eases, including tiodazosin, nesapidil, antibiotics
HIV integrase inhibitors, and angiogenesis in-
hibitors [16], we describe here an efficient method
for S-ethylation of 2-mercapto-1,3,4-thiadiazoles
and 2-mercapto-1,3,4-oxadiazoles with diethyl phos-
phite, in the presence of 4-dimethylaminopyridine
(DMAP) as catalyst.
RESULTS AND DISCUSSION
Initially, we chose the reaction of 1,3,4-thiadiazole-
2-thiol 1a with diethyl phosphite as a model reac-
tion to optimize the reaction conditions. The results
are summarized in Table 1. An extensive investiga-
tion of a range of solvents and catalysts was carried
out. The reaction between 1a and diethyl phosphite
did not occur in refluxing benzene, tetrahydrofu-
ran (THF), and ethanol in the presence of pyridine.
Interestingly, when the reaction of 1a with diethyl
phosphite was carried out in the presence of pyri-
dine in tetrachloroethylene (TCE), the reaction was
cleanly completed within 12 h and led to the selective
preparation of 2-(ethylthio)-1,3,4-thiadiazoles 2a in
55% yield and formation of 3-ethyl-1,3,4-thiadiazole-
2(3H)-thione 3a in 16% yield (entry 1 in Table 1).
Thus, to improve the regioselectivity of the thioethy-
lation, we thenperformed the reaction using several
different bases. When Et3N, NaH, or K2CO3 was used
According to Kornblum’s rule [17], we presumed
that direct alkylation of the SH group in the presence
of a base would be expected; in a kinetically favored
charge-controlled process, N-alkylation occurs and
is followed by a transformation to more thermody-
namically stable S-ethylated products.
Heteroatom Chemistry DOI 10.1002/hc

Alkylation of SH-Heterocycles with Diethyl Phosphite Using Tetrachloroethylene as an Efficient Solvent 655
TABLE 1 Reaction of HS-Heterocycles with Diethyl Phosphite
Isolated Yield (%)
Entry
1
Base
2
3
1
2
3
4
5
Py
NaH
Et3N
K2CO3
DMAP
55
16
1a
1a
1a
1a
47
46
50
73
17
20
23
16
6
DMAP
76
78
10
7
DMAP
DMAP
DMAP
DMAP
13
8
76
10
9
73
11
10
86
11a
12b
DMAP
DMAP
76
78
aReaction was carried out in tetrachloroethylene.
bReaction was carried out in toluene.
CONCLUSION
that two competing reactions have occurred, giv-
ing S-alkylated heterocycles as major products, and
N-alkylated products when 1,3,4-oxadiazole-2-thiol
and 1,3,4-thiadiazole-2-thiol were used. This proto-
col utilized diethyl phosphite as an ethylated sub-
strate giving high yield products and avoiding the
use of strong bases and highly toxic agents such as
ethyl halides or diethyl sulfate.
In conclusion, we have described an efficient method
for the synthesis of heterocyclic thioethers starting
from diethyl phosphite and SH-heterocycles. This
chemistry is compatible with a wide range of hete-
rocycles such as 1,3,4-oxadiazole, 1,3,4-thiadiazole,
and benzo[d]thiazole. We have also demonstrated
Heteroatom Chemistry DOI 10.1002/hc

656 Quan et al.
EXPERIMENTAL
General
for C11H12N2OS2 (252.04): Calcd. C 52.35, H 4.79, N
11.10. Found: C 52.42, H 4.83, N 11.03.
All reagents were obtained commercially and were
used without further purification. Melting points
were determined on an XT-4 electrothermal mi-
cromelting point apparatus (Beijing Electrothermal
Company, Beijing, China) and were uncorrected.
NMR spectra were recorded at 400 (1H) and 100
(13C) MHz, respectively, on a Varian Mercury plus-
400 instrument (Agilent Technologies, Inc., Santa
Clara, CA) using CDCl3 as a solvent and tetram-
ethylsilane as the internal standard. Mass spec-
tra were recorded on a TRACE DSQ instrument
(Thermo Fisher Scientific, Inc.). All commercially
available substrates were used as received. Thin-
layer chromatography (TLC) was performed on 5 ×
10 cm aluminum plates coated with silica gel 60F-
254, in an appropriate solvent. 1,3,4-Thiadiazole-2-
thiols and 1,3,4-oxadiazole-2-thiols were synthesized
by our group [18].
2-((2-Chlorobenzyl)oxy)-5-(ethylthio)-1,3,4-thia-
diazole (2b). Yellow solid, mp 64–66◦C, yield 76%
(ethyl acetate/petroleum ether = 1/1); 1H NMR
(400 MHz, CDCl3): δ = 7.41–7.39 (m, 1H, HAr), 7.27–
7.22 (m, 1H, HAr), 7.06–6.96 (m, 2H, HAr), 5.49 (s,
2H, OCH ), 3.38–3.33 (m, 2H, CH CH3), 1.57–1.46
2
2
(m, 3H, CH2CH ); 13C NMR (100 MHz, CDCl3):
3
δ = 166.0, 153.0, 130.6, 127.9, 122.9, 114.2, 65.8,
28.6, 14.4. MS: m/z = 286 (M+). Anal. calcd for
C11H11ClN2OS2 (286.00): Calcd. C 46.07, H 3.87, N
9.77. Found: C 46.16, H 3.84, N 9.81.
5-((2-Chlorobenzyl)oxy)-3-ethyl-1,3,4-thiadiazole-2
(3H)-thione (3b). Yellow solid, mp 90–92◦C, yield
10% (ethyl acetate/petroleum ether = 1/15); 1H
NMR (400 MHz, CDCl3): δ = 7.42–7.39 (m, 1H, HAr),
7.26–7.22 (m, 1H, HAr), 7.03–6.96 (m, 2H, HAr), 5.19
(2H, OCH ), 4.36 (q, J = 7.2 Hz, 2H, CH CH3), 1.43
2
2
(t, J = 7.2 Hz, 3H, CH2CH ); 13C NMR (100 MHz,
3
CDCl3): δ = 186.0, 155.9, 152.8, 130.8, 127.8, 123.8,
123.4, 114.5, 65.7, 46.4, 12.9. MS: m/z = 286 (M+).
Anal. calcd for C11H11ClN2OS2 (286.00): Calcd. C
46.07, H 3.87, N 9.77. Found: C 46.18, H 3.91, N
9.70.
General Experimental Procedure for the
Reaction of 1,3,4-Oxadiazole-2-thiols with
Diethyl Phosphite
To
a
solution of 1,3,4-thiadiazole-2-thiol (1)
(1 mmol) and DMAP (0.2 mmol) in tetrachloroethy-
lene (2 mL), diethyl phosphite (2 mmol) was added.
After being stirred for 12 h at 110◦C, the reaction
mixture was concentrated under reduced pressure.
Purification by chromatography on silica gel using
ethyl acetate in petroleum ether (boiling point 60–
90◦C) gave pure samples of products 2 and 3.
2-(Ethylthio)-5-((4-methylbenzyl)oxy)-1,3,4-thia-
diazole (2c). Yellow solid, mp 64–66◦C, yield: 78%;
(ethyl acetate/petroleum ether = 1/20); 1H NMR
(400 MHz, CDCl3): δ = 7.10 (d, J = 6.8 Hz, 2H, HAr),
6.87 (d, J = 6.8 Hz, 2H, HAr), 5.39 (2H, OCH ), 3.34
2
(q, J = 7.2 Hz, 2H, CH CH3), 2.29 (s, 3H, CH3), 1.46
2
(t, J = 7.2 Hz, 3H, CH2CH ); 13C NMR (100 MHz,
3
CDCl3): δ = 167.3, 166.9, 155.2, 131.4, 130.1, 114.6,
64.9, 28.5, 20.4, 14.4. MS: m/z = 266 (M+). Anal.
calcd for C12H14N2OS2 (266.05): Calcd. C 54.11, H
5.30, N 10.52. Found: C 54.02, H 5.34, N 10.46.
2-(Benzyloxy)-5-(ethylthio)-1,3,4-thiadiazole (2a).
Yellow liquid, yield 73% (ethyl acetate/petroleum
ether
=
1/15); 1H NMR (400 MHz, CDCl3):
δ = 7.33–6.97 (m, 5H, HAr), 5.42 (2H, OCH ),
2
3.34 (q, J = 7.6 Hz, 2H, CH CH3), 1.46 (t, J =
3-Ethyl-5-((4-methylbenzyl)oxy)-1,3,4-thiadiazo-
le-2(3H)-thione (3c). Yellow solid, mp 86–88◦C,
yield 13% (ethyl acetate/petroleum ether = 1/20); 1H
NMR (400 MHz, CDCl3): δ = 7.10 (d, J = 6.4 Hz,
2H, HAr), 6.84 (d, J = 6.4 Hz, 2H, HAr), 5.10 (2H,
OCH ), 4.36 (q, J = 7.2 Hz, 2H, CH CH3), 2.29 (s,
2
7.6 Hz, 3H, CH2CH ); 13C NMR (100 MHz, CDCl3):
3
δ = 167.4, 166.6, 157.3, 129.6, 114.7, 112.0, 64.7,
28.5, 14.4. MS: m/z = 252 (M+). Anal. calcd for
C11H12N2OS2 (252.04): Calcd. C 52.35, H 4.79, N
11.10. Found: C 52.24, H 4.85, N 11.01.
2
2
3H, CH3), 1.43 (t, J = 7.2 Hz, 3H, CH2CH ); 13C
3
2-(Benzyloxy)-5-(ethylthio)-1,3,4-thiadiazole (3a).
NMR (100 MHz, CDCl3): δ = 185.8, 156.8, 155.0,
131.8, 130.1, 114.7, 64.7, 46.3, 20.4, 12.9. MS:
m/z = 266 (M+). Anal. calcd for C12H14N2OS2
(266.05): Calcd. C 54.11, H 5.30, N 10.52. Found: C
54.19, H 5.34, N 10.46.
Yellow solid, mp 78–80◦C, yield: 16% (ethyl ac-
1
etate/petroleum ether = 1/15); H NMR (400 MHz,
CDCl3): δ = 7.34–7.30 (m, 2H, HAr), 7.06–7.03
(m, 1H, HAr), 6.97–6.94 (m, 2H, HAr), 5.13 (2H,
OCH ), 4.37 (q, J = 0.8 Hz, 2H, CH CH3), 1.45
2
2
(t, J = 0.8 Hz, 3H, CH2CH ); 13C NMR (100 MHz,
2-(Ethylthio)benzo[d]thiazole
(2d). Colorless
3
CDCl3): δ = 185.8, 157.0, 156.5, 129.7, 122.3, 114.8,
64.5, 46.3, 12.9. MS: m/z = 252 (M+). Anal. calcd
liquid, yield: 76% (ethyl acetate/petroleum ether =
1/30); 1H NMR (400 MHz, CDCl3): δ = 7.88–7.85
Heteroatom Chemistry DOI 10.1002/hc

Alkylation of SH-Heterocycles with Diethyl Phosphite Using Tetrachloroethylene as an Efficient Solvent 657
(m, 1H, HAr), 7.75–7.73 (m, 1H, HAr), 7.42–7.38 (m,
4-(Ethylthio)-N-(1,2,2-trichlorovinyl)aniline (2g).
Yellow liquid, yield: 76% (ethyl acetate/petroleum
ether = 1/15); 1H NMR (400 MHz, CDCl3): δ =
7.33–7.32 (m, 2H, HAr), 6.58–6.55 (m, 2H, HAr), 3.96
1H, HAr), 7.29–7.25 (m, 1H, HAr), 3.38–3.32 (m, 2H,
CH CH3), 1.51–1.45 (m, 3H, CH2CH ); 13C NMR
2
3
(100 MHz, CDCl3): δ = 166.9, 153.3, 135.1, 125.9,
124.0, 121.4, 120.8, 27.8, 14.4. MS: m/z = 195 (M+).
Anal. calcd for C9H9NS2 (195.02): Calcd. C 55.35, H
4.64, N 7.17. Found: C 55.48, H 4.59, N 7.11.
(br, 1H, NH), 3.19–3.15 (m, 2H, CH CH3), 1.30–1.25
2
(m, 3H, CH2CH ). 13C NMR (100 MHz, CDCl3): δ =
3
149.5, 136.4, 133.6, 129.5, 120.8, 118.0, 115.6, 112.9,
38.1, 29.6, 14.6.0. MS: m/z = 281 (M+) (60%), 283
(M + 2) (59%), 285 (M + 4) (24%), 266 (M – Me)
(100%), 268 (M – Me + 2) (98%), 270 (M – Me + 4)
(36%). Anal. calcd for C10H10Cl3NS (280.96): Calcd.
C 42.50, H 3.75, N 3.96, Found: C 42.61, H 6.64, N
4.85.
3-Ethylbenzo[d]thiazole-2(3H)-thione (3d). Col-
orless liquid, yield: 10%(ethyl acetate/petroleum
1
ether = 1/30); H NMR (400 MHz, CDCl3): δ = 7.50
(d, J = 8.0 Hz, 1H, HAr), 7.42 (t, J = 8.0 Hz, 1H, HAr),
7.30 (q, J = 8.0 Hz, 1H, HAr), 7.25 (t, J = 8.0 Hz,
1H, HAr), 4.51 (q, J = 7.6 Hz, 2H, CH CH3), 1.46
2
(t, J = 7.6 Hz, 3H, CH2CH ); 13C NMR (100 MHz,
Experimental Procedure for the Synthesis of Com-
pound 2h. To a solution of 4-aminobenzenethiol
(1g) (1 mmol) and DMAP (0.2 mmol) in toluene (2
mL), diethyl phosphite (2 mmol) was added. After
being stirred for 12 h at 110◦C, the reaction mixture
was concentrated under reduced pressure. Purifica-
tion by chromatography on silica gel using ethyl ac-
etate in petroleum ether (60–90◦C) gave pure sam-
ples of product 2h.
4-(Ethylthio)benzenamine (2h). Brown liquid,
yield: 78% (ethyl acetate/petroleum ether = 1/20);
1H NMR (400 MHz, CDCl3): δ = 7.29–7.28 (m, 2H,
HAr), 6.52–6.48 (m, 2H, HAr), 3.68 (br, 2H, NH), 3.13
3
CDCl3): δ = 188.8, 141.1, 128.0, 126.9, 124.6, 121.4,
112.2, 41.3, 11.8. MS: m/z = 195 (M+). Anal. calcd
for C9H9NS2 (195.02): Calcd. C 55.35, H 4.64, N 7.17.
Found: C 55.29, H 4.67, N 7.11.
2-(Benzofuran-2-yl)-5-(ethylthio)-1,3,4-oxadiazo-
le (2e). Colorless solid, mp 62–64◦C, yield: 73%
(ethyl acetate/petroleum ether = 1/15); 1H NMR
(400 MHz, CDCl3): δ = 7.82 (d, J = 0.8 Hz, 1H,
Hfuran), 7.70–7.34 (m, 4H, HAr), 3.36 (q, J = 7.6 Hz,,
2H, CH CH3), 1.58–1.52 (m, 3H, CH2CH ); 13C NMR
2
3
(100 MHz, CDCl3): δ = 154.3, 130.0, 124.7, 124.0,
122.2, 113.5, 112.0, 109.8, 108.8, 27.1, 14.6. MS:
m/z = 246 (M+). Anal. calcd for C12H10NO2S (246.05):
Calcd. C 58.52, H 4.09, N 11.37. Found: C 58.64, H
4.04, N 11.43.
(q, J = 7.2 Hz, 2H, CH CH3), 1.23 (d, J = 7.2 Hz,
2
3H, CH2CH ); 13C NMR (100 MHz, CDCl3): δ = 148.8,
3
134.4, 123.9, 115.4, 38.1, 14.6.0. MS: m/z = 153 (M+).
Anal. calcd for C8H11NS (153.06): Calcd. C 62.70, H
7.24, N 9.14, Found: C 62.81, H 7.29, N 9.05.
5-(Benzofuran-2-yl)-3-ethyl-1,3,4-oxadiazole-2
(3H)-thione (3e). Colorless solid, mp 122–124◦C,
yield: 11% (ethyl acetate/petroleum ether = 1/15);
1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J =
0.8 Hz, 1H, Hfuran), 7.72–7.29 (m, 4H, HAr), 4.26–4.20
(m, 2H, CH CH3), 1.57–1.48 (m, 3H, CH2CH ); 13C
NMR (100 MHz, CDCl3): δ = 175.3, 155.8, 152.4,
140.1, 130.6, 127.7, 126.8, 124.3, 113.5, 112.0,
29.6, 12.5. MS: m/z = 246 (M+). Anal. calcd for
C12H10NO2S (246.05): Calcd. C 58.52, H 4.09, N
11.37. Found: C 58.62, H 4.13, N 11.45.
REFERENCES
[1] (a) Kosolapoff, G. M.; Maier, L. (Eds.). Organic Phos-
phorus Compounds; Wiley-Interscience: New York,
1976; (b) Corbridge, D. E. C. Phosphorus: An Out-
line of Its Chemistry, Biochemistry and Uses, 5th
ed.; Elsevier: Amsterdam, 1995; (c) Swaminathan, S.;
Narayanan, K. V. Chem Rev 1971, 71, 429; (d) Bhat-
tacharya, A. K.; Thyagarajan, G. Chem Rev 1981, 81,
415.
[2] For elected examples of reaction of imines and ke-
timines, see: (a) Merino, P.; Marque´s-Lo´pez, E.;
Herrera, R. P. Adv Synth Catal 2008, 350, 1195;
(b) Ordo´n´ez, M.; Rojas-Cabrera, H.; Cativiela, C.
Tetrahedron 2009, 65, 17; (c) Nakamura, S.; Hayashi,
M.; Hiramatsu, Y.; Shibata, N.; Funahashi, Y.;
2
3
O,O-Diethyl S-p-tolyl phosphorothioate (2f).
Yellow liquid, yield: 86% (ethyl acetate/petroleum
ether
=
1/15); 1H NMR (400 MHz, CDCl3):
Toru, T.
J Am Chem Soc 2009, 131, 18240;
δ = 7.43 (dd, J = 0.8 Hz, J = 8.0 Hz, 2H, HAr), 7.15
(c) Gambecka, J.; Kafarski, P. Mini-Rev Med Chem
2001, 1, 133.
(d, J = 8.0 Hz, 2H, HAr), 4.22–4.13 (m, 4H,
[3] For selected examples of addition to carbonyl com-
pounds, see: (a) Wiemer, D. F. Tetrahedron 1997,
53, 16609; (b) Gro¨ger, H.; Hammer, B. Chem Eur
J 2000, 6, 943; (c) Rath, N. P.; Spilling, C. D. Tetrahe-
dron Lett 1994, 35, 227; (d) Qian, C.; Huang, T.; Zhu,
C.; Sun, J. J Chem Soc, Perkin Trans 1 1998, 2097;
OCH CH3), 2.34 (s, 3H, CH3), 1.35–1.23 (m, 3H,
2
CH2CH ). 13C NMR (100 MHz, CDCl3): δ = 139.2,
3
134.5, 130.1, 122.7, 63.9, 21.1, 16.0. MS: m/z = 260
(M+). Anal. calcd for C11H17PO3S (260.05): Calcd. C
50.76, H 6.58, Found: C 50.88, H 6.53.
Heteroatom Chemistry DOI 10.1002/hc

658 Quan et al.
(e) Yamagishi, T.; Yokomatsu, T.; Suemune, K.;
(c) Murty, M. S. R.; Rao, R. V.; Ram, K. R.; Reddy, N.
R.; Yada, J. S.; Sridhar, B. Synth Commun 2010, 40,
2914.
Shibuya, S. Tetrahedron 1999, 55, 12125; (f) Cermak,
D. M.; Du, Y.; Wiemer, D. F. J Org Chem 1999, 64, 388;
(g) Zhou, X.; Liu, Y.; Chang, L.; Zhao, J.; Shang, D.;
Liu, X.; Lin, L.; Feng, X. Adv Synth Catal 2009, 351,
2567.
[11] Kumar, R.; Chauhan, P. M. S. Tetrahedron Lett 2008,
49, 5475.
[12] (a) Freerksen, R. W.; Selikson, S. J.; Wroble, R. R.
J Org Chem 1983, 48, 4087; (b) Jung, M. E.; Lam,
P. Y.-S.; Mansuri, M. M.; Speltz, L. M. J Org Chem
1985, 50, 1087.
[13] (a) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56,
8033; (b) Enders, D.; Lu¨ttgen, K.; Narine, A. A. Syn-
thesis 2007, 959; (c) Kanemasa, S.; Oderaotoshi, Y.;
Wada, E. J Am Chem Soc 1999, 121, 8675; (d) Emori,
E.; Arai, T.; Sasai, H.; Shibasaki, M. J Am Chem Soc
1998, 120, 4043.
[14] (a) Trost, B. M.; Scanlan, T. S. Tetrahedron Lett 1986,
27, 4141; (b) Gais, H.-J.; Jagusch, T.; Spalthoff, N.;
Gerhards, F.; Frank, M.; Raabe, G. Chem Eur J 2003,
9, 4202.
[15] Robertson, F.; Wu, J. Org Lett 2010, 12, 2668.
[16] (a) Vardan, S.; Mookherjee, S.; Eich, R. Clin Pharm
Ther 1983, 34, 290; (b) Schlecker, R.; Thieme, P. C.
Tetrahedron 1988, 44, 3289; (c) Ogata, M.; Atobe, H.;
Kushida, H.; Yamamoto, K. J Antibiot 1971, 24, 443;
(d) Johns, B. A. PCT Int Appl WO 101512, 2004; (e)
Chen, C.; Senanayake, C. H.; Bill, T. J.; Larsen, R.
D.; Verhoeven, T. R.; Reider, P. J. J Org Chem 1994,
59, 3738; (f) Holla, B. S.; Gonsalves, R.; Shenoy, S.
Eur J Med Chem 2000, 35, 267; (g) Rostom, S. A.
F.; El-Ashmawy, I. M.; El Razik, H. A. A.; Badr, M.
H.; Ashour, H. M. A. Bioorg Med Chem 2009, 17,
882.
[4] (a) Wang, F.; Liu, X.; Cui, X.; Xiong, Y.; Zhou, X.;
Feng, X. Chem Eur J 2009, 15, 589; (b) Maerten, E.;
Cabrera, S.; Kjarsgaard, A.; Jørgensen, K. A. J Org
Chem 2007, 72, 8893; (c) Zhao, D.; Yuan, Y.; Chan, A.
S. C.; Wang, R. Chem Eur J 2009, 15, 2738; (d) Zhao,
D.; Wang, Y.; Mao, L.; Wang, R. Chem Eur J 2009,
15, 10983.
[5] (a) Pudovik, A. N.; Konovalova, I. V. Synthesis 1979,
81; (b) Enders, D.; Saint-Dizier, A.; Lannou, M. I.;
Lenzen, A. Eur J Org Chem 2006, 29; (c) Zhu, Y.;
Malerich, J. P.; Rawal, V. H. Angew Chem, Int Ed
2010, 49, 153.
[6] (a) Kagayama, T.; Nakano, A.; Sakaguchi, S.; Ishii, Y.
Org Lett 2006, 8, 407; (b) Das, B.; Satyalakshmi,
G.; Suneel, K.; Damodar, K. J Org Chem 2009,
74, 8400; (c) Tayama, O.; Nakano, A.; Iwahama,
T.; Sakaguchi, S.; Ishii, Y. J Org Chem 2004, 69,
5494.
[7] (a) Palacios, F.; Alonso, C.; de los Santos, J. M. Chem
Rev 2005, 105, 899; (b) Moonen, K.; Laureyn, I.;
Stevens, C. V. Chem Rev 2004, 104, 6177; (c) Kalek,
M.; Jezowska, M.; Stawinski, J. Adv Synth Catal 2009,
351, 3207.
[8] (a) Kashman, Y.
J Org Chem 1972, 37, 912;
(b) Hayashi, M.; Yamauchi, K.; Kinoshita, M. Bull
Chem Soc Jpn 1977, 50, 1510.
[9] Arsanious M. H. N. Heterocycl Commun 2001, 7, 341.
[10] (a) Kato, D.-I.; Mitsuda, S.; Ohta, H. J Org Chem
2003, 68, 7234; (b) Nicolai, E.; Goyard, J.; Benchetrit,
T.; Teulon, J.-M.; Caussade, F.; Virone, A.; Delcham-
bre, C.; Cloarec, A. J Med Chem 1993, 36, 1175;
[17] Kornblum, N.; Smiley, R. A.; Blackwood, R. K.;
Iffland, C. J Am Chem Soc 1955, 77, 6269.
[18] Wang, X.-C.; Wang, S.-Q.; Ding, X.-M.; Chen. X.-F.
Phosphorus, Sulfur Silicon Relat Elem 2010, 185,
1788.
Heteroatom Chemistry DOI 10.1002/hc