A new convenient preparation of thiol esters utilizing N-acylbenzotriazoles

Article abstract of DOI:10.1055/s-2004-829126

Diverse thiol esters were synthesized in good to excellent yields (76-99%) by reactions of thiophenol, benzyl mercaptan, ethyl mercaptoacetate, and mercaptoacetic acid with N-acylbenzotriazoles under mild conditions. These results demonstrate the utility of N-acylbenzotriazoles as mild S-acylating agents, especially when the corresponding acid chlorides are not readily available.

Full text of DOI:10.1055/s-2004-829126

1806
PAPER
A New Convenient Preparation of Thiol Esters Utilizing N-Acylbenzotriazoles
Preparation of
Thi
l
ol Ester
a
s
U
tilizing
n
N
-Acylbenzotriazo
R
les . Katritzky,* Aleksandr A. Shestopalov, Kazuyuki Suzuki
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
Fax +1(352)3929199; E-mail: katritzky@chem.ufl.edu
Received 25 February 2004
We now report a new convenient procedure for prepara-
Abstract: Diverse thiol esters were synthesized in good to excellent
yields (76–99%) by reactions of thiophenol, benzyl mercaptan,
ethyl mercaptoacetate, and mercaptoacetic acid with N-acylbenzo-
triazoles under mild conditions. These results demonstrate the util-
tion of thiol esters (including examples which cannot be
easily prepared by the methods discussed above) by the
reactions of N-acylbenzotriazoles with thiols (Scheme 1).
ity of N-acylbenzotriazoles as mild S-acylating agents, especially Many of the previously reported S-acylation reactions6–12
when the corresponding acid chlorides are not readily available.
require acyl halides. Although such reactions can give thi-
ol esters in high yields, this preparation of the thiol esters
is limited by the availability of the acyl halides. N-Acyl-
benzotriazole derivatives are available directly from car-
boxylic acids,14a,17 including those whose acyl halides are
not easy to prepare, thus affording a considerable advan-
tage.
Key words: benzotriazole methodology, N-acylbenzotriazoles,
acylating agent, S-acylation, thiol esters
Thiol esters are important intermediates in the synthesis of
heterocycles1and diverse ketones,2 asymmetric aldols,3
acyl radicals,4 and biologically active compounds.2e,5
Most previous preparations of thiol esters were from an
activated acyl derivative such as: (i) acyl halides with thi-
ol sodium salts,6 and (ii) coupling reactions of acyl halides
and thiols with catalysts such as thallium,7a tin mercap-
tides,7b or Zn.7c Alternatively, (iii) carboxylic acids may
be activated by diphosgene,8 or polyphosphate ester.9 (iv)
Instead of the thiol, a thiocyanate can be used advanta-
geously.10 However, methods (i)–(iv) often fail to give
high yields, and are either limited by the use of substrate
specific catalysts or require harsh conditions and intensive
workup processes. In addition, (v) coupling reactions of
carboxylic acids with thiols using carbodiimides such as
DCC and EDC {1-[3-(dimethylamino)propyl]-3-ethylcar-
bodiimide hydrochloride} are also common.11 Although
the procedure gives thiol esters in good yield (50–80%),11
ureas as by-product are often difficult to remove from the
reaction mixture due to their solubility in solvents. A re-
cent method (vi) for the synthesis of thiol esters12 using
CsF-Celite-assisted reactions of thiols with acyl halides,
gave the corresponding thiol esters in 49–89% yields.
Et3N
O
O
S
R1
+
HS R2
R1
Bt
R2
CH2Cl2, r.t.
1a-g
2a-g, 3a-g, 4a-g, 5a-g
1 = phenyl, aryl groups contained heteroatoms (N, O)
R2 = phenyl, benzyl, CH2CO2Et, and CH2CO2H
R
N
N
N
Bt =
Scheme 1
The present work includes common arylcarbonyl deriva-
tives such as phenyl 1a and 2-methoxyphenyl 1b, together
with some less studied arylcarbonyl and heterocyclocar-
bonyl compounds, and cases where the corresponding
acyl halides are not stable or are inconvenient to prepare,
for instance, 2-pyridyl 1c, 2-indolyl 1d and 4-diethylami-
nophenyl 1f. The starting N-acylbenzotriazoles 1a–g
(R1 = phenyl, 2-methoxyphenyl, 2-pyridyl, 2-indolyl, 2-
furyl, 4-diethylaminophenyl, 1,3-benzenedicarbonyl)
were prepared from the corresponding carboxylic acids
by treatment with 1-(methylsulfonyl)benzotriazole
(MeSO2Bt) following the reported one-step general pro-
cedure;13a,d however the indole derivative 1d was synthe-
sized by reaction of 1H-indole-2-carboxylic acid with
BtH and SOCl2 following a recently reported procedure16
to prevent formation of dimerized by-product.
N-Acylbenzotriazoles have been reported by us as effi-
cient neutral coupling reagents for: (i) N-acylation in the
preparation of primary, secondary, and tertiary amides,13a
Weinreb amides,13b trifluoroacylation,13c chiral amino
acylation,13d peptide coupling in organic/aqueous solu-
tion,13e and cinnamoyl hydrazide;13f (ii) regioselective C-
acylation of a) ketone enolates to give b-diketones,14a b)
pyrroles and indoles,14b c) sulfones,13c d) 2-methylfuran
and thiophene14d and e) primary and secondary alkyl cya-
nides;14 and (iii) O-acylation of aldehydes15a (see also
Ref.15b).
Preparation of thiol esters utilized thiophenol for 2a–g,
benzyl mercaptan for 3a–g, and ethyl 2-mercaptoacetate
for 4a–g. Coupling reactions of N-acylbenzotriazoles 1a–
g with thiophenol (Table 1) were carried out in CH2Cl2 at
25 °C for 1 hour in the presence of catalytic amount (10–
20% mol) of Et3N. The reaction proceeded without Et3N,
but it required 5–24 h for completion. The reactions of N-
acylbenzotriazoles 1c, 1d, and 1f, where the correspond-
ing acyl halides are not readily available, gave the corre-
sponding thiol esters 2c, 2d, and 2f in 90, 93, and 86%
yield, respectively. In the reaction of 1g, the diacylated
SYNTHESIS 2004, No. 11, pp 1806–1813
x
x.
x
x
.
2
0
0
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Advanced online publication: 01.07.2004
DOI: 10.1055/s-2004-829126; Art ID: M01304SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Preparation of Thiol Esters Utilizing N-Acylbenzotriazoles
1807
Table 1 Preparation of Thiol Esters by Reaction of 1a–g with Phe-
Table 2 Preparation of Thiol Esters by Reaction of 1a–g with Ben-
nyl Mercaptan
zyl Mercaptan
Et3N
Et3N
O
O
S
O
Ph
O
S
R1
+
HS Ph
R1
R1
+
HS
R1
Bt
Ph
Bt
CH2Cl2,
CH2Cl2,
Ph
1 h, 25 °C
12 h, 25 °C
1a-g
2a-g
1a-g
3a-g
Entry R1 of reactant
R1COBt
Product
Previous Work
Entry R1COBt Product Previous Work
(Yield, %)a
(Yield, %)a
Yield (%)a
73
Reagent
Yield (%)a Ref.
Reagent
7c
1
2
C6H5 (1a)
2a (92)
PhCOCl, Zn 91
Me3SiSPh, 85c
–
–
1
1a
3a (98)
1,2-benzisoxazol-3-ol
derivativesb
16
2-MeOC6H4 (1b) 2b (99)
b
AlCl3
2
3
4
5
6
7
1b
1c
1d
1e
1f
3b (99)
3c (85)
3d (95)
3e (89)
3f (96)
3g (85)
succinic anhydridec
78
–
3
4
5
2-pyridyl (1c)
2-indolyl (1d)
2-furyl (1e)
2c (90)
2d (93)
2e (93)
–
–
–
–
–
–
–
–
–
–
17
20
PhCOCl,
NaOH
50
2-furoyl chloride, POCl3
66
–
–
6
7
4-Et2NC6H4 (1f)
m-C6H4 (1g)d
2f (86)
2g (90)
–
–
–
–
d
1g
–
–
18,19
isophthaloyl 96
dichloridee
a Isolated yield.
b A reaction of benzoic acid and benzyl mercaptan with 1,2-benz-
isoxazol-3-yl dipheyl phosphate.21
a Isolated yield.
b 2-MeC6H4CO2Et.
c PhCH2SNa was used.22
c Use of Me3SiSEt gave 91% yield.
d m-C6H4(COBt)2.
d The compound is known, but its procedure and properties were not
found in our literature search.23
e With bis(tributyltin) oxide.
Table 3 Preparation of Thiol Esters by Reaction of 1a–g with Ethyl
2-Mercaptoacetate
product 2g was obtained in 90% yield, and the mono-acyl-
ated product was not obtained.
O
Et3N
O
R1
CO2Et
R1
+
Similarly, compounds 3a–g (Table 2) were prepared by
the reactions of 1a–g with benzyl mercaptan in CH2Cl2 at
25 °C for 12 hours in the presence of one equivalent of
Et3N following the preparative methods for 2a–g des-
cribed above. However, no reaction occurred during 24
hours without Et3N presumably due to the relatively low
nucleophilicity of benzyl mercaptan. The reactions of 1c,
1d, 1f, and 1g gave the corresponding thiol esters 3c, 3d,
3f, and 3g in 85, 95, 96, and 85% yields, respectively.
S
HS
Bt
CH2Cl2,
1.5 h, 25 °C
CO2Et
1a-g
4a-g
R1COBt
Product (Yield, %)a Mp (°C)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
4a (93)
4b (85)
4c (90)
4d (93)
4e (87)
4f (91)
4g (98)
–
–
31-32
134-135
–
a-Acyl thiol esters can be used for the preparation of syn-
thetic intermediates of biologically active compounds.23
The reactions of 1a–g with ethyl 2-mercaptoacetate gave
4a–g (average 91% yield) in CH2Cl2 at 25 °C during 1.5 h
in the presence of Et3N (Table 3). The reaction time was
shorter than that required with benzyl mercaptan, indicat-
ing the relatively higher reactivity of the thiol at the a-po-
sition of the acetate compared to the thiol at the a-position
of a benzyl group. Thiol esters 2c, 2d, 2f (from thiophe-
nol), 3c, 3d, 3f (from benzyl mercaptan), and 4b–g (from
ethyl 2-mercaptoacetate) are novel compounds, and were
fully characterized by 1H and 13C NMR spectroscopy and
elemental analysis.
N-Acylbenzotriazoles are stable to moisture,13e which is
often an advantage. Mercaptoacetic acid was, therefore,
allowed to react with 1a–g in mixed organic/water solu-
tion MeCN–H2O at 25 °C for 1 hour in the presence of 2
equivalent of Et3N to give N-acylsulfanylacetic acids 5a–
41-42
52-53
1g
a Isolated yield.
g in 35–97% yields (Table 4). The crude products of
5a,b,e, and g were extracted with ethyl acetate after acid-
ification by 2 N HCl aqueous solution. Compound 5d and
5f were precipitated from the reaction mixture on acidifi-
cation with 2 N HCl aqueous solution, and further purified
by recrystallization from chloroform–hexanes. Com-
pound 5c was isolated in 35% yield by recrystallization
1
from chloroform–hexanes. According to the H NMR
spectrum of the crude product, 5c was obtained in >90%
Synthesis 2004, No. 11, 1806–1813 © Thieme Stuttgart · New York

1808
A. R. Katritzky et al.
PAPER
yield; however, it could not be purified by washing be- the methyl group in L-Ala fragment, Cbz-L-Phe-D-Ala-
cause it was soluble in acidic (<3 pH) and basic aqueous SPh (7i) gave a single doublet at 1.26 ppm for the methyl
solution (>9 pH). Further more, it was difficult to separate in D-Ala fragment. Each of the 1H NMR spectra showed
from benzotriazole by column chromatography.
no peaks corresponding to racemization. When the racem-
ic mixture Cbz-L-Phe-DL-Ala-Bt was utilized, Cbz-L-Phe-
DL-Ala-SPh gave the expected two sets of equal intensity
doublets for the methyl groups at 1.36 and 1.26 ppm.
Table 4 Preparation of S-Acyl Derivatives 5a–g from Mercaptoace-
tic Acid
O
O
R1
Et3N (2 equiv)
CO2H
Table 5 Preparation of Thiol esters 7a–j from N-Boc-L-Phe-Bt
(6a), N-Cbz-L-Phe-Bt (6b), N-Cbz-L-Phe-L-Ala-Bt (6c), and N-Cbz-
L-Phe-D-Ala-Bt (6d)
R1
+
S
HS
CH3CN/H2O
1 h, 25 °C
Bt
CO2H
1a-g
5a-g
Et3N
O
O
R1
6a-d
R1COBt =
BocHN Bt
+
HS R2
R1
Entry
R1COBt
Product
Mp (°C)
Bt
S
R2
CH2Cl2, r.t.
(Yield, %)a
7a-j
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
5a (97)
5b (92)
5c (35)b
5d (89)
5e (88)
5f (82)c
5g (96)
105-106
73-74
Ph
Ph
Ph
Ph
O
O
O
O
Bt
HN
CbzHN
CbzHN
HN
Bt
CbzHN
O
O
116-117
210-211
112-113
144-145
185-186
Bt
R2 = phenyl, benzyl, CH2CO2Et, and CH2CO2H
Boc = tert-butyloxycarbonyl, Cbz = benzyloxycarbonyl
Entry Reactant Thiol
R1COBt
Producta
Mp (°C)
102-103
92-93
(Yield, %)b
1g
1
2
3
4
5
6
7
8
9
6a
6a
6a
6b
6b
6b
6b
6c
6d
PhSH
Boc-Phe-SPh
7a (76)
a Isolated yield.
b >90% yield of crude product was calculated from 1H NMR spec-
PHCH2SH
Boc-Phe-SCH2Ph
7b (97)
trum.
c Reflux for 5 h.
HSCH2CO2Et Boc-Phe-SCH2CO2Et 77-78
7c (85)
We have previously reported the preparation of N-protect-
ed (aminoacyl)benzotriazoles including N-Boc-Phe-Bt
(6a),13d N-Cbz-Phe-Bt (6b), N-Cbz-Phe-Ala-Bt (6c),13e
which were confirmed to be >97% enantiomerically pure
by NMR spectroscopy.13e N-Cbz-Phe-D-Ala-Bt 6d was
prepared from enantiomerically pure N-Cbz-Phe-D-Ala-
OH for comparison of thiol esters 7i and 7j by NMR to de-
tect racemization during the coupling reaction. The meth-
yl protons are resonated at 1.61 ppm as a single doublet in
the1H NMR spectrum (DMSO-d6) of 6c, when the methyl
protons of 6d appeared at 1.48 ppm as a single doublet.
PhSH
Cbz-Phe-SPh
7d (86)
100-101
PhCH2SH
Cbz-Phe-SCH2Ph
7e (93)
119-120
HSCH2CO2Et Cbz-Phe-SCH2CO2Et 55-56
7f (84)
HSCH2CO2H Cbz-Phe-SCH2CO2H
98-99
7g (94)
PhSH
PhSH
Cbz-Phe-Ala-SPh
7h (94)
169-170
1
These H and 13C NMR spectra indicated absence of the
peaks corresponding to less than 3% racemization.
Cbz-Phe-D-Ala-SPh 178-179
7i (95)
We further investigated the preparation of chiral thiol es-
ters derived from N-Boc- or Cbz-phenylalanine and
dipeptides. Thiol esters 7a–i were prepared in 76–97%
yield (Table 5) by following the reaction conditions used
in the synthesis of thiol esters 2–5.
a Configuration of the products is L, unless specified otherwise.
b Isolated yield.
In summary, N-acylbenzotriazoles have been introduced
as new efficient S-acylating reagents. The reactions have
been demonstrated under mild conditions to give diverse
thiol esters in excellent yield, and the integrity of the
chiral center when amino acid or peptide derivatives were
used has been demonstrated by NMR study. Thiol esters
2c, 2d, 2f from reactions of N-acylbenzotriazole (2-py-
ridyl 1c, 2-indolyl 1d, and 4-Et2NC6H4 1f) with thiophe-
nol, 3c, 3d, 3f derived from benzyl mercaptan, and 4b–g
from 2-mercaptoacetate are novel compounds. Although
We have already demonstrated N-acylation of amino ac-
ids and dipeptides with N-(Cbz-aminoacyl)benzotriaz-
oles, where the coupling reactions were performed
without detectable racemization in the presence of Et3N at
25 °C.13e Likewise, to confirm the absence of racemiza-
tion in the thiol esters, we carried out 1H NMR analysis of
the crude dipeptide thiol esters obtained by their coupling
with both enantiomerically pure Cbz-Phe-L-Ala-Bt (6c)
and Cbz-Phe-D-Ala-Bt (6d). While Cbz-L-Phe-L-Ala-SPh
(7h) derived from 6c gave a single doublet at 1.36 ppm for
Synthesis 2004, No. 11, 1806–1813 © Thieme Stuttgart · New York

PAPER
Preparation of Thiol Esters Utilizing N-Acylbenzotriazoles
1809
Anal. Calcd for C20H12N6O2: C, 65.21; H, 3.28; N, 22.81. Found: C,
65.04; H, 3.22; N, 22.92.
thiol esters derived from pyridine, indole, and dimethyl-
aminobenzene can be found in literature,6c reactions with
their acid chlorides suffer low yield presumably due to the
low stability of the acid chlorides. Carbodiimides can be
effective direct coupling reagents for the thiol esters,11 but
ureas often complicate purification process. Novel com-
pounds 5a–g have been prepared by reactions with 2-mer-
captoacetic acid in partially aqueous solution. Novel thiol
esters of amino acids 7c, 7e, 7f and peptides 7h, 7i have
also been prepared without detectable recemization. We
have shown that this methodology is highly applicable,
and provides thiol esters in high yield with easy workup
process.
tert-Butyl N-[(1S)-2-(1H-1,2,3-Benzotriazol-1-yl)-1-benzyl-2-
oxoethyl]carbamate (Boc-Phe-Bt, 6a)
Yield: 89%; colorless needles from CHCl3–hexanes; mp 144–145
°C (Lit.13d mp 144–145 °C.
Benzyl N-[(1S)-2-(1H-1,2,3-Benzotriazol-1-yl)-1-benzyl-2-oxo-
ethyl]carbamate (Cbz-Phe-Bt, 6b)
Yield: 89%; white plates from CHCl3–hexanes; mp 151–152 °C
(Lit.13e mp 151–152 °C).
Benzyl N-((1S)-2-{[(1S)-2-(1H-1,2,3-Benzotriazol-1-yl)-1-meth-
yl-2-oxoethyl]amino}-1-benzyl-2-oxoethyl)carbamate (Cbz-
Phe-Ala-Bt, 6c)
Yield: 85%; microcrystals; mp 180–181 °C (Lit.13e mp 180–
181 °C); [a]D23 –57.1 (c = 0.83, CHCl3).
Melting points were determined on a capillary point apparatus
equipped with a digital thermometer. NMR spectra were recorded
1
in CDCl3 or DMSO-d6 with TMS for H (300 MHz) and 13C (75
Benzyl N-((1S)-2-{[(1S)-2-(1H-1,2,3-Benzotriazol-1-yl)-1-meth-
yl-2-oxoethyl]amino}-1-benzyl-2-oxoethyl)carbamate (Cbz-
Phe-D-Ala-Bt, 6d)
MHz) as the internal reference unless specified otherwise. Optical
rotation values were measured with the use of the sodium D line.
THF was distilled from sodium metal in the presence of benzophe-
none under nitrogen atmosphere immediately prior to use. CH2Cl2
was distilled in the presence of CaH2 under N2 prior to use. Config-
uration of chiral amino acids and peptides are L unless specified oth-
erwise.
Yield: 90%; microcrystals; mp 156–157 °C, [a]D23 +36.9 (c = 1.56,
CHCl3).
1H NMR (CDCl3): d = 1.48 (d, J = 7.0 Hz, 3 H), 3.03–3.21 (m, 2 H),
4.54 (d, J = 7.0 Hz, 1 H), 5.11 (s, 2 H), 5.40 (br s, 1 H), 5.81–5.90
(m, 1 H), 6.50 (d, J = 7.0 Hz, 1 H), 7.22–7.35 (m, 10 H), 7.52 (t,
J = 8.1 Hz, 1 H), 7.66 (d, J = 8.1 Hz, 1 H), 8.13 (d, J = 7.5 Hz, 1 H),
8.20 (d, J = 7.5 Hz, 1 H).
13C NMR (CDCl3): d = 18.5, 38.6, 48.9, 56.2, 67.2, 114.3, 120.3,
126.5, 127.2, 128.0, 128.2, 128.5, 128.8, 129.3, 130.7, 131.1, 136.1,
136.3, 146.0, 156.0, 170.5, 171.4.
Compounds 1a–g and 6a–d; General Procedure
N-Acylbenzotriazoles 1a–f and 6a–d were prepared by following
previously reported methods.13a,e,16 Compound 1g was prepared by
following a previously reported procedure with MeSO2Bt in the
presence of Et3N in refluxing THF.13a
Anal. Calcd for C26H25N5O4: C, 66.23; H, 5.34; N, 14.85. Found: C,
66.18; H, 5.45; N, 14.68.
1H-1,2,3-Benzotriazol-1-yl(phenyl)methanone (1a)
Yield: 86%; white crystals from CHCl3–hexanes; mp 112–113 °C
(Lit.24 mp 112–113 °C).
Thiol Esters 2a–g; General Procedure
To a solution of N-acylbenzotriazole (5.0 mmol) in CH2Cl2 (30 mL)
in the presence of Et3N (5.0 mmol), was added thiophenol (5.0
mmol), and the mixture was stirred at 25 °C for 1 h. To the mixture
was added CH2Cl2 (10 mL), and the CH2Cl2 layer was washed with
aq 10% Na2CO3, aq sat. NH4Cl, and dried (MgSO4). After evapora-
tion of solvents, thiol esters 2a–f were obtained in 86–99% yield.
Two equivalents of phenyl mercaptan and Et3N were used to give
2g in 90% yield. The products 2a–g were frequently obtained with-
out any further purification and gave satisfactory results on elemen-
tal analysis. Otherwise, recrystallization from CH2Cl2–hexanes, or
column chromatography (eluent: EtOAc–hexanes, 1:2; silica gel)
was used.
1H-1,2,3-Benzotriazol-1-yl(2-methoxyphenyl)methanone (1b)
Yield: 71%; colorless flakes from EtOH; mp 96–97 °C (Lit.13a mp
96–97 °C).
1H-1,2,3-Benzotriazol-1-yl(2-pyridinyl)methanone (1c)
Yield: 90%; needles from EtOH; mp 98–100 °C (Lit.24 mp 97–100
°C).
1H-1,2,3-Benzotriazol-1-yl(1H-indol-2-yl)methanone (1d)
Yield: 85%; yellowish crystals from CHCl3; mp 215–216 °C (Lit.14b
mp 215–216 °C).
1H-1,2,3-Benzotriazol-1-yl(2-furyl)methanone (1e)
Yield: 92%; white needles from CHCl3–hexanes; mp 171–173 °C
(Lit.24 mp 171–173 °C).
S-Phenyl Benzenecarbothioate (2a)
Yield: 92%; white crystals; mp 54–58 °C (Lit.25 mp 57–59 °C).
1H NMR (CDCl3): d = 7.44–7.54 (m, 7 H), 7.60 (t, J = 7.4 Hz, 1 H),
8.01–8.04 (m, 2 H).
13C NMR (CDCl3): d = 127.6, 127.7, 128.9, 129.4, 129.7, 133.8,
135.3, 136.8, 190.3.
1H-1,2,3-Benzotriazol-1-yl[4-(diethylamino)phenyl]metha-
none (1f)
Yield: 88%; yellow needles from EtOH–hexanes; mp 86–87 °C
(Lit.13a mp 86–87 °C).
S-Phenyl 2-Methoxybenzenecarbothioate (2b)17
Yield: 99%; colorless oil.
1H NMR (CDCl3): d = 3.94 (s, 3 H), 6.98–7.04 (m, 2 H), 7.41–7.54
(m, 6 H), 7.84 (dd, J = 8.1, 1.4 Hz, 1 H).
13C NMR (CDCl3): d = 55.8, 112.0, 120.5, 126.3, 128.7, 129.0,
129.2, 129.9, 133.9, 134.9, 158.1, 189.1.
1H-1,2,3-Benzotriazol-1-yl[3-(1H-1,2,3-benzotriazol-1-ylcarbo-
nyl)phenyl]methanone (1g)
Yield: 93%; white powder from propan-2-ol; mp 205–206 °C.
1H NMR (DMSO-d6): d = 7.68 (t, J = 7.7 Hz, 2 H), 7.86 (t, J = 7.7
Hz, 2 H), 7.93 (t, J = 7.8 Hz, 1 H), 8.31 (d, J = 8.2 Hz, 2 H), 8.36 (d,
J = 8.2 Hz, 2 H), 8.56 (d, J = 7.8 Hz, 2 H), 9.07 (s, 1 H).
13C NMR (DMSO-d6): d = 115.0, 120.6, 126.8, 128.9, 130.9, 132.2,
132.4, 135.2, 136.4, 146.0, 165.7.
S-Phenyl 2-Pyridinecarbothioate (2c)
Yield: 90%; white crystals; mp 93–94 °C.
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1H NMR (CDCl3): d = 7.43–7.59 (m, 6 H), 7.87 (dt, J = 7.7, 1.6 Hz,
1 H), 7.96 (d, J = 7.7 Hz, 1 H), 8.74–8.76 (m, 1 H).
S-Benzyl 2-Pyridinecarbothioate (3c)
Yield: 85%; white crystals; mp 60–61 °C.
13C NMR (CDCl3): d = 121.0, 128.3, 128.4, 129.4, 129.6, 135.2,
1H NMR (CDCl3): d = 4.28 (s, 2 H), 7.20–7.32 (m, 3 H), 7.36–7.42
(m 2 H), 7.46–7.50 (m, 1 H), 7.83 (dt, J = 1.5, 7.7 Hz, 1 H), 7.96 (d,
J = 7.7 Hz, 1 H), 8.65 (d, J = 4.7 Hz, 1 H).
13C NMR (CDCl3): d = 33.3, 120.6, 127.3, 128.0, 128.7, 129.2,
137.4, 137.7, 149.3, 152.0, 193.1.
137.6, 149.4, 151.9, 192.2.
Anal. Calcd for C12H9NOS: C, 66.95; H, 4.21; N, 6.51. Found: C,
67.20; H, 4.09; N, 6.51.
S-Phenyl 1H-Indole-2-carbothioate (2d)
Yield: 93%; white crystals; mp 197–198 °C.
1H NMR (DMSO-d6): d = 7.14 (t, J = 7.4 Hz, 1 H), 7.31–7.36 (m, 1
H), 7.47–7.60 (m, 7 H), 7.75 (d, J = 8.1 Hz, 1 H), 12.11 (br s, 1 H).
Anal. Calcd for C13H11NOS: C, 68.10; H, 4.84; N, 6.11. Found: C,
67.77; H, 4.76; N, 5.72.
S-Benzyl 1H-Indole-2-carbothioate (3d)
Yield: 93%; fine needles; mp 162–163 °C.
13C NMR (DMSO-d6): d = 108.4, 112.9, 120.7, 122.6, 125.8, 126.4,
126.7, 129.4, 129.7, 133.0, 135.0, 137.9, 180.8.
1H NMR (CDCl3): d = 4.36 (s, 2 H), 7.10 (t, J = 7.7 Hz, 1 H), 7.23–
7.37 (m, 5 H), 7.42 (d, J = 7.3 Hz, 2 H), 7.47 (d, J = 8.4 Hz, 1 H),
7.69 (d, J = 8.1 Hz, 1 H), 12.4 (br s, 1 H).
13C NMR (CDCl3): d = 31.8, 107.6, 112.8, 120.6, 122.5, 125.5,
126.7, 127.2, 128.5, 128.9, 133.6, 137.7, 137.8, 182.4.
Anal. Calcd for C15H11NOS: C, 71.12; H, 4.38; N, 5.53. Found: C,
70.83; H, 4.26; N, 5.34.
S-Phenyl 2-Furancarbothioate (2e)17
Yield: 93%; microcrystals; mp 51–52 °C (Lit.18 mp 54–55 °C).
HRMS: m/z calcd for C16H13NOS: 267.0717 (M); found: 267.0717.
1H NMR (CDCl3): d = 6.56–6.59 (m, 1 H), 7.26 (d, J = 3.6 Hz, 1 H),
7.43–7.54 (m, 5 H), 7.63 (s, 1 H).
S-Benzyl 2-Furancarbothioate (3e)22
Yield: 89%; colorless oil.
1H NMR (CDCl3): d = 4.29 (s, 2 H), 6.51–6.52 (m, 1 H), 7.19 (d,
J = 3.6 Hz, 1 H), 7.22–7.38 (m, 5 H), 7.56 (s, 1 H).
13C NMR (CDCl3): d = 112.6, 116.4, 126.4, 129.5, 129.9, 135.3,
146.7, 150.6, 178.8.
S-Phenyl 4-(Diethylamino)benzenecarbothioate (2f)
Yield: 86%; yellowish crystals; mp 98–99 °C.
1H NMR (CDCl3): d = 1.20 (t, J = 7.0 Hz, 6 H), 3.41 (q, J = 7.0 Hz,
4 H), 6.63 (d, J = 9.1 Hz, 2 H), 7.39–7.45 (m, 3 H), 7.48–7.53 (m, 2
H), 7.88–7.93 (m, 2 H).
13C NMR (CDCl3): d = 32.5, 112.5, 115.9, 127.6, 128.8, 129.2,
137.5, 146.4, 150.8, 180.1.
Anal. Calcd for C12H10O2S: C, 66.03; H, 4.62. Found: C, 65.72; H,
4.59.
13C NMR (CDCl3): d = 12.7, 44.8, 110.4, 123.4, 128.7, 129.2, 130.2,
135.5, 151.9, 187.5.
S-Benzyl 4-(Diethylamino)benzenecarbothioate (3f)
Yield: 86%; yellow solid; mp 51–54 °C.
Anal. Calcd for C17H19NOS: C, 71.54; H, 6.71; N, 4.91. Found: C,
71.20; H, 6.74; N, 4.98.
1H NMR (CDCl3): d = 1.17 (t, J = 7.0 Hz, 6 H), 3.38 (q, J = 7.1 Hz,
4 H), 4.28 (s, 2 H), 6.58 (d, J = 9.0 Hz, 2 H), 7.21–7.38 (m, 5 H),
7.85 (d, J = 9.0 Hz, 2 H).
13C NMR (CDCl3): d = 12.4, 32.8, 44.5, 110.1, 123.5, 126.9, 128.5,
128.9, 129.7, 138.4, 151.4, 188.6.
S1,S3-Diphenyl 1,3-Benzenedicarbothioate (2g)19
Yield: 90%; white powder; mp 102–103 °C.
1H NMR (CDCl3): d = 7.41–7.56 (m, 10 H), 7.63 (t, J = 7.8 Hz, 1
H), 8.24 (dd, J = 7.8, 1.8 Hz, 2 H), 8.67 (t, J = 1.8 Hz, 1 H).
13C NMR (CDCl3): d = 126.6, 126.9, 129.6, 129.9, 132.2, 135.2,
137.4, 189.5.
Anal. Calcd for C18H21NOS: C, 72.20; H, 7.07; N, 4.68. Found: C,
72.25; H, 7.14; N, 4.69.
S1,S3-Dibenzyl 1,3-Benzenedicarbothioate (3g)23
Yield: 86%; white powder; mp 81–82 °C.
Anal. Calcd for C20H14O2S2: C, 68.54; H, 4.03. Found: C, 68.21; H,
3.98.
1H NMR (CDCl3): d = 4.34 (s, 4 H), 7.24–7.40 (m, 10 H), 7.53 (t,
J = 7.8 Hz, 1 H), 8.13 (dd, J = 7.8, 1.6 Hz, 2 H), 8.54 (t, J = 1.6 Hz,
1 H).
13C NMR (CDCl3): d = 33.8, 126.4, 127.7, 128.9, 129.2, 129.3,
131.9, 137.3, 137.4, 190.6.
Thiolesters 3a–g; General Procedure
Thiol esters 3a–g were prepared by the same procedure as described
for 2a–g.
S-Benzyl Benzenecarbothioate (3a)20
Yield: 98%; colorless oil.
Anal. Calcd for C22H18O2S2: C, 69.81; H, 4.79. Found: C, 69.53; H,
4.96.
1H NMR (CDCl3): d = 4.32 (s, 2 H), 7.24–7.46 (7 H), 7.53–7.58 (m,
1 H), 7.95–7.98 (m, 2 H).
Compounds 4a–g; General Procedure
To a solution of N-acylbenzotriazole (5.0 mmol) in CH2Cl2 (30 mL)
in the presence of catalytic amount of Et3N (10–20%mol), was add-
ed ethyl 2-mercaptoacetate (5.1 mmol) and the mixture was stirred
at 25 °C for 2 h. After the usual work-up, the titled products 4a–f
were obtained in 85–93% yields. Compound 4g was obtained in
98% yield using two equivalents of ethyl sulfanylacetate. The prod-
ucts 4a–g were usually obtained without any further purification
and gave satisfactory results in elemental analysis. Alternatively,
the products were purified in the manner described above.
13C NMR (CDCl3): d = 33.3, 127.3, 127.3, 128.6, 128.7, 129.0,
133.4, 136.8, 137.5, 191.3.
S-Benzyl 2-Methoxybenzenecarbothioate (3b)
Yield: 99%; colorless oil (Lit.21 mp 47–48 °C).
1H NMR (CDCl3): d = 3.91 (s, 3 H), 4.28 (s, 2 H), 6.96–7.02 (m, 2
H), 7.23–7.40 (m, 5 H), 7.43–7.50 (m, 1 H), 7.81 (dd, J = 8.0, 1.5
Hz, 1 H).
13C NMR (CDCl3): d = 33.9, 55.7, 111.9, 120.4, 127.1, 128.5, 129.0,
129.8, 133.7, 137.6, 157.9, 190.3.
Ethyl 2-(Benzoylsulfanyl)acetate (4a)26
Yield: 93%; colorless oil.
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Preparation of Thiol Esters Utilizing N-Acylbenzotriazoles
1811
1H NMR (CDCl3): d = 1.29 (t, J = 7.1 Hz, 3 H), 3.88 (s, 2 H), 4.22
(q, J = 7.1 Hz, 2 H), 7.42–7.47 (m, 2 H), 7.58 (t, J = 7.4 Hz, 1 H),
7.95–7.99 (m, 2 H).
1H NMR (CDCl3): d = 1.31 (t, J = 7.1 Hz, 6 H), 3.92 (s, 4 H), 4.24
(q, J = 7.1 Hz, 4 H), 7.60 (t, J = 7.8 Hz, 1 H), 8.19 (dd, J = 7.8, 1.6
Hz, 2 H), 8.56 (s, 1 H).
13C NMR (CDCl3): d = 14.2, 31.5, 61.9, 127.5, 128.8, 133.9, 136.2,
168.8, 190.1.
13C NMR (CDCl3): d = 14.3, 31.7, 62.2, 126.4, 129.5, 132.2, 136.8,
168.5, 189.3.
Anal. Calcd for C11H12O3S: C, 58.91; H, 5.39. Found: C, 59.19; H,
5.51.
Anal. Calcd for C16H18O6S2: C, 51.88; H, 4.90. Found: C, 51.84; H,
5.04.
Ethyl 2-[(2-Methoxybenzoyl)sulfanyl]acetate (4b)
Compounds 5a–g; General Procedure
Yield: 83%; colorless oil.
N-Acylbenzotriazole (5.0 mmol) was added to a solution of mercap-
toacetic acid (5.0 mmol) in a solution of MeCN (20 mL) and H2O
(10 mL) in the presence of Et3N (10.0 mmol), and the mixture was
stirred at 25 °C for 1 h. Acetonitrile was evaporated under reduced
pressure, and the remaining solution was acidified to pH 2 by addi-
tion of aq 2 N HCl, and then extracted with EtOAc (3 × 15 mL). The
organic solution was washed with aq 4 N HCl, H2O, brine and dried
(MgSO4). After evaporation of solvents, compounds 5a–g were ob-
tained and purified by recrystallization from CHCl3–hexanes.
1H NMR (CDCl3): d = 1.29 (t, J = 7.1 Hz, 3 H), 3.81 (s, 2 H), 3.94
(s, 3 H), 4.22 (q, J = 7.1 Hz, 2 H), 6.97–7.04 (m, 2 H), 7.50 (dt,
J = 8.0, 1.6 Hz, 1 H), 7.87 (dd, J = 7.7, 1.6 Hz, 1 H).
13C NMR (CDCl3): d = 14.3, 32.3, 55.9, 61.8, 112.2, 120.7, 125.5,
130.2, 134.5, 158.7, 169.4, 188.9.
Anal. Calcd for C12H14O4S: C, 56.68; H, 5.55. Found: C, 56.35; H,
5.77.
Benzoylmercaptoacetic Acid (5a)
Yield: 97%; white crystals; mp 103–104 °C (Lit.23 mp 103–
104 °C).
1H NMR (CDCl3): d = 3.93 (s, 2 H), 7.43–7.50 (m, 2 H), 7.60 (t,
J = 7.4 Hz, 1 H), 7.95–8.00 (m, 2 H), 11.56 (br s, 1 H).
Ethyl 2-[(2-Pyridinylcarbonyl)sulfanyl]acetate (4c)
Yield: 90%; white crystals; mp 31–35 °C.
1H NMR (CDCl3): d = 1.30 (t, J = 7.1 Hz, 3 H), 3.84 (s, 2 H), 4.22
(q, J = 7.1 Hz, 2 H), 7.55 (t, J = 6.3 Hz, 1 H), 7.87 (t, J = 7.7 Hz, 1
H), 7.96 (d, J = 7.7 Hz, 1 H), 8.70 (d, J = 4.1 Hz, 1 H).
13C NMR (CDCl3): d = 31.3, 127.6, 128.9, 134.2, 136.0, 175.2,
190.2.
13C NMR (CDCl3): d = 14.2, 31.4, 61.8, 120.6, 128.3, 137.4, 149.3,
151.2, 169.0, 192.4.
Anal. Calcd for C9H8O3S: C, 55.09; H, 4.11. Found: C, 54.70; H,
3.99.
Anal. Calcd for C10H11NO3S: C, 53.32; H, 4.92; N, 6.22. Found: C,
52.93; H, 5.15; N, 5.91.
2-[(2-Methoxybenzoyl)sulfanyl]acetic Acid (5b)
Yield: 92%; white microcrystals; mp 73–74 °C.
Ethyl 2-[(1H-Indol-2-ylcarbonyl)sulfanyl]acetate (4d)
Yield: 93%; white microcrystals; mp 134–135 °C.
1H NMR (CDCl3): d = 3.88 (s, 2 H), 3.92 (s, 3 H), 6.96–7.03 (m, 2
H), 7.46–7.52 (m, 1 H), 7.88 (d, J = 7.8 Hz, 1 H), 12.09 (br s, 1 H).
13C NMR (CDCl3): d = 32.1, 55.9, 112.2, 120.7, 125.0, 130.2, 134.8,
158.9, 174.8, 189.2.
1H NMR (DMSO-d6): d = 1.23 (t, J = 7.1 Hz, 3 H), 4.01 (s, 2 H),
4.16 (q, J = 7.0 Hz, 2 H), 7.12 (t, J = 7.5 Hz, 1 H), 7.29–7.35 (m, 1
H), 7.41 (d, J = 1.4 Hz, 1 H), 7.48 (d, J = 8.4 Hz, 1 H), 7.72 (d,
J = 8.1 Hz, 1 H), 12.5 (s, 1 H).
13C NMR (DMSO-d6): d = 14.0, 30.5, 61.2, 108.1, 112.8, 120.7,
122.6, 125.8, 126.7, 133.1, 137.7, 168.5, 181.6.
Anal. Calcd for C10H10O4S: C, 53.09; H, 4.45. Found: C, 53.28; H,
4.24.
Anal. Calcd for C13H13NO3S: C, 59.30; H, 4.98; N, 5.32. Found: C,
59.45; H, 5.06; N, 5.15.
2-[(2-Pyridinylcarbonyl)sulfanyl]acetic Acid (5c)
Washing the crude reaction mixture with aq HCl resulted in loss of
5c. Therefore, crude 5c was washed with hot hexanes to remove 1H-
benzotriazole, and purified by crystallization from CHCl3–hexanes.
The titled product could not be isolated by column chromatography
(SiO2,) since Rf values of 1H-benzotriazole and 5c were very simi-
lar on TLC (Rf = 0.25, eluent: EtOAc–hexanes, 1:2). Isolated yield:
35% (>90% yield was expected from crude 1H NMR); crystals; mp
116–117 °C.
1H NMR (CDCl3): d = 3.88 (s, 2 H), 7.53–7.57 (m, 1 H), 7.88 (dt,
J = 7.7, 1.6 Hz, 1 H), 7.67 (d, J = 7.7 Hz, 1 H), 8.71 (d, J = 4.8 Hz,
1 H), 11.0 (br s, 1 H).
Ethyl 2-[(2-Furylcarbonyl)sulfanyl]acetate (4e)
Yield: 87%; brown oil.
1H NMR (CDCl3): d = 1.29 (t, J = 7.1 Hz, 3 H), 3.86 (s, 2 H), 4.22
(q, J = 7.1 Hz, 2 H), 6.57 (dd, J = 3.6, 1.8 Hz, 1 H), 7.24 (d, J = 3.6
Hz, 1 H), 7.61 (d, J = 1.8 Hz, 1 H).
13C NMR (CDCl3): d = 14.2, 30.6, 62.1, 112.6, 116.4, 146.8, 150.3,
168.7, 178.7.
Anal. Calcd for C9H10O4S: C, 50.46; H, 4.70. Found: C, 50.52; H,
4.82.
13C NMR (CDCl3): d = 31.0, 120.7, 128.3, 137.3, 149.2, 150.9,
Ethyl 2-{[4-(Diethylamino)benzoyl]sulfanyl}acetate (4f)
Yield: 90%; yellow crystals; mp 41–42 °C.
1H NMR (CDCl3): d = 1.19 (t, J = 7.0 Hz, 6 H), 1.28 (t, J = 7.1 Hz,
3 H), 3.40 (q, J = 7.0 Hz, 4 H), 3.84 (s, 2 H), 4.21 (q, J = 7.1 Hz, 2
H), 6.60 (d, J = 9.1 Hz, 2 H), 7.85 (d, J = 9.1 Hz, 2 H).
13C NMR (CDCl3): d = 12.6, 14.3, 31.2, 44.7, 61.8, 110.3, 123.0,
130.0, 151.9, 169.6, 187.2.
174.1, 192.3.
Anal. Calcd for C8H7NO3S: C, 48.72; H, 3.58; N, 7.10. Found: C,
48.42; H, 3.44; N, 6.84.
2-[(1H-Indol-2-ylcarbonyl)sulfanyl]acetic Acid (5d)
The titled product was collected as precipitate from the reaction
mixture. Yield: 89%; yellowish microcrystals; mp 210–211 °C.
1H NMR (DMSO-d6): d = 3.92 (s, 2 H), 7.08–7.13 (m, 1 H), 7.27–
7.33 (m, 1 H), 7.39 (d, J = 1.4 Hz, 1 H), 7.47 (d, J = 8.4 Hz, 1 H),
7.71 (d, J = 7.7 Hz, 1 H), 12.03 (s, 1 H), 12.88 (br s, 1 H).
Anal. Calcd for C15H21NO3S: C, 60.99; H, 7.17; N, 4.74. Found: C,
61.07; H, 7.42; N, 5.12.
Ethyl 2-[(3-{[(2-Ethoxy-2-oxoethyl)sulfanyl]carbonyl}ben-
zoyl)sulfanyl]acetate (4g)
Yield: 98%; white powder; mp 52–53 °C.
13C NMR (DMSO-d6): d = 30.8, 107.9, 112.8, 120.7, 122.6, 125.7,
126.7, 133.3, 137.7, 169.7, 181.8.
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PAPER
Anal. Calcd for C11H9NO3S: C, 56.16; H, 3.86; N, 5.95. Found: C,
56.21; H, 3.74; N, 6.07.
13C NMR (CDCl3): d = 23.4, 28.5, 28.7, 33.5, 38.6, 61.0, 80.6,
127.3, 127.5, 128.7, 128.8, 129.1, 129.6, 135.7, 200.7.
Anal. Calcd for C21H25NO3S: C, 67.90.16; H, 6.78; N, 3.77. Found:
C, 67.68; H, 6.88; N, 3.73.
2-[(2-Furylcarbonyl)sulfanyl]acetic Acid (5e)27
Yield: 88%; white microcrystals; mp 112–113 °C.
1H NMR (CDCl3): d = 3.90 (s, 2 H), 6.58 (apparent s, 1 H), 7.22–
Ethyl 2-({(2S)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpro-
panoyl}sulfanyl)acetate (7c)
7.28 (m, 1 H), 7.62 (s, 1 H), 10.43 (br s, 1 H).
Yield: 85%; white microcrystals; mp 77–78 °C, [a]D23 –1.14 (c =
2.18, CHCl3).
13C NMR (CDCl3): d = 30.5, 112.8, 115.3, 116.8, 126.6, 147.0,
174.3.
1H NMR (CDCl3): d = 1.28 (t, J = 7.0 Hz, 3 H), 1.40 (s, 9 H), 3.01–
3.23 (m, 2 H), 3.63 (AB d, J = 16.2 Hz, 1 H), 3.73 (AB d, J = 16.2
Hz, 1 H), 4.19 (q, J = 7.0 Hz, 2 H), 4.63–4.71 (m, 1 H), 4.99 (d,
J = 8.5 Hz, 1 H), 7.14–7.21 (m, 2 H), 7.23–7.34 (m, 3 H).
13C NMR (CDCl3): d = 14.2, 28.4, 31.5, 38.1, 61.0, 61.9, 80.6,
127.3, 128.8, 129.5, 135.7, 155.1, 168.7, 200.0.
Anal. Calcd for C7H6O4S: C, 45.16; H, 3.25. Found: C, 44.77; H,
3.03.
2-{[4-(Diethylamino)benzoyl]sulfanyl}acetic Acid (5f)
The titled product was precipitated from acidified reaction mixture
(pH 2) after evaporation of the acetonitrile, and further purified by
recrystallization from CHCl3–hexanes. Yield: 82%; white needles;
mp 144–145 °C.
1H NMR (CDCl3): d = 1.19 (t, J = 7.0 Hz, 6 H), 3.41 (q, J = 7.0 Hz,
4 H), 3.85 (s, 2 H), 6.60 (d, J = 9.0 Hz, 2 H), 7.84 (d, J = 9.0 Hz, 2
H), 10.5 (br s, 1 H).
Anal. Calcd for C18H25NO5S: C, 58.83; H, 6.86; N, 3.81. Found: C,
58.66; H, 6.93; N, 3.77.
S-Phenyl (2S)-2-{[(Benzyloxy)carbonyl]amino}-3-phenylpro-
panethioate (7d)24
Yield: 86%; white microcrystals; mp 100–101 °C; [a]D23 –60.8 (c =
1.92, CHCl3).
13C NMR (CDCl3): d = 12.4, 30.9, 44.6, 110.2, 122.4, 130.1, 151.9,
174.5, 187.9.
1H NMR (CDCl3): d = 3.05–3.15 (m, 2 H), 4.72–4.80 (m, 1 H), 5.04
(s, 2 H), 5.18 (d, J = 8.9 Hz, 1 H), 7.07–7.11 (m, 2 H), 7.15–7.35
(m, 13 H).
Anal. Calcd for C13H17NO3S: C, 58.40; H, 6.41; N, 5.24. Found: C,
58.40; H, 6.43; N, 5.27.
2-[(3-{[(2-Hydroxy-2-oxoethyl)sulfanyl]carbonyl}benzoyl)sul-
fanyl]acetic Acid (5g)28
13C NMR (CDCl3): d = 38.6, 61.5, 67.5, 127.2, 127.5, 128.3, 128.4,
128.7, 129.0, 129.5, 129.6, 129.8, 134.8, 135.5, 136.2, 155.8, 199.0.
The titled product was precipitated from acidified reaction mixture
(pH 2) after evaporation of the MeCN, and further purified by re-
crystallization from CHCl3–hexanes. Yield: 96%; white powder;
mp 185–186 °C.
1H NMR (DMSO-d6): d = 3.97 (s, 4 H), 7.79 (t, J = 7.7 Hz, 1 H),
8.25 (dd, J = 7.7, 1.4 Hz, 2 H), 8.34 (s, 1 H), 12.98 (br s, 2 H).
Anal. Calcd for C23H21NO3S: C, 70.56; H, 5.41; N, 3.58. Found: C,
70.16; H, 5.70; N, 3.49.
S-Benzyl (2S)-2-{[(Benzyloxy)carbonyl]amino}-3-phenylpro-
panethioate (7e)
Yield: 93%; white needles; mp 119–120 °C; [a]D23 –44.8 (c = 1.68,
CHCl3).
13C NMR (DMSO-d6): d = 31.6, 124.5, 130.6, 132.1, 136.3, 169.4,
189.5.
1H NMR (CDCl3): d = 3.06–3.13 (m, 2 H), 4.09 (s, 2 H), 4.71–4.77
(m, 1 H), 5.07 (s, 2 H), 5.18 (d, J = 8.8 Hz, 1 H), 7.03–7.05 (m, 2
H), 7.19–7.31 (m, 13 H).
13C NMR (CDCl3): d = 33.4, 38.4, 61.3, 67.2, 127.2, 127.4, 128.1,
128.3, 128.6, 128.7, 128.8, 129.0, 129.4, 135.3, 136.1, 137.0, 155.7,
200.0.
Anal. Calcd for C12H10O6S2: C, 45.85; H, 3.21. Found: C, 45.85; H,
3.13.
Compounds 7a–i; General Procedure
Following the procedures for compound 2, 3, 4, and 5 depending on
thiols, thiol esters 7a–i were obtained in 76–94% yields.
Anal. Calcd for C24H23NO3S: C, 71.09; H, 5.72; N, 3.45. Found: C,
70.92; H, 5.72; N, 3.47.
S-Phenyl (2S)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpro-
panethioate (7a)29
Ethyl 2-[((2S)-2-{[(Benzyloxy)carbonyl]amino}-3-phenylpro-
panoyl)sulfanyl]acetate (7f)
Yield: 76%; white microcrystals; mp 102–103 °C; [a]D23 –1.62 (c =
1.54, CHCl3).
Yield: 84%; white microcrystals; mp 55–56 °C; [a]D23 –27.6 (c =
1.98, CHCl3).
1H NMR (CDCl3): d = 1.44 (s, 9 H), 3.09–3.21 (m, 2 H), 4.72–4.80
(m, 1 H), 4.98 (d, J = 8.8 Hz, 1 H), 7.19 (d, J = 6.6 Hz, 2 H), 7.24–
7.49 (m, 8 H).
13C NMR (CDCl3): d = 28.5, 38.6, 61.1, 80.7, 127.4, 127.5, 128.9,
129.4, 129.6, 129.7, 134.8, 135.8, 155.2, 199.5.
1H NMR (CDCl3): d = 1.18 (t, J = 7.1 Hz, 3 H), 2.93–3.15 (m, 2 H),
3.54 (AB d, J = 16.1 Hz, 1 H), 3.63 (AB d, J = 16.1 Hz, 1 H), 4.10
(q, J = 7.1 Hz, 2 H), 4.64–4.70 (m, 1 H), 4.99 (s, 2 H), 5.24 (d,
J = 8.5 Hz, 1 H), 7.03–7.08 (m, 2 H), 7.13–7.28 (m, 8 H).
Anal. Calcd for C20H23NO3S: C, 67.20; H, 6.49; N, 3.92. Found: C,
66.92; H, 6.55; N, 4.08.
13C NMR (CDCl3): d = 14.2, 31.6, 38.1, 61.5, 62.0, 67.4, 127.4,
128.1, 128.3, 128.6, 128.9, 129.4, 135.4, 136.1, 155.8, 168.5, 199.4.
Anal. Calcd for C21H23NO5S: C, 62.82; H, 5.77; N, 3.49. Found: C,
62.61; H, 6.03; N, 3.38.
S-Benzyl (2S)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpro-
panethioate (7b)30
Yield: 97%; white microcrystals; mp 92–93 °C; [a]D23 –0.69 (c =
1.31, CHCl3).
2-{[(2S)-2-{[(Benzyloxy)carbonyl]amino}-3-phenylpro-
panoyl]sulfanyl}acetic Acid (7g)25
1H NMR (CDCl3): d = 1.39 (s, 9 H), 3.07–3.12 (m, 2 H), 4.07 (AB
d, J = 12.5 Hz, 1 H), 4.13 (AB d, J = 12.5 Hz, 1 H), 4.62–4.69 (m,
1 H), 4.86 (d, J = 8.5 Hz, 1 H), 7.06–7.09 (m, 2 H), 7.21–7.33 (m, 8
H).
Yield: 94%; white microcrystals; mp 98–99 °C; [a]D23 –31.2 (c =
1.96, CHCl3).
1H NMR (CDCl3): d = 3.13–3.28 (m, 2 H), 3.70–3.86 (m, 2 H), 4.83
(m, 1 H), 5.15 (s, 2 H), 5.27 (d, J = 8.7 Hz, 1 H), 7.19 (m, 2 H),
7.27–7.39 (m, 8 H), 10.19 (br s, 1 H).
Synthesis 2004, No. 11, 1806–1813 © Thieme Stuttgart · New York

PAPER
Preparation of Thiol Esters Utilizing N-Acylbenzotriazoles
1813
13C NMR (CDCl3): d = 31.3, 38.1, 61.5, 67.6, 127.6, 128.3, 128.5,
128.8, 129.0, 129.5, 135.1, 136.1, 156.0, 173.9, 199.5.
(8) Ravi, D.; Rama Rao, N.; Reddy, G. S. R.; Sucheta, K.;
Jayathirtha Rao, V. Synlett 1994, 856.
(9) Imamoto, T.; Kodera, M.; Yokoyama, M. Synthesis 1982,
134.
(10) Grieco, P. A.; Yokoyama, Y.; Williams, E. J. Org. Chem.
1978, 43, 1283.
(11) (a) Jew, S.; Park, B.; Lim, D.; Kim, M. G.; Chung, I. K.;
Kim, J. H.; Hong, C. I.; Kim, J.-K.; Park, H.-J.; Lee, J.-H.;
Park, H. Bioorg. Med. Chem. Lett. 2003, 13, 609.
(b) Hondal, R. J.; Nilsson, B. L.; Raines, R. T. J. Am. Chem.
Soc. 2001, 123, 5140. (c) Ouihia, A.; René, L.; Guilhem, J.;
Pascard, C.; Badet, B. J. Org. Chem. 1993, 58, 1641.
(d) Ozaki, S.; Yoshinaga, H.; Matsui, E.; Adachi, M. J. Org.
Chem. 2001, 66, 2503.
S-Phenyl (2S)-2-{[(2S)-2-{[(Benzyloxy)carbonyl]amino}-3-phe-
nylpropanoyl]amino}propanethioate (7h)
Yield: 94%; white microcrystals; mp 169–170 °C; [a]D23 –22.6 (c =
1.35, CHCl3).
1H NMR (CDCl3): d = 1.36 (d, J = 7.0 Hz, 3 H), 3.03–3.17 (m, 2 H),
4.55 (d, J = 6.7 Hz, 1 H), 4.71–4.79 (m, 1 H), 5.06 (s, 2 H), 5.46 (d,
J = 6.6 Hz, 1 H), 6.78 (br s, 1 H), 7.17–7.43 (m, 15 H).
13C NMR (CDCl3): d = 18.7, 38.3, 55.1, 56.2, 67.3, 126.9, 127.3,
128.2, 128.4, 128.7, 128.9, 129.4, 129.6, 129.8, 134.8, 136.2, 136.3,
156.3, 171.1, 198.6.
(12) Shah, S. T. A.; Khan, K. M.; Heinrich, A. M.; Voelter, W.
Tetrahedron Lett. 2002, 43, 8281.
Anal. Calcd for C26H26N2O4S: C, 67.51; H, 5.67; N, 6.06. Found: C,
67.75; H, 5.72; N, 5.99.
(13) (a) Katritzky, A. R.; He, H.-Y.; Suzuki, K. J. Org. Chem.
2000, 65, 8210. (b) Katritzky, A. R.; Yang, H.; Zhang, S.;
Wang, M. Arkivoc 2002, xi, 39; www.arkat-usa.org.
(c) Katritzky, A. R.; Yang, B.; Semenzin, D. J. Org. Chem.
1997, 62, 726. (d) Katritzky, A. R.; Wang, M.; Yang, H.;
Zhang, S.; Akhmedov, N. G. Arkivoc 2002, viii, 134;
www.arkat-usa.org. (e) Katritzky A. R., Suzuki K., Singh K.
S.; Submitted (f) Katritzky, A. R.; Wang, M.; Zhang, S.
Arkivoc 2001, ix, 19; www.arkat-usa.org.
(14) (a) Katritzky, A. R.; Pastor, A. J. Org. Chem. 2000, 65,
3679. (b) Katritzky, A. R.; Suzuki, K.; Singh, K. S. J. Org.
Chem. 2003, 68, 5720. (c) Katritzky, A. R.; Suzuki, K.;
Singh, K. S. Croat. Chem. Acta in press. (d) Katritzky, A.
R.; Abdel-Fattah, A. A. A.; Wang, M. J. Org. Chem. 2003,
68, 4932.
(15) (a) Katritzky, A. R.; Pastor, A.; Voronkov, M. V. J.
Heterocycl. Chem. 1999, 36, 777. (b) Katritzky, A. R.;
Denisko, O. V.; Fang, Y.; Zhang, L.; Wang, Z. Arkivoc
2001, xi, 41; www.arkat-usa.org.
(16) Katritzky, A. R.; Zhang, Y.; Singh, S. K. Synthesis 2003,
2795.
(17) Mukaiyama, T.; Takeda, T.; Atsumi, K. Chem. Lett. 1974,
187.
(18) Sumrell, G.; Zief, M.; Huber, E. J.; Ham, G. E.; Schramn, C.
H. J. Am. Chem. Soc. 1959, 81, 4313.
S-Phenyl (2R)-2-{[(2S)-2-{[(Benzyloxy)carbonyl]amino}-3-phe-
nylpropanoyl]amino}propanethioate (7i)
Yield: 95%; white microcrystals; mp 178–179 °C; [a]D23 +18.7 (c =
1.52, CHCl3).
1H NMR (CDCl3): d = 1.26 (d, J = 7.0 Hz, 3 H), 3.03–3.14 (m, 2 H),
4.48 (apparent quint, J = 6.9 Hz, 1 H), 4.67–4.77 (m, 1 H), 5.08 (s,
2 H), 5.41 (d, J = 7.1 Hz, 1 H), 6.33 (d, J = 6.9 Hz, 1 H), 7.19–7.41
(m, 15 H).
13C NMR (CDCl3): d = 18.4, 38.4, 54.8, 56.2, 67.2, 126.6, 127.1,
128.0, 128.2, 128.5, 128.8, 129.2, 129.3, 129.6, 134.6, 136.0, 136.3,
156.0, 170.5, 198.5.
Anal. Calcd for C26H26N2O4S: C, 67.51; H, 5.67; N, 6.06. Found: C,
67.36; H, 5.65; N, 6.14
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Synthesis 2004, No. 11, 1806–1813 © Thieme Stuttgart · New York