LETTER
Synthesis of O-Ethyl Thioformate
3141
thioformate as a yellow oil (135 g, 97 wt%, 83% yield from trieth-
ylorthoformate; contains 3 wt% ethyl formate).
H
S
NH2
N
H
DBU (0.1 equiv)
+
H
OEt
MeCN
20 °C
18 h
1H NMR (400 MHz, CDCl3): d = 9.74 (s, 1 H), 4.59 (qd, J = 7.1, 1.1
Hz, 2 H), 1.44 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): d = 206.7, 66.3, 13.4 ppm. IR (neat): 2983, 1381, 1294,
1218, 1151, 1105, 1009, 981, 906, 810, 626 cm–1. HRMS (EI): m/z
calcd for C3H6OS [M]: 90.0139; found: 90.0135. Bp 89–91 °C.
S
N
N
2p
1
3p
81% yield
<5% yield observed under acidic conditions
Equation 1 Base-catalyzed thioformylation
Representative Procedure for the Thioformylation of Amines
Using Ethanolic O-Ethyl Thioformate: Synthesis of N-Phenyl-
methanethioamide (3a)
This methodology was further expanded to the synthesis
of thiazoles.24 For example, the condensation of ortho-
bromoaniline with O-ethyl thioformate produced the thio-
amide 3g that was amenable to cyclization to benzothia-
zole (4) in 96% assay yield using copper-catalyzed
conditions (Equation 2). By judicious application of this
chemistry, a wide variety of benzothiazoles could be ac-
cessed quickly.
To a crude ethanolic solution of O-ethyl thioformate (19.49 g, 40
wt%, 86.5 mmol), was added aniline (2.62 mL, 28.8 mmol) via sy-
ringe under an atmosphere of N2. The mixture was stirred at r.t.
(20 °C) for 24 h, after which the reaction was concentrated to a res-
idue. The resulting residue was recrystallized from EtOAc–heptane
to yield N-phenylmethanethioamide (3.75 g, 95%) as a yellow solid.
1H NMR (400 MHz, CDCl3): d = 9.82 (d, J = 14.6 Hz, 1 H), 9.51 (br
s, 1 H), 7.41 (t, J = 7.8 Hz, 2 H), 7.22–7.30 (m, 1 H), 7.16 (d, J = 8.0
Hz, 2 H) ppm. 13C NMR (101 MHz, CDCl3): d = 187.4, 138.5,
130.0, 126.3, 118.9, 117.5 ppm. IR (neat): 1692, 1600, 1560, 1496,
1481, 1449, 1354, 1330, 1317, 1263, 1244, 1217, 1180, 1059, 1011,
943, 924, 891, 744, 683, 598, 573, 503, 432 cm–1. ESI-HRMS: m/z
calcd for C7H8NS [M + H]: 138.03720; found: 138.03666. Mp
136 °C.
Br
CuI (10 mol%)
S
N
S
ligand (20 mol%)
Cs2CO3, DME
85 °C
N
H
3g
H
24 h
4
96% assay
yield
ligand = 1,10-phenanthroline
Representative Procedure for the Thioformylation of Amines
Using Neat O-Ethyl Thioformate: Synthesis of N-(1-Adaman-
tyl)methanethioamide (3l)
Equation 2 Copper-catalyzed benzothiazole formation
H2SO4 (41 mg, 0.42 mmol, 96 wt%) was added to a mixture of 1-
adamantylamine (2.19 g, 14.0 mmol) and O-ethyl thioformate (3.79
In summary, an efficient synthesis of O-ethyl thioformate
has been developed. This process allows safe generation g, 42.0 mmol) in MeCN (11 mL) under an atmosphere of N2. The
mixture was stirred at r.t. (20 °C) for 22 h, after which the reaction
of the reagent on preparative scales (1.80 mol). The thio-
was concentrated to a residue. The resulting residue was recrystal-
late can be used directly as an ethanolic solution or further
lized from toluene–heptane to yield N-(1-adamantyl)methanethio-
purified to a neat oil. This flexibility allows thioformyla-
amide as a white solid (2.40 g, 88%). 1H NMR (400 MHz, CDCl3):
tions to be performed under a variety of conditions, in-
d = 9.27 (d, J = 15.6 Hz, 1 H), 7.82 (br s, 1 H), 2.19 (br s, 3 H), 1.86
(d, J = 2.5 Hz, 6 H), 1.53–1.81 (m, 6 H) ppm. 13C NMR (101 MHz,
CDCl3): d = 186.4, 56.2, 42.9, 35.6, 29.1 ppm. IR (neat): 3144,
3059, 3004, 2903, 2850, 1568, 1449, 1384, 1330, 1306, 1262, 1130,
1090, 1043, 972, 947, 934, 815, 619, 455, 422 cm–1. ESI-HRMS:
m/z: calcd for C11H18NS [M + H]: 196.11545; found: 196.11450.
Mp 246 °C.
creasing the utility of this simple reagent and allowing
access to a variety of substrates. We anticipate the appli-
cations of O-ethyl thioformate will increase as a result of
this simple, safe procedure for its preparation. Other ex-
amples of its utility will be reported in due course.
Supporting Information for this article is available online at
Procedure for the Preparation of Ethanolic O-Ethyl Thiofor-
mate (1)
Triethylorthoformate (300 mL, 1.80 mol) and H2SO4 (98%, 0.96
mL, 0.018 mol) were charged to a pressure vessel and stirred under
an atmosphere of N2. The vessel was then pressurized to 2.1 bar
with H2S gas. Additional H2S was charged to the vessel as needed
to maintain the internal pressure at 1.7–2.1 bar. When no additional
H2S charges were required to maintain reaction pressure for 30 min
(3 h from initial H2S charge), the reactor was vented and purged
with a nitrogen sweep. (Note: All gases were vented through an
aqueous scrubber containing NaOH and NaOCl.) A yellow solution
was isolated (336 g) that contained 46 wt% O-ethyl thioformate
(95% yield).
Acknowledgment
We would like to thank Kyle Baucom for his assistance in experi-
mental evaluation of published methods for the preparation of O-
ethyl thioformate. We would like to thank Dr. Kevin Turney and
Jason Simiens for their assistance with HRMS measurements and
Dr. Tiffany Correll and Vivian Ku for their assistance with FTIR
measurements.
References and Notes
Procedure for the Isolation of Neat O-Ethyl Thioformate (1)
The ethanolic solution of O-ethyl thioformate (336 g, 46 wt%), was
washed with combined sat. aq NaHCO3 (100 mL) and sat. NaCl (50
mL) three times. The organic solution was then washed with sat. aq
NaCl (2 × 50 mL). The resulting yellow liquid (146 g) contained 93
wt% O-ethyl thioformate (84% yield from triethylorthoformate)
and was distilled at atmospheric pressure (1 bar) to yield O-ethyl
(1) (a) Hurd, R. N.; DeLaMater, G. Chem. Rev. 1961, 61, 45.
(b) Zou, J. P.; Zeng, R. S.; Lu, Z. E.; Chen, K. Q. Trends
Heterocycl. Chem. 2001, 7, 107.
(2) Seebach, D.; Lubosch, W.; Enders, D. Chem. Ber. 1976, 109,
1309.
(3) Scott, M. K.; Joacoby, H. I.; Mills, J. E.; Bonfilio, A. C.;
Rasmussen, C. R. J. Med. Chem. 1983, 26, 535.
Synlett 2009, No. 19, 3139–3142 © Thieme Stuttgart · New York