Synthesis of primary thioamides from nitriles and hydrogen sulfide catalyzed by anion-exchange resin

Article abstract of DOI:10.1055/s-2002-33649

A new method has been developed for converting nitriles into primary thioamides. Treatment of various nitriles (Table 1, entries 1-12) with gaseous hydrogen sulfide in a mixture of methanol-water or ethanol-water and in the presence of anion-exchange resin (Dowex 1X8, SH^- form) at room temperature and ambient pressure gave the corresponding thioamides in 25-96% yield.

Full text of DOI:10.1055/s-2002-33649

SHORT PAPER
1649
Synthesis of Primary Thioamides from Nitriles and Hydrogen Sulfide
Catalyzed by Anion-Exchange Resin
S
R
ynthesisof Prim
a
a
ry
T
hioam
d
ides ek Liboska, Daniel Zyka, Miroslav Bobek*
Grace Cancer Drug Center, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, USA
Fax +1(716)8458857; E-mail: miroslav.bobek@roswellpark.org
Received 22 March 2002; revised 5 June 2002
The known base-catalyzed syntheses of thioamides from
nitriles and hydrogen sulfide frequently suffer from the
disadvantage of requiring the reaction to occur under high
Abstract: A new method has been developed for converting nitriles
into primary thioamides. Treatment of various nitriles (Table 1, en-
tries 1–12) with gaseous hydrogen sulfide in a mixture of methanol–
water or ethanol–water and in the presence of anion-exchange resin pressure or high temperature. We now report that the re-
–
(
Dowex 1X8, SH form) at room temperature and ambient pressure action of nitriles with hydrogen sulfide can be accom-
gave the corresponding thioamides in 25–96% yield.
Key words: thioamides, addition reactions, nitriles, nucleosides, solvents at room temperature and atmospheric pressure
plished in the presence of anion-exchange resin in polar
ion exchange resins
(Scheme 1) and, depending on the structure of the starting
nitrile, this method provides the thioamides in 25–96%
yields. In a typical experiment, Dowex 1X8 SH was add-
–
ed to a solution of a nitrile in a mixture of methanol–water
Several methods for preparation of thioamides from ni-
triles have been reported (review ). In general, these
1
(
3:2) or in a mixture of ethanol–water (1:1). A slow
stream of gaseous hydrogen sulfide was then introduced
into the reaction mixture for 0.5–6 hours at room temper-
ature and ambient pressure. After work-up of the reaction
methods involve heating the nitrile in an alcoholic solu-
tion in the presence of an alkali-metal hydrogen sulfide or
ammonium sulfide and usually under pressure in a closed
2
reactor. Under these conditions, the formation of aliphat- mixture, the corresponding thioamides were obtained as
ic thioamides requires use of high pressure and the meth- crystalline compounds.
3
od is facile only with aromatic nitriles containing
4
electron-withdrawing substituents. Reaction of nitriles
with hydrogen sulfide under phase-transfer conditions at
a pressure of 1–2 atm and 70 ºC provided aromatic thioa-
mides in high yields and aliphatic thioamides in moderate
5
to good yields. Alternatively, use of triethylamine or py-
ridine as catalysts for the direct addition of hydrogen sul-
Scheme 1
fide to nitriles at atmospheric pressure is useful only for
We found (Table 1) that the time required to complete the
reaction (90–100% conversion, confirmed by TLC using
iodine vapor detection) varied from 0.5 hours (entry 12) to
aromatic nitriles and has little value for the preparation of
6
7,8
aliphatic thioamides. Thioacids have been explored as
a source of hydrogen sulfide for this conversion but have
found only limited application. In contrast, thioacetamide
was found equally applicable to aliphatic and aromatic
6
hours (entry 8). In some cases, incomplete conversion of
nitrile to thioacetamide was achieved (entries 1,2). This
difference in conversion rate and yields reflects the well
known different behavior of aliphatic and aromatic ni-
triles in base-catalyzed reactions with hydrogen sul-
fide.1 To avoid loss of the volatile thioamides during
evaporation of the methanol–water reaction mixtures at
work-up, we attempted to use only methanol as the sol-
vent but this modification did not lead to improvement of
yields or to shortening of the reaction time.
9
nitriles as a source of hydrogen sulfide in a similar con-
version of nitriles under acidic conditions in N,N-dimeth-
ylformamide (saturated with dry hydrogen chloride).
,11
1
0a,b
Diphenylphosphinodithioic acid,
O,O-dialkyldithio-
and a new thionation reagent
P S )Na , prepared in situ by reaction of phosphorus
1
0c,d
phosphoric acid
1
0e
(
4
11
2
decasulfide and sodium sulfide, were also used for con-
version of nitriles to thioamides under mild conditions.
1
0f,g
Recently, a new method
was described for converting
Our method appears to be best suited for compounds con-
taining an aromatic ring and compounds that are insoluble
nitriles into thioamides by sodium trimethylsilanethiolate
in 1,3-dimethyl-2-imidazolidinone at room temperature
with yields of 27–80%.
6
in pyridine or in organic solvents such as benzene, 1,2-
dichlorobenzene, diphenyl ether etc. used for phase trans-
5
fer catalyzed reaction, such as nucleosides toyocamycin
and 5 -deoxy-5 -fluorotoyocamycin (entries 11,12). As an
alternative method to using high pressure hydrogen sul-
fide combined with heating of the nitrile in an alcoholic
solution in the presence of an alkali-metal hydrogen sul-
Synthesis 2002, No. 12, Print: 06 09 2002.
Art Id.1437-210X,E;2002,0,12,1649,1651,ftx,en;M01102SS.pdf.
2
©
Georg Thieme Verlag Stuttgart · New York
fide or an ammonium sulfide, the present method offers
ISSN 0039-7881

1
650
R. Liboska et al.
SHORT PAPER
Table 1 Preparation of Thioamides from Nitriles
Entry
1
R
Time (h)
Conv. (%)
Yielda
%)
Thioamide
mp (ºC)
Thioamide
Ref. mp (ºC)
(
CH (CH )
3
6
30–40
50–60
25
70–72
66–6712
3
2 6
2b
211–212 dec. 9
976
NCCH2
PhCH2
3
3
80
38
69
210–212 dec.
99–101
3
90–100
9
6–975,10f
1
3
4
5
BnO(CO)NHCH2
Ph
3
90–100
90–100
94
61
145–146
117–118
146.5–148
1
4
1
44–146
1
1
1
5
5
6
7
1.5
118–119
1
1
1
1
1
1
17–118
16–118
16–117
16
14–116
13–115
,18
6
1
1
9
0f
1
1
6
6
6
4-Cl-C H4
3
90–100
75
129–130
131–132
6
8
1
1
1
1
1
30–131
29–130
,15
1
9
27.5–129.5
1
5
0f,17
28–129
26–127
5
1
1
1
7
8
4-Me-C H4
3
6
90–100
80
67
80
169–170
148–149
169–170
6
7,19
8
1
1
1
68–169
66–168
65–167
0f
1
1
6
8
4-MeO-C H
151–152
6
4
1
1
1
1
1
49–151
9
48.5–149.5
48–149.5
19
6
,17
49
48–149
1
0f
1
1
5
9
2-pyridyl
3-pyridyl
3
3
90–100
90–100
91
93
138–139
190–192
136–137
0f
1
24–125
5
1
1
1
1
0
1
2
191–192
0f
5
1
1
1
90–192
90–191
83
6
4-amino-7-( -D-ribo-
furanosyl)-7H-pyr-
rolo[2,3-d]pyrimi-
dine-5-yl
2
90–100
90–100
96
96
235–238 dec.
135–138 dec.
238–24020
1
4-amino-7-(5-deoxy-5-fluoro- -D- 0.5
ribofuranosyl)-7H-pyrrolo [2,3-d]
pyrimidine-5-yl
235–238 dec. 21
a
Yield of isolated product.
b
Yield and mp of dithiomalonamide (mono- and di-thioamide in the mixture were observed confirmed by MS EI, mostly momo-derivative).
mild reaction conditions, a simple work-up and, in most The reaction of nitriles with hydrogen sulfide in the pres-
cases, high yields.
ence of an anion-exchange resin in polar solvent such as
water, methanol, ethanol or their mixtures under mild con-
ditions provides a convenient synthetic method for the
preparation of primary thioamides carrying various sub-
stituents.
No attempt has been made to optimize the yields which
are based on the introduced nitrile and are of pure isolated
products after chromatography or crystallization.
Synthesis 2002, No. 12, 1649–1651 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of Primary Thioamides
1651
1
cluding H NMR, MS (EI or FAB for nucleosides), IR spectra and
reported melting points.
Melting points were determined with a Mel-Temp capillary point
block and are uncorrected. The following instruments were used for
recording spectral data: IR; Perkin-Elmer 457 infrared spectropho-
1
tometer, H NMR; Varian 390 (90 MHz) spectrometer, MS; Es- Acknowledgement
quire-LC
(Bruker
Daltonics)
spectrometer.
Thin-layer
This investigation was aided in part by Core Grant CA16056 from
the National Cancer Institute.
chromatography was carried out using TLC aluminum sheets, Silica
gel 60 F254 (EM Science). Column chromatography was performed
on silica gel 60 (230–400 mesh; EM Science). Analytical samples
were dried over P O at 25 °C for 24 h. Evaporations were conduct-
ed on a vacuum rotary evaporator at bath temperatures below 30 ºC.
Dowex 1X8–400 (200–400 mesh) was purchased from Aldrich
Chem. Comp. Milwaukee, WI, USA. All reagents were of reagent
grade and purified prior to use. Nucleosides (entries 11,12) were ob-
tained by previously described procedures.21,22
2
5
References
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Dowex SH ; General Procedure
Dowex 1X8 Cl (10 mL) was washed with 2 M aq NaOH (100 mL)
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–
followed by washing with large amount of double distilled H O
2
–
(
200 mL) and stored (OH form) at 4 ºC in MeOH H O (20%).
2
–
Only the necessary amount of Dowex 1X8 OH was converted to
–
the SH form just before the experiment by washing with double
distilled H O (50 mL), suspending in H O (10 mL Dowex:100 mL
2
2
H O), and then by treating a gently stirred suspension with gaseous
2
–
hydrogen sulfide. The resulted Dowex 1X8 SH was filtered,
washed with double distilled H O (50 mL) and immediately used in
2
the next step.
Thioamides (Entries 1–12); General Procedure
The freshly prepared Dowex 1X8 SH (ca. 10 mL) was added to a
–
soln of nitrile (5 mmol) in a H O–MeOH mixture [2:3, 50 mL, nu-
2
cleoside derivatives were dissolved in a H O–EtOH, 1:1 (500 mL)
2
mixture]. A slow stream of hydrogen sulfide was introduced into the
gently stirred suspension at r.t. The progress of conversion was
monitored by TLC. Compounds were visualized by iodine vapors or
by a UV lamp for UV-light absorbing compounds. The resin was fil-
tered off and washed with MeOH (3 50 mL), the less soluble nu-
cleoside derivatives were washed from the resin with a hot mixture
of H O–EtOH (1:1, 3 × 150 mL) and malonothioamides were
2
washed with warm EtOH (3 × 50 mL). After evaporation of the sol-
vent from the mixture, the crystalline products (white needles for al-
iphatic or yellow needles for aromatic thioamides) were collected
by filtration (mostly in high yield and purity). Thioamides that did
not crystallize readily were isolated by washing the mixtures of wa-
ter and products with CH Cl (3 × 30 mL), drying the extracts with
(15) Pappalardo, G. C.; Gruttadauria, S. J. Chem. Soc., Perkin
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(19) Papadopoulos, E. P. J. Org. Chem. 1976, 41, 962.
2
2
anhyd Na SO , and subsequent careful (<30 ºC bath) evaporation of
2
4
the solvent.
(
(
(
20) Hinshaw, B. C.; Gerster, J. F.; Robins, R. K.; Townsend, L.
Thioamides (entries 1,2,3) were purified by flash column chroma-
tography on silica gel column (hexane–EtOAc, 5:1). The other thio-
amides were purified by crystallization from a mixture of EtOH–
H O or H O only. Analytical samples were recrystallized from the
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21) Sharma, M.; Li, Y. X.; Ledvina, M.; Bobek, M. Nucleosides
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2
2
22) Sharma, M.; Bloch, A.; Bobek, M. Nucleosides Nucleotides
appropriate solvents (heptane, toluene–heptane, toluene or MeOH–
H O, EtOH–H O, H O). The products were identical to authentic
1993, 12, 643.
2
2
2
samples as confirmed by comparing their physico-chemical data in-
Synthesis 2002, No. 12, 1649–1651 ISSN 0039-7881 © Thieme Stuttgart · New York