Facile one-pot synthesis of S-alkyl thiocarbamates

Article abstract of DOI:10.1021/jo026813i

We report a novel one-pot two-step synthesis of a variety of S-alkyl thiocarbamates. This method offers a two-directional approach making use of trichloroacetyl chloride, requires no complex starting material, incorporates a variety of substituents, and proceeds in high yields.

Full text of DOI:10.1021/jo026813i

of other methods; however, most require the preparation
of complex starting materials.15 Carbon monoxide and
elemental sulfur are frequently employed in such prepa-
rations; however, these methods involve multistep ap-
proaches which incorporate metal catalysts or proceed
in low yields.10,16 The most widely used method for
preparation of these compounds makes use of gaseous
carbonyl sulfide (COS), which condenses with a secondary
amine, followed by subsequent treatment with base and
an alkyl halide.8,17 Furthermore, production of many
other S-alkyl thiocarbamates have received considerable
attention in the patent literature.18
F a cile On e-P ot Syn th esis of S-Alk yl
Th ioca r ba m a tes
J ames H. Wynne,* Samuel D. J ensen, and
Arthur W. Snow
Chemistry Division, Naval Research Laboratory,
4555 Overlook Avenue, SW, Code 6120,
Washington, D.C. 20375
jwynne@ccs.nrl.navy.mil
Received December 6, 2002
Condensation of a thiol with an isocyanate affords the
corresponding thiocarbamate; however, this route was
only demonstrated when alkoxy and aroxysulfonyl iso-
cyanates were employed.6 Moreover, the hydration of a
variety of organic thiocyanates has been reported to
afford the desired compound in the presence of hydrogen
chloride; however, this method is limited to only N,N-
unsubstituted thiocarbamates.19,20 N,N-Disubstituted S-
alkyl thiocarbamates have also been prepared from salts
of dithiocarbamic acid, which are prepared by the addi-
tion of secondary amines to carbon disulfide (SCS).20
Despite numerous variations, there is no simple compre-
hensive synthetic approach for the facile preparation of
N-substituted, N,N-disubstituted, and N,N-unsubstituted
S-alkyl thiocarbamates.
While investigating various thiol-protecting groups, we
discovered that unique product formation occurs follow-
ing attempted deprotection of a trichloroacetylalkane
thiol adduct with an amine. Rather than achieving
deprotection, nucleophilic substitution resulted, affording
the corresponding S-alkyl thiocarbamate in high yield.
Therefore, we sought to develop an efficient one-pot
synthetic approach to S-alkyl thiocarbamates, which
would allow for direct control of character and degree of
substitution. It was likewise desirable to afford a library
of thiocarbamates through the use of commercially avail-
able reagents in a single straightforward, simple, high-
yielding process, employing less toxic materials and
preferably nongaseous reagents.
Abstr a ct: We report a novel one-pot two-step synthesis of
a variety of S-alkyl thiocarbamates. This method offers a
two-directional approach making use of trichloroacetyl
chloride, requires no complex starting material, incorporates
a variety of substituents, and proceeds in high yields.
S-Alkyl thiocarbamates (S-alkyl thiourethanes) are an
important class of compounds that have received consid-
erable attention in the literature.1,2 Such compounds are
of interest due to their numerous biological effects
including anesthetic,3 fungicidal,2,4 bactericidal,5,6 pesti-
cidal,7,8 and antiviral.9 Despite the aforementioned rea-
sons, these compounds are most noted for their use as
commercial herbicides.8,10,11
Many reports illustrate the intramolecular rearrange-
ment of various derivatives to afford S-alkyl thiocarbam-
ates; however, these rearrangements are extremely
limited in starting substrates.12 Transition-metal species
containing elements such as palladium,13 nickel,14 and
rhodium13b have also been employed to promote re-
arrangement and product formation. There are a variety
* To whom correspondence should be addressed. Fax: (202) 767-
0594.
(1) For review see: Walter, W.; Bode, K.-D. Angew. Chem., Int. Ed.
Engl. 1967, 6, 281-384.
(2) Erian, A. W.; Sherif, S. M. Tetrahedron 1999, 55, 7957-8024.
(3) Wood, T. F.; Gardner, J . H. J . Am. Chem. Soc. 1941, 63, 2741-
2742.
(4) Heyns, A. J .; Carter, G. A.; Rothwell, K.; Wain, R. L. Ann. Appl.
Biol. 1960, 57, 33. Watts, J . C. (du Pont) US Pat. 3265562; Chem. Abstr.
1966, 65, 12810.
The trichloroacetyl protecting group for alcohols and
amines can be introduced in high yield and easily cleaved
with ammonia or potassium hydroxide.21 It was believed
that nucleophilic substitution of trichloroacetyl chloride
(5) Bowden, K.; Chana, R. S. J . Chem. Soc., Perkin Trans. 2 1990,
2163-2166.
(6) Beji, M.; Sbihi, H.; Baklouti, A.; Cambon, A. J . Fluorine Chem.
1999, 99, 17-24.
(7) The Pesticide Manual, 9th ed.; Worthing, C. R., Ed.; British Crop
Protection Council: London, 1991.
(8) Chen-Hsien, W. Synthesis 1981, 622-623.
(15) Ottmann, G.; Hooks, H., J r. Angew. Chem., Int. Ed. Engl. 1966,
5, 250. Batey, R. A.; Yoshina-Ishii, C.; Taylor, S. D.; Santhakumar, V.
Tetrahedron Lett. 1999, 40, 2669-2672. Akiba, K.-Y.; Inamoto, N. J .
Chem. Soc., Chem. Commun. 1973, 13.
(16) Mizuno, T.; Nishiguchi, I.; Sonoda, N. Tetrahedron 1994, 50,
5669-5680.
(17) Tilles, H. J . Am. Chem. Soc. 1959, 81, 714-727. Reddy, T. I.;
Bhawal, B. M.; Rajappa, S. Tetrahedron Lett. 1992, 33, 2857-2860.
(18) (a) Maeda, T. (Kumiai Chemical Industry Co., Ltd.) DE Pat.
1817662; Chem. Abstr. 1970, 74, 12864. (b) Konnai, M.; Kamata, H.;
Kado, M. (Ihara Chemicals Co., Ltd.) US Pat. 3582314; Chem. Abstr.
1971, 75, 75215.
(19) Zil’berman, E. N.; Lazaris, A. Y. J . Gen. Chem. USSR 1963,
33, 1012-1014.
(20) Advanced Organic Chemistry, 5th ed.; Smith, M. B., March, J .,
Eds.; Wiley-Interscience: New York, 2001; Chapter 16.
(21) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; Wiley-Interscience: New York, 1999; Chapters 1 and
7.
(9) Goel, A.; Mazur, S. J .; Fattah, R. J .; Hartman, T. L.; Turpin, J .
A.; Huang, M.; Rice, W. G.; Appella, E.; Inman, J . K. Bioorg. Med.
Chem. Lett. 2002, 12, 767-770.
(10) Mizuno, T.; Nishiguchi, I.; Okushi, T.; Hirashima, T. Tetra-
hedron Lett. 1991, 32, 6867-6868.
(11) Chen, Y. S.; Schuphan, I.; Casida, J . E. J . Agric. Food Chem.
1979, 27, 709-712.
(12) Kwart, H.; Evans, E. R. J . Org. Chem. 1966, 31, 410-413.
Newman, M. S.; Karnes, H. A. J . Org. Chem. 1966, 31, 3980-3984.
Newman, M. S.; Hetzel, F. W. J . Org. Chem. 1969, 34, 3604-3606.
Hackler, R. E.; Balko, T. W. J . Org. Chem. 1973, 38, 2106-2109.
(13) (a) J ones, W. D.; Reynolds, K. A.; Sperry, C. K.; Lachicotte, R.
J .; Godleski, S. A.; Valente, R. R. Organometallics 2000, 19, 1661-
1669. (b) Kuniyasu, H.; Hiraike, H.; Morita, M.; Tanaka, A.; Sugoh,
K.; Kurosawa, H. J . Org. Chem. 1999, 64, 7305-7308. (c) Bo¨hme, A.;
Gais, H.-J . Tetrahedron: Asymmetry 1999, 10, 2511-2514.
(14) J acob, J .; Reynolds, K. A.; J ones, W. D.; Godleski, S. A.; Valente,
R. R. Organometallics 2001, 20, 1028-1031.
10.1021/jo026813i CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/05/2003
J . Org. Chem. 2003, 68, 3733-3735
3733

TABLE 2. Su m m a r y of Rea ction s Sta r tin g w ith
Dieth yla m in e (4)
SCHEME 1
entry
thiol
T (°C)
time (h)
product
yield (%)
1
2
3
1d
1f
1h
60
100
80
4
8
6
3d
3f
3h
59
63
54
as further illustrated in Scheme 1. While this sequence
was successful, it did have several limitations. The
addition of amine (4) to the solution of trichloroacetyl
chloride must be done at a reduced temperature and at
a slow rate to prevent amine salt formation (Table 2).
Also, the use of a solvent system was necessary to allow
control of the rate of reaction. Subsequent treatment of
(5) with the corresponding thiol (1) affords compound (3),
with a substantially decreased yield combined with a
significantly increased reaction time.
TABLE 1. Su m m a r y of Rea ction s Sta r tin g w ith Th iol
(1)
S-
time
(h) (°C) (%)
T
yield
entry thiol
R1
ester R2 R3 prod
1
2
3
4
5
6
7
8
1a nC6H13
1a nC6H13
1a nC6H13
1a nC6H13
1b Ph-
1b Ph-
1c pClPhCH2- 2c
1c pClPhCH2- 2c
-
-
-
-
2a
2a
2a
2a
2b
2b
H
H
H
H
3a
.25 rt
.25 rt
.25 rt
rt
100
87
83
94
98
90
99
91
nBu 3b
tBu
3c
3d
3e 12
3f
3g
3h
Et Et
H
Et Et
H
1
H
60
Exp er im en ta l Section
12
4
4
60
60
60
H
Gen er a l Meth od s. Methanol was distilled from calcium
hydride under nitrogen. Moisture-sensitive reactions were con-
ducted in oven-dried glassware under a nitrogen atmosphere
unless otherwise noted. Analytical thin-layer chromatography
was performed on precoated silica gel sheets, and flash column
chromatography was accomplished using silica gel, 60 Å (200-
400 mesh). External elemental analyses were performed by
Atlantic Microlab, Inc., Norcross, GA 30091. All melting points
are uncorrected. Unless otherwise noted, 1H and 13C NMR
spectra were taken in CDCl3 at 300 and 75 MHz, respectively,
with a TMS internal standard. Chemical shifts are reported in
units downfield from TMS. Coupling constants, J , are reported
in units of hertz (Hz).
Et Et
with a variety of thiols would result in the corresponding
thioesters (Scheme 1). Reaction of 1 equiv of thiol (1) with
an excess of trichloroacetyl chloride, in a solventless
system, afforded an exothermic reaction that proceeded
to completion within 45 min or less in all cases. The
product was purified by heating the resulting mixture
in the same reaction vessel under vacuum to facilitate
the removal of excess trichloroacetyl chloride and residual
hydrogen chloride, affording the corresponding pure
product 2 in quantitative yields.
The formation of compound 2 proceeded rapidly with-
out solvent, with an observed rate of consumption of the
thiol in the order of alkyl > benzyl . phenyl. Reaction
with the alkanethiol was complete within 15 min, whereas
the benzyl thiol required 30 min and the phenyl deriva-
tive required approximately 45 min to achieve complete
conversion. Lesser reaction times resulted in significantly
diminished yields.
The second step involves the displacement of the
trichloromethyl group by a haloform displacement upon
treatment with an amine. A variety of compounds can
be synthesized from a single intermediate (2) by simply
altering the amine employed. Ammonium hydroxide, a
variety of primary amines, and a secondary amine are
used to illustrate the versatility of this method (Table
1). Several solvent systems were also investigated rang-
ing from neat to extremely polar. When concentrated
ammonium hydroxide was employed, the water-insoluble
product was easily isolated by filtration. When substi-
tuted amines were employed in neat, aqueous, and
methanolic systems, respectively, the methanolic system
afforded the highest yields, while aqueous media afforded
only trace product formation due to amine insolubility.
Our results indicated that primary amines function best
in solventless systems, while secondary amines work best
in methanolic solvent systems. Products were purified
by simple recrystallization, distillation, or column chro-
matography.
Gen er a l P r oced u r e for P r ep a r a tion of 2 fr om 1. A 3.08
g (16.9 mmol) quantity of chilled trichloroacetyl chloride was
transferred into a 25 mL round-bottomed flask equipped with
magnetic stir bar and a drying tube. After the mixture was
warmed to room temperature, the dropwise addition of thiol (1)
(8.46 mmol) was made via a syringe over a period of 15 min.
The mildly exothermic reaction was stirred for 2 h, followed by
distillation (120 °C/5 mmHg) of excess reagent and byproducts,
leaving a quantitative yield of the product (2). Additional
purification was not necessary for subsequent reactions.
Tr ich lor oth ioa cetic Acid S-Hexyl Ester (2a ). FTIR: 2961,
2929, 2851, 1693, 1467, 1035, 857, 785, 750, 619 cm-1. 1H NMR
δ: 3.04 (t, J ) 6, 2H), 2.68 (dt, 2H), 1.48-1.27 (m, 6H), 0.92 δ
(t, J ) 6, 3H). 13C NMR δ: 189.3, 94.9, 31.7, 31.2, 28.5, 28.4,
22.4, 13.9 δ. Bp: 137 °C/1 Torr (lit.22 bp 104 °C/0.4 Torr).
Tr ich lor oth ioa cetic Acid S-P h en yl Ester (2b). FTIR:
3420, 3061, 1705, 1479, 1447, 1095, 1023 cm-1 1H NMR δ:
.
7.46-7.46 δ (m, 5H). 13C NMR δ: 187.7, 134.7, 130.5, 129.7,
125.9, 94.1. Mp: 55-57 °C (lit.23 mp 53-55 °C; bp 115-118 °C/1
Torr).
Tr ich lor oth ioa cetic a cid S-(4-Ch lor oben zyl) Ester (2c).
FTIR: 3029, 2977, 2930, 1776, 1689, 1594, 1487, 1408, 1241,
1198, 1099, 1039, 1011, 852, 781, 745, 690 cm-1 1H NMR δ:
.
7.31-7.25 (m, 4H), 4.18 δ (s, 2H). 13C NMR δ: 188.5, 133.8,
133.6, 130.3, 129.1, 94.4, 35.3. Anal. Calcd for C9H6Cl4OS: C,
35.56; H, 1.99. Found: C, 35.89; H, 1.96.
Gen er a l P r oced u r e for P r ep a r a tion of 3 fr om 2. A
solution of trichlorothioacetic ester (2) (1.90 mmol) in 10 mL of
methanol was prepared in
a 50 mL round-bottomed flask
equipped with magnetic stirring bar, thermometer, and N2 inlet.
(22) Kuliev, A. M.; Zeinalova, G. A.; Kuliev, A. B.; Hasanov, M. S.
Neftekhimiya 1971, 11, 906-910.
(23) Talley, J . J . Synthesis 1981, 7, 549-549. Shchepin, V. V.;
Efremov, D. I.; Desyatkov, D. A. Russ. J . Org. Chem. (Eng.) 1993, 29,
342. Ward, L. F., J r.; Whetstone, R. R.; Pollard, G. E.; Phillips, D. D.
J . Org. Chem. 1968, 33, 4470-4475.
In an attempt to examine alternative routes, we
reversed the order of thiol and amine reagent addition
3734 J . Org. Chem., Vol. 68, No. 9, 2003

After the mixture was stirred for 5 min at rt, 3.80 mmol of the
corresponding amine was rapidly added. The reaction was
rapidly stirred at the indicated temperature for 24 h (see Table
1). The reaction was worked up by concentration to dryness on
the rotary evaporator followed by distillation employing the
short-path distillation head to remove excess reagent and
byproducts. Additional purification was made by either recrys-
tallization or flash column chromatography for the aryl com-
pounds. Yields ranged from 70 to 97%.
Th ioca r ba m ic Acid S-(4-Ch lor oben zyl) Ester (3g).
1
FTIR: 3176, 3025, 1657, 1486, 1408, 1328, 1091, 329 cm-1. H
NMR δ: 7.89 (bs, 2NH), 7.41 (d, J ) 7, 2H), 7.33 (d, J ) 7, 2H),
3.78 δ (s, 2H). 13C NMR δ: 205.4, 135.3, 131.9, 129.9, 127.5,
40.8. Mp: 130-133 °C (lit.28 mp 137-139 °C).
Dieth ylth iocar bam ic Acid S-(4-Ch lor oben zyl) Ester (3h ).
FTIR: 3017, 2977, 2819, 1657, 1491, 1368, 1206, 1091, 1015
1
cm-1. H NMR δ: 7.28 (d, J ) 6, 2H), 7.15 (d, J ) 6, 2H), 3.67
(s, 2H), 3.07 (q, J ) 6, 4H), 1.40 δ (t, J ) 6, 6H). 13C NMR δ:
168.0, 134.8, 131.7, 129.6, 127.3, 42.1, 36.3, 10.2 δ. Mp: 161-
164 °C. FTIR and NMR data are in agreement with that
previously reported.27,29
Th ioca r ba m ic Acid S-Hexyl Ester (3a ). FTIR (neat): 3366,
1
3326, 3247, 2971, 2943, 2589, 1653 cm-1. H NMR δ: 6.62 (bs,
1NH), 6.08 (bs, 1NH), 2.65 (t, J ) 7, 2H), 1.63-1.59 (m, 4H),
1.27-1.16 (m, 4H), 0.86 δ (t, J ) 7, 3H). 13C NMR δ: 163.6,
39.2, 31.4, 29.2, 28.2, 22.2, 14.0. Mp: 99-102 °C (lit.24 mp 105
°C).
2,2,2-Tr ich lor o-N,N-d iet h yla cet a m id e (5). A solution of
1.00 g diethylamine (13.67 mmol) in 20 mL methanol was
prepared in a 50 mL two-necked round-bottomed flask equipped
with a stirring bar, thermometer, nitrogen inlet, condenser, and
septum. After the mixture was cooled to 0 °C and stirred for 10
min, 4.97 g of trichloroacetyl chloride (27.34 mmol) was added
dropwise via syringe over a 45 min, followed by stirring under
the indicated conditions. The reaction was worked up by
concentration to dryness through a short path still head, diluting
the residual product with CH2Cl2 (30 mL), and washing with
water (3 × 10 mL). The organic layer was dried over MgSO4
and concentrated under reduced pressure. The crude product
was purified by flash column chromatography (hexane/EtOAc)
to afford the desired product (5) in a 45% yield. FTIR: 2989,
2937, 1708, 1519, 1455, 1364, 1268, 12114, 912, 821, 733, 682
n -Bu tylth ioca r ba m ic Acid S-Hexyl Ester (3b). FTIR:
3308, 2958, 2926, 1651, 1523, 1463, 1463, 1372, 1150, 921 cm-1
.
1H NMR δ: 8.20 (bs, 1NH), 3.03 (t, J ) 6, 2H), 2.69 (t, J ) 6,
2H), 1.82-1.65 (m, 2H), 1.62-1.57 (m, 4H), 1.47-1.29 (m, 6H),
0.96 (t, J ) 6, 3H), 0.90 δ (t, J ) 6, 3H). 13C NMR δ: 164.3,
44.7, 39.5, 38.8, 30.9, 29.2, 27.9, 22.2, 19.5, 13.7, 13.2. Mp: 142-
148 °C dec. FTIR and NMR data are in agreement with that
previously reported.25
t-Bu t ylt h ioca r b a m ic Acid S-H exyl E st er (3c). FTIR
(neat): 2958, 2922, 2858, 1667, 1450, 1265 cm-1 1H NMR δ:
.
5.80 (bs, 1NH), 2.268 (t, J ) 7, 2H), 1.77-1.54 (m, 4H), 1.40 (s,
9H), 1.32-1.29 (m, 4H), 0.89 δ (t, J ) 6, 3H). 13C NMR δ: 163.0,
67.0, 52.4, 39.1, 31.4, 31.3, 29.0, 22.7, 14.0. Mp: 212-124 °C.
Anal. Calcd for C11H23NOS: C, 60.78; H, 10.66; N, 6.44. Found:
C, 60.84; H, 10.37; N, 6.79.
1
cm-1. H NMR δ: 3.77 (q, J ) 6, 4H), 1.15 δ (t, J ) 6, 6H). 13C
NMR δ: 160.3, 93.1, 52.8, 25.4 δ. Bp: 79 °C/2 Torr (lit.30 bp 109
°C/Torr).
Dieth ylth ioca r ba m ic Acid S-Hexyl Ester (3d ). FTIR:
Gen er a l P r oced u r e for P r ep a r a tion of 3 fr om 5. A
solution of 1.00 g of compound 5 (4.58 mmol) in 15 mL of freshly
distilled THF was prepared in a 50 mL round-bottomed flask.
After the mixture was stirred at rt for 15 min, thiol (1) (6.86
mmol) was added dropwise via syringe over 15 min. The reaction
was refluxed for 4 h followed by 12 h of stirring under nitrogen.
The reaction mixture was diluted with CH2Cl2 (30 mL) and
washed with water (3 × 10 mL). The organic layer was dried
over MgSO4 and concentrated under reduced pressure to afford
a brown oil. Subsequent purification ensued employing flash
column chromatography to afford the desired product (3).
1
2969, 2819, 2794, 1646, 1487, 1372, 1205, 1094, 1011 cm-1. H
NMR δ: 3.05 (q, J ) 6, 4H), 2.68 (t, J ) 6, 2H), 1.70-1.48 (m,
2H), 1.43 (t, J ) 6, 6H), 1.41-1.35 (M, 2H), 1.30-1.15 (m, 4H),
0.89 δ (t, J ) 6, 3H). 13C NMR δ: 162.7, 42.1, 38.5, 30.8, 28.7,
27.8, 22.1, 13.8, 12.1. Mp: 64-66 °C. Anal. Calcd for C11H23
-
NOS: C, 60.78; H, 10.66; N, 6.44. Found: C, 60.98; H, 10.36; N,
6.68.
Th ioca r ba m ic Acid S-P h en yl Ester (3e). FTIR: 3648,
1
3623, 3068, 2984, 1687, 1574, 1475, 1435, 1071, 1019 cm-1. H
NMR (acetone-d6) δ: 9.97 (bs, 2NH), 7.51 (d, J ) 6, 2H), 7.36 (t,
J ) 6, 2H), 7.23 δ (d, J ) 7, 1H). 13C NMR (acetone-d6) δ: 176.3,
128.9, 127.3, 127.0, 127.0, 126.8. Mp: 98-100 °C (lit.26 mp 96-
98 °C).
Ack n ow led gm en t. The Office of Naval Research is
greatly acknowledged for financial support.
Dieth ylth ioca r ba m ic Acid S-P h en yl Ester (3f). FTIR:
2973, 2819, 2775, 2482, 2391, 1657, 1483, 1360, 1210, 1063 cm-1
.
J O026813I
1H NMR δ: 9.39 (bs, 1NH), 7.43 (d, J ) 6, 2H), 7.27-7.22 (m,
3H), 2.97 (q, J ) 6, 4H), 1.38 δ (t, J ) 6, 6H). 13C NMR 168.7,
133.2, 130.3, 128.9, 128.1, 42.20, 11.1. Mp: 46-49 °C. FTIR and
NMR data are in agreement with that previously reported.27
(27) Mizuno, T.; Nishiguchi, I.; Hirashima, T. Tetrahedron 1993, 49,
2403-2412.
(28) Ishikawa, K.; Okuda, I.; Kuwatsuka, S. Agric. Biol. Chem. 1973,
37, 165-173.
(24) Riemschneider, R. Monatsh. Chem. 1953, 84, 1228-1233.
(25) Kochansky, J .; Feldmesser, J . J . Nematol. 1989, 21, 158-163.
(26) Lewis, E. S.; Cooper, J . E. J . Am. Chem. Soc. 1962, 84, 3847-
3852. Riemschneider, R.; Wojahn, F.; Orlick, G. J . Am. Chem. Soc.
1951, 73, 5905-5907.
(29) Kodama, S.; Yamamoto, A.; Matsunaga, A. J . Agric. Food.
Chem. 1997, 45, 990-994. Mizuno, T.; Nishiguchi, I.; Sonoda, N.
Tetrahedron 1994, 50, 5669-5680.
(30) Bergmann, F.; Haskelberg, L. J . Am. Chem. Soc. 1941, 63,
1437-1439.
J . Org. Chem, Vol. 68, No. 9, 2003 3735