A convenient method for the preparation of primary and symmetrical N,N'-disubstituted thioureas

Article abstract of DOI:10.1055/s-2000-7607

A convenient process for the preparation of both primary thioureas 2 and symmetrical N,N'-disubstituted thioureas 6 based on the condensation of amine hydrohalides 5 with potassium thiocyanate has been developed. This approach tolerates sterically bulky primary amine substrates (both chiral and achiral), and the products can usually be isolated by a simple filtration of the reaction mixture. This method is an especially attractive alternative for the synthesis of thioureas when the corresponding isothiocyanates are unavailable, or difficult to prepare. It is also worth noting that a wide variety of amine hydrohalides, which are used in this procedure, are commercially available.

Full text of DOI:10.1055/s-2000-7607

PAPER
1569
A Convenient Method for the Preparation of Primary and Symmetrical
N,N’-Disubstituted Thioureas
R. Jason Herr, J. Louise Kuhler, Harold Meckler,* Chester J. Opalka
Chemical Development Department, Albany Molecular Research, Inc., Albany, New York 12203, USA
Fax +1(518)4640289; E-mail: hmeckler@albmolecular.com
Received 8 November 1999; revised 15 May 2000
to primary thioureas 28 or by addition of amines to N-sub-
stituted isothiocyanates 4.9 Other methods for the direct
preparation of symmetrical and unsymmetrical bis-substi-
tuted thioureas also have been reported.10-11
Abstract: A convenient process for the preparation of both primary
thioureas 2 and symmetrical N,N’-disubstituted thioureas 6 based
on the condensation of amine hydrohalides 5 with potassium thio-
cyanate has been developed. This approach tolerates sterically
bulky primary amine substrates (both chiral and achiral), and the
products can usually be isolated by a simple filtration of the reaction
mixture. This method is an especially attractive alternative for the
synthesis of thioureas when the corresponding isothiocyanates are
unavailable, or difficult to prepare. It is also worth noting that a
wide variety of amine hydrohalides, which are used in this proce-
dure, are commercially available.
A common method for the preparation of primary thio-
ureas has made use of ammonium thiocyanate (NH4SCN),
which undergoes thermal rearrangement to produce thio-
urea in situ (Scheme 1).1a,8a This intermediate then reacts
with amines in a variety of solvents, including water,12 to
eliminate ammonia gas and provide primary thioureas.
While these few scattered reports have shown that prima-
ry thioureas can be made by the condensation of aniline
hydrochlorides with ammonium thiocyanate,1a,8 a general
method was never published with regard to the prepara-
tion of primary aliphatic thioureas from the corresponding
hydrohalide with alkali thiocyanate. Interestingly, two
different groups found that the reaction of aliphatic am-
monium chlorides with ammonium thiocyanate to provide
imidazoline thiones did result in large amounts of primary
thioureas as byproducts, but were never investigated for
this purpose.13
Key words: primary thioureas, symmetrical thioureas, potassium
thiocyanate, amine hydrohalide
Over the last few years, the thiourea moiety has been of
interest as a structural modification to molecules designed
as receptor antagonists, as natural product mimics, or as
synthetic intermediates to amidines or guanidines.1 Often
the construction of primary thioureas 2 has been achieved
by the reaction of primary amines 1 with alkali metal thio-
cyanates in the presence of acid,2 or by the addition of am-
monia to separately prepared isothiocyanates 43 (Scheme
1). The preparation of isothiocyanates, however, typically
requires the use of thiophosgene,4 carbon disulfide,5 chlo-
rothioformates,6 or thiocarbamoyl chlorides.7 These nox-
ious reagents make isothiocyanates somewhat difficult or
less than pleasant to prepare.
S
KSCN
N
NH2
H
THF, reflux
NH2•HCl
R
2
R
S
5
S
S
KSCN
R2 NH2
N
N
MSCN
H2SO4
R1
R1
R2
H
H
R1 NH2
xylenes
reflux
N
NH2
N
H
N
H
∆
H
R
R
6
1
2
3
Synthesis of Primary and Symmetrical Thioureas from Amine
Hydrohalides
S
CS2
R2 NH2
base
R1 NH2
R1
N C S
R1
R2
N
H
N
H
∆
Scheme 2
4
3
1
S
NH4SCN
S
In our efforts to prepare multi-gram quantities of a prima-
ry thiourea for small manufacturing purposes, we attempt-
ed the reaction of a benzylamine with ammonium
thiocyanate. Due to the large volume of ammonia off-gas,
we soon decided to investigate the reaction of this amine
with potassium thiocyanate (KSCN), which would pro-
vide potassium halide as a benign side product. After a bit
of experimentation, we ultimately found that our substi-
tuted benzylamine hydrochloride 5, isolated as the salt
during the purification of a previous synthetic manipula-
1 +
R1 NH2
R1
N
NH2
∆
-NH3
H2N
NH2
H
1
2
Synthesis of Unsymmetrical Thioureas 3
Scheme 1
Similarly, the preparation of unsymmetrical disubstituted
thioureas 3 has typically involved the addition of amines
Synthesis 2000, No. 11, 1569–1574 ISSN 0039-7881 © Thieme Stuttgart · New York

1570
R. J. Herr et al.
PAPER
tion, could be reacted with potassium thiocyanate in re-
fluxing toluene to afford primary thiourea 2 in good yield
(Scheme 2). Part of our initial approach was designed to
drive off the significant levels of water contained in com-
mercially available potassium thiocyanate, due to the in-
solubility of the amine substrate and the product thiourea
in wet toluene. In fact, we later found that the removal of
the excess water by means of a Dean-Stark trap was re-
quired to drive the process to completion. Interestingly,
when we sought to accelerate this operation by heating of
the reaction mixture at reflux in xylene, a significant
amount of the disubstituted byproduct 6 was observed.
When this reaction was subjected to prolonged heating,
even more of this byproduct was produced. The symmet-
rical product 6 could be readily formed preferentially
when two equivalents of the amine hydrochloride were
used.
Table 1 Primary Thioureas 2 from Amine Hydrohalides 5
Primary Thioureas 2
Entry
Amine
Hydrohalides 5
(yield, %)a,b
H3C
H3C
S
1
NH2
NH2•HCl
N
H
2a (74%)
5a
5b
Br
Br
S
2
NH2
NH2•HCl
NH2•HCl
N
H
2b (96%)
In order to test the scope of this process for the general
preparation of both primary and disubstituted thiourea
products, we reacted a series of commercially available
aniline hydrochlorides and alkylamine hydrohalides with
potassium thiocyanate under reflux conditions in several
solvent systems. The results of this study are reported in
Tables 1 and 2. It was found that the reaction of amine hy-
drohalides 5 with one equivalent of potassium thiocyanate
was most effective in refluxing THF, providing excellent
yields of primary thioureas 2a-h. In most cases, the pure
primary thioureas could be isolated by an aqueous quench
and precipitation, eliminating the need for further purifi-
cation. For the efficient construction of several N,N’-dis-
ubstituted thioureas 6, it was necessary to react the
substrates 5 with potassium thiocyanate in a 2:1 molar ra-
tio. As a result, condensation of these reagents in reflux-
ing xylene consistently provided symmetrical products
6a-h in good yields. In some of these latter cases, howev-
er, flash column chromatography of the crude reaction
residue was necessary to achieve pure samples for full
characterization. It should be mentioned that during the
course of the development of this method, a paper by a
team of Romanian chemists surfaced in which a benzylic
amine hydrochloride was reacted with KSCN in refluxing
methanol to provide a primary thiourea.14 Interestingly,
this observation was not pursued to the eventual develop-
ment of a method surrounding this discovery.
S
NH2
N
H
3
2c (91%)
5c
S
4
5
EtO2C
N
H
NH2
EtO2C
NH2•HCl
5d
5e
2d (84%)
S
NH2•HBr
NH2
N
H
2e (86%)
S
6
NH2•HCl
N
H
NH2
2f (76%)
5f
S
NH2
N
NH2•HCl
In conclusion, this methodology extends the scope of a lit-
tle-known method for the formation of primary aryl thio-
ureas to the preparation of various alkyl primary thioureas
with potassium thiocyanate. In addition, this method pro-
vides a more environmentally friendly process for the di-
rect manufacture of symmetrical disubstituted thioureas
with benign side products and with overall greater atom
economy. This approach tolerates sterically bulky prima-
ry amine substrates, and the products can usually be iso-
lated by a simple filtration of the reaction mixture.
Products which would typically be insoluble in water
(e.g., 2f, 6f) are also available by this protocol. This meth-
od is an attractive alternative to the synthesis of thioureas
when the corresponding isothiocyanates are unavailable
H
7
N
N
H
H
5g
2g (73%)
CH3
NH2•HCl
CH3
S
N
H
NH2
8
5h
2h (87%)
a Isolated yields.
b Method: 1 equiv 5, 1 equiv KSCN, THF, reflux.
Synthesis 2000, No. 11, 1569–1574 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Convenient Method for the Preparation and Symmetrical N,N’-Disubstituted Thioureas
Table 2 Symmetrical Disubstituted Thioureas 6 from Amine Hydrohalides 5
1571
Symmetrical Thioureas 6
Amine
Hydrohalides 5
Entry
(yield, %)a,b
H3C
H3C
CH3
S
1
NH2•HCl
N
N
H
H
5a
6a (69%)
Br
Br
Br
S
2
3
N
N
NH2•HCl
NH2•HCl
H
H
5b
6b (66%)
S
N
N
H
H
5c
6c (86%)
S
4
5
EtO2C
N
N
CO2Et
EtO2C
NH2•HCl
NH2•HBr
H
H
5d
6d (69%)
S
N
N
H
H
5e
5f
6e (66%)
S
6
N
H
N
H
NH2•HCl
NH2•HCl
6f (89%)
S
N
H
N
H
7
N
H
N
N
H
H
5g
6g (96%)
CH3
NH2•HCl
CH3
CH3
S
8
N
N
H
H
5h
6h (90%)
a Isolated yields.
b Method: 2 equiv 5, 1 equiv KSCN, xylene, reflux.
Synthesis 2000, No. 11, 1569–1574 ISSN 0039-7881 © Thieme Stuttgart · New York

1572
R. J. Herr et al.
PAPER
Table 3 Selected Physical and Spectral Data of Primary Thioureas 2
Entry
Yield (%)
74
1H NMR (CDCl3 or DMSO-d6), d,
J (Hz), 300 MHz
13C NMR (CDCl3 or
DMSO-d6), d, 75 MHz
IR (KBr) n (cm−1)
Reference
2a
2.37 (s, 3 H), 6.04 (s, 2 H) , 7.12 (d,
J = 10.1, 2 H), 7.24 (d, J = 10.1, 2 H),
7.81 (s, 1 H)
20.5, 123.3, 129.2,
133.6, 136.6, 181.1
3439, 3276, 3168,
1614, 1535, 1466,
1241, 804, 557, 501
2d, 1b
2b
96
6.05 (s, 2 H), 7.14 (d, J = 10.2, 2 H),
7.21 (d, J = 10.2, 2 H), 7.62 (s, 1 H)
116.4, 124.7, 131..3,
138.7, 181.2
3409, 3307, 3166,
1621, 1528, 1486,
817, 508
15a, 16
2c
91
84
4.61 (s, 2 H), 6.12 (s, 2 H), 7.17-7.42
42.3, 128.5, 128.6,
128.8, 133.9, 176.1
3404, 3239, 3178,
1622, 1491, 748, 697
15a, 17
18
(m, 6 H)
2d
1.30 (t, J = 7.3, 3 H), 4.23 (q, J = 7.3,
2 H), 4.26 (s, 2 H), 6.06 (s, 2 H), 7.10
(s, 1 H)
14.1, 45.6, 60.3, 169.9,
182.1
3412, 3322, 3200,
1726, 1628, 1444,
1224, 1018, 960
2e
2f
86
76
73
87
0.81-1.91 (m, 10 H), 3.72 (m, 1 H),
23.9, 24.8, 30.6, 49.6,
130.7
3349, 3240, 3179,
2939, 1619, 1508,
1446, 1238
17a, 19
20
6.72 (s, 2 H), 7.32 (s, 1 H)
1.54-1.68 (m, 8 H), 2.09-2.50 (m,
7 H), 6.50 (s, 2 H), 7.78 (s, 1 H)
28.3, 35.0, 38.9, 51.0,
164.4
3403, 3320, 3111,
1613, 1514, 1451,
1372
a
2g
2h
2.81-3.02 (m, 4 H), 6.50 (s, 2 H), 6.91-
7.87 (m, 7 H)
23.0, 109.4, 111.4,
118.3, 121.0, 123.2,
126.8, 136.2, 172.1
3301, 3294, 1506,
1458, 744, 668
-
1.48 (d, J = 7.1, 3 H), 2.04 (s, 1 H),
4.48 (q, J = 7.2, 1 H), 6.11 (s, 2 H),
7.31-7.42 (m, 5 H)
24.8, 51.7, 124.2, 126.1,
129.0, 148.9, 180.2
3365, 3281, 1451,
861, 763, 700, 591
21, 22
a C11H13N3S (219.3): calcd C, 60.24; H, 5.97; N, 19.16; found C, 60.48; H, 6.02; N, 18.87.
Table 4 Selected Physical and Spectral Data of Symmetrical Disubstituted Thioureas 6
Entry
Yield (%)
69
1H NMR (CDCl3 or DMSO-d6), d,
J (Hz), 300 MHz
13C NMR (CDCl3 or
DMSO-d6), d, 75 MHz
IR (KBr) n (cm−1)
Reference
15a, 23
6a
2.35 (s, 6 H), 7.42 (d, J = 10.1, 4 H),
7.63 (d, J = 10.1, 4 H), 10.11 (s, 2 H)
20.5, 123.8, 128.8,
133.5, 136.8, 179.6
3348, 3150, 1558,
1250,
812, 704, 532
6b
6c
6d
66
86
69
7.44 (d, J = 10.2, 4 H), 7.62 (d, J =
10.2, 4 H), 10.21 (s, 2 H)
116.5, 125.6, 131.2,
138.7, 179.6
3378, 3209, 3190,
1534, 1486, 822, 722
10a, 24
10a, 11g, 25
26
4.60 (s, 4 H), 7.13-7.45 (m, 10 H),
10.06 (s, 2 H)
56.6, 136.4, 136.8,
137.8, 148.9, 192.7
3290, 3109, 1556,
1454, 741, 698
1.29 (t, J = 7.3, 6 H), 4.24 (q, J = 7.3,
4 H), 4.56 (s, 4 H), 8.25 (s, 2 H)
13.9, 41.3, 61.1, 172.0,
182.5
3305, 3184, 1765,
1540, 1428, 1227,
898, 691
6e
6f
66
89
96
0.92-1.41 (m, 12 H), 1.67-1.82 (m,
22.0, 22.7, 28.5, 47.7,
129.1
3304, 3140, 2939,
1508, 1439, 1019
27
28
29
8 H), 3.14 (m, 2 H), 8.81 (s, 2 H)
1.65-1.83 (m, 16 H), 1.94-2.19 (m,
14 H), 8.80 (s, 2 H)
30.5, 36.6, 41.7, 53.1,
126.2
3412, 3310, 1613,
1514, 1452, 812
6g
2.85-3.17 (m, 10 H), 6.90-7.61 (m,
10 H), 8.75 (s, 2 H)
23.1, 109.3, 111.5,
118.0, 121.1, 123.4,
126.8, 136.3
3391, 3333, 3207,
1618, 1505, 1458,
745
6h
90
1.56 (d, J = 7.1, 6 H), 2.14 (s, 2 H),
4.28 (q, J = 7.2, 2 H), 7.34-7.47 (m,
10 H)
25.9, 51.8, 60.3, 126.5,
127.4, 129.3, 148.2,
180.4
3364, 3328, 3026,
1452, 764, 701, 591
30
Synthesis 2000, No. 11, 1569–1574 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Convenient Method for the Preparation and Symmetrical N,N’-Disubstituted Thioureas
1573
Crider, A. M. J. Med. Chem. 1998, 41, 4693.
or difficult to prepare. A wide variety of amine hydroha-
lides are commercially available for use in this process.
(e) Walpole, C.; Ko, S. Y.; Brown, M.; Beattie, D.; Campbell,
E.; Dickenson, F.; Ewan, S.; Hughes, G. A.; Lemaire, M.;
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1999, 7, 761.
Reagents and solvents were used as received from commercial ven-
dors, and no further attempts were made to purify or dry these items.
TLC was performed using 1” î 3” Analtech GF 350 silica gel
plates with fluorescent indicator. TLC plates were visualized with
either iodine vapors or UV light. Column chromatography was per-
formed on silica gel (Merck, 70-230 mesh). 1H and 13C NMR spec-
tra were recorded on a Bruker AC 300 MHz Nuclear Magnetic
Resonance Spectrometer, using either CDCl3 or DMSO-d6 as sol-
vent with TMS as an internal reference. Melting points were ob-
tained using an Electrothermal melting point apparatus and are
uncorrected. IR were obtained as KBr pellets and obtained on a Per-
kin-Elmer Spectrum 1000 FT-Infrared Spectrophotometer. Low
resolution mass spectroscopic analyses were performed on a Shi-
madzu QP-5000 GC/Mass Spectrometer (CI, methane) by direct in-
sertion. Elemental analyses were performed by Quantitative
Technologies Inc., Whitehouse, NJ.
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Primary Thioureas 2a-h; p-Tolylthiourea (2a); Typical Proce-
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(b) Moore, M. L.; Crossley, F. S. Org. Synth. 1955, Collect.
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(c) See also: Cressman, W. J. Org. Synth. 1955, Collect. Vol.
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To a magnetically stirred solution of 5a (10.0 g, 69.6 mmol) in THF
(150 mL) was added KSCN (10.1 g, 104 mmol). The mixture was
heated at reflux for 24 h at which point TLC analysis (1:1 EtOAc/
hexane) indicated the complete consumption of the starting materi-
al. The mixture was diluted with H2O (100 mL) and extracted with
EtOAc (2 î 100 mL). The interfacial solids and EtOAc extracts
were combined and washed with 1 N HCl (100 mL) and brine
(50 mL). The organic layer was dried (Na2SO4) and concentrated
under reduced pressure to afford 8.6 g of 2a as a yellow solid (74%);
mp 181-185 ∞C (Lit.2d,1b mp 188-189 ∞C) (Tables 1 and 3).
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Symmetrical Disubstituted Thioureas 6a-h; N, N’-Bis(p-
tolyl)thiourea (6a); Typical Procedure
(b) Itoh, K.; Lee, I.K.; Matsuda, I.; Sakai, S.; Ishii, Y.
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To a stirred solution of 5a (5.0 g, 34.8 mmol) in xylenes (100 mL)
was added KSCN (1.6 g, 16.6 mmol). The solution was heated at re-
flux for 24 h at which point TLC analysis (1:1 EtOAc/hexane) indi-
cated the complete consumption of the starting material. The
mixture was cooled to r.t., diluted with H2O (100 mL) and extracted
with EtOAc (2 î 100 mL), collecting the interfacial precipitate
with the organic phase. The interfacial solid material and the EtOAc
extracts were combined, washed with 1 N HCl (100 mL) and brine
(50 mL). The organic phase was concentrated under reduced pres-
sure to afford 2.9 g of 6a as a yellow solid (69%); mp 176-181 ∞C
(Lit.15a,23 mp 182-184 ∞C) (Tables 2 and 4).
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Acknowledgement
We thank Drs. Michael J. Sherrod and Donald E. Kuhla for valuable
suggestions concerning the preparation of this text.
(e) For a review on the use of carbon disulfide, see: Schmitt,
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Synthesis 2000, No. 11, 1569–1574 ISSN 0039-7881 © Thieme Stuttgart · New York

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Article Identifier:
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