N-arylation by aryl isocyanates as a general reaction: Useful route to disubstituted S,N-diarylisothioureas

Article abstract of DOI:10.3987/com-02-9521

N-Arylation of guanidines, isoureas and isothioureas by aryl isocyanates is demonstrated to have generality. Novel N′-arylations of S-arylisothioureas (16) with aryl isocyanates provide a new general route to biologically active S,N′-diarylisothioureas (13). Formation of (13) is explained as [2+2] cycloaddition of isoureas (16) to isocyanates followed by elimination of HNCO.

Full text of DOI:10.3987/com-02-9521

HETEROCYCLES, Vol. 57, No. 10, 2002, pp. 1799 – 1806, Received, 27th May, 2002
N-ARYLATION BY ARYL ISOCYANATES AS A GENERAL REACTION:
USEFUL ROUTE TO DISUBSTITUTED S,N-DIARYLISOTHIOUREAS
Alan R. Katritzky,*a Xiaohong Cai,a Vladimir Y. Vvedensky,b Boris V. Rogovoy,a
Behrouz Forood,b and Normand Hebertb
a Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, FL 32611-7200, USA; E-mail: katritzky@chem.ufl.edu
b Lion Bioscience Inc., 9880 Campus Point Drive, San Diego, CA 92121, USA; E-mail:
normand.hebert@lionbioscience.com
Abstract - N-Arylation of guanidines, isoureas and isothioureas by aryl isocyanates is
demonstrated to have generality. Novel N′-arylations of S-arylisothioureas (16) with aryl
isocyanates provide a new general route to biologically active S,N′-diarylisothioureas
(13). Formation of (13) is explained as [2+2] cycloaddition of isoureas (16) to
isocyanates followed by elimination of HNCO.
Reactions of C=NH containing guanidines (1, X = NR), isoureas (1, X = O) and isothioureas (1, X = S) with
isocyanates R4NCO to form the expected ureidoguanidines (2, X = NR), isobiurets (2, X = O) or isothiobiurets
(2, X = S) by simple addition (Scheme 1; Table 1) are well recognized.1
O
R4
H
N
N
N
R4
H
N C O
NR1
R2X
NR1
R2X
2
2
1
2
Scheme 1
By contrast, scattered previous work has shown that compounds (3), analogous to (1), but carrying a substituent
on the nitrogen, can react with isocyanates in a dramatically different manner leading to a replacement of this
N-substitutent. Thus, penta- substituted guanidines (3) (X = NR, R3 = Alk, Ar) react with tosyl (Table 2, Entries
1 2), benzoyl (Table 2, Entry 3) and thiobenzoyl isocyanates (Table 2, Entries 4, 5) with the loss of the original

Table 1. Addition reaction of isocyanates to imino compounds (1) (literature data).
Entry#
R1, R1
R2
X
O
O
O
O
O
O
O
O
O
O
S
R3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
R4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Ph
Conditions 2ref
1
2
Me, Me Me
Me, I-Pr Me
-(CH2)5- Me
a
a
a
a
a
a
b
c
a
d
e
e
e
e
a
621a
N/a1a
N/a1a
841a
N/a 1a
N/a1a
751b
751c
961c
941d
751e
701e
711e
781e
651f
3
4
H, H
Me
5
Me, H Me
i-Pr, H Me
All, All Ph
6
7
8
H, H
H, H
Me
Me
Me
Bn
Bn
H
9
Me
10
11
12
H, H
R*
Ph, Ph
Et, Et
Ph
S
Ph
13 n-Bu, n-Bu Bn
S
Ph
14
15
Me, Ph Bn
S
Ph
Me, Me Me MeN
Ph
Conditions: a) Et2O,rt; b) petrol ether, rt; c) benzene, refl, 1 h, d) CHCl3, rt, 1 h; e) PhH, refl, 4 h.
N′-substituent (R3) as isocyanate to give tosyl-, benzoyl- and thiobenzoylguanidines (6).3 The mechanism of
this reaction has been explained2a,3 as a [2+2] cycloaddition followed by the scission of intermediate (5) into
compounds (6) and R3NCO.
R4
R2
R3
N
XR2
NR1
X
N
R1
R3
O C N
R4
- R3NCO
NR1
N
N
N
2
R1
O
2
R2
N
R4
R1 N
N
O
X
XR2
2
R3
R4
3
5
6
4
Scheme 2
Two examples (Table 2, Entries 6 and 7) were reported of the analogous formation of S-methylisothiourea. A
single previously known formation of a O- phenylisourea (8) started from a N′-unsubstituted precursor (7) (Table
2, Entry 8):3 reaction 7→8 was accompanied by the formation of triuret (9) as a result of sequential addition of
the HNCO formed and of PhNCO to isourea (7) (Scheme 3)

Table 2. Reactions of imino compounds (3) with isocyanates via the formation of intermediates
of [2+2] cycloaddition (literature data)
Entry#
R1, R1
R2
X
R3
n-Bu
Ph
R4
Conditions
6ref.
83.52a
722a
932b
762b
522b
912c
902c
403
1
2
3
4
5
6
7
8
Me, Me Me MeN
Me, Me Me MeN
Me, Me Me MeN
Me, Me Me MeN
4-MeC6H4SO2
4-MeC6H4SO2
PhC=O
f
f
Me
Ph
g
h
h
i
PhC=S
Me, Me Me MeN 4-MeO-C6H4
PhC=S
Me, Me Me
Me, Me Me
S
S
Me
Me
H
4-MeC6H4SO2
2,6-MeC6H4SO2
Ph
i
Et, Et
Ph
O
a
Conditions: a)Et2O, rt; b) petrol ether, rt; c) benzene, refl, 1 h, d) CHCl3, rt, 1 h; e) PhH, refl, 4 h; f) 1,2-ClC6H3,
refl; g) Et2O, -78 oC - rt; h) xylol : Et2O = 1 : 3, rt, 1 h; i) Et2O, -30 oC – rt; j) MePh, 100 oC, 18 h; k) MePh, 100 oC, 24
h; l) MePh, refl, 24 h; m) THF, rt, 24 h.
NH
Et2N
OPh
7
O
O
OPh
N NEt2
i) 7
Ph
PhNCO -HNCO
NPh
N
H
N
H
ii) PhNCO
9
Et2N
OPh
8
Scheme 3
In some of this previous work (Table 2, Entries 1, 2), the intermediate adducts (5) (R3 ≠ H) were completely
characterized and required refluxing in 1,2-dichlorobenzene for conversion into compounds (6). However, most
transformations of 5→6 proceed spontaneously.
The eight examples in Table 2 were reported in four different papers without cross referencing. The generality
of reactions of this type was not previously recognized for various compounds of structure (3).
Isothioureas are useful as antivirals (in particular, against AIDS),4 antihistamines,5 insecticides,6 acaricides,7
and as herbicides.8 The activity of isothioureas as selective blockers of nitric oxide synthase, and medicinal
applications of this effect are widely reviewed,9 and patented (e.g.10). Most of the isothioureas tested
biologically are S-alkyl derivatives; this is probably explained by their easy preparation by S-alkylation of
thioureas.

S-Arylisothioureas also show very interesting biological effects, such as antiviral4 and antianginal10f activities.
However, extensive biological screening of S-arylisothioureas has been restricted by synthetic limitations in
their preparation. In contrast to the S-alkyl analogs, S-arylisothioureas can be prepared by direct arylation only
from haloarenes activated e.g. by nitro groups.11 S-(Dihydroxyaryl)isothioureas can be obtained by the addition
of thioureas to quinones.12 Similar reactions with 1,4-benzoquinone monooxime allow the synthesis of S-(5-
amino-2-hydroxyphenyl)-substituted isothioureas.13 These synthetic routes to S-arylisothioureas lack generality;
the only known general procedure for the synthesis of S-arylisothioureas (particularly S,N-diarylisothioureas
13) is the S-arylation of N-phenylthioureas with diazonium salts.14 However, this reaction gives the desired
derivatives in 9-50% yields after column chromatography,14a or in 26–60% yields as picrate salts.14b
Recently, we disclosed examples of convenient preparations of N′,S-diarylisothioureas (13) starting from aryl
isonitriles (10) followed by sequential reactions of intermediate chlorides (11) with amines, and intermediate
benzotriazolecarboximidamides (12) with aromatic thiols (Scheme 4, route A).15 However, the limited
availability of isonitriles decreases the diversity possible at the N′-position.
BtCl
Bt
Bt
-
2
HNR2
+
Ar N C
ArN
NR2
12
ArN
Cl
10
11
A
Ar1
Ar1SH
S
R
ArN
HN
N
R
ArNCO
B
13
SAr1
NR2
Bt
Ar1SH
NR2
Bt
HNR2
HN
HN
Bt
14
16
15
Scheme 4
In the present work, we report versatile methodology for the N′-arylation of easily available N,N-disubstituted
S-arylisothioureas of type (16) by their reaction with aryl isocyanates, a new general synthetic route to S,N-
diaryl isothioureas (13) (Scheme 4, route B). Reaction of isothioureas (16a-d) with phenyl isocyanate in toluene
at 100 oC for 18 h led to N′-phenyl derivative (13a,d-f) in 42-60% yield after column chromatography (Scheme
2). Similar reactions with 4-chlorophenyl isocyanate and 4-methoxyphenyl isocyanate gave the desired
compounds (13b) and (13c) in 39% and 54% yields respectively. These results show the low sensitivity to the
nature of a substituent in the aryl isocyanate; therefore, a variety of inexpensive, commercially available aryl

isocyanates can be applied for N′-arylation of isothioureas (16). Such N′-arylations of isothioureas by
isocyanates were not previously reported (Scheme 5, Table 3, Entries 1-6).
NAr2
Ar2-N=C=O
NH
R2N
R2N
S Ar1
16a-d
1
S
Ar
13a-f
Scheme 5
Table 3. Products from the reactions of isothioureas (16) and (benzotriazol-1-
yl)carboximidamides (15a,b) with isocyanates.
Entry
Product
13a
R2
Ar1
4-ClC6H4
4-ClC6H4
4-ClC6H4
3-MeOC6H4
Ph
Ar2
Yield,%
42
1
2
3
4
5
6
7
8
O(CH2CH2)2
O(CH2CH2)2
O(CH2CH2)2
(CH2)4
Ph
13b
13c
4-ClC6H4
39
4-MeOC6H4
54
13d
13e
Ph
Ph
Ph
Ph
Ph
56
Et, Et
60
13f
i-Pr, i-Pr
4-MeOC6H4
Bt1
45
17a
O(CH2CH2)2
Bn, Bn
61
17b
Bt1
85
These novel N′-arylations of isothioureas (16) to diaryl derivatives (13) (Scheme 4) depends on the electron-
withdrawing properties of the ArS group. This type of reaction is not usual for less activated imino derivatives
such as S-alkylisothioureas, or the benzotriazole derivatives (15a,b): these compounds reacted with phenyl
isocyanate to give exclusively products of normal addition (17a,b) (Scheme 6) (Table 3, Entries 7,8).
NR2 O
NH
NR2
15a,b
PhNCO
Ph
Bt1
N
N
H
Bt1
17a,b
R,R = morpholino (a); Bn, Bn (b)
Scheme 6
In summary, we have uncovered, rationalized, and placed within its literature context a synthetically useful N′-
arylation of S-arylisothioureas which should allow facile first time access to a wide variety of S,N′-
diarylisothioureas.

EXPERIMENTAL
1
General comments: H, 13C NMR spectra were recorded on a 300 MHz NMR spectrometer (300 and 75 MHz
respectively) using CDCl3 as a solvent. Tetrahydrofuran (THF) was distilled under nitrogen immediately before
use from sodium/benzophenone. Compounds (15a,b) and (16a-d) were prepared according to our previously
described protocols.16,17 All other reagents and solvents were obtained from commercial sources and were used
without purification.
General procedure for the preparation of compounds (13a-c).
To a vigorously stirred solution of isothiourea (16a-d) (1 g, 3.9 mmol) in 60 mL of dry toluene, an appropriate
isocyanate (3.9 mmol) was added at rt and the reaction mixture was heated at 100−110 oC for 18-24 h. Residue
obtained after removal of toluene on rotary evaporator was purified by column chromatography on silica gel
using 1:1 ethyl acetate/hexanes mixture as eluent. For the microanalytical purposes samples of compounds 13a-
c,f were additionally recrystallized from DCM.
Compound (13a). 4-Chlorophenyl-N-phenyl-4-morpholine-carbimidothioate. Colorless prisms, 42%, mp
77-79 °C. 1H NMR δ 3.59 (br s, 8H), 6.71 (d, J = 7.7 Hz, 2H), 6.97 (t, J = 7.3 Hz, 1H), 7.08 - 7.19 (m, 6H); 13C
NMR δ 48.5, 66.4, 121.7, 122.7, 128.4, 129.0, 131.2, 132.4, 133.3, 149.6, 153.0. Anal. Calcd for
C17H17N2OClS: C, 61.35; H, 5.15; N, 8.42. Found: C, 61.39; H, 5.35; N, 8.41.
Compound (13b). 4-Chlorophenyl-N-(4-chlorophenyl)-4-morpholinecarbimidothioate. Colorless prisms,
39%, mp 85-86 °C. 1H NMR δ 3.53-3.60 (m, 8H), 6.60 (d, J = 8.5 Hz, 2H), 7.02-7.15 (m, 6H); 13C NMR δ 48.1,
66.1, 122.8, 127.5, 128.1, 128.8, 130.5, 132.2, 133.1, 148.0, 153.2. Anal. Calcd for C17H16N2OCl2S: C, 55.59;
H, 4.39; N, 7.63. Found: C, 55.38; H, 4.47; N, 7.55.
Compound (13c). 4-Chlorophenyl-N-(4-methoxyphenyl)-4-morpholinecarbimidothioate. Colorless prisms,
54%, mp 76-78 °C. 1H NMR δ 3.57 (br s, 8H), 3.75 (s, 3H), 6.65 (d, J = 8.5 Hz, 2H), 6.74 (d, J = 8.5 Hz, 2H),
13
7.11 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H); C NMR δ 48.4, 55.4, 66.4, 113.7, 122.5, 129.0, 131.4,
132.3, 133.2, 143.0, 153.3, 155.5. Anal. Calcd for C18H19N2O2ClS: C, 59.58; H, 5.28; N, 7.72. Found: C, 59.65;
H, 5.46; N, 7.69.
1
Compound (13d). 3-Methoxyphenyl-N-phenyl-1-pyrrolidinecarbimidothioate. Colorless oil, 56%. H
NMR δ 1.87 (m, 4H), 3.55 (m, 4H), 3.71 (s, 3H), 6.62-6.70 (m, 2H), 6.72-6.82 (m, 3H), 6.91 (t, J=7.4Hz, 1H),
13
7.06-7.17 (m, 3H); C NMR δ 25.2, 49.0, 55.1, 112.3, 115.1, 122.0, 122.1, 122.5, 128.2, 129.6, 134.4, 148.3,
150.5, 159.7. Anal. Calcd for C18H20N2OS: C, 69.20; H, 6.45; N, 8.97. Found: C, 69.22; H, 6.76; N, 9.36.
1
Compound (13e). 1-[(Diethylamino)(phenylimino)methyl]sulfanylbenzene. Colorless oil, 60%. H NMR δ
1.14 (t, J=7.0Hz, 6H), 3.56 (q, J=7.0Hz, 4H), 6.66 (d, J=7.6Hz, 2H), 6.86 (t, J=7.3Hz, 1H), 7.04-7.16 (m, 7H);

13C NMR δ 13.4, 44.1, 121.6, 122.1, 126.4, 128.1, 128.6, 130.4, 133.5, 150.6, 150.8. Anal. Calcd for
C17H20N2S: C, 71.79; H, 7.09; N, 9.85. Found: C, 72.11; H, 7.48; N, 10.15.
Compound (13f). 1-{[(Diisopropylamino)(phenylimino)methyl]sulfanyl}-4-methoxybenzene. Colorless
prisms, 45%, mp 73-75oC. 1H NMR δ 1.26 (d, J=6.6 Hz, 12H), 3.74 (s, 3H), 4.13-4.24 (m, 2H), 6.61-6.76 (m,
4H), 6.81 (t, J=7.2 Hz, 1H), 7.00-7.20 (m, 4H); 13C NMR δ 21.1, 49.4, 55.3, 114.3, 121.1, 121.8, 124.1, 128.1,
133.4, 150.2, 150.6, 158.8. Anal. Calcd for C20H26N2OS: C, 70.14; H, 7.65; N, 8.18. Found: C, 70.38; H, 7.94;
N, 8.03.
General procedure for the preparation of compounds (17a,b).
Benzotriazole-1-carboximidamide (15a,b) (3.9 mmol) was dissolved in dry THF (40 mL) and phenyl
isocyanate (465 mg, 3.9 mmol) was added under vigorous stirring. The resulting solution was allowed to react
for 24 h at rt. Residue obtained after removal of toluene on rotary evaporator was purified by column
chromatography on silica gel using 1:1 ethyl acetate/hexanes mixture as the eluent. For the microanalytical
purposes samples of compounds (17a,b) were additionally recrystallized from acetone.
Compound (17a). N-Benzotriazol-1-yl(morpholino)methylidene-N′-phenylurea. Colorless prisms, 61%, mp
1
158-160 °C. H NMR δ 3.54 (br s, 4H), 3.84-3.87 (m, 4H), 7.00 (t, J = 7.0 Hz, 1H), 7.19-7.32 (m, 4H), 7.43
(t, J = 7.6 Hz, 1H), 7.56 (t, J = 8.2 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 8.12 (d, J = 8.5 Hz, 1H), signal of NH
13
group does not appear; C NMR δ 47.7, 66.3, 110.6, 118.9, 120.6, 123.4, 125.1, 128.8, 129.5, 132.7, 138.4,
145.4, 147.3, 157.4. Anal. Calcd for C18H18N6O2: C, 61.70; H, 5.18; N, 23.99. Found: C, 61.84; H, 5.44; N,
23.44.
Compound (17b). N-Benzotriazol-1-yl(dibenzylamino)methylidene-N′-phenylurea. Colorless prisms (85%),
mp 215-217 °C. 1H NMR δ 4.57 (s, 4H), 6.98 (t, J = 6.5 Hz, 1H), 7.17-7.41 (m, 15H), 7.44-7.55 (m, 2H), 8.08
13
(d, J = 8.4 Hz, 1H), signal of NH group does not appear; C NMR δ 52.1, 110.2, 118.9, 120.5, 123.3, 124.8,
128.0, 128.1, 128.8, 128.9, 129.3, 133.0, 135.2, 138.5, 145.3, 148.6, 157.0. Anal. Calcd for C28H24N6O: C,
73.02; H, 5.25; N, 18.25. Found: C, 72.88; H, 5.48; N, 18.02.
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