A facile and new approach to synthesize 2-amino-4-(4-amoinophenyl)-1H-1,3- diazol-1-yl-alkylaminomethanethiones

Article abstract of DOI:10.1007/s00044-007-9003-1

An "intellectual connection" approach to design a facile and new synthesis of suitably substituted 2-aminoimidazole-based precursors of expected anti-asthmatic agents through a benzidine type of rearrangement of 2-phenylazoimidazole and subsequent coupling of the product thus obtained with alkylisothiocyanates involving a degenerative operation, thereby improving the time frame of the overall synthetic sequence, is reported. The alkylisothiocyanates required in this synthetic sequence are prepared using a best combination of reported methods. The compounds reported here can be used to produce derivatives of other biological agents. Birkhaeuser 2007.

Full text of DOI:10.1007/s00044-007-9003-1

Med Chem Res (2007) 15:483–491
DOI 10.1007/s00044-007-9003-1
A facile and new approach to synthesize 2-amino-4-(4-
amoinophenyl)-1H-1,3-diazol-1-yl-
alkylaminomethanethiones
Raman K. Verma Æ Monika Aggarwal Æ Manisha Bansal Æ Inder Preet Kaur
Received: 24 July 2006 / Accepted: 19 January 2007 / Published online: 26 May 2007
¨
ꢀ Birkhauser Boston 2007
Abstract An ‘‘intellectual connection’’ approach to design a facile and new syn-
thesis of suitably substituted 2-aminoimidazole-based precursors of expected anti-
asthmatic agents through a benzidine type of rearrangement of 2-phenylazoimidazole
and subsequent coupling of the product thus obtained with alkylisothiocyanates
involving a degenerative operation, thereby improving the time frame of the overall
synthetic sequence, is reported. The alkylisothiocyanates required in this synthetic
sequence are prepared using a best combination of reported methods. The compounds
reported here can be used to produce derivatives of other biological agents.
Keywords Airway hyperresponsiveness Á Alkyl-isothiocyanates Á
2-Aminoimidazole Á Antiasthmatic agents Á Benzidine Á Eosinophils Á
Interleukin-5
Introduction
Current therapies for asthma provide only symptomatic relief to patients and do not
control inflammation. Modern treatment of asthma is directed toward lessening
inflammation, thereby reducing airway reactivity and asthma severity. Recently
there has been increasing clinical and experimental evidence that human eosinophils
play a key role in the pathogenesis of bronchial asthma and airway hyperrespon-
siveness. Once recruited from the circulation, these eosinophils are primed for
ligand-mediated generation of increased amounts of cysteinyl leukotrienes and for
cytotoxicity to other cells such as airway epithelium (Sanderson et al., 1985; Walker
et al., 1991; Hallsworth et al., 1992; Sanderson, 1992; Walsh and Wardlaw, 1997;
Park et al., 1998).
R. K. Verma (&) Á M. Aggarwal Á M. Bansal Á I. P. Kaur
Synthetic Organic and Medicinal Chemistry Laboratory, Department of Chemistry, Punjabi
University, Patiala 147002 (Pb), India
e-mail: raman_verma58@yahoo.com

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Med Chem Res (2007) 15:483–491
An increased number of eosinophils in circulation and bronchoalveolar lavage
fluids (BALFs) have been reported as a characteristic feature of chronic bronchial
asthma (Youichiro et al., 1996). The mechanism of eosinophilia in circulation and
BALFs is unclear, but recent research findings offer several explanations
(Sanderson et al., 1985; Walker et al., 1991; Hallsworth et al., 1992; Sanderson,
1992; Youichiro et al., 1996; Walsh and Wardlaw, 1997; Park et al., 1998). Because
inhibitors of eosinophils will hopefully provide novel agents for the treatment of
chronic bronchial asthma and because inhibiting eosinophil survival induced by
interleukin-5 (IL-5) is a recent development and an upcoming therapy for asthma
(Rogers and Giembycz, 1995), we initiated a program to design a facile and new
approach to synthesize suitably substituted precursors of 2-aminoimidazole (I) and
2-aminoimidazoline (II)-based expected antiasthmatic agents.
Recent reports (Youichiro et al., 1996; Fumihiko et al., 1998) on highly active
and potent triazole and triazolotriazine derivatives (Fig. 1A–D) in inhibiting
eosinophilia attracted our attention. The structure–activity relationship (SAR)
reported in these studies prompted us to synthesize suitably substituted
2- aminoimidazole and 2-aminoimidazoline-based compounds (I) and (II) rather
than the corresponding improperly and incompletely substituted imidazole- and
purine (Fig. 1E and F)-based compounds. As per theoretical SAR, the amino group
must be present on the carbon bonded to two nitrogens of the five-membered ring
and the alkylaminothicarbonyl group must be attached to the nitrogen next to the
carbon-bearing the amino group, unlike (E) and (F), which show the least activity
and potency (Youichiro et al., 1996; Fumihiko et al., 1998). Further, no attempt was
S
S
NHMe
NH2
Me
N
N
N
N
N
N
A
N
N
Cl
N
Cl
B
S
S
S
S
NHMe
NH2
Me
Me
N
HN
NHMe
HN
N
N
N
N
N
NH2
N
N
N
N
N
D
C
E
F
S
S
NHR'
NH2
N
NHR'
NH2
N
N
II
N
I
R
R
Fig. 1 Investigational (A-F) and designed agents (I and II)

Med Chem Res (2007) 15:483–491
485
made to place a 4-substituted phenyl on (E) and (F) as the comparison was made
only with (C) and (D). We also planned to incorporate this important structural
feature in the compounds, synthesized through the functionalization of an amino
group of a suitably placed 4-aminophenyl moiety.
2-Aminoimidazole (III) is of particular interest, especially within the realm of
medicinal chemistry. For example, several classes of marine natural products
possessing this structure were recently discovered and identified (Little and Webber,
1994). Many of these compounds display a broad range of biological properties
including antibacterial, antiinflammatory, anticancer, and antiviral activity.
The additional feature of the synthetic strategy designed was the possible use of
the compounds (1, 2, and 4a–e) reported here to generate derivatives of other classes
of biologically active compounds (Fig. 2, III–IX) (Lancini et al., 1969; Cavalleri
et al., 1977; Little and Webber, 1994; Slee et al., 2001; Vaillancourt et al., 2001;
Almansa et al., 2003). 2-Nitroimidazole (IV, azomycin), a naturally occurring
antibiotic, and its derivatives show good antiprotozoal activity (Lancini et al., 1969)
and compound (V), having antidiabetic activity (Vaillancourt et al., 2001), can be
easily produced from (1). 2-Amino-5-phenylimidazole (VI) possesses broad-
spectrum antimicrobial activity (Cavalleri et al., 1977) and can be directly
produced from compound (2). This can also be derivatized to (VII and VIII)-based
precursors of agents with antiinflammatory (selective COX-II inhibitors and p-
selectin inhibitors) (Slee et al., 2001; Almansa et al., 2003) activities, respectively.
Finally, all five compounds (4a–e) reported in this article can be converted to
compounds of type (IX) with expected antiasthmatic activities (Fumuhiko et al.,
1998).
Br
N
H2N
N
F
N
H2N
N
Br
H
S
Y
(VIII)
(VII)
NH
R
N
N
N
R = H
N
N
H
N
H2N
NH2
N
H
N
NH2
H2N
R
(1)
(4a-e)
From dihydrochloride (2)
R = Cl
H2N
S
R
N
N
N
N
H2N
N
N
H
N
N
H
X
(III)
(VI)
(IX)
H
N
O
H2N
N
N
N
OH
O2N
N
H
(V)
(IV)
Fig. 2 Use of agents (1,2, and 4a–e) reported to produce derivatives of other biological agents

486
Med Chem Res (2007) 15:483–491
The work related to the synthesis of suitably substituted precursors of 2-
aminoimidazole (Fig. 1, I)-based compounds carried out by us is reported.
Chemistry, Results, and Discussion
We planned to synthesize properly substituted 2-amino-4-(4-chlorpphenyl)imidaz-
ole based precursor of the desired compounds of type (I) by the reaction of a-
bromo-p-chloroacetophenone (Brians et al., 1991) with guanidine (Scheme 1), like
the one reported for the synthesis of 2-amino-4-methylthiazole (Byers and Dickey,
1943) using a-chloroacetophenone and thiourea. The aim here was to design a
reaction that significantly increases the complexity of the product relative to the
starting materials. This method suffered from lesser yields (10–15%) of the required
product and hence was not used in further experiments.
O
N
Br
NH2
NH
Dry Methanol
N
H
NH2
+
H2N
Stirring 0.5h
Reflux 18h
Cl
Cl
Scheme 1
A short and efficient method was then planned, in which we synthesized 2-
phenylazoimidazole (1) by trapping benzene diazoniumchloride (1a) with com-
mercially available imidazole (Scheme 2).
NaHCO3 -10%
Stirring - 40 min
N
N
+
-
N
N2Cl
+
N
H
N
o
N
H
0 - 5 C
(1)
(1a)
Rectified spirit
SnCl2/Conc. HCl
Reflux 1.5h
+
NH
N
H
NH2
+
H3N
-
2Cl
(2)
Scheme 2
The product (1) was obtained in 38–40% yield only, but had served as an
important precursor for the desired 2-amino-4-(4-aminophenyl)imidazole dihydro-
chloride (2) in 85% yield (Scheme 2), through a benzidine type of rearrangement,
which it underwent on treatment with stannous chloride in the presence of conc.
hydrochloric acid, as it lacks any p-substituent, and represent a good substrate for
the benzidine rearrangement.

Med Chem Res (2007) 15:483–491
487
This idea originated from the need to incorporate a 4-aminophenyl moiety, which
can be best achieved via benzidine rearrangement, properly placed, as required
because of the degeneracy of C-4 and C-5 positions of imidazole ring.
Compound (2) has almost all the structural feature required—the imidazole ring
with a suitably located amino group and a properly positioned 4-aminophenyl
moiety except the alkylaminothiocarbonyl group. This group in turn was introduced
at the appropriate nitrogen through its coupling with various alkylisothiocyanates
(3a–e) under strongly alkaline conditions (Scheme 4), thereby generating the
desired compounds (4a–e). The 4-amino group of 4-aminophenyl moiety of all
theses compounds (4a–e) can then be functionalized to 4-chloro, 4-bromo, and 4-
cyano derivatives with expected antiasthmatic activity.
0OC
-
+
RNH2
CS2
+
(C2H5)3N
+
RNHCS2 HN(C2H5)3
Stirring 2h
+
-
+
-
Steam
Distillation
RNHCS2 HN(C2H5)3
HNO3
PbS
+
Pb(NO3)2
RNCS
(C2H5)3NH NO3
+
+
+
(3a): R = Me, (3b): R = Et, (3c): R = nPr
(3d): R = iPr, (3e): R = tBu
Scheme 3
The method we sought for the preparation of alkylisothiocyanates, involving
reaction of alkyl amines with carbon disulfide in the presence of triethylamine and
treating the salts thus obtained with lead nitrate and subsequent steam distillation,
represents the best combination of reported methods (Dains et al., 1941; Moore and
Crossley, 1955; Hodgkins and Reeves, 1964) to get reasonably good yields of pure
alkylisothiocynates (3a–e), as confirmed from Fourier transform infrared
1
spectroscopy (FTIR) and H nuclear magnetic resonance (NMR) spectral studies.
S
+
R
NH
THF-NaOH
Stirring RT 1h
N
N
H
NH2
N
H
NH2
N
RNCS
(3a-e)
+
Reflux 4-6 h
+
H3N
-
H2N
2Cl
(2)
(4a): R = Me, (4b): R = Et, (4c): R = nPr
(4d): R = iPr, (4e): R = tBu
Scheme 4
Experimental Procedures
The melting/boiling points reported here were recorded using an open conc. sulfuric
acid bath and are uncorrected. The infrared, 1H NMR spectra, and elemental
analyses of the compounds were carried out on Perkin Elmer Spectrum RX FTIR
spectrophotometer, AC300F, 300MHz Bruker spectrometer, and Perkin Elmer 2400
CHN Elemental Analyzer, respectively at RSIC, Panjab University, Chandigarh.
Liquid chromatography-mass spectroscopy (LC–MS) of these compounds was

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Med Chem Res (2007) 15:483–491
recorded on a LC–MS LCQ Finnigan Matt (APCI +ve mode) at Central
Instrumentation Lab, NIPER, SAS Nagar, Mohali, Punjab.
Preparation of 2-phenylazoimidazole (1)
2-Phenylazoimidazole was prepared from benzenediazonium chloride (Ia) and
imidazole via the following procedure.
Benzene diazonium chloride (1a): To (9.3 g, 0.1 mol) of aniline taken in a 500-
ml RB flask was added 60 ml of 50% HCl. The clear solution obtained was stirred
and chilled to –58C. To this solution was added an ice-cold solution of sodium
nitrite (7.245 g, 0.12 mol) in 45 ml of water from a dropping funnel (the stem of
which extends below the surface of the liquid) at a rate such that the temperature
should not rise above 08C. The solution stirred for additional 0.5 h after the addition
of sodium nitrite and then a mixture of 20 ml of ice-cold water, 0.2 g of urea, and 20
g of crushed ice was added successively.
2-Phenylazoimidazole (1): The cold diazonium chloride solution thus prepared
was added very slowly to a vigorously stirred and cold (08C) solution of imidazole
(6.8 g, 0.1 mol) in 10% of sodium bicarbonate (45 ml) taken in a 250-ml RB flask
immersed in an ice salt bath (assisted by direct addition of 25 g of crushed ice).
When all the diazonium salt solution was added the contents of the flask were stirred
for additional 0.5 h and allowed to stand in an ice bath for about 0.5 h. The reddish
brown solid separated was filtered, washed with water, dried, and on recrystalli-
zation from glacial acetic acid gave 40% of (2): mp 1208C; FTIR (KBr): 3350–
2450, 3410, 3055, and 3140, 1586, 1501, 1480, 1414, 1325, 1453, 917 and 835, 764,
1
and 681 cmÀ1; H NMR (CDCl3) dppm: 13.25 (brÁs, 1H, exchangeable), 7.87–
7.85(m, 2H), 7.49–7.42(m, 3H), 7.19(s, 2H); LC–MS m/z: 345 (2M + H+).
2-Amino-4-(4-aminophenyl)imidazole dihydrochloride (2): A warm solution of
tin (II) chloride (18.9 g, 0.1 mol) in 40 ml of conc. HCl was added to a gently
boiling solution (8.6 g, 0.05 mol) of 2-phenylazoimidazole (2) in rectified spirit (80
ml) taken in a 250-ml RB flask provided with a reflux condenser. The contents of
the flask were refluxed for 1.5 h and the reaction mixture was allowed to cool and
then chilled to –58C, during which time crystallization took place. The separated
solid was filtered, washed with ether, dried, and on recrystallization from 20% hot
absolute alcohol gave 85% of (4): mp 2058C (decomp.); FTIR (KBr): 3491,3250–
1
2800, 3133 and 3060; 1670 and 1627, 1514, 1478, 1407, 1335, and 828 cmÀ1; H
NMR (D2O) d: 7.48(d, 2H, J = 7.76 Hz), 7.36(d, 2H, J = 7.64), 7.00(s, 1H); LC-MS
of 2-amino-4-(4-aminophenyl)imidazole m/z: 175 (M+H+).
Preparation of alkylisothiocyanates (3a–e): A mixture solution of alkyl amine
(0.25 mol) and triethylamine (22.25 g, 0.25 mol) taken in a dropping funnel was
added dropwise with stirring to carbon disulfide (40 ml, placed in a 250-ml RB flask
surrounded by an ice salt cooling bath) over about 15 min. Stirring continued for
another 2 h at 08C and the heavy solid separated during this time was filtered,
washed with ether, and dried. It was then dissolved in water and to this solution lead
(II) nitrate (82.75 g, 0.25 mol) was added in portions. The contents of the flask were
distilled with steam into a receiving RB flask (500-ml, containing 5–6 ml of 1 N

Med Chem Res (2007) 15:483–491
489
H2SO4) for as long as any oil came out. The oil was extracted with ether, washed
with distilled water, dried over anhydrous Na2SO4, filtered, and the filtrate on
evaporation gave 25–35% of required alkylisothiocyanates (3a–e) as yellow oils.
Methylisothiocyanate (3a): Methylisothiocyanate (3a) was prepared (4.562 g,
24.997%) as per the general procedure described in the preceding text, starting from
methylamine (40%; 7.75 g, 0.25 mol) as a yellow oil: bp 118–1198C; IR (neat):
2983 and 2874, 2070, 1445, and 1366 cmÀ1; 1H NMR (CDCl3) d: 3.325 (s, 3H).
Ethyl isothiocyanate (3b): Ethyl isothiocyanate (3b) was prepared (26%) as per the
general procedure described in the preceding text, starting from ethylamine (70%;
11.25 g, 0.25 mol) as a yellow oil: bp 134–1358C; IR (neat): 2970 and 2907, 2938, and
2877, 1463, 1448, and 1388 cmÀ1; 1H NMR (CDCl3) d: 3.582 (q, 2H), 1.425 (t, 3H).
n-Propylisothiocyanate (3c): n-Propylisothiocyanate (3c) was prepared (34%) as
per the general procedure described in the preceding text, starting from n-
propylamine (14.75 g, 0.25 mol) as a yellow oil: bp 155–1578C; IR (neat): 2970 and
2907, 2938 and 2877, 2096, 1463, 1450, and 1385 cmÀ1; 1H NMR (CDCl3) d: 3.445
(t, 2H,). 1.708 (sext, 2H), 1.007 (t, 3H).
Isopropylisothiocyanate (3d): Isopropylisothiocyanate (3d) was prepared (40%)
as per the general procedure described in the preceding text, starting from
isopropylamine (14.74 g, 0.25 mol) as a yellow oil: bp 135–1378C; IR (neat): 2983
1
and 2875, 2091, 1387, and 1370 cmÀ1; H NMR (CDCl3) d: 3.926 (septet, 1H),
1.426 (d, 6H).
tert-Butylisothiocyanate (3e): tert-Butylisothiocyanate (3e) was prepared (45%)
as per the general procedure described in the preceding text, starting from tert-
butylamine (18.25 g, 0.25 mol) as a yellow oil: bp 144–146 8C; IR (neat): 2982 and
1
2874, 2004, 1397, and 1369 cmÀ1; H NMR (CDCl3) d: 1.436 (s, 9H).
Synthesis of 2-aminoÀ4-(4-aminophenyl)-1H-1,3-diazol-1-yl-
alkylaminomethanethiones (4a–4e)
2-Amino-4-(4-aminophenyl)-1H-1,3-diazol-1-yl-methylaminomethanethione (4a):
To a solution of sodium hydroxide (3.0 g, 0.75 mol) in 10 ml of water taken in a
100-ml RB flask was added a solution of 2-amino-4-(4-aminophenyl) imidazole
dihydrochloride (6.175 g, 0.025 mol) in 10 ml of water. Methylisothiocyanate
(1.898 g, 0.026 mol) in tetrahydrofuran (10 ml) was added to the above mixture
solution with stirring. The reaction mixture solution was stirred at reflux for 4 h,
neutralized with 1 N HCl, and extracted with ethyl acetate (3 · 50 ml). The
combined ethyl acetate extract was washed with distilled water, dried over
anhydrous sodium sulfate, filtered, and the solvents were removed by distillation.
On recrystallization from methanol, the residue gave (24%) of (4a): mp 185–1908C;
FTIR (KBr): 3400–3100, 2958, and 2870; 1600–1325, 1540, 1255, 1071, and 835
cmÀ1; 1H NMR (CDCl3+DMSO-d6) d: 7.93 (brÁs, 1H), 7.78 (brÁs, 2H), 7.21 (d, 2H,
J = 9.2), 6.94 (d, 2H, J = 9.2), 6.56 (s, 1H), 5.40 (brÁs, 2H), 1.25 (s, 3H); LC–MS m/z
248 (M + H+); anal. calcd. for C11H13N5S: C, 53.42; H, 5.30; N, 28.32. Found: C,
53.61; H, 5.57; N, 28.19.
2-Amino-4-(4-aminophenyl)-1H-1,3-diazol-1-yl-ethylaminomethanethione (4b):
2-Amino-4-(4-aminophenyl)-1H-1,3-diazol-1-yl-ethylaminomethanethione (4b)

490
Med Chem Res (2007) 15:483–491
was prepared (24%) as per the procedure described for the preparation of (4a)
starting from ethylisothiocyanate (2.262 g, 0.025 mol): mp 190–1958C; FTIR
(KBr): 3450–3100, 2971, and 2871; 2930, 1600–1355, 1541, 1257, 1092, and 836
cmÀ1; 1H NMR (CDCl3, DMSO-d6) d: 7.96 (brÁs, 1H), 7.75 (brÁs, 2H), 7.45 (d, 2H, J
= 7.5), 7.13 (d, 2H, J = 8.5), 6.62 (s, 1H), 5.35 (brÁs, 2H), 3.72 (q, 3H),1.20 (t, 2H);
anal. calcd. for C12H15N5S: C, 55.15; H, 5.79; N, 26.80. Found: C, 55.39; H, 5.91;
N, 27.03.
2-Amino-4-(4-aminophenyl)-1H-1,3-diazol-1-yl-n-propylaminomethanethione
(4c): 2-Amino-4-(4-aminophenyl)-1H-1,3-diazol-1-yl-n-propylaminomethanethione
(4c) was prepared (25%) as per the procedure described for the preparation of (4a)
starting from n-propylisothiocyanate (2.626 g, 0.026 mol): mp 195–2008C; FTIR
(KBr): 3400–3100, 2958 and 2870; 2928, 1600–1350, 1541, 1251,1071, and 835
cmÀ1; 1H NMR (CDCl3+DMSO-d6) d: 7.96 (brÁs, 1H), 7.55 (brÁs, 2H), 7.22 (d, 2H,
J = 7.3), 7.04 (d, 2H, J = 8.4), 6.84 (s, 1H), 5.60 (brÁs,2H), 3.56 (t, 2H), 1.62 (sextet,
2H), 0.96(t, 3H); anal. calcd. for C13H17N5S: C, 56.70; H, 6.22; N, 25.43. Found: C,
56.97; H, 6.29; N, 25.19.
2-Amino-4-(4-aminophenyl)-1H-1,3-diazol-1-yl-isopropylaminomethanethione
(4d): 2-Amino-4-(4-aminophenyl)-1H-1,3-diazol-1-yl-isopropylaminomethanethi-
one (4d) was prepared (25%) as per the procedure described for the preparation
of (4a) starting from isopropylisothiocyanate (2.626 g, 0.026 mol): mp 185–1888C;
FTIR (KBr): 3550–3150, 2970, and 2870, 1650–1300, 1540, 1252,1050, and 840
cmÀ1; 1H NMR (DMSO-d6) d: 8.13 (brÁs, 1H), 7.43 (d, 2H, J = 9.9), 7.23 (d, 2H, J =
8.4), 7.15 (brÁs, 2H), 6.93 (s, 1H), 5.35 (brÁs, 2H), 3.79 (septet, 1H), 1.32 (d, 6H);
anal. calcd. for C13H17N5S: C, 56.70; H, 6.22; N, 25.43. Found: C, 56.86; H, 6.41;
N, 25.37.
2-Amino-4-(4-aminophenyl)-1H-1,3-diazol-1-yl-tert-butylaminomethanethione
(4e): 2-Amino-4-(4-aminophenyl)-1H-1,3-diazol-1-yl-tert-butylaminomethanethi-
one (4e) was prepared (24%) as per the procedure described for the preparation
of (4a) starting from tert-butylisothiocyanate (2.990 g, 0.026 mol): mp 200–2048C;
FTIR (KBr): 3575–3175, 2980, and 2875; 1675–1300, 1526, 1261,1075, and 845
cmÀ1; 1H NMR (DMSO-d6) d: 8.30 (brÁs, 1H), 6.94 (brÁs, 2H), 7.60 (d, 2H, J = 9.3),
7.19 (d, 2H, J = 9.3), 6.86 (s, 1H), 5.39 (brÁs, 2H), 1.53 (s, 9H); anal. calcd. for
C14H19N5S: C, 58.10; H, 6.62; N, 24.20. Found: C, 57.97; H, 6.52; N, 24.33.
Acknowledgments The authors thank Head, Department of Chemistry and the Director RSIC, Panjab
University, Chandigarh and Director NIPER, SAS Nagar, Mohali, Punjab respectively for providing the
facilities for the analysis of various compounds reported in this article. M.A. thanks UGC New Delhi for
providing a research fellowship (JRF).
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