A facile, sequential multicomponent approach to N-aminoamidinothioureas- versatile synthons to bioactive heterocycles

Article abstract of DOI:10.1080/10426500903329237

A sequential, three-component approach for the rapid and convenient one-pot synthesis of N-aminoamidinothioureas is reported. The improved synthetic strategy involves the selective blocking of amino functionality in aminoguanidine by Schiff base formation with carbonyl compounds to generate corresponding N-(alkylidene/arylidene)aminoguanidines and their subsequent in situ condensation with isothiocyanate. The structural motif incorporates three points for diversity multiplication, making it a suitable candidate for combinatorial synthesis. The generality of the improved procedure was established by synthesizing a series of diverse compounds through solution phase parallel synthesis by varying the carbonyl and isothiocyanate components. The newly synthesized compounds were characterized by spectral methods. The developed synthetic procedure employs mild reaction conditions, and individual steps are carefully optimized for easy automation. Copyright

Full text of DOI:10.1080/10426500903329237

This article was downloaded by: [Dicle University]
On: 15 November 2014, At: 12:10
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Phosphorus, Sulfur, and Silicon and the
Related Elements
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/gpss20
A Facile, Sequential
Multicomponent Approach to N-
Aminoamidinothioureas—Versatile
Synthons to Bioactive Heterocycles
K. G. Sreejalekshmi a
a Department of Chemistry , University of Kerala, Kariavattom ,
Thiruvananthapuram, India
b Department of Applied Sciences , Indian Institute of Space Science
and Technology, ISRO Post , Thiruvananthapuram, India
Published online: 25 Aug 2010.
To cite this article: K. G. Sreejalekshmi (2010) A Facile, Sequential Multicomponent Approach to N-
Aminoamidinothioureas—Versatile Synthons to Bioactive Heterocycles, Phosphorus, Sulfur, and Silicon
and the Related Elements, 185:9, 1830-1837, DOI: 10.1080/10426500903329237
To link to this article: http://dx.doi.org/10.1080/10426500903329237
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &

Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Phosphorus, Sulfur, and Silicon, 185:1830–1837, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500903329237
A FACILE, SEQUENTIAL MULTICOMPONENT APPROACH
TO N-AMINOAMIDINOTHIOUREAS—VERSATILE
SYNTHONS TO BIOACTIVE HETEROCYCLES
K. G. Sreejalekshmi
Department of Chemistry, University of Kerala, Kariavattom,
Thiruvananthapuram, India and Department of Applied Sciences, Indian Institute
of Space Science and Technology, ISRO Post, Thiruvananthapuram, India
A sequential, three-component approach for the rapid and convenient one-pot synthesis of
N-aminoamidinothioureas is reported. The improved synthetic strategy involves the selective
blocking of amino functionality in aminoguanidine by Schiff base formation with carbonyl
compounds to generate corresponding N-(alkylidene/arylidene)aminoguanidines and their
subsequent in situ condensation with isothiocyanate. The structural motif incorporates three
points for diversity multiplication, making it a suitable candidate for combinatorial synthe-
sis. The generality of the improved procedure was established by synthesizing a series of
diverse compounds through solution phase parallel synthesis by varying the carbonyl and
isothiocyanate components. The newly synthesized compounds were characterized by spec-
tral methods. The developed synthetic procedure employs mild reaction conditions, and
individual steps are carefully optimized for easy automation.
Keywords N-Aminoamidinothiourea; combinatorial synthesis; condensation; diversity; se-
quential multicomponent reaction
INTRODUCTION
Amidinothioureas are known to serve as precursors to bioactive heterocyclic
compounds.1 Our continuing endeavor in the direction of developing versatile
synthons2–4 to access bioactive heterocycles5,6 has resulted in devising novel and
improved syntheses of many interesting members of the thiourea family. A litera-
ture search indicated that synthesis of N-aminoamidinothioureas of the type 4, also
referred to as 1-arylthiocarbamoyl-3-[N-(alkylidene/arylideneamino) guanidine or N-
(alkylidene/arylideneamino)-Nꢁ-(arylthiocarbamoyl)guanidine, has received only scarce
mention, except for two older reports from Godfrey and Kurzer,7,8 which employ extreme
reaction conditions. With the growing interest in combinatorial design and evaluation of
library members for different properties,9 the synthetic routes to these molecules demand
Received 24 June 2009; accepted 11 September 2009.
The author thanks University Grants Commission, Government of India for financial assistance, and Prof.
K. N. Rajasekharan and Dr. Mercyamma Francis for useful discussions and support.
Address correspondence to K. G. Sreejalekshmi, Department of Applied Sciences, Indian Institute of Space
Science and Technology, ISRO Post, Thiruvananthapuram 695022, India. E-mail: sreeja@iist.ac.in; sreejalekshmi
@gmail.com
1830

FACILE APPROACH TO N-AMINOAMIDINOTHIOUREAS
1831
O
NH
S
NH2
R1
R2
R1
R2
R3NCS
reflux
NHR3
H2NHN
NH2.HNO3
N
NHN
Na, reflux
Scheme 1 Godfrey and Kurzer’s method for the synthesis of N-(isopropylideamino)-N’-
(phenylthiocarbamoyl)guanidine 4a.
greater refinement. Thus it was felt useful to have an improved procedure to access the
title compounds. Moreover, the elements of diversity incorporated by the core structure
4 appeared to be very attractive to fit into a combinatorial scenario based on parallel
synthesis, which further facilitates high throughput screening (HTS) of the members for
bioactivity.
The existing procedure available for the synthesis of N-aminoamidinothioureas in-
volves refluxing a solution of metallic sodium in acetone and aminoguanidine sulfate to
form N-(isopropylidene)aminoguanidine, which upon refluxing with isothiocyanate affords
1-arylthiocarbamoyl-3-[N-(isopropylidene)aminoguanidine]. This method is limited to the
synthesis of isopropylidene derivatives only, thus limiting diversity multiplication, and so
the synthetic scheme (Scheme 1) would require refinement before being applied in a parallel
synthesis. A more general route following less drastic conditions and affording a diverse
set of target molecules, preferably through a multicomponent approach,10 was designed.
The title compounds could be accessed from aminoguanidine, carbonyl compound,
and isothiocyanate. The multisite reactivity of the reagents suggested the possibility of
formation of different products if a multicomponent route is adopted. Thus, to access the
desired compounds, it was decided to employ a sequential multicomponent route (SMCR).11
A SMCR is a sensible modification of a multicomponent reaction (MCR) in which the
functional groups in a reactant are selectively made to react with different reagents in a
sequence to generate a specific compound. Such reactions are usually carried out through
one-pot tandem procedures without any intermediate or product isolation.
Studies in our laboratories have made useful contributions to the chemistry of sulfur-
containing compounds. For accessing thioureas and related compounds, simple routes and
mild reaction conditions were developed. Amidinothioureas were accessed by reacting
guanidine salts with isothiocyanates in dimethyl formamide containing powdered KOH.4
It was decided to test the applicability of a similar strategy in the present case.
RESULTS AND DISCUSSION
The sequence of reactions in the planned route may give a product that can exist in
two tautomeric forms—either the azo form or the hydrazino form (Chart 1). The present
study may shed light into the actual structure of the products.
S
S
NH
NH2
R1
R2
R1
R2
NHR3
NHR3
N
N
N
N
NHN
H
hydrazino form
azo form
Chart 1 Tautomers possible for compound 4.

1832
K. G. SREEJALEKSHMI
Scheme 2 Synthesis of N-(aminoamidino)thioureas 4a–l through SMCR approach.
Aminoguanidine 1 was reacted with a particular carbonyl compound 2 in DMF con-
taining NaOH. The corresponding hydrazone derivatives formed were reacted subsequently
with isothiocyanates 3 to afford the title compounds 4 in good yield as the sole major prod-
uct (Scheme 2). The synthesis required stirring of the reaction mixture for 2 h at room
temperature. This was indeed an excellent modification of the existing literature procedure.
The variables incorporated by the core structure are summarized in Table I.
The isolated products were purified by simple crystallization from aqueous ethanol.
The structures of all the new compounds were confirmed on the basis of analytical data and
spectral studies of the compounds. For example, IR spectra of 4a showed NH stretching
at 3300 and 3200 cm−1. An aryl CH bending band at 735 cm−1 indicated the presence
of a phenyl group. The presence of C N groups was suggested by a band at 1620 cm−1
.
1
The H NMR spectrum displayed two singlets at 2.02 and 2.07 δ integrating for three
protons each, which suggested the presence of two methyl groups in the compound. These
signals strongly indicated that the compound existed in the hydrazino form instead of the
azo tautomeric form. A broad band at 6.43 δ was assigned to NH2 protons. The triplet-
triplet-doublet pattern in the aryl region suggested a C6H5NH group in the compound. Two
more broad signals at 7.90 and 12.95 δ were assigned to C NNH and NH-aryl protons,
respectively. These data confirmed the formation of product 4a. A similar spectral study
was carried out for establishing the structures of the other products (see the Experimental
section).
The efficiency of the newly developed synthetic sequence prompted us to ex-
plore its validity in a parallel library synthesis. Since we had two elements for diversity
multiplication—the carbonyl compound and the isothiocyanate—two different approaches
for combinatorial library synthesis were laid out. In the first approach, different carbonyl
Table I Different elements of diversity incorporated in N-aminoamidinothioureas 4a–l
Compound
no.
Isothiocyanate
component
Carbonyl component
4
a
b
c
d
e
f
g
h
i
R1
CH3
CH3
CH3
R2
CH3
CH3
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
R3
C6H5
4-CH3OC6H4
C6H5
4-CH3CH2OC6H4
C6H5
4-CH3CH2OC6H4
4-ClC6H4
C6H5
4- ClC6H4
C6H5
CH3
CH3CH2
CH3CH2
CH3CH2
−(CH2)5−
−(CH2)5−
j
k
l
C6H5
C6H5
C6H5
H
H
H
4-CH3C6H4
4-CH3OC6H4

FACILE APPROACH TO N-AMINOAMIDINOTHIOUREAS
1833
NH
H2NHN
NH2.HNO3
DMF, NaOH
I; R1= R2 = CH3
O
II; R1= CH3, R2= CH3CH2
III; R1= R2= CH3CH2
IV; R1= R2= -(CH2)5-
R1
R2
I - IV
R3NCS
R3 = C6H5
NH2
S
R1
2R
NHN
N
NHR3
4a, 4c, 4e, 4h
Scheme 3 Structural diversity possible by varying carbonyl compounds.
compounds were used to demonstrate the synthesis of a small library (Scheme 3) by keeping
the isothiocyanate component the same. Equimolar quantities of aminoguanidine nitrate
and NaOH were stirred in DMF, to which a mixture of four carbonyl compounds (0.25
molar equivalent each) was added. A particular isothiocyanate was added in quantities
slightly less than one molar equivalent after the completion of the hydrazone formation
reaction. The reaction mixture upon workup afforded a solid product.
The formation of the expected products in the library was sufficiently established
through HPLC analysis of the crude product. For mixed melting point analysis, already
prepared and characterized compounds were used as standards. This was sufficient enough
to establish our objective to create a library that could be further extended by the use of vari-
ous carbonyl compounds commercially available in large numbers. In the second approach,
different isothiocyanates were employed for generating chemical diversity (Scheme 4).
With the intention of making the library synthesis more attractive, we next decided
to resort to a split-pool approach,12 which would incorporate both the variations in a single
reaction scheme. Thus work on elaborating the library synthesis, its screening (preliminary
screening of the members has given promising results), and application of the newly
developed precursors in heterocycle synthesis is being pursued, and the results will be
published summarily.
EXPERIMENTAL
All chemicals employed were of commercial grade. Melting points are uncorrected
and were determined by open capillary method. TLC was performed using silica gel-G
(E. Merck, India) coated on glass plates or commercial plastic plates from Kodak. The

1834
K. G. SREEJALEKSHMI
NH
O
+
R1
R2
H2NHN
NH2.HNO3
DMF, NaOH
R3 NCS
1
R3 NCS
2
R3 NCS
3
R1= R2= CH3CH2
NH2
S
R3 = C6H5
R1
R2
1
R3 = 4-ClC6H4
NHR3
1-3
2
NHN
N
R3 = 4-CH3CH2OC6H4
3
Scheme 4 Structural diversity possible by varying isothiocyanates.
spots were visualized in iodine vapor or under UV light. IR spectra were obtained from a
Nicolet 400 D FT-IR spectrophotometer using KBr pellets. 1H NMR spectra were recorded
on a Jeol DRX 300 MHz spectrometer in CDCl3 using TMS as the internal standard. Mass
spectrum was recorded on a Jeol D-300 spectrometer by electron impact technique, and
elemental analysis was carried out using an Elementar Vario EL III CHN analyzer.
Synthesis of 1-Aryl-3-[N-(alkyl/arylidene)aminoguanidines] (4a–l)
To a well-stirred suspension of aminoguanidine nitrate (1.37g, 0.01 mol) and sodium
hydroxide (400 mg, 0.01 mol) in DMF (5 mL), the appropriate carbonyl compound (0.01
mol) was added, and the mixture was stirred for 1 h. This was followed by the addition of
isothiocyanates (0.009 mol), and stirring was continued for another 50 min. The reaction
mixture was worked up to afford the title compounds, which were purified by crystallization
from and ethanol/water 2:1 mixture.
N-(Isopropylideneamino)-Nꢀ-(phenylthiocarbamoyl)guanidine (4a)
Off-white shining crystals. Yield 70%. Mp 167–168◦C (d.). Lit.[7] Mp 167–169◦C
(d.). IR (KBr) υ cm−1: 3300, 3200 (NH), 2840 (C H aliphatic), 1620 (C N), 1550, 1400
(CH aromatic) 1300, 1230, 1185 (C N), 1100 (C S), 830,735 (aromatic). 1H NMR: 300
MHz, (CDCl3): δ 2.02 (s, 3H, CH3), 2.07 (s, 3H, CH3), 6.43 (br, 2NH), 7.10 (t, 1ArylH, J
= 6.9 Hz), 7.31 (t, 2 ArylH, J = 9 Hz), 7.47 (d, 2 ArylH, J = 9 Hz), 7.90 (br, 1NH), 12.95
(br, 1NH). Anal. calcd. for C11H15N5S (249.33): C, 52.99; H, 6.06; N, 28.09%. Found: C,
52.77; H, 6.23; N, 28.30%.
N-(Isopropylideneamino)-Nꢀ-(p-methoxylphenylthiocarbamoyl)
guanidine (4b)
Off-white shining crystals. Yield 62%. Mp 161–163◦C. IR (KBr) υ cm−1: 3400, 3235
(NH), 2832 (C H aliphatic), 1648, 1629 (C N), 1528, 1438, 1426 (CH aromatic), 1297,

FACILE APPROACH TO N-AMINOAMIDINOTHIOUREAS
1835
1177 (C N), 1110, 1034 (C S), 823, 668, 572 (aromatic). 1H NMR: 300 MHz, (CDCl3):
δ 2.01 (s, 3H, CH3), 2.06 (s, 3H, CH3), 3.79 (s, 3H, OCH3), 6.35 (br, 2NH), 6.81–6.84
(m, 2ArylH), 7.30–7.32 (m, 2 ArylH), 7.75 (br, 1NH), 12.39 (br, 1NH). Anal. calcd. for:
C12H17N5OS (279.36): C, 51.58; H, 6.13; N, 25.07%. Found C, 51.45; H, 6.04; N, 25.02%.
N-(Isobutylideneamino)-Nꢀ-(phenylthiocarbamoyl)guanidine (4c)
Off-white shining crystals. Yield 56%. Mp 153–154◦C (d.). Lit.[7] Mp 153–155◦C
(d.). IR (KBr) υ cm−1: 3395, 3295 (NH), 3180 (C H aromatic), 2830 (C H aliphatic),
1615 (C N), 1520, 1480, 1390 (CH aromatic), 1300, 1235, 1180 (C N), 1115, 1012
(C S), 740, 685 (aromatic). Anal. calcd. for: C12H17N5S (263.36): C, 54.73; H, 6.51; N,
26.59. Found: C, 54.94; H, 6.71; N, 26.79:
N-(p-Ethoxyphenylthiocarbamoyl)-Nꢀ-(isobutylideneamino)guanidine
(4d)
Off-white shining crystals. Yield 55%. Mp. 147–148◦C (d.). IR (KBr) υ cm−1: 3263
(NH), 2987, 2940, 2802 (C H aliphatic), 1650 (C N), 1445, 1400 (CH aromatic), 1297,
1231, 1179 (C N), 1113, 1049 (C S), 827, 733 (aromatic). 1H NMR: 300 MHz, (CDCl3):
δ 1.12 (t, J = 7.4 Hz, 3H, CH3), 1.40 (t, J = 7 Hz, 3H, CH3), 2.02 (s, 3H, CH3), 2.34 (q, J =
7.4 Hz, 2H, CH2), 4.01 (q, J = 7 Hz, 2H, OCH2), 6.41 (br, 2NH), 6.83 (d, 2ArylH, J = 6 Hz),
7.32 (d, 2ArylH, J = 6 Hz), 7.79 (br, 1NH) 12.22 (br, 1NH). EIMS: m/z (%): 307(M+, 14),
273(9), 236(5), 180(13), 179(83), 171(14), 152(13), 151(100), 150(16), 137(46), 128(32),
119(10), 109(17), 108(24), 99(16). Anal. calcd. for: C14H21N5OS (307.41): C, 54.70; H,
6.89; N, 22.78%. Found: C, 54.89; H, 7.03; N, 22.54%.
N-(Isopentylideneamino)-Nꢀ-(phenylthiocarbamoyl)guanidine (4e)
Off-white shining crystals. Yield 58%. Mp 155–156◦C. IR (KBr) υ cm−1: 3567,
3311, 3221 (NH), 2972 (C H aliphatic), 1718, 1617 (C N), 1534, 1450 (CH aromatic),
1
1122 (C N), 1076 (C S), 832, 743, 690 (aromatic). H NMR: 300 MHz, (CDCl3): δ
1.11–1.22 (m, 6H, 2CH3), 2.32–2.42 (m, 4H, 2CH2), 6.03–6.45 (br, 2NH), 7.08–7.10 (m,
1ArylH), 7.29–7.31 (m, 2ArylH), 7.45 (d, 2ArylH, J = 7.4 Hz), 7.86 (br, 1NH), 12.75
(br, 1NH). EIMS: m/z (%): 243(11), 185(10), 142(22), 135(99), 113(16), 93(22), 91(10),
77(100), 60(15), 59(45), 45(73). Anal. calcd. for: C13H19N5S (277.38): C, 56.28; H, 6.90;
N, 25.25%. Found: C, 56.01; H, 7.14; N, 25.44%.
N-(p-Ethoxyphenylthiocarbamoyl)-Nꢀ-(isopentylideneamino)guanidine
(4f)
Off-white shining crystals. Yield 58%. Mp 145–146◦C. IR (KBr) υ cm−1: 3568, 3230
(NH), 2977, 2928 (C H aliphatic), 2799, 1870, 1774, 1734, 1718 (C N), 1528, 1479 (CH
aromatic), 1253 (C N), 1122 (C S), 828, 696 (aromatic). 1H NMR: 300 MHz, (CDCl3):
δ 1.11–1.21 (m, 6H, 2CH3), 1.41 (t, J = 7Hz, 3H, CH3), 2.06–2.41 (m, 4H, 2CH2), 4.01
(q, J = 7Hz, 2H, OCH2), 6.41 (br, 2NH), 6.81 (d, 2ArylH, J = 6 Hz), 7.29 (d, 2ArylH, J
= 8 Hz), 7.72 (br, 1NH), 12.68 (br, 1NH). EIMS: m/z (%): 178(64), 152(12), 151(100),
150(14), 142(16), 137(18), 134(10), 122(18), 113(14), 108(15), 65(26), 63(12), 59(14),

1836
K. G. SREEJALEKSHMI
58(55), 56(32), 45(26), 44(70). Anal. calcd. for: C15H23N5OS (321.44): C, 56.05; H, 7.21;
N, 21.79%. Found: C, 56.35; H, 7.34; N, 21.67%.
N-(p-Chlorophenylthiocarbamoyl)-Nꢀ-(isopentylideneamino)guanidine
(4g)
Off-white shining crystals. Yield 60%. Mp 132–133◦C. IR (KBr) υ cm−1: 3566, 3219
(NH), 2973 (C H aliphatic), 1716, 1616 (C N), 1539, 1488 (CH aromatic), 1283 (C N),
1
1122, 1021 (C S), 820, 659 (aromatic). H NMR: 300 MHz, (CDCl3): δ 1.12–1.22 (m,
6H, 2CH3), 2.33–2.42 (m, 4H, 2CH2), 6.00–6.48 (br, 2NH), 7.24 (d, 2ArylH, J = 9 Hz),
7.41 (d, 2ArylH, J = 8.4 Hz), 7.80 (br, 1NH), 12.73 (br, 1NH). EIMS: m/z (%): 279(5),
277(11), 172(9), 171(36), 169(100), 142(18), 127(15), 113(24), 111(39), 75(27), 58(46).
Anal. calcd. for: C13H18ClN5S (311.83): C, 50.07; H, 5.82; N, 22.46%. Found: C, 49.91;
H, 5.95; N, 22.2%.
N-(Cyclohexylideneamino)-Nꢀ-(phenylthiocarbamoyl)guanidine (4h)
Off-white shining crystals. Yield 69%. Mp 160–162◦C. IR (KBr) υ cm−1: 3350, 3160
(NH), 3090, 2990, 2850, 2750 (C H aliphatic), 1620 (C N), 1550, 1400 (CH aromatic),
1300, 1230 (C N), 1180, 1000 (C S), 735, 680 (aromatic). 1H NMR: 300 MHz, (CDCl3):
δ 1.62–1.77 (m, 6H, cyclohexyl), 2.33–2.46 (m, 4H, cyclohexyl), 6.29–6.47 (br, 2 NH),
7.09 (t, 1 ArylH, J = 6 Hz), 7.30 (t, 2 ArylH, J = 6 Hz), 7.47 (d, 2ArylH, J = 9 Hz), 7.87(br,
1NH), 12.50(br, 1NH). EIMS: m/z (%): 289(M+, 10), 256(17), 255(27), 197(39), 196(10),
192(29), 154(36), 135(100), 119(10), 111(26), 102(10), 98(18), 96(31), 93(31), 86(14),
77(80). Anal. calcd. for: C14H19N5S (289.39): C, 58.10; H, 6.62; N, 24.20%. Found: C,
58.32; H, 6.47; N, 23.96%.
N-(p-Chlorophenylthiocarbamoyl)-Nꢀ-(cyclohexylideneamino)
guanidine (4i)
Off-white shining crystals. Yield 70%. Mp 166–168◦C (d.). IR (KBr) υ cm−1: 3309,
3235 (NH), 2928 (C H aliphatic), 1645 (C N), 1569, 1523, 1488, 1391 (CH aromatic),
1284 (C N), 1180, 1086 (C S), 828, 730, 649 (aromatic). 1H NMR: 300 MHz, (CDCl3):
δ 1.68–1.75 (m, 6H, cyclohexyl), 2.33–2.46 (m, 4H, cyclohexyl), 6.20–6.46 (br, 2NH), 7.22
(m, 2ArylH), 7.40 (d, 2ArylH, J = 6 Hz), 7.82 (br, 1NH), 12.64 (br, 1NH). EIMS: m/z (%):
289(6), 287(14), 274(16), 231(35), 210(15), 208(46), 195(12), 153 (50), 151(16), 137(20),
128(18), 126(66), 115(79), 111(10), 110(64), 96(7), 95(28), 82(19), 81(22), 43(100). Anal.
calcd. for: C14H18ClN5S (323.84): C, 59.99; H, 5.61; N, 21.63%. Found: C, 51.66; H, 5.44;
N, 21.82%.
N-(Benzylideneamino)-Nꢀ-(phenylthiocarbamoyl)guanidine (4j)
Pale green shining crystals. Yield 43%. Mp 169–170◦C (d.). Lit.[7] Mp. 168–170◦C
(d.). IR (KBr) υ cm−1: 3425, 3398 (NH), 3041 (C H aromatic), 1619 (C N), 1591, 1560,
1464 (CH aromatic), 1310 (C N), 1095 (C S), 807, 748, 686 (aromatic). Anal. calcd. for:
C15H15N5S (297.37): C, 60.58; H, 5.08; N, 23.55%. Found: C, 60.83; H, 5.26; N, 23.75%.

FACILE APPROACH TO N-AMINOAMIDINOTHIOUREAS
1837
N-(Benzylideneamino)-Nꢀ-(p-methylphenylthiocarbamoyl)guanidine
(4k)
Pale green shining crystals. Yield 50%. Mp 156–158◦C. IR (KBr) υ cm−1: 3400
(NH), 3080 (C H aromatic), 1610, 1600 (C N), 1580, 1550, 1500, 1435 (CH aromatic),
1090 (C S), 805, 750, 680 (aromatic). 1H NMR: 300 MHz, (CDCl3): δ 2.33 (s, 3H, CH3),
6.6 (br, 1NH), 7.43 (m, 3 ArylH), 7.65 (m, 2 ArylH), 7.93 (br, 2 NH), 8.51 (br, 1NH). EIMS:
m/z (%):195(9), 162(35), 161(20), 150(14), 149(100), 148(42), 119(15), 117(12), 106(12),
92(13), 91(97), 90(34), 89(30), 85(25), 77(20). Anal. calcd. for: C16H17N5S (311.40): C,
61.71; H, 5.50; N, 22.49%. Found: C, 61.52; H, 5.63; N, 22.30%.
N-(Benzylideneamino)-Nꢀ-(p-methoxyphenylthiocarbamoyl)guanidine
(4l)
Pale green shining crystals. Yield 45%. Mp 165–66◦C. IR (KBr) υ cm−1: 3427, 3225
(NH), 2830, 1720, 1621 (C N), 1534, 1509 (CH aromatic), 1110, 1099 (C S), 835, 800,
751, 690 (aromatic). 1H NMR: 300 MHz, (CDCl3): δ 3.80 (s, 3H, OCH3), 6.56 (br, 1NH),
6.85–6.87 (m, 2 ArylH), 7.38–7.46 (m, 4 ArylH), 7.60–7.68 (m, 3ArylH), 7.89–8.01 (br,
1H, CH = N + 2 NH), 8.54 (br, 1NH). EIMS: m/z (%): 293(17), 292(53), 277(18), 250(17),
249(36), 210(27), 205(21), 195(30), 189(45), 166(7), 163(19), 162(46), 160(20), 119(10),
104(30), 91(100), 90(30), 77(40). Anal. calcd. for: C16H17N5OS (327.40): C, 58.69; H,
5.23; N, 21.39%. Found: C, 58.42; H, 5.48; N, 21.27%.
REFERENCES
1. (a) J. C. Kaila, A. B. Baraiya, K. K. Vasu, and V. Sudarsanam, Tetrahedron Lett., 49(50), 7220
(2008); (b) J. C. Kaila, A. B. Baraiya, A. N. Pandya, H. B. Jalani, K. K. Vasu, and V. Sudarsanam,
Tetrahedron Lett., 50(27), 3955 (2009).
2. R. Binu, K. K. Thomas, G. C. Jenardanan, and K. N. Rajasekharan, Org. Prep. Proc. Int., 30, 93
(1998).
3. K. N. Rajasekharan, K. P. Nair, and G. C. Jenardanan, Synthesis, 353 (1986).
4. G. C. Jenardanan, M. Francis, S. Deepa, and K. N. Rajasekharan, Synth. Commun., 27, 3457
(1997).
5. S. Sengupta, S. L. Smitha, N. E. Thomas, T. R. Santhoshkumar, S. K. C. Devi, K. G. Sreejalek-
shmi, and K. N. Rajasekharan, Br. J. Pharmacol., 145, 1076 (2005).
6. S. K. C. Devi and K. N. Rajasekharan, Synth. Commun., 32, 1523 (2002).
7. L. E. A. Godfrey and F. Kurzer, J. Chem. Soc., 3437 (1960).
8. L. E. A. Godfrey and F. Kurzer, J. Chem. Soc., 4558 (1963).
9. C. Pinilla, J. R. Appel, E. Borra`s, and R. A. Houghten, Nature Medicine, 9, 118 (2003).
10. (a) Do¨mling and I. Ugi, Angew. Chem. Intl. Ed., 39, 3168C (2000); (b) C. Hulme and V. Gore,
Current Med. Chem., 10, 51 (2003).
11. A. Volonterio and M. Zanda, Org. Lett., 9(5), 841 (2007).
12. Y. Sun, B. C. Chan, R. Ramnarayanan, W. M. Leventry, and T. E. Mallouk, J. Comb. Chem.,
4(6), 569 (2002).