O-Iodoxybenzoic acid mediated oxidative condensation: Synthesis of guanidines using 1,-3-disubstituted thiourea precursors

Article abstract of DOI:10.1016/j.tetlet.2012.09.130

An efficient and mild oxidative condensation procedure using o-iodoxybenzoic acid and triethylamine or ammonia as base has been developed for the synthesis of guanidines starting from easily synthesizable 1,3-disubstituted thioureas and amines or ammonia.

Full text of DOI:10.1016/j.tetlet.2012.09.130

Tetrahedron Letters 53 (2012) 6765–6767
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Tetrahedron Letters
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o-Iodoxybenzoic acid mediated oxidative condensation: synthesis
of guanidines using 1,-3-disubstituted thiourea precursors
⇑
Prasad S. Dangate, Krishnacharya G. Akamanchi
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga, Mumbai 400019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and mild oxidative condensation procedure using o-iodoxybenzoic acid and triethylamine or
ammonia as base has been developed for the synthesis of guanidines starting from easily synthesizable
1,3-disubstituted thioureas and amines or ammonia.
Received 23 August 2012
Revised 26 September 2012
Accepted 28 September 2012
Available online 5 October 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
o-Iodoxybenzoic acid
Guanidines
Oxidation
Condensation
Thiourea
Amines
Chemistry and biology of guanidine derivatives, reviewed peri-
odically, is an attractive area of research and development.1 Guani-
dine derivatives are widely used as ancillary ligands2 for
stabilization of a variety of metal complexes. They also find applica-
tions as an important pharmacophore with improved pharmacoki-
netic properties in medicinal chemistry.3 Guanidine moiety is
present in many biologically active natural products such as saxi-
toxin, a toxic marine natural product that targets multitude of
receptors4 showing CNS5 and anti-Helicobacter pylori6 activity; in
polyamine based analogues useful as biochemical probes and po-
tential therapeutics,7 in alkaloids like bromopyrroles,8 in drugs
such as anigrilide used for the treatment of essential thrombocyto-
sis and chronic myeloid leukaemia.9 Guanidine moiety is also found
in amino acids such as arginine and in peptides as an important
building block. Many methods are reported in the literature for
the synthesis of guanidines starting from thioureas, isothioureas,
carbodiimides, cyanamides, pyrrazole-1-carboximidamides and
triflylguanidines.10 Combination of thioureas and amines has been
used for the synthesis of guanidines via desulfurization using re-
agents such as Mukaiyama’s reagent,11 diiodomethane,12 hydrogen
peroxide,13 metal salts like copper chloride or mercuric chloride14
and copper sulfate.15 Drawbacks of these methods are use of toxic
metals, lower yields and longer reaction times. Newer methods
for guanidine synthesis are reported recently using guanylating
agents such as N,–N00,–N000-tri-Boc-guanidine,16 bis-(benzotriazole-
1-yl)methylene amines and benzotriazole-1-carboxamidines.17
Hypervalent iodine reagents and in particular organo-iodine (V) re-
agents, are finding wide applications in organic transformations
and synthesis of natural products. This growing interest, as indi-
cated by many recent review articles, is due to their nontoxic, mild
and highly chemoselective oxidizing property coupled with, easy
work–up procedures and eco-friendly features.18
Our research group is actively engaged in exploring the utility of
hypervalent iodine reagents especially, o-iodoxybenzoic acid (IBX)
and Dess-Martin periodinane (DMP).19 Recently we have reported
a mild and efficient oxidative desulfurization of 1,-3-disubstituted
thioureas to carbodiimides20a and synthesis of azoles20b by using
IBX in the presence of base such as triethylamine (TEA). As an
extension to this, it was hypothesized that, a one pot synthesis of
guanidine can be realized, if carbodiimides are generated in the
presence of amines or ammonia and trap them to form guanidines.
This hypothesis was tested by adding a solution of IBX/NH3 drop
wise to a solution of 1,-3-diphenylthiourea in acetonitrile at room
temperature, and expected N,–N00-diphenylguanidine was formed
in 90% yield with precipitation of sulfur (Scheme 1).
On the same line when a solution of IBX/TEA in acetonitrile was
added to a solution of 1,-3-diphenylthiourea and aniline in aceto-
nitrile, N,–N00,–N000-triphenylguanidine was obtained in 78% yield
(Scheme 2).
IBX is not compatible with amines21 however the present suc-
cess is attributed to the rapid desulfurization of thiourea to form
carbodiimide. To establish generality of the protocol,22 a variety
⇑
Corresponding author. Tel.: +91 22 33612214; fax: +91 22 33611020.
E-mail addresses: kgap@rediffmail.com, kg.akamanchi@ictmumbai.edu.in (K.G.
Akamanchi).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.130

6766
P. S. Dangate, K. G. Akamanchi / Tetrahedron Letters 53 (2012) 6765–6767
H
N
H
N
H
N
H
N
IBX/NH3
ACN, rt
NH3
rt
N
C N
S
+
NH
S
Scheme 1. Oxidative desulfurization and formation of N,–N00-diphenylguanidine from 1,3-diphenylthiourea with IBX/NH3 system.
H
N
H
N
H
N
H
N
Ph-NH2
rt
IBX/TEA
ACN, rt
N
C N
S
+
N
S
Ph
Scheme 2. Oxidative condensation of 1,3-diphenylthiourea and aniline with IBX/TEA to form N,–N00,–N000-triphenylguanidine.
of 1,-3-disubstituted thioureas were studied and the results are
summarized in Table 1. In general reactions were very fast and
yields were comparable irrespective of the nature of substituents
on the aromatic rings. For example substrates carrying methyl,
methoxy and chloro substituents at ortho-, meta- and para-
positions reacted equally efficient (Table 1, entries 2–8). Reaction
proceeded smoothly with cyclohexyl and benzyl substituted
thioureas (Table 1, entries 9–10). Reaction was equally efficient
in formation of the tri-substituted (Table 1, entries 11–15) as well
as the tetra-substituted guanidines (Table 1, entry 16). However
reaction was not smooth and gave a complex mixture with
monosubstituted and 1,-3-dicyclohexyl thioureas. As far as amine
component is concerned reaction occurred efficiently with all,
including ammonia, aliphatic amines, anilines and cyclohexyl amine.
A plausible mechanism for the formation of guanidines from 1,-
3-disubstituted thioureas is presented in Scheme 3. Precipitation of
sulfur during the reaction and observation of spot corresponding to
carbodiimide on TLC, taken immediately after addition of IBX,
support the postulated mechanism. Recovery of the generated
trivalent iodine A for recycling after re-oxidation to IBX by Oxone
was also possible.
H
NEt3
OH
O
OH
I
O
I
O
O
S
O
S
R1
R2
O
R1
R2
N
N
H
N
H
N
H
NEt3
NEt3
O
HNEt3
I
O
Et3N
+
+
R1
N
C
N
R2
H2O
+
S
+
O
NH2R3
A
H
H
N
N
R1
R2
NR3
Scheme 3. Plausible mechanism for the formation of guanidines via carbodiimides,
from 1,-3-disubstituted thiourea.
Table 1
Preparation of guanidines from 1,-3-disubstituted thioureas
H
H
N
H
N
N
N
IBX (TEA or NH3)
ACN, rt
In summary, an efficient one pot method based on oxidative
condensation of 1,-3-disubstituted thioureas and ammonia/amines
using IBX as oxidant has been developed for one pot synthesis of
guanidines with mild reaction conditions, ease of isolation and
suitability for a wide range of substrates. IBX oxidations are selec-
tive and tolerate a wide range of functional groups therefore; this
method has the potential to be extended to complex substrates.
R1
R2
R1
R2
R3R4NH
+
N
S
R3
R4
Entry R1
R2
R3
R4
Methoda Yieldb
1
2
3
4
5
6
7
8
C6H5
m-ClC6H4
p-ClC6H4
C6H5
m-ClC6H4
p-ClC6H4
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
B
90
88
90
86
88
86
88
90
85
88
78
82
78
85
80
85
Spectral data of selected guanidines
p-CH3OC6H4 p-CH3OC6H4
1,3-bis(3-Chlorophenyl)guanidine (Table 1, entry 2): Mp 140 °C
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H11
C6H5
C6H5
C6H5
C6H5
C6H11
o-ClC6H4
p-ClC6H4
o-CH3C6H4
p-CH3OC6H4
C6H11
Bn
C6H5
Bn
C6H5
C6H5
(lit.23 Mp 139 °C). IR (KBr): 3434, 1586, 1524 and 1472 cmꢀ1 1H
.
NMR (400 MHz, DMSO-d6) d = 7.18 (m, 2H), 7.33–7.66 (m, 6H),
7.66 (s, 2H), 10.03 (s, 1H).
9
H
H
N,N0-di-p-Chlorophenylguanidine (Table 1, entry 3): Mp 140 °C
10
11
12
13
14
15
16
17
18
(lit.23 Mp 139 °C). IR (KBr): 3434, 1586, 1524 and 1472 cmꢀ1 1H
.
C6H5
C6H5
C6H11
CH3
C4H9
(CH3)2CH (CH3)2CH
C6H5
C6H5
NMR (400 MHz, DMSO-d6): d = 7.30 (m, 4H), 7.34–7.57 (m, 4H),
8.25 (s, br, 2H), 10.03 (s, 1H).
1,3-bis(4-Methoxyphenyl)guanidine (Table 1, entry 4): Mp
156 °C (lit.24 Mp 157 °C). IR (KBr): 3436, 1628, 1613 and
C6H5
C6H5
H
C6H11
1402 cmꢀ1 1H NMR (400 MHz, DMSO-d6) d = 3.74 (s, 6H), 6.89 (d,
.
c
H
H
—
c
—
4H), 7.30 (d, 4H), 9.40 (s, 1H).
a
b
c
1-(2-Chlorophenyl)-3-phenylguanidine (Table 1, entry 5): Mp
For general procedures see Ref. 22.
Isolated yields.
Complex mixture.
127 °C (lit.25 Mp 129 °C). IR (KBr): 3457, 1635, 1578 and1468 cmꢀ1
.
1H NMR (300 MHz, DMSO-d6) d = 7.18 (m, 1H), 7.21 (m, 2H), 7.35

P. S. Dangate, K. G. Akamanchi / Tetrahedron Letters 53 (2012) 6765–6767
6767
(m, 2H), 7.49 (m, 2H), 7.61 (m, 2H), 8.87 (s, br, 1H), 9.35 (s, br, 1H),
References and notes
10 (s, br, 1H).
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2. Zhu, X.; Xu, F.; Shen, Q. Chin. J. Chem. 2009, 27, 19.
3. Durant, G. J. Chem. Soc. Rev. 1985, 14, 375.
1-(4-Chlorophenyl)-3-phenylguanidine (Table 1, entry 6): Mp
148 °C (lit.26 Mp 150 °C). IR (KBr): 3440, 1656 and 1584 cmꢀ1 1H
.
NMR (400 MHz, DMSO-d6) d = 7.2 (m, 1H), 7.31 (m, 1H), 7.36 (m,
3H), 7.5 (m, 2H), 7.58 (m, 2H), 9.39 (s, 1H), 9.99 (s, 2H).
4. Llewellyn, L. E. Nat. Prod. Rep. 2006, 23, 200.
1-(4-Methoxyphenyl)-3-phenylguanidine (Table 1, entry 8): Mp
137 °C (lit.25 Mp 140 °C). IR (KBr): 3460, 1638, 1585, 1551 and
5. Clement, J. A.; Yoder, B. J.; Kingston, D. G. I. Mini-Rev. Org. Chem. 2004, 1, 183.
6. Muri, E. M. F.; Williamson, J. S. Mini-Rev. Med. Chem. 2004, 4, 201.
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8. Aiello, A.; Fattorusso, E.; Menna, M.; Taglialatela-Scafati, O. In Modern Alkaloids;
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2008; pp 271–304. Chapter 10.
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10. Katritzky, A. R.; Rogovoy, R. F. ARKIVOC 2005, 49.
1498 cmꢀ1 1H NMR (300 MHz, DMSO-d6) d = 3.80 (s, 3H), 6.86
.
(m, 2H), 7.17 (m, 1H), 7.25 (m, 4H), 7.43 (m, 2H), 9.60 (s, br, 2H),
10.63 (s, br, 1H).
1-Cyclohexyl-3-phenylguanidine (Table 1, entry 9): Mp 133 °C
(lit.13 Mp 134 °C). IR (KBr): 3402, 1651, 1582 and 1484 cmꢀ1 1H
.
NMR (300 MHz, DMSO-d6) d = 1.25 (m, 4H), 1.51 (m, 2H), 1.7 (m,
2H), 1.89 (m, 2H), 2.44 (m, 1H), 7.14 (m, 1H), 7.33 (m, 2H), 7.43
(m, 2H), 7.61 (m, 1H), 9.33 (s, br, 2H), 10 (s, br, 1H).
11. Yong, Y. F.; Kowalski, J. A.; Lipton, M. A. J. Org. Chem. 1997, 62, 1540.
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1-Benzyl-3-phenylguanidine (Table 1, entry 10): Mp 123 °C
(lit.27 Mp 124 °C). IR (KBr): 3441,1588,1536,1499 and 1659 cmꢀ1
.
14. Kim, K. S.; Qian, L. Tetrahedron Lett. 1993, 34, 7677.
1H NMR (300 MHz, DMSO-d6) d = 4.73 (s, 2H), 7.11 (m, 1H), 7.24–
7.34 (m, 7H), 7.43 (m, 2H), 8.14 (s, br, 1H), 8.96 (s, br, 1H), 9.59
(s, br, 1H).
15. Ramadas, K.; Srinivasan, N. Tetrahedron Lett. 1995, 36, 2841.
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17. Katritzky, A. R.; Khashab, N. M.; Bobrov, S. Helv. Chim. Acta 2005, 88, 1664.
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F. Angew. Chem., Int. Ed. 2011, 50, 1524; (c) Miura, T.; Nakashima, K.; Tada, N.;
Itoh, A. Chem. Commun. 1875, 2011, 47.
19. (a) Deshmukh, S. S.; Huddar, S. N.; Bhalerao, D. S.; Akamanchi, K. G. ARKIVOC
2010, ii, 118; (b) Patil, P. C.; Bhalerao, D. S.; Dangate, P. S.; Akamanchi, K. G.
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Akamanchi, K. G. Tetrahedron Lett. 2011, 42, 4533.
20. (a) Chaudhari, P. S.; Dangate, P. S.; Akamanchi, K. G. Synlett 2010, 20, 3065; (b)
Chaudhari, P. S.; Pathare, S. P.; Akamanchi, K. G. J. Org. Chem. 2012, 77, 3716.
21. Drouet, F.; Fontaine, P.; Masson, G.; Zhu, J. Synthesis 2008, 8, 1370.
22. Method A: General experimental procedure for guanidines (entries 1–10): To a
stirred solution of 1,3-disubstituted thiourea (5 mmol) in acetonitrile (10 mL)
was added drop wise a solution of IBX (5.5 mmol), in aqueous ammonia (10 mL
of a 28–30% solution) at rt over a period of 10 min. After completion of reaction
as analysed by TLC (reaction time 30 min) the mixture was extracted with
(2 ꢁ 15 mL) ethyl acetate. The organic layer was washed with 10% aqueous
sodium bicarbonate solution (2 ꢁ 15 mL), evaporated and chromatographed to
afford the pure product.
1,2,3-Triphenylguanidine (Table 1, entry 11): Mp 146 °C (lit.28
Mp 144 °C). IR (KBr): 3060, 3030 and 1659 cmꢀ1 1H NMR
.
(400 MHz, DMSO-d6) d = 6.95 (m, 2H), 7.07 (m, 4H), 7.17 (m, 4H),
7.27 (m, 5H), 7.43 (m, 1H), 7.84 (m, 1H).
1-Benzyl-2,3-diphenylguanidine (Table 1, entry 12): Mp 101 °C
(lit.29 Mp 103 °C). IR (KBr): 3432, 1667, 1494 and 1441 cmꢀ1 1H
.
NMR (400 MHz, DMSO-d6) d = 3.9 (s, 2H), 6.94 (m, 2H), 7.06 (m,
4H), 7.17 (m, 4H), 7.32 (m, 5H), 7.52 (m, 1H), 7.84 (m, 1H).
2-Methyl-1,3-diphenylguanidine (Table 1, entry 14): Mp 108 °C
(lit.29 Mp 109 °C). IR (KBr): 3441, 1588, 1531 and1484 cmꢀ1 1H
.
NMR (300 MHz, DMSO-d6) d = 2.85 (s, 3H), 7.20 (m, 6H), 7.37 (m,
4H).
2-Butyl-1,3-diphenylguanidine (Table 1, entry 15): Mp 127 °C
(lit.30 Mp 129 °C). IR (KBr): 3420, 1530 and 1494 cmꢀ1 1H NMR
.
Method B: General experimental procedure for guanidines (entries 11–18): To a
stirred solution of 1,3-disubstituted thiourea (5 mmol) and amine (5 mmol) in
acetonitrile (10 mL) was added drop wise a solution of IBX (5.5 mmol), in
triethylamine (15 mmol) at rt over a period of 10 min. After completion of
reaction as analysed by TLC (reaction time 30 min) the mixture was extracted
with (2 ꢁ 15 mL) ethyl acetate. The organic layer was washed with 10%
aqueous sodium bicarbonate solution (2 ꢁ 15 mL), evaporated and
chromatographed to afford the pure product.
(300 MHz, DMSO-d6) d = 0.85 (t, 3H), 1.05 (q, 2H), 1.29 (m, 2H),
2.5 (m, 2H), 6.75 (m, 4H), 7.10–7.40 (m, 10H), 7.68 (m, 1H), 8.50
(s, 1H).
1,1-Diisopropyl-2,3-diphenylguanidine (Table 1, entry 16): Mp
48 °C (lit.29 Mp 50 °C). IR (KBr): 3448, 2950, 1650, 1588 cmꢀ1 1H
.
NMR (300 MHz, DMSO-d6) d = 1.91 (m, 2H), 1.34 (m, 8H), 1.47 (m,
2H), 2.97 (m, 2H), 6.30 (s, 1H), 6.53 (s, 1H), 6.72 (m, 1H), 6.99 (m,
5H), 7.20 (m, 1H), 7.44 (m, 1H), 8.22 (s, br, 1H), 8.77 (s, br, 1H).
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Acknowledgments
One of the authors (D.P.S.) is grateful to CSIR for financial assis-
tance. We are also thankful to M/S Omkar Chemicals in Badlapur,
Thane, India, for generous gift of IBX.