Copper(i) iodide-catalyzed synthesis of N,N′-disubstituted guanidines from n-substituted cyanamides

Article abstract of DOI:10.1071/CH14197

A facile and effective synthesis of N-alkyl-N′-arylguanidines was accomplished by the reaction of N-arylcyanamides with various primary and secondary alkylamines, under the catalysis of copper(i) iodide and Xantphos in DMF. This methodology provides a direct access to versatile N,N′- disubstituted guanidine derivatives from N-arylcyanamides that can be readily prepared from the corresponding nitriles via Tiemann rearrangement. CSIRO 2014.

Full text of DOI:10.1071/CH14197

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem.
Communication
http://dx.doi.org/10.1071/CH14197
Copper(I) Iodide-Catalyzed Synthesis of N,N9-Disubstituted
Guanidines from N-Substituted Cyanamides*
A
A
A
Cian-Jhe Zeng, Chia-Jung Chen, Chih-Wei Chang,
B C
,
A C
,
Hui-Ting Chen,
and Tun-Cheng Chien
A
Department of Chemistry, National Taiwan Normal University, Taipei 11677, Taiwan.
Department of Fragrance and Cosmetic Science, Kaohsiung Medical University,
Kaohsiung 80708, Taiwan.
B
C
Corresponding authors. Email: htchen@kmu.edu.tw; tcchien@ntnu.edu.tw
A facile and effective synthesis of N-alkyl-N0-arylguanidines was accomplished by the reaction of N-arylcyanamides with
various primary and secondary alkylamines, under the catalysis of copper(I) iodide and Xantphos in DMF. This
methodology provides a direct access to versatile N,N0-disubstituted guanidine derivatives from N-arylcyanamides that
can be readily prepared from the corresponding nitriles via Tiemann rearrangement.
Manuscript received: 1 April 2014.
Manuscript accepted: 2 June 2014.
Published online: 30 June 2014.
Guanidine is an important nitrogen-containing functionality
and characteristic structural motif which commonly exists in
natural products and biologically active compounds.[1–3] In
addition, N-substituted guanidines have been extensively used
as reactive CN3 building blocks and organocatalysts[4–6] in
organic synthesis, as well as bidentate ligands in coordination
chemistry. Despite their versatile applications, only a few syn-
thetic approaches for the preparation of N-substituted guani-
dines have been practically utilized in the literature. The most
straightforward approach involves the direct nucleophilic attack
of amines to various activated CN2 guanidinylating reagents,
usually derived from ureas or thioureas.[7,8] Unactivated car-
bodiimides and cyanamides are less reactive CN2 guanidiny-
lating reagents.[9] Their reactions with amines require higher
temperature,[10–13] acidic condition,[14–19] or the assistance of
nucleophilic reagents such as fluoride ion or N-hetero-azoles
(pyrazoles, imidazoles, or benzotriazoles).[20]
Recent studies have shown that guanidine formation from
the reaction of carbodiimides with amines can be effectively
catalyzed by various metal salts or metal complexes, includ-
ing zinc,[21] aluminium,[22,23] titanium,[24] vanadium,[25] and
several rare earth metals.[26,27] In contrast, the metal-catalyzed
guanidine formation from cyanamides and amines was only
recently reported by Li and Neuville, in which the trisubstituted
guanidines can be obtained from copper(II) chloride-catalyzed
three-component reaction of cyanamides, arylboronic acids,
and amines.[28] Lately, we reported a general procedure for
the preparation of N-substituted cyanamides via Tiemann rear-
rangement.[29] In a continuous effort to explore the potential
synthetic application of cyanamides, we embarked on an inves-
tigation of a general and practical synthesis of guanidines via
metal-catalyzed reaction.
Our study focussed on the reaction of N-arylcyanamides with
amines and N-(4-methylphenyl)cyanamide (1a) and benzyla-
mine (2a) were chosen as model substrates to investigate the
guanidine formation reaction. In our initial attempts, the direct
addition of benzylamine (2a) to N-(4-methylphenyl)cyanamide
(1a) under the catalysis of tertiary amines and N-heterocycles
was examined. The results showed that the reactions gave only
poor to moderate yields (entries 1–5 in Table 1). We rationalized
that, unlike the carbodiimides, N-monosubstituted cyanamides
possess an acidic proton that gets deprotonated under these
conditions, thus deactivating the cyanamides from the nucleo-
philic addition of amines. We then shifted our focus to metal-
catalyzed guanidine formation from cyanamides and amines.
The screening of the reaction conditions started with copper,
nickel, and iron salts as the catalysts with various solvents,
temperatures, and ligands/additives (part of the results are
summarized in Table 1). The survey of the conditions con-
cluded that maximal yield was obtained when the reaction was
carried out in DMF with copper(I) iodide as the catalyst, and
Xantphos as the ligand under argon atmosphere at 1408C (entry
16 in Table 1). We postulated that the copper(I) salt played the
role of a Lewis acid to activate the cyano group to facilitate
the addition reaction.
With the optimized condition established, the scope and
generality of the reaction was explored. A wide variety of
N-arylcyanamides 1a–k, prepared from the corresponding car-
bonitriles via Tiemann rearrangement,[29] were subjected to the
reaction, under the optimized condition (entry 16 in Table 1),
with various primary and secondary amines 2a–g. Our investi-
gation showed that N-arylcyanamides 1a–j could react with
primary and secondary alkylamines 2a–f to give good yields of
the targeted N,N0-disubstituted guanidines in free-base form.
*This paper is dedicated to Professor Ming-Chang P. Yeh on the occasion of his 60th birthday.
Journal compilation Ó CSIRO 2014
www.publish.csiro.au/journals/ajc

B
C.-J. Zeng et al.
Table 1. Survey and optimization of the reaction conditions
Benzylamine
Me
Me
(2a, 1 equiv.)
HN
Ph
NH2
Catalyst
(ligand or additive)
temperature, 3 h
CN
N
N
H
1a
3aa
Entry
Catalyst
[equiv.]
Ligand or additive
[equiv.]
Temperature
Solvent
Yield
[%]A,B
[8C]
1
–
Et3N (1)
100
100
100
100
100
100
100
100
100
100
110
120
120
120
140
140
140
140
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Toluene
50 (11)
46 (17)
28 (33)
50 (17)
39 (26)
50 (18)
53 (14)
56 (9)
40C
2
–
DABCO (1)
DBU (1)
3
–
4
–
Benzotriazole (1)
DMAP (0.1)
Xantphos (0.1)
Xantphos (0.1)
Xantphos (0.1)
Xantphos (0.1)
Xantphos (0.1)
Xantphos (0.1)
Xantphos (0.1)
Xantphos (0.1)
Xantphos (0.1)
Xantphos (0.1)
Xantphos (0.05)
–
5
–
6
CuCl2 (0.1)
CuCl (0.1)
CuI (0.1)
NiCl2 (0.1)
FeCl3 (0.1)
CuI (0.1)
CuI (0.1)
CuI (0.1)
CuCl (0.1)
CuI (0.1)
CuI (0.05)
CuI (0.05)
CuCl2 (0.1)
7
8
9
10
11
12
13
14
15
16
17
18
13C
31
Chlorobenzene
DMF
15
60 (20)
56 (7)
66
DMF
DMF
DMF
69C
DMF
16
Xantphos (0.1)
DMF
51
AUnless specified otherwise, the yields were determined by 1H NMR analysis of the crude products using
1,3,5-trimethoxybenzene as an internal standard.
BNumbers in parentheses represent the unreacted cyanamides, if denoted.
CIsolated yield.
R2
N
R3
CuI (0.05 equiv.)
R1
CN
R2
R3
N
ꢀ
N
H
N
H
R1
Xantphos (0.05 equiv.)
DMF (0.2 M), Ar, 3 h
NH2
1
2
3
Bu
Bn
R
Bn
Me
HN
HN
HN
NEt2
HN
N
N
NH2
N
NH2 MeO
N
NH2
N
NH2
N
NH2
3aa R ꢁ Me 69 %
3ba
3ca R ꢁ Cl 56 %
3da R ꢁ NO2 73 %
3fa R ꢁ CF3 66 %
3ae 61 %
3gc 40 %
Cl
Cl
3hb 57 %
3ja 59 %
R ꢁ H
59 %
O
R
HN
Me
N
N
N
N
N
NH2
N
N
NH2
N
NH2 MeO
N
NH2
Me
Me
3ia R ꢁ Bn 73 %
3ib R ꢁ Bu 83 %
HN
3af 79 %
3gd 85 %
Cl
3jd 57 %
N
NH2
Bu
3ac 62 %
HN
NEt2
NH2
NEt2
NH2
N
MeO
N
NH2 MeO
N
N
N
NH2
3gb
3ge 87 %
R
51 %
Cl
3je
N
Me
3id 81 %
46 %
N
NH2
OMe
3ad R ꢁ Me 95 %
R
HN
3cd R ꢁ Cl
92 %
Me
HN
N
Bn
3dd
R ꢁ NO2 90 %
N
NH2
Bn
3ed R ꢁ MeO 84 %
3fd R ꢁ CF3 95 %
N
NH2
3ag 0 %
N
NH2
3kd 0 %
3ka R ꢁ Bn 0 %
3kb R ꢁ Bu 0 %
Scheme 1.

N,N0-Disubstituted Guanidines
C
R1
TsOH⋅H2O R1
R2
which is amenable to the preparation of various N,N0-disubsti-
tuted guanidine derivatives.
HN
(1 equiv.)
2
ꢀ
CN
R
NH2
N
H
N
4
Toluene
reflux, 5 h
NH2⋅TsOH
1
2
Experimental
General Procedure for the Preparation of N-Alkyl-N0-
arylguanidines 3 from N-Arylcyanamides 1 (Scheme 1)
R
R
Me
Cl
To a solution of N-arylcyanamide[29] (1, 1.0 mmol) in DMF
(5 mL) was added Xantphos (0.05 mmol, 0.05 equiv.), CuI
(0.05 mmol, 0.05 equiv.), and amine (2, 1.0 mmol, 1 equiv.). The
resulting mixture was stirred under argon atmosphere at 1408C
for 3 h. The reaction mixture was concentrated under reduced
pressure and the residue was purified by flash column
chromatography.
HN
HN
N
NH2⋅TsOH
N
NH2⋅TsOH
4ag R ꢁ OMe 94 %
4cg R ꢁ OMe 89 %
4ci R ꢁ Me
4ah R ꢁ H
52 %
89 %
91 %
4ai R ꢁ Me
OMe
O2N
Me
HN
N
HN
N
General Procedure for the Preparation of N,N0-
Diarylguanidines 4 from N-Arylcyanamides 1 (Scheme 2)
NH2⋅1/ TsOH
NH2⋅TsOH
2
A mixture of N-arylcyanamide[29] (1, 1.0 mmol), amine
4dg 68 %
4aa 95 %
.
(2, 1.0 mmol, 1 equiv.), and p-TsOH H2O (1.0 mmol, 1 equiv.)
Scheme 2.
in toluene (5 mL) was stirred at reflux temperature for 5 h. The
reaction mixture was concentrated under reduced pressure and
the residue was purified by flash column chromatography.
The yields of the reaction can be correlated with the electro-
philicity of the cyanamide carbon and the nucleophilicity of the
amine nitrogen. In general, the N-arylcyanamides possessing
electron-withdrawing substituents as the electrophiles or the
secondary amines as the nucleophiles could result in better yields
(Scheme 1). It is notable that, although the reactions of
N-arylcyanamides with alkylamines proceeded flawlessly under
the optimized condition, our attempts to apply the same condition
to the reaction with primary arylamines were unsuccessful. In
contrastto the primary and secondaryalkylamines, wespeculated
that this failure could be attributed to the reduced nucleophilicity
of the arylamines. Moreover, the reaction of N-alkylcyanamides
1k with primary and secondary alkylamines also failed to givethe
desired N,N0-dialkylguanidines. (Scheme 1)
Supplementary Material
1H and 13C NMR spectra of representative compounds are
available on the Journal’s website.
Acknowledgements
This work was supported by Research Grants 102–2113-M-003–004- and
102–2113-M-037–003- from Ministry of Science and Technology, Taiwan,
and NTNU100-D-06 from National Taiwan Normal University. We also
thank Professor Choon Hong Tan (Nanyang Technological University) for
his helpful discussion and Mr Ting-Shen Kuo (National Taiwan Normal
University) for his assistance with X-ray crystallographic analysis.
In a continuous screening of catalytic conditions for the
reaction of N-(p-tolyl)cyanamide (1a) with p-anisidine (2g), we
found that only the commonly used acid-catalyzed reac-
tions[14–19] could give an acceptable yield of the desired product,
while the copper salts were unable to effectively catalyse the
guanidine formation. The acid-catalyzed guanidine formation
gave the product in its salt form and our attempts to remove the
acidic counterpart were unsuccessful. Nevertheless, our investi-
gation chose a stoichiometric amount of p-toluenesulfonic acid
(TsOH) as the catalyst, by which the counterion of the resulted
References
[1] R. G. S. Berlinck, A. E. Trindade-Silva, M. F. C. Santos, Nat. Prod.
Rep. 2012, 29, 1382. doi:10.1039/C2NP20071F
[2] R. G. S. Berlinck, A. C. B. Burtoloso, A. E. Trindade-Silva,
S. Romminger, R. P. Morais, K. Bandeira, C. M. Mizuno, Nat. Prod.
Rep. 2010, 27, 1871. doi:10.1039/C0NP00016G
[3] R. G. S. Berlinck, A. C. B. Burtoloso, M. H. Kossuga, Nat. Prod. Rep.
2008, 25, 919. doi:10.1039/B507874C
[4] D. Leow, C. H. Tan, Synlett 2010, 1589. doi:10.1055/S-0029-1219937
[5] D. Leow, C. H. Tan, Chem. Asian J. 2009, 4, 488. doi:10.1002/
ASIA.200800361
[6] T. Ishikawa, T. Kumamoto, Synthesis 2006, 737. doi:10.1055/
S-2006-926325
[7] A. R. Katritzky, B. V. Rogovoy, ARKIVOC 2005, 2005, 49.
doi:10.3998/ARK.5550190.0006.406
[8] A. R. Katritzky, N. M. Khashab, S. Bobrov, Helv. Chim. Acta 2005, 88,
1664. doi:10.1002/HLCA.200590131
1
guanidine salts can be quantitated by H NMR spectroscopy.
Hence, the reaction of N-arylcyanamides 1a, c, d with anilines
2 g–i was carried out in the presence of TsOH in toluene under
0
.
reflux temperature to afford a series of N,N -diphenylguanidine
TsOH salts 4 in good yields. The reaction protocol is also
applicable to alkylamines as nucleophiles (Scheme 2).
In summary, our investigation has provided a facile and
practical synthesis of N-alkyl-N0-arylguanidine derivatives, in
which copper(I) iodide and Xantphos were used as catalysts for
the nucleophilic addition of primary or secondary alkylamines
to N-arylcyanamides. N-Arylcyanamides are readily available
via Tiemann rearrangement of amidoximes that were prepared
directly from the corresponding nitriles.[29] Although the
CuI-catalyzed reaction was not applicable to the synthesis of
N,N0-diarylguanidines, we have also demonstrated that the
TsOH-catalyzed nucleophilic addition of anilines to N-aryl
cyanamides could be employed as a supplementary route.
Our investigation successfully provided a viable synthesis
[9] Y. Yamamoto, H. Mizuno, T. Tsuritani, T. Mase, Tetrahedron Lett.
2009, 50, 5813. doi:10.1016/J.TETLET.2009.07.147
[10] D. Begue, G. G. Qiao, C. Wentrup, J. Am. Chem. Soc. 2012, 134, 5339.
doi:10.1021/JA2118442
[11] X. Liu, X. Wang, Q. Li, M. P. Kozar, V. Melendez, M. T. O’Neil,
A. J. Lin, J. Med. Chem. 2011, 54, 4523. doi:10.1021/JM200111G
[12] L. Zhang, R. Sathunuru, T. Luong, V. Melendez, M. P. Kozar,
A. J. Lin, Bioorg. Med. Chem. 2011, 19, 1541. doi:10.1016/
J.BMC.2010.12.028
[13] L. C. Henderson, F. M. Pfeffer, J. Li, R. L. Nation, T. Velkov, Chem.
Commun. 2010, 46, 3197. doi:10.1039/B925135A
[14] F. Dumont, A. Sultana, R. N. Waterhouse, Bioorg. Med. Chem. Lett.
2002, 12, 1583. doi:10.1016/S0960-894X(02)00235-4

D
C.-J. Zeng et al.
[15] S. Padmanabhan, M. E. Perlman, L. Zhang, D. Moore, D. Zhou,
J. B. Fischer, G. J. Durant, R. N. McBurney, Bioorg. Med. Chem. Lett.
2001, 11, 501. doi:10.1016/S0960-894X(00)00695-8
[16] A. Tanatani, K. Yamaguchi, I. Azumaya, R. Fukutomi, K. Shudo,
H. Kagechika, J. Am. Chem. Soc. 1998, 120, 6433. doi:10.1021/
JA9806534
[22] L. K. Mannepalli, V. Dupati, S. J. Vallabha, V. M. Sunkara, J. Chem.
Sci. 2013, 125, 1339. doi:10.1007/S12039-013-0501-Z
[23] X. H. Zhu, F. Xu, Q. Shen, Chin. Sci. Bull. 2012, 57, 3419.
doi:10.1007/S11434-012-5332-7
[24] H. Shen, Y. Wang, Z. W. Xie, Org. Lett. 2011, 13, 4562. doi:10.1021/
OL201752E
[17] N. L. Reddy, W. Fan, S. S. Magar, M. E. Perlman, E. Yost, L. Zhang,
D. Berlove, J. B. Fischer, K. Burke-Howie, T. Wolcott, G. J. Durant,
J. Med. Chem. 1998, 41, 3298. doi:10.1021/JM980134B
[18] L.-Y. Hu, J. Quo, S. S. Magar, J. B. Fischer, K. J. Burke-Howie,
G. J. Durant, J. Med. Chem. 1997, 40, 4281. doi:10.1021/JM970459C
[19] N. L. Reddy, L.-Y. Hu, R. E. Cotter, J. B. Fischer, W. J. Wong,
R. N. McBurney, E. Weber, D. L. Holmes, S. T. Wong, J. Med. Chem.
1994, 37, 260. doi:10.1021/JM00028A009
[25] F. Montilla, D. del Rio, A. Pastor, A. Galindo, Organometallics 2006,
25, 4996. doi:10.1021/OM060535M
[26] J. Chen, Y. B. Wang, Y. J. Luo, Chin. J. Chem. 2013, 31, 1065.
doi:10.1002/CJOC.201300302
[27] W. X. Zhang, M. Nishiura, Z. M. Hou, Chem. – Eur. J. 2007, 13, 4037.
doi:10.1002/CHEM.200601383
[28] J. Li, L. Neuville, Org. Lett. 2013, 15, 6124. doi:10.1021/OL4029622
[29] C.-C. Lin, T.-H. Hsieh, P.-Y. Liao, Z.-Y. Liao, C.-W. Chang,
Y.-C. Shih, W.-H. Yeh, T.-C. Chien, Org. Lett. 2014, 16, 892.
doi:10.1021/OL403645Y
[20] S. K. Philip, K. N. Rajasekharan, Synth. Commun. 2011, 41, 1593.
doi:10.1080/00397911.2010.488312
[21] D. Z. Li, J. Guang, W. X. Zhang, Y. Wang, Z. F. Xi, Org. Biomol.
Chem. 2010, 8, 1816. doi:10.1039/B923249B