Versatile synthesis of 5-aminoimidazole-4-carboxylic acid derivatives

Article abstract of DOI:10.1055/s-0031-1289528

5-Amino imidazole 4-substituted carboxamidines and 4-substituted imidoyl cyanides were selectively obtained under mild experimental conditions from reaction of the easily accessible 5-amino-4-cyanoformimidoyl imidazoles with primary aliphatic and aromatic amines, ammonia, and amino acids in a one-pot reaction. When alcohols were used, the corresponding 5-aminoimidazole 4-carboximidates were isolated. An equally simple reaction occurred when the starting imidazoles were combined with water to give 5-aminoimidazole 4-acyl cyanides. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289528

LETTER
2675
Versatile Synthesis of 5-Aminoimidazole-4-carboxylic Acid Derivatives
5
-Aminoimidazole
l
-4-carb
i
oxylic
c
A
cid Deriv
e
atives M. Dias,* A. Sofia Vila-Chã, A. Luísa Costa, Daniela P. Cunha, Nádia Senhorães, M. Fernanda Proença
Departamento de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
Fax +351(253)678983; E-mail: ad@quimica.uminho.pt
Received 3 June 2011
Imidazoles 1 are easily prepared following a previously
developed method.9 These imidazoles react with second-
ary amines at the imine carbon atom of the cyanoformim-
idoyl substituent with subsequent elimination of HCN.9d
Abstract: 5-Amino imidazole 4-substituted carboxamidines and 4-
substituted imidoyl cyanides were selectively obtained under mild
experimental conditions from reaction of the easily accessible 5-
amino-4-cyanoformimidoyl imidazoles with primary aliphatic and
aromatic amines, ammonia, and amino acids in a one-pot reaction. We now report the incorporation of primary amines, ami-
When alcohols were used, the corresponding 5-aminoimidazole 4-
no acids, ammonia, alcohols, and water into the substitu-
carboximidates were isolated. An equally simple reaction occurred
ent in the 4-position of the imidazole ring using
when the starting imidazoles were combined with water to give 5-
trifluoroacetate and hydrochloride salts of imidazoles 1 as
aminoimidazole 4-acyl cyanides.
key intermediates.
Key words: heterocycles, imidazole, carboxamidine, carboximi-
During studies on the reaction of imidazoles 1 with anhy-
drides,9c,10b,c we realized that imidazolium trifluoroacetate
1a·TFA was generated in 95% yield from trifluoroacetic
anhydride (TFAA) and not the desired imidazole 2a
(Table 1). The reaction of 1a with trifluoroacetic acid
(TFA) led to the same salt in 88% yield. From preliminary
studies on the reactivity of 1a·TFA, two important results
emerged. In the presence of methanol the carboximidate
3a·TFA was isolated in 76% yield after three days at room
temperature; whereas, in the presence of water, a slow re-
action occurred and a white solid, identified as the acyl
cyanide 4a, was isolated in 60% yield after 13 days at 40
°C.
date, imidoyl cyanides
Imidazoles are key components in a large number of bio-
molecules and pharmacologically active compounds.
They can be considered important scaffolds in heterocy-
clic synthesis and drug discovery.1,2 Examples include the
essential amino acid histidine and related compounds, bi-
otin, imidazole alkaloids, antifungal ketoconazole, antiul-
cerative agent cimetidine, and the proton-pump inhibitor
omeprazole.1,2d
The a-iminonitriles (also referred to as imidoyl cyanides)
are an important class of functionalized compounds used
as precursors for a-keto acids, amides, N-alkylketene imi-
nes, cyanoenamides, amidines, etc.3 These compounds are
usually obtained through multistep processes, with limit-
ed application scope.
Attempts to prepare 2c from 1c and ethyl chloroformate in
the presence of pyridine generated the imidazolium salt
1c·HCl as a contaminant. We realized that this contami-
nant could be responsible for the formation of the 4-car-
boxamidino imidazole 5c·HCl, when the mixture was
combined with benzylamine. The salt 1c·HCl was gener-
ated from 1c and HCl and, after treatment with benzyl-
amine in acetonitrile at room temperature, the product
5c·HCl was isolated in 60% yield.
Amidines, important synthons in heterocyclic chemistry,
are mostly prepared from nitriles (Pinner synthesis) via
imidates and usually require activated nitriles or forcing
conditions.4 The synthesis of a series of triazolo-3-(N-
substituted) carboxamidines incorporating different alkyl
amines and amino acids has been reported and involves a
carboximidate as a key intermediate, prepared from the
corresponding carbonitrile.5
These results demonstrated that imidazolium salts 1·HX
undergo easy nucleophilic attack in the presence of alco-
hols, water, and primary amines. The formation of imi-
date/amidine vs. acyl cyanide groups was rationalized on
the basis of two selective pathways from a common tetra-
hedral intermediate (7, Scheme 1): HCN elimination
(pathway a) and NH3 elimination (pathway b). Aiming to
explore these two new routes for structural modifications
on the 4-substituent, we investigated the reactivity of im-
idazoles 1 with nucleophiles in the presence of acid.
The chemistry of 5-aminoimidazoles has not received
much attention and this has been attributed to their lower
stability, as compared to other classes of aminoazoles.2e,6,7
Nevertheless, the synthesis of 5-aminoimidazole 4-car-
boxamidine from a carbonitrile via a carboximidate has
been reported.8 Herein we describe a new, more facile,
and versatile synthesis of 5-aminoimidazole 4-carboxam-
idines from 5-amino-4-cyanoformimidoyl imidazoles 1.
Different 1·TFA salts were allowed to react with ethanol
and water. Ethyl carboximidates 3b,d,e (isolated as TFA
salts) were obtained in moderate to good yields, after two
days at room temperature or one day at 40 °C, from im-
idazoles 1 and one equivalent of TFA in ethanol. Acyl cy-
anides 4b and 4d were obtained in very good yield from
1b·TFA (method A) or by addition of TFA to 1d (method
SYNLETT 2011, No. 18, pp 2675–2680
Advanced online publication: 19.10.2011
DOI: 10.1055/s-0031-1289528; Art ID: D17011ST
x
x
.x
x
.2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

2676
A. M. Dias et al.
LETTER
B) in water, after one to two days at room temperature
(Table 1).
To reproduce the synthesis of 5c·HCl, 1b·HCl (method
C) was combined with benzylamine under similar reac-
tion conditions. The product could not be isolated, but
TLC analysis supported the expected formation of salt
5b·HCl. These results prompted us to examine the one-
pot synthesis of amidines 5b starting from 1 and TFA
(method B). Treatment of imidazole 1b with TFA (1
equiv) in acetonitrile at 0 °C to 20 °C led to a yellow-green
suspension due to the formation of the imidazolium salt
and, after addition of benzylamine, a white solid of the
corresponding ammonium salt precipitated from the reac-
tion mixture. After one day, the resulting suspension of
the carboxamidinium salt 5b·TFA was isolated in 84%
yield. In an attempted synthesis of 5a·TFA by the same
method, only a homogeneous green solution was obtained
and two different products were observed by TLC. The
high solubility of both products and their extensive degra-
dation in solution prevented their isolation from the reac-
tion mixture. When TFA was added to imidazole 1b at ca.
30 °C, immediate addition of benzylamine gave selective-
ly one of the products. The pale green solid was identified
as the N-substituted a-iminonitrile 6b (58% yield).
Figure 1 X-ray crystal structure of carboxamidine 5m
tate salt of 5f was prepared in the presence of one equiva-
lent of acetic acid after 20 minutes at 40 °C (76%, method
D), and the neutral form was obtained in the presence of a
catalytic amount of the same acid after nine hours at 40 °C
(63%, method E). Phenylalanine was incorporated into
imidazole 1b to give the zwitterionic amidino imidazole
5l after one day in a mixture of acetonitrile and water at 40
°C (48%) or in aqueous sodium bicarbonate solution
(72%). Combining imidazoles 1a,b with ammonium ace-
tate in dimethyl sulfoxide led to white solids after 18
hours at 40 °C that were identified as the unsubstituted
carboxamidinium imidazole salts 5i,j·AcOH.11 The salt
5i·AcOH was crystallized from a mixture of ethanol–
dimethyl sulfoxide, and X-ray diffraction analysis of a
crystal confirmed the proposed structure (Figure 2).17
In order to extend these results to the synthesis of N-aryl-
amidino imidazoles 5 and N-arylimidoyl cyanides 6, a
systematic study starting from imidazole 1b and aniline in
the presence of TFA and acetic acid was carried out.
When one equivalent of TFA was used at different tem-
peratures, only the green solid 6m was obtained. This
compound was selectively generated, as evidenced by
TLC, but its high solubility in acetonitrile resulted in a
moderate isolated yield. In the presence of a catalytic
amount of TFA a slower reaction occurred, and the com-
petitive formation of 5m was detected, but product 6m
was still the major component of the mixture. Acetonitrile
and ethanol were examined as solvents, and the results
demonstrated that formation of 6m was favored in aceto-
nitrile. Acetic acid was used as catalyst, and the reaction
was performed under reflux in ethanol giving 5m as the
major product and traces of 6m (by TLC). Extensive deg-
radation prevented the isolation of these products. Parallel
experiments using a catalytic amount of acetic acid were
then carried out in ethanol, acetonitrile, tetrahydrofuran,
and dimethyl sulfoxide at room temperature. All the ex-
periments led to 5m as the only product, but a much faster
reaction was observed when dimethyl sulfoxide was used
as solvent. Product 5m crystallized from dimethyl sulfox-
ide, and X-ray analysis confirmed the assigned structure
(Figure 1).17
Figure 2 X-ray crystal structure of carboxamidine 5i·AcOH
Aromatic substituents were incorporated into the amidine
function, by analogy with the synthesis of 5m, starting
from akyl and aryl imidazoles 1 and electron-rich and
electron-poor anilines in the presence of a catalytic
amount of acetic acid (method E) in dimethyl sulfoxide.
Compounds 5n,o were isolated in excellent yield, con-
firming the wide scope of the method.
The method selected to prepare different N-arylimidoyl
cyanides 6 involved the combination of imidazoles 1 and
aromatic amines in the presence of one equivalent of TFA
(method B). Compound 6m was prepared at room temper-
ature, and the syntheses of 6p–r were performed under re-
flux. (Table 1)
Based on these studies, carboxamidines 5d,g,h were iso-
lated as their TFA salts in the presence of one equivalent
of TFA (method B). Neutralization of 5b·TFA and
5d·TFA was successfully achieved in the presence of
aqueous sodium carbonate (2 equiv) in a mixture of water
and ethanol affording the neutral forms 5b and 5d. Ace-
Synlett 2011, No. 18, 2675–2680 © Thieme Stuttgart · New York

LETTER
5-Aminoimidazole-4-carboxylic Acid Derivatives
2677
Table 1 Synthesis of Compounds 3–612–16
R1
N
NH2
NCOR
R1
R1
N
NH2
NH2
N
N
CN
2a, R = CF3
NH
N
O
N
2c, R = OEt
R2OH
H2O
OR2
3
CN
4
(i) (CF3C)2O
(iii) ClCO2Et
R1
N
R1
R1
NH2
NH
R2NH2
R2NH2
NH2
NR2
NH2
N
N
N
NH
N
N
CN
HX
CN
6
NHR2
5
1
1⋅HX
(ii)
Compound
R1
(CH2)2OH
R2
–
Reaction conditions
Yield (%)
1a·TFA
i: (CF3C)2O (1 equiv), CHCl3, 20 min, 0 °C
ii: TFA (1 equiv), CHCl3, 20 min, 0 °C
95
88
1b·TFA
1b·HCl
4-MeOC6H4
4-MeOC6H4
–
–
ii: TFA (1 equiv), MeCN, 5 min, r.t.
ii: HCl (1 equiv), MeCN, 10 min, r.t.
80
85
O
O
1c·HCl
–
iii. pyridine (1.5 equiv), ClCO2Et (1.2 equiv),1 h, 0 °C
35
1d·TFA
3a·TFA
3b·TFA
3d·TFA
4-FC6H4
–
ii: TFA (1 equiv), MeCN, 5 min, r.t.
method A: MeOH, 3 d, r.t.
method B: EtOH, 1 d, 40 °C
method B: EtOH, 2 d, r.t.
76
76
69
46
(CH2)2OH
4-MeOC6H4
4-FC6H4
Me
Et
Et
OH
3e·TFA
Et
method B: EtOH, 1 d, 40 °C
76
OH
4a
(CH2)2OH
–
method A: H2O, 13 d, 4 °C
60
4b
4-MeOC6H4
4-FC6H4
–
method A: H2O, 1 d, r.t.
83
4d
–
method B: H2O, 2 d, r.t.
85
5a + 6a
5b·HCl
5b·TFA
5b
(CH2)2OH
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
Bn
Bn
Bn
Bn
method B: R2NH2 (1.2 equiv), MeCN, 1 d, r.t.
method C: R2NH2 (1.4 equiv), EtOH, 2 h, r.t., 2 d, –18 °C
method B: R2NH2 (1.2 equiv), MeCN, 1 d, r.t.
from 5b·TFA: Na2CO3 (2 equiv), EtOH–H2O (1:12), 1 h, r.t.
not isolated
not isolated
84
93
O
O
5c·HCl
Bn
method C: R2NH2 (1.4 equiv), EtOH, 2 d, r.t.
method B: R2NH2 (2 equiv), MeCN, 1 d, 10 °C
60
79
5d·TFA
5d
4-FC6H4
4-FC6H4
Bn
Bn
from 5d·TFA: Na2CO3 (2 equiv), EtOH–H2O (1:6), 30 min, r.t.
71
53
method E: R2NH2 (1.2 equiv), MeCN, 3 h, 40 °C
5f·AcOH
5f
Ph
Bn
Bn
method D: R2NH2 (1.2 equiv), MeCN, 20 min, 40 °C
method E: R2NH2 (1.2 equiv), MeCN, 9 h, 40 °C
method B: R2NH2 (1.2 equiv), MeCN, 1 d, r.t.
76
63
76
Ph
5g·TFA
4-MeOC6H4
cyclopentyl
Synlett 2011, No. 18, 2675–2680 © Thieme Stuttgart · New York

2678
A. M. Dias et al.
LETTER
Table 1 Synthesis of Compounds 3–612–16 (continued)
R1
NH2
N
NCOR
R1
R1
N
NH2
NH
NH2
N
N
CN
2a, R = CF3
O
N
N
2c, R = OEt
R2OH
H2O
OR2
3
CN
4
(i) (CF3C)2O
(iii) ClCO2Et
R1
N
R1
R1
NH2
NH
R2NH2
R2NH2
NH2
NR2
NH2
N
N
N
NH
N
N
CN
HX
CN
6
NHR2
5
1
1⋅HX
(ii)
Compound
5h·TFA
5i·AcOH
5j·AcOH
5l
R1
R2
Reaction conditions
Yield (%)
4-MeOC6H4
4-MeOC6H4
(CH2)2OH
(CH2)2OMe
method B: R2NH2 (1.2 equiv), MeCN, 1 d, r.t.
NH4Ac (4 equiv), DMSO, 18 h, 40 °C
NH4Ac (4 equiv), DMSO, 18 h, 40 °C
79
99
99
H
H
4-MeOC6H4
CH(Bn)CO2H
Phe (1.1 equiv), MeCN–H2O, 1 d, 40 °C
Phe (1.1 equiv), NaHCO3 (aq) (1.2 equiv), 1 d, 40 °C
48
72
5m
5n
5o
4-MeOC6H4
Ph
Ph
method E: R2NH2 (1.2 equiv), MeCN, 7 h, 40 °C
method E: R2NH2 (1.2 equiv), MeCN, 8 h, 40 °C
method E: R2NH2 (1.2 equiv), 8 h, 40 °C
66
99
96
58
44
68
65
52
4-MeOC6H4
4-FC6H4
Bn
Me
6b
6m
6p
6q
6r
4-MeOC6H4
4-MeOC6H4
(CH2)2OH
(CH2)2OH
4-MeOC6H4
method B: R2NH2 (1.2 equiv), MeCN, 18 h, 30 °C
method B: R2NH2 (1.2 equiv), MeCN, 1 d, r.t.
method B: R2NH2 (1.2 equiv), MeCN, 30 min, reflux
method B: R2NH2 (1.2 equiv), MeCN, 30 min, reflux
method B: R2NH2 (1.2 equiv), MeCN, 30 min, reflux
Ph
Ph
4-FC6H4
4-MeOC6H4
These results demonstrate that H+ ions are essential to ini- of the method and the diversity of functional groups incor-
tiate the nucleophilic attack, and a catalytic amount of hy- porated at the 4-position of 5-aminoimidazoles opens new
drogen ion favors the HCN elimination pathway giving
compounds 3/5 (a), while high concentration of hydrogen
ion facilitates NH3 elimination pathway (b) providing
R1
R1
R1
compounds 4/6. We postulate that protonation on the im-
idazole ring (1A·HX) is favored under acidic conditions
activating the nucleophilic attack to generate the tetrahe-
dral intermediate 7.
NH2
CN
NH2
CN
NH2
CN
N
H+
N
N
+N
H
N
N
+NH
NH
HN
H
Higher acidic conditions led to the protonation of one of
the amino groups of the newly formed compound 7
(7·HX) that evolves to compounds 4/6 by elimination of
ammonia (Scheme 1).
1
1A⋅HX
1B⋅HX
NuH
R1
N
R1
R1
NH2
Nu
NH2
Nu
NH2
N
N
a
b
– HCN
– NH3
In conclusion, an efficient and versatile method has been
developed to generate N-substituted carboxamidines and
carboximidates from an imidoyl cyanide precursor in a
one-step reaction. Additionally, selective synthesis of
N-substituted imidoyl cyanides and acyl cyanides was
also achieved from the same easily accessible 5-amino-4-
cyanoformimidoyl imidazole precursor 1. The wide scope
CN
Nu
N
N
N
NC
4, 6
HN
H2N
7
7⋅HX
3⋅HX
5⋅HX
Scheme 1 Proposed mechanism for the formation of compounds 3–
6 from imidazoles 1 in acidic medium
Synlett 2011, No. 18, 2675–2680 © Thieme Stuttgart · New York

LETTER
5-Aminoimidazole-4-carboxylic Acid Derivatives
2679
with Et2O to give compound 1·TFA (76–88%).
[5-Amino-1-(2-hydroxyethyl)-1H-imidazol-4-yl]
routes for structural modifications on this heterocyclic
scaffold.
(Cyano)methaniminium 2,2,2-Trifluoroacetate (1a·TFA)
Mp >110 °C (dec.). 1H NMR (300 MHz, DMSO-d6):
d = 10.21 (br s, 1 H), 8.79 (br s, 2 H), 7.91 (s, 1 H), 7.32 (t,
J = 50 Hz, 0.2 H), 5.20 (s, 1 H), 4.11 (t, J = 4.7 Hz, 2 H),
3.83 (t, J = 4.7 Hz, 2 H). 13C NMR (75 MHz, DMSO-d6):
d = 158.08 (q, J = 32 Hz), 152.62, 141.68, 131.83, 118.58,
116.44 (q, J = 300 Hz), 112.51, 57.74, 45.59. Anal. Calcd for
C9H8F3N5O3·H2O: C, 36.9; H, 3.0; F, 23.9; N, 19.90. Found:
C, 36.9; H, 3.4; F, 23.6; N, 20.2. IR (mull): 3422, 3092,
3059, 1690 (CO), 1663, 1576 cm–1.
Acknowledgment
The authors gratefully acknowledge the financial support by the
University of Minho and ‘Fundação para a Ciência e Tecnologia’,
in particular through the Portuguese NMR network (RNRMN).
References and Notes
(13) General Procedure for the Synthesis of 3b⋅TFA
(1) De Luca, L. Curr. Med. Chem. 2006, 13, 1.
(2) (a) Al-Shaar, A. H.; Gilmour, D. W.; Lythgoe, D. J.;
McClenaghan, I.; Ramsden, C. A. J. Chem. Soc., Perkin
Trans. 1 1992, 2779. (b) Al-Shaar, A. H.; Chambers, R. K.;
Gilmour, D. W.; Lythgoe, D. J.; McClenaghan, I.; Ramsden,
C. A. J. Chem. Soc., Perkin Trans. 1 1992, 2789.
(c) McLaughlin, M.; Mohareb, R. M.; Rapoport, H. J. Org.
Chem. 2003, 68, 50. (d) Zuliani, V.; Cocconcelli, G.;
Fantini, M.; Ghiron, C.; Rivara, M. J. Org. Chem. 2007, 72,
4551. (e) Soh, C. H.; Chui, W. K.; Lam, Y. J. Comb. Chem.
2006, 8, 464.
(3) (a) De Corte, B.; Denis, J.-M.; De Kimpe, N. J. Org. Chem.
1987, 52, 1147. (b) Alonso, E. R.; Tehrani, K. A.; Boelens,
M.; Knight, D. W.; Yu, V.; De Kimpe, N. Tetrahedron Lett.
2001, 42, 3921. (c) Jursic, B. S.; Douelle, F.; Bowdy, K.;
Stevens, E. D. Tetrahedron Lett. 2002, 43, 5361.
(d) Roychowdhury, A.; Kumar, V. V.; Bhaduri, A. P. Synth.
Commun. 2006, 36, 715. (e) Fontaine, P.; Chiaroni, A.;
Masson, G.; Zhu, J. Org. Lett. 2008, 10, 1509.
(4) Wang, J.; Xu, F.; Cai, T.; Shen, Q. Org. Lett. 2008, 10, 445.
(5) Gabrielsen, B.; Phelan, M. J.; Barthel-Rosa, L.; See, C.;
Huggins, J. W.; Kefauver, D. F.; Monath, T. P.; Ussery, M.
A.; Chmurny, G. N.; Schubert, E. M.; Upadhya, K.; Kwong,
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1971, 150. (b) Barder, T. E.; Peng, P.; Okamoto, A.; Ealick,
S. E.; Stubbe, J. Biochemistry 2007, 46, 2842.
Method B
TFA (1 equiv) was added to a suspension of imidazole 1b
(1.7 mmol) in EtOH (3 mL), and the mixture was stirred for
1 d at r.t. The solid was filtered and washed with EtOH and
Et2O (3b⋅TFA, 69%).
[5-Amino-1-(4-methoxyphenyl)-1H-imidazol-4-yl]
(Ethoxy)methaniminium 2,2,2-Trifluoroacetate
(3b·TFA)
Mp 241–242 °C. 1H NMR (300 MHz, DMSO-d6): d = 9.94
(br s, 1 H), 9.57 (br s, 1 H), 7.58 (s, 1 H), 7.40 (d, J = 9.0 Hz,
2 H), 7.13 (d, J = 8.7 Hz, 2 H), 6.61 (s, 2 H), 4.52 (q, J = 6.9
Hz, 2 H), 3.82 (s, 3 H), 1.30 (t, J = 6.9 Hz, 3 H). 13C NMR
(75 MHz, DMSO-d6): d = 165.64, 159.88, 157.94 (q, J = 31
Hz), 148.05, 135.50, 127.73, 125.69, 117.94 (q, J = 299 Hz),
115.22, 105.10, 67.36, 55.66, 13.96. Anal. Calcd for
C15H17N4O4: C, 48.13; H, 4.58; N, 14.97. Found: C, 48.55;
H, 4.44; N, 15.23. IR (mull): 3471, 3108, 2700, 1673, 1634,
1513 cm–1.
(14) Typical Procedure for the Synthesis of 4a
Method A
A suspension of 1a·TFA (2.4 mmol) in cold H2O (4–5 mL)
was stirred at 4 °C. After 13 d the solid was filtered and
washed with cold H2O to give 4a (60%).
5-Amino-1-(2-hydroxyethyl)-1H-imidazole-4-carbonyl
Cyanide 4a
Mp >196 °C (dec.). 1H NMR (300 MHz, DMSO-d6):
d = 7.71 (br s, 2 H), 7.42 (s, 1 H), 5.15 (br s, 1 H), 4.02 (t,
J = 4.8 Hz, 2 H), 3.73 (t, J = 4.8 Hz, 2 H). 13C NMR (75
MHz, DMSO-d6): d = 155.49, 151.48, 137.58, 121.29,
115.68, 59.37, 46.09. Anal. Calcd for C7H8N4O2: C, 46.67;
H, 4.48; N, 31.10. Found: C, 46.70; H, 4.31; N, 30.82. IR
(mull): 3409, 3316, 3235, 3160, 3125, 2221, 1642, 1613,
1563, 1527 cm–1.
(7) Baxter, R. L.; Scott, A. I. Comprehensive Heterocyclic
Chemistry, Vol. 1; Katritzky, A. R.; Rees, C. W., Eds.;
Pergamon Press: Oxford, 1984, 87.
(8) Kadir, K.; Shaw, G.; Wright, D. J. Chem. Soc., Perkin Trans.
1 1980, 2728.
(15) Typical Procedure for the Synthesis of Amidines 5
Method B
(9) (a) Alves, M. J.; Booth, B. L.; Freitas, A. P.; Proença, M. F.
J. Chem. Soc., Perkin Trans. 1 1992, 913. (b) Booth, B. L.;
Dias, A. M.; Proença, M. F. J. Chem. Soc., Perkin Trans. 1
1992, 2119. (c) Booth, B. L.; Cabral, I. M.; Dias, A. M.;
Freitas, A. P.; Matos-Beja, A. M.; Proença, M. F.; Ramos-
Silva, M. J. Chem Soc., Perkin Trans. 1 2001, 1241.
(d) Alves, M. J.; Carvalho, M. A.; Carvalho, S.; Dias, A. M.;
Fernandes, F. H.; Proença, M. F. Eur J. Org. Chem. 2007,
4881.
(10) (a) Dias, A. M.; Cabral, I. M.; Vila-Chã, A. S.; Proença, M.
F. Synlett 2007, 1231. (b) Dias, A. M.; Cabral, I. M.; Vila-
Chã, A. S.; Cunha, D.; Senhorães, N.; Nobre, S.; Sousa, C.;
Proença, M. F. Synlett 2010, 2792. (c) Senhorães, N.; Dias,
A. M.; Conde, L. M.; Proença, M. F. Synlett 2011, 181.
(11) Zhao, L.; Liang, F.; Bi, X.; Sun, S.; Liu, Q. J. Org. Chem.
2006, 71, 1094.
TFA (1.0 equiv) was added to a suspension of 1b (1.36
mmol) in MeCN (4.0 mL). The mixture was stirred at r.t.
leading to a yellow precipitate. Addition of benzylamine
resulted in a white solid. The mixture was stirred at r.t. for 1
d. The solid was filtered and washed with MeCN and Et2O
to give 5b·TFA (84%). A solution of aq Na2CO3 (1.4 mL, 2
equiv) was added to a suspension of 5b·TFA (0.34 mmol) in
EtOH (0.5 mL) at r.t., under magnetic stirring. After 5 min,
the solution was kept in an ice bath for 1 h. The precipitate
was filtered and washed with ice water (93%).
Method D
AcOH (1 equiv) was added to a suspension of imidazole 1f
(2.70 mmol) in MeCN (2 mL) followed by addition of
benzylamine. The mixture was stirred at ca. 40 °C for 20
min. After 10 min at 0 °C, the solid was filtered and washed
with cold MeCN and cold Et2O to give 5f·AcOH (76%).
Method E
(12) General Procedure for the Synthesis of 1·TFA Salts
TFA (1.0 equiv) was added to a suspension of imidazole 1
(1.0–2.0 mmol) in CH2Cl2 or MeCN (3.0–5.0 mL) at r.t.
leading to a homogeneous solution. After 1 min, a yellow
solid precipitated from solution and was filtered and washed
A catalytic amount of AcOH was added to a suspension of
imidazole 1f (1.52 mmol) in MeCN (2 mL) followed by
Synlett 2011, No. 18, 2675–2680 © Thieme Stuttgart · New York

2680
A. M. Dias et al.
LETTER
addition of benzylamine (1.2 equiv). The mixture was stirred
at ca. 40 °C for 9 h followed by 10 min at 0 °C. After addition
of EtOH (1 mL) the solid was filtered and washed with cold
MeCN and ice-cold Et2O to give 5f·AcOH (63%).
5-Amino-N-benzyl-1-(4-methoxyphenyl)-1H-imidazole-
4-carboximidamide 2,2,2-Trifluoroacetate (5b·TFA)
Mp 163–164 °C. 1H NMR (300 MHz, DMSO-d6): d = 9.00
(br s, 1 H), 8.27 (br s, 1 H), 7.59 (s, 1 H), 7.42–7.36 (m, 6 H),
7.30 (m, 1 H), 7.13 (d, J = 8.7 Hz, 2 H), 6.31 (br s, 2 H), 4.67
(s, 2 H), 3.83 (s, 3 H). 13C NMR (75 MHz, DMSO-d6):
d = 159.78, 157.91 (q, J = 30.5 Hz), 155.94, 143.11, 136.95,
133.77, 128.53, 127.90, 127.40, 127.12, 125.92, 117.35 (q,
J = 299.0 Hz), 115.12, 106.92, 55.60, 44.10. Anal. Calcd for
C20H20F3N5O3: C, 55.17; H, 4.63; N, 16.08. Found: C, 55.27;
H, 4.75; N, 16.04. IR (mull): 3394, 3311, 3203, 1676, 1645
(CO), 1616 cm–1.
21.79. Found: C, 67.35; H, 5.83; N, 21.57. IR (mull): 3495,
3390, 3321, 3262, 3117, 1623, 1588, 1517 cm–1.
(16) Typical Procedure for the Synthesis of 6b
TFA (1 equiv) was added to a suspension of 1b (1.4 mmol)
at 30 °C. Benzylamine was added, and the solution was
stirred at r.t. for 18 h. The product was filtered and washed
with EtOH, MeCN, and Et2O (6b, 58%).
5-Amino-N-benzyl-1-(4-methoxyphenyl)-1H-imidazole-
4-carbimidoyl Cyanide (6b)
Mp 163–165 °C. 1H NMR (300 MHz, DMSO-d6): d = 7.39
(s, 1 H), 7.41 (dt, J = 9.6, 2.1 Hz, 2 H), 7.36–7.34 (m, 4 H),
7.26–7.25 (m, 1 H), 7.10 (dt, J = 9.3, 2.1 Hz, 2 H), 6.45 (br
s, 2 H), 4.95 (s, 2 H), 3.81 (s, 3 H). 13C NMR (75 MHz,
DMSO-d6): d = 159.34, 143.43, 139.34, 138.11, 132.17,
128.59, 127.63, 127.08, 126.64, 126.49, 115.78, 115.04,
110.02, 59.84, 55.57. Anal. Calcd for C19H17N5O: C, 68.87;
H, 5.17; N, 21.13. Found: C, 68.87; H, 5.03; N, 21.14. IR
(mull): 3307, 3184, 3127, 3065, 3029, 1614, 1580, 1539,
1518 cm–1.
5-Amino-N-benzyl-1-(4-methoxyphenyl)-1H-imidazole-
4-carboximidamide (5b)
Mp 157–158 °C. 1H NMR (300 MHz, DMSO-d6): d = 7.40
(d, J = 9.0 Hz, 2 H), 7.37 (d, J = 6.9 Hz, 2 H), 7.30 (t, J = 7.8
Hz, 2 H), 7.26 (s, 1 H), 7.19 (t, J = 7.2 Hz, 1 H), 7.08 (d,
J = 9.0 Hz, 2 H), 6.02 (br s, 2 H), 5.90 (br s, 2 H), 4.32 (s, 2
H), 3.80 (s, 3 H). 13C NMR (75 MHz, DMSO-d6):
(17) CCDC 825265 and 825266 contain the supplementary
crystallographic data for this paper (compounds 5i·AcOH
and 5m, respectively). These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting
The Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: +44 (1223)336033.
d = 158.76, 154.60 (br), 142.31 (br), 139.55, 128.64, 128.12,
127.85, 127.30, 126.07, 125.99, 114.85, 114.20, 55.51,
49.11 (br). Anal. Calcd for C18H19N5O: C, 67.27; H, 5.96; N,
Synlett 2011, No. 18, 2675–2680 © Thieme Stuttgart · New York

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