Synthesis of derivatives of 2-aminoimidazole and 2-iminoimidazolidine by cyclization of 1-aryl-2-(4,6-dimethylpyrimidin-2-yl)guanidines with α-bromocarbonyl compounds

Article abstract of DOI:10.1007/s10593-011-0723-2

Cyclization of 1-aryl-2-(4,6-dimethylpyrimidin-2-yl)guanidines with α-bromoacetophenone and ethyl bromoacetate gave derivatives of 1,4-diphenyl-1H-imidazole-2-amine and 2-amino-1-phenylimidazolidin- 4-one respectively. The mechanism of the reaction was de

Full text of DOI:10.1007/s10593-011-0723-2

Chemistry of Heterocyclic Compounds, Vol. 47, No. 1, April, 2011 (Russian Original Vol. 47, No. 1, January, 2011)
SYNTHESIS OF DERIVATIVES OF 2-AMINOIMIDAZOLE
AND 2-IMINOIMIDAZOLIDINE BY CYCLIZATION OF
1-ARYL-2-(4,6-DIMETHYLPYRIMIDIN-2-YL)GUANIDINES
WITH α-BROMOCARBONYL COMPOUNDS
A. S. Shestakov1*, I. S. Bushmarinov2, O. E. Sidorenko1,
Kh. S. Shikhaliev1, and M. Yu. Antipin2
Cyclization of 1-aryl-2-(4,6-dimethylpyrimidin-2-yl)guanidines with α-bromoacetophenone and ethyl
bromoacetate gave derivatives of 1,4-diphenyl-1H-imidazole-2-amine and 2-amino-1-phenylimidazolidin-
4-one respectively. The mechanism of the reaction was determined on the basis of quantum-chemical
calculations, NOESY NMR spectroscopy, and X-ray crystallography.
Keywords: 2-aminoimidazole, 1-aryl-2-(4,6-dimethylpyrimidin-2-yl)guanidines, 2-iminoimidazoidine,
phenacyl bromide, ethyl bromoacetate, ab initio calculations, NOESY, X-ray crystallography,
cyclization.
2-Aminoimidazole and its derivatives have been the center of attention for the last two decades for
specialists in the field of organic synthesis. The reason for this is the antiviral and anticancer activity observed in
alkaloids isolated from the marine sponge Leucetta. The structural bases of these alkaloids are derivatives of
1-R-2-aminoimidazole [1-4].
Among the preparative methods for preparing 2-aminoimidazole and its derivatives the interaction of
α-bromoacetophenone with derivatives of aminoguanidines [5, 6] or acylguanidines [7, 8] are preferred.
2-Aminopyimidine may be considered as a structural analog of cyclic guanidines, alkylation of which with
α-bromoacetophenones with subsequent recyclation leads to good yields of the required 2-aminoimidazoles
[9, 10].
The basic problem associated with the preparation of derivatives of 2-aminoimidazole on the basis of
substituted guanidines is the presence in the structure of the latter of three reactive nucleophilic nitrogen atoms,
which gives rise to a mixture of regioisomers. As it turned out, the use of N'-aryl-N"-(4,6-dimethylpyrimidin-
2-yl)guanidines in reaction with phenacylbromides and ethyl bromoacetate led to the regioselective synthesis of
derivatives 2-aminoimidazole.
_______
* To whom correspondence should be addressed, e-mail: schas@vmail.ru.
1Voronezh State University, Universitestskaya Pl., 1, Voronezh 394006, Russia.
2A. N. Nesmeyanov Institute of Organoelement Compounds, 28 Vavilova Str., Moscow 119991, Russia; e-mail:
bush_i@yandex.ru.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, 107-116, January, 2011. Original
article submitted February 4, 2010.
82
0009-3122/11/4701-0082©2011 Springer Science+Business Media, Inc.

The 1-aryl-2-(4,6-dimethylpyrimidin-2-yl)guanidines 1 used in this work were obtained in good yield by
the reaction of 4,6-dimethylpyrimidin-2-ylcyanamide with arylamines [11, 12] or arylbiguanides with pentane-
2,4-dione [13, 14].
As a preliminary we carried out quantum-chemical calculations of the geometry and electronic structure
of the guanidines 1 using the GAUSSIAN 03 complex program [15]. The calculations were carried out by the
functional density method using the B3LYP function. Complete optimization of the geometry of the molecules
was carried out in the 3-21G* basis set. Calculation of the electronic structures was carried out in the 6-31G*
basis set. The choice of basis sets and the method of calculation were determined by the circumstance that
further increase in the precision of the calculation did not lead to significant change in the values of the energies
of the highest occupied molecular orbitals (HOMO) and the lowest unoccupied molecular orbitals (LUMO).
The calculations showed that the region where the wave function of the HOMO differed from zero was
concentrated on atoms N(1) and N(3). So, with orbital control of the reaction these two atoms should participate
in the formation of the ring.
Heating of α-bromoacetophenones 2 with guanidines 1 in dioxane for 8-10 h led to the formation of the
corresponding 2-aminoimidazoles 3. The excess guanidine acted as acceptor for the hydrogen bromide liberated
and could be easily regenerated.
Me
Me
N
3
2
N
N
Ar
NH2
N
Ar
N
N
Me
N
N
O
+
H
NH
1
Me
R1
4
Br
R
R
2
R1
1
Me
Me
Ar
Ar
N
N
N
HN
N
N
Me
N
N
Me
N
N
H
A
B
R1
R1
R
3 a–f
R
3 a R = R1 = H, Ar = p-BrC6H4, b R = m-Me, R1 = p-Me, Ar = p-EtC6H4, c R = m-Me,
R1 = p-Me, Ar = p-BrC6H4, d R = H, R1 = o-Br, Ar = p-EtC6H4, e R = H, R1 = p-Cl,
Ar = 2-naphthyl, f R = H, R1 = p-O-Ph, Ar = Ph
Strictly speaking, the products of this reaction, along with 1,4-diaryl-1H-imidazole-2-amine 3, are 5
other isomeric 2-aminoimidazoles, but the quantum-chemical calculations described above allowed us to
exclude four of the six possible cyclization products, and to discuss only compounds 3 and 4. Analysis of the
literature data showed that the interaction of α-bromoacetophenones 2 with heterocyclic amidines [16, 17],
2-aminopyridines [28, 29], 2-aminopyrimidines [9, 10], and 2-aminoimidazoles [20-22], the carbon atom in
compound 2 bonded to the bromine atom invariably formed a bond with the endocyclic nitrogen atom in the
heterocyclic starting material. Subsequent interaction of the carbonyl carbon atom with exocyclic nitrogen atom
led to the formation of an annelated imidazole. It may be suggested that in our case the interaction of guanidine
1 with the α-bromoacetophenone begins with electrophilic attack at the secondary atom N(1) and concludes with
the formation of a bond between the carbonyl carbon atom and the primary atom N(3) to give formation of
compound 3.
83

To confirm these suggestions we the used the NOESY experiment. In the spectrum of compound 3c
intense correlation peaks were observed at δ 7.19/9.20 and 7.24/9.20 ppm which corresponded to the interaction
of the phenyl group ortho protons with the imidazole fragment proton. This interaction is possible only for the
regioisomer 3. The data of this experiment, namely, the presence of cross peaks at 7.19/9.20 and 7.24/9.20 ppm
permitted the conclusion that this isomer existed in the tautomeric form A. In fact such spin interactions are only
possible for the ortho protons of the phenyl groups and the proton on the exocyclic nitrogen atom.
Me
Et
O
N
HN
1
O
O
+
N
O
Me
N
N
Br
R1
5
7
R
Me
N
Me
O
N
N
N
HN
N
N
Me
N
Me
N
N
H
D
R1
C
R1
R
R
6 a–e
6 a R = H, R1 = p-Me, b R = H, R1 = p-MeO, c R = m-Me, R1 = p-Me,
d R = o-Cl, R1 = p-Cl, e R = m-Cl, R1 = p-F
The other possible asymmetric two-carbon electrophile is ethyl bromoacetate 5, which on reaction with
guanidine 1 gave 2-iminoimidazolidin-4-ones 6. As with phenacyl bromide, the reaction occurred with a two-
fold molar excess of the guanidine.
The formation of the regioisomer 6 (and not 7) was confirmed by the result of the NOESY experiment,
as in the previous example. The interaction of the methylene protons with the protons of the ortho-phenyl group,
which is possible only for the iminoimidazolidinone 6, is expressed by the presence of intense correlation peaks
at δ 4.44/7.47 and 4.44/7.63 ppm in the spectrum of compound 6c.
Br
Me
Me
O
N
N
N
HN
CH2
CH
Me
N
N
N
N
Me
N
N
H
CH
CH
HC
HC
Me
Me
Me
Me
3c
6c
84

TABLE 1. Characteristics of Compounds 3a-f and 6a-c
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield, %
С
Н
N
C21H18BrN5
59.88
60.01
75.67
75.54
61.69
61.61
61.52
61.61
70.62
70.50
74.81
74.81
64.95
65.07
61.67
61.72
4.38
4.32
6.77
6.85
4.87
4.95
5.02
4.95
4.79
4.73
5.42
5.35
5.83
5.80
5.47
5.50
16.54
16.66
17.60
17.62
15.63
15.62
15.51
15.62
16.34
16.44
16.12
16.15
23.82
23.71
22.42
22.49
225-227
209-210
234-236
192-193
235-236
180-181
197-198
171-172
153-154
208-209
195-196
71
81
66
55
76
64
64
59
56
34
52
3a
3b
3c
3d
3e
3f
C25H27N5
C23H22BrN5
C23H22BrN5
C25H20ClN5
C27H23N5O
C16H17N5O
C16H17N5O2
C17H19N5O
C15H13Cl2N5O
C15H13ClFN5O
6a
6b
6c
6d
6e
65.89
66.00
51.52
51.45
53.97
53.98
6.04
6.19
3.81
3.74
3.99
3.93
22.69
22.64
19.93
20.00
21.09
20.98
TABLE 2. 1H NMR Spectra of Compounds 3a-f and 6a-c
Com
pound
Chemical shifts, δ, ppm (J, Hz)*
2.09 (6H, s, 2CH3); 6.42 (1H, s, H-5 Pyr); 7.30 (1H, t, J = 7.5, H-4 Ar);
7.36-7.49 (4H, m, Ar); 7.58 (2H, d, J = 8.8, H-3,5 Ar'); 7.76 (2H, d, J = 8.8, H-2,6 Ar');
7.98 (1H, s, H-4 Im); 9.28 (1H, s, NH)
3a
3b
1.21 (3H, t, J = 7.6, CH3); 2.12 (6H, s, 2CH3); 2.20 (6H, s, 2CH3);
2.61 (2H, q, J = 7.6, CH2); 6.46 (1H, s, H-5 Pyr); 7.14 (2H, d, J = 7.5, H-3,5 Ar');
7.19-7.28 (3H, m, H-2,5,6 Ar); 7.69 (1H, s, H-4 Im); 7.72 (2H, d, J = 7.5, H-2,6 Ar');
9.07 (1H, s, NH)
3c
2.11 (6H, s, 2CH3); 2.18 (6H, s, 2CH3); 6.44 (1H, s, H-5 Pyr);
7.13 (2H, d, J = 9.5, H-5,6 Ar); 7.24 (1H, s, H-2 Ar); 7.55 (2H, d, J = 8.2, H-3,5 Ar');
7.75 (2H, d, J = 8.2, H-2,6 Ar'); 7.90 (1H, s, H-4 Im); 9.20 (1H, s, NH)
1.25 (3H, t, J = 7.6, CH3); 2.19 (6H, s, 2CH3); 2.66 (2H, q, J = 7.6, CH2);
6.31 (1H, s, H-5 Pyr); 7.15 (2H, d, J = 7.7, H-3,5 Ar'); 7.21 (1H, d, J = 7.8, H-6 Ar);
7.31 (1H, t, J = 7.6, H-4 Ar); 7.45 (1H, s, H-4 Im); 7.51 (1H, d, J = 7.8, H-3 Ar);
7.63-7.69 (3H, m, H-5 Ar + H-2,6 Ar'); 9.09 (1H, s, NH)
3d
2.12 (6H, s, 2CH3); 6.46 (1H, s, H-5 Pyr); 7.41-7.57 (6H, m, H Ar);
7.82-8.05 (5H, m, H Ar); 8.31 (1H, s, H-4 Im); 9.32 (1H, s, NH)
3e
3f
2.14 (6H, s, 2CH3); 6.42 (1H, s, H-5 Pyr); 6.89 (2H, d, J = 7.6, H Ar);
6.98 (2H, d, J = 7.7, H Ar); 7.11 (1H, t, J = 7.5, H Ar); 7.19 (1H, t, J = 7.6, H Ar);
7.33 (4H, m, H Ar); 7.46 (2H, d, J = 7.6, H Ar); 7.68 (1H, s, H-4 Im);
7.79 (2H, d, J = 7.5, H Ar); 9.09 (1H, s, NH)
2.33 (3H, s, CH3); 2.39 (6H, s, 2CH3); 4.41 (2H, s, CH2); 6.70 (1H, s, H-5 Pyr);
7.18 (2H, d, J = 8.7, H-3,5 Ar); 7.71 (2H, d, J = 8.7, H-2,6 Ar); 11.47 (1H, br. s, NH)
6a
6b
6c
2.40 (6H, s, 2CH3); 3.81 (3Н, s, ОСН3); 4.42 (2H, s, CH2); 6.69 (1H, s, H-5 Pyr);
6.93 (2H, d, J = 8.8, H-3,5 Ar); 7.71 (2H, d, J = 8.6, H-2,6 Ar); 11.62 (1H, br. s, NH)
2.20 (3H, s, CH3); 2.23 (3H, s, CH3); 2.34 (6H, s, 2CH3); 4.44 (2H, s, CH2);
6.78 (1H, s, H-5 Pyr); 7.14 (1H, d, J = 8.5, H-6 Ar); 7.47 (1Н, s, H-2 Ar);
7.63 (1H, d, J = 8.0, H-5 Ar); 11.44 (1H, br. s, NH)
2.41 (6H, s, 2CH3); 4.40 (2H, s, CH2); 6.72 (1H, s, H-5 Pyr); 7.46 (2H, d, J = 9.2, H-6 Ar);
7.59 (1H, s, H-3 Ar); 7.68 (1H, d, J = 9.4, H-5 Ar); 11.65 (1H, br. s, NH)
6d
6e
2.42 (6H, s, 2CH3); 4.46 (2H, s, CH2); 6.69 (1H, s, H-5 Pyr); 7.27 (1H, m, H Ar);
7.94 (1H, m, H Ar); 8.28 (1H, m, H Ar); 11.77 (1H, br. s, NH)
_______
* Im – imidazolyl.
85

The absence of cross-peaks, corresponding to the interaction of the proton of the exocyclic nitrogen
atom and the ortho protons of the phenyl group allows the conclusion that compound 6 exists in the tautomeric
form C. The presence in character and disposition of the signals of the NH protons in the spectra of compounds
6 and 3 is in complete agreement with this suggestion. Thus the proton on the exocyclic nitrogen atom of
compound 3 gives a sufficiently narrow singlet in the 9.05-9.35 ppm range. The broad signal of the proton on
this nitrogen atom in compound 6 is found at a weaker field (11.40-11.80 ppm).
A final confirmation that compounds 6 are formed during the course of the reaction between guanidines
1 and ethyl bromoacetate 5 was provided by the X-ray crystallographic data for compounds 6a and 6c (Fig. 1).
Fig. 1. General view of molecules 6a and 6c in the crystals. Atoms are shown as thermal ellipsoids (p = 50%).
Compounds 6a and 6c crystallized as crystal hydrates containing one molecule of dioxane for two
molecules of compound. The parameters of the unit cells of compounds 6a and 6c are close (Table 3) which is
explained by the very similar character of the crystal packing in the crystals of these compounds. The bond
lengths in both compounds are close and demonstrate typical values for C–C, C–N and C=O (Table 4). In both
compound 6a and compound 6c the rotation angles of the phenyl and imidazole units are not large and equal
6-7°, whereas the rotation angles of the pyrimidine unit relative to the imidazole ring are considerably larger,
40.8(2)° in compound 6a and 29.8(2)° in compound 6c. In the crystals of both compounds the hydrogen atom
H(4N) forms a forked hydrogen bond, participating in an intramolecular interaction with atom N(2) and an
intermolecular interaction with atom O(1). The remaining spatial contacts in the crystals are exhausted by weak
van der Waals interactions.
EXPERIMENTAL
1H NMR spectra were recorded with a Bruker AC-300 (300 MHz) in DMSO-d6 at 20°C with TMS as
internal standard, and 2D 1H NMR spectra with a Bruker DRX-500 (500 MHz) in DMSO-d6 at 20°C. Purity of
86

synthesized compounds and the course of experiments were monitored by TLC on Merck UV-254 plates (20:1
chloroform–methanol as eluent).
TABLE 3. Basic Crystallographic Data and Refinement Parameters of
Compounds 6a and 6c
6a
6c
Empirical formula
C16H17N5O20.5C4H8O2
339.40
C17H19N5O0.5C4H8O2
353.42
М
T, K
120
120
Crystal system
Triclinic
P-1
Triclinic
P-1
Space group
Z
2
2
a, Å
7.2819(7)
10.9886(10)
11.1754(11)
73.387(2)
77.977(2)
89.190(2)
837.12(14)
1.346
7.2350(15)
10.909(2)
11.645(2)
100.613(4)
104.681(5)
92.587(4)
869.8(3)
1.349
b, Å
c, Å
, deg.
, deg.
, deg.
V, Å3
dcalc, gcm–3
, cm–1
0.92
0.91
F(000)
360
376
2max, deg.
58
58
Number of reflections
measured
9556
9923
independent
with I>2σ(I)
Number of parameters refined
R1
4631
4791
4022
3923
229
243
0.0538
0.1601
1.002
0.0568
0.1603
1.000
wR2
GOOF
Residual electron density
0.664/-0.350
0.501/-0.273
eÅ–3 (dmin/dmax
)
TABLE 4. Basic Bond Lengths (l) in Compounds 6a and 6c
l, Å
Bond
6a
6c
O(1)–C(8)
N(1)–C(2)
N(1)–C(6)
N(2)–C(6)
N(2)–C(4)
N(3)–C(7)
N(3)–C(6)
N(4)–C(8)
N(4)–C(7)
N(5)–C(7)
N(5)–C(10)
N(5)–C(9)
1.2176(14)
1.3385(15)
1.3485(15)
1.3425(14)
1.3484(14)
1.2853(14)
1.3908(14)
1.3627(15)
1.4004(13)
1.3737(14)
1.4146(13)
1.4581(13)
1.2156(16)
1.3401(16)
1.3462(16)
1.3469(16)
1.3501(16)
1.2897(16)
1.3936(15)
1.3621(16)
1.3967(16)
1.3771(15)
1.4176(15)
1.4600(16)
87

Table 5. Bond Angles (ω) in Compounds 6a and 6c
, deg
Angle
6a
6c
C(2)–N(1)–C(6)
C(6)–N(2)–C(4)
C(7)–N(3)–C(6)
C(8)–N(4)–C(7)
C(7)–N(5)–C(10)
C(7)–N(5)–C(9)
C(10)–N(5)–C(9)
N(1)–C(2)–C(3)
N(1)–C(2)–C(1)
N(2)–C(4)–C(3)
N(2)–C(4)–C(5)
N(2)–C(6)–N(1)
N(2)–C(6)–N(3)
N(1)–C(6)–N(3)
N(3)–C(7)–N(5)
N(3)–C(7)–N(4)
N(5)–C(7)–N(4)
O(1)–C(8)–N(4)
O(1)–C(8)–C(9)
N(4)–C(8)–C(9)
N(5)–C(9)–C(8)
C(11)–C(10)–N(5)
C(15)–C(10)–N(5)
116.13(10)
116.59(10)
121.63(10)
112.56(9)
128.14(9)
110.70(9)
120.86(9)
121.72(10)
116.85(10)
121.08(11)
116.73(10)
126.43(10)
119.93(10)
113.57(10)
124.21(10)
128.81(10)
106.90(9)
127.11(11)
126.52(10)
106.37(9)
103.14(9)
118.16(10)
123.03(10)
116.41(11)
116.83(11)
121.24(11)
112.88(10)
128.55(10)
110.36(10)
120.63(10)
121.59(12)
117.75(12)
121.04(12)
117.40(11)
126.01(11)
113.65(11)
120.31(11)
124.34(11)
128.61(11)
107.02(10)
127.01(12)
126.91(11)
106.08(10)
103.35(9)
117.96(11)
123.36(11)
X-ray Crystallographic Investigation of Compounds 6a and 6c. Monocrystals of compounds 6a and
6c, suitable for X-ray crystallography, were obtained from dioxane. Low temperature X-ray diffraction studies
of the compounds were carried out with a SMART APEX 1000 CCD diffractometer (MoKα-radiation, graphite
monochromator, ω-scanning). The structures were determined by direct methods and refined by least squares
analysis in the anisotropic complete matrix approximation with F2hkl. Hydrogen atoms by geometric
considerations and refined by the "riding" model, with the exception of the hydrogen atoms of the NH groups
which were found from a difference Fourier map. The structures of compounds 6a and 6c have been deposited
in the Cambridge Structure Database (deposits CCDC 762873 and 762874 respectively). All calculations were
carried out with the SHELXTL PLUS complex of programs [23].
N-(1,4-Diaryl-1H-imidazol-2-yl)-4,6-dimethylpyrimidine-2-amines 3a-f (General Method). A
solution of the corresponding guanidine 1 (20 mmol) and the corresponding phenacyl bromide 2 (11 mmol) in
dioxane (40 ml) was heated at 90°C for 10 h. The guanidine hydrobromide which precipitated on cooling was
filtered off and the filtrate was evaporated. The residue was recrystallized from a mixture of 2-propanol
and DMF, to give N-[4-(4-bromophenyl)-1-phenyl-1H-imidazol-2-yl]-4,6-dimethylpyrimidine-2-amine (3a),
N-[1-(3,4-dimethylphenyl)-4-(4-ethylphenyl)-1H-imidazol-2-yl]-4,6-dimethylpyrimidine-2-amine (3b), N-[4-(4-
bromophenyl)-1-(3,4-dimethylphenyl)-1H-imidazol-2-yl]-4,6-dimethylpyrimidine-2-amine (3c), N-[1-(2-bromo-
phenyl)-4-(4-ethylphenyl)-1H-imidazol-2-yl]-4,6-dimethylpyrimidine-2-amine (3d), 4,6-dimethyl-N-[1-(4-
chlorophenyl)-4-(2-naphthyl)-1H-imidazol-2-yl]pyrimidine-2-amine (3e), and 4,6-dimethyl-N-[1-(4-phenoxy-
phenyl)-4-phenyl-1H-imidazol-2-yl]-pyrimidine-2-amine (3f).
2-[4,6-Dimethylpyrimidin-2-yl)imino]-1-phenylimidazolidin-4-ones 6a-e (General Method). The
ester 5 (1.2 ml, 11 mmol) was added dropwise to a solution of the corresponding guanidine 1 (20 mmol) in
dioxane (40 ml) and the mixture was heated at 90°C for 5 h. The guanidine hydrobromide which separated on
cooling was filtered off and the filtrate was evaporated. The residue was recrystallized twice from 2-propanol to
give 2-[(4,6-dimethylpyrimidin-2-yl)imino]-1-p-tolylimidazolidin-4-one (6a), 2-[(4,6-dimethylpyrimidin-2-yl)-
88

imino]-1-(3-methoxyphenyl)imidazolidin-4-one (6b), 1-(3,4-dimethylphenyl)-2-[(4,6-dimethylpyrimidin-2-
yl)-imino]imidazolidin-4-one (6c), [1-(2,4-dichlorophenyl)-2-(4,6-dimethylpyrimidin-2-yl)imino]imidazolidin-
4-one (6d), and 2-[(4,6-dimethylpyrimidin-2-yl)imino]-1-(3-chloro-4-fluorophenyl)imidazolidin-4-one (6e).
REFERENCES
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