Properties of 8-cyano-5-phenyl-7-trifluoromethyl-2,3-dihydroimidazo [1,2-a]pyridines

Article abstract of DOI:10.1023/A:1019977505210

The alkylation, acylation, halogenation, nitration, oxidation, and hydrolysis reactions of 8-cyano-5-phenyl-7-trifluoromethyl-2,3-dihydroimidazo[1,2-a]pyridine have been studied. It was found that the 6-halo derivatives add alcohol to give covalent solvates. X-ray analysis has been carried out on one of the solvates (6-chloro-8-cyano-7-ethoxy-5-phenyl-7-trifluoromethyl-1,2,3,7- tetrahydroimidazo[1,2-a]-pyridine) as well as on 8-cyano-5-phenyl-7-trifluoromethyl-2,3-dihydroimidazo[1,2-a]pyridine trifluoroacetate.

Full text of DOI:10.1023/A:1019977505210

Chemistry of Heterocyclic Compounds, Vol. 38, No. 6, 2002
PROPERTIES OF 8-CYANO-5-PHENYL-
7-TRIFLUOROMETHYL-2,3-DIHYDRO-
a
IMIDAZO[1,2- ]PYRIDINES
J. Suloeva1, M. Jure1, E. Gudriniece1, M. Petrova1, and A. Kemme2
The alkylation, acylation, halogenation, nitration, oxidation, and hydrolysis reactions of 8-cyano-5-
phenyl-7-trifluoromethyl-2,3-dihydroimidazo[1,2-a]pyridine have been studied. It was found that the
6-halo derivatives add alcohol to give covalent solvates. X-ray analysis has been carried out on one of
the solvates (6-chloro-8-cyano-7-ethoxy-5-phenyl-7-trifluoromethyl-1,2,3,7-tetrahydroimidazo[1,2-a]-
pyridine) as well as on 8-cyano-5-phenyl-7-trifluoromethyl-2,3-dihydroimidazo[1,2-a]pyridine
trifluoroacetate.
Keywords: 2,3-dihydroimidazo[1,2-a]pyridines, covalent solvates, 2,3-dihydroimidazo[1,2-a]-
pyridinium salts, X-ray analysis.
According to data in [1, 2] 2,3-dihydroimidazo[1,2-a]pyridines are a little studied heterocyclic system.
This prompted us to study, in more detail, the chemical and physical properties of 8-cyano-5-phenyl-7-
trifluoromethyl-2,3-dihydroimidazo[1,2-a]pyridine (1).
We have previously shown that the imidazo[1,2-a]pyridine 1 is readily protonated by acids [3, 4]. With
alkylhalides, the imidazopyridine 1, similarly to other 2,3-dihydroimidazo[1,2-a]pyridines [2], gives the 1-alkyl-
8-cyano-5-phenyl-7-trifluoromethyl-2,3-dihydroimidazo[1,2-a]pyridine salts 2a,b (Table 1). Up to this time,
only in the study [5] there had been reported the acylation of 2,3-dihydroimidazo[1,2-a]pyridines (which occurs
at the N(1) atom). By refluxing the imidazopyridine
1
in acetyl chloride we obtained the
1-acetylimidazopyridinium chloride (3a) as colorless, crystalline needles. Heating the imidazopyridine 1 in
acetonitrile with an equimolar amount of benzoyl chloride gave 2-(2-benzoyloxyethylamino)-3-cyano-6-phenyl-
4-trifluoromethylpyridine (previously reported by us [3]) in 73% yield. Exchange of acetonitrile for chloroform
led to the formation of the 1-benzoylimidazopyridinium salt 3b.
The imidazopyridine 1 takes part in an electrophilic substitution in the pyridine ring. Hence bromination
in DMF and chlorination in dioxane gives the yellow salts 4, from which the corresponding 6-bromo- and
6-chloroimidazopyridines 5a,b were obtained by basification. Depending on reaction conditions, the salts 4 can
contain a varying amount of complex-bounded bromine and we were able to separate the compound 4c (n = 3).
We also obtained the salts 4a,b by treatment of the imidazopyridines 5a,b with the corresponding acids
(Scheme 1).
1
In the H NMR spectra of the 1-substituted imidazopyridinium salts 2-4 (Table 2) there is a
characteristic splitting of the signals of the methylene group protons of the NCH2NCH2 into two multiplets. It is
apparent that the structure of the compounds 2a,b, 3a,b, and the salts 4a,b is similar to the structure of the
____________________________________________________________________________________________
1
2
Riga Technical University, Riga LV-1048, Latvia; e-mail: mara@ktf.rtu.lv. Latvian Institute of
Organic Synthesis, Riga LV-1006, Latvia; e-mail: akemme@osi.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 6, pp. 811-821, June 2002. Original article submitted May 16, 2001.
714
0009-3122/02/3806-0714$27.00©2002 Plenum Publishing Corporation

Scheme 1
CF3
CF3
N
_
CN
CN
_
Y
X
O
+
+
R
Ph
Ph
N
N
N
R1
2a–d
R1COY
3a,b
CF3
RX
CF3
N
CF3
_
Hal
Ph
CN
CONH2
N
CN
N
Haln
Hal2
KOH/EtOH
.
nEtOH
+
H
Ph
Ph
N
N
N
6a,b
4a–c
1
CF3
N
OEt
F3C
OR2
F3C
CN
Hal
Ph
CN
N
Hal
R2OH
CN
2b
∆
Ph
Pr
N
N
Ph
H
N
N
8
7a–e
5a,b
2 a R = Me, X = I, b R = Pr, X = I, c R = H, X = CF3COO [4], d R = H, X = HSeO3;
3 a R1 = Me, Y = Cl, b R1 = Ph, Y = Cl; 4 a Hal = Cl, n = 1, b Hal = Br, n = 1, c Hal = Br, n = 3;
5 a Hal = Cl, b Hal = Br; 6 a n = 0 [3], b n = 1; 7 a Hal = Cl, b-e Hal = Br;
a, c, R2 = Et, b R2 = Me, d R2 = Bu, e R2 = Ph
previously reported [3, 4] salt 2 (R = H). For a full identification we used X-ray crystallographic analysis. From
all of the imidazopyridinium salts prepared by us [3, 4] we selected for X-ray analysis the 8-cyano-5-phenyl-7-
trifluoromethyl-2,3-dihydroimidazo[1,2-a]pyridinium trifluoroacetate (2c) which forms stable crystals thanks to
a branched system of strong hydrogen bonds. The spatial model for the molecule and the atomic numbering are
shown in Fig. 1. The coordinates and equivalent isotropic thermal parameters for the atoms are given in Table 3.
Judging by the bond lengths and valence angle values (Tables 4 and 5), the positive charge is localized on the
N(1) atom (N(2) in Fig. 1). The investigated molecule has a strong hydrogen bond between the anionic and the
cationic parts: d(H(2)···O(2')) = 1.97 Å, ω (N(2)–H(2)···O(2')) = 166°. Additionally, in the molecule of the salt there is
a disturbance of the conjugation of the phenyl substituent and the heterocyclic system; the dihedral angle
between the ring planes is 132° and the length of the inter ring bond is 1.484 Å.
Attempts to prepare a nitro derivative of the imidazopyridine 1 were unsuccessful. Treatment of the
imidazopyridine 1 with nitric acid in acetic anhydride at room temperature or nitrating mixture in the cold gave
the 8-cyano-5-phenyl-7-trifluoromethyl-2,3-dihydroimidazo[1,2-a]pyridinium nitrate previously reported by us
[3]. In order to carry out the nitration we also tried more rigid conditions by heating in nitric acid, a mixture of
nitric acid and acetic anhydride, and in nitrating mixture. In none of the examples listed above could the 6-nitro
derivative be prepared.
Attempts to prepare the 2,3-dehydro derivative of compound 1 were also unsuccessful. Heating the
imidazopyridine 1 with chloranil in dioxane gave the product of cleavage of the imidazole ring, i.e. the previously
reported [3] 2-(2-chloroethylamino)-3-cyano-6-phenyl-4-trifluoromethylpyridine. Similarly, attempts to oxidise
715

TABLE 1. Characteristics for the Compounds Synthesized
Found, %
——————
Com-
pound
Empirical
formula
Yield, %
(method)
Calculated, %
mp, °C
C
H
N
C16H13F3IN3
44.35
44.57
2.90
3.04
9.53
9.75
208-210
(dec.)
87
2a
C18H17F3IN3
46.90
4.01
8.80
95-97 (dec.) 26
2b
2d
47.08
3.73
9.15
C15H10F3N3·H2SeO3
42.80
43.08
3.10
2.89
9.89
103-105
(dec.)
69
79
67
10.05
C17H13ClF3N3O
C22H15ClF3N3O
C15H9ClF3N3·HCl
C15H9BrF3N3·HBr
C15H9BrF3N3·HBr3
C15H9ClF3N3
55.63
3.50
11.49
130-132
3a
3b
4а
4b
4c
5a
5b
6b
7а
7b
7c
7d
7e
8
55.52
3.56
11.43
(dec.)
61.42
61.48
3.38
3.52
9.75
9.78
150-152
(dec.)
49.82
2.93
11.54
232-234
48 (A),
90 (B)
82
50.02
2.80
11.67
(dec.)
40.02
40.12
2.36
2.24
9.10
9.36
253-254
(dec.)
29.28
1.15
6.71
160-163
48
29.59
1.66
6.90
(dec.)
55.03
55.66
2.78
2.80
12.79
12.98
158-160
172-173
11 (А),
72 (B)
C15H9BrF3N3
47.96
2.51
11.40
20 (А),
48.94
2.46
11.40
72 (B)
C15H12F3N3O·C2H5OH
C17H15Cl F3N3O
C16H13BrF3N3O
C17H15BrF3N3O
C19H19BrF3N3O
C21H15BrF3N3O
C20H22F3N3O
56.97
57.79
5.13
5.13
11.77
11.89
217-218
(dec.)
61
55
46
53
54
56
50
55.03
4.00
11.19
146-148
55.22
4.09
11.36
(dec.)
48.35
48.02
3.35
3.27
10.43
10.50
126-128
(dec.)
49.27
3.50
10.14
151-152
49.29
3.65
10.14
(dec.)
51.55
51.60
4.15
4.33
9.50
9.50
179-180
(dec.)
55.32
3.21
9.26
178-180
54.56
3.27
9.09
(dec.)
63.30
63.65
5.66
5.86
11.06
11.13
93-95
(dec.)
the imidazopyridine 1 with SeO2 caused opening of the imidazole ring to give the known [6] 2-cyano-6-phenyl-
4-trifluoromethylpyridin-2-one. Milder conditions gave the selenious acid salt 2d.
According to data in [2], 2,3-dihydroimidazo[1,2-a]pyridines react with various nucleophiles and
cleavage of the imidazole ring usually occurs to give 2-alkylaminopyridines or 1-alkyl-2-iminopyridines.
However, heating the imidazopyridine 1 in ethanolic base solution gives only hydrolysis of the cyano group.
The amide 6 formed in the reaction mixture was separated as a solvate with a molecule of ethanol. The solvate
6b is also formed by recrystallization from ethanol of the amide 6a which had been prepared by the acid
hydrolysis of the nitrile 1 [3]. When heated in vacuo at 100°C, compound 6b loses the molecule of alcohol.
When studying the reactions of the 2,3-dihydroimidazo[1,2-a]pyridines with nucleophiles we observed
an unusual effect, i.e. the addition of alcohols to form covalent solvates which are also called pseudo bases. The
formation of pseudo bases of this bicyclic system has only been reported once [7] as the addition of water to the
C(8a)=N(1) bond though the effect has been well known in other heterocyclic series for a long time. In our
example, the addition of the alcohol molecule occurs at the C(7)=C(8)–C(8a)=N(1) conjugated system to give the
compounds 7a-e and 8. This reaction is reversible and takes place with electron-deficient 2,3-dihydroimidazo[1,2-a]-
pyridines (the 6-halo derivatives 5a,b and salt 2b). Compounds 7a-e lose the alcohol molecule when heated in
716

Figure 1. Spatial model for compound 2c.
Figure 2. Spatial model for compound 7a.
717

TABLE 2. Spectroscopic Parameters for the Compounds Synthesized
Com-
IR spectrum, ν, cm-1
1Н NMR spectrum, δ, ppm, J, Hz*
pound
3030, 2938, 2238, 1634,
1580
3.64 (3H, s, CH3); 4.40 (2H, t, J = 6, CH2);
4.69 (2H, t, J = 6, CH2); 6.89 (1H, s, –CH=);
7.33 (3H, m, С6Н5); 7.78 (2H, m, С6Н5)
2a
3030, 2971, 2171, 1646
1556
0.98 (3H, t, J = 6, CH3); 1.81 (2Н, sextet, J = 6, CH2);
3.89 (2H, t, J = 6, CH2); 4.12 (2H, m, CH2);
4.61 (2H, m, CH2); 7.52 (1H, s, –CH=);
7.74 (5H, m, С6Н5)
2b
3323, 2222, 1639, 1540
3.74-4.32 (4H, m, 2CH2); 6.09 (1H, s, –CH=);
2d
3a
7.16 (2H, br. s, NH, HSeO3); 7.65 (5H, m, C6H5)
3079, 2235, 1678, 1596,
1552
2.16 (3H, s, CH3); 3.83 (2H, t, J = 6, CH2);
4.29 (2H, t, J = 6, CH2); 7.58 (3H, m, С6Н5);
8.05 (3H, m, С6Н5, –CH=)
3070, 2968, 2231, 1668,
1634, 1596, 1576, 1554
4.07 (2H, t, J = 6, CH2); 4.52 (2H, t, J = 6, CH2);
7.45 (5H, m, С6Н5); 7.69 (3H, m, С6Н5);
8.36 (2H, m, С6Н5); 8.47 (1H, s, –CH=)
3b
2550, 2226, 1654, 1580
4.01 (2H, m, CH2); 4.43 (2H, m, CH2);
4a
4b
7.65 (5H, m, С6Н5); 8.02 (1H, br. s, NH)
3483, 3063, 2239, 1632,
1570, 1524
3.87 (2H, m, CH2); 4.29 (2H, m, CH2);
7.44 (2H, m, С6Н5);
7.64 (3H, m, С6Н5); 9.07 (1H, br. s, NH)
3521, 3241, 3175-2830,
2229, 1647, 1571, 1533
2.91-3.56 (4H, m, CH2CH2); 5.89 (5H, m, С6Н5);
4c
5a
5b
6b
8.60 (1H, br. s, NH)
2892, 2220, 1639, 1543,
3.87 (4H, m, CH2CH2); 7.24 (2H, m, С6Н5);
1517
7.47 (3H, m, С6Н5)
3054, 2926, 2230, 1632,
1544, 1518
3.71 (4H, m, CH2CH2); 7.53 (5H, m, С6Н5)
3250, 3120, 2976, 1691,
1.07 (3H, t, J = 7, CH3); 3.74 (2H, q, J = 7, CH2);
3.85 (4H, m, 2CH2); 4.36 (1Н, br. s, ОН);
5.61 (1H, s, –CH=); 7.56 (5H, m, С6Н5);
8.01 (2H, br. s, NH2)
1641, 1585, 1557
3284, 2980, 2936, 2900,
2188, 1657, 1607, 1593
1.21 (3H, t, J = 7, CH3);
7a
3.41-3.76 (6H, m, CH2, NCH2CH2N);
7.36 (2H, m, С6Н5); 7.49 (3H, m, С6Н5); 7.81 (1H, s, NH)
3270, 2930, 2900, 2190,
1651, 1605, 1589
3.20 (3H, s, CH3); 3.40 (4H, m, CH2CH2);
7b
7c
7.23 (2H, m, С6Н5); 7.58 (3H, m, С6Н5); 7.83 (1H, s, NH)
3283, 2965, 2883, 2171,
1.23 (3H, t, J = 7, CH3);
1653, 1605, 1589, 1541
3.38-3.72 (6H, m, CH2, NCH2CH2N);
7.29 (2H, m, С6Н5); 7.49 (3H, m, С6Н5); 7.78 (1H, s, NH)
3275, 2959, 2875, 2187,
1652, 1604, 1588, 1560
0.89 (3H, t, J = 7, CH3); 1.23-1.69 (4H, m, CH2CH2);
3.43 (6H, m, CH2, NCH2CH2N); 7.34 (2H, m, С6Н5);
7.52 (3H, m, С6Н5); 7.78 (1H, s, NH)
3.76 (4H, m, CH2CH2); 6.81 (3H, m, С6Н5);
7.21 (2H, m, С6Н5); 7.54 (5H, m, С6Н5);
9.32 (1H, s, NH)
0.89 (3H, t, J = 6, CH3); 1.21 (3H, t, J = 7, CH3);
1.65 (2H, sextet, J = 6, CH2); 2.87-3.74 (8H, m, 4CH2);
5.16 (1Н, s, =СН–); 7.41 (5H, m, С6Н5)
7d
7e
8
3282, 2223, 1632, 1602,
1588, 1542, 1524
3084, 2968, 2880, 2180,
1646, 1556, 1466
_______
1
* H NMR spectra for compounds 2a,b, 3a,b, 5a,b, 8 were recorded in
CDCl3; the remainder in DMSO-d6.
vacuo at 100°C. The formation of pseudo bases with water, malononitrile, isopropanol, and amines under
analogous conditions has not been observed. The covalent solvates 7a-e are less strongly colored than the
imidazopyridines 5a,b. They all melt with decomposition in the range 93-163°C. The IR spectra of compounds 7
show characteristic maxima for C≡N stretching in the range 2171-2190 and N–H stretching at 3270-3284 cm-1.
718

TABLE 3. Coordinates (×104) and Equivalent Isotropic Thermal Parameters
(Å2×103) for the Atoms in the Molecule of Compound 2c
Atom
x
y
z
U(eq)
N(1)
C(2)
C(3)
C(4)
C(14)
F(1)
6663(4)
5913(6)
4464(6)
3856(6)
2329(7)
1163(4)
2475(5)
1805(5)
4651(6)
6067(6)
6944(6)
6105(7)
6863(8)
8442(9)
9250(8)
8518(7)
6705(5)
3690(6)
3090(6)
8046(7)
8221(7)
8498(6)
7338(7)
6067(5)
7460(8)
8246(8)
6038(6)
7997(6)
8719(3)
8630(4)
8095(4)
7698(4)
7090(5)
7584(3)
6233(3)
6868(4)
7814(4)
8332(4)
8472(4)
8813(4)
8926(5)
8683(6)
8315(6)
8214(5)
9101(4)
8008(4)
7954(5)
9432(5)
9502(5)
9949(5)
9633(4)
9346(4)
9566(5)
8788(4)
9458(4)
10400(4)
1735(2)
959(3)
42(1)
42(1)
43(1)
43(1)
56(2)
94(1)
127(2)
112(2)
46(1)
44(1)
44(1)
54(2)
71(2)
81(2)
80(2)
65(2)
54(1)
52(1)
75(2)
67(2)
61(2)
125(2)
55(2)
78(1)
64(2)
158(3)
119(2)
121(2)
914(3)
1668(3)
1653(4)
1275(3)
1238(4)
2426(3)
2442(3)
2482(3)
3302(3)
4015(3)
4795(4)
4871(4)
4180(4)
3388(4)
348(3)
F(2)
F(3)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
C(12)
N(2)
C(13)
N(3)
C(15)
C(16)
O(1')
C(2')
O(2')
C(1')
F(1')
F(2')
F(3')
93(3)
-565(3)
1628(3)
668(3)
-1327(3)
-1678(3)
-1370(2)
-2648(4)
-2924(3)
-3035(2)
-3009(3)
1
In their H NMR spectra the pseudobases 7 are characterized by the appearance of a broad N–H signal at low
field in the range 7.78-9.32 ppm. The signal for the methylene protons appears as a multiplet in the range
3.40-3.76 ppm.
TABLE 4. Mean Atomic Distances in the Molecule of Compound 2c
Bond
d, Å
Bond
d, Å
Bond
d, Å
C(6)–N(1)
C(2)–N(1)
C(15)–N(1)
N(2)–C(2)
C(4)–C(3)
C(13)–C(3)
C(5)–C(4)
C(3)–C(2)
C(14)–C(4)
F(1)–C(14)
F(2)–C(14)
F(3)–C(14)
C(6)–C(5)
1.362(6)
1.367(6)
1.498(7)
1.313(6)
1.381(7)
1.437(7)
1.383(7)
1.406(7)
1.510(7)
1.311(6)
1.293(7)
1.313(6)
1.371(7)
C(8)–C(7)
C(7)–C(6)
C(12)–C(7)
C(9)–C(8)
C(10)–C(9)
C(11)–C(10)
C(12)–C(11)
N(2)–C(16)
N(3)–C(13)
C(15)–C(16)
C(15)–H(15A)
C(15)–H(15B)
C(16)–H(16A)
1.387(7)
1.484(6)
1.374(7)
1.379(7)
1.371(9)
1.360(9)
1.383(8)
1.465(7)
1.142(6)
1.503(7)
0.9700
C(16)–H(16B)
C(8)–H(8)
C(9)–H(9)
C(10)–H(10)
C(11)–H(11)
C(12)–H(12)
N(2)–H(2)
C(2')–O(1')
C(2')–O(2')
C(2')–C(1')
C(1')–F(1')
C(1')–F(2')
C(1')–F(3')
0.9700
0.9300
0.9300
0.9300
0.9300
0.9300
0.82(5)
1.191(6)
1.231(6)
1.514(8)
1.284(7)
1.346(7)
1.302(7)
0.9700
0.9700
719

TABLE 5. Valence Angles in the Molecule of Compound 2c
Angle
ω, deg.
Angle
ω, deg.
Angle
ω, deg.
C(2)–N(1)–C(6)
N(1)–C(2)–C(3)
N(1)–C(2)–N(2)
C(6)–N(1)–C(15)
C(2)–N(1)–C(15)
C(3)–C(2)–N(2)
C(2)–C(3)–C(4)
C(4)–C(3)–C(13)
C(2)–C(3)–C(13)
C(3)–C(4)–C(5)
C(5)–C(4)–C(14)
C(3)–C(4)–C(14)
F(1)–C(14)–F(2)
F(2)–C(14)–F(3)
F(1)–C(14)–F(3)
C(4)–C(14)–F(2)
C(4)–C(14)–F(1)
C(4)–C(14)–F(3)
C(4)–C(5)–C(6)
N(1)–C(6)–C(5)
N(1)–C(6)–C(7)
C(5)–C(6)–C(7)
C(8)–C(7)–C(12)
123.4(4)
119.0(4)
111.4(5)
127.7(4)
108.2(4)
129.6(4)
117.8(4)
123.8(5)
118.4(5)
121.2(5)
118.8(5)
120.0(4)
105.8(5)
107.4(5)
105.4(5)
112.2(5)
112.8(5)
112.8(5)
120.8(5)
117.7(4)
120.2(4)
122.1(5)
119.6(5)
C(6)–C(7)–C(12)
C(6)–C(7)–C(8)
C(7)–C(8)–C(9)
C(8)–C(9)–C(10)
C(9)–C(10)–C(11)
C(10)–C(11)–C(12)
C(7)–C(12)–C(11)
C(2)–N(2)–C(16)
C(3)–C(13)–N(3)
N(1)–C(15)–C(16)
C(15)–C(16)–N(2)
H(2)–N(2)–C(2)
H(2)–N(2)–C(16)
H(5)–C(5)–C(6)
H(5)–C(5)–C(4)
H(8)–C(8)–C(9)
H(8)–C(8)–C(7)
H(9)–C(9)–C(10)
H(9)–C(9)–C(8)
H(10)–C(10)–C(11)
H(10)–C(10)–C(9)
H(11)–C(11)–C(10)
H(11)–C(11)–C(12)
122.2(5)
118.2(5)
120.1(6)
119.9(6)
120.0(6)
120.9(6)
119.5(6)
111.4(4)
178.7(6)
103.1(4)
103.2(4)
124(4)
123(4)
119.6
119.6
120.0
120.0
120.0
120.0
120.0
H(12)–C(12)–C(7)
H(12)–C(12)–C(11)
H(15A)–C(15)–N(1)
H(15A)–C(15)–C(16)
H(15B)–C(15)–N(1)
H(15B)–C(15)–C(16)
H(15A)–C(15)–H(15B)
H(16A)–C(16)–N(2)
H(16A)–C(16)–C(15)
H(16B)–C(16)–N(2)
H(16B)–C(16)–C(15)
H(16A)–C(16)–H(16B)
O(2')–C(2')–O(1')
C(1')–C(2')–O(1')
C(1')–C(2')–O(2')
F(3')–C(1')–F(1')
120.3
120.3
111.2
111.2
111.2
111.2
109.1
111.1
111.1
111.1
111.1
109.1
129.8(6)
114.7(5)
115.5(5)
109.4(6)
103.1(6)
101.7(5)
114.5(5)
113.9(5)
112.9(5)
F(2')–C(1')–F(1')
F(2')–C(1')–F(3')
C(2')–C(1')–F(1')
C(2')–C(1')–F(3')
120.0
119.5
119.5
C(2')–C(1')–F(2')
TABLE 6. Coordinates (×104) and Equivalent Isotropic Thermal Parameters
(Å2×103) for the Atoms in the Molecule of Compound 7a
Atom
x
y
z
U(eq)
Cl(1)
O
506(1)
805(1)
2342(1)
-466(2)
-350(2)
1097(2)
1601(2)
1631(2)
68(3)
-2464(3)
445(3)
-168(3)
421(3)
1661(3)
2205(3)
3398(3)
3320(4)
4418(4)
5598(4)
5696(4)
4603(3)
2109(3)
923(4)
-1435(3)
692(3)
-881(4)
-1791(7)
3629(1)
3453(1)
2089(1)
1866(1)
2536(1)
5494(2)
5828(2)
3938(2)
5197(2)
4314(2)
3652(2)
4166(2)
5019(2)
5534(2)
6352(3)
6807(3)
6453(4)
5666(5)
5193(3)
6400(3)
6722(3)
4091(2)
2529(2)
4371(3)
4011(4)
62(1)
45(1)
62(1)
63(1)
67(1)
40(1)
50(1)
67(1)
38(1)
40(1)
41(1)
42(1)
38(1)
40(1)
59(1)
77(1)
78(1)
97(2)
75(1)
47(1)
61(1)
48(1)
45(1)
59(1)
97(1)
F(1)
1431(1)
8489(1)
1637(1)
1889(1)
2465(1)
1989(1)
2015(1)
1717(1)
1223(1)
1105(1)
1415(1)
1284(1)
1049(1)
907(2)
1000(2)
1244(2)
1384(2)
2284(1)
2624(2)
1861(1)
1282(1)
645(2)
F(2)
F(3)
N(1)
N(2)
N(3)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
C(12)
C(13)
C(14)
C(15)
C(16)
C(17)
C(18)
209(2)
720

TABLE 7. Mean Atomic Distances in the Molecule of Compound 7a
Bond
d, Å
Bond
d, Å
Bond
d, Å
Cl(10)–C(5)
O–C(4)
O–C(17)
1.727(3)
1.419(3)
1.436(4)
1.330(3)
1.330(3)
1.333(3)
1.364(3)
1.395(3)
1.465(3)
1.345(3)
1.445(4)
0.85(3)
C(3)–C(15)
C(3)–C(4)
C(4)–C(5)
C(4)–C(16)
C(5)–C(6)
C(6)–C(7)
C(7)–C(8)
C(7)–C(12)
C(8)–C(9)
C(8)–H(8)
C(9)–C(10)
C(9)–H(9)
C(10)–C(11)
C(10)–H(10)
1.417(4)
1.514(4)
1.518(4)
1.541(4)
1.339(4)
1.488(4)
1.370(4)
1.373(4)
1.380(5)
0.91(3)
1.351(6)
0.95(4)
1.353(6)
0.94(4)
C(11)–C(12)
C(11)–H(11)
C(12)–H(12)
C(13)–C(14)
C(13)–H(13A)
C(13)–H(13B)
C(14)–H(14A)
C(14)–H(14B)
C(17)–C(18)
C(17)–H(17A)
C(17)–H(17B)
C(18)–H(18A)
C(18)–H(18B)
C(18)–H(18C)
1.385(6)
0.91(4)
1.00(4)
1.521(5)
0.93(3)
0.91(3)
0.95(3)
0.92(4)
1.478(6)
1.02(4)
0.92(3)
0.94(4)
1.05(4)
0.95(6)
F(1)–C(16)
F(2)–C(16)
F(3)–C(16)
N(1)–C(2)
N(1)–C(6)
N(1)–C(13)
N(2)–C(2)
N(2)–C(14)
N(2)–H(2)
N(3)–C(15)
C(2)–C(3)
1.151(4)
1.369(4)
In order to determine the crystalline molecular structure of the covalent solvates we carried out an X-ray
analysis of compound 7a (Fig. 2). The coordinates and equivalent isotropic thermal parameters for the atoms are
given in Table 6 and the mean interatomic distances and valence angles in Tables 7 and 8. The dihedral angle
between the planes of the phenyl substituent and the heterocyclic system was 96° and the C6–C7 bond length
1.488 Å which points to a disturbance of the conjugation between the aromatic ring and the bicyclic system.
TABLE 8. Valence Angles in the Molecule of Compound 7a
Angle
ω, deg.
Angle
ω, deg.
Angle
ω, deg.
C(4)–O–C(17)
C(2)–N(1)–C(6)
C(2)–N(1)–C(13)
C(6)–N(1)–C(13)
C(2)–N(2)–C(14)
C(2)–N(2)–H(2)
C(14)–N(2)–H(2)
N(2)–C(2)–N(1)
N(2)–C(2)–C(3)
N(1)–C(2)–C(3)
C(2)–C(3)–C(15)
C(2)–C(3)–C(4)
C(15)–C(3)–C(4)
O–C(4)–C(3)
115.0(2)
120.9(2)
111.5(2)
127.5(2)
111.8(3)
120(2)
C(8)–C(7)–C(6)
C(12)–C(7)–C(6)
C(7)–C(8)–C(9)
C(7)–C(8)–H(8)
C(9)–C(8)–H(8)
C(10)–C(9)–C(8)
C(10)–C(9)–H(9)
C(8)–C(9)–H(9)
C(9)–C(10)–C(11)
C(9)–C(10)–H(10)
C(11)–C(10)–H(10)
C(10)–C(11)–C(12)
C(10)–C(11)–H(11)
C(12)–C(11)–H(11)
C(7)–C(12)–C(11)
C(7)–C(12)–H(12)
C(11)–C(12)–H(12)
N(1)–C(13)–C(14)
N(1)–C(13)–H(13A)
C(14)–C(13)–H(13A)
N(1)–C(13)–H(13B)
C(14)–C(13)–H(13B)
C(14)–C(13)–H(13A)
N(1)–C(13)–H(13B)
C(14)–C(13)–H(13B)
H(13A)–C(13)–H(13B)
120.6(3)
121.4(3)
121.1(4)
118(2)
121(2)
120.2(4)
118(3)
121(3)
119.5(4)
123(2)
118(2)
120.8(4)
123(3)
N(2)–C(14)–C(13)
N(2)–C(14)–H(14A)
C(13)–C(14)–H(14A)
N(2)–C(14)–H(14B)
C(13)–C(14)–H(14B)
H(14A)–C(14)–H(14B)
N(3)–C(15)–C(3)
F(2)–C(16)–F(1)
F(2)–C(16)–F(3)
F(1)–C(16)–F(3)
F(2)–C(16)–C(4)
F(1)–C(16)–C(4)
F(3)–C(16)–C(4)
O–C(17)–C(18)
O–C(17)–H(17A)
C(18)–C(17)–H(17A)
O–C(17)–H(17B)
C(18)–C(17)–H(17B)
H(17A)–C(17)–H(17B)
C(17)–C(18)–H(18A)
C(17)–C(18)–H(18B)
H(18A)–C(18)–H(18B)
C(17)–C(18)–H(18C)
H(18A)–C(18)–H(18C)
H(18B)–C(18)–H(18C)
103.6(3)
107.4(19)
113.3(19)
113(3)
112(3)
107(3)
178.0(3)
106.2(2)
106.5(2)
106.7(2)
113.8(2)
112.2(2)
111.1(2)
107.2(3)
108(2)
113(2)
111(2)
112(2)
106(3)
106(2)
101(2)
126(2)
108.6(2)
129.3(3)
122.1(2)
117.9(2)
122.1(2)
119.8(2)
112.2(2)
112.9(2)
109.5(2)
101.7(2)
109.9(2)
110.5(2)
124.9(2)
119.1(2)
115.9(19)
119.8(2)
124.1(2)
116.1(2)
118.1(3)
116(3)
120.2(4)
117(2)
O–C(4)–C(5)
C(3)–C(4)–C(5)
O–C(4)–C(16)
C(3)–C(4)–C(16)
C(5)–C(4)–C(16)
C(6)–C(5)–C(4)
C(6)–C(5)–Cl(1)
C(4)–C(5)–Cl(1)
C(5)–C(6)–N(1)
C(5)–C(6)–C(7)
N(1)–C(6)–C(7)
C(8)–C(7)–C(12)
122(2)
102.2(2)
108.9(18)
113.7(17)
109(2)
115(2)
113.7(17)
109(2)
115(2)
108(3)
109(3)
115(4)
107(4)
119(5)
721

EXPERIMENTAL
IR spectra were taken on a Specord IR-75 instrument in paraffin oil (NaCl prism, 1500-1800 cm-1
region) or hexachlorobutadiene (LiF prism, 2000-3600 cm-1 region). 1H NMR spectra were recorded on a Bruker
WH-90/DS spectrometer (90 MHz) using TMS or HMDS internal standards. Monitoring of the reaction course
and the purity of the compounds obtained was carried out using TLC on Silufol UV-254 plates in the system
ethanol–chloroform (1:9). The unit cell parameters and intensities of the reflections were measured on a Syntex
P21 automatic diffractometer using monochromatic molybdenum irradiation (graphite monochromator) and the
ω-scanning method. The structure was solved by a direct method [8] and refined by the least squares method in
a full matrix, anisotropic approximation. All calculations were carried out using the program package [9].
Data for the synthesized compound is collated in Tables 1 and 2.
a
8-Cyano-1-methyl-5-phenyl-7-trifluoromethyl-2,3-dihydroimidazo[1,2- ]pyridinium Iodide (2a).
Methyl iodide (0.04 ml) was added to a solution of the imidazopyridine 1 (0.2 g, 0.69 mmol) in chloroform
(5 ml). The reaction mixture was held at room temperature for 24 h. Solvent was distilled off in vacuo and the
oil produced was recrystallized from diethyl ether.
a
8-Cyano-5-phenyl-1-propyl-7-trifluoromethyl-2,3-dihydroimidazo[1,2- ]pyridinium Iodide (2b).
Propyl iodide (0.34 ml, 3.5 mmol) was added to a solution of the imidazopyridine 1 (0.2 g, 0.69 mmol) in
acetonitrile (5 ml) and refluxed for 8 h. The reaction mixture was evaporated to dryness in vacuo and water
(50 ml) was added to the residue. The precipitate was recrystallized from ethanol and the aqueous filtrate was
used in the synthesis of compound 8.
a
8-Cyano-5-phenyl-7-trifluoromethyl-2,3-dihydro-(1H)-imidazo[1,2- ]pyridinium
Hydroselenite
(2d). A solution of the imidazopyridine 1 (0.5 g, 1.73 mmol) and selenium dioxide (0.2 g, 1.73 mmol) in
tetrahydrofuran (5 ml) was held at room temperature for 7 h. The precipitate was filtered off.
a
1-Acetyl-8-cyano-5-phenyl-7-trifluoromethyl-2,3-dihydroimidazo[1,2- ]pyridinium Chloride (3a).
A solution of the imidazopyridine 1 (0.2 g, 0.69 mmol) in freshly distilled acetyl chloride (5 ml) was refluxed
for 4 h. The reaction mixture has poured into crushed ice (50 g) and the precipitate was recrystallzed from
ethanol.
a
1-Benzoyl-8-cyano-5-phenyl-7-trifluoromethyl-2,3-dihydroimidazo[1,2- ]pyridinium Chloride
(3b). A solution of the imidazopyridine 1 (0.2 g, 0.69 mmol) and benzoyl chloride (0.1 ml, 0.9 mmol) in
chloroform (5 ml) was refluxed for 1 h. The solvent was evaporated off in vacuo and the residue was
recrystallized from ethanol.
a
6-Chloro-8-cyano-5-phenyl-7-trifluoromethyl-2,3-dihydroimidazo[1,2- ]pyridinium
Chloride
(4a). A. A solution of chlorine (0.06 g, 0.9 mmol) in absolute dioxane (5 ml) was added to a solution of the
imidazopyridine 1 (0.2 g, 0.69 mmol) in dioxane (5 ml). The reaction mixture was held at room temperature for
24 h and the precipitate was filtered off. The filtrate was used for the preparation of compound 5a.
a
8-Cyano-6-halo-5-phenyl-7-trifluoromethyl-2,3-dihydroimidazo[1,2- ]pyridinium halides (4a,b).
B. The corresponding acid (0.69 mmol) was added to a solution of the imidazopyridine 5a or 5b (0.69 mmol) in
tetrahydrofuran (5 ml). The reaction mixture was held at room temperature for 4 h and the crystals formed were
filtered off.
a
6-Bromo-8-cyano-5-phenyl-7-trifluoromethyl-2,3-dihydroimidazo[1,2- ]pyridinium Tribromide
(4c). Bromine (0.04 ml, 0.69 mmol) was added to a solution of the imidazopyridine 1 (0.2 g, 0.69 mmol) in
DMF (5 ml). The reaction mixture was held at room temperature for 24 h, the solution was poured into water
(50 ml), and the precipitate was filtered off. The filtrate was used for the preparation of compound 5b.
a
A. The
8-Cyano-6-halo-5-phenyl-7-trifluoromethyl-2,3-dihydroimidazo[1,2- ]pyridines (5a,b).
filtrate obtained in the synthesis of compound 4a (method A) or 4c was basified with aqueous ammonia to
pH 8-9 and left for 1 h at room temperature. The precipitate was recrystallized from isopropanol.
722

B. The imidazopyridinium salt (4a-c) (0.2 g) was dissolved with heating in water (10 ml). The solution
was basified with aqueous ammonia to pH 8-9 and left for 1 h at room temperature. The precipitate was
recrystallized from isopropanol.
a
A
8-Aminocarbonyl-5-phenyl-7-trifluoromethyl-2,3-dihydroimidazo[1,2- ]pyridine·EtOH (6b).
solution of the imidazopyridine 1 (0.2 g, 0.69 mmol) and KOH (0.04 g) in ethanol (5 ml) was heated for 4 h.
The reaction mixture was cooled to room temperature and the precipitate was filtered off.
a
7-Alkoxy-8-cyano-6-halo-5-phenyl-7-trifluoromethyl-1,2,3,7-tetrahydroimidazo[1,2- ]pyridines
(7a-d). A solution of the imidazopyridine 5a,b (0.2 g) in the corresponding alcohol (5 ml) was heated to reflux
and allowed to stand at room temperature for 24 h. The crystals formed were filtered off.
a
6-Bromo-8-cyano-7-phenoxy-5-phenyl-7-trifluoromethyl-1,2,3,7-tetrahydroimidazo[1,2- ]pyridine
(7e). Phenol (0.05 g, 0.54 mmol) was added to a solution of the imidazopyridine 5b (0.2 g, 0.54 mmol) in
chloroform (5 ml), the product was heated to reflux, and allowed to stand for 24 h at room temperature. The
bright red crystals formed were filtered off and washed on the filter with chloroform.
a
8-Cyano-7-ethoxy-5-phenyl-1-propyl-7-trifluoromethyl-1,2,3,7-tetrahydroimidazo[1,2- ]pyridine
(8). The aqueous filtrate obtained in the synthesis of compound 2b was basified with aqueous ammonia to pH
8-9 and allowed to stand for 1 h at room temperature. The precipitate formed was recrystallized from ethanol.
a
X-ray Structural Analysis of 8-Cyano-5-phenyl-7-trifluoromethyl-2,3-dihydroimidazo[1,2- ]-
pyridinium Trifluoroacetate (2c). Crystals of the investigated compound are monoclinic. Unit cell parameters:
a = 8.421(2), b = 13.005(3), c = 15.546(3) Å; β = 90.10(3)°; V = 1702.5(7) Å3; dcalc = 1.573 mg/m3; Z = 4; space
group P2(1)c. 2145 Independent reflections were obtained, 2θmax = 25.05°, final R-factor 0.0724.
X-ray Structural Analysis of 6-Chloro-8-cyano-7-ethoxy-5-phenyl-7-trifluoromethyl-1,2,3,7-
a
Crystals of the investigated compound are monoclinic. Unit cell
tetrahydroimidazo[1,2- ]pyridine (7a).
parameters: a = 26.650(5), b = 10.352(2), c = 13.095(3) Å; β = 104.30(3); V = 3500.7(12) Å3;
d
calc = 1.403 mg/m3; Z = 8; space group C2/c. 2450 Independent reflections were obtained, 2θmax = 25.06°, final
R-factor 0.0451.
REFERENCES
1.
2.
3.
E. Suloeva, M. Yure, and E. Gudriniece, Khim. Geterotsikl. Soedin., 1299 (1999).
E. Suloeva, M. Jure, and E. Gudriniece, Khim. Geterotsikl. Soedin., 1011 (2000).
E. Suloyeva, M. Jure, E. Gudriniece, S. Belyakov, M. Petrova, and I. Kalnite, Khim. Geterotsikl.
Soedin., 358 (2001).
4.
J. Sulojeva, M. Petrova, E. Gudriniece, and M. Jure, RTU Zinatniskie raksti. Materialzinatne un lietiska
kimija, Vol. 1, Riga (2000), p. 121.
5.
6.
7.
8.
9.
T. Kato, and T. Sakamoto, Yakagaku Zasshi, 91, 1174 (1971); Chem. Abstr., 76, 46141 (1971).
S. Portnoy, J. Org. Chem., 3377 (1965).
O. Bremer, Liebigs Ann. Chem., 521, 286 (1936).
A. F. Mishnev and S. V. Belyakov, Kristallografiya, 33, 835 (1988).
P. Gluzinsky, Ya. Kraevsky, A. Kemme, and A. Mishnev, in: Precise Structural Investigations of
Crystals [in Russian], Summary Report, Second All Soviet Conference, Riga (1990), p. 30.
723