Synthesis of 5-phenyl-7-trifluoromethyl-2,3-dihydro- imidazo[1,2-a]pyridines

Article abstract of DOI:10.1023/A:1017511217288

Syntheses are reported for a series of 2-alkylamino-6-phenyl-4-trifluoromethylpyridines. The reaction of 3-cyano-2-(hydroxyalkylamino)-6-phenyl-4-trifluoromethylpyridines with thionyl chloride gave the corresponding 2-(chloroalkylamino)pyridines, 8-cyano-5-phenyl-7-trifluoromethyl-2,3-dihydro- imidazo[1,2-a]pyridines, and 9-cyano-6-phenyl-8-trifluoromethyl-2,3,4-trihydropyrido[1,2-a]- pyrimidines. X-ray diffraction structural analysis was used to study 8-cyano-5-phenyl-7- trifluoromethyl-2,3-dihydroimidazo[1,2-a]pyridine.

Full text of DOI:10.1023/A:1017511217288

Chemistry of Heterocyclic Compounds, Vol. 37, No. 3, 2001
SYNTHESIS OF 5-PHENYL-
7-TRIFLUOROMETHYL-2,3-DIHYDRO-
a
IMIDAZO[1,2- ]PYRIDINES
E. Suloeva1, M. Yure1, E. Gudriniece1, S. Belyakov2, M. Petrova1, and I. Kalnite1
Syntheses are reported for a series of 2-alkylamino-6-phenyl-4-trifluoromethylpyridines. The reaction
of 3-cyano-2-(hydroxyalkylamino)-6-phenyl-4-trifluoromethylpyridines with thionyl chloride gave the
corresponding
2-(chloroalkylamino)pyridines,
8-cyano-5-phenyl-7-trifluoromethyl-2,3-dihydro-
imidazo[1,2-a]pyridines,
and
9-cyano-6-phenyl-8-trifluoromethyl-2,3,4-trihydropyrido[1,2-a]-
pyrimidines. X-ray diffraction structural analysis was used to study 8-cyano-5-phenyl-7-
trifluoromethyl-2,3-dihydroimidazo[1,2-a]pyridine.
Keywords: 2,3-dihydroimidazo[1,2-a]pyridines, 2,3,4-trihydropyrido[1,2-a]pyrimidines, X-ray
structural analysis.
Our previous studies [1, 2] on 2- and 3-amino-6-phenyl-4-trifluoromethylpyridines have shown that
these compounds have antiviral activity. In a continuation of this work, 2-chloro-3-cyano-6-phenyl-4-
trifluoromethylpyridine (1) and 3-aminocarbonyl-2-chloro-6-phenyl-4-trifluoromethylpyridine (2) were used to
synthesize previously unreported 2-alkylaminopyridines including a series of β- and γ-hydroxyalkylamino
derivatives 3b-e,h,i, 4d,j (Tables 1 and 2) according to our previous methods [1, 3, 4]. Products 3f,g, and 4f
were obtained in a modification of the hydroxyl substituent in 2-(2-hydroxyethylamino)pyridine 4a, which has
antiviral activity [1], and its analog 3a [3] by acylation with acetyl chloride and benzoyl chloride.
Replacement of the hydroxyl group by a chlorine atom in pyridine 3a by treatment with thionyl chloride
proved more difficult. 2-(2-Chloroethylamino)pyridine 5a was not isolated upon heating pyridine 3a with 46
equivalents of thionyl chloride at reflux. This reaction provided 8-cyano-5-phenyl-7-trifluoromethyl-2,3-
dihydroimidazo[1,2-a]pyridinium chloride (6), which gave imidazopyridine 7a upon treatment with aqueous
ammonia. If this reaction is carried out with only one-third the amount of thionyl chloride, it leads to both
bicyclic compound 7a and chloro derivative 5a, although the yield of 5a does not exceed ~20%. Intramolecular
cyclization proceeds even upon cooling the reagents to -5°C (the ratio of pyridine 3a to thionyl chloride is 1:1 or
1:2). This procedure yields a mixture of pyridines 3a and 5a and imidazopyridinium chloride 6. Even lower
yields of chloro derivative 5 were obtained upon heating pyridines 3a,b,d,e in POCl3. The major reaction
products in this case are bicyclic compounds 7.
Intramolecular alkylation with formation of a bicyclic system occurs upon heating 3a in concentrated
sulfuric acid for 1 h, which leads to a mixture of compounds difficult to separate. The major components in this
mixture are 4a and 2,3-dihydroimidazo[1,2-a]pyridine 8 (the convergent synthesis of 8 was carried out by
heating imidazopyridine 7a with concentrated sulfuric acid). Similar cyclization occurs upon heating pyridine
____________________________________________________________________________________________
1
2
Riga Technical University, LV-1048 Riga, Latvia; e-mail: mara@ktf.rtu.lv. Latvian Institute of
Organic Synthesis, LV-1006 Riga, Latvia; e-mail: serg@osi.lv. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 3, pp. 358-367, March, 2001. Original article submitted March 30, 2000.
0009-3122/01/3703-0329$25.00©2001 Plenum Publishing Corporation
329

CF3
N
CF3
CF3
CN
CN
CN
Cl
Ph
NH
(CH2)n
Ph
N
NRR'
Ph
N
1
Cl
3a–e,h,i
R"
5a–e
3a
3f,g
CF3
CF3
CF3
CN
N
CONH2
N
CN
_
HX
X
+
N
Ph
N
Ph
N
B:
Ph
NH
(CH2)n
(CH2)n
8
R"
7a,b,d,e
R"
6, 9, 10
CF3
CF3
CONH2
NRR'
CONH2
Cl
Ph
N
Ph
N
2
4a,d,j
4f
4a
3, 4 a R = CH2CH2OH, R' = H; b R = CH2CHMeOH, R' = H; c R = CH2CH(Ph)OH, R' = H;
d R = CH2CH2CH2OH, R' = H; e R = CH2CH2CHMeOH, R' = H; f R = CH2CH2OCOMe, R' = H;
g R = CH2CH2OCOPh, R' = H; h R = Me, R' = H; i R = CH2CH=CH2, R' = H; j R = Et,
R' = Et; 5, 7 a n = 1, R'' = H; b n = 1, R'' = CH3; c n = 1, R'' = Ph; d n = 2, R'' = H; e n = 2,
R'' = Me; 6 n = 1, R'' = H, X = Cl; 9 n = 1, R'' = H, X = NO3; 10 n = 1, R'' = H, X = ClO4
3a in acetic acid in the presence of concentrated sulfuric acid. In this case imidazopyridine 7a was isolated in
21% yield in addition to acylated pyridine 3f. The cyclization of N-(2-pyridyl)aminoethanols to give the
imidazo[1,2-a]pyridine system upon the action of concentrated sulfuric acid or acetic acid has not yet been
reported although it has been carried out with hydrochloric and polyphosphoric acids [5, 6].
A survey of the data on 2,3-dihydroimidazo[1,2-a]pyridines [7, 8] showed that these heterocyclic
compounds have not been studied extensively and this led us to treat other 2-(hydroxyalkylamino)pyridines 3b-e
with thionyl chloride. Both 2-(chloroalkylamino)pyridines 5b-e and condensed bicyclic heterocyclic derivatives,
(in the case of 2-(γ-hydroxyalkylamino)-
pyridines 3d,e) were obtained (Tables 1 and 2). However, intramolecular cyclization was not observed in the
case of a phenyl substituent at the carbon atom bearing the hydroxyl group in 3c.
namely, imidazopyridine 7b and pyrido[1,2-a]pyrimidines 7d,e
The imidazopyridine and pyridopyrimidine salts formed in the reactions with thionyl chloride were
converted without isolation into the free bases. An exception was found for imidazopyridine 6, which both as
nitrate 9 and perchlorate 10 was obtained upon treatment of imidazopyridine 7a with the corresponding
acids. Colored bicyclic products were obtained. The melting points found for bright yellow salts 6, 9, and 10
range from 172°C for the nitrate to 283°C for the perchlorate. Dark red imidazopyridines 7 (n = 1) melt in the
range from 110 to 143°C. The melting points of orange pyridopyrimidines 7 (n = 2) are somewhat higher
(136-198°C).
330

TABLE 1. Physico-chemical Characteristics of 6-Phenyl-4-trifluoromethyl-
pyridines 3a-3i, 4a,d,f,j
Found, %
Calculated, %
H
Reaction
time, h
——————
Com-
Empirical
Yield, %
(method)
mp, °C
pound formula
(method)
C
N
C15H12F3N3O
134-136
78
3a
(134-136 [3])
C16H14F3N3O
C21H16F3N3O
C16H14F3N3O
C17H16F3N3O
C17H14F3N3O2
59.62
59.81
4.40
4.39
12.96
13.08
124-125
125-127
134-135
146-147
167-170
2
4
5
2
89
81
87
85
3b
3c
3d
3e
3f
65.46
4.12
10.67
65.79
4.21
10.96
59.76
59.81
4.15
4.39
13.01
13.08
60.97
4.83
12.59
60.89
4.81
12.53
58.15
58.45
3.98
4.04
11.91
12.03
2 (A),
4 (B)
54 (A),
82 (B)
C22H16F3N3O2
C14H10F3N3
63.94
3.86
10.17
181-184
220-221
118-119
8
2
1
2
53
79
77
80
3g
3h
3i
64.23
3.92
10.21
60.57
60.65
3.63
3.64
15.10
15.16
C16H12F3N3
63.27
3.97
13.81
63.36
3.99
13.86
C15H14F3N3O2
203-204
(201 [1])
4a
C16H16F3N3O2
C17H16F3N3O3
C17H18F3N3O
56.50
56.63
4.78
4.75
12.29
12.38
152-153
215-218
158-159
6
1
3
66
84
88
4d
4f
4j
55.68
4.37
11.43
55.59
60.52
60.53
4.39
5.45
5.38
11.44
12.42
12.46
TABLE 2. Spectral Characteristics of 6-Phenyl-4-trifluoromethylpyridines
3b-i, 4d,f,j
IR spectrum,
Com-
pound
1H NMR spectrum (CDCl3), δ, ppm, J (Hz)
ν, cm-1
1
2
3
3414, 2978, 2926,
2218, 1594, 1522
1.27 (3Н, d, J = 5, CН3); 2.58 (1Н, br. s, ОН);
3b
3.34-4.07 (3Н, m, CН2–CН); 6.00 (1Н, t, J = 5, NH);
7.29 (1H, s, =CH–); 7.49 (3H, m, Ph); 7.98 (2H, m, Ph)
3c
3362, 2930, 2222,
1592, 1578, 1540
2.88 (1Н, br. s, ОН); 3.71 (1Н, ddd, J = 5, J = 8, J = 14, CН);
4.11 (1Н, ddd, J = 3.5, J = 6.5, J = 14, CН);
5.04 (1Н, dd, J = 3.5, J = 8, CН); 6.00 (1Н, t, J = 5, NH);
7.24-7.53 (9H, m, Ph + =CH–); 7.98 (2H, m, Ph)
3d
3e
3f
3376, 3072, 2904,
2216, 1644, 1588,
1576, 1544, 1536
3358, 2970, 2934,
2886, 2226, 1594,
1574, 1546
3389, 2341, 2221,
1731, 1693, 1593,
1579, 1537
3381, 2365-2329,
2221, 1715, 1593,
1577, 1533
1.76-2.02 (2Н, m, CН2); 2.28 (1Н, t, J = 5, ОН);
3.67-3.89 (4Н, m, 2CН2); 6.00 (1Н, t, J = 5, NH);
7.22 (1H, s, =CH–); 7.42 (3H, m, Ph); 7.93 (2H, m, Ph)
1.27 (3Н, d, J = 7, CН3); 1.80 (2Н, m, CН2); 2.42 (1Н, br. s, ОН);
3.44-4.29 (3Н, m, CН2–CН); 6.20 (1Н, t, J = 5, NH);
7.26 (1H, s, =CH–); 7.49 (3H, m, Ph); 8.02 (2H, m, Ph)
2.07 (3Н, s, CН3); 3.98 (2Н, q, J = 6, CН2); 4.36 (2Н, t, J = 6, CН2);
5.91 (1Н, t, J = 6, NH); 7.38 (1H, s, =CH–); 7.53 (3H, m, Ph);
8.07 (2H, m, Ph)
3g
3h
4.07 (2Н, q, J = 6, CН2); 4.60 (2Н, t, J = 6, CН2);
5.93 (1Н, t, J = 5, NH); 7.24-7.64 (7H, m, Ph + =CH–);
8.00 (4H, m, Ph)
3372, 2944, 2900,
2216, 1605, 1589,
1578
3.13 (3Н, d, J = 5, CН3); 6.00 (1Н, br. s, NН); 7.31 (1H, s, =CH–);
7.53 (3H, m, Ph); 8.00 (2H, m, Ph)
331

TABLE 2 (continued)
1
2
3
3209, 3101, 2972,
2216, 1644, 1588,
1576, 1544, 1536
3388, 3180, 2956,
2932, 2872, 1638,
1620, 1582, 1516
3469, 3333, 3101,
2985, 2969, 1673,
1597, 1583
4.29 (2Н, m, CН2); 5.04-5.48 (2Н, m, =CН2);
3i
5.63 (1Н, t, J = 5, NH); 5.78-6.27 (1Н, m, =CН–);
7.31 (1H, s, =CH–); 7.49 (3H, m, Ph); 8.03 (2H, m, Ph)
4d
4f
4j
1.73 (2Н, t, J = 6, CН2); 3.49 (4Н, m, 2CН2); 4.46 (1Н, t, J = 6, ОН);
6.24 (1Н, t, J = 6, NH); 7.21 (1H, s, =CH–); 7.43 (3H, m, Ph);
7.69 (1Н, br. s, NH); 8.02 (3H, m, Ph + NH)*
2.00 (3Н, s, CН3); 3.38 (2Н, q, J = 6, CН2); 4.22 (2Н, t, J = 6, CН2);
6.50 (1Н, t, J = 6, NH); 7.38 (1H, s, =CH–); 7.50 (3H, m, Ph);
7.80 (1Н, br. s, NH); 8.10 (3H, m, Ph + NH)*
1.16 (6Н, t, J = 7, 2CН3); 3.53 (4Н, q, J = 7, 2CН2);
5.89 (1Н, br. s, NH); 6.22 (1Н, br. s, NH);
7.40 (4H, m, Ph + =CH–); 8.00 (2H, m, Ph)
3368, 3172, 2964,
2932, 2880
_______
* 1H NMR spectrum taken in DMSO.
Bicyclic products 7 are highly soluble in organic solvents and partially soluble in water. Thus, these
compounds are often difficult to remove from solution.
TABLE 3. Physico-chemical Characteristics of Compounds 5a-e, 6,
7a,b,d,e, and 8-10
Found, %
——————
Com-
Empirical
Yield, %
(method)
mp, °C
Calculated, %
pound formula
C
H
N
C15H11ClF3N3
54.69
55.31
3.33
3.40
12.63
12.90
170-173 (dec.)
127-130 (dec.)
20 (A)
5a
5b
C16H13ClF3N3
55.68
3.72
11.87
60 (A)*,
10 (B)
57 (A)
56.56
3.86
12.37
C21H15ClF3N3
C16H13ClF3N3
61.87
62.77
3.68
3.76
9.87
182-185 (dec.)
129-131 (dec.)
5c
10.46
56.27
3.92
12.32
52 (A)*,
12 (B)
5d
56.56
3.86
12.37
C17H15ClF3N3
C15H11ClF3N3
C15H10F3N3
57.41
57.72
4.20
4.27
11.72
11.88
142-143 (dec.)
231-232 (dec.)
142-143
53 (A)*,
5e
6
8 (B)
54.99
3.36
12.01
62 (А)*,
55.31
3.40
12.90
76 (B)
62.15
62.29
3.59
3.48
14.58
14.15
92 (А),
78 (B')*,
83 (C)
7a
C16H12F3N3
C16H12F3N3
C17H14F3N3
63.37
63.36
3.96
3.99
13.98
13.85
108-110
196-198
136-138
17 (B'),
7b
7d
7e
39 (C)*
63.13
3.92
13.78
4 (B'),
63.36
3.99
13.85
42 (C)*
64.13
64.35
4.40
4.45
13.17
13.24
13 (B')*,
36 (C)
C15H12F3N4О
C15H11F3N4O3
C15H11ClF3N3O4
58.67
3.96
13.77
214-216
62
70
74
8
58.63
3.94
13.68
51.05
51.14
3.29
3.15
15.72
15.90
172-174 (dec.)
290-292 (dec.)
9
46.07
2.76
10.72
10
46.23
2.85
10.78
_______
* Elemental analysis corresponds to sample obtained by this method.
332

The IR spectra of imidazopyridines 7 show characteristic bands at 1640-1644 cm-1 for the C=N bond
1
and 2210-2226 cm-1 for the C≡N stretching vibrations. A special feature of the H NMR spectrum of the
N–CH2–CH2–N fragment in imidazopyridines 7 (Table 4) is the gradual transformation of the AA'BB' system
upon gradual replacement of the solvent in CDCl3–DMSO–C6D6.
Thus, the methylene protons in the N–CH2–CH2–N fragment in dioxane and deuterochloroform
solutions are virtually equivalent in their chemical shifts and are seen as narrow signals at 3.91 and 4.01 ppm,
respectively.
TABLE 4. Spectral Characteristics of Compounds 5a-e, 6, 7a,b,d,e, and 8-10
IR spectrum,
Com-
pound
1H NMR spectrum (CDCl3), δ, ppm, J (Hz)
ν, cm-1
3349, 2973, 2225,
1589, 1577, 1533
3.67-3.82 (2H, m, CH2); 3.89-4.09 (2H, m, CH2);
5.91 (1H, t, J = 5, NH); 7.33 (1H, s, =CH–); 7.51 (3H, m, Ph);
7.98 (2H, m, Ph)
1.60 (3H, d, J = 6, CH3); 3.58-4.47 (3H, m, CH2–CH);
6.00 (1H, t, J = 7, NH); 7.36 (1H, s, =CH–); 7.52 (3H, m, Ph);
8.03 (2H, m, Ph)
5a
5b
5c
5d
5e
3362, 3090, 2930,
2222, 1590, 1558,
1538
3354, 3070, 2226,
1590, 1578, 1542,
1498
3.87-4.47 (2H, m, CH2); 5.16-5.31 (1H, m, CH);
5.96 (1H, br. s, NH); 7.48 (8H, m, Ph); 8.07 (3H, m, Ph)
3359, 2959, 2219,
2.16 (2H, q, J = 6, CH2); 3.58–3.94 (4H, m, J = 6, 2CH2);
5.74 (1H, br. t, J = 6, NH); 7.39 (1H, s, =CH–); 7.52 (3H, m, Ph);
8.07 (2H, m, Ph)
1.58 (3H, d, J = 7, CH3); 1.84-2.36 (2H, m, CH2);
3.56-4.02 (2H, m, CH2); 3.93-4.29 (1Н, m, CH);
5.72 (1H, t, J = 5, NH); 7.32 (1H, s, =CH–); 7.94 (3H, m, Ph);
8.07 (2H, m, Ph)
1593, 1579, 1543
3356, 2984, 2220,
1591, 1577, 1543
3000-2400, 2250,
1640, 1585
4.22 (2H, m, CH2); 4.91 (2H, m, CH2); 6.93 (1H, s, =CH–);
6
7.56-7.67 (5H, m, Ph); 11.07 (1H, br. s, NH)*2
7a*
3100-2700, 2210,
4.01 (4H, m, 2CH2); 5.71 (1H, s, =CH–); 7.40 (2H, m, Ph);
7.53 (3H, m, Ph); 3.53 (4H, m, 2CH2); 5.74 (1H, s, =CH–);
7.50 (5H, m, Ph)*3; 3.76-3.87 (2H, m, CH2); 3.98-4.09 (2H, m, CH2);
5.86 (1H, s, =CH–); 7.52-7.64 (5H, m, Ph)*2; 2.67 (2H, t, CH2);
3.41 (2H, t, CH2); 5.04 (1H, s, =CH–); 6.58-6.62 (2H, m, Ph);
6.91-6.95 (3Н, m, Ph)*4
1640, 1530, 1460
3066, 2930, 2870,
2226, 1644, 1586,
1562, 1538
3066, 2940, 2860,
2232, 1622, 1576,
1542, 1516
2974, 2938, 2866,
2234, 1622, 1578,
1546, 1518
0.92 (3H, d, J = 6, CH3); 3.63 (1H, dd, J = 15, J = 4, CH);
4.16 (1H, dd, J = 15, J = 10, CH); 4.65 (1H, m, CH);
5.72 (1H, s, =CH–); 7.52 (5H, m, Ph)
7b
7d*
7e
1.82 (2H, q, J = 6, CH2); 3.61 (4H, t, J = 6, 2CH2);
5.68 (1H, s, =CH–); 7.24 (2H, m, Ph); 7.45 (3H, m, Ph)
1.09 (3H, d, CH3); 1.53-2.02 (2H, m, CH2); 3.31-3.82 (2H, m, CH2);
4.11-4.33 (1H, m, CH); 5.63 (1H, s, =CH–); 7.36 (2H, m, Ph);
7.56 (3H, m, Ph)
3331, 3067, 1689,
3.96 (4H, m, CH2); 5.87 (1H, s, =CH–); 5.93 (1Н, br. s, NH);
8
1645, 1581, 1557
7.44 (5H, m, Ph); 8.40 (1Н, br. s, NH)
3099-2650, 2235,
1657, 1587
3238, 3098, 2926,
2238, 1654, 1560,
1544
3.96 (2H, m, CH2); 4.64 (2H, m, CH2); 7.39 (1H, s, =CH–);
7.69 (5H, m, Ph); 10.67 (1H, br. s, NH)*2
9
4.18 (2H, m, CH2); 4.71 (2H, m, CH2); 6.87 (1H, s, =CH–);
10
7.58 (5H, m, Ph); 11.10 (1H, br. s, NH)*2
_______
1
* H NMR spectrum taken on a Varian-Mercury BB spectrometer at
200 MHz.
*2 1H NMR spectrum taken in DMSO-d6.
*3 1H NMR spectrum taken in dioxane-d8.
*4 1H NMR spectrum taken in C6D6.
333

TABLE 5. Atomic Coordinates* in Molecules A and B in 7a (×104)
Molecule A
Molecule B
Atom
x
y
z
x
y
z
N(1)
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)
N(2)
C(15)
N(3)
C(16)
F(1)
1210(11)
1954(13)
1949(14)
1498(14)
858(15)
696(12)
-50(13)
552(14)
-274(17)
-1656(17)
-2317(17)
-1560(15)
1398(14)
2221(16)
2463(12)
2596(14)
2989(16)
1645(20)
740(18)
758(15)
3207(15)
0470
4375(2)
4674(2)
4679(2)
4396(2)
4096(2)
4092(2)
3793(2)
3459(2)
3182(2)
3226(3)
3548(3)
3837(2)
4420(2)
4781(2)
4908(2)
4992(2)
5252(3)
4381(3)
4606(3)
4113(2)
4375(4)
3875
4835(8)
5787(10)
7337(11)
7899(12)
6928(11)
5429(11)
4359(10)
4890(11)
3981(15)
2515(13)
1944(12)
2918(12)
3349(10)
3535(12)
5094(9)
8197(12)
8778(13)
9517(12)
9850(11)
9821(10)
10549(10)
7399
-3818(10)
-4051(12)
-5554(13)
-6417(13)
-6053(13)
-4760(13)
-4389(13)
-4106(13)
-3818(15)
-3834(17)
-4193(17)
-4444(17)
-2212(14)
-1634(15)
-2933(12)
-5928(14)
-6277(16)
-7869(17)
-7321(14)
-8841(14)
-9188(13)
-6822
3122(2)
2802(2)
2780(2)
3072(2)
3391(2)
3409(2)
3728(2)
4029(2)
4340(2)
4346(2)
4052(3)
3744(3)
3084(2)
2707(3)
2560(2)
2443(3)
2178(3)
3063(3)
2988(4)
3350(2)
2846(3)
3610
5488(8)
4741(10)
3184(11)
2513(10)
3336(10)
4845(11)
5747(11)
5124(11)
5923(16)
7394(14)
7974(13)
7225(14)
7078(11)
7000(12)
5495(10)
2482(12)
1925(12)
838(13)
-111(10)
443(9)
F(2)
F(3)
H(5)
684(11)
2771
H(8)
H(9)
1651
0200
3425
2932
6012
4411
-4123
-3564
4025
4572
3957
5453
H(10)
H(11)
H(12)
H(131)
H(132)
H(141)
H(142)
-2251
-3421
-2127
0096
2237
1346
3005
3579
4085
4406
4230
4946
1843
0823
2545
2360
3202
2612
-3543
-4287
-4705
-1163
-2613
-0299
4575
4062
3519
3259
3113
2705
8097
9075
7775
7255
8033
7044
3487
4769
3439
-1626
2562
7950
In DMSO, these signals are shifted by 0.21 ppm and appear as two multiplets centered at 4.03 and
1
3.82 ppm. In C6D6, all the signals in the H NMR spectrum are shifted upfield due to the anisotropic effect of
the solvent and the difference in the chemical shifts of these methylene protons is 0.74 ppm; these signals
appear as triplets at 2.67 and 3.41 ppm and the splitting between the components is 10.4 Hz. The nature of the
absorption of the methylene protons in imidazopyridinium salts 6, 9, and 10 is the same as for 7a in DMSO.
TABLE 6. Averaged Interatomic Distances (d) in Molecule 7a
Bond
d, Å
Bond
d, Å
Bond
d, Å
Bond
d, Å
C(2)–N(1)
C(6)–N(1)
C(13)–N(1)
C(3)–C(2)
N(2)–C(2)
C(4)–C(3)
1.433
1.373
1.468
1.449
1.280
1.334
C(15)–C(3)
C(5)–C(4)
C(16)–C(4)
C(6)–C(5)
C(7)–C(6)
C(8)–C(7)
1.430
1.434
1.465
1.349
1.485
1.402
C(12)–C(7)
C(9)–C(8)
C(10)–C(9)
C(11)–C(10) 1.378
C(12)–C(11) 1.413
C(14)–C(13) 1.532
1.396
1.360
1.366
N(2)–C(14)
N(3)–C(15)
F(1)–C(16)
F(2)–C(16)
F(3)–C(16)
1.470
1.128
1.260
1.361
1.225
334

TABLE 7. Bond Angles (ω) in Molecule
7a
Angle
ω, deg.
Angle
ω, deg.
Angle
ω, deg.
N(1)–C(2)–C(3)
N(1)–C(2)–N(2)
C(2)–N(1)–C(6)
C(2)–N(1)–C13
N(1)–C(6)–C(5)
N(1)–C(6)–C(7)
C(6)–N(1)–C(13)
N(1)–C(13)–C(14)
C(2)–C(3)–C(4)
C(2)–C(3)–C(15)
C(3)–C(2)–N(2)
C(2)–N(2)–C(14)
116.9
113.7
121.2
107.8
119.7
17.5
130.2
102.4
119.8
114.7
129.1
108.9
C(3)–C(4)–C(5)
C(3)–C(4)–C(16)
C(4)–C(3)–C(15)
C(3)–C(15)–N(3)
C(4)–C(5)–C(6)
C(5)–C(4)–C(16)
C(4)–C(16)–F(1)
C(4)–C(16)–F(2)
C(4)–C(16)–F(3)
C(5)–C(6)–C(7)
C(6)–C(7)–C(8)
C(6)–C(7)–C(12)
120.5
121.3
125.2
174.2
121.1
118.0
114.9
115.0
114.9
122.7
120.3
119.7
C(7)–C(8)–C(9)
C(8)–C(7)–C(12)
C(7)–C(12)–C(11)
C(8)–C(9)–C(10)
C(9)–C(10)–C(11)
120.4
119.1
119.3
120.4
121.5
C(10)–C(11)–C(12) 118.7
C(13)–C(14)–N(2)
F(1)–C(16)–F(2)
F(1)–C(16)–F(3)
F(2)–C(16)–F(3)
106.9
93.9
109.4
106.3
Fig. 1. Three-dimensional model of molecule 7a.
However, the signals of the protons in the N–CH2–CH2–N fragment, which appear as two multiplets, are now
displaced by 0.53-0.69 ppm and are found at 3.96-4.22 and 4.64-4.91 ppm. A characteristic for salts downfield
signal is observed for the NH proton at 10.67-11.10 ppm.
Since no data were available in the literature for X-ray structural studies of 2,3-dihydroimidazo[1,2-a]-
pyridines, we analyzed crystals of 7a grown from ethanol and showed that there are two crystallographically
independent molecules A and B in the unit cell (Fig. 1). The atomic coordinates are given in Table 5, the
averaged interatomic distances (bond lengths) and bond angles in molecules A and B are given in Tables 6 and
7, respectively. The angle between the planes of the phenyl substituent and heterocyclic system is 132°.
In further investigations, we shall study the chemical behavior of these imidazo[1,2-a]pyridines.
EXPERIMENTAL
The IR spectra were taken on a Specord IR-75 spectrometer in paraffin oil using a NaCl prism for the
1
1500-1800 cm-1 region and LiF prism for the 2000-3600 cm-1 region. The H NMR spectra were recorded on
Bruker WH-90/DS and Varian-Mercury BB spectrometers at 200 MHz with TMS and HMDS as the internal
standards. The reaction course and purity of the samples were checked using thin-layer chromatography on
Silufol UV-254 plates and 1:9 ethanol–chloroform as the eluent.
335

The data for the products are summarized in Tables 1 and 2 for 3 and 4 and Tables 3 and 4 for 5-10.
X-ray Diffraction Analysis of Imidazopyridine 7a. The unit cell parameters for monoclinic crystals of
β = 114.859(8)°;
7a are as follows: a = 8.087(2), b = 38.880(4), c = 9.334(1) Å;
V = 2662.9(8) Å3,
d
calc = 1.443 g/cm3; Z = 8, space group P21/c. The unit cell parameters and intensities of 3189 independent
reflections were measured on a Syntex P21 automatic diffractometer with monochromatic molybdenum
radiation, graphite monochromator, and ω-scanning to 2θmax
= 50°. The structure was solved by the direct
method [9] (the initial R-factor was 0.38) and refined by the full-matrix anisotropic method of least squares. The
hydrogen atoms were found from the difference map. The final R-factor was 0.099. The calculations were
carried out using the program package given by Gluzinskii et al. [10].
2-Alkylamino-6-phenyl-4-trifluoromethylpyridines (3a-e,h,i, 4a,d,j). A solution of chloropyridine 1
or 2 (3.5 mmol) and of the corresponding amine (4.2 mmol) in dioxane (10 ml) was heated at reflux for 1-6 h
and poured into water (100 ml). The precipitate was recrystallized from ethanol.
2-(2-Acyloxyethylamino)-6-phenyl-4-trifluoromethylpyridines (3f,g, 4f). A. A solution of
hydroxyethylaminopyridine 3a (1 g, 3 mmol) in acetic acid (10 ml) with a drop of concentrated sulfuric acid
was heated at reflux for 1 h, cooled, and poured into water (100 ml). The precipitate was recrystallized from
ethanol to give 0.3 g (54%) of compound 3f. A precipitate was obtained when aqueous ammonia was added to
the filtrate to bring it to pH 8-9. Recrystallization from ethanol gave 0.1 g (21%) of imidazopyridine 7a.
B. A solution of hydroxyethylaminopyridine 3a (1 g, 3 mmol) in dioxane (10 ml) and corresponding
acyl chloride (6 mmol) was heated at reflux for 2-8 h, cooled, and poured into water (100 ml). The precipitate
was recrystallized, 3f from ethanol and 3g from 1:1 ethanol–dioxane.
The reaction of pyridine 4a and acetyl chloride according to method B gave 4f, which was recrystallized
from ethanol.
2-(Chloroalkylamino)-3-cyano-6-phenyl-4-trifluoromethylpyridines (5a-e). A. A solution of
hydroxyethylaminopyridines 5a-e (5.2 g, 20 mmol) in thionyl chloride (20 ml) was heated at reflux for 1 h.
Thionyl chloride was distilled off. At the end of the distillation, dioxane (20 ml) was added and the mixture was
poured into ground ice (50 g). The precipitate was recrystallized from ethanol. The filtrates were used to obtain
compounds 7a,b,d,e (method B).
B. A solution of hydroxyethylaminopyridines 3a,b,d,e (0.2 g, 0.69 mmol) in POCl3 (5 ml) was heated at
reflux for 1 h. The reaction mixture was cooled to room temperature and poured into ground ice (50 g). Products
5a,b,d,e were filtered off and recrystallized from ethanol. The filtrates were used for the synthesis of 7a,b,d,e
(method B).
a
A. A
8-Cyano-5-phenyl-7-trifluoromethyl-2,3-dihydroimidazo[1,2- ]pyridinium chloride (6).
solution of pyridine 3a (1 g, 3 mmol) in thionyl chloride (10 ml) was heated at reflux for 1 h. Thionyl chloride
was distilled off. At the end of the distillation, dioxane (20 ml) was added and the mixture was filtered to give
0.69 g (62%) of yellow crystalline 6.
B. Hydrogen chloride was bubbled through a solution of imidazopyridine 7a (0.2 g, 0.69 mmol) in abs.
dioxane (10 ml) for 10 min. The crystalline precipitate was filtered off to give 0.17 g (76%) of salt 6.
a
8-Cyano-5-phenyl-7-trifluoromethyl-2,3-dihydroimidazo[1,2- ]pyridines (7a,b) and 9-Cyano-6-
a
A. A sample of imidazopyridinium
phenyl-8-trifluoromethyl-2,3,4-trihydropyrido[1,2- ]pyrimidines (7d,e).
chloride 6 (1 g) was dissolved in water (50 ml) and brought to pH 8-9 by adding aqueous ammonia. The
precipitate was recrystallized from ethanol.
B'. The filtrate obtained in the synthesis of 5a (method A) was brought to pH 8-9 by adding aqueous
ammonia and left at room temperature for 1 h. The precipitate was crystallized from ethanol to give 3.8 g (78%)
of imidazopyridine 7a.
C. Imidazopyridine 7a was isolated as in method B' using the filtrate obtained in the synthesis of 5a
(method B).
Products 7b,d,e were obtained analogously using method B' or C.
336

a
A sample of
8-Aminocarbonyl-5-phenyl-7-trifluoromethyl-2,3-dihydroimidazo[1,2- ]pyridine (8).
imidazopyridine 7a (0.69 g, 2 mmol) in conc. sulfuric acid (5 ml) was heated for 1 h at 120°C on an oil bath and
poured into ground ice (50 g). The solution was brought to pH 8-9 by adding aqueous ammonia. The precipitate
was recrystallized from ethanol to give 0.13 g (62%) of orange crystals.
a
8-Cyano-5-phenyl-7-trifluoromethyl-2,3-dihydroimidazo[1,2- ]pyridinium Nitrate (9) and
Perchlorate (10). A sample of nitric acid (0.2 ml) or perchloric acid (0.4 ml) was added to a solution of
imidazopyridine 7a (0.2 g, 0.69 mmol) in abs. dioxane (10 ml). The mixture was maintained at room
temperature for 24 h and the precipitate was filtered off.
Samples of identical compounds synthesized by different methods had the same melting point and
identical IR and 1H NMR spectra.
REFERENCES
1.
2.
3.
4.
E. Yu. Gudriniece, M. Yu. Lidak, M. V. Yure, G. V. Vladyko, S. N. Nikolaev, E. I. Boreko, and
P. G. Rytik, USSR Inventor's Certificate No. 1769515; Byul. Izobr., No. 10 (1992).
E. Yu. Gudriniece, M. Y. Lidak, M. V. Yure, G. V. Vladyko, E. I. Boreko, and V. I. Botykov, USSR
Inventor's Certificate No. 1704417; Byul. Izobr., No. 1 (1992).
A. V. Guttsait, S. V. Belyakov, A. F. Mishnev, Ya. Ya. Breidelis, and E. Yu. Gudriniece, Khim.
Geterotsikl. Soedin., 1233 (1987).
M. V. Yure, E. Yu. Gudriniece, M. V. Petrova, E. K. Rantsane, and E. B. Mazheika, Izv. Akad. Nauk
LatvSSR, Ser. Khim., 439 (1990).
O. Bremer, Liebigs Ann. Chem., 521, 286 (1936).
5.
6.
L. Cossey, R. L. N. Harris, J. L. Hupatz, and J. N. Phillips, Austr. J. Chem., 29, 1039 (1976).
E. Suloeva, M. Yure, and E. Gudriniece, Khim. Geterotsikl. Soedin., 1299 (1999).
E. Suloeva, M. Yure, and E. Gudriniece, Khim. Geterotsikl. Soedin., 1011 (2000).
A. F. Mishnev and S. V. Belyakov, Kristallografiya, 33, 835 (1988).
7.
8.
9.
10.
P. Gluzinskii, Ya. Kraevskii, A. Kemme, and A. Kemme, in: Abstracts of the Second All-Union
Conference on Precision Studies of Crystal Structure [in Russian], Riga (1990), p. 30.
337