Synthesis of 2,3-dihydroimidazo-[1,2-a]pyridines from 1,3-diketones

Article abstract of DOI:10.1023/A:1012455709358

A series of 2-hydroxy-, 2-chloro-, and 2-(2-hydroxyethylamino)-6-aryl-4-polyfluoroalkyl-3-cyanopyridines has been synthesized. The latter react with phosphorus oxychloride to give fluorine containing 2,3-dihydroimidazo[1,2-a]pyridines.

Full text of DOI:10.1023/A:1012455709358

Chemistry of Heterocyclic Compounds, Vol. 37, No. 7, 2001
SYNTHESIS OF 2,3-DIHYDROIMIDAZO-
a
[1,2- ]PYRIDINES FROM 1,3-DIKETONES
E. Suloeva1, M. Yure1, E. Gudriniece1, M. Petrova1, and A. Gutcaits2
A
series of 2-hydroxy-, 2-chloro-, and 2-(2-hydroxyethylamino)-6-aryl-4-polyfluoroalkyl-3-
cyanopyridines has been synthesized. The latter react with phosphorus oxychloride to give fluorine
containing 2,3-dihydroimidazo[1,2-a]pyridines.
Keywords: 2-(2-hydroxyethylamino)pyridines, 2,3-dihydroimidazo[1,2-a]pyridines, pyridin-2-ones,
2-chloropyridines.
In a continuing investigation of the little studied 2,3-dihydroimidazo[1,2-a]pyridines [1-3] we have
synthesized a series of novel derivatives which contain fluorinated substituents. We have used the fluorine
containing 1,3-diketones 1a-g as starting materials and condensed them with cyanoacetamide in the presence of
base [4-6] to get pyridin-2-ones. The reaction was carried out by refluxing the components in ethanol in the
presence of ammonium acetate. The pyridin-2-ones 2a-g are yellowish, crystalline materials which have a light
blue fluorescence both in solutions and in the crystalline state. The position of the aryl and polyfluoroalkyl
substituent in the pyridin-2-ones 2a-g has been correlated by us with previous X-ray studies for the series in
question [7, 8].
R
R
R
CN
O
CN
O
CN
Cl
O
+
H2N
Ar
N
Ar
N
Ar
O
H
2a–g
1a–g
3a–c,e,f
R
R
CN
CN
OH
Ar
N
N
H
Ar
N
N
4a–c,e,f
5a–c,f
1–5 a R = CF3, Ar = p-MeC6H4; b R = C3F7, Ar = Ph; c R = C4F9, Ar = Ph; d R = C6F13,
Ar = Ph; e R = (CF2)2H, Ar = Ph; f R = (CF2)4H, Ar = Ph; g R = CF3, Ar = p-BrC6H4
__________________________________________________________________________________________
1
2
Riga Technical University, Riga LV-1048, Latvia; e-mail: mara@ktf.rtu.lv. Latvian Institute of
Organic Synthesis, Riga LV-1006; e-mail: guttsait@osi.lv. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 7, pp. 947-951, July, 2001. Original article submitted January 11, 2001.
872
0009-3122/01/3707-0872$25.00©2001 Plenum Publishing Corporation

TABLE 1. Characteristics of the Compounds Synthesized
Found, %
——————
Com-
pound
Empirical
formula
Reaction
time, h
Yield,
%
mp, °C
Calculated, %
C
H
N
C14H9F3N2O
C15H7F7N2O
C16H7F9N2O
C18H7F13N2O
C14H8F4N2O
60.70
60.44
3.03
3.26
10.00
10.07
296-298
254-255
242-245
238-240
3
5
5
6
4
75
52
57
76
48
2a
2b
2c
2d
2e
48.66
2.06
8.13
49.47
1.94
7.69
46.60
46.39
1.73
1.70
6.69
6.76
42.69
1.40
5.38
42.04
1.37
5.45
56.63
56.77
2.52
2.74
9.36
9.46
251-253
(243-244[4])
C16H8F8N2O
47.97
2.34
7.00
208-210
269-271
159-160
92-94
6
5
8
8
8
8
8
6
4
3
6
4
1
1
1
1
55
70
44
85
74
58
88
92
80
66
70
86
73
60
87
67
2f
48.50
2.04
7.07
C13H6BrF3N2O 44.97
45.51
1.74
1.76
8.12
8.16
2g
3a
3b
3c
3e
3f
C14H8ClF3N2
C15H6ClF7N2
C16H6ClF9N2
C14H7ClF4N2
C16H7ClF8N2
C16H14F3N3O
C17H12F7N3O
C18H12F9N3O
C16H13F4N3O
C18H13F8N3O
C16H12F3N3
56.67
2.70
9.43
56.68
2.72
9.44
47.61
47.08
1.60
1.58
7.24
7.32
44.99
1.33
6.35
86-88
44.42
1.40
6.47
53.19
53.44
2.14
2.24
8.79
8.90
104-106
78-80
46.19
1.90
6.60
46.34
1.70
6.76
59.76
59.81
4.42
4.39
13.11
13.08
157-158
144-145
110-112
110-112
122-123
156-158
182-184
158-160
134-136
4a
4b
4c
4e
4f
50.20
2.94
10.25
50.13
2.97
10.32
47.22
47.28
2.58
2.65
9.11
9.19
55.79
3.66
12.02
56.64
3.86
12.38
49.01
49.21
2.93
2.98
9.49
9.57
63.21
3.97
13.76
5a
5b
5c
5f
63.36
3.99
13.85
C17H10F7N3
52.45
52.45
2.47
2.59
10.75
10.79
C18H10F9N3
49.16
2.31
9.50
49.22
2.29
9.57
C18H11F8N3
51.32
51.32
2.57
2.63
9.92
9.97
Substitution of the hydroxy group for chlorine in the 2-hydroxypyridines (pyridin-2-ones) 2a-c,e,f has
been achieved by refluxing them with an excess of POCl3 in the presence of DMF. The corresponding
chloropyridines 3a-c,e,f were obtained in 44-88% yields.
Thanks to the presence of an electron acceptor substituent at C(3) in the 2-chloropyridines, the atom C(2)
becomes an active center in reactions with nucleophiles. Treatment of the 2-chloro-3-cyanopyridines 3a-c,e,f
with aminoethanol under previously reported conditions [1, 9] gave the corresponding
2-(2-hydroxyethylamino)pyridines 4a-c,e,f in 66-92% yields. Reaction of the latter with phosphorus oxychloride
then gave the previously unreported series of 2,3-dihydroimidazo[1,2-a]pyridines 5a-c,f which contained
fluorinated substituents. The dark red imidazopyridines melt at 134-138°C. Their IR spectra are characterized by
absorption bands for the stretching of the C=N bond in the region 1642-1648 and for the C N bond in the region
≡
1
2219-2243 cm-1. In the H NMR spectra of these compounds in chloroform, the methylene protons of the
N–CH2–CH2–N fragment are virtually equivalent in chemical shift and are observed as a narrow multiplet signal
873

TABLE 2. Spectroscopic Characteristics for the Compounds Synthesized
Com-
IR spectrum, ν, cm-1
1H NMR spectrum (CDCl3), δ, ppm, J (Hz)
pound
2a*
3200-2600, 2235, 1660, 2.38 (3H, s, CH3); 7.22 (1H, s, =CH–); 7.38 (2H, m, J = 7.5,
1625, 1580, 1560 C6H4); 7.91 (2H, m, J = 7.5, C6H4); 13.47 (1H, br. s, NH)
2b*
2c*
2d*
2e*
2f*
2g*
3a
3200-2650, 2237, 1650, 7.13 (1H, s, =CH–); 7.57 (3H, m, C6H5); 7.97 (2H, m, C6H5);
1630, 1608, 1575, 1553 12.63 (1H, br. s, NH)
3200-2600, 2236, 1650, 7.19 (1H, s, =CH–); 7.58 (3H, m, C6H5); 7.99 (2H, m, C6H5);
1605, 1578, 1542, 1524 13.38(1H, br. s, NH)
3150-2600, 2227, 1653, 7.08 (1H, s, =CH–); 7.53 (3H, m, C6H5); 7.94 (2H, m, C6H5);
1605, 1577, 1549
13.30 (1H, br. s, NH)
3250-2650, 2240, 1670, 6.91 (1H, tt, J = 52.5, J = 3.8, CF2–H); 7.02 (1H, s, =CH–);
1625, 1590, 1565
7.58 (3H, m, C6H5); 7.94 (2H, m, C6H5); 12.33 (1H, br. s, NH)
3200-2650, 2236, 1648, 7.08 (1H, s, =CH–); 7.22 (1H, tt, J = 55, J = 5, CF2–H);
1630, 1604, 1576, 1533 7.58 (3H, m, C6H5); 7.99 (2H, m, C6H5); 13.55 (1H, br. s, NH)
3220-2700, 2240, 1658, 7.36 (1H, s, =CH–); 7.84 (4H, m, C6H4); 11.93 (1H, br. s, NH)
1620, 1575, 1540
3087, 2231, 1593, 1543 2.38 (3H, s, CH3); 7.38 (2H, m, J = 8, C6H4);
8.14 (2H, m, J = 8, C6H4); 8.45 (1H, s, =CH–)
3079, 2239, 1585, 1537 7.53 (3H, m, C6H5); 7.92 (1H, s, =CH–); 8.07 (2H, m, C6H5)
3b
3c
3e
2231, 1583, 1543
2235, 1594, 1542
7.54 (3H, m, C6H5); 7.89 (1H, s, =CH–); 8.07 (2H, m, C6H5)
6.18 (1H, tt, J = 54, J = 2, CF2–H); 7.56 (3H, m, C6H5);
7.92 (1H, s, =CH–); 8.09 (2H, m, C6H5)
3059, 3031, 2239, 1587, 6.09 (1H, tt, J = 52, J = 5, CF2–H); 7.52 (3H, m, C6H5);
3f
1537 7.89 (1H, s, =CH–); 8.07 (2H, m, C6H5)
3391, 2951, 2215, 1585, 2.32 (1H, br. m, OH); 2.38 (3H, s, CH3); 3.85 (4H, m, 2CH2);
4a
1531
5.94 (1H, br. m, NH); 7.27 (1H, s, =CH–); 7.32 (2H, m, J = 8,
C6H4); 7.89 (2H, m, J = 8, C6H4)
3363, 2939, 2219, 1590, 2.56 (1H, br. m, OH); 3.89 (4H, m, 2CH2); 6.09 (1H, br. s, NH);
1576, 1542 7.25 (1H, s, =CH–); 7.59 (3H, m, C6H5); 8.04 (2H, m, C6H5)
3411, 2943, 2211, 1577, 2.40 (1H, br. s, OH); 3.89 (4H, m, 2CH2); 6.05 (1H, br. m, NH);
1529 7.29 (1H, s, =CH–); 7.54 (3H, m, C6H5); 8.03 (2H, m, C6H5)
4b
4c
4e
3575, 3335, 3011, 2975, 2.69 (1H, br. m, OH); 3.89 (4H, m, 2CH2); 6.12 (2H, tt, J = 54,
2939, 2891, 2219, 1580, J = 3, CF2–H, br. m, NH); 7.27 (1H, s, =CH–);
1532
7.54 (3H, m, C6H5); 8.05 (2H, m, C6H5)
3539, 3383, 2223, 1580, 2.43 (1H, br. t, J = 5, OH); 3.87 (4H, m, 2CH2); 6.07 (1H, br. m,
4f
1573, 1537
NH); 6.17 (1H, tt, J = 52, J = 5, CF2–H); 7.29 (1H, s, =CH–);
7.59 (3H, m, C6H5); 8.05 (2H, m, C6H5)
2219, 1645, 1541, 1519 2.41 (3H, s, CH3); 4.07 (4H, m, 2CH2); 5.81 (1H, s, =CH–);
5a
7.34 (4H, m, C6H4)
2243, 2648, 1536
2223, 1642, 1542
2223, 1648, 1536
4.05 (4H, m, 2CH2); 5.69 (1H, s, =CH–); 7.49 (5H, m, C6H5)
4.09 (4H, m, 2CH2); 5.72 (1H, s, =CH–); 7.52 (5H, m, C6H5)
5b
5c
5f
4.05 (4H, m, 2CH2); 5.67 (1H, s, =CH–);
6.12 (1H, tt, J = 52, J = 5, CF2–H); 7.52 (5H, m, C6H5)
_______
* 1H NMR spectrum recorded in DMSO-d6.
in the range 4.03-4.09 ppm. The proton signals for the aryl substituent appear as a multiplet centred in the range
7.34-7.52 ppm. The signal for the pyridine ring hydrogen atom is seen as a singlet in the range 5.67-5.74 ppm,
thus showing a characteristic high field shift when compared with the C(5) proton signal in the pyridines 2-4.
EXPERIMENTAL
IR spectra were taken on a Specord IR-75 spectrometer using vaseline oil (NaCl prism, region
1500-1800 cm-1) or hexachlorobutadiene (LiF prism, region 2000-3600 cm-1). 1H NMR spectra were recorded on
a Bruker WH-90/DS (90 MHz) spectrometer with HMDS as internal standard. Monitoring of the reaction course
874

and the purity of the compounds obtained was carried out by TLC on Silufol UV-254 plates in the system
ethanol–chloroform (1:9).
Characteristics of the synthesized compounds are reported in Tables 1 and 2.
6-Aryl-3-cyano-4-polyfluoroalkylpyridin-2-ones (2a-g). A mixture of the corresponding diketone
1a-g (15 mmol), cyanoacetamide (1.5 g, 18 mmol), and ammonium acetate (1.4 g, 18 mmol) was refluxed in
ethanol (5 ml) for 3-6 h. The reaction mixture was allowed to stand for 8 h at room temperature. The precipitate
was recrystallized from a mixture of DMF and water (2:1) to give the yellowish, crystalline materials 2a-g.
6-Aryl-2-chloro-3-cyano-4-polyfluoroalkylpyridines (3a-c,e,f). DMF (15 mmol) was added slowly to
a solution of the pyridone 2a-c,e,f (6 mmol) and freshly distilled POCl3 (5 ml) at 125-130°C (oil bath) and then
heated for 8 h. The product was cooled and gradually poured onto finely crushed ice (200 g). The precipitate
was washed on the filter with water and recrystallized from ethanol to give the colorless, needle shaped
crystalline pyridines 3a-c,e,f.
6-Aryl-3-cyano-2-(2-hydroxyethylamino)-4-polyfluoroalkylpyridines (4a-c,e,f). A solution of the
chloropyridine 3a-c,e,f (3.5 mmol) and the corresponding amine (4.2 mmol) in dioxane (5 ml) was refluxed for
3-6 h and poured into water (100 ml). The precipitate was recrystallized from ethanol.
a
A solution of the
5-Aryl-8-cyano-7-polyfluoroalkyl-2,3-dihydroimidazo[1,2- ]pyridines (5a-c,f).
hydroxyethylaminopyridine 4a-c,f (0.2 g) in POCl3 (5 ml) was refluxed for 1 h. The reaction mixture was
cooled to room temperature and poured onto finely crushed ice (50 g). The solution obtained was basified with
an aqueous solution of ammonia to pH 8-9 and left for 1 h at room temperature. The precipitate was
recrystallized from ethanol to give the dark red, crystalline imidazopyridines 5a-c,f.
REFERENCES
1.
E. Suloeva, M. Yure, E. Gudriniece, S. Belyakov, M. Petrova, and I. Kalnite, Khim. Geterotsikl. Soedin.,
358 (2001).
2.
3.
4.
E. Suloeva, M. Yure, and E. Gudriniece, Khim. Geterotsikl. Soedin., 1299 (1999).
E. Suloeva, M. Yure, and E. Gudriniece, Khim. Geterotsikl. Soedin., 1011 (2000).
E. Yu. Gudriniece, A. V. Gutcaits, S. V. Belyakov, and A. N. Fomenko, Izv. Akad. Nauk LatvSSR., Ser.
Khim., 245 (1983).
5.
E. Yu. Gudriniece, A. V. Gutcaits, and S. V. Belyakov, Izv. Akad. Nauk LatvSSR., Ser. Khim., 611
(1984).
6.
7.
8.
A. V. Guttsait, Dissertation for Candidates in Chemical Sciences [in Russian], Riga (1987).
A. F. Mishnev, S. V. Belyakov, Ya. Ya. Bleidelis, and S. K. Apinitis, Kristallografiya, 31, 297 (1986).
S. V. Belyakov and A. V. Gutcaits, in: First Conference for Young Scientists in the RPI Chemistry
Faculty [in Russian], Abstracts, Riga (1985).
9.
A. V. Gutcaits, S. V. Belyakov, A. F. Mishnev, Ya. Ya. Bleidelis, and E. Yu. Gudriniece, Khim.
Geterotsikl. Soedin., 1233 (1987).
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