Reaction of 2-aryl-4-dichloromethylidene-1,3-oxazol-5(4H)-ones with 2-aminopyridine

Article abstract of DOI:10.1134/S1070363210010160

Reactions of multicenter electrophilic substrates, 2-aryl-4- dichloromethylidene-1,3-oxazol-5(4H)-ones, with 2-aminopyridine, involved cleavage of the dihydrooxazole ring by the primary amino group of nucleophilic reagent and subsequent cyclization to imi

Full text of DOI:10.1134/S1070363210010160

ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 1, pp. 121–126. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © V.M. Prokopenko, S.G. Pil’o, V.S. Brovarets, A.N. Vasilenko, B.S. Drach, 2010, published in Zhurnal Obshchei Khimii, 2010,
Vol. 80, No. 1, pp. 127–132.
Reaction of 2-Aryl-4-dichloromethylidene-1,3-oxazol-5(4H)-ones
with 2-Aminopyridine
V. M. Prokopenko, S. G. Pil’o, V. S. Brovarets, A. N. Vasilenko, and B. S. Drach†
Institute of Bioorganic and Petroleum Chemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kiev, 02660 Ukraine
e-mail: drach@bpci.kiev.ua
Received February 24, 2009
Abstract—Reactions of multicenter electrophilic substrates, 2-aryl-4-dichloromethylidene-1,3-oxazol-5(4H)-
ones, with 2-aminopyridine, involved cleavage of the dihydrooxazole ring by the primary amino group of
nucleophilic reagent and subsequent cyclization to imidazopyridine derivatives. The latter reacted with
morpholine and its analogs via recyclization with formation of 5-amino-2-aryl-N-(pyridin-2-yl)-1,3-oxazole-4-
carboxamides.
DOI: 10.1134/S1070363210010160
In continuation of our systematic studies on reac-
tions of chlorine-containing unsaturated azlactones I
with difunctional nucleophiles [1–4], in the present
communication we report for the first time on the
reaction of electrophilic substrates Ia and Ib with 2-
aminopyridine. This reaction was expected to produce
two intermediate products II and III, depending on the
direction of initial attack by 2-aminopyridine which is
capable of reacting at the amino group or endocyclic
nitrogen atom (cf. [5, 6]). Intermediate enamides could
then be converted into isomeric structures IV/V, VI/
VII, and VIII/IX (Scheme 1).
and unambiguously prove its structure by NMR
spectroscopy using homo- and heteronuclear correla-
tion techniques (COSY, NOESY, HMQC, HMBC; see
figure).
Signals from the (CH3)3CC(O)NHC=CCl2 fragment
in compound XI were assigned on the basis of the
following HMBC correlations, δ, δC, ppm: 1.14 (CH3)
↔ 177.24 (CO), 9.17 (NH) ↔ 118.42 (CCl2), 9.17
(NH) ↔ 177.25 (CO), which are consistent with the
NOESY correlations δ 1.14 (CH3) ↔ ppm 9.17 (NH).
Likewise, signals belonging to the C(O)NH–(Py-2)
fragment were identified on the basis of the HMBC
correlations (δ, δC, ppm) 10.91 (NHC5H4N) ↔ 152.16
Integrated spectral and chemical studies on the final
(C2H) and 10.91 (NHC5H4N)
↔
161.61
products obtained from azlactones
I
and 2-
(CONHC5H4N) [NOESY: δ 10.91 (NHC5H4N) ↔
aminopyridine led us to clearly prefer the
transformation sequence I → II → IV → VI which
resembles consecutive reactions occurring upon
treatment of azlactones I with benzamidine, guanidine,
2-aminothiazole, and other nucleophiles having an
amidine moiety [1, 4, 7]. We also found that azlactone
X containing a tert-butyl group in position 2 instead of
aryl residue reacted with 2-aminopyridine to give
enamide XI rather than isomeric compound XII
(Scheme 2).
8.01 ppm (C3H)].
Thus, at least in the examined case, cleavage of the
azlactone ring occurs as a result of attack by the
exocyclic nucleophilic center in 2-aminopyridine most
probably on the C5 electrophilic center in I. The
formation of imidazopyridines VI can be easily ratio-
nalized assuming an important role of enamide–N-
acylimine tautomerism which is responsible for many
transformations of enamides (Scheme 1). The structure
of compounds VI, as well as of their isomers VII, is
Compound XI is less reactive than its analogs II,
presumably for steric reasons. Therefore, we suc-
ceeded in isolating enamide XI as individual substance
1
consistent with their IR and H NMR spectra. The
spectral data indicate the presence of a carbonyl group
(νC=O 1700–1714 cm–1) and formation of a dichloro-
methyl group (δCHCl 6.50–6.56 ppm) as a result of
† Deceased.
121

122
PROKOPENKO et al.
Scheme 1.
Cl
Cl
N
Ar
O
O
Ia, Ib
NH2
N
NH2
N
, Et3N
, Et3N
Δ
Δ
H
N
O
Cl
O
N
Cl
O
H
N
Cl
N
N
NH H
Cl
Ar
Ar
O
IIIa, IIIb
IIa, IIb
H
N
O
O
CHCl2
O
N
N
N
N
CHCl2
N
Ar
H
Ar
O
IVa, IVb
Va, Vb
N
N
O
N
O
CHCl2
CHCl2
Ar
N
N
N
O
H
H
O
Ar
VIa, VIb
VIIa, VIIb
R2NH (excess), Δ
R2NH (excess), Δ
O
H
N
NR2
O
N
O
N
N
NH
NR2
O
N
Ar
IXa_IXf
Ar
VIIIa_VIIIf
Ar = Ph (a, c, e), 4-MeC6H4 (b, d, f); R2N = pyrrolidin-1-yl (a, b), piperidino (c, d), morpholino (e, f).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 1 2010

REACTION OF 2-ARYL-4-DICHLOROMETHYLIDENE-1,3-OXAZOL-5(4H)-ONES
123
139.01
intramolecular cyclization IV → VI or V → VII. More
definite information on the structure of the final
products was obtained by studying their reactions with
morpholine, piperidine, and pyrrolidine (Table 1).
Among two possible product structures VIII and IX,
preference should be given to the former. In the IR
spectra of the products we observed only one
absorption band assignable to stretching vibrations of
amide carbonyl group (1630–1700 cm–1). Structures
IX should give rise to two strong bands in the same
region due to carbonyl group and imine fragment.
Moreover, it is hardly probable that the amide bond in
IX would remain unchanged on prolonged heating
with excess morpholine. Finally, the complex trans-
formation of compounds VI in reaction with
morpholine and its analogs includes cleavage of the
dihydroimidazole fragment and subsequent recycliza-
tion to form a new oxazole ring. The presence of the
7.78
114.52
8.01
7.12
120.54
H
H
177.24
132.19
4
5
H
H
3
2
6
8.31
148.64
H3C
O
N
O
N
39.08
H3C
N
152.16
10.91
H
H
H
27.45
H
Cl
H
1.14
Cl
118.42
161.61
9.07
Principal correlations (shown with arrows) and signal
1
assignment (δ, δC, ppm) in the H and 13C NMR spectra of
compound XI.
Scheme 2.
Cl
Cl
NH2
+
N
O
O
t-Bu
X
×
H
N
O
O
Cl
N
H
Cl
N
O
N
N
NH
H
Cl
Bu-t
O
t-Bu
XI
XII
Scheme 3.
O
O
H
OCH3
OCH3
Cl
N
O
3 HN
O
N
4-CH3C6H4
4-CH3C6H4
N
O
O Cl
XIII
XIV
O
NH
N
H2N
N
, CH3ONa
N
4-CH3C6H4
N
O
O
VIIIf
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 1 2010

124
PROKOPENKO et al.
Table 1. Yields, melting points, and elemental analyses of compounds VI, VIII, X, and XI
Found, %
Calculated, %
H
Comp.
no.
Yield,
%
mp, °C (solvent)
Formula
C
H
N
C
N
a
69
72
223–226 (AcOH)
214–216 (AcOH)
176–179 (EtOH)
174–176 (EtOH)
176–179 (i-PrOH)
189–192 (EtOH)
178–181 (EtOH)
234–237 (MeCN)
92–94 (Ac2O)
53.41
54.72
68.44
68.87
69.38
70.18
65.35
65.80
42.98
3.45
3.89
5.45
5.84
5.86
6.18
5.12
5.64
4.48
4.81
12.41
11.50
16.67
15.97
15.78
15.26
15.89
15.48
6.20
C15H11Cl2N3O2
53.59
54.88
68.25
68.95
68.95
69.59
65.13
65.99
43.27
49.38
3.30
12.50
12.00
16.76
16.08
16.08
15.46
15.99
15.37
6.31
VIa
b
C16H13Cl2N3O2
C19H18N4O2
C20H20N4O2
C20H20N4O2
C21H22N4O2
C19H18N4O3
C20H20N4O3
3.74
VIb
40
5.43
VIIIa
VIIIb
VIIIc
VIIId
VIIIe
VIIIf
X
35
5.79
54
5.79
61
6.12
60
5.18
65, 30c
5.53
d
75
C8H9Cl2NO2
4.09
e
71
205–206 (EtOH)
49.44
13.52
C13H15Cl2N3O2
4.78
13.29
XI
a
b
c
d
Found, %: Cl 20.77. Calculated, %: Cl 21.09. Found, %: Cl 19.96. Calculated, %: Cl 20.25. Method b. Found, %: Cl 31.78.
Calculated, %: Cl 31.93. e Found, %: Cl 22.35. Calculated, %: Cl 22.43.
latter in compound VIIIf was rigorously proved by
EXPERIMENTAL
independent synthesis (Scheme 3).
The IR spectra were recorded in KBr on a Vertex 70
1
The cyclocondensation XIII→XIV is a particular
case of the general synthesis of many 5-amino-1,3-
oxazole derivatives whose formation is favored by
high mobility of chlorine atoms in the Cl2C=C–C=O
system and appropriate arrangement of the amide
fragment with respect to the carbonyl group [8].
Probably, the same factors are important in the
recyclization VI→VIII; cleavage of the dhydro-
imidazole ring in structure A by the action of nitrogen-
centered nucleophile could give rise to enamide inter-
mediate like B which is capable of being converted
into substituted oxazole C as shown in Scheme 4.
spectrometer. The H NMR spectra were measured on
1
a Varian-300 instrument. The H–13C heteronuclear
correlation spectra were obtained on a Varian Mercury-
1
400 spectrometer (400 and 100 MHz for H and 13C,
respectively) using DMCO-d6 as solvent and
tetramethylsilane as internal reference (Tables 2, 3).
3-Aroylamino-3-dichloromethyl-2,3-dihydroimi-
dazo[1,2-α]pyridin-2-ones VIa and VIb (general
procedure). A mixture of 0.004 mol of compound Ia or
Ib [9], 0.004 mol of 2-aminopyridine, and an equi-
molar amount of triethylamine in 10 ml of dioxane was
heated for 7 h under reflux. The mixture was cooled,
and the precipitate was filtered off, washed with water,
and purified by recrystallization. An additional amount
of the product may be isolated from the filtrate.
Obviously, further studies are necessary to identify
all intermediate products in the transformation of
imidazopyridines VI into oxazoles VIII.
Scheme 4.
N
N
H
N
H
O
O
O
NR2
NR2
Cl
2 R2NH
2 R2NH
N
N
N
CHCl2
O
Δ
Δ
H
N
N
N
O
O
H
B
A
C
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 1 2010

REACTION OF 2-ARYL-4-DICHLOROMETHYLIDENE-1,3-OXAZOL-5(4H)-ONES
Table 2. IR and 1H NMR spectra of compounds VI, VIII, X, and XI
125
Comp.
no.
IR spectrum (KBr), ν, cm–1
1H NMR spectrum, δ, ppm (DMSO-d6)
1627 (C=O), 1714 (C=O), 3200 6.56 s (1H, CHCl2), 6.82–8.18 m (9Harom), 9.61 s (1H, NH)
(NHas)
VIa
1630 (C=O), 1700 (C=O), 3360 2.39 s (3H, CH3), 6.50 s (1H, CHCl2), 6.75–8.15 m (8Harom), 9.36 s (1H, NH)
(NHas)
VIb
1682 (C=O), 3378 (NHas)
1682 (C=O), 3387 (NHas)
1667 (C=O), 3330 (NHas)
1670 (C=O), 3373 (NHas)
1676 (C=O), 3363 (NHas)
1667 (C=O), 3383 (NHas)
1810 (C=O)a
1.95 br.s, 3.76 br.s [8H, (CH2)4N], 7.10–8.34 m (9Harom), 9.26 s (1H, NH)
1.95 br.s, 3.76 br.s [8H, (CH2)4N], 2.36 s (3H, CH3), 7.08–8.31 m (8Harom), 9.25 s (1H, NH)
1.65 br.s, 3.75 br.s [10H, (CH2)5N], 7.10–8.34 m (9Harom), 9.41 s (1H, NH)
VIIIa
VIIIb
VIIIc
VIIId
VIIIe
VIIIf
X
1.66 br.s, 3.75 br.s [10H, (CH2)5N], 2.36 s (3H, CH3), 7.08–8.32 m (8Harom), 9.38 s (1H, NH)
3.80 m [8H, O(CH2)4N], 7.12–8.34 m (9Harom), 9.44 s (1H, NH)
2.39 s (3H, CH3), 3.79 br.s [8H, O(CH2)4N], 7.10–8.29 m (8Harom), 9.35 s (1H, NH)
1.29 s (9H, 3CH3)
b
1673 (C=O), 3277 (NHas)
–
XI
a
Band with a shoulder. b For 1H NMR spectrum of XI, see Table 3.
Table 3. Correlations in the NOESY, HMQC, and HMBC spectra of compound XIa
1H, δ, ppm
13C, δC, ppm
HMBC
1H, δ, ppm
COSY
NOESY
HMQC
1.14 (CH3)
7.12 (C5H)
7.78 (C4H)
8.01 (C3H)
8.31 (C6H)
9.17 (NH)
–
7.78, 8.31
7.12, 8.01
7.78
9.17
7.78, 8.31
7.12, 8.01
10.91, 7.78
7.12
27.45
120.54
139.01
114.52
148.64
–
39.08 [C(CH3)3], 177.24 (CO)
114.52 (C3H), 152.16 (C2H)
152.16 (C2H), 148.64 (C6H)
120.54 (C5H)
139.01 (C4H), 152.16 (C2H)
7.12
–
1.14
118.42 (CCl2), 161.61 (CONHC5H4N), 177.25 (CO)
114.52 (C3H), 152.16 (C2H), 161.61 (CONHC5H4N)
10.91 (NHC5H4N)
–
8.01
–
a
For signal assignment, see figure.
2-Aril-N-(pyridin-2-yl)-5-(pyrrolidin-1-yl)-1,3-
b. Compound XIV, 0.0015 mol, 2-aminopyridine,
0.0015 mol, and dioxane, 10 ml, were added to a
solution of 0.0015 mol of sodium methoxide in 1 ml of
methanol. The mixture was heated for 6 h under reflux,
and the precipitate was filtered off, washed with water,
and purified by recrystallization. Samples of VIIIf
prepareed as described in a and b showed no
depression of the melting point on mixing, and their IR
and 1H NMR spectra were identical.
oxazole-4-carboxamides VIIIa and VIIIb (general
procedure). A mixture of 0.003 mol of compound VIa
or VIb, 5 ml of pyrrolidine, and 10 ml of dioxane was
heated for 8 h under reflux. The solvent and excess
pyrrolidine were removed under reduced pressure, the
residue was treated with water, and the precipitate was
filtered off and purified by recrystallization.
2-Aryl-5-piperidino(morpholino)-N-(pyridin-2-
yl)-1,3-oxazole-4-carboxamides VIIIc–VIIIf (general
procedure). a. A mixture of 0.003 mol of compound
VIa or VIb and 10 ml of piperidine or morpholine was
heated for 8 h under reflux. Excess nucleophile was
removed under reduced pressure, the residue was
treated with water, and the precipitate was filtered off
and purified by recrystallization.
2-tert-Butyl-4-dichloromethylidene-1,3-oxazol-
5(4H)-one (X) was synthesized as described in [9] for
compound Ia using acetic anhydride instead of
phosphorus pentachloride.
3,3-Dichloro-2-(2,2-dimethyl-1-oxopropylamino)-
N-(pyridin-2-yl)prop-2-enamide (XI). A mixture of
0.004 mol of azlactone X, 0.004 mol of 2-amino-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 1 2010

126
PROKOPENKO et al.
5. Huntress, E.H. and Walter, H.C., J. Org. Chem., 1948,
pyridine, and an equimolar amount of N,N-diethyl-
aniline in 5 ml of acetonitrile was stirred for 12 h at
room temperature. The precipitate was filtered off and
recrystallized from appropriate solvent.
vol. 13, no. 5, p. 735.
6. Lur’e, S.I., Zh. Obshch. Khim., 1950, vol. 20, no. 1,
p. 195.
7. Sviripa, V.N., Cand. Sci. (Chem.) Dissertation, Kiev,
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