Synthesis and some properties of 5-alkylamino-2-(phthalimidoalkyl)-1,3- oxazole-4-carbonitriles

Article abstract of DOI:10.1007/s10593-011-0869-y

5-Alkylamino-1,3-oxazole-4-carbonitriles containing a 2-phthalimidoethyl or 3-phthalimidopropyl substituent at position 2 of the oxazole ring were synthesized. In the reaction of 5-(morpholin-4-yl)-2-(2-phthalimidoethy)l-1,3- oxazole-4-carbonitrile with hydrazine hydrate, 2-(2-aminoethyl)-5-(morpholin-4- yl)-1,3-oxazole-4-carbonitrile is formed. In the case of the 3-phthalimidopropyl analog, the recyclization product 3-amino-2-(morpholin-4-ylcarbonyl)-6,7- dihydro-5H-pyrrolo[1,2-a]imidazole is formed.

Full text of DOI:10.1007/s10593-011-0869-y

Chemistry of Heterocyclic Compounds, Vol. 47, No. 8, November, 2011 (Russian Original Vol. 47, No. 8, August, 2011)
SYNTHESIS AND SOME PROPERTIES OF
5-ALKYLAMINO-2-(PHTHALIMIDOALKYL)-
1,3-OXAZOLE-4-CARBONITRILES
S. A. Chumachenko1, O. V. Shablykin1, A. N. Vasilenko1, and V. S. Brovarets1*
5-Alkylamino-1,3-oxazole-4-carbonitriles containing a 2-phthalimidoethyl or 3-phthalimidopropyl
substituent at position 2 of the oxazole ring were synthesized. In the reaction of 5-(morpholin-4-yl)-2-(2-
phthalimidoethy)l-1,3-oxazole-4-carbonitrile with hydrazine hydrate, 2-(2-aminoethyl)-5-(morpholin-
4-yl)-1,3-oxazole-4-carbonitrile is formed. In the case of the 3-phthalimidopropyl analog, the
recyclization product 3-amino-2-(morpholin-4-ylcarbonyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole is
formed.
Keywords: 5-alkylamino-2-(phthalimidoalkyl)-1,3-oxazole-4-carbonitriles, 2-(2-aminoethyl)-5-(morpholin-
4-yl)-1,3-oxazole-4-carbonitrile, 2-(morpholin-4-ylcarbonyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-
3-amine, recyclization.
The intensive development of the chemistry of functional derivatives of 1,3-oxazole in the last 20 years
is due to searches for effective biologically active substances. The role of 1,3-oxazole derivatives in life
processes has proven much more significant than previously supposed, in that numerous derivatives of the
oxazole series have been isolated from natural materials [1-4]. Moreover a large number of the synthesized
oxazole derivatives exhibit high cytostatic, antimicrobial, immunostimulating, analgesic, and other types of
biological activity [5]. For this reason functionalization of the oxazole ring is one of the most important
directions in the synthesis of prospective novel compounds in the search for bioactive products.
The aim of the present work was to synthesize 2-phthalimidoalkyl-substituted oxazoles for the
production of the corresponding amines after removal of the phthalimide protecting group. For this purpose we
used the known method for the synthesis of substituted 5-aminooxazoles from the amides of carboxylic acids
and chloral [6]. In this condensation we used for the first time the amides of phthalimidoalkylcarboxylic acids
[7]. The choice of a phthalimide protecting group was not incidental since it is resistant to thionyl chloride and
to the aqueous-alkaline solution of potassium cyanide used at various stages of the reactions in the chain of
transformations shown in the scheme for the production of compounds 5. It is also important that the
5-aminooxazole fragment is stable to the action of hydrazine hydrate under the conditions for the removal of the
phthalimide group.
_______
*To whom correspondence should be addressed, e-mail: brovarets@bpci.kiev.ua.
1Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
1 Murmanska St., Kyiv 02660, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1238-1247, August, 2011.
Original article submitted May 13, 2011.
1020
0009-3122/11/4708-1020©2011 Springer Science+Business Media, Inc.

We established that phthalimidopropionamide (1a) and phthalimidobutyramide (1b) react readily with
chloral and give high yields of the corresponding hydroxymethyl derivatives 2a,b (Table 1). In the reaction of
the latter with thionyl chloride, compounds 3a,b are formed, and their treatment with an aqueous solution of
potassium cyanide in acetone leads to good yields of 3,3-dichloro-2-phthalimidoacylaminoacrylonitriles 4a,b.
By analogy with the already known heterocyclization [8, 9], the acrylonitriles 4a,b were used for the production
of the substituted alkylaminooxazoles 5a-j.
O
O
O
SOCl2
CCl3CHO
Cl
CCl3
PhthN
OH
CCl3
(CH2)n
CN
PhthN
PhthN
1a,b
(CH2)n
2a,b
(CH2)n
N
H
3a,b
N
H
NH2
O
N
O
KCN
RR1NH/Et3N
R1
N
CN
Cl
PhthN
(CH2)n
PhthN
(CH2)n
N
H
R
Cl
5a–j
4a,b
1a–4a, 5a–e n = 2; 1b–4b, 5f–j n = 3;
5a,f R = H, R1 = PhCH2; b,g R = H, R1 = Ph(CH2)2; c,h R+R1 = –(CH2)5–;
d,i R+R1 = –(CH2)2N(Me)(CH2)2–; e,j R+R1 = –(CH2)2O(CH2)2–
In the case of compounds 5e,j, a substantial difference was found in the chemical behavior of the
2-aminoethyl- and 2-aminopropyloxazoles formed after the removal of the phthalimide protection. When
compound 5e is boiled with a small excess of hydrazine hydrate, 2-(2-aminoethyl)-5-(morpholin-4-yl)-
1,3-oxazole-4-carbonitrile (6) is formed with a moderate yield. Its structure was confirmed by spectral and mass-
spectrometric methods (Tables 2, 3) and also by conversion into the corresponding amides 7a,b and dioxazolyl-
substituted ethylamines 8a,b.
CN
N
N2H4 · H2O
5e
H2N
(CH2)2
O
N
O
6
R3CONHC(CCl2)CN
Et3N
R2COCl
Et3N
CN
N
CN
N
O
CN
N
R2
N
N
(CH2)2
N
R3
O
N
H
(CH2)2
H
O
O
8a,b
O
O
7a,b
7a R2 = Ph, b R2 = 4-MeC6H4; 8a R3 = Me, b R3 = Ph
In the case of the hydrazinolysis of 2-(3-phthalimidopropyl)-1,3-oxazole-4-carbonitrile 5j, the amine 9
is evidently formed initially. On account of the favorable disposition of the aminopropyl fragment in relation to
the oxazole ring, this compound is susceptible to intramolecular attack from the primary amino group at the C-2
atom of the oxazole. Here cleavage of the oxazole ring and simultaneous formation of the pyrrolidine fragment
of compound 10 are observed. A similar transformation was observed earlier for derivatives of 2-(3-amino-
propyl)-4,5-diphenyl-1,3-oxazole [10, 11]. In the intermediate 10, which contains a nucleophilic amidine
fragment, attack then occurs at the nitrile group, leading to the formation of the amine 11.
1021

TABLE 1. Characteristics of Compounds Synthesized
Found, %
——————
Com-
pound
Empirical
formula
Calculated, %
mp, ºС*
Yield, %
C
H
N
Cl
C13H11Сl3N2O4
C14H13Сl3N2O4
C13H10Сl4N2O3
C14H12Сl4N2O3
C14H9Сl2N3O3
C15H11Сl2N3O3
C21H16N4O3
C22H18N4O3
C19H18N4O3
C19H19N5O3
C18H16N4O4
C22H18N4O3
C23H20N4O3
C20H20N4O3
C20H21N5O3
C19H18N4O4
C10H14N4O2
C17H18N4O3
C18H20N4O3
C15H16N6O3
C20H18N6O3
42.85
42.71
3.14
3.03
7.52
7.66
29.18
29.09
140-142
150-152
180-182
145-147
177-179
193-195
118-120
122-124
105-107
107-109
151-153
114-115
106-108
Oil
75
82
64
68
85
88
75
78
75
74
80
80
81
87
77
85
52
77
68
43
38
2a
2b
3a
3b
4a
4b
5a
5b
5c
5d
5e
5f
44.39
44.29
3.57
3.45
7.41
7.38
28.10
28.02
40.57
40.66
2.65
2.62
7.33
7.29
36.99
36.93
42.12
42.24
2.89
3.04
7.13
7.04
35.68
35.62
49.76
49.73
2.52
2.68
12.44
12.43
20.99
20.97
51.17
51.16
3.27
3.15
11.85
11.93
20.03
20.13
67.79
67.73
4.30
4.33
15.09
15.05
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
68.34
68.38
4.75
4.70
14.60
14.50
65.00
65.13
5.11
5.18
16.03
15.99
62.31
62.46
5.22
5.24
19.05
19.17
61.24
61.36
4.63
4.58
16.05
15.90
68.24
68.38
4.71
4.70
14.57
14.50
68.97
68.99
5.20
5.03
14.11
13.99
5g
5h
5i
65.84
65.92
5.41
5.53
15.47
15.37
63.33
63.31
5.69
5.58
18.45
18.46
105-106
106-108
Oil
62.38
62.29
4.85
4.95
15.27
15.29
5j
54.15
54.04
6.21
6.35
25.34
25.21
6
62.64
62.57
5.68
5.56
17.09
17.17
119-121
147-149
Oil
7a
7b
8a
8b
63.40
63.52
5.84
5.92
16.39
16.46
54.69
54.87
4.83
4.91
25.67
25.60
61.44
61.53
4.66
4.65
21.59
21.53
200-203
(decomp.)
C11H16N4O2
C18H20N4O3
C19H22N4O3
55.83
55.92
6.69
6.83
23.88
23.71
—
—
—
231-233
161-163
187-189
65
32
30
11
63.59
63.52
5.96
5.92
16.31
16.46
12a
12b
64.45
64.39
6.46
6.26
15.95
15.81
_______
*Solvent: EtOH (compounds 2a,b), PhMe (compounds 3a,b, 4a,b), EtOH–H2O,
1:1 (compounds 5a-g,i,j, 11), 2-PrOH (compounds 7a,b, 8b, 12a,b).
Compound 11 undergoes acylation by carboxylic acid chlorides with the formation of the amides 12a, b
just as readily as compound 6, indicating the presence of an amino function in the starting compound 11.
1022

TABLE 2. 1H NMR Spectra of Compounds Synthesized
Com-
Chemical shifts, δ, ppm (J, Hz)
pound
1
2a
2b
2
2.66 (2H, t, J = 6.5, CH2); 3.74-3.88 (2H, m, NCH2); 5.73 (1H, dd, J = 5.9, J = 8.9, CH);
7.69 (1H, d, J = 5.9, OH); 7.77-7.91 (4H, m, H Ar); 8.89 (1H, d, J = 8.9, NH)
1.83-1.88 (2H, m, CH2); 2.28 (2H, t, J = 7.8, CH2); 3.61 (2H, t, J = 7.0, NCH2);
5.73 (1H, dd, J = 5.5, J = 9.0, CH); 7.65 (1H, d, J = 5.5, OH);
7.79-7.93 (4H, m, H Ar); 8.69 (1H, d, J = 9.0, NH)
3a
3b
2.74-2.92 (2H, m, CH2); 3.93-4.21 (2H, m, NCH2); 6.54 (1H, d, J = 9.5, CH);
6.83 (1H, d, J = 9.5, NH); 7.68-7.80 (2H, m, H Ar); 7.80-7.95 (2H, m, H Ar)
1.98-2.16 (2H, m, CH2); 2.38 (2H, t, J = 6.5, CH2); 3.88-3.72 (2H, m, NCH2);
6.59 (1H, d, J = 10.0, CH); 7.54 (1H, d, J = 10.0, NH); 7.71-7.79 (2H, m, H Ar);
7.82-7.92 (2H, m, H Ar)
4a
4b
5a
5b
2,74-2.91 (2H, m, CH2); 3,94-4.17 (2H, m, NCH2); 7.73-7.80 (2H, m, H Ar);
7.80-7.86 (2H, m, H Ar)
2.03-2.16 (2H, m, CH2); 2.41 (2H, t, J = 6.0, CH2); 3.83 (2H, t, J = 5.5, NCH2);
7.73-7.82 (2H, m, H Ar); 7.82-7.95 (4H, m, H Ar); 8.14 (1H, br. s, NH)
2.93 (2H, t, J = 5.8, CH2); 3.86 (2H, t, J = 5.8, NCH2); 4.38 (2H, d, J = 5.5, CH2);
7.22-7.41 (5H, m, H Ar); 7.79-7.94 (4H, m, H Ar); 8.68 (1H, br. t, J = 5.0, NH)
2.81 (2H, t, J = 6.4, CH2); 2.91 (2H, t, J = 5.7, CH2); 3.35-3.43 (2H, m, CH2);
3.86 (2H, t, J = 5.7, NCH2); 7.13-7.36 (5H, m, H Ar); 7.76-7.94 (4H, m, H Ar);
8.24 (1H, br. t, J = 5.5, NH)
5c
5d
5e
5f
1.38-1.67 (6H, m, 3CH2 piperidine); 2.95 (2H, t, J = 6.0, CH2);
3.25-3.41 (4H, m, 2CH2 piperidine); 3.87 (2H, t, J = 6.0, NCH2); 7.72-7.97 (4H, m, H Ar)
2.25 (3H, c, CH3); 2.39-2.48 (4H, m, 2CH2); 2.97 (2H, t, J = 6.5, CH2);
3.31-3.42 (4H, m, 2CH2); 3.88 (2H, t, J = 6.5, NCH2); 7.72-7.96 (4H, m, H Ar)
2.98 (2H, t, J = 6.0, CH2); 3.30-3.39 (4H, m, 2CH2 morpholine);
3.61-3.70 (4H, m, 2CH2 morpholine); 3.89 (2H, t, J = 6.0, NCH2); 7.78-7.96 (4H, m, H Ar)
1.87-2.04 (2H, m, CH2); 2.64 (2H, t, J = 7.0, CH2); 3.66 (2H, t, J = 6.3, NCH2);
4.40 (2H, d, J = 5.5, CH2); 7.19-7.43 (5H, m, H Ar); 7.73-7.92 (4H, m, H Ar);
8.61 (1H, br. t, J = 5.0, NH)
5g
5h
5i
1.91-2.02 (2H, m, CH2); 2.62 (2H, t, J = 7.3, CH2); 2.82 (2H, t, J = 7.3, CH2);
3.40 (2H, t, J = 6.0, CH2); 3.66 (2H, t, J = 6.5, NCH2); 7.15-7.34 (5H, m, H Ar);
7.76-7.89 (4H, m, H Ar); 8.15 (1H, t, J = 5.5, NH)
1.49-1.65 (6H, m, 3CH2 piperidine); 1.94-2.06 (2H, m, CH2);
2.66 (2H, t, J = 6.8, CH2); 3.31-3.40 (4H, m, 2CH2 piperidine);
3.67 (2H, t, J = 6.3, NCH2); 7.77-7.88 (4H, m, H Ar)
1.93-2.06 (2H, m, CH2); 2.25 (3H, c, CH3); 2.38-2.49 (4H, m, 2CH2);
2.67 (2H, t, J = 7.0, CH2); 3.31-3.44 (4H, m, 2CH2); 3.67 (2H, t, J = 6.3, NCH2);
7.77-7.90 (4H, m, H Ar)
5j
6
1.95-2.08 (2H, m, CH2); 2.70 (2H, t, J = 7.0, CH2); 3.35-3.44 (4H, m, 2CH2 morpholine);
3.63-3.77 (6H, m, NCH2, 2CH2 morpholine); 7.77-7.92 (4H, m, H Ar)
2.65 (2H, t, J = 7.0, CH2); 2.83 (2H, t, J = 7.0, NCH2);
3.35-3.55 (4H, m, 2CH2 morpholine); 3.64-3.86 (4H, m, 2CH2 morpholine)
7а
2.89 (2H, t, J = 6.2, CH2); 3.39 (4H, m, 2CH2 morpholine); 3.57 (2H, m, NCH2);
3.68 (4H, m, 2CH2 morpholine); 7.40-7.63 (3H, m, H Ar); 7.75-7.92 (2H, m, H Ar);
8.63 (1H, t, J = 5.5, NH)
7b
8a
2.35 (3H, c, CH3); 2.88 (2H, t, J = 5.8, CH2); 3.38-3.45 (4H, m, 2CH2 morpholine);
3.51-3.59 (2H, m, NCH2); 3.63-3.73 (4H, m, 2CH2 morpholine);
7.27 (2H, d, J = 7.0, H Ar); 7.73 (2H, d, J = 7.0, H Ar); 8.56 (1H, t, J = 5.0, NH)
2.25 (3H, s, CH3); 2.91 (2H, t, J = 6.0, CH2); 3.39-3.48 (4H, m, 2CH2 morpholine);
3.52-3.60 (2H, m, NCH2); 3.67-3.76 (4H, m, 2CH2 morpholine);
8.18 (1H, br. t, J = 5.0, NH)
1023

TABLE 2 (continued)
1
2
8b
2.97 (2H, t, J = 4.0, CH2); 3.29-3.43 (4H, m, 2CH2 morpholine);
3.60-3.75 (6H, m, NCH2, 2CH2 morpholine); 7.42-7.59 (3H, m, H Ar);
7.71-7.85 (2H, m, H Ar); 8.60 (1H, br. s, NH)
11
2.39-2.48 (2H, m, CH2); 2.61 (2H, t, J = 7.0, CH2); 3.50-3.64 (4H, m, 2CH2 morpholine);
3.74 (2H, t, J = 7.0, NCH2); 3.78-4.12 (4H, m, 2CH2 morpholine); 6.60 (2H, br. s, NH2)
12а
2.50 (2H, m, CH2); 2.80 (2H, t, J = 6.0, CH2); 3.55-3.69 (8H, m, 4CH2 morpholine);
4.09 (2H, t, J = 5.0, NCH2); 7.49-7.72 (3H, m, H Ar); 7.91-8.03 (2H, m, H Ar);
10.84 (1H, s, NH)
12b
2.30-2.44 (5H, m, CH3, CH2); 2.77 (2H, t, J = 6.0, CH2);
3.48-3.71 (8H, m, 4CH2 morpholine); 4.06 (2H, t, J = 5.0, NCH2);
7.35 (2H, d, J = 6.0, H Ar); 7.85 (2H, d, J = 6.0, H Ar); 10.77 (1H, s, NH)
Such an unexpected result of the transformation of compound 5j with the formation of the recyclization
product 11 required substantial spectral and chemical evidence. The NMR spectra of compounds 6 and 11 differ
significantly. Thus, in the 1H NMR spectra of the amines 6 and 11, the signals of the NCH2 methylene protons in
the latter are shifted appreciably downfield relative to compound 6 (Table 2). The 13C NMR spectrum of the
amine 6 contains signals at 85.0 (oxazole C-4) and 116.5 ppm (CN), while the spectrum of compound 11
contains only one signal in the region of 70-120 ppm at 115.6 ppm (C–NH2), which could be assigned
erroneously to the nitrile. However, this does not agree with the data from the IR spectrum of compound 11, in
which there is no signal for the nitrile group in the region of 2100-2300 cm−1 (Table 3).
O
CN
N
O
N
N2H4 · H2O
N
5j
O
N
C
..
NH2
:
N
O
N
H
9
10
O
O
N
N
N
R2COCl/Et3N
N
O
N
N
O
NH
NH2
R2
11
12a,b
O
12a R2 = Ph, b R2 = 4-MeC6H4
Significant evidence for the structure of the obtained compounds is obtained by comparison of the
spectral characteristics of the amides 7 and 12. Thus, the signal for the proton of the amide group of compounds
1
7a,b in the H NMR spectra is a triplet, while that of compounds 12a,b is a singlet (Table 2). The chemical
shifts and the multiplicity of the amide protons indicate the presence of the C(O)NHCH2 fragment in compounds
7a,b and of the C(O)NHC fragment in compounds 12a,b, where C is an sp2-hybridized carbon atom. In the 13C
NMR spectra of compound 7a there is a signal for the carbon of a nitrile group at 116.5 ppm, but it is not
observed in the spectrum of compound 12a.
1024

TABLE 3. IR and Mass Spectra of Compounds 2-8, 11, and 12
IR spectrum, ν, cm –1
Com-
pound
m/z [M+H]+
C=O
CN
NH
2a
2b
1640, 1709 sh
1666, 1713 sh
1652, 1715 sh
1667, 1717 sh
1670, 1704 sh
1669, 1699 sh
1657*, 1716 sh
1645*, 1710 sh
1642*, 1721 sh
1632*, 1716 sh
1636*, 1713 sh
1652*, 1718 sh
1652*, 1708 sh
1645*, 1711 sh
1636*, 1703 sh
1624*, 1715 sh
1636*
—
—
3056–3515
3111–3529
3106–3358
3214–3378
3176–3335
3089–3347
3091–3316
3027–3305
—
365
379
383
397
338
352
373
387
351
366
353
387
401
365
380
367
223
327
341
329
391
237
341
355
3a
—
3b
—
4a
2232
2234
2213
2209
2231
2210
2206
2218
2212
2214
2215
2217
2213
2209
2214
2216 sh
2218 sh
—
4b
5a
5b
5c
5d
—
5e
—
5f
3066–3466
3057–3472
—
5g
5h
5i
—
5j
—
6
3072
7a
1631 sh*2
1633 sh*2
3061–3385
3129–3456
3087–3324
3114–3298
3327, 3429
3025–3215
3027–3345
7b
8a
1638 sh*
8b
1656 sh*
11
1622
12a
12b
_______
1625, 1676
—
1623, 1673
—
* The band corresponds to the 5-amino-1,3-oxazole fragment [8].
*2 Superimposition of the absorption bands of the 5-amino-1,3-oxazole
fragment and the amide C=O group.
b
a
2.80
131.1
23.2
H
134.8
O
166.8
O
H
3.57
37.2
H
7.64
149.8
H
164.8
N
N
153.0
132.9
7
N
7a
H
H
2.50
26.1
H
6
7.54
131.7
H
C
5
N
7.97
128.1
H
H
N
126.4
N
10.84
H
4.09
45.8
161.1
N
H
H
8.63
H
7.82
127.6
O
O
N
H
H
2.89
O
29.0
H
O
H
H
3.39
46.6
H
HMBC
NOESY
3.68
65.4
1
Fig. 1. The main correlations and assignment of the signals in the H and 13C spectra of
compounds 7a (a) and 12a (b).
1025

TABLE 4. Correlations in the COSY, NOESY, HSQC, and HMBC
Spectra of Compounds 7a and 12a
1H, δ, ppm
NOESY
Compound 7a
7.47
13C, δ, ppm
HMBC
1H, δ, ppm
COSY
HSQC
7.54
7.47
7.82
8.63
3.57
2.89
3.39
3.68
7.47
131.7
128.8
127.6
—
127.6
7.54, 7.82
7.47
7.54, 7.82
7.47, 8.63
3.57, 7.82
2.89, 8.63
3.57
128.8, 134.8
127.6, 131.7, 166.8
166.8
3.57
2.89, 8.63
3.57
37.2
28.0
46.6
65.4
166.8, 28.0, 153.0
37.2, 153.0
3.68
3.68
46.6, 65.4, 161.1
46.6, 65.4
3.39
3.39
Compound 12a
7.64
7.57
7.97
10.84
3.61
2.80
2.50
4.09
7.57
7.57
132.9
129.9
128.1
—
128.1
7.64, 7.97
7.57
7.64, 7.97
7.57, 10.84
7.97
129.9, 133.5
128.1, 132.9, 164.8
164.8
—
—
—
66.9
23.2
26.1
45.8
66.9
2.50
2.50
26.1, 149.8
23.2, 149.8
149.8
2.80, 4.09
2.50
2.80, 4.09
2.50
Complex NMR analysis (NOESY, COSY, HSQC, HMBC) was also used for compounds 7a and 12a
(Fig. 1, Table 4). The formation of a pyrrolidine ring through the aminopropyl fragment in compound 12a is
indicated by HMBC correlations of 7-CH2 with C-7a, 6-CH2 with C-7a, and 5-CH2 with C-7a. It should be
mentioned that it was not possible to find correlations for C-2 and C-3 in the HMBC spectra, and they were
therefore assigned according to the residual principle. The discovery of the aminoethyl fragment in the side
chain of the heterocycle 7a is confirmed by NOESY correlations of CONH with NCH2, and NCH2 with CH2C
and by HMBC correlation of NCH2 with C=O, NCH2 with C-2, and NCH2 with CH2C.
EXPERIMENTAL
The IR spectra were recorded in KBr pellets (compounds 2a,b-4a,b, 5a-g,i,j, 7a,b, 8b, 11, 12a,b) and
1
CHCl3 (compounds 5h, 6, 8a) on a Vertex 70 spectrometer. The H and 13C NMR spectra were obtained in
DMSO-d6 solution (compounds 2a,b, 5a-j, 6, 7a,b, 8a,b, 11, 12a,b) and CDCl3 solution (compounds 3a,b, 4a,b)
on a Bruker Avance DRX-500 instrument (500 and 125 MHz respectively) with TMS as internal standard. The
COSY, NOESY, HSQC, and HMBC spectra were measured by the standard procedure with gradient isolation of
the signal. For the NOESY spectra τmix = 500 ms, while for the HMBC spectra τmix = 125 ms. The measurement
temperature was 20°C. The chromato-mass spectra were recorded on a Agilent 1100 Series high-performance
liquid chromatograph with a diode matrix and an Agilent LC/MSD SL mass-selective detector. Parameters of
chromato-mass analysis: Zorbax SB-C18 1.8 μ, 4.6×15 mm column; solvents A – acetonitrile–water, 95:5, 0.1%
trifluoroacetic acid, B – 0.1% aqueous trifluoroacetic acid; eluent flow rate – 3 ml/min; injection volume – 1 μl;
UV detectors – 215, 254, 285 nm; ionization method – chemical ionization at atmospheric pressure (APCI). The
melting points were measured on a Fisher–Johns apparatus.
The amides 1a,b were synthesized by the known method [7].
1026

2,2,2-Trichloro-1-(3-phthalimidoalkanoylamino)ethanols 2a,b (General Method). A mixture of the
amide 1a or 1b (0.5 mol) and chloral hydrate (182 g, 1.1 mol) was heated on an oil bath (95-100°C) for 5 h. The
reaction mixture was cooled, washed thoroughly with water, and purified by recrystallization.
1,2,2,2-Tetrachloro-1-(3-phthalimidoalkanoylamino)ethanes 3a,b (General Method). Thionyl
chloride (0.8 ml, 11 mmol) was added with stirring to a suspension of compound 2a or 2b (5 mmol) in dry
toluene (50 ml). The mixture was boiled with stirring for 2 h. The solvent was removed under reduced pressure,
and the residue was purified by recrystallization.
3,3-Dichloro-2-(3-phthalimidoalkanoylamino)acrylonitriles 4a,b. Compound 3a or 3b (5 mmol) was
added with stirring in portions to a suspension of KCN (0.715 g, 11 mmol) in acetone (15 ml) cooled to -15°C.
Water (3 ml) was then added dropwise to the reaction mixture. The suspension was stirred at -5°C for 1 h, after
which the temperature of the mixture was brought to room temperature. A portion of water (50 ml) was added to
the reaction mixture, and the precipitate was filtered off, washed with water, and purified by recrystallization.
5-Alkylamino-2-(2-phthalimidoethyl)-1,3-oxazole-4-carbonitriles
5a-e
(General
Method).
Triethylamine (1.5 ml, 11 mmol) and then corresponding amine (5 mmol) were added to a suspension of
compound 4a (1.685 g, 5 mmol) in acetonitrile (20 ml) with stirring and cooling to 0°C. The mixture was stirred
for 12 h, the acetonitrile was removed at reduced pressure, and the residue was dissolved in 15 ml of CH2Cl2.
The extract was washed with water (4×5 ml), dried with Na2SO4, evaporated, and the residue was purified by
recrystallization.
5-Alkylamino-2-(3-phthalimidopropyl)-1,3-oxazole-4-carbonitriles 5f-j (General Method). The
compounds were obtained similarly to the oxazoles 5a-e from compound 4b. Compound 5h was obtained in the
form of an oil, which was analyzed without further purification.
2-(2-Aminoethyl)-5-(morpholin-4-yl)-1,3-oxazole-4-carbonitrile (6). Hydrazine hydrate (0.25 ml,
5.2 mmol) was added to a suspension of compound 5e (1.76 g, 5 mmol) in ethanol (15 ml). The mixture was
boiled for 6 h and cooled, and then ethanol was removed at reduced pressure. The residue was suspended in a
4% aqueous solution of HCl and filtered off, and a 25% aqueous solution of NaOH was added to the mother
solution to pH ~ 10. The solution was extracted with CH2CH2 (5×5 ml) and dried with Na2SO4, and the solvent was
removed at reduced pressure. A yellow oil was obtained and was used for further transformations without
additional purification. 13C NMR spectrum, δ, ppm: 31.0 (NCH2CH2); 39.0 (NCH2CH2); 46.5 (NCH2 morpholine);
65.5 (OCH2 morpholine); 85.0 (C-4 oxazole); 116.5 (CN); 153.6 (C-2 oxazole); 161.0 (C-5 oxazole).
N-{2-[4-Cyano-5-(morpholin-4-yl)-1,3-oxazol-2-yl]ethyl}benzamides 7a,b. Triethylamine (0.515 g,
5.1 mmol) and then corresponding acid chloride (5.1 mmol) were added with stirring and cooling to a solution of
compound 6 (1.11 g, 5 mmol) in 10 ml of CH2Cl2. The mixture was stirred for 6 h, the solvent was removed at
13
reduced pressure, and the residue was washed with water and purified by recrystallization. C NMR spectrum,
δ, ppm: 28.0; 37.2; 46.6; 65.4; 85.2 (С-4 oxazole); 116.5 (CN); 127.6; 128.8; 131.7; 134.8; 153.0; 161.1; 166.8
(С=О).
2-{2-[(4-Cyano-2-methyl-1,3-oxazol-5-yl)amino]ethyl}-5-(morpholin-4-yl)-1,3-oxazole-4-carbonitrile
(8a). Triethylamine (1.5 ml, 11 mmol) and then a solution of compound 6 (1.11 g, 5 mmol) in acetonitrile
(10 ml) were added with stirring and cooling (10-15°C) drop by drop to a solution of 2-acetylamino-
3,3-dichloroacrylonitrile [8] (0.895 g, 5 mmol) in acetonitrile (10 ml). The mixture was stirred for 12 h, and the
solvent was removed under reduced pressure. The residue was dissolved in 10 ml of CH2Cl2 and washed with a
5% aqueous citric acid solution (10 ml). A yellow oil was obtained and was analyzed without further
purification.
5-({2-[4-Cyano-5-(morpholin-4-yl)-1,3-oxazol-2-yl]ethyl}amino)-2-phenyl-1,3-oxazole-4-carbonitrile
(8b) was obtained similarly to compound 8a from 2-benzoylamino-3,3-dichloroacrylonitrile [12] in the form of
a solid substance, which was purified by recrystallization.
2-(Morpholin-4-ylcarbonyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-amine (11) was obtained
similarly to compound 6 from the oxazole 5j. 13C NMR spectrum, δ, ppm: 22.7 (NCH2CH2CH2); 26.3
(NCH2CH2CH2); 42.3 (NCH2 morpholine); 67.1 (ОСН2 morpholine); 115.6 (C–NH2); 144.8; 144.9; 164.4
(С=0).
1027

N-[2-(Morpholin-4-ylcarbonyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl]benzamides
12a,b
were obtained similarly to the amides 7a,b from compound 11. 13C NMR spectrum, δ, ppm: 23.2; 26.1; 45.8;
66.9; 126.4; 128.1; 129.9; 131.1 (C–NHCO); 132.9; 133.5; 149.8; 163.4 (С=0); 164.8 (С=0).
REFERENCES
1.
2.
H. T. Clarke, in: Chemistry of Penicillin, Princeton Univ. Press, Princeton (1949), p. 688.
I. J. Turchi, in: The Chemistry of Heterocyclic Compounds: Oxazoles, John Wiley, New York (1986),
vol. 45, p. 109.
3.
4.
5.
6.
I. J. Turchi, in: The Chemistry of Heterocyclic Compounds: Oxazoles, John Wiley, New York (1986),
vol. 45, p. 1064.
D. C. Palmer, in: Oxazoles: Synthesis, Reactions, and Spectroscopy, John Wiley, Hoboken (2003), vol.
60, part A, p. 255.
M. Negwer, Organic-Chemical Drugs and Their Synonyms (an International Survey), 7th revised,
enlarged ed., Academie Verlag, Berlin (1994).
B. S. Drach, V. S. Brovaretz, and O. B. Smolii, Syntheses of Nitrogen-Containing Heterocyclic
Compounds based on Amidoalkylating Agents [in Russian], Naukova Dumka, Kiev (1992).
C. O. Usifoh, D. M. Lambert, J. Wouters, and G. K. E. Scriba, Arch. Pharm., 334, 323 (2001).
B. S. Drach, E. P. Sviridov, A. A. Kisilenko, and A. V. Kirsanov, Zh. Org. Khim., 9, 1818 (1973).
B. S. Drach and G. N. Mis’kevich, Zh. Org. Khim., 13, 1398 (1977).
T. Sasaki, M. Ohno, and E. Ito, J. Chem. Soc, Perkin Trans. 1, 3027 (1983).
T. Sasaki, E. Ito, and K. Asai, Heterocycles, 21, 373 (1984).
7.
8.
9.
10.
11.
12.
B. S. Drach, E. P. Sviridov, and T. Ya. Lavrenyuk, Zh. Org. Khim., 10, 1271 (1974).
1028