Reactions of β-aminopropionic acid N′-acylhydrazides with carbonyl compounds

Article abstract of DOI:10.1023/B:RUCB.0000035649.77800.28

The reactions of β-aminopropionic acid N′-acylhydrazides with aromatic and heterocyclic aldehydes and acetone afford compounds that exist in solutions predominantly as mixtures of 2-substituted 3- acylaminotetrahydropyrimidin-4-ones (ATHP) and tautomeric Schiff's bases. These compounds in the crystalline state probably have structures of ATHP. The ratio of tautomers depends on the type of substituent in the aromatic ring and solvent. The reactions of 2-aryl-3-benzamidotetrahydropyrimidin-4-ones with carboxylic or sulfonic acid chlorides afford derivatives of 1-acyl- and 1-tosyl-3-benzamidotetrahydropyrimidin-4-ones.

Full text of DOI:10.1023/B:RUCB.0000035649.77800.28

Russian Chemical Bulletin, International Edition, Vol. 53, No. 3, pp. 635—640, March, 2004
635
Reactions of βꢀaminopropionic acid N´ꢀacylhydrazides
with carbonyl compounds
G. A. Smirnov,ꢀ E. P. Sizova, and O. A. Luk´yanov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp. 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. Eꢀmail: smir@ioc.ac.ru
The reactions of βꢀaminopropionic acid N´ꢀacylhydrazides with aromatic and heterocyclic
aldehydes and acetone afford compounds that exist in solutions predominantly as mixtures of
2ꢀsubstituted 3ꢀacylaminotetrahydropyrimidinꢀ4ꢀones (ATHP) and tautomeric Schiff´s bases.
These compounds in the crystalline state probably have structures of ATHP. The ratio of
tautomers depends on the type of substituent in the aromatic ring and solvent. The reactions of
2ꢀarylꢀ3ꢀbenzamidotetrahydropyrimidinꢀ4ꢀones with carboxylic or sulfonic acid chlorides afꢀ
ford derivatives of 1ꢀacylꢀ and 1ꢀtosylꢀ3ꢀbenzamidotetrahydropyrimidinꢀ4ꢀones.
Key words: 3ꢀacylaminotetrahydropyrimidinꢀ4ꢀones, βꢀaminopropionic acid N'ꢀbenzoylꢀ
hydrazide, βꢀaminopropionic acid N'ꢀacetylhydrazide, ketones, aldehydes, Nꢀacylation,
Nꢀtosylation, Schiff´s bases, tautomeric equilibrium.
1
Earlier,1 we have studied the reactions of N'ꢀacylꢀ and
N'ꢀtosylꢀsubstituted hydrazides of 2ꢀaminobenzoic acid
with aliphatic and aromatic aldehydes and aliphatic keꢀ
tones. These reactions were shown to have a general charꢀ
acter and afford 2,3ꢀdisubstituted 1,2ꢀdihydroquinazolinꢀ
4ꢀones (DHQ).
To extend this reaction to aliphatic analogs, viz.,
N'ꢀacylhydrazides of βꢀamino acids, we studied the reacꢀ
tions of βꢀaminopropionic acid N'ꢀacylhydrazides 1а,b
with carbonyl compounds.
The H NMR spectra of hydrazides 1а,b clearly exꢀ
hibit signals of protons of the R substituent and CH2
groups; however, signals of the amino and hydrazide
groups are presented as one broadened singlet. The strucꢀ
tures of hydrazides 1а,b were confirmed by the synthesis
of compounds 5—7 using the reactions of hydrazide 1b
with respective electrophiles (Scheme 2).
Scheme 2
Previously undescribed hydrazides 1a,b were syntheꢀ
sized according to Scheme 1.
Scheme 1
Aldehydes and ketones of the aliphatic, aromatic, and
aliphaticꢀaromatic series were used as carbonyl compounds
in the reactions with hydrazides 1а,b. The reactions of
1а,b with aromatic aldehydes in anhydrous PriOH refluxꢀ
ing for 6—8 h afforded condensation products 8а—i in
35—85% yields. Products 8а—i are characterized by rather
R = Me (a), Ph (b); Z = PhCH2OCO
Reagents and yields: i. RCONHNH2, 70—80%;
ii. HBr—AcOH, 50—100%; iii. MeONa, 100%.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 606—611, March, 2004.
1066ꢀ5285/04/5303ꢀ0635 © 2004 Plenum Publishing Corporation

636
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
Smirnov et al.
Table 1. Melting points, yields, and elemental analysis data for
2ꢀarylꢀsubstituted 3ꢀacylaminotetrahydropyrimidinꢀ4ꢀones 8a—i
Scheme 3
Comꢀ M.p.
pound /°С
Yield
(%)
Found
Calculated
Molecular
formula
(%)
N
C
H
8a
8b
8c
8d
8e
8f
226—229
222—225
146—148
166—169
162—164
213—215
173—175
177—181
158—160
35
53
35
36
66
85
76
35
40
59.27 6.44 16.02 С13H17N3O3
59.30 6.51 15.96
51.75 4.98 20.24 С12H14N4O4
51.80 5.07 20.13
68.85 5.75 14.41 С17H17N3O2
69.14 5.80 14.23
65.49 5.44 13.78 С17H17N3O3
65.58 5.50 13.50
66.54 5.59 13.02 С18H19N3O3
66.65 5.59 12.96
59.52 4.92 16.43 С17H16N4O4
59.82 5.02 16.41
63.95 5.95 11.62 С19H21N3O4
64.21 5.96 11.82
47.40 3.21 19.78 С17H14N6O8
47.45 3.28 19.53
R1 = Me (1a), Ph (1b)
R1
R2
R1
R2
8a
8b
8c
Me
Me
Ph
4ꢀMeOꢀC6H4
4ꢀO2NꢀC6H4
Ph
8f
8g
8h
Ph
Ph
4ꢀO2NꢀC6H4
(3,4ꢀMeO)2ꢀC6H3
Ph (2,4,6ꢀO2N)3ꢀC6H2
8d
8e
Ph
Ph
3ꢀHOꢀC6H4
8i
Ph
8g
8h
8i
4ꢀMeOꢀC6H4
narrow intervals of melting points (Table 1). The NMR
spectra of solutions of compounds 8а—i in CDCl3 and
DMSOꢀd6 contained a set of signals of two substances.
63.00 5.31 14.54 С15H15N3O3
63.15 5.30 14.73
1
Table 2. Signals of isomers A in the H NMR spectra of 2ꢀarylꢀsubstituted 3ꢀacylaminotetrahydropyrimidinꢀ4ꢀones 8a—i (atoms are
numbered in Scheme 3)
Comꢀ Solꢀ
pound vent
δ, J/Hz
N(1)H C(2)H C(5)H2 C(6)H2 N(7)H
R1(9)
R2(10)
8a CDCl3
8b CDCl3
8c CDCl3
6.95
(m)
7.55
(m)
7.40
(m)
5.55
(s)
5.75
(s)
5.70
(s)
5.32
(s)
5.40
(s)
5.72
(s)
5.45
(s)
5.85
(s)
2.55
(m)
2.70
(m)
2.70
(m)
2.60
(m)
2.60
(m)
2.70
(m)
2.55
(m)
3.23
(m)
3.25
(m)
3.25
(m)
3.90
(m)
3.80
(m)
3.70
(m)
3.75
(m)
9.80
(s)
9.90
(s)
1.90 (s, 3 Н, СН3)
4ꢀMeOꢀC6H4: 3.90 (s, 3 Н);
6.95 (m, 2 Н); 7.25 (m, 2 Н)
4ꢀNO2ꢀC6H4: 7.95, 8.22 (both d,
2 H each, J = 7.3)
Ph: 7.30 (m, 3 Н);
7.45 (d, 2 Н, J = 7.4)
1.95 (s, 3 Н, СН3)
8.60
(br.s)
10.0
(br.s)
9.90
(br.s)
8.70
(br.s)
9.20
(br.s)
9.22
7.40 (m, 3 Н);
7.80 (d, 2 Н, J = 7.4)
7.45 (m, 3 Н);
7.90 (d, 2 Н, J = 7.4)
7.50 (m, 3 Н);
7.65 (d, 2 Н, J = 7.4)
7.40 (m, 3 Н);
7.70 (d, 2 Н, J = 7.4)
7.30 (m, 3 Н);
7.75 (d, 2 Н, J = 7.4)
7.40 (m, 3 Н);
7.60 (d, 2 Н, J = 7.4)
7.40 (m, 3 Н);
7.55 (d, 2 Н, J = 7.4)
7.45 (m, 3 Н);
7.55 (d, 2 Н, J = 7.4)
7.45 (m, 3 Н);
DMSOꢀd6 7.40
7.45 (m, 3 Н); 7.75 (d, 2 Н, J = 7.4)
(br.s)
8d DMSOꢀd6 7.20
(m)
3ꢀНOꢀC6H4: 6.82 (d, 1 Н, J = 7.8);
7.20 (m, 2 Н); 7.15 (s, 1 Н)
4ꢀMeOC6H4: 3.85 (s, 3 Н);
6.95, 7.45 (both d, 2 H each, J = 7.7)
3.80 (s, 3 Н); 6.95, 7.45 (both d,
2 H each, J = 7.7)
4ꢀNO2ꢀC6H4: 7.80, 8.20 (both d,
2 H each, J = 7.3)
7.75, 8.20 (both d, 2 H each, J = 7.3)
8e CDCl3
7.30
(m)
DMSOꢀd6 7.40
(m)
8f
CDCl3
7.25
(m)
2.70 (t, 3.25 (t,
J = 7.0) J = 7.0) (br.s)
10.1
J = 8.1) J = 7.0) J = 7.0) (br.s)
DMSOꢀd6 7.45
(m)
CD3OD
5.65 (d, 2.55 (t, 3.1 (t,
7.45
(m)
7.20
(s)
7.25
(br.s)
7.45
(m)
5.75
(s)
5.70
(s)
5.75
(s)
5.82 (d,
J = 7.9)
5.60
(s)
2.75
(m)
2.60
(m)
2.45
(m)
2.65
(m)
3.0
3.25
(m)
3.25
(m)
3.70
(m)
3.25
(m)
3.50
(m)
9.50
(br.s)
9.80
(br.s)
9.55
(s)
8.95
(br.s)
10.0
(br.s)
7.85, 8.35 (both d, 2 H each, J = 7.3)
8g CDCl3
8h CDCl3
(3,4ꢀMeO)2ꢀC6H4: 3.85, 4.00 (both s,
3 H each); 6.90 (m, 2 Н); 7.3 (s, 1 Н)
(2,4,6ꢀNO2)3ꢀC6H2: 9.35 (br.s, 2 Н)
7.60 (d, 2 Н, J = 7.4)
7.25 (br.s, 5 Н)
8i
CDCl3
7.45 (m, 3 Н);
7.65 (d, 2 Н, J = 7.4)
7.45 (m, 3 Н);
C4H3О: 6.35, 6.45 (both s, 1 H each);
7.45 (m, 1 Н)
6.40, 6.50 (both s, 1 H each);
7.50 (br.s, 1 Н)
DMSOꢀd6 7.45
(br.s)
(m)
7.75 (d, 2 Н, J = 7.4)

Reactions of βꢀaminopropionic acid N´ꢀacylhydrazides Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
637
1
Table 3. Signals of isomers B in the H NMR spectra of Schiff´s bases 8a—i (atoms are numbered in Scheme 3)
Comꢀ
pound vent
Solꢀ
δ, J/Hz
C(1)H С(3)Н2N C(4)H2CO N(6)H—
R1(9)
R2(10)
=N
—N(7)H
8a
8b
8c
CDCl3
8.25
(s)
3.80 (t,
J = 7.0)
3.75 (t,
J = 7.0)
3.95
(m)
3.85
(m)
3.90
2.65 (t,
J = 7.0)
2.32(t,
J = 7.0)
2.70
(m)
2.40
(m)
2.70
9.90
(s)
9.50
(br.s)
9.90
(s)
9.50
(br.s)
9.60
(br.s)
10.0
2.1 (s,
3 Н, СН3)
1.75 (s,
3 Н, СН3)
2.05 (s,
3 Н, СН3)
1.75 (s,
3 Н, СН3)
4ꢀMeOꢀC6H4: 3.95 (s, 3 Н);
6.95, 7.75 (both m, 2 H each)
3.75 (s, 3 Н); 6.95, 7.65 (both d,
2 H each, J = 7.1)
4ꢀNO2ꢀC6H4: 8.00, 8.25 (both d,
2 H each, J = 7.3)
DMSOꢀd6 8.25
(s)
CDCl3
8.40
(s)
DMSOꢀd6 8.50
(t)
CDCl3
8.00, 8.25 (both d, 2 H each, J = 7.3)
8.30
(s)
7.40 (m, 3 Н);
7.80 (d, 2 Н, J = 7.4)
7.45 (m 3 Н);
Ph: 7.30 (m, 3 Н);
7.45 (d, 2 Н, J = 7.4)
7.45 (m, 3 Н);
(m)
3.85
(m)
2.60
DMSOꢀd6 8.45
(s)
DMSOꢀd6 8.30
(s)
(br.s)
3.80
(m)
3.80
(m)
3.70
(m)
3.95 (t,
J = 7.0)
3.95
(br.s)
2.60
(m)
2.70
(m)
2.60
(m)
2.70 (t,
J = 7.0)
2.65
(br.s)
9.95
(br.s)
9.90
(br.s)
10.00
(br.s)
9.75
(br.s)
10.05
(br.s)
9.60
(br.s)
10.00
(br.s)
9.90
(br.s)
9.55
7.90 (d, 2 Н, J = 7.4)
7.50 (m, 3 Н);
7.95 (d, 2 Н, J = 7.4)
7.40 (m, 3 Н);
7.80 (d, 2 Н, J = 7.4)
7.45 (m, 3 Н);
7.95 (d, 2 Н, J = 7.4)
7.45 (m, 3 Н);
7.65 (d, 2 Н, J = 7.4)
7.40 (m, 3 Н);
7.65 (d, 2 Н, J = 7.4)
7.45 (m, 3 Н);
7.75 (d, 2 Н, J = 7.4)
7.45 (m, 3 Н);
7.80 (d, 2 Н, J = 7.4)
7.50 (m, 3 Н);
7.85 (d, 2 Н, J = 7.4)
7.25 (br.s, 5 Н)
7.75 (d, 2 Н, J = 7.4)
8d
8e
3ꢀНOꢀC6H4: 6.90 (d, 1 Н, J = 7.8);
7.20 (m, 2 Н); 9.95 (br.s, 1 Н)
4ꢀMeOC6H4: 3.85 (s, 3 Н);
6.95, 7.45 (both d, 2 H each, J = 7.7)
3.80 (s, 3 Н); 6.95, 7.45 (both d,
2 H each, J = 7.7)
4ꢀNO2ꢀC6H4: 7.80, 8.20 (both d,
2 H each, J = 7.3)
7.75, 8.20 (both d, 2 H each, J = 7.3)
CDCl3
8.23
(s)
DMSOꢀd6 8.30
(s)
8f
CDCl3
8.40
(s)
DMSOꢀd6 8.55
(s)
(m)
(m)
CD3OD
8.53
(s)
4.00 (t,
J = 7.0)
3.85
(m)
3.80
(m)
4.05
(m)
2.75 (t,
J = 7.0)
2.70
(m)
2.60
(m)
3.65
(m)
7.85, 8.35 (both d, 2 H each, J = 7.3)
8g
CDCl3
8.25
(s)
(3,4ꢀMeO)2ꢀC6H4: 3.85, 4.00 (both s,
3 H each); 6.90 (m, 2 Н); 7.30 (s, 1 Н)
3.80 (s, 6 Н); 7.00, 7.25 (both m,
1 H each); 7.40 (s, 1 Н)
DMSOꢀd6 8.30
(s)
8h
8i
CDCl3
9.15
(s)
(2,4,6ꢀNO2)3ꢀC6H2: 9.35 (br.s, 2 Н)
(s)
9.00
(br.s)
10.00
(br.s)
CDCl3
8.10
(s)
3.85 (t,
J = 6.8)
3.85
2.70 (t,
J = 6.8)
2.60
7.45 (m, 3 Н);
7.80 (d, 2 Н, J = 7.4)
7.45 (m, 3 Н);
C4H3О: 6.50, 6.90 (both s, 1 H each);
7.45 (m, 1 Н)
6.60, 6.90 (both s, 1 H each);
7.50 (m, 1 Н)
DMSOꢀd6 8.25
(s)
(m)
(m)
7.85 (m, 2 Н, J = 7.4)
Table 4. Ratio of tautomers A and B of compounds 8а—i in
solutions according to the H NMR spectroscopic data
Taking into account the results of elemental analysis of
compounds 8а—i, we can assume that these substances
are mixtures of 3ꢀacylaminotetrahydropyrimidinꢀ4ꢀone
derivatives (А), whose NMR spectra are characterized by
signals at 5.4—5.9 ppm for protons at the C(2) atom, and
the corresponding tautomeric Schiff´s bases (B), whose
NMR spectra contain signals at 8.2—9.1 ppm for protons
at the C(1) atom (Scheme 3, Tables 2 and 3). The ratio of
tautomers A and B depended on the nature of solvent and
substituents R1 and R2 (Table 4).
In solutions of compounds 8а—i in DMSOꢀd6, linear
tautomer B was predominant. In CDCl3, the fraction of
heterocycle A increased, which was especially noticeable
for the compounds containing electronꢀwithdrawing subꢀ
stituents in the aromatic ring of R2. Trinitrophenyl deꢀ
1
Comꢀ
pound
A : B ratio
CDCl3
DMSOꢀd6
8a
8b
8c
8d
8e
8f
8g
8h
8i
27 : 73
50 : 50
50 : 50
—
31 : 69
50 : 50
18 : 82
70 : 30
33 : 66
<1 : 99
<1 : 99
7 : 93
12 : 88
5 : 95
23 : 77
<1 : 99
—
8 : 92

638
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
Smirnov et al.
Table 5. Melting points, yields, and elemental analysis data
for 1ꢀacyl(1ꢀtosyl)ꢀ3ꢀbenzoylaminotetrahydropyrimidinꢀ4ꢀ
ones 10a—f
rivative 8h existed in a CDCl3 solution predominantly in
cyclic form A.
Although compounds 8a—i are characterized by rather
high melting points, they are partially decomposed being
recrystallized and chromatographed on silica gel, which
did not allow us to obtain a sample appropriate for estabꢀ
lishing the structures of compounds 8а—i in the crystalꢀ
line state by Xꢀray diffraction analysis.
Compounds 8е,f react with carboxylic and sulfonic
acid chlorides 9a—d to form 1ꢀacylꢀ and 1ꢀtosylꢀ3ꢀ
acylaminotetrahydropyrimidinꢀ4ꢀone derivatives 10a—f
(Scheme 4).
Comꢀ M.p.
pound /°С
Yield
(%)
Found
Calculated
Molecular
formula
(%)
N
C
H
10a 179—182
10b 185—187
10c 268—269
10d 158—160
10e 137—140
10f* 211—213
54
62
80
55
50
60
65.24 5.79 11.22 С20H21N3O4
65.38 5.76 11.44
69.79 5.50 10.02 С25H23N3O4
69.92 5.40 9.78
59.61 4.70 14.62 С19H18N4O5
59.68 4.76 14.65
64.60 4.54 12.49 С24H20N4O5
64.80 4.54 12.61
61.73 4.73 10.90 С26H24N4O7
61.90 4.80 11.10
58.35 4.45 11.38 С24H22N4O6S
58.29 4.48 11.33
Scheme 4
* Found: S, 6.26%; calculated: S, 6.48%.
sis, IR spectrum, and 13С NMR spectrum of compound
8j (which exhibits signals of the C(2) atom corresponding
to the cyclic form of 3ꢀacylaminoꢀ2,2ꢀdimethyltetraꢀ
hydropyrimidinꢀ4ꢀone (δ 76.47) and C=N group of isoꢀ
meric Schiff´s base (δ 165.43)), this compound in soluꢀ
tion is also a mixture of tautomeric cyclic (A) and linꢀ
ear (B) forms (see Table 4).
8: R1 = 4ꢀMeOꢀC6H4 (e), 4ꢀO2NꢀC6H4 (f)
9: R2 = Ac (a), Bz (b), (3,4ꢀMeO)2ꢀC6H3CO (c), Ts (d)
R1
R2
R1
R2
Bz
10a 4ꢀMeOꢀC6H4 Ac 10d 4ꢀO2NꢀC6H4
10b 4ꢀMeOꢀC6H4 Bz 10e 4ꢀO2NꢀC6H4 (3,4ꢀMeO)2ꢀC6H3CO
10c 4ꢀO2NꢀC6H4 Ac 10f 4ꢀO2NꢀC6H4 Ts
The structures of compounds 10a—f were established
from the data of elemental analysis and 1Н NMR spectra
(Tables 5 and 6). The latter contained signals of protons
at the С(2) atom in a region of δ 6.45—7.05 characteristic
of ATHP.
Scheme 5
A specific feature of the IR spectra of compounds
10c,d,f in KBr pellets is the presence of a band with the
frequency ∼1600 cm–1 and two bands at 1648—1656 and
1696—1704 cm–1 with the ratio of intensities ∼1 : 5 : 3,
which correspond to the CONNHCO fragment.2 A simiꢀ
lar spectrum in a region of 1600—1700 cm–1 is characterꢀ
istic of compound 8f in the crystalline state. At the
same time, the IR spectrum of compound 6 having the
CONHNHCO fragment differs substantially in this reꢀ
gion. In our opinion, this comparison suggests that crysꢀ
tals of compound 8f and, perhaps, other condensation
products 8 in the crystalline state have the structure of
cyclic tautomer A rather than Schiff´s base B.
NꢀBenzoylhydrazone of acetophenone 11 turned out
to be the main product of the reaction of hydrazide 1b
with acetophenone (a representative of aliphaticꢀaromatic
ketones) under similar conditions (Scheme 6).
Of aliphatic carbonyl compounds, we studied formalꢀ
dehyde, acetaldehyde, acetone, cyclopentanone, and
cyclohexanone in the reactions with 1b. As previously,
the reactions were carried out in boiling PriOH. We sucꢀ
ceeded to isolate the individual reaction product 8j only
when acetone was used, but its yield was only 10%
(Scheme 5). As follows from the data of elemental analyꢀ
Scheme 6

Reactions of βꢀaminopropionic acid N´ꢀacylhydrazides Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
639
1
Table 6. H NMR spectroscopic data for 2ꢀarylꢀsubstituted 1ꢀacyl(1ꢀtosyl)ꢀ3ꢀbenzoylaminotetrahydropyrimidinꢀ4ꢀones 10a—f*
Comꢀ
Solꢀ
δ, J/Hz
pound vent
C(2)H
C(4)H2,
C(5)H2
(m, 1 Н)
N(7)H
(s)
Ph(9)
R2(10)
R1(11)
10a
10b
10c
10d
10e
10f
DMSOꢀd6
6.90
(s)
2.35, 2.60,
2.75, 3.40
10.65
10.75
10.75
10.85
9.70
7.50 (m, 3 Н);
7.85 (d, 2 Н,
J = 7.4)
7.50 (m, 3 Н);
7.82 (d, 2 Н,
J = 7.4)
7.50 (m, 3 Н);
7.75 (d, 2 Н,
J = 7.4)
7.50 (m, 3 Н);
7.80 (d, 2 Н,
J = 7.4)
СОCH3
2.15 (s, 3 Н)
4ꢀMeOꢀC6H4: 3.80 (s, 3 Н);
6.95 (d, 2 Н, J = 7.7);
7.50 (m, 2 Н)
4ꢀMeOꢀC6H4: 3.78 (s, 3 Н);
7.00 (d, 2 Н, J = 7.7);
7.50 (m, 2 Н)
DMSOꢀd6
DMSOꢀd6
DMSOꢀd6
CDCl3
6.80
(br.s)
2.60, 2.75;
3.40 (2 Н)
СОPh
7.50 (m, 5 Н)
7.05
(s)
2.60, 2.83,
3.45, 3.90
СОCH3
2.20 (s, 3 Н)
4ꢀNO2ꢀC6H4: 7.90,
8.25 (both d, 2 H each, J = 9.0)
7.00
(s)
2.60, 2.80,
3.45, 3.80
СОPh
7.50 (m, 5 Н)
4ꢀNO2ꢀC6H4: 7.90,
8.30 (both d, 2 H each, J = 9.0)
6.85
(s)
2.65, 2.90,
3.35, 4.10
7.40 (m, 3 Н);
7.75 (m, 2 Н)
(3,4ꢀMeO)2ꢀС6H4
3.90 (s, 6 Н); 7.12 (m, 8.20 (both d, 2 H each, J = 9.0)
2 Н); 7.25 (m, 1 Н)
4ꢀCH3ꢀС6H4SO2
2.45 (c, 3 Н); 7.45 (d, 8.35 (both d, 2 H each, J = 9.0)
J = 8.5); 7.70 (m, 2 Н)
4ꢀNO2ꢀC6H4: 7.75,
CDCl3
7.05
(s)
2.20, 2.45,
3.25, 3.75
8.70
7.35 (t, 3 Н,
J = 7.7);
7.70 (m, 2 Н)
4ꢀNO2ꢀC6H4: 8.15,
* Atoms are numbered in Scheme 4.
Hydrobromides of βꢀaminopropionic acid N'ꢀacetylꢀ (4a) and
Experimental
N'ꢀbenzoylhydrazide (4b). A 0.3 М solution of HBr in AcOH
(15 mL) was added to a solution of compound 3a (3b) (0.02 mol)
in AcOH (15 mL). The reaction mixture was stirred for 0.5—1.5 h
at ~20 °C (TLC monitoring), and anhydrous Et2O (160 mL) was
added. The precipitate that formed was filtered off, dried in
air, recrystallized from a mixture of EtOH (15 mL) and
Et2O (40 mL), successively washed with mixtures of EtOH
(10 mL)/Et2O (40 mL) and EtOH (3 mL)/Et2O (30 mL), and
dried in air. Compound 4a was obtained in 94% yield (4.2 g,
m.p. 207—210 °С) and compound 4b was obtained in 83% yield
(4.78 g, m.p. 132—134 °С). Compound 4a. Found (%): С, 26.76;
Н, 5.34; N, 18.53; Br, 35.48. С5Н12BrN3O2. Calculated (%):
С, 26.56; Н, 5.35; N, 18.59; Br, 35.34. 1Н NMR (DMSOꢀd6), δ:
1.85 (s, 3 H, CH3); 2.45 (t, 2 H, CH2С, J = 7.1 Hz); 3.00 (m,
2 H, CH2N, J = 7.1 Hz); 7.87 (br.s, 3 H, NH3+Br–); 9.70, 9.85
(both s, 1 H each, CONH). Compound 4b. Found (%): С, 41.58;
Н, 5.01; N, 14.56; Br, 27.23. С10Н14BrN3O2. Calculated (%):
С, 41.46; Н, 4.89; N, 14.57; Br, 27.43. 1H NMR (DMSOꢀd6), δ:
2.60 (t, 2 H, CH2С, J = 6.9 Hz); 3.05 (m, 2 H, CH2N,
J = 6.9 Hz); 7.50 (m, 3 H, PhC); 7.80—7.95 (m, 2 H,
PhC + NH3+Br–); 10.10, 10.30 (both s, 1 H each, NHCO).
βꢀAminopropionic acid N'ꢀacetylꢀ (1а) and N'ꢀbenzoylꢀ
hydrazides (1b). A solution of MeONa (0.030 mol) in anhydrous
MeOH (15 mL) was added dropwise to a solution of compound
4a or 4b (0.025 mol) in anhydrous MeOH (20 mL). The resultꢀ
ing mixture was stirred for 1 h at ~20 °C. The solvent was
evaporated, and the residue was dissolved in anhydrous PriOH
(40 mL). A precipitate of NaBr was filtered off and washed with
anhydrous PriOH (30 mL). The mother liquor was concentrated
to dryness, and the resulting product was dried and stored in
vacuo. Compound 1a was obtained in 100% yield (3.62 g, m.p.
69—72 °С) and compound 1b was obtained in 100% yield (5.17 g,
1
H NMR spectra were recorded on Bruker ACꢀ200
(200.13 MHz) and Bruker AMꢀ300 (300.13 MHz) spectromꢀ
eters. 13C NMR spectra were measured on a Bruker AMꢀ250
spectrometer (62.9 MHz). Signals of protons, whose multiplicꢀ
ity is not given, are strongly broadened (perhaps, due to dynamic
processes). IR spectra were recorded on a Specord М80 specꢀ
trometer in KBr pellets. Melting points were measured
on a Boetius hotꢀstage apparatus and were uncorrected.
A CHCl3—MeOH (16 : 1) mixture was used for TLC. Comꢀ
pound 2 was synthesized by a described procedure.3
NꢀBenzyloxycarbonylꢀβꢀaminopropionic acid N'ꢀacetylꢀ (3a)
and N'ꢀbenzoylhydrazides (3b). Hydrazide of acetic (benzoic) acid
(0.05 mol) was added to a solution of ester 2 (17.2 g, 0.05 mol) in
DMF (80 mL). The resulting solution was stirred for 5 h at 100 °С
and cooled to ~20 °C. The solvent was evaporated in vacuo, and
the residue was first crystallized twice from ethyl acetate (50 mL)
and then twice from ethanol (50 mL). Compound 3a was obꢀ
tained in 65% yield (9.06 g, m.p. 174—176 °С) or compound 3b
was obtained in 70% yield (11.9 g, m.p. 164—166 °С). Compound
3a. Found (%): С, 56.05; Н, 6.08; N, 14.71. С13Н17N3O4. Calꢀ
culated (%): С, 55.91; Н, 6.14; N, 14.94. 1H NMR (DMSOꢀd6),
δ: 1.87 (s, 3 H, CH3); 2.30 (t, 2 H, CH2С, J = 6.0 Hz); 3.25 (m,
2 H, CH2N, J = 6.0); 5.00 (s, 2 H, CH2O); 7.17 (br.s, 1 H,
NHCO2); 7.35 (m, 5 H, Ph); 9.70 (br.s, 2 H, NHNH). Comꢀ
pound 3b. Found (%): С, 63.35; Н, 5.64; N, 12.25. С18Н19N3O4.
Calculated (%): С, 63.33; Н, 5.61; N, 12.31. 1Н NMR
(DMSOꢀd6), δ: 2.40 (t, 2 H, CH2C, J = 6.1 Hz); 3.35 (m, 2 H,
CH2N); 5.05 (s, 2 H, CH2O); 7.20 (br.s, 1 H, NHCO2); 7.35 (m,
5 H, PhCH2); 7.55 (m, 3 H, PhCO); 7.90 (d, 2 H, PhCO, J =
7.4 Hz); 9.95, 10.30 (both br.s, 1 H each, NHCO).

640
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
Smirnov et al.
m.p. 104—106 °С). Compound 1a. Found (%): С, 41.65; Н, 7.77;
IR spectra (ν/cm–1) of compounds 8a: 1608 (CONH), 1648
(COCH2); 8b: 1348 (NO2), 1528 (NO2), 1604 (CONH), 1644
(COCH2); 8d: 1648 (CONH), 1696 (COCH2); 8e: 1648
(CONH), 1668 (COCH2); 8f: 1348 (NO2), 1516 (NO2), 1656
(CONH), 1696 (COCH2); 8g: 1644 (CONH), 1688 (COCH2);
8j: 1644 (CONH), 1692 (COCH2).
N, 28.79. С5Н11N3O2. Calculated (%): С, 41.37; Н, 7.64;
1
N, 28.95. Н NMR (DMSOꢀd6), δ: 1.72 (s, 3 H, CH3); 2.12 (t,
2 H, CH2С, J = 6.2 Hz); 2.70 (m, 2 H, CH2N 6.2), 4.50 (br.s,
4 H, NHNH + NH2). Compound 1b. Found (%): С, 57.85;
Н, 6.29; N, 20.17. С10Н13N3O2. Calculated (%): С, 57.96;
Н, 6.32; N, 20.28. 1H NMR (DMSOꢀd6), δ: 2.30 (t, 2 H, CH2С,
J = 6.0 Hz); 2.82 (m, 2 H, CH2N, J = 6.0 Hz); 6.00 (br.s, 4 H,
NHNH + NH2); 7.50 (m, 3 H, PhCO); 7.90 (d, 2 H, PhCO,
J = 7.4 Hz).
NꢀPhenylcarbamoylꢀβꢀaminopropionic acid N'ꢀbenzoylhydrꢀ
azide (5). Phenyl isocyanate (0.26 mL, 0.29 g, 2.4 mmol) was
added to a solution of hydrazide 1b (0.5 g, 2.4 mmol) in pyridine
(4.7 mL). The resulting solution was stirred for 3.5 h at 20 °C
and poured into a 5% solution of HCl (110 mL). The precipiꢀ
tate that formed was filtered off and crystallized from an
EtOH—EtOAc (1 : 4) mixture. Compound 5 was obtained in
50% yield (0.37 g, m.p. 215—218 °С). Found (%): С, 62.73;
Н, 5.49; N, 16.92. С17Н18N4O3. Calculated (%): С, 62.57;
Н, 5.56; N, 17.17. 1H NMR (DMSOꢀd6), δ: 2.40 (t, 2 H, CH2C,
J = 6.5 Hz); 3.35 (m, 2 H, CH2N); 6.20 (t, 1 H, NH, J =
5.8 Hz); 6.95, 7.20 (both t, 2 H each, PhN, J = 8.8 Hz); 7.40 (d,
2 H, PhN, J = 7.8 Hz); 7.55 (m, 3 H, PhC); 7.90 (d, 2 H, PhC,
J = 6.9 Hz); 8.55 (s, 1 H, NH); 9.95, 10.30 (both br.s,
1 H each, NH).
3ꢀBenzoylaminoꢀ2,2ꢀdimethyltetrahydropyrimidinꢀ4ꢀone (8j).
Anhydrous acetone (5 mL) was added to a solution of hydrazide
1b (0.51 g, 2.5 mmol) in anhydrous PriOH (5 mL). The resulting
mixture was refluxed for 6 h and cooled. The solvent was evapoꢀ
rated, and the residue was recrystallized from a CHCl3—Et2O
(1 : 4) mixture. Compound 8j was obtained in 10% yield (0.06 g,
m.p. 243—246 °С). Found (%): С, 63.01; Н, 7.05; N, 16.75.
С13Н17N3O2. Calculated (%): С, 63.14; Н, 6.93; N, 16.99.
1H NMR (DMSOꢀd6), δ: isomer A: 1.80, 1.82 (both s, 3 H each,
CH3); 2.45, 3.45 (both m, 2 Н each, CH2); 7.20 (s, 1 H, NH);
7.30 (br.s, 3 Н, Ph); 7.90 (br.s, 2 Н, Ph); 9.20 (br.s, 1 Н, NH);
isomer B: 1.80, 1.95 (both s, 3 H each, CH3); 3.10, 3.40 (both t,
2 Н each, CH2, J = 7.0 Hz); 7.30 (br.s, 3 Н, Ph); 7.90 (br.s, 2 Н,
Ph); 9.20 (br.s, 2 Н, NHNH). 13С NMR (СDСl3), δ: isomer A:
25.31 (СH3), 26.27 (CH3), 34.18 (CH2N), 36.43 (CH2C), 76.47
(C(CH3)2), 127.42, 128.37, 131.83 (Ph), 167.21 (CH2CO),
168.86 (NHCO); isomer B: 25.51 (СH3), 30.90 (CH3), 37.88
(CH2C); 64.10 (CH2N), 127.64, 131.37, 131.96 (Ph), 165.43
(CMe2), 168.86 (NHCO), 171.10 (CH2CO). IR, ν/cm–1: 1636
(CONH), 1696 (COCH2).
NꢀTosylꢀ (6) and Nꢀ(3,4ꢀdimethoxybenzoyl)ꢀβꢀaminopropꢀ
ionic acid N'ꢀbenzoylhydrazides (7). Pyridine (2.9 mmol) and the
corresponding acid chloride (2.4 mmol) were successively added
to a solution of hydrazide 1b (0.5 g, 2.4 mmol) in anhydrous
dioxane (10 mL). The resulting solution was stirred for 4 h at
~20 °C, the solvent was evaporated, and the residue was crystalꢀ
lized from a water—EtOH (1 : 1) mixture. Compound 6 was
obtained in 46% yield (0.4 g, m.p. 139—142 °С) and comꢀ
pound 7 was obtained in 50% yield (0.44 g, m.p. 187—188 °С).
Compound 6. Found (%): С, 56.54; Н, 5.34; N, 11.69, S, 8.78.
С17Н19N3O4S. Calculated (%): С, 56.50; Н, 5.30; N, 11.63;
S, 8.87. 1H NMR (DMSOꢀd6), δ: 2.30 (s, 3 Н, СН3); 2.35 (t,
2 H, CH2С, J = 6.6 Hz); 2.95 (m, 2 H, CH2N); 7.50 (m, 8 H,
SO2NH + Ph + C6H4S); 7.90 (d, 2 H, Ph J = 6.9 Hz); 9.95,
10.35 (both s, 1 H each, NHCO). Compound 7. Found (%):
С, 61.22; Н, 5.57; N, 11.05. С19Н21N3O5. Calculated (%):
2ꢀArylꢀsubstituted 1ꢀacylꢀ and 1ꢀtosylꢀ3ꢀbenzoylaminotetraꢀ
hydropyrimidinꢀ4ꢀones (10a—f) (general procedure). Pyridine
(0.11 mL, 1.2 mmol) and the corresponding acid chloride 9a—d
(1 mmol) were successively added to a solution of compound 8e
(or 8f) (1.0 mmol) in anhydrous dioxane (10 mL). The resulting
mixture was stirred for 6 h at ~20 °С, the solvent was evapoꢀ
rated, and the residue was recrystallized from a water—EtOH
1
(1 : 1) mixture. The yields, melting points, and H NMR specꢀ
troscopic and elemental analysis data for the products are preꢀ
sented in Tables 5 and 6.
NꢀBenzoylhydrazone of acetophenone (11). Acetophenone
(0.29 g, 2.4 mmol) was added to a solution of hydrazide 1b (0.5 g,
2.4 mmol) in anhydrous PriOH (10 mL). The residue was treated
with a mixture of PriOH (6 mL) and EtOAc (10 mL), and the
undissolved residue was filtered off. The solvent was evaporated
from the mother liquor, and the residue was twice recrystallized
from PriOH (6 mL). Compound 11 was obtained in 41% yield
(0.24 g, m.p. 155—157 °С). Found (%): С, 75.44; Н, 5.91;
N, 11.52. С15Н14N2O. Calculated (%): С, 75.60; Н, 5.92;
N, 11.76. 1Н NMR (DMSOꢀd6), δ: 2.30 (s, 3 H, CH3); 7.50 (m,
6 H, PhC + PhCO); 7.85 (m, 4 H, PhCO); 10.22 (s, 1 H, NH).
1
С, 61.45; Н, 5.70; N, 11.31. H NMR (DMSOꢀd6), δ: 2.50 (t,
2 H, CH2С, J = 6.4 Hz); 3.50 (m, 2 H, CH2N); 3.85 (s, 6 H,
2 CH3O); 7.00 (d, 1 H, (3,4ꢀMeO)2ꢀC6H3, J = 8 Hz); 7.50 (m,
5 H, Ph + (3,4ꢀMeO)2ꢀC6H3); 7.90 (d, 2 H, Ph, J = 7.4 Hz);
8.30, 9.90, 10.30 (all s, 1 H each, NH).
2ꢀSubstituted 3ꢀacylaminotetrahydropyrimidinꢀ4ꢀones (8a—i)
(general procedure). An equimolar amount of aldehyde was
added to a solution of the corresponding hydrazide (1а or 1b)
(2.5 mmol) in anhydrous PriOH (10 mL). The mixture was
refluxed for 6 h in the case of compounds 8a—g,i and for 8 h in
the case of 8h. When synthesizing compounds 8b, 8f, and 8h, the
precipitate that formed was filtered off, washed with a mixture
of PriOH (6 mL) and hexane (6 mL), and dried. For compounds
8a, 8c, 8e, 8g, and 8i, the solvent was evaporated, and the
residue was recrystallized from a PriOH—hexane mixture. For
compound 8d, the solvent was evaporated, and the residue was
recrystallized from a CHCl3—Et2O (1 : 4) mixture. The yields,
melting points, and 1H NMR spectroscopic and elemental
analysis data for the synthesized compounds are presented in
Tables 1—3.
References
1. G. A. Smirnov, E. P. Sizova, O. A. Luk´yanov, I. V. Fedyanin,
and M. Yu. Antipin, Izv. Akad. Nauk, Ser. Khim., 2003, 2311
[Russ. Chem. Bull., Int. Ed., 2003, 52, 2444].
2. N. B. Colthup, L. H. Dally, and S. E. Wilberley, Introduction
to Infrared and Raman Spectroscopy, New York—Lonꢀ
don, 1964.
3. O. L. Salerni, B. E. Smart, A. Post, and C. C. Cheng, J. Chem.
Soc., C, 1968, 12, 1399.
Received February 11, 2004;
in revised form March 15, 2004