Reaction of spirocyclic isopropylidene malonates with urea and N,N′-disubstituted ureas

Article abstract of DOI:10.1023/A:1022685226097

Unsubstituted and N-substituted amides of 2-aryl-4-methyl-4-cyclohexene-1-carboxylic acids are formed during the fusion of 2′-aryl-2,2,4′-trimethyl-1,3-dioxan-5-spirocyclohex-4 ′-ene-4,6-diones with urea and N,N′-disubstituted ureas.

Full text of DOI:10.1023/A:1022685226097

Chemistry of Heterocyclic Compounds, Vol. 38, No. 12, 2002
REACTION OF SPIROCYCLIC
ISOPROPYLIDENE MALONATES WITH
UREA AND N,N'-DISUBSTITUTED UREAS
Z. Tetere, D. Zicane, I. Ravina, M. Petrova, and E. Gudriniece
Unsubstituted and N-substituted amides of 2-aryl-4-methyl-4-cyclohexene-1-carboxylic acids are
formed during the fusion of 2'-aryl-2,2,4'-trimethyl-1,3-dioxan-5-spirocyclohex-4'-ene-4,6-diones with
urea and N,N'-disubstituted ureas.
Keywords: amides, barbituric acid, N,N'-disubstituted ureas, isopropylidene malonate, urea,
cyclohexene.
The main method for the production of 5,5-disubstituted barbituric acids, which include a large number
of pharmaceutical products [1, 2], involves the reaction of disubstituted malonic acids or their esters with
derivatives of urea [1].
The 2'-aryl-2,2,4'-trimethyl-1,3-dioxan-5-spirocyclohex-4'-ene-4,6-diones 1a-e that we synthesized
earlier [3] are derivatives of cyclic esters of malonic acid. We therefore assumed that spirocyclic barbituric
acids (2'-aryl-4'-methylhexahydropyrimidine-5-spirocyclohex-4'-ene-2,4,6-triones) 2a-e would be formed in
their reactions with ureas.
However, the spirocyclic isopropylidene malonates 1a-e did not react with the ureas 3a-c when boiled in
ethanol, dioxan, or DMF.
R'
O
Ar
O
Ar
R–NHCONH–R
O
O
N
N
3a–c
Me
O
Me
O
R'
O
1a–e
2a–e
3a
Ar
3b
NH4OH
Ar
3c
PhNH2
H
Ar
Ar
O
H
Me
Me
N
O
DMF
H2N
O
Ph
N
O
H2N
Me
Me
Me
∆
HOOC
5a–e
6a–e
4a–e
7a–e
1, 2, 4–7 a Ar = Ph, b Ar = C6H4F-p, c Ar = C6H4Cl-p, d Ar = C6H4Br-p,
e Ar = C6H4NO2-p, 3a R = H, b R = Me, c R = Ph
__________________________________________________________________________________________
Riga Technical University, Riga, Latvia; e-mail: gudr@ktf.rtu.lv, marina@osi.lv. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1640-1642, December, 2002. Original article submitted
November 8, 2001.
1448
0009-3122/02/3812-1448$27.00©2002 Plenum Publishing Corporation

TABLE 1. The Characteristics of Compounds 4a-e and 5a-e
Found, %
——————
Com-
pound
Empirical
formula
Yield, %
Calculated, %
mp, °С
С
Н
N
Hal
C14H17NO
78.17
78.10
7.90
7.96
6.39
6.51
125-127
139-140
150-151
127-129
160-161
165-166
181-183
159-161
167-168
232-235
55.6
70.2
67.6
60.0
71.4
58.3
74.1
57.1
59.8
60.0
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
C14H16FNO
C14H16ClNO
C14H16BrNO
C14H16N2O3
C15H19NO
72.21
6.72
5.86
8.22
8.14
72.08
6.91
6.00
67.17
67.33
6.33
6.46
5.47
5.61
14.31
14.20
27.26
27.16
56.90
4.84
5.39
57.16
4.76
5.48
57.80
57.93
5.21
5.56
9.49
9.65
71.69
7.20
5.49
71.79
7.39
5.40
C15H18FNO
C15H18ClNO
C15H18BrNO
C15H18N2O3
75.16
75.28
7.28
7.34
5.71
5.66
7.57
7.68
70.49
6.91
5.13
13.27
70.58
6.88
5.31
13.44
61.71
61.60
6.01
5.89
4.71
4.54
25.78
25.93
60.90
5.76
9.03
61.17
5.96
9.21
The reaction of the compounds in methanol or ethanol in the presence of sodium methoxide or sodium
ethoxide according to the usual procedures [4-6] led to the formation of mixtures of products, from which it was
not possible to isolate individual products. Various modifications of the methods also did not give positive
results.
TABLE 2. The Spectral Characteristics of Compounds 4a-e and 5a-e
Com-
1Н NMR spectrum, δ, ppm, CCSS, J (Hz)
pound
1.64 (3H, s, CH3); 2.26-2.37 (4H, m, 2СН2); 2.48 (1Н, m, СН); 3.33 (1Н, m, СН);
5.42 (1Н, m, =СН); 6.71 (1Н, br. s, NH); 7.22 (5H, m, C6H5); 11.5 (1Н, br. s, NH)
4a
4b
4c
4d
4е
1.64 (3H, s, CH3); 2.00-2.22 (4H, m, 2СН2); 2.68 (1Н, m, СН); 3.33 (1Н, m, СН);
5.42 (1Н, m, =СН); 6.68 (1Н, br. s, NH); 6.91-7.31 (4H, m, C6H4); 7.52 (1Н, br. s, NH)
1.75 (3H, s, CH3); 2.27-2.53 (4H, m, 2СН2); 2.79 (1Н, m, СН); 3.52 (1Н, m, СН);
5.35 (2Н, br. s, NH2); 5.59 (1Н, m, =СH); 7.20 (4Н, m, С6H4)
1.68 (3H, s, CH3); 2.17-2.37 (4H, m, 2СН2); 2.71 (1Н, m, СН); 3.34 (1Н, m, СН);
5.20 (1Н, m, =СН); 5.43 (2Н, br. s, NH2); 7.02-7.37 (4H, m, C6H4)
1.75 (3H, s, CH3); 2.08-2.37 (4H, m, 2СН2); 2.75 (1Н, m, СН); 3.55 (1Н, m, СН);
5.51 (1Н, m, =СН); 6.06 (2Н, br. s, NH2); 7.42 (2H, d, J = 8, C6H4);
8.11 (2Н, d, J = 8, C6H4)
1.71 (3H, s, CH3); 2.08-2.37 (4H, m, 2СН2); 2.58 (3Н, d, J = 5, СН3); 2.60 (1Н, m, СН);
5а
5b
5с
5d
3.40 (1Н, m, СH); 5.02 (1Н, d, J = 5, NH); 5.44 (1Н, m, =СH); 7.13 (5H, m, С6Н5)
1.72 (3H, s, CH3); 2.07-2.27 (4H, m, 2СН2); 2.60 (3Н, d, J = 5, СН3); 2.62 (1Н, m, СН);
3.39 (1Н, m, СH); 5.02 (1Н, d, J = 5, NH); 5.43 (1Н, m, =СH); 6.68-7.37 (4H, m, С6Н4)
1.64 (3H, s, CH3); 1.93-2.17 (4H, m, 2СН2); 2.40 (3Н, d, J = 5, СН3); 2.71 (1Н, m, СН);
3.37 (1Н, m, СH); 5.15 (1Н, d, J = 5, NH); 5.47 (1Н, с, =СH); 7.06 (4H, m, С6Н4)
1.71 (3H, s, CH3); 2.00-2.33 (4H, m, 2СН2); 2.62 (3Н, d, J = 5, СН3); 2.64 (1Н, m, СН);
3.42 (1Н, m, СH); 5.20 (1Н, d, J = 5, NH); 5.48 (1Н, m, =СH); 7.04 (2H, d, J = 8, С6Н4);
7.42 (2H, d, J = 8, С6Н4)
1.77 (3H, s, CH3); 2.13-2.44 (4H, m, 2СН2); 2.70 (3Н, d, J = 5, СН3); 2.73 (1Н, m, СН);
3.62 (1Н, m, СH); 5.28 (1Н, d, J = 5, NH); 5.55 (1Н, m, =СH); 7.33 (2H, d, J = 8, С6Н4);
8.08 (2H, d, J = 8, С6Н4)
5е
1449

We found that the malonates 1a-e reacted with the ureas 3a-e at the melting point of their mixture with
the formation not of the barbituric acid derivatives 2 but of 2-aryl-4-methylcyclohex-4-ene-1-carboxamides 4a-e
or their N-methyl or N-phenyl derivatives 5a-e and 6a-e respectively. The formation of these products is
probably due to decomposition of the ureas 3a-c at the melting point of the reaction mixture to ammonia or
amines, which react with the malonates 1a-e to form the familiar monoamides of cyclohexenecarboxylic acids
7a-e [7]. The latter then undergo decarboxylation to the amides 4a-e and 5a-e and the previously described
amides 6a-e {obtained by the prolonged boiling of 1a-e and aniline in DMF [7]}.
The structure of the synthesized compounds 4a-e and 5a-e is confirmed by the results from elemental
analysis (Table 1) and the 1H NMR spectra (Table 2). In the case of the products 4a-e it was also confirmed by
decarboxylation of the monoamides 7a-e (by boiling in DMF).
EXPERIMENTAL
The 1H NMR spectra were obtained on a Bruker WH/90DS instrument (90 MHz) with
deuterochloroform and DMSO as solvents and HMDS as internal standard. The individuality of the obtained
compounds was checked by TLC on Silufol plates in the following solvent systems: 9:1:1 chloroform–acetone–
glacial acetic acid for compounds 4a-e; 24:2:1 chloroform–methanol–glacial acetic acid for compounds 5a-e
and 6a-e.
Amides of 2-Aryl-4-methylcyclohex-4-en-1-carboxylic Acids (4a-e), N-Methylamides of 2-Aryl-4-
methylcyclohex-4-ene-1-carboxylic Acids (5a-e), and N-Phenylamides of 2-R-4-Methylcyclohex-4-ene-1-
carboxylic Acids (6a-e) (General Procedure). A mixture of equimolar amounts of the spirocyclic
isopropylidene malonate 1a-e and the urea 3a-c was kept at the melting point for 2 h (during the synthesis of
compounds 5a, b), 2.5 h (4a, c and 5c, d), 3 h (4b, d, e), and 4 h (6a-e).
The amides 4a-e–6a-e were isolated from the reaction mixture by the addition of water followed by
filtration. They were purified by recrystallization from methanol (4a), a 1:1 mixture of methanol and water
(4b-e), acetonitrile (5a-d), or a 1:1 mixture of ethanol and water (5e, 6a-e).
The properties and chemical characteristics of compounds 6a-e agree with those for previously
obtained samples [7].
Compounds 4a-e were also synthesized by boiling the monoamides 7a-e (obtained by the method in [7])
for 2 h in DMF followed by addition to iced water, filtration, and drying. Compounds 4a-e were
chromatographically uniform without recrystallization.
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