Three-component condensation of hetarylguanidines with aldehydes (ketones) and dicarbonyl compounds

Article abstract of DOI:10.1007/s10593-006-0245-5

The three-component condensation of benzoxa(thia)zolylguanidines, aldehydes (ketones), and β-dicarbonyl compounds (acetyl-and benzoylacetone, ethyl acetoacetate, acetoacetanilides, cyclohexanedione-1,3 and its derivatives) has been studied.

Full text of DOI:10.1007/s10593-006-0245-5

Chemistry of Heterocyclic Compounds, Vol. 42, No. 10, 2006
THREE-COMPONENT CONDENSATION
OF HETARYLGUANIDINES WITH ALDEHYDES
(KETONES) AND DICARBONYL COMPOUNDS
A. Yu. Potapov, Kh. S. Shikhaliev, D. V. Krylsky, and M. Yu. Krisin
The three-component condensation of benzoxa(thia)zolylguanidines, aldehydes (ketones), and
β-dicarbonyl compounds (acetyl- and benzoylacetone, ethyl acetoacetate, acetoacetanilides,
cyclohexanedione-1,3 and its derivatives) has been studied.
Keywords: acetoacetanilides, acetylacetone, aldehydes, benzoxazolylguanidine, benzoylacetone,
benzthiazolylguanidine, cyclohexanedione-1,3, β-dicarbonyl compounds, ethyl acetoacetate, ketones,
three-component condensation.
Reactions involving nitrogen-containing binucleophiles opens the way to the design of various linear
and condensed heterocyclic systems possessing a wide range of biological activity. In consequence these
reactions have been studied intensively [1-10]. (Thio)ureas and their alkyl derivatives [1-3], 3-amino-1,2,4-
triazole [4,5], aminopyrazol and aminotetrazole [6], and 2-aminobenzimidazole [7,8] have been used in three-
component condensations with aldehydes and β-dicarbonyl compounds (ethyl acetoacetate, dimedone). In
contrast, guanidine and its derivatives, which have considerable synthetic potential [9], have been studied
comparatively little in such reactions. We have previously studied three-component condensations of
benzoxa(thia)zolylguanidines (1a,b), triethyl orthoformate, and β-dicarbonyl compounds [10]. The objective of
the present work was to study the reactivity of the guanidines 1a,b in three-component condensation reactions
with aldehydes (ketones) and β-dicarbonyl compounds: acetyl- and benzoylacetone, ethyl acetoacetate,
acetoacetanilides, cyclohexanedione-1,3 and it derivatives.
It was found that boiling equimolar mixtures of a guanidine 1a,b, cyclohexanedione (dimedone) 2, and
aromatic aldehydes
3
gave the 4-aryl-2-[1,3-benzoxa(thia)zol-2-ylamino]-1,4,5,6,7,8-hexahydro-5-
quinazolinones 6a-c in 40-70% yields. Use of cyclopenta(hexa)nones 4a,b or isatin 5 in place of the aldehyde
gave the corresponding spirocondensed systems 7 and 8 on boiling in 2-propanol. In the latter likely the more
reactive β-carbonyl group of isatin took part in the condensation (Scheme 1).
Reaction of the guanidine 1 – aldehyde 3 – acetylacetone system did not give the expected
acetyldihydropyrimidine 9. The reaction products in this case were the 4,6-dimethyl-2-
benzoxa(thia)zolylaminopyrimidines 10, the synthesis of which from 1 and acetylacetone we have described
previously [11]. However in the case of benzoylacetone, which reacted with great difficulty in a two-component
__________________________________________________________________________________________
Voronezh State University, Voronezh 394006, Russia; e-mail: chocd261@chem.vsu.ru. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 10, 1549-1554, October 2006. Original article submitted July 15,
2004; revision submitted February 26, 2006.
1338
0009-3122/06/4210-1338©2006 Springer Science+Business Media, Inc.

Scheme 1
R3
H
N
N
N
X
HN
O
6 a–c
R2
R1
O
CHO
3 a,b
R3
O
N
X
H
N
+
NH
R2
R1
H2N
1 a,b
2 a–c
O
O
O
n
N
H
5
4 a,b
H
N
H
n
N
N
N
N
NH
N
X
HN
O
X
HN
O
O
R1
R2
7 a,b
R1
R2
8
1 a X = O, b X = S; 2 a R1 = R2 = H, b R1 = R2 = Me, с R1 = H, R2 = 4-FC6H4;
3 a R3 = H, b R3 = 2-Cl; 4 a n = 0, b n = 1; 6 a X = O, R1 = R2 = R3 = H; b X = O,
R1 = R2 = Me, R3 = 2-Cl; c X = S, R1 = R3 = H, R2 = 4-FC6H4; 7 a X = O, R1 = R2 = Me, n = 0,
b X = S, R1 = R2 = H, n = 1; 8 X = S, R1 = R2 = Me
condensation with the guanidines 1, product was isolated in high yield from the three-component condensation.
Since the acetyl group in this case is considerably more reactive than the benzoyl group, the product was
assigned structure 12 (Scheme 2).
Boiling an equimolar mixture of the guanidines 1a,b, ethyl acetoacetate, and benzaldehyde again did not
give the product of the component condensation 15, but the product of the cyclization of guanidine with ethyl
acetoacetate 14, which had been described previously [11], was isolated. However, when acetoacetanilides 16
were used the reaction gave the expected products, dihydropyrimidinedicarboxamides 17.
Signals of the aromatic protons were observed in the 7.0-7.9 ppm range and the two NH protons in the
1
ranges 9.9-10.3 and 10.0-11.3 ppm respectively were observed in the H NMR spectra of the synthesized
compounds 6-8, 12, and 17. Beside that, in compound 8 the singlet of NH proton of the isatin fragment was
observed at 9.52 ppm, and compounds 17a,b gave carboxamide NH proton singlets at 9.64 and 9.57 ppm
respectively. The protons on C(4) of the dihydropyrimidine unit in compounds 6, 12, and 17 gave characteristic
signals in the 5.7-5.9 ppm region. In compounds 6b and 8 the two CH2 groups of the hexahydroquinazoline unit
1339

Scheme 2
N
X
N
X
H
N
H
N
N
N
Ar
O
HN
N
10
9
(MeCO)2CH2
1 a,b
3 a
+
N
X
N
MeCOCH2COPh
H
N
H
N
N
X
N
Ph
O
HN
Ph
O
HN
13
12 a,b
N
H
N
X
N
N
11
12 a X = S, b X = O
TABLE 1. Characteristics of the Compounds Synthesized
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
М*
mp, °С
Yield, %
М1
С
Н
N
6а
C21H18N4O2
C23H21ClN4O2
C27H21FN4OS
C21H24N4O2
C20H22N4OS
C24H21N5O2S
C25H20N4OS
C25H20N4O2
C25H21N5OS
C31H25N5O3
70.53
70.38
65.41
65.63
69.54
69.21
69.41
69.21
65.14
65.55
65.12
64.99
70.47
70.73
73.56
73.51
5.01
5.06
5.03
5.11
4.52
4.45
6.64
6.56
6.05
6.11
4.77
4.88
4.75
4.58
4.94
4.95
15.35
15.63
13.32
13.31
12.01
11.96
15.65
15.37
15.23
15.29
15.85
15.79
13.25
13.20
13.65
13.72
_358_
358.41
_420_
420.96
_468_
468.56
_364_
364.47
_366_
366.50
_443_
443.53
_424_
424.48
_408_
408.46
287-289
>300
68
65
59
61
32
30
67
64
39
34
6b
6c
274-276
265-267
>300
7a
7b
8
240-242
270-272
264-266
262-263
259-261
12a
12b
17a
17b
68.42
68.32
72.44
72.22
4.82
4.58
4. 89
4.78
15.78
15.93
13.56
13.58
_439_
439.54
_515_
515.58
_______
* M – found, M1 – calculated.
1340

form two separate AB systems, the signals of which have the characteristic form of a double of doublets in the
2.1-2.3 and 2.4-2.6 ppm regions. In compound 7a the signals of the protons of the cyclopentane unit overlap this
region.
N
H
N
N
H
N
N
O
X
X
N
Ph
O
HN
O
HN
15
14
O
O
N
O
NH
X
+
3 a
1 a,b
N
HN
Ph
O
O
O
HN
N
R4
H
16 a,b
R4
17 a,b
16 a R4 = H, b R4 = 4-PhO; 17 a X = S, R4 = H, b X = O, R4 = 4-PhO
TABLE 2. 1H NMR Spectra of the Compounds Synthesized
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
6a
6b
2.02-2.35 (6Н, m, aliph.); 5.69 (1Н, s, C(4)-pyrimidine); 7.10-7.45 (9H, m, arom.);
9.92 (1Н, s, NH); 10.56 (1Н, s, NH)
1.10 (6Н, s, 2 СН3); 2.19 (1Н, d, J = 18.0, СН2); 2.26 (1Н, d, J = 18.0, СН2);
2.52 (1Н, d, J = 14.0, СН2); 2.60 (1Н, d, J = 14.0, СН2); 5.92 (1Н, s, C(4)-pyrimidine);
7.09-7.51 (8H, m, arom.); 10.22 (1Н, s, NH); 10.63 (1Н, s, NH)
6c
7a
7b
2.60-2.95 (5Н, m, aliph.); 5.72 (1Н, s, C(4)-pyrimidine); 7.08-7.55 (13H, m, arom.);
9.98 (1Н, s, NH); 10.65 (1Н, s, NH)
1.03 (6Н, s, 2СН3); 1.60-1.95 (6Н, m, aliph.); 2.20-2.55 (6Н, m, aliph.); 7.10-7.22 (2H, m,
arom.); 7.42 (2H, t, J = 7.2, arom.); 10.01 (1Н, s, NH); 10.35 (1Н, s, NH)
1.26-2.44 (16Н, m, aliph.); 7.24 (1H, t, J = 7.2, arom.); 7.41 (1H, t, J = 7.2, arom.);
7.64 (1H, d, J = 7.2, arom.); 7.86 (1H, d, J = 7.2, arom.); 10.11 (1Н, s, NH);
10.39 (1Н, s, NH)
8
1.06 (3Н, s, СН3); 1.12 (3Н, s, СН3); 2.15 (1Н, d, J = 18.0, СН2); 2.22 (1Н, d, J = 18.0,
СН2); 2.50 (1Н, d, J = 14.0, СН2); 2.63 (1Н, d, J = 14.0, СН2); 7.06-7.39 (6H, m, arom.);
7.61 (1H, d, J = 7.2, arom.); 7.81 (1H, d, J = 7.2, arom.); 9.52 (1Н, s,
NH); 10.21 (1Н, s, NH); 11.35 (1Н, s, NH)
12a
12b
17a
17b
1.86 (3Н, s, СН3); 5.79 (1Н, s, C(4)-pyrimidine); 7.05-7.70 (14H, m, arom.);
10.20 (1Н, s, NH); 10.32 (1Н, s, NH)
1.80 (3Н, s, СН3); 5.74 (1Н, s, C(4)-pyrimidine); 7.10-7.75 (14H, m, arom.);
9.98 (1Н, s, NH); 10.13 (1Н, s, NH)
2.16 (3Н, s, СН3); 5.78 (1Н, s, C(4)-pyrimidine); 6.98-7.15 (5H, m, arom.);
7.32-7.47 (9H, m, arom.); 9.64 (1Н, s, NH); 10.02 (1Н, s, NH); 10.18 (1Н, s, NH)
2.21 (3Н, s, СН3); 5.83 (1Н, s, C(4)-pyrimidine); 6.86-7.17 (7H, m, arom.);
7.27-7.44 (9H, m, arom.); 7.62 (2H, d, J = 7.2, arom.); 9.57 (1Н, s, NH);
9.92 (1Н, s, NH); 10.03 (1Н, s, NH)
1341

EXPERIMENTAL
The course of the reactions and the purity of the products were monitored by TLC on Merck UV-254
1
plates. H NMR spectra were recorded on a Bruker AC-300 (300 MHz) (IOKh, Moscow) in DMSO-d6 with
TMS as internal standard, and mass spectra were recorded with an LKB 9000 machine with 70 eV energy of the
ionizing electrons.
4-Aryl-2-(1,3-benzoxa(thia)zol-2-ylamino)- 1,4,5,6,7,8-hexahydro-5-quinaxolinones 6a-c. A mixture
of guanidine 1 (5 mmol), cyclohexanedione 2 (5 mmol), and arylaldehyde 3 (5.5 mmol) in dioxane (15 ml) was
boiled for 3 h, the precipitate was filtered off, washed with dioxane, and crystallized from DMF.
2-(1,3-Benzoxazol-2-ylamino)-4,4'-spirocyclopentano-7,7-dimethyl-1,4,5,6,7,8-hexahydro-5-quina-
zolinone (7a), 2-(1,3-Benzthiazol-2-ylamino)-4,4'-spirocyclohexano-7,7-dimethyl-1,4,5,6,7,8-hexahydro-5-
quinazolinone
(7b),
and
2-(1,3-Benzthiazol-2-ylamino)-4,4'-spiro[3-(2-indolinone)]-7,7-dimethyl-
1,4,5,6,7,8-hexahydro-5-quinazolinone (8) were synthesized by the preceding method using the corresponding
ketone, 2-propanol as solvent, and were crystallized from dioxane.
2-(1,3-Benzoxa(thia)zol-2-ylamino)-5-benzoyl 6-methyl-4-phenyl-1,4-dihydro-pyrimidine 12a,b. A
mixture of guanidine 1 (5 mmol), benzoylacetone (5 mmol), and arylaldehyde 3 (5.5 mmol) in dioxane (5 ml)
was boiled for 5 h, precipitate was filtered off, and crystallized from a dioxane–DMF mixture.
N-5-Aryl-2-(1,3-benzoxa(thia)zol-2-ylamino)-4-aryl-6-methyl-1,4-dihydro-5-pyrimidinedicarbox-
amides 17a,b were obtained analogously to compounds 7, 8.
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