Mannich Reaction with
5,5-Dimethyl-3-phenylamino-2-cyclohexen-l-one
W. S. Hamama, M. Hammouda*, and E. M. Afsah
Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt
Z. Naturforsch. 4 3 b , 483-486 (1988); received August 18, 1986/October 26, 1987
Mannich Bases of Enaminones, Octahydro-9H-pyrimido[5,4-b]-azepines,
Tetrahydro-4H-[3,l]benzoxazin-5(6H)-one, Nitrogen Heterocycles
Mannich reaction of the title compound 1 with morpholine, piperidine or piperazine gave the
keto-bases 2—4, respectively. Whereas, such reaction with primary amines afforded the
quinazolinones 5 and 6. Compound 1 reacts with isonicotinic acid hydrazide and formalin to give
7. Schmidt reaction of 4 and 5 a gave 8 and 9, respectively. Reduction of the latter afforded the
9H-pyrimido[5,4-b]azepine ring system 10. The reaction of 1 with formalin was investigated.
Kametani [1] devised an interesting synthesis
of 3,3-dimethyl-2,3,4,5,10,l 1-hexahydro-l H-dibenzo[b,eJ[l,4]-diazepin-l-one, involving a Mannich
type cyclization of 3-(o-aminoanilino)-5,5-dimethyl2-cyclohexen-l-one with formaldehyde. The only reported case of a Mannich reaction with dimedone
enamine is that of Roth and Hägen [2].
From a synthetic point of view, the Mannich bases
of 5,5-dimethyl-3-phenylamino-2-cyclohexen-l-one
could conceivably function as intermediates for the
synthesis of some condensed heterocycles having a
pyrimido or azepino nucleus.
The existence of 1 in the enaminone form [3] is
demonstrated by the presence of three very strong
IR absorption bands in the range 1610—1540 cm" 1 ,
characteristic of enaminones derived from cyclohexan-l,3-diones [4, 5]. Its 'H NMR spectrum features a
singlet at d 5.56 (vinyl H-2) and the 13C NMR spectrum showes peaks at ö 197.9 (C-l), 129.2 (C-2) and
168.7 (C-3).
The Mannich reaction of the title compound I with
morpholine, piperidine or piperazine and formalin
affordes the Mannich bases 2—4 which have structural features related to the respiratory stimulant drug
spiractin [6]. Since compound 1 contains an other
reactive center at C-6, the reaction was repeated by
using amine acetate and formalin in a molar ratio of
1:2:2 in the hope of isolating a bis Mannich base.
However, the mono base 2 was always the sole product.
On the other hand, treatment of 1 with ammonium
acetate of benzylamine acetate and formalin in a
* Reprint requests to Dr. M. Hammouda.
Verlag der Zeitschrift für Naturforschung, D-7400 Tübingen
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molar ratio of 1:1:2 gave hexahydro-7,7-dimethyl-lphenylquinazolin-5(6H)-ones (5a—b) via a double
Mannich reaction. The involvement of both C-2 and
the phenylamino group in this reaction is in line with
our recent work [7] on the Mannich reaction with
l-phenylamino-3-indenone, and the work of Roth
and Hägen [2] on 3-amino-5,5-dimethyl-2-cyclohexen-l-one. In addition, when 1 was subjected to a
double Mannich reaction using ethylenediamine it
afforded the
3.3'-ethylenebis-(hexahydro-7,7-dimethyl-l-phenylquinazolin-5(6H)-one) (6). In particular, the 13C NMR spectrum of 5 a displays five
singlet peaks due to C-5, C-4a, C-8a, C-7 and substituted aromatic carbon atom.
Attempts have also been made to prepare the ring
system of 5 having an isonicotinamide residue at
N-3 by using isonicotinic acid hydrazide in the
double Mannich reaction, but the only product
obtained was 7.
In continuation of our studies on ketonic Mannich
bases as synthetic intermediates [8—11], and in line
with the synthesis of 2,5-bis(piperidinomethyl)piperidine [8]. Compound 4 was subjected to
Schmidt reaction to afford 8. The assignment of the
NH group between the (CO) group and the substituted carbon atom in 8, is based on previous studies
by Schmid et al. [12] on 2-aminomethyl-l-tetralone
and 1-indanone derivatives. In addition, the hexahydro-quinazolin-5-one (5a) is a reasonable and attractive intermediate in the synthesis directed towards the 9H-pyrimido[5,4-b]azepine ring system,
via treatment of 5a with hydrazoic acid (Schmidt
reaction) to give the enamide 9. Insertion of the
(NH) group between the pyrimido nucleus and the
(CO) group in 9 is based on the rule that, in Schmidt
reaction the group which preferentially migrates
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484
W . S. Hamama et al. • Mannich Reaction with 5.5-Dimethyl-3-phenylamino-2-cyclohexen-l-one
from carbonyl to nitrogen is the one which has the
greatest bulk [13], and also by analogy with the formation of homocarbostyril [14] and tetrahydro-1benzazocin-2-one [15] from a-tetralone and benzsuberanone, respectively. Reduction of 9 with
lithium aluminium hydride afforded octahydro-8,8dimethyl-l-phenyl-9H-pyrimido[5,4-b]azepine (10).
An examination of the literature pointed up
the existence of only three pyrimido-azepine ring
systems: 2,3,4,6,7,8,9,10-octahydropyrimido[l,2a]azepine [16, 17], 5,6,7,8-tetrahydro-9H-pyrimido[4,5-b]azepines [18, 19] and 5,6,8,9-tetrahydro-7Hpyrimido[4,5-d]azepines [20], which are isomeric
with our new system 10.
In the course of our investigation, we have found
that the reaction of 1 with formaldehyde led to the
formation of the tetrahydro-4H-[3,l]-benzoxazin-5(6H)-one (11) or the hydroxymethyl derivative 12,
depending on the reaction conditions. Formation of
11 is in line with the work of Greenhill [3] on the
reaction of acetaldehyde with 3-amino-5,5-dimethyl2-cyclohexen-l-one.
Experimental
All melting points (°C) are uncorrected and were
taken in a Gallenkamp electric melting point apparatus. IR spectra were performed on a Unicam
SP 2000 Infrared Spectrophotometer using KBr.
10
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W . S. Hamama et al. • Mannich Reaction with 5,5-Dimethyl-3-phenylamino-2-cyclohexen-l-one
'H NMR spectra were obtained in CDCI3 solutions
with a Perkin-Elmer R 32 NMR Spectrometer
90 MHz. 13C NMR was detected on Jeol PFT
100 MHz.
5,5-Dimethyl-2-(N-morpholinomethyl)-3-phenylanilino-2-cyclohexen-l-one
(2);
5,5-dimethyl-2-(N-piperidinomethyl)-3-phenylanilino-2-cyclohexen-l-one
(3) and
N,N'
-bis(5,5-dimethyl-3-phenylanilino-2-cyclohexen(4)
1 -one-2-ylmethyl)piperazine
A solution of 1 (0.65 g; 0.003 mol) in ethanol
(50 ml) was successively treated with morpholine
acetate (0.44 g; 0.003 mol), piperdine acetate
(0.43 g; 0.003 mol) or piperazine acetate (0.13 g;
0.0015 mol) respectively, and 40% formalin (0.09 g;
0.003 mol). The reaction mixture was refluxed for
one hour, and left to stand overnight at room temperature. The mixture was diluted with water (60 ml)
and basified with ammonia to pH 8. The product
that separated was recrystallized from ethanol.
Compound 2, 75% yield (0.71 g), m.p. 160 °C.
C19H26N202
(314.42)
Calcd
C 72.57
Found C 72.41
H 8.34
H 8.22
N 8.91,
N 8.73.
Compound 3, 78% yield (0.73 g), m.p. 125 °C.
C20H28N2O (312.44)
Calcd
C 76.88
Found C 76.59
H 9.03
H9.ll
N 8.97,
N 8.78.
Compound 4, 70% yield (0.57 g), m.p. 220 °C.
'H NMR (CDC1,): Ö 1.03 [s, 6 H , Me], 2.17 [ s , 4 H .
2(6-H 2 )], 2.25 [s, 4 H , 2(4-H 2 )], 2.45 (s, 8 H ,
C H 2 - C H 2 of piperazine), 2.5 (broad s, 1 H, NH), 3.5
(s, 4 H , C H 2 - N of side chains) and 7.2 (m, 10H,
aromatic protons).
C34H44N402 (540.72)
Calcd
C 75.52
Found C 75.39
H 8.20
H 8.08
N 10.36,
N 10.29.
' H N M R ( C D C U ) : ö 1.01 (s, 6 H , M e ) , 2 . 1 5 (s,
1H, NH), 2.3 (s, 4 H , 4-H 2 and 6-H 2 ), 2.4 (s, 4 H ,
2-H 2 and 8-H 2 ) and 7.4—7.1 (m, 5 H , aromatic protons'); 13C NMR (CDCI3): ö 28 (Me), 32 (Me), 58.06
(C-7), 103.26 (C-6), 104.29 (C-8), 127.65 (C-2),
129.21 (C-4), 129.68 (substituted aromatic carbon),
142.82 (C-4a), 161.51 (C-8a) and 194.24 (C-5).
C16H20N2O (256.34)
Calcd
C 74.96
Found C 74.78
H 7.86
H 7.99
N 10.93,
N 10.81.
Compound 5b, 68% yield (0.71 g), m.p. 187 °C.
'H NMR (CDCI3): (3 1.0 (s, 6 H , Me), 2.33 (s, 4 H ,
4-H 2 and 6-H 2 ), 2.45 (broad s, 4 H , 2-H : and 8-H : ),
3.57 (s, 2 H , "benzylic CH 2 ) and 7 . 1 - 7 . 4 (m, 10H,
aromatic protons).
C23H26N20 (346.46)
Calcd
C 79.72
Found C 79.56
H 7.57
H 7.65
N 8.09,
N 8.00.
3,3'-Ethylenebis-[1,2,3,4,7,8-hexahydro7,7-dimethyl-l-phenylquinazolin-5(6
H)-one] (6)
This compound was obtained in the same manner
as above, from 1 (0.65 g; 0.003 mol), ethylenediamine diacetate (0.27 g; 0.0015 mol) and 40%
formalin (0.2 g; 0.006 mol). The product was crystallized from methanol to give 6,77% yield (0.62 g), m.p.
198 °C.
CuH42N402
(538.71)
Calcd
C 75.80
Found C 75.64
H 7.86
H 7.78
N 10.40,
N 10.31.
5,5-Dimethyl-2-(N-isonicotinoyl-N'-hydrazomethyl)3-phenylamino-2-cyelohexen-l-one
(7)
The same procedure as described for 5 was followed but isonicotinic acid hydrazide (0.41 g;
0.003 mol) was used instead of the amine acetate.
Compound 7 crystallized from ethanol, 64% yield
(0.70 g), m.p. 157 °C.
CvHuN40,
(364.43)
Calcd
C 69.21
Found C 68.95
1,2,3,4,7,8-Hexahydro-7,7-dimethyl-l-phenylquinazolin-5(6H)-one
(5a) and 1,2,3,4,7,8-hexahydro-3-benzyl-7,7-dimethyl-l-phenylquinazolin5(6 H)-one (5b)
Schmidt reaction on 4 and 5 a: Formation of 8 and 9
To a solution of 1 (0.65 g; 0.003 mol) in ethanol
(60 ml) was added ammonium acetate (0.3 g;
0.004 mol)
or
benzylamine
acetate
(0.5 g;
0.003 mol) and 40% formalin (0.18 g; 0.006 mol).
The resulting solution was refluxed for 4 h, then left
to stand overnight at room temperature. The reaction mixture was worked up as in case of 2. The
product that separated was crystallized from ethanol.
Compound 5a, 52% yield (0.40 g), m.p. 115 °C.
To a stirred mixture of sulphuric acid (10 ml, 90%)
and chloroform (20 ml) at 0 °C was added a solution
of 4 (2.16 g; 0.004 mol) or 5a (1 g; 0.004 mol), followed by addition of sodium azide (0.26 g;
0.004 mol). After stirring for 1 h at 0 °C and 4 h at
25 °C the reaction mixture was diluted with ice water, basified with ammonia (40%) and extracted with
ether. The ethereal solution was dried on (Na 2 S0 4 )
and evaporated to give a solid product which was
H 6.64
H 6.56
N 15.37,
N 15.23.
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W . S. Hamama et al. • Mannich Reaction with 5,5-Dimethyl-3-phenylamino-2-cyclohexen-l-one 486
crystallized from ether-pet. ether to give 8 (1.60 g) and
9 (0.76 g) in a 70% yield.
Compound 8, m.p. 218 °C.
CuH46N602
(570.76)
Calcd
C 71.54
Found C 71.43
H 8.12
H 8.03
N 14.73,
N 14.56.
Compound 9, m.p. 132 °C.
Ci6HvNIO
(271.35)
Calcd
C 70.82
Found C 70.62
H 7.80
H 7.93
N 15.49,
N 15.31.
1,2,3,4,5,6,7,8-Octahydro-8,8-dimethyl-l-phenyl(10)
9 H-pyrimido-/5,4-b/azepine
To a stirred solution of lithium aluminium hydride
(0.2 g: 0.005 mol) in ether (20 ml), there was added
a solution of 9 (0.4 g; 0.0015 mol) in dry dioxane.
The reaction mixture was refluxed for 7 h, cooled,
poured into (80 ml) ice water, basified with (5%)
N a O H solution and filtered. The filtrate was evaporated, extracted with ether, dried on (K 2 C0 3 ) and
evaporated to give a yellow oil. Treating with pet.
ether (40—60) gave a white solid which was crystallized from ethyl acetate to give 10 (0.17 g) in 45% yield,
m.p. 92 °C.
IR (KBr): showed a broad band at 3440-3370 c m - 1
characteristic of (NH) groups.
Cj6H23N3 (257.36)
Calcd
C 74.67
Found C 74.59
H 9.01
H 9.11
N 16.33,
N 16.30.
[1] T. Kametani. M. Ihara, and K. Takahashi. Chem.
Pharm. Bull. Jpn. 20, 1588 (1972).
[2] H. J. Roth and H. E . Hägen. Arch. Pharm. 304, 331
(1971).
[3] J. V. Greenhill. J. Chem. Soc. (C) 1971, 2699.
[4] D. L. Ostercamp. J. Org. Chem. 35, 1632 (1970).
[5] J. Dabrowski and K. Kamienska-Trela, Spectrochim.
Acta 22, 211 (1966).
[6] The Merk Index of Chemicals and Drugs. 9th ed.. item
no. 7262. p. 972. Rahway, N. J.: Merk and Co. Inc.
(1976).
[7] M. Hammouda. W . S. Hamama. and E. M. Afsah. Z.
Naturforsch. 42b, 94 (1987).
[8] E. M. Afsah. M. A. Metwally, and M. M. Khalifa.
Monatsh. Chem. 115, 303 (1984).
[9] E. M. Afsah. M. Hammouda. and M. M. Abou-Elzahab, ibid. 115, 581 (1984).
[10] E. M. Afsah. H. M. Hassan. S. A. El-Agizv. and
M. T. Zimaity. J. Prakt. Chem. 326, 841 (1984).
[11] E . M. Afsah. M. Hammouda. and W . S. Hamama.
Monatsh. Chem. 116, 851 (1985).
1,2,7,8-Tetrahydro-7,7-dimethyl-l-phenvl4H-[3,l]-benzoxazin-5(6H)-one
(11)
A solution of the enaminone 1 (0.65 g; 0.003 mol),
formalin (40%) (0.27 g; 0.009 mol) in ethanol
(50 ml) and few drops of acetic acid (0.5 ml) was
heated for 2 h on a steam bath, kept overnight at
room temperature. The mixture was diluted with water (60 ml), basified with ammonia to pH 8. The
product that separated was crystallized from ethanol
to give 11 as a yellowish powder, 60% yield (0.46 g),
m.p. 191 °C.
CI6HivM02 (257.32)
Calcd
C 74.68
Found C 74.53
H 7.44
H 7.48
N 5.44,
N 5.36.
5,5-Dimethyl-2-hydroxymethyl-3-phenylamino2-cyclohexen-l-one (12)
A solution of the enaminone 1 (0.65 g; 0.003 mol),
paraformaldehyde (0.27 g; 0.009 mol) in glacial acetic acid (30 ml), was heated for 2 h on a steam bath,
kept overnight at room temperature. The reaction
mixture was worked up as above. The precipitated
product was filtered off and crystallized from ethanol
to give 12 as a yellow powder, 66% yield (0.49 g),m.p.
101 °C (decomp.).
IR (KBr): 3950 cm" 1 ( O H ) .
C,5Hl9N02
(245.31)
Calcd
C 73.44
Found C 73.26
H 7.81
H 7.65
N 5.71,
N 5.53.
[12] H. Schmid. A. Hunger, and K. Hoffmann, Helv.
Chem. Acta 39, 607 (1956).
[13] C. V. Buehler and D. E . Pearson. Survey of Organic
Syntheses. Vol. l . p . 925. Wiley-Interscience. London
(1970).
[14] P. A . S. Smith. J. Am. Chem. Soc. 70, 320 (1948).
[15] P. A. S. Smith and W . L. Berry. Org. Chem. 26, 27
(1961).
[16] H. Oedigar and Fr. Moller. Angew. Chem., Int. Ed.
Engl. 6, 76 (1967).
[17] Farbenfabriken Bayer A G , Fr. 1491791; C. A. 69,
67412 (1968).
[18] V. G. Granik and R. G. Glushkov. Kim. Farm. Zh. 1,
21 (1967).
[19] K. Morita. S. Kobayashi. H. Shimadzu. and
M. Ochiai. Tetrahedron Lett. 1970, 861.
[20] H. Yamamoto. M. Nakata. S. Morosawa. and A. Yokoo. Bull. Chem. Soc. Jpn. 44, 153 (1971).
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