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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. 43b, 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 5a 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-diben-zo[b,eJ[l,4]-diazepin-l-one, involving a Mannich type cyclization of 3-(o-aminoanilino)-5,5-dimethyl-2-cyclohexen-l-one with formaldehyde. The only re-ported 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 cyclohex-an-l,3-diones [4, 5]. Its 'H NMR spectrum features a singlet at d 5.56 (vinyl H-2) and the 13C NMR spec-trum 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 structur-al 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 prod-uct.

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 0932 - 0776/88/0400 - 0483/$ 01.00/0

molar ratio of 1:1:2 gave hexahydro-7,7-dimethyl-l-phenylquinazolin-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-cyclo-hexen-l-one. In addition, when 1 was subjected to a double Mannich reaction using ethylenediamine it afforded the 3.3'-ethylenebis-(hexahydro-7,7-di-methyl-l-phenylquinazolin-5(6H)-one) (6). In par-ticular, the 13C NMR spectrum of 5 a displays five singlet peaks due to C-5, C-4a, C-8a, C-7 and substi-tuted 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 substi-tuted 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 hexa-hydro-quinazolin-5-one (5a) is a reasonable and at-tractive intermediate in the synthesis directed to-wards 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

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 for-mation of homocarbostyril [14] and tetrahydro-1-benzazocin-2-one [15] from a-tetralone and benz-suberanone, respectively. Reduction of 9 with lithium aluminium hydride afforded octahydro-8,8-dimethyl-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-7H-pyrimido[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-dimethyl-2-cyclohexen-l-one.

Experimental All melting points (°C) are uncorrected and were

taken in a Gallenkamp electric melting point ap-paratus. IR spectra were performed on a Unicam SP 2000 Infrared Spectrophotometer using KBr.

10

W. S. Hamama et al. • Mannich Reaction with 5,5-Dimethyl-3-phenylamino-2-cyclohexen-l-one 485

'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-phenyl-anilino-2-cyclohexen-l-one (2); 5,5-dimethyl-2-(N-piperidinomethyl)-3-phenyl-anilino-2-cyclohexen-l-one (3) and N,N' -bis(5,5-dimethyl-3-phenylanilino-2-cyclohexen-1 -one-2-ylmethyl)piperazine (4)

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 tem-perature. 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 H 8.34 N 8.91, Found C 72.41 H 8.22 N 8.73.

Compound 3, 78% yield (0.73 g), m.p. 125 °C.

C20H28N2O (312.44) Calcd C 76.88 H 9.03 N 8.97, Found C 76.59 H 9 . l l N 8.78.

Compound 4, 70% yield (0.57 g), m.p. 220 °C. 'H NMR (CDC1,): Ö 1.03 [s, 6H, Me], 2.17 [s ,4H.

2(6-H2)], 2.25 [s, 4H, 2(4-H2)], 2.45 (s, 8H, C H 2 - C H 2 of piperazine), 2.5 (broad s, 1 H, NH), 3.5 (s, 4H, C H 2 - N of side chains) and 7.2 (m, 10H, aromatic protons).

C34H44N402 (540.72) Calcd C 75.52 H 8.20 N 10.36, Found C 75.39 H 8.08 N 10.29.

1,2,3,4,7,8-Hexahydro-7,7-dimethyl-l-phenyl-quinazolin-5(6H)-one (5a) and 1,2,3,4,7,8-hexa-hydro-3-benzyl-7,7-dimethyl-l-phenylquinazolin-5(6 H)-one (5b)

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 reac-tion 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.

' H N M R ( CDCU ) : ö 1.01 (s , 6 H , M e ) , 2 . 1 5 (s , 1H, NH), 2.3 (s, 4H, 4-H2 and 6-H2), 2.4 (s, 4H, 2-H2 and 8-H2) and 7.4—7.1 (m, 5H, aromatic pro-tons'); 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 H 7.86 N 10.93, Found C 74.78 H 7.99 N 10.81.

Compound 5b, 68% yield (0.71 g), m.p. 187 °C. 'H NMR (CDCI3): (3 1.0 (s, 6H, Me), 2.33 (s, 4H,

4-H2 and 6-H2), 2.45 (broad s, 4H, 2-H : and 8-H :), 3.57 (s, 2H, "benzylic CH2) and 7 .1 -7 .4 (m, 10H, aromatic protons).

C23H26N20 (346.46) Calcd C 79.72 H 7.57 N 8.09, Found C 79.56 H 7.65 N 8.00.

3,3'-Ethylenebis-[1,2,3,4,7,8-hexahydro-7,7-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), ethyl-enediamine diacetate (0.27 g; 0.0015 mol) and 40% formalin (0.2 g; 0.006 mol). The product was crystal-lized from methanol to give 6,77% yield (0.62 g), m.p. 198 °C. CuH42N402 (538.71)

Calcd C 75.80 H 7.86 N 10.40, Found C 75.64 H 7.78 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 fol-lowed 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 H 6.64 N 15.37, Found C 68.95 H 6.56 N 15.23.

Schmidt reaction on 4 and 5 a: Formation of 8 and 9 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), fol-lowed 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 wa-ter, basified with ammonia (40%) and extracted with ether. The ethereal solution was dried on (Na2S04) and evaporated to give a solid product which was

486 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 H 8.12 N 14.73, Found C 71.43 H 8.03 N 14.56.

Compound 9, m.p. 132 °C.

Ci6HvNIO (271.35) Calcd C 70.82 H 7.80 N 15.49, Found C 70.62 H 7.93 N 15.31.

1,2,3,4,5,6,7,8-Octahydro-8,8-dimethyl-l-phenyl-9 H-pyrimido-/5,4-b/azepine (10)

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%) NaOH solution and filtered. The filtrate was evapo-rated, extracted with ether, dried on (K 2C0 3) and evaporated to give a yellow oil. Treating with pet. ether (40—60) gave a white solid which was crystal-lized 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 cm - 1

characteristic of (NH) groups.

Cj6H23N3 (257.36) Calcd C 74.67 H 9.01 N 16.33, Found C 74.59 H 9.11 N 16.30.

1,2,7,8-Tetrahydro-7,7-dimethyl-l-phenvl-4H-[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 wa-ter (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 H 7.44 N 5.44, Found C 74.53 H 7.48 N 5.36.

5,5-Dimethyl-2-hydroxymethyl-3-phenylamino-2-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 ace-tic 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 (OH).

C,5Hl9N02 (245.31) Calcd C 73.44 H 7.81 N 5.71, Found C 73.26 H 7.65 N 5.53.

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