5',6',7',8'-Tetrahydro-1'H,3'H-spiro[cyclohexane-1,2'-quinazolin]-4'-one in Mannich reaction

Article abstract of DOI:10.1007/s10593-012-1078-z

The Mannich aminomethylation of 5',6',7,'8'-tetrahydro-1'H,3'H- spiro[cyclohexane-1,2'-quinazolin]-4'-one leads to formation of a heterocyclic system containing an annelated azabicyclic fragment. Hydrolysis of the indicated spirans gives 3-azabicyclo[3.3.1]nonanes.

Full text of DOI:10.1007/s10593-012-1078-z

Chemistry of Heterocyclic Compounds, Vol. 48, No. 6, September, 2012 (Russian Original Vol. 48, No. 6, June, 2012)
5',6',7',8'-TETRAHYDRO-1'H,3'H-SPIRO[CYCLOHEXANE-
1,2'-QUINAZOLIN]-4'-ONE IN MANNICH REACTION
V. I. Markov1 and O. K. Farat1*
The Mannich aminomethylation of 5',6',7,'8'-tetrahydro-1'H,3'H-spiro[cyclohexane-1,2'-quinazolin]-
4'-one leads to formation of a heterocyclic system containing an annelated azabicyclic fragment.
Hydrolysis of the indicated spirans gives 3-azabicyclo[3.3.1]nonanes.
Keywords: alkaloids, 3-azabicyclo[3.3.1]nonane, cage amines, quinazolin-4(3H)-ones, Mannich reaction.
3-Azabicyclo[3.3.1]nonanes show a variety of biological activity (analgesic, antimicrobial), possess
ganglioblocking and hypotensive properties, and behave as sedative and antipyretic agents [1-2]. In addition, the
special interest in this group of compounds relates to the alkaloids of aconitine series, which also have a
3-azabicyclononane fragment and show high antiarrhythmic activity [2]. It is known that many contemporary
antiarrhythmics used in medical practice have a number of drawbacks, the most significant of which is their
high toxicity and hence a rather narrow field of therapeutic use. Hence there is significant interest in developing
methods for preparing novel polycyclic 3-azabicyclo[3.3.1]nonanes.
Cyclic ketones are key synthons in the preparation of 3-azabicyclo[3.3.1]nonanes and a series of other
biologically active heterocyclic compounds [2-8]. A synthon of this type is 5',6',7',8'-tetrahydro-1'H,3'H-spiro-
[cyclohexane-1,2-quinazolin]-4'-one (1). Only one example has been reported in the literature of the reaction of
compound 1 with formaldehyde and methylamine in ethanol to give the product 2a in 44% yield [9].
We have studied in detail the Mannich aminoalkylation reaction of compound 1 with primary amines
containing different aliphatic and heterocyclic substituents.
R
H
N
N
A. RNH2·HCl, CH2O, MeOH, 
B. RNH2, AcOH, CH2O, rt
N
NH
–H2O
N
H
O
O
1
2a–p
a R = Me, b R = Et, c R = Pr, d R = t-Bu, e R = CH2Ph, f R = CH2CH2Ph, g R = CH(Ph)2,
h R = CH2CH2Br, i R = CH2COOEt, j R = C6H11, k R = C18H37, l R = CH2CH2ОН,
CH2
CH2
m R = CH2CH2CH2ОН, n R =
, o R =
, p R = 3,4-(MeO)2C6H3CH2CH2
O
O
_______
*To whom correspondence should be addressed, e-mail: faratok@mail.ru.
1Ukrainian State Chemical and Technological University, 8 Gagarin Ave., Dnepropetrovsk 49005, Ukraine.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 995-1000, June, 2012. Original
article submitted April 16, 2011; revision submitted October 21, 2011.
0009-3122/12/4806-0925©2012 Springer Science+Business Media New York
925

The aminoalkylation was carried out using different alcohols (methyl, ethyl, isopropyl, and isobutyl).
The best yield was obtained when methanol was used as solvent. In the case of the use of amines containing
3-aminopyridinyl, 4-amino-1,2,4-triazolyl, or 3-amino-1-phenylpyrazolyl heteroaryl fragments the reaction did
not occur under the reported conditions.
1
The structure of the aminoalkylation products was proved by H NMR spectroscopy and by elemental
1
analysis (Tables 1 and 2). The H NMR spectra of compounds 2a-p showed a signal for the NH proton in the
region 8.13-8.15 ppm, which did not contradict the proposed structure.
A more certain proof of the structure of the products obtained was reached through acid hydrolysis of
the derivatives 2a,c,e,j. Hence refluxing of the amine 2a in 50% sulfuric acid gave compound 3. Heating the
amines 2a,c,e,j with a 10% solution of hydrochloric acid gave the carboxamides 4a-d.
R
N
Me
O
N
1. H2SO4, H2O, 
1. HCl, H2O, 
2a
O
2a,c,e,j
2. NaOH, H2O
2. NH3, H2O
NH2
3
O
4a–d
4 а R = Me, b R = Pr, c R = CH2Ph, d R = С6Н11
The structure of the compounds 4a-d obtained was proved by spectroscopic methods (IR, 1H NMR) and
confirmed from elemental analysis data (Tables 1 and 2). The IR spectra of the products showed absorption
bands for the carbonyl and for the carboxamide groups at 1703-1710 and 1648-1663 cm-1, respectively. The
1H NMR spectra showed the two carboxamide group protons at 7.85 ppm.
Derivatives 4a-d were also obtained in good yields by a counter synthesis from the carboxamide 5.
OH
O
CH2O, RNH2
4a–d
O
O
NH2
NH2
5
Based on a single example in the study [9], it was shown that the aminomethylation of compound 1 with
dimethylamine occurs at the 1'-nitrogen atom. We have found that the analogous reaction gives the products of
substitution 6a-f at the C-8' carbon atom.
NR2
H
8'
H
N
N
7'
CH2O, R2NH
MeOH
1'
2'
NH
6'
NH
3'
4'
5'
O
O
1
6a–f
а R = Me, b R = Et, c R = CH2Ph, d R2N =
N
, e R N =
, f R N =
O
2
N
2
N
1
The structures of compounds 6a-f were confirmed from H NMR spectroscopy and elemental analysis
1
(Tables 1 and 2). The H NMR spectra showed downfield signals for the two NH group protons to and so
excludes the possibility of this reaction occurring at nitrogen atom.
926

TABLE 1. Physicochemical Characteristics of the Synthesized Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Mp, °С
Yield*, %
С
H
N
С17Н27N3O
70.63
70.55
71.33
71.25
71.93
71.88
75.25
75.18
75.65
75.58
78.69
78.65
55.53
55.44
65.72
65.68
73.51
73.43
77.23
77.14
66.93
66.85
67.74
67.68
69.64
69.53
70.27
70.35
70.65
70.56
61.31
61.20
64.20
64.26
71.02
70.56
68.25
68.15
69.19
69.28
70.85
70.78
78.37
78.28
71.95
71.88
67.75
67.68
9.48
9.40
9.70
9.63
9.91
9.84
8.37
8.32
8.60
8.55
7.82
7.78
7.21
7.12
8.45
8.41
9.74
9.68
11.67
11.57
9.01
8.91
9.21
9.15
9.15
9.04
7.84
7.97
8.33
8.29
8.27
8.22
8.90
8.99
7.53
7.40
9.19
9.15
9.74
9.81
10.32
10.23
8.32
8.21
9.90
9.84
9.21
9.15
14.59
14.52
13.90
13.85
13.33
13.24
12.03
11.95
11.58
11.50
9.91
9.83
11.57
11.41
12.15
12.09
12.27
12.23
8.23
8.18
13.85
13.76
13.20
13.15
12.23
12.16
12.25
12.31
9.82
9.87
14.35
14.27
12.41
12.49
10.36
10.29
10.67
10.60
15.10
15.15
13.81
13.76
9.85
9.78
13.30
13.24
13.10
13.15
160-162
135-136
115-118
163-164
172-173
187-188
125-128
175-179
172-174
78-80
67
70
36
87
55
31
50
30
74
46
33
47
35
38
74
57
51
68
53
72
64
47
70
35
37
2b
2c
2d
2e
2f
С18Н29N3О
С19Н31N3O
С22Н29N3O
С23Н31N3O
С28Н33N3O
С17Н26BrN3O
С19Н29N3O3
С21Н33N3O
С33Н59N3O
С17Н27N3O2
С18Н29N3O2
С20Н31N3O2
С20Н27N3O2
С25Н35N3O3
С10Н16N2O2
С12Н20N2O2
С16Н20N2O2
С15Н24N2O2
С16Н27N3O
С18Н31N3O
С28Н35N3O
С19Н31N3O
С18Н29N3O2
С23Н31N3O
2g
2h
2i
2j
2k
2l
137-140
125-128
143-147
172-175
142-145
210-211
210-215
158-160
143-145
162-165
147-150
105-108
220-224
260-263
163-165
2m
2n
2o
2p
4а
4b
4c
4d
6а
6b
6c
6d
6e
6f
75.60
75.58
8.63
8.55
11.60
11.50
_______
* Yield of compounds 2b-p and 4a-d by the method A.
Hence examples of an efficient strategy for using the Mannich reaction in a targeted synthesis of
potentially biologically active 3-azabicyclo[3.3.1]nonanes and analogs of natural compounds have been
described. It was also shown that the reaction of 5',6',7',8'-tetrahydro-1'H,3'H-spiro[cyclohexane-1,2'-quin-
azolin]-4'-one with secondary amines under Mannich conditions occurs at a carbon atom rather than the nitrogen
atom indicated previously.
927

TABLE 2. 1H NMR Spectra of the Synthesized Compounds
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
0.95 (3Н, t, J = 6.8, СН3); 1.21-3.21 (23H, m, 11СН2, 8'-CH); 8.15 (1Н, s, NH)
0.93 (3Н, t, J = 6.8, СН3); 1.05-3.23 (25H, m, 12CН2, 8'-CH); 8.14 (1Н, s, NH)
0.91 (9Н, s, 3СН3); 1.05-3.22 (21H, m, 10СН2, 8'-CH); 8.15 (1Н, s, NH)
1.05-3.65 (23H, m, 11СН2, 8'-CH); 7.33-7.51 (5Н, m, H Ph); 8.15 (1Н, s, NH)
1.00-3.25 (25Н, m, 12CН2, 8'-CH); 7.11-7.46 (5Н, m, H Ph); 8.15 (1Н, s, NH)
1.00-3.25 (22Н, m, 10CН2, 2CH); 7.52-7.83 (10Н, m, H Ph); 8.13 (1Н, s, NH)
1.00-3.51 (25Н, m, 12CН2, 8'-CH); 8.15 (1Н, s, NH)
2b
2c
2d
2e
2f
2g
2h
2i
0.94 (3Н, t, J = 7.0, CH2СН3); 1.22-3.25 (23H, m, 11СН2, 8'-CH);
4.23 (2Н, q, J = 7.0, СН2СН3); 8.15 (1Н, s, NH)
1.20-3.18 (32Н, m, 15CН2, 2CH); 8.15 (1Н, s, NH)
2j
0.95-3.21 (58Н, m, CH3, 27CН2, 8'-CH); 8.14 (1Н, s, NH)
1.10-3.25 (25H, m, 12СН2, 8'-CH); 4.72 (1Н, s, ОН); 8.15 (1Н, s, NH)
1.07-3.15 (27H, m, 13СН2, 8'-CH); 4.81 (1Н, s, ОН); 8.15 (1Н, s, NH)
2k
2l
2m
2n
1.10-3.19 (27H, m, 13СН2, 8'-CH); 3.73 (2Н, m, OCHСН2);
4.03 (1Н, t, J = 7.1, OCHCH2); 8.15 (1Н, s, NH)
1.10-3.19 (23H, m, 11СН2, 8'-CH); 6.06 (1Н, d, J = 6.7, H-3''); 6.25 (1Н, t, J = 7.0, H-4'');
7.32 (1Н, d, J = 7.1, H-5''); 8.14 (1Н, s, NH)
2o
2p
1.10-3.24 (25H, m, 12СН2, 8'-CH); 3.73 (6Н, s, 2ОСН3); 6.52-6.61 (3Н, m, H Ar);
8.15 (1Н, s, NH)
4а*
4b*
4c*
4d*
6а
1.50-2.60 (11Н, m, 5CН2, 5-CH); 2.27 (3Н, s, СН3); 7.85 (2Н, s, NH2)
0.95 (3Н, s, СН3); 1.21-2.58 (15Н, m, 7CН2, 5-CH); 7.85 (2Н, s, NH2)
1.50-2.60 (13Н, m, 6CН2, 5-CH); 7.21-7.63 (5Н, m, H Ph); 7.85 (2Н, s, NH2)
1.20-2.74 (22Н, m, 10CН2, 2CH); 7.85 (2Н, s, NH2)
0.95-2.60 (19Н, m, 9СН2, 8-CH); 2.27 (6Н, s, 2СН3); 6.70 (1Н, s, NH); 7.73 (1Н, s, NH)
1.00 (6Н, s, 2СН3); 1.22-2.65 (23Н, m, 11СН2, 8-CH); 6.70 (1Н, s, NH); 7.72 (1Н, s, NH)
6b
1.20-2.65 (23Н, m, 11СН2, 8-CH); 6.71 (1Н, s, NH); 7.06-7.14 (10Н, m, H Ph);
7.73 (1Н, s, NH)
6c
1.00-2.60 (29Н, m, 14СН2, 8-CH); 6.70 (1Н, s, NH); 7.73 (1Н, s, NH)
1.00-2.60 (27Н, m, 13СН2, 8-CH); 6.70 (1Н, s, NH); 7.72 (1Н, s, NH)
6d
6e
6f
1.00-2.48 (25Н, m, 12СН2, 8-CH); 6.70 (1Н, s, NH); 6.54-6.94 (4Н, m, H Ar);
7.73 (1Н, s, NH)
_______
* IR spectra of compounds 4 (, cm-1): a 1703, 1663; b 1705, 1648; c 1710,
1654; d 1710, 1650.
EXPERIMENTAL
IR spectra were recorded on a Bruker ALPHA FT-IR spectrometer in the ATR mode for KBr pellets. 1H
NMR spectra were recorded on a Varian VXR 200 instrument (200 MHz) using DMSO-d6 with TMS as internal
standard. The purity of the prepared compounds was established using TLC on Merck 60 F254 plates in the
system chloroform–ethyl acetate (10:1).
The spiro compound 1 was prepared from cyclohexanone and urea with azeotropic distillation of water
using toluene [10-11]. Compound 2a was prepared in methanol using method [9] in 60% yield, and the
carboxamide 5 was obtained by acid hydrolysis of the spirane 1 [12].
5',6',7',8'-Tetrahydro-4a',8'-(2-ethyl-2-azapropano)-3'H-spiro[cyclohexane-1,2'-quinazolin]-4'-one
(2b). A. Compound 1 (2.200 g, 0.01 mol) and a 36% formalin solution (1.6 ml) were added to a solution of
EtNH2·HCl (0.815 g, 0.01 mol) in MeOH (10 ml) and refluxed on a water bath for 40 min. Solvent was distilled
off under reduced pressure, and the residue was dissolved in water, filtered, and treated with 10% ammonia
solution. The precipitated compound 2b was filtered off, washed with water, and recrystallized from a mixture
of water and methanol. Yield 1.940 g (67%).
928

Compounds 2c-f,h-k,n-p were obtained similarly (in the case of compound 2g using the amine
hydrobromide). Compounds 2l,m were obtained from the corresponding free amine with addition of an
equivalent amount of HCl solution. After the completion of the process, the reaction mixture was neutralized
and extracted with dichloromethane (310 ml). The combined extracts were washed with water, dried over
MgSO4, and the solvent was distilled off. The oil obtained was triturated with hexane.
B. A mixture of 70% aqueous EtNH2 (0.65 g, 0.01 mol) and glacial acetic acid (3 ml) was cooled in an
ice bath, and there were added in sequence formalin solution (36%, 1.6 ml, 0.02 mol) and compound 1 (2.20 g,
0.01 mol) at 5ºC. The reaction mixture was maintained for 1 day at 20ºC. Then the reaction mixture was
neutralized with 10% KOH aqueous solution in the cold. The oily compound 2b rapidly crystallized and was
recrystallized from a mixture of water and methanol. Yield 1.73 g (60%).
Compounds 2c,f,i,j,n-p were prepared similarly in the following yields: 2c 59%, 2f 51%, 2i 33%, 2j
63%, 2n 41%, 2o 58%, and 2p 72%.
3-Methyl-3-azabicyclo[3.3.1]nonan-9-one (3). Compound 2a (2.75 g, 0.01 mol) was dissolved in a
50% aqueous H2SO4 solution (15 ml) and gently refluxed for 5 h. The cooled solution was filtered and extracted
with diethyl ether (110 ml). The aqueous layer was basified using a 40% aqueous NaOH solution to pH 8-9
and extracted with chloroform (310 ml). The obtained extract was washed with saturated NaCl solution and
then water, and dried over CaCl2. Removal of solvent by distillation gave the product 3 as a light-yellow oil,
1
which was distilled in vacuo at 85ºC (2 mm Hg). H NMR spectrum, , ppm: 1.21-2.33 (10H, m, 5CH2); 2.25
(3H, s, NCH3); 2.68-2.80 (2H, m, 2CH). Found, %: C 70.49; H 9.83; N 9.10. C9H15NO. Calculated, %: C 70.55;
H 9.87; N 9.14.
Reaction of compound 3 with 2,4-dinitrophenylhydrazine gave the corresponding hydrazone. Yield
0.69 g (45%); mp 178-180ºC (mp 178ºC [13]).
3-Methyl-9-oxo-3-azabicyclo[3.3.1]nonane-1-carboxamide (4a). A. Compound 2a (2.75 g, 0.01 mol)
was dissolved in a 10% aqueous HCl solution (10 ml). The solution was placed in a Wurtz flask and heated until
azeotropic distillation of cyclohexanone ceased. The cooled aqueous solution was treated with ammonia
solution and extracted with CH2Cl2 (310 ml). The extract was washed with water and dried over MgSO4.
Solvent was distilled off and light petroleum ether was added to the oily compound 4a obtained. The mixture
was brought to reflux with vigorous stirring, and then it crystallized. Yield 1.12 g (57%). It was purified by
recrystallization from hexanes.
The derivatives 4b-d were prepared similarly. At the end of the reactions, the mixtures were neutralized.
The precipitated solid products were collected by filtration and purified by recrystallization from water–
methanol. A greater degree of purification was achieved by conversion of these compounds to their perchlorates
with subsequent recrystallization from a water–DMF mixture and isolation of the free amines.
B. A mixture of compound 5 (1.41 g, 0.01 mol), 40% aqueous MeNH2 solution (0.78 g), and a 36%
formalin solution (1.6 ml, 0.02 mol) in AcOH (5 ml) was left for 1 day. Then the mixture was neutralized using
a saturated K2CO3 solution. Subsequent workup and purification was carried out by the same procedure
described in method A. Yield 1.05 g (54%).
Compounds 4b-d were prepared similarly. Workup and purification of the compounds were carried out
as described in method A. The yields were: 4b 75%, 4c 48%, 4d 57%.
8'-(N,N-Dimethylaminomethyl)-5',6',7',8'-tetrahydro-1'H,3'H-spiro[cyclohexane-1,2'-quinazolin]-
4'-one (6a). A 36% formalin solution (0.8 ml) and compound 1 (2.203 g, 0.01 mol) were added to Me2NH·HCl
(0.815 g, 0.01 mol) in MeOH (10 ml). The mixture was refluxed on a water bath for 2 h. The reaction mixture
was then cooled and poured into a solution of ammonia and ice. Compound 6a (2.000 g, 72%) was filtered off
and recrystallized from H2O–MeOH,
Compounds 6b-f were prepared similarly.
929

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