Stereoselective synthesis of new spiro-fused heterocyclic systems, 2,3,4,4a,5.6-hexahydro-6H-spiro[benzo[c]quinolizine-5,4′-pyrazol] -5′-ones

Article abstract of DOI:10.1007/s10593-007-0011-3

The synthesis of 2,3,4,4a,5,6-hexahydro-6H-spiro[benzo[c]quinolizine-5, 4′-pyrazol]-5′-ones has been achieved by the reaction of 2-piperidinobenzaldehydes with 2-aryl-5-methyl-2,4-dihydropyrazol-3-one via the "tert-amino effect" mechanism.

Full text of DOI:10.1007/s10593-007-0011-3

Chemistry of Heterocyclic Compounds, Vol. 43, No. 1, 2007
STEREOSELECTIVE SYNTHESIS OF NEW SPIRO-FUSED
HETEROCYCLIC SYSTEMS, 2,3,4,4a,5.6-HEXAHYDRO-6H-
SPIRO[BENZO[c]QUINOLIZINE-5,4'-PYRAZOL]-5'-ONES
T. V. Glukhareva, P. E. Kropotina, M. F. Kosterina, Yu. I. Nein,
E. V. Deeva, and Yu. Yu. Morzherin
The synthesis of 2,3,4,4a,5,6-hexahydro-6H-spiro[benzo[c]quinolizine-5,4'-pyrazol]-5'-ones has been
achieved by the reaction of 2-piperidinobenzaldehydes with 2-aryl-5-methyl-2,4-dihydropyrazol-3-one
via the "tert-amino effect" mechanism.
Keywords: pyrazol-3-one, spiroheterocycles, quinolizine, tert-amino effect, Knoevenagel condensation.
The term "tert-amino effect" was proposed by Meth-Cohn and Suschitzky [1] for the general reaction of
cyclization of some derivatives of ortho-substituted N,N-dialkylanilines. The cyclization which occurs at the
unsaturated α-carbon atom of the dialkylamino group, was described for compounds with an unsaturated (A=B)
ortho substituent, including at least one heteroatom (nitroso-, azo-, azomethino-, nitro-, amino-, or carbonyl
functions) [2]. Professor Reinhoudt's group established that cyclization also took place with N,N-dialkylanilines
with a vinyl substituent in the ortho position [3]. This reaction is an original method for the formation of a C–C
bond with an unactivated NCH2 group [4].
We have shown previously [5-8] that the Knoevenagel condensation occurs in tandem with cyclization
via the tert-amino effect mechanism when 2-dialkylaminobenzaldehydes react with cyclic CH-active compounds
(derivatives of 1,3-cyclohexandione, Meldrum's acid, barbituric acid) [9]. These reactions were shown to occur
stereoselectively [4, 10-12].
The aim of the current work was to investigate the reaction of 2-piperidinobenzaldehydes 1a-d with 2-
aryl-5-methyl-2,4-dihydropyrazol-3-ones 2a-c. The reactions were carried out in boiling butanol. 3'-Methyl-1'-
phenyl-2,3,4,4a,5,6-hexahydro-6H-spiro[benzo[c]quinolizine-5,4'-pyrazol]-5'-ones 3a-j (Table 1) were formed
as a result. The reaction products contain two asymmetric centers, so it is consequently possible to form two
diastereoisomers. It was shown that the reaction proceeded stereoselectively and led predominantly to a single
diastereomer (up to 95-98%).
1
In the H NMR spectrum of the basic reaction product (Table 2) the signal of the proton on the carbon
atom 4a appears as a doublet of doublets in the 3.13-3.18 ppm region. This proton interacts with a large coupling
constant of 11.2-11.5 Hz with the axial hydrogen in position 4 and with a small coupling constant of 2.3-2.5 Hz
with the equatorial hydrogen in the same position. Hence the hydrogen in position 4a occupies an axial position.
_______
* On the 70th Birthday of Professor E. Lukevics.
__________________________________________________________________________________________
Ural State Technical University, Ekaterinburg 62002, Russia; e-mail: morzherin@htf.ustu.ru. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 90-95, January, 2007. Original article submitted
August 27, 2005.
76
0009-3122/07/4301-0076©2007 Springer Science+Business Media, Inc.

N
R1
O
CHO
N
N
*
R1
+
N
BuOH
4a
R
O
N
*
N
R
4
2a–c
3a–j
1a–d
1 a R = H, b R = Cl-4, c R = Br-5, d R = CF3-5; 2 a R1 = H, b R1 = Cl, c R1 = CO2Et; 3 a-c R = H,
a R1 = H, b R1 = Cl, c R1 = CO2Et; d R = Cl-9, R1 = H, e-g R = Br-8, e R1 = H, f R1 = Cl,
g R1 = CO2Et; h-j R = CF3-8, h R1 = H, i R1 = Cl, j R1 = CO2Et
The signal of the proton in position 4a of the minor isomer is observed as a doublet with J = 10 Hz and is
shifted to weak field in comparison with the proton of the major isomer. It is possible that the proton of the
major isomer falls within the shielding cone of the anisotropic carbonyl group, as a result of which its signal is
shifted to strong field. It is most likely that the oxygen atom of the keto group of the minor product lies in the
axial position.
Thus we have developed a stereoselective method for the synthesis of new heterocyclic system, 1'-aryl-
3'-methyl-2,3,4,4a,5,6-hexahydro-6H-spiro[benzo[c]quinoliizine-5,4'-pyrazol]-5'-one.
TABLE 1. Characteristics of Compounds 3a-j
Found, %
Calculated, %
H
Mass
spectrum,
m/z (I, %)
——————
Com-
pound
Empirical
formula
mp, °С
Yield, %
C
N
3a
3b
3c
3d
3e
3f
C22H23N3O
76.52
76.49
69.85
69.56
72.11
71.92
69.66
69.56
6.79
6.71
6.07
5.84
6.77
6.52
5.98
5.84
5.54
5.23
4.87
4.61
12.25
12.16
11.23
11.06
10.34
10.06
11.38
11.06
10.12
9.90
9.17
9.16
95
122
123
76
345 (100)
85
85
90
87
85
77
C22H22ClN3O
C25H27N3O3
C22H22ClN3O
C22H22BrN3O
381 (31), 379 (100)
417 (98)
381 (38), 379 (100)
425 (100), 423 (97)
62.35
62.27
96
C22H21BrClN3O 57.98
57.60
180
461 (22), 459 (100),
457 (97)
3g
3h
3i
C25H26BrN3O3
C23H22F3N3O
60.67
60.49
66.94
66.82
5.37
5.28
5.52
5.36
5.01
4.73
5.51
5.40
8.77
8.46
10.28
10.16
9.55
9.38
9.02
8.65
113
109
168
97
497 (100), 495 (98)
76
78
82
75
C23H21ClF3N3O 61.78
61.68
C26H26F3N3O3
3j
64.48
64.32
77

78

79

EXPERIMENTAL
The course of reactions and the purity of the compounds synthesized were monitored by TLC on Silufol
UV-254 plates with (1:10) and (1:5) ethyl acetate–hexane eluents. 1H NMR spectra of DMSO-d6 solutions with
TMS as internal standard were recorded with Bruker WM-250 (250 MHz) and Bruker DRX-500 (500 MHz)
spectrometers and mass spectra with a Varian MAT 311A with an ionizing current of 70eV with direct injection
of the sample into the source.
Preparation of 2-Dialkylamino Derivatives of Benzaldehyde 1a-d. (General Method). Piperidine
(15.55 mmol) and potassium carbonate (2.17 g, 15.55 mmol) were added to a solution of the corresponding
2-fluorobenzaldehyde (14.14 mmol) in DMSO (8.0 ml). The mixture was boiled for 5 h and the end of the
reaction was determined by TLC. The reaction mixture was cooled to room temperature, water (75 ml) was
added, and the product was extracted with ethyl acetate (3 × 60 ml). The combined extracts were washed with
ammonium chloride solution. The organic layer was dried over Na2SO4, and the solvent was removed in
vacuum. The products were crystallized from ethanol.
2-Piperidinobenzaldehyde (1a). Yield 87%; mp 95°C. 1H NMR spectrum, δ, ppm (J, Hz): 10.19 (1H, s,
CHO); 7.66 (1H, dd, J = 6.1, J = 1.5, ArH); 7.40-7.55 (1H, m, ArH); 7.00-7.15 (2H, m, ArH); 2.87-3.05 (4H, m,
2CH2); 1.30-1.81 (6H, m, 3CH2). Found, %: C 76.21; H 8.03; N 7.55. C12H15NO. Calculated, %: C 76.16; H
7.99; N 7.40.
1
4-Chloro-2-piperidinobenzaldehyde (1b). Yield 94%, oil. H NMR spectrum, δ, ppm (J, Hz): 10.15
(1H, s, CHO); 7.74 (1H, d, J = 2.5, ArH); 7.61 (2H, dd, J = 9.2, J = 2.3, 2ArH); 7.18 (1H, d, J = 9.2, ArH); 3.00-
3.04 (4H, m, 2CH2); 1.32-1.86 (6H, m, 3CH2). Found, %: C 64.65; H 6.39; N 6.35. C12H14ClNO. Calculated, %:
C 64.43; H 6.31; N 6.26.
1
5-Bromo-2-piperidinobenzaldehyde (1c). Yield 53%; mp 75°C. H NMR spectrum, δ, ppm (J, Hz):
10.10 (1H, s, CHO); 7.72 (1H, d, J = 2.3, ArH); 7.59 (2H, dd, J = 8.8, J =2.8, 2ArH); 7.07 (1H, d, J =8.5, ArH);
3.08 (4H, m, 2CH2); 1.30-1.81 (6H, m, 3CH2). Found, %: C 53.86; H 5.29; N 5.31. C12H14BrNO. Calculated, %:
C 53.75; H 5.26; N 5.22.
1
2-Piperidino-5-trifluoromethylbenzaldehyde (1d). Yield 78%; mp 82°C. H NMR spectrum, δ, ppm
(J, Hz): 10.10 (1H, s, CHO); 7.90 (1H, s, ArH); 7.73 (2H, d, J = 8.6, ArH); 7.25 (1H, d, J = 8.6, ArH); 3.13-3.18
(4H, m, 2CH2); 1.50-1.88 (6H, m, 3CH2). Found, %: C 60.82; H 5.55; N 5.55. C13H14F3NO. Calculated, %: C
60.70; H 5.49; N 5.44.
Preparation
of
1'-Aryl-3'-methyl-2,3,4,4a,5,6-hexahydro-6H-spiro[benzo[c]quinolizine-5,4'-
pyrazole]-5'-ones 3a-j. (General Method). 2-Aryl-5-methyl-2,4-dihydropyrazol-3-one 2a-c (2.3 mmol) was
added to a solution of benzaldehyde 1a-d (2.3 mmol) in butanol (20 ml) and the reaction mixture was boiled for
3 h. The end of the reaction was determined by TLC. The reaction mixture was then cooled to room temperature,
the solvent was evaporated in vacuum and the residue was extracted with ethanol. The physicochemical and
spectroscopic characteristics are cited in Tables 1 and 2.
The authors thank the Fund for the Development of National Science and the President Council of the
Russian Federation (grant MK-1280.2005.3).
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