Stereoselective synthesis of spirofused 3-substituted 2,3,4,4a,5,6- hexahydro-6H-benzo[c]quinolizine using the tert-amino effect

Article abstract of DOI:10.1070/MC2006v016n02ABEH002247

The interaction of 2-(4-R-piperidino)benzaldehyde and cyclic CH-active compounds occurred as a tandem of Kn?venagel condensation and cyclization by tert-amino effect and led to spiro-fused 3-substituted 2,3,4,4a,5,6- hexahydro-6H-benzo[c]quinolizine.

Full text of DOI:10.1070/MC2006v016n02ABEH002247

, 2006, 16(2), 82–83
Stereoselective synthesis of spirofused 3-substituted 2,3,4,4a,5,6-hexahydro-
6H-benzo[c]quinolizine using the tert-amino effect
Elisaveta V. Deeva,a Tatiana V. Glukhareva,a Alexey V. Tkachevb and Yury Yu. Morzherin*a
a Department of Technology of Organic Synthesis, Urals State Technical University, 620002 Ekaterinburg, Russian Federation.
Fax: +7 343 374 5483; e-mail: morjerine@htf.ustu.ru
b N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences,
630090 Novosibirsk, Russian Federation. E-mail: atkachev@nioch.nsc.ru
DOI: 10.1070/MC2006v016n02ABEH002247
The interaction of 2-(4-R-piperidino)benzaldehyde and cyclic CH-active compounds occurred as a tandem of Knövenagel condensa-
tion and cyclization by tert-amino effect and led to spiro-fused 3-substituted 2,3,4,4a,5,6-hexahydro-6H-benzo[c]quinolizine.
New strategies for the stereoselective synthesis of nitrogen-
CN
CN
containing heterocycles are of interest in organic chemistry, and
CHO
various methods have been proposed.1–3 The α-cyclization of
CN
CN
∆
∆
BuOH
N
N
toluene
X
X
Ph
Ph
CN
Ph
CHO
N
O
O
1
4
O
O
X
X
∆
CN
CN
H
toluene
CN
Ph
N
N
N
1
2a,b
H
Ph
Ph
H
H
5
6
Scheme 2
tertiary amines is a mechanistically intriguing and synthetically
useful cyclization.4 Meth-Cohn and Suschitzky5 have coined the
term ‘tertiary amine effect’ to describe such processes, which have
been further developed by Verboom and Reinhoudt.6 The use of
the tert-amino effect for preparation of pyrido-fused ring systems
has been well documented.7,8 The stereochemical studies on
the cyclization of derivatives of type 1 substituted at the atom
adjacent to the nitrogen of tert-amine moieties revealed high
regio- and stereoselectivity of the reaction.9 We found that in
the case when substituted at the β-carbon of cyclic amino group
X
X
X
X
X
X
O
XX
O
O
O
N
N
H
H
H
Ph
a X = O
b X = CH2
Ph
Scheme 1
H
3a,b
82 Mendeleev Commun. 2006

, 2006, 16(2), 82–83
the reaction is also stereoselective.10 Here, we report a stereo-
selective reaction of 2-(4-phenylpiperidino)benzaldehyde 1†
and cyclic CH-active compounds 2a,b, which led to a single
isomer‡ with an axiality hydrogen in the 3- and 4a-positions of
benzo[c]quinolizine (Scheme 1). The structures of 3a,b were
determined by 2D correlation NMR spectroscopy (DEPT,
COSY, HETCOR) and ax-eq coupling constants.
In contrast to the cyclization of 1 with 2a,b, the reaction of 1
and malononitrile led to benzylidene malononitrile 5, similarly
to published data.9 The cyclization of 4§ led to a mixture¶ of
two isomers 5 and 6 in a ratio of 1:1 (Scheme 2).
References
1
2
A. Domling, Chem. Rev., 2006, 106, 17.
E. Garcia, S. Arrasate, E. Lete and N. Sotomayor, J. Org. Chem., 2005,
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3
4
K. Tatsuta and S. Hosokawa, Chem. Rev., 2005, 105, 4707.
N. Kaval, B. Halasz-Dajka, G. Vo-Thanh, W. Dehaen, J. Van der Eycken,
P. Mátyus, A. Loupyc and E. Van der Eycken, Tetrahedron, 2005, 61,
9052.
5
6
7
8
9
O. Melh-Cohn and H. Suschitzky, Adv. Heterocycl. Chem., 1972, 14,
211.
W. Verboom and D. N. Reinhoudt, Recl. Trav. Chim. Pays-Bas, 1990,
109, 311.
O. Elias, L. Karolyhazy, G. Horvath, V. Harmat and P. Mtyus, J.
Molecular Structure (Theochem), 2003, 666–667, 625.
A. V. Tverdokhlebov, A. P. Gorulya, A. A. Tolmachev, A. N. Kostyuk,
A. N. Chernega and E. B. Rusanov, Synthesis, 2005, 37, 2161.
W. H. N. Nijhuis, W. Verboom, D. N. Reinhoudt and S. Harkema, J. Am.
Chem. Soc., 1987, 109, 3136.
Our present results indicate that the cyclization of benzal-
dehyde 1 and CH-active compounds occurred stereoselectively
for reaction with cyclic CH-active compounds but not for one
of malononitrile.
†
4-Phenylpiperidine (0.160 mg, 0.988 mmol) and potassium carbonate
10 E. V. Deeva, T. V. Glukhareva, N. A. Zybina and Yu. Yu. Morzherin,
Izv. Akad. Nauk, Ser. Khim., 2005, 1492 (Russ. Chem Bull., Int. Ed.,
2005, 54, 1537).
(0.138 g, 0.988 mmol) were added to a solution of 2-fluorobenzaldehyde
(0.118 g, 0.949 mmol) in DMF (1.0 ml). The reaction mixture was refluxed
in a glycerol bath at 150 °C for 20 h. The completion of the reaction was
judged from TLC. The reaction mixture was cooled to ~20 °C, water
(15 ml) was added, and the product was extracted with ethyl acetate
(3×20 ml). The combined organic extract was washed with a solution of
ammonium chloride. The organic layer was dried with Na2SO4, and the
solvent was removed in vacuo. Data for 1: 2-(4-phenylpiperidino)-
benzaldehyde. Yield, 75%; mp 122 °C. 1H NMR ([2H6]DMSO) d:
10.26 (s, 1H, CHO), 7.70 (dd, 1H, HAr, J 7.7 and 1.7 Hz), 7.61 (ddd, 1H,
HAr, J 8.3, 8.5 and 1.7 Hz), 7.30–7.33 (m, 4H, HAr), 7.25 (d, 1H, HAr
J 8.3 Hz), 7.21 (ddd, 1H, HAr, J 7.7, 7.0 and 4.7 Hz), 7.14 (dd, 1H, HAr
,
,
J 7.7 and 8.5 Hz), 3.32–3.38 (m, 2H, 2NCH), 3.01 (ddd, 2H, 2NCH,
J 11.9, 11.8 and 2.9 Hz), 2.64–2.74 (m, 1H, CH), 1.87–1.99 (m, 4H,
2CH2). 13C NMR ([2H6]DMSO) d: 33.09 (CH2), 41.28 (CH2Ph), 54.64
(NCH2), 119.33 (ArH), 121.90 (ArH), 126.10 (Ph), 126.74 (Ph), 127.86
(Ph), 128.34 (Ph), 128.97 (ArH), 135.07 (ArH), 145.82 (Ar), 155.86
(Ar), 190.80 (CHO). MS, m/z: 265 (M+). Found (%): N, 5.15. Calc. for
C18H19NO (%): N, 5.28.
‡
Meldrum’s acid (or dimedone) (2.3 mmol) was added to a solution of
benzaldehyde 1 (0.608 g, 2.3 mmol) in toluene (20 ml). The reaction
mixture was refluxed for 3 h. The completion of the reaction was deter-
mined by TLC. The reaction mixture was cooled to ~20 °C and con-
centrated in vacuo. The residue was triturated with ethanol.
3-Phenyl-2',2'-dimethyl-2,3,4,4a,5,6-hexahydro-6H-spiro(benzo[c]-
quinolizine-5,5'-[1,3]dioxane)-4',6'-dione 3a. Yield, 80%; mp 240 °C.
1H NMR (CDCl3) d: 7.27 (dd, 2H, HPh, J 7.4 and 7.4 Hz), 7.19 (tt, 1H,
HPh, J 7.4 and 1.9 Hz), 7.15 (ddd, 1H, HAr, J 8.2, 6.9 and 1.3 Hz),
7.09–7.12 (m, 2H, HAr), 6.97 (d, 1H, HAr, J 7.3 Hz), 6.93 (d, 1H, HAr
,
J 8.3 Hz), 6.74 (ddd, 1H, HAr, J 7.4, 7.4 and 1.0 Hz), 4.10 [ddd, 1H,
CH(1), J 12.8, 4.6 and 2.6 Hz], 3.52 [d, 1H, CH(6), J 16.4 Hz], 3.43 [dd,
1H, CH(4a), J 11.8 and 2.4 Hz], 3.11 [d, 1H, CH(6), J 16.4 Hz], 2.72
[ddd, 1H, CH(1), J 12.8, 12.8 and 2.6 Hz], 2.60 [dd, 1H, CH(4), J 13.7
and 6.0 Hz], 2.50 [dd, 1H, CH(3), J 13.7 and 7.8 Hz], 1.76 (s, 3H, Me),
1.75 (s, 3H, Me), 1.72–1.78 [m, 1H, CH(4)], 1.36 [ddd, 1H, CH(2),
J 12.8, 12.8 and 4.6 Hz], 1.15 [ddd, 1H, H(2), J 12.8, 12.8 and 12.8 Hz].
13C NMR (CDCl3) d: 169.28 (CO), 164.78 (CO), 144.60 (Ar), 139.46
(Ar), 129.06 (ArH), 128.71 (ArH), 128.37 (ArH), 127.67 (ArH), 126.23
(ArH), 119.50 (Ar), 118.49 (ArH), 113.52 (ArH), 61.24 (C4a), 52.21
(OCO), 48.27 (C1), 43.00 (C5), 37.63 (C3), 34.72 (C6), 34.56 (C4), 30.62
(C2), 30.28 (Me), 28.20 (Me). MS, m/z: 391 (M+). Found (%): N, 3.58.
Calc. for C24H25NO4 (%): N, 3.58.
Received: 3rd October 2005; Com. 05/2585
§
2-[2-(4-Phenylpiperidino)benzylidene]malononitrile 4. Yield, 85%;
mp 116 °C. 1H NMR ([2H6]DMSO) d: 8.26 (s, 1H, CH=), 7.98 (dd, 1H,
HAr, J 8.1 and 1.2 Hz), 7.58 (ddd, 1H, HAr, J 8.4, 7.4 and 1.2 Hz),
7.00–7.30 (m, 7H, HAr), 3.20–3.26 (m, 2H, 2NCH), 2.94–3.06 (m, 2H,
2NCH), 2.60–2.70 (m, 1H, CH), 1.90–2.08 (m, 4H, 2CH2). 13C NMR
([2H6]DMSO) d: 33.07 (CH2), 41.26 (CH2Ph), 54.22 (NCH2), 81.10
(C=), 113.32 (CN), 114.51 (CN), 119.58 (ArH), 122.18 (ArH), 124.37
(Ph), 126.13 (Ph), 126.76 (Ph), 128.34 (Ph), 129.00 (ArH), 134.84 (ArH),
145.75 (Ar), 154.59 (Ar), 158.34 (C=). MS, m/z: 313 (M+). Found (%):
N, 13.51. Calc. for C21H19N3 (%): N, 13.41.
3-Phenyl-5',5'-dimethyl-2,3,4,4a,5,6-hexahydro-6H-spiro(benzo[c]-
quinolizine-5,2'-cyclohexane)-1',3'-dione 3b. Yield, 68%; mp 230 °C.
1H NMR ([2H6]DMSO) d: 7.23 (dd, 2H, HPh, J 7.6 and 7.6 Hz), 7.16 (tt,
1H, HPh, J 7.6 and 1.3 Hz), 7.07 (d, 1H, HAr, J 7.6 Hz), 7.05–7.10 (m,
¶
A solution of vinyl compound 4 (0.225 g, 0.72 mmol) in BuOH (10 ml)
was heated at 100 °C for 3 h and then filtered with charcoal. The solvent
was evaporated, and the residue was recrystallised from ethyl acetate.
A mixture of 3-phenyl-2,3,4,4a,5,6-hexahydro-6H-benzo[c]quinolizine-
5,5-dicarbonitriles 5, 6: Yield, 91%; mp 115 °C. 1H NMR ([2H6]DMSO)
d: two isomers 6.90–7.40 (m, 7H, HAr), 6.78 (d, 1H, HAr, J 7.0 Hz),
6.74 (dd, 1H, HAr, J 7.0 and 7.0 Hz), 4.18 (d, 0.5H, CH, J 12.5 Hz),
3.50–3.90 (m, 3.5H, CH), 3.35–3.40 (m, 1H, CH), 2.80–3.12 (m,
1H, CH), 2.58–2.65 (m, 1H, CH), 2.10–2.38 (m, 3H, CH). 13C NMR
([2H6]DMSO) d: 144.37, 142.39, 129.13, 128.58, 127.37, 126.62, 126.12,
118.75, 116.59, 115.21, 114.69, 113.89, 54.44, 43.52, 36.41, 35.34, 33.71,
32.99, 28.49, isomer 144.47, 143.78, 129.35, 129.12, 128.62, 128.40,
126.55, 118.89, 116.59, 115.18, 114.46, 114.03, 58.10, 47.45, 36.51,
35.78, 34.78, 34.13, 31.24. MS, m/z: 313 (M+). Found (%): N, 13.19.
Calc. for C21H19N3 (%): N, 13.41.
2H, HAr), 7.00 (ddd, 1H, HAr, J 7.9, 7.2 and 1.3 Hz), 6.86 (d, 1H, HAr
,
J 7.9 Hz), 6.66 (ddd, 1H, HAr, J 7.3, 7.4 and 1.0 Hz), 4.59 [dd, 1H,
CH(1), J 12.2 and 3.1 Hz], 4.13 [d, 1H, CH(4a), J 14.5 Hz], 3.48 [d, 1H,
CH(6), J 13.3 Hz], 3.11–3.32 (m, 3H, 3CH), 3.11 [d, 1H, CH(6),
J 13.3 Hz], 2.64 [d, 1H, CH(4'), J 16.9 Hz], 2.27 (dd, 1H, CH, J 13.8 and
2.1 Hz), 2.14 (dd, 1H, CH, J 13.8 and 2.1 Hz), 1.47–1.59 (m, 2H, 2CH),
1.18–1.23 (m, 2H, 2CH), 1.23 (s, 3H, Me), 0.68 (s, 3H, Me). 13C NMR
([2H6]DMSO) d: 205.99 (CO), 205.01 (CO), 145.22 (Ar), 141.67 (Ar),
129.32 (ArH), 128.37 (ArH), 126.45 (ArH), 125.37 (ArH), 126.15 (ArH),
122.32 (Ar), 117.66 (ArH), 113.22 (ArH), 67.32 (C4a), 60.09 (C1), 50.83
(C5), 49.09 (C4'), 48.09 (C6'), 42.11 (C5'), 31.14 (C3), 30.69 (C6), 29.46
(C4), 27.91 (C5), 26.18 (Me), 23.56 (Me). MS, m/z: 387 (M+). Found (%):
N, 3.47. Calc. for C26H29NO2 (%): N, 3.61.
Mendeleev Commun. 2006 83