A new method for the synthesis of α-aryl-substituted pyrrolines and tetrahydropyridines

Full text of DOI:10.1023/A:1021118204730

Doklady Chemistry, Vol. 387, Nos. 1–3, 2002, pp. 289–292. Translated from Doklady Akademii Nauk, Vol. 387, No. 1, 2002, pp. 61–64.
Original Russian Text Copyright © 2002 by Koldobskii, Vakhmistrov, Solodova, Shilova, Kalinin.
CHEMISTRY
A New Method for the Synthesis of a-Aryl-Substituted Pyrrolines
and Tetrahydropyridines
A. B. Koldobskii, V. E. Vakhmistrov, E. V. Solodova, O. S. Shilova, and V. N. Kalinin
Presented by Academician V. V. Lunin July 18, 2002
Received July 10, 2002
2-Aryl-substituted cyclic imines and amines are amounts and in high yield merely by refluxing the cor-
important classes of biologically active compounds and responding unsubstituted lactams with an excess of tri-
are of great interest for biochemistry and medicine [1– ethyl orthoformate in the presence of catalytic amounts
3]. The reported methods for the synthesis of similar of p-toluenesulfonic acid with simultaneous removal of
compounds involve the cyclization of γ-amino ketones ethanol.
resulting from the catalytic hydrogenation of β-
(CH2)n
(CH2)n
HC(OEt)3, TsOH
t, °C, –EtOH
cyanoketones [4, 5] and the reaction of organolithium
compounds with N-vinyl- or N-trimethylsilyl-substi-
tuted lactams, followed by hydrolysis of the reaction
mixtures [6, 7]. 2-Arylpyrrolines were also obtained
via Claisen condensation of N-vinylpyrrolidone with
arylcarboxylic esters, followed by hydrolysis and
decarboxylation of the intermediates [8].
60–70%.
N
H
O
N
O
HC(OEt)2
(1a, 1b); a: n = 1; b: n = 2.
It should be noted that lactams (1a, 1b) were described
earlier; however, they were obtained in small amounts
by time-consuming chromatographic separation, and
However, we found that the above methods of syn- the yield was only 25% in the case of 1b [9].
thesis failed to result in 2-thiazolyl-substituted pyrro-
lines and tetrahydropyridines. In particular, the reaction
of 2-thiazolyllithium with N-trimethylsilyl-substituted
lactams leads mainly to silylated heterocycles, whereas
in the case of N-vinyl-substituted lactams, the process
is complicated by side reactions of acetaldehyde
appearing in the hydrolysis stage.
We found that a series of lithiated aromatic and het-
eroaromatic compounds react with lactams 1a and 1b
even at low temperatures, and their subsequent treat-
ment leads to the formation of 2-aryl-substituted pyrro-
lines and tetrahydropyridines in good yields (table).
It is obvious that the addition of organolithium com-
pound to the carbonyl group of lactams 1a and 1b takes
To overcome the difficulties, we suggested two new place at the first stage, and subsequent acidic hydrolysis
heterocyclizing reagents: N-diethoxymethylpyrroli- gives rise to a salt of ω-amino ketone, which undergoes
done-2 (1a) and N-diethoxymethylvalerolactam (1b). ring closure upon alkaline treatment to give cyclic
We found that both reagents could be obtained in large imine.
(CH2)n
R
(CH2)nNH3+
(CH2)n
(CH2)n
OH–
H2O, H+
RLi
R
N
O
N
OLi
N
(3–7)
R
O
HC(OEt)2
HC(OEt)2
1a, 1b
It is interesting that the yields of target products do not ether–hexane solutions are much higher than in tetrahy-
drofuran as a solvent.
increase in this reaction as the basicity of organolithium
compounds rises. Moreover, the least basic thiazolyl-
lithium, which decomposes at temperatures higher than
–50°C, gives the highest yields of cyclic imines 2a and
2b. It was also shown experimentally that the yields in
EXPERIMENTAL
All manipulations with organolithium compounds
were carried out in an argon atmosphere with the use of
anhydrous solvents. The structure of the resulting com-
pounds was confirmed by elemental analysis data and
1H NMR spectra. The yields and boiling and melting
points of cyclic imines 3–7 are given in the table.
Nesmeyanov Institute of Organoelement Compounds,
Russian Academy of Sciences, ul. Vavilova 28, Moscow,
119991 Russia
0012-5008/02/0011-0289$27.00 © 2002 åÄIä “Nauka /Interperiodica”

290
KOLDOBSKII et al.
Synthesis of 2-aryl-substituted cyclic amines
R
n
Product
Tb, °C (mmHg), Tm, °C
Yield, %
79
72/1
N
N
1
S
N
39
S
S
(2a)
80/1
N
N
2
1
80
59
46
S
N
N
(2b)
(3a)
68/1
38–40
N
N
2
1
2
78/1
64
60
52
N
S
N
N
N
S
(3b)
(4a)
72/1
58
85–86/1
67
S
N
S
(4b)
(5a)
74/1
38–39
86/1
F
F
1
2
60
62
F
F
N
N
30–31
(5b)
(6a)
(6b)
(7a)
F
F
F
1
2
1
73/1
56
69
48
N
F
MeO
MeO
92–93/1
114/1
N
N
N
MeO
MeO
2
124/1
50
(7b)
DOKLADY CHEMISTRY Vol. 387 Nos. 1–3 2002

A NEW METHOD FOR THE SYNTHESIS
291
N-Diethoxymethylpyrrolidone-2 (1a) and N- increase above –70°C. The mixture was stirred for
diethoxymethyl-d-valerolactam (1b). A solution of 40 min at –70°C and then was allowed to warm to
170 g (2 mol) of 2-pyrrolidone or 198 g (2 mol) of δ- −40°C while remaining in a cooling bath, and a solution
valerolactam was heated at reflux in 1.5 L of triethyl of 50 mL of concentrated HCl in 60 mL of water cooled
orthoformate in the presence of 2 g of p-toluenesulfonic to 0°C was added in one portion. The mixture was
acid hydrate in a flask equipped with a distilling column shaken vigorously; the aqueous layer was separated,
attached to a descending condenser until ethanol distil- extracted with 50 mL of ether, and allowed to stand for
lation ceased. The temperature of reaction mixture rose 36–40 h. Then, a solution of 30 g of NaOH in 40 mL of
to 150–153°C (8–12 h). The reaction mixture was water was added dropwise with stirring to the aqueous
cooled and the major portion of triethyl orthoformate layer, with prevention of the temperature growth above
was distilled off in a vacuum of 10–20 mmHg at 50°C. 30–40°C. The organic layer was separated, and the
The triethyl orthoformate distillate may be used in the aqueous layer was extracted with ether (3 × 50 mL).
same synthesis again. The residue was cooled, diluted The combined extract was dried with potassium car-
with a triple volume of benzene, and washed quickly in bonate, the ether was distilled off in vacuum, and the
a separating funnel with a cooled 10% K2CO3 solution residue was distilled in a vacuum. After distillation, the
(2 × 200 mL). The organic layer was separated, dried substance became a crystalline solid. The yield of com-
with Na2SO4, concentrated in vacuum, and distilled, a pound 2a was 12.0 g. 2-(3,4,5,6-Tetrahydropyridin-2-
small head fraction being removed, to give 254 g of yl)thiazole (2b), 2-(∆1-pyrrolin-2-yl)pyridine (3a), and
compound 1a (68%), bp 84–86°C/1 mmHg, or 250 g of 2-(3,4,5,6-tetrahydropyridin-2-yl)pyridine (3b) were
compound 1b (62%), bp 94°C/1 mmHg.
obtained similarly.
2-(2-Thien-2-yl)-∆1-pyrroline (4a). A solution of
compound 1a (19.6 g, 0.105 mol) in a double volume
of anhydrous ether was added rapidly at –90°C to a
solution of 2-thienyllithium prepared from 8.4 mL
(8.8 g, 0.105 mol) of thiophene by the above procedure.
The mixture was stirred for 40 min at –70°C, allowed
to warm spontaneously to –35°C, and poured into a
solution of 75 mL of concentrated HCl in 150 mL of
water cooled to 0°C. The mixture was stirred for 5 min,
the ether and hexane were removed in vacuum, and the
residual hydrochloric solution was kept for one day at
20°C. A solution of 66 g (1.65 mol) of NaOH in 166 mL
of water was added to the resulting solution with stir-
ring, while the temperature of the mixture was pre-
vented from increasing above 35–40°C. The organic
layer was separated, and the aqueous layer was
extracted with ether (4 × 40 mL). The combined extract
was dried with potassium carbonate, the ether was
removed in vacuum, and the residue was distilled in
vacuum.After distillation, the substance became a crys-
talline solid. The yield of compound 4a was 8.2 g. 2-(2-
Thienyl)-3,4,5,6-tetrahydropyridine (4b) was obtained
similarly.
Preparation of Lithiated Arenes
2-Thiazolyllithium. A 100-mL portion of ether was
added dropwise with stirring to 62.5 mL of a 1.6 N n-
butyllithium solution in hexane (0.1 mol), with a tem-
perature of <0°C maintained. The solution was cooled
to –80°C, a solution of 17.8 g (0.105 mol) of thiazole in
20 mL of ether was added dropwise, and the reaction
mixture was stirred for 30–40 min at –75°C.
2-Pyridyllithium. A 80-mL portion of ether was
added to 62.5 mL of a 1.6 N n-butyllithium solution in
hexane (0.1 mol) at 0°C, the mixture was cooled to
−70°C, a solution of 15.8 g (0.1 mol) of 2-bromopyri-
dine in 20 mL of ether was added dropwise, and the
mixture was stirred at –70°C for 40 min.
2-Thienyllithium. Thiophene (9.24 g, 0.11 mol)
was added dropwise to a mixture of 62.5 mL of a 1.6 N
n-butyllithium solution in hexane (0.1 mol) and 80 mL
of ether at 0°C, and the mixture was stirred at 20°C
for 1 h.
3-Fluorophenyllithium, 4-fluorophenyllithium,
and 3-anisyllithium. 3-Bromofluorobenzene (17.5 g,
0.1 mol) was added dropwise with stirring to a mixture
of 62.5 mL of a 1.6 N n-butyllithium solution in hexane
(0.1 mol) and 80 mL of ether at –30°C, the cooling bath
was removed, the solution was allowed to warm spon-
taneously to 20°C, and the mixture was stirred at this
temperature for 15 min. 4-Fluorophenyllithium and 3-
anisyllithium were obtained similarly.
2-(4-Fluorophenyl)-∆1-pyrroline (5a). A solution
of 20.6 g (0.11 mol) of compound 1a in an equal vol-
ume of anhydrous ether was added at –90°C to a solu-
tion of 4-fluorophenyllithium obtained from 10.9 mL
(17.5 g, 0.1 mol) of 1-bromo-4-fluorobenzene by the
above procedure; the mixture was stirred for 40 min at
–70°C and allowed to warm spontaneously to −40°C.
Then, it was cooled to –60°C, and a solution of 51 mL
of concentrated HCl in 51 mL of water was added. The
mixture was warmed to ambient temperature, and the
General Procedure for the Synthesis of Cyclic Amines
2-(∆1-Pyrrolin-2-yl)thiazole (2a). To a solution of solvent was distilled off at atmospheric pressure until
2-thiazolyllithium obtained from 7.1 mL (8.5 g, the temperatures of the vapor and the distillation resi-
0.1 mol) of thiazole by the above procedure, a solution due became 105°C and 108°C, respectively. Then, the
of 20.6 g (0.11 mol) of compound 1a in an equal vol- mixture was cooled and allowed to stand overnight and
ume of anhydrous ether was added with stirring at a solution of 25 g of NaOH in 30 mL of water was
−90°C, while the temperature was not allowed to added with stirring, with the mixture temperature main-
DOKLADY CHEMISTRY Vol. 387 Nos. 1–3 2002

292
KOLDOBSKII et al.
2. Xu, Y-Z., Choi, J., Calaza, M.I., et al., J. Org. Chem.,
tained at not higher than 35°C. The organic layer was
separated, and the aqueous layer was extracted with
ether (4 × 40 mL). The extract was dried with potas-
sium carbonate, and the ether was removed in a vac-
uum. The residue was distilled in vacuum. After distil-
lation, the substance became a crystalline solid. The
yield of compound 5a was 10.6 g. 2-(4-Fluorophenyl)-
3,4,5,6-tetrahydropyridine (5b), 2-(3-fluorophenyl)-∆1-
pyrroline (6a), 2-(3-fluorophenyl)-3,4,5,6-tetrahydro-
pyridine (6b), 2-(3-anisyl)-∆1-pyrroline (7a), and 2-(3-
anisyl)-3,4,5,6-tetrahydropyridine (7b) were obtained
similarly.
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DOKLADY CHEMISTRY Vol. 387 Nos. 1–3 2002