Stereoelective conversion of ethyl pipecolinate into (±)-α- and (±)-β-conhydrins

Article abstract of DOI:10.1023/A:1020359725353

Reaction of ethyl N-benzhydrylpipecolinate with ethylmagnesium bromide in the presence of catalytic amount of titanium(IV) isopropoxide furnished in a high yield the corresponding hydroxypropyl-substituted piperidine that by treating with alcoholic alkali

Full text of DOI:10.1023/A:1020359725353

Russian Journal of Organic Chemistry, Vol. 38, No. 6, 2002, pp. 875 879. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 6, 2002,
pp. 918 922.
Original Russian Text Copyright
2002 by Lysenko, Bekish, Kulinkovich.
Stereoelective Conversion of Ethyl Pipecolinate
into ( )- - and ( )- -Conhydrins
I. L. Lysenko, A. V. Bekish, and O. G. Kulinkovich
Belorussian State University, Minsk, 220050, Belarus
Received December 27, 2001
Abstract Reaction of ethyl N-benzhydrylpipecolinate with ethylmagnesium bromide in the presence of
catalytic amount of titanium(IV) isopropoxide furnished in a high yield the corresponding hydroxypropyl-
substituted piperidine that by treating with alcoholic alkali was quantitatively converted into 1-benzhydryl-
2-propionylpiperidine. The reduction in the latter of carbonyl group with lithium aluminum hydride or
sodium borohydride in methanol gave rise prevailingly to threo-aminoalcohol. With sodium borohydride
in the presence of cerium chloride an erythro-aminoalcohol was the main product. Deprotection of the
nitrogen atom from the benzhydryl group of the aminoalcohols obtained provided racemic - and
-conhydrines.
We established recently that an ester moiety in the
esters of N-benzyl-substituted amino acids cleanly
underwent cyclopropanation when treated with
ethylmagnesium bromide in the presence of catalytic
amount of titanium(IV) isopropoxide [1]. The
removal of one or two protection benzhydryl groups
by catalytic hydrogenolysis occurred without opening
of the three-membered ring thus providing a pos-
sibility of preparation of a wide range of 1-amino-
alkyl-substituted cyclopropanols [1, 2]. Esposito and
Taddei [3] also successfully applied these reagents for
cyclopropanation of N-acyl-substituted -amino acids.
Taking into account the simplicity of preparation of
1-aminoalkylcyclopropanols the development of
conditions for the opening of the three-membered ring
would ensure their efficient application as inter-
mediates in the synthesis of nitrogen-containing
compounds of other classes.
and reduction of the carbonyl group in the latter by
complex metal hydrides. The building up of the
hydroxypropyl moiety of conhydrines by reduction of
the carbonyl group was previously performed by
hydrogenation of 2-propionylpyridine on platinum
catalyst [6, 9].
Compound I was prepared from ethyl pipecolinate
by a standard procedure [10]. Its reaction with ethyl-
magnesium bromide in the presence of catalytic
amount of titanium(IV) isopropoxide in contrast to
the process with ethyl N-benzylpipecolinate [1] occur-
red cleanly in diethyl ether providing in good yield a
crystalline cyclopropanol III that was easily separated
from the reaction mixture. The three-membered
carbocycle in compound III activated by the presence
of a hydroxy group underwent heterolytic cleavage
by potassium hydroxide in ethanol [8] affording
1-benzhydryl-2-propionylpiperidine (IV) in quantita-
tive yield. The reduction of carbonyl group in ketone
IV by lithium aluminum hydride in ethyl ether at
room temperature occurred with low selectivity yield-
ing virtually equimolar mixture of diastereomers of
1-benzhydryl-2-hydroxypropylpiperidines Va, b (see
table, run no. 1).
We report here on conversion of cyclopropanation
product obtained from ethyl N-benzhydrylpipecoli-
nate (I) into erythro-2-(1-hydroxypropyl)piperidine
(IIa), racemic form of (+)- -conhydrin that was
isolated from poison hemlock (Conium maculatum)
[4]. This compound is a representative of biologically
active alkaloids widely occurring in nature possessing
in their structure 2-(1-hydroxyalkyl)piperidine frag-
ment [5]. We also prepared the corresponding threo-
isomer, ( )- -conhydrin (IIb) [6, 7]. The key stages
of synthesis of compounds IIa, b were cyclopropan-
ation of ester I, isomerization of the arising alcohol
III catalyzed by base [8] providing ethyl ketone IV,
The mixture of compound Va, b obtained was
separated by fractional crystallization of their hydro-
chlorides, and thereafter the protective benzhydryl
group was removed by hydrogenation on palladium
hydroxide on carbon [1, 11]. Therewith compounds
Va and Vb were converted into ( )- -conhydrin IIa
and ( )- -conhydrin IIb respectively. Basing on these
1070-4280/01/3806-875$27.00 2002 MAIK Nauka/Interperiodica

876
LYSENKO et al.
data to compound Va was ascribed erythro structure,
and to compound Vb threo structure.
stereochemically controlled at the stage of reduction
of a chelate complex formed by metal halide with the
substrate molecule, whereas threo-isomer Vb should
arise from nonchelated aminoketone IV. However
the assumption of better chelate complex formation
between compound IV and metal halides in methanol
than in ethyl ether seems dubious. The reversion of
hydride addition direction to the carbonyl group of
aminoketone IV is caused presumably by complexing
of magnesium or cerium halides with the solvent thus
increasing the acidity of the latter and favoring more
efficient protonation of the nitrogen atom in the
substrate. The formation of an internal hydrogen
bond with the carbonyl group of the protonated
aminoketone IV would increase the reactivity of the
carbonyl group in reduction with the borohydride
[14]. Therewith the reduction stereochemistry is also
controlled by the molecule conformation in the
chelate form; however the chelating agent here is the
proton.
The signals of methine protons from the benzhydr-
yl groups of compounds IV, Va, and Vb in the
1H NMR spectra of reaction mixtures were easily
distinguishable and possessed considerably different
chemical shifts (see EXPERIMENTAL). Therefore
this analysis was applied to evaluation of products
composition in the reaction mixture after reduction
of ketone IV. The results obtained showing the effect
of the reducing reagent and solvent on the ratio of
erythro-, Va, and threo-, Vb, aminoalcohols are
listed in the table. The reduction of ketone IV with
LiAlH4, LiAlH(OBu-t)3 and LiAlH(OPh)3 in ethyl
ether or benzene was of low stereoselectivity (runs
nos. 1 4). In tetrahydrofuran the reduction of ketone
IV was more stereoselective, and as the main product
threo-aminoalcohol Vb was obtained (run no. 5). The
latter was also formed in larger amount at reduction
of ketone IV with LiAlH4 in ethyl ether in the
presence of MgBr2 (runs nos. 6, 7). Similar stereo-
selectivity was attained by reducing ketone IV with
sodium borohydride in methanol, but the yield of
alcohols was low even at large excess of the reductant
(run no. 8). Note that reduction of aminoketone IV
with NaBH4 in the presence of MgBr2 afforded in low
yield predominantly erythro-aminoalcohol Va (run
no. 9). Replacing CeCl3 for MgBr2 significantly
increased the yield of reduction product retaining
prevailing formation of erythro-aminoalcohol Va;
therewith at increased relative amount of metal halide
the stereoselectivity of reaction grew (cf. runs
no. 6, 7, and 10 13).
Thus in the present study the building up of
erythro- and threo-2-(1-hydroxypropyl)-piperidine
moieties was efficiently performed by a succession
of reactions of cyclopropanation of the ester function
in ethyl N-benzhydrylpipecolinate, base-catalyzed
isomerization of the arising 1-piperidyl-substituted
cyclopropanol into the corresponding aminoketone,
and stereoselective reduction in the latter of the
carbonyl group by complex metal hydrides.
EXPERIMENTAL
1H NMR spectra were registered on spectrometer
Bruker AC 200 (200 MHz) from solutions of com-
pounds I IV in deuterochloroform. IR spectra were
recorded on spectrophotometer Specord 75IR from
solutions in carbon tetrachloride or chloroform. Ethyl
Within a framework of the developed stereo-
chemical model of nucleophilic addition to a carbonyl
group in -dialkylaminoaldehydes and ketones [12,
13] the formation of erythro-isomer Va should by
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 6 2002

STEREOELECTIVE CONVERSION OF ETHYL PIPECOLINATE
877
Stereochemistry of reduction of benzhydryl-2-propionylpiperidine (IV) by complex metal hydrides
Run
no.
Reducing
agent
Molar ratio of reagents:
(IV)-complex hydride-
metal halide
Solvent
Ratio
Yieldb
(V a+b), %
Va:Vba
1
LiAlH4
1/0.75/0
1/2/0
Et2O
40: 60
55: 45
40: 60
50: 50
25: 75
25: 75
10: 90
15: 85
75: 25
60: 40
70: 30
80: 20
97
96
94
98
97
94
97
24
26
45
55
85
2
LiAlH(OBu-t)3
LiAlH(OPh)3
LiAlH4
Et2O
3
1/2/0
Et2O
4
1/0.5/0
1/0.75/0
1/0.5/1.5
1/0.75/4
1/3/0
C6H6
5
LiAlH4
THF
6
LiAlH4/MgBr2
LiAlH4/MgBr2
NaBH4
Et2O
7
Et2O
8
MeOH
MeOH
MeOH
MeOH
MeOH
9
NaBH4/MgBr2
NaBH4/CeCl3
NaBH4/CeCl3
NaBH4/CeCl3
1/3/6
10
11
12
1/1/1
1/1.5/4
1/3/6
a
1
Isomer ratio Va: Vb was estimated from integral intensity of methine protons of benzhydryl groups in the H NMR spectra of
reaction mixtures.
Yield of the crude product according to 1H NMR data.
b
ether and benzene were dried and distilled from
sodium metal, tetrahydrofuran was distilled from
lithium aluminum hydride. Ethyl N-benzhydrylpipe-
colinate (I) was prepared from ethyl pipecolinate and
benzhydryl bromide [10].
50 ml of 20% aqueous ammonia and 70 ml of di-
chloromethane. The organic layer was separated and
dried with sodium sulfate. The solvent was distilled
off, the residue was recrystallized from 95% ethanol.
Yield of compound II 4.0 g (77%), mp 109 110 C.
1
1
IR spectrum (CHCl3): 3490 cm
( O-H). H NMR
Ethyl N-benzhydrylpipecolinate (I). IR spectrum
spectrum (CDCl3, TMS), , ppm: 0.32 0.48 m (1H),
0.70 0.88 m (2H), 0.94 1.06 m (2H), 1.06 1.24 m
(1H), 1.40 2.02 m (6H), 2.22 d.d (1H, J 8, 4 Hz),
2.82 2.98m (1H), 3.06 br.s (1H), 5.98 s (1H), 7.08
7.44m(10H). Found, %: C 81.94; H8.21. C21H25NO.
Calculated, %: C 82.04; H 8.20.
1
(CCl4): 1710 cm ( C=O). 1H NMR spectrum
(CDCl3, TMS), , ppm: 1.20 t (3H, J 7 Hz), 1.20
2.06 m (6H), 2.52 2.68 m (1H), 2.84 3.02 m (1H),
3.43 t (1H, J 4 Hz) 4.10 q (2H, J 7 Hz) 5.10 s (1H),
7.10 7.40 m (8H), 7.42 7.56 (2H). Found, %: C
80.03; H 7.82. C21H25NO2. Calculated, %: C 77.99;
H 7.79.
1-Benzhydryl-2-propionylpiperidine (IV).
A solution of 3.7 g (12 mmol) of compound III and
1.8 g of potassium hydroxide in 30 ml of ethanol was
boiled for 15 min. On removing the solvent under
reduced pressure to the residue was added 50 ml of
water, the reaction product was extracted into di-
chloromethane (2 25 ml), and the extract was dried
with sodium sulfate. The solvent was distilled off in a
vacuum, the residue was dissolved in benzene, and
the solution was passed through 1.5 g of silica gel.
On removing the solvent we obtained 3.6 g (97%) of
1-(Benzhydryl-2-(1-hydroxycyclopropyl)piperi-
dine (III). To a solution of 5.65 g (16.7 mmol) of
ethyl 1-benzhydrylpipecolinate (I) and 0.95 ml
(3.3 mmol) of titanium(IV) isopropoxide in 50 ml of
ether was added within 1.5 2 h at room temperature
while stirring a solution of 50 mmol of ethylmagnes-
ium bromide in 30 ml of ether. The stirring was
continued for 3 h, the reaction mixture was cooled to
0 C and treated with 40 ml of 2 N hydrochloric acid.
The mixture was stirred for 2 h, and the formed
precipitate of compound II hydrochloride was filtered
off, washed with 2 N hydrochloric acid, then with
water and ether. Then the precipitate was treated with
ketone IV, mp 67.5 68 C (from petroleum ether). IR
1
spectrum (CCl4): 1705 cm
(
C= O). 1H NMR
spectrum (CDCl3, TMS), , ppm: 0.96 t (3H, J 7 Hz),
1.34 1.66 m (4H), 1.68 1.88 m (2H), 2.24 2.44 m
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 6 2002

878
LYSENKO et al.
(3H), 2.96 d.d.d (1H, J 12, 9, 3.5 Hz), 3.30 t (1H, J
5 Hz), 4.98 s (1H), 7.12 7.36 m (8H), 7.42 7.54 m
(2H). Found, %: C 82.07; H 8.23. C21H25NO. Cal-
culated, %: C 82.00; H 8.18.
afford 1.43 g (95%) of a mixture of Va and Vb
alcohols in 1: 9 ratio (according to H NMR spec-
trum). After recrystallization of the alcohols mixture
in hydrochloride form from chloroform containing
1
4 5% of ethyl ether we isolated 1.22 g (85%) of
erythro-1-Benzhydryl-2-hydroxypropylpiperi-
dine (Va). In 30 ml of methanol at heating was dis-
solved 1.5 g (4.9 mmol) of ketone IV and 11.0 g
(29.4 mmol) of cerium chloride heptahydrate. The
mixture was cooled to 20 C and while stirring
0.56 g (14.7 mmol) of sodium borohydride was added
by portions within 20 30 min. After the mixture was
stirred for 1 h it was slowly warmed to room tempera-
ture, stirred for 5 h and boiled for 2 h. The solvent
was distilled off, to the residue 30 ml of 2 N hydro-
chloric acid was added, and the reaction product was
extracted into dichloromethane (2 15 ml). The
organic solution was washed with 10 ml of 20%
aqueous ammonia, dried with sodium sulfate, and the
solvent was distilled off in a vacuum. The residue
was subjected to chromatography on a column
charged with 10 g of silica gel (eluent benzene). We
obtained 1.28 g (85%) of a mixture containing dia-
stereomeric alcohols Va and Vb in 4: 1 ratio (accord-
1
alcohol Vb. IR spectrum (CCl4): 3320 cm
( O H).
1H NMR spectrum (CDCl3, TMS) , ppm: 0.90 t
(3H, J 7 Hz), 0.96 1.36 m (3H), 1.40 1.90 m (5H),
2.54 d.d (1H, J 10, 5 Hz), 2.66 2.96 m (2H),
3.90 d.d.d (1H, J 11, 8, 2.5 Hz), 4.82 br.s (1H),
5.20 s (1H), 7.04 7.34 m (6H), 7.34 7.54 m (4H).
Found, %: C 81.45; H 8.82. C21H27NO. Calculated,
%: C 81.51; H 8.79
erythro-2-(1-Hydroxypropyl)piperidine (IIa)
[( )- -conhydrin]. A mixture of 1 g of aminoalcohol
Va hydrochloride and 80 mg of 20% Pd(OH)2 on
carbon in 10 ml of methanol was stirred under hydro-
gen atmosphere at 1 at pressure. After the hydrogen
absorption ceased the catalyst was filtered off, and
the filtrate was evaporated. The residue was washed
with anhydrous ether, then dissolved in 10 ml of
anhydrous dichloromethane, and the solution was
treated with gaseous ammonia. The precipitate was
filtered off, the solvent was removed in a vacuum,
and the residue was recrystallized. We obtained
0.35 g (85%) of ( )- -conhydrin IIa, mp 98 99 C
1
ing to H NMR spectrum). A single fractional crystal-
lization of the mixture of alcohols Va, b hydro-
chlorides from chloroform with ether as additive
1
afforded a mixture with Va to Vb ratio of 7: 1. IR
(from ether). H NMR spectrum (CDCl3, TMS), ,
1
spectrum (CCl4): 3320 cm
(
O H). 1H NMR
ppm: 0.96 t (3H, J 7.5 Hz), 1.20 1.90 m (8H), 2.44
2.76 m (2H), 3.02 3.30 m (3H), 3.36 3.50 m (1H).
Published data [7, 9]: mp 98 100 C (from ether).
spectrum (CDCl3, TMS) , ppm: 1.00 t (3H, J
7.5 Hz), 1.10 1.80 m (8H), 2.00 2.20 m (1H), 2.34
2.64 m (2H), 2.80 2.96 m (1H), 4.16 4.28 m (1H),
5.52 s (1H), 7.04 7.50 m (10H). Found, %: C
81.60; H 8.68. C21H27NO. Calculated, %: C 81.51;
H 8.79
threo-2-(1-Hydroxypropyl)piperidine (IIb) [( )-
-conhydrin] was prepared by hydrogenation of
threo-1-benzhydryl-2-hydroxypropylpiperidine
(Vb) as described for compound IIa. Yield 88%.
mp 86 88 C (from hexane). 1H NMR spectrum
(CDCl3, TMS), , ppm: 1.00 t (3H, J 7.5 Hz).[( )- -
conhydrin]. 1.08 1.92 m (8H), 2.28 2.46 m (1H),
2.48 2.68 m (1H), 3.04 3.18 m (1H), 3.22 t.d (1H,
J 7.5, 2 Hz), 3.62 br.s (2H). Published data [6, 7]:
mp 87 88 C (from hexane).
threo-1-Benzhydryl-2-hydroxypropylpiperidine
(Vb). To a solution of 29.2 mmol of magnesium
bromide in 10 ml of ether obtained from 0.71 g
(29.2 mmol) of magnesium and 5,5 g (29.3 mmol) of
1,2-dibromoethane was added in one portion 0.14 g
(3.68 mmol) of lithium aluminum hydride. After
5 min the mixture was cooled to 20 C and while
stirring was added dropwise within 5 10 min 1.5 g
(4.9 mmol) of ketone IV in 10 ml of ether. The mix-
ture was warmed to room temperature within 30 min,
and the solvent was removed under reduced pressure.
To the residue was slowly added at 0 C 25 ml of 2 N
hydrochloric acid, and the reaction product was
extracted into dichloromethane (2 25 ml). The
organic solution was washed with 10 ml of 20%
aqueous ammonia and dried with sodium sulfate.
Then the solvent was distilled off in a vacuum to
REFERENCES
1. Lysenko, I.L. and Kulinkovich, O.G., Zh. Org.
Khim., 2001, vol. 37, no. 9, pp. 1306 1311.
2. Kulinkovich, O.G. and de Maijere, A., Chem. Rev.,
2000, vol. 100, no. 8, pp. 2789 2834.
3. Esposito, A. and Taddei, M., J. Org. Chem., 2000,
vol. 65, no. 26, pp. 9245 9248.
4. Willstatter, R., Ber., 1901, vol. 34, p. 3166.
5. Comins, D.L. and Williams, A.L., TetrahedronLett.,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 6 2002

STEREOELECTIVE CONVERSION OF ETHYL PIPECOLINATE
879
2000, vol. 41, pp. 2839 2842.
6. Prasad, K.B. and Shaw, S.C., Chem. Ber., 1965,
vol. 98, no. 9, pp. 2822 2824.
7. Pilard, S. and Vaultier, M., Tetrahedron Lett., 1984,
vol. 25, no. 15, pp. 1555 1556.
8. Gibson, D.H. and de Puy, C.H., Chem. Rev., 1974,
vol. 74, no. 6, pp. 605 624.
9. Galinovski, F. and Mulley, H., Monatsh. Chem.,
1948, vol. 79, no. 5, pp. 426 429.
10. Moragues, J., Prieto, J., and Spickett, R.G.W.,
J. Chem. Soc., Perkin Trans. I, 1976, no. 9, p. 939.
11. Yoshida, K., Nakajima, Sh., Wakamatsu, T., Ban, Y.,
and Shibasaki, M., Heterocycles, 1988, vol. 27,
no. 5, pp. 1167 1168.
12. Reetz, M.T., Chem. Rev., 1999, vol. 99, no. 5,
pp. 1121 1162.
13. Barluenga, J., Baragana, B., and Concellon, J. M.,
J. Org. Chem., 1995, vol. 60, no. 21, pp. 6696 6699.
14. Gemal, A.L. and Luche, J-L., J. Am. Chem. Soc.,
1981, vol. 103, no. 18, pp. 5454 5459.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 6 2002