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A New and DiastereoselectiveSynthesis of Threo-Aryl-2-Piperidylmethanol DerivativesAntonio Delgado a , Susana Hospital a , DavidMauleon a & Francese Pérez aa Laboratoric de Quimica Farmacéutica.Departamento de Farmacología, y QuímicaTerapéutica. Facultad de Farmacia., Avda. Diagonals/n., 08028, Barcelona, SPAIN

Version of record first published: 05 Dec 2006

To cite this article: Antonio Delgado, Susana Hospital, David Mauleon &Francese Pérez (1988): A New and Diastereoselective Synthesis of Threo-Aryl-2-Piperidylmethanol Derivatives, Synthetic Communications: An International Journalfor Rapid Communication of Synthetic Organic Chemistry, 18:16-17, 2017-2026

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SYNTHETIC COMMUNICATIONS 18(16&17) 7 2017-2026 (1988)

A NEW AND DIASTEREOSELECTIVE SYNTHESIS OF

T/~RE~-ARYL-~-PIPERIDYLHETHANOL DERIVATIVES

Antonio Delgado, susana Hospital, David Maulebn', and Francesc P6rez

Laboratorio de Quimica Farmac6utica. Departamento de Farmacologia y Quimica TerapEutica. Facultad de Farmacia.

AVda. Diagonal S/n. 08028 Barcelona (SPAIN).

Abs t rac t : A d iastereoselect ive synthesis o f t h reo -a ry l - -2-piper idyl- and ary l -1 ,2,3,6- te t rahydro-2-pyr id~ lmet t Ianol derivatives is described. The stereochemistry is control led by intramolecuiarly assisted NaBH4 redUCttOn o f the interme- diate carbamates 3.

In the course o f our investigations upon conformatio-

nally de f ined adrenergic agents, we became interested on the

elaboration o f several aryl-2-piperidyl- o r a r y 1-1,2,3,6-te-

t rahydro-2-pyridylmethanol derivatives (la-c) o f t h r e o

stereochemistry. Although several methods have been described

in the l t terature f o r the synthesis o f such o r re la ted

it Author t o whom correspondence should be addressed.

2017

Copyright 0 1988 by Marcel Dekker, Inc.

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DELGADO ET AL. 2018

systems,'-4 the vast majority o f them lead t o mixtures o f

e ry th ro and threo derivatives which USUallY require a tedious

chromatographic separation either o f the f r e e aminoalcohols

or their r j -acy~ derivative^.^ In thls paper, we wish t o

r e p o r t a new and stereoselective general method f o r the

synthesis o f thre0-18-C which avoids the above mentioned

drawbaclts.

Our previous resul ts concerning t o the synthesis o f

aminoalcohols structural ly related t o 1 by reduction o f ary l

l j -a lKylated 2-piperidy16 o r l l2 ,3 ,6 - te t rahYdr0-2-Py~idyl

ketones4 indicated that the stereochemistry o f the major

resulting products can be rationalized on the basis o f either

the V Y C I ~ C " ~ o r the mopen-chain1'8 postulated models f o r the

reduct ion o f a-aminocarbonyl derivatives, the worKing

model being related t o the nature o f both the substrate and

the reducing agent. In this context,, we considered t h a t

carbonyl group reductions w i t h NaBH4 in N-phenoxycarbonyl

ketones 3 would proceed w i t h greater stereoselectivity than

in their lj-alkyl analogues. Thus, the axial disposition o f

the ~(2)subst i tuent in lj-acylpiperidine derivatives9 as well

as the postulated complexation between NaBH4 and tne

carbamate moiety during the reduction o f a-carbamoyl Keto-

nes10 a f f o r d the possibility o f stereocnemical control. In

this context, MM2 f o r c e field calculations o f 3a Predict the

conformation depicted in Scheme 1 as the most stable one.

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THREO-ARYL-2-PIPERIDYLMETHANOL DERIVATIVES 2019

Complexation o f NaBH4 f OllOWed by intramolecular reduction o f

the ketone group would be expected t o a f f o r d a single product

o f threo stereochemistry (Scheme 1).

Synthesis o f the t a r g e t carbamoyl derivatives 3

s ta r ted w i t h the addition o f the appropriate organolithium

compound t o a-aminonitriles 5a.b. initial at tempts o f

condensation between 3,4-dimethoxyphenyl lithium and 5b by

addition o f the aminonitrile over excess organolithium

compound were unsuccessful, being veratrol and the start ing

aminonitrile 5b the major products. This resu l t can be

explained by assuming an acid-base reaction in which C(2)H

proton o f 5b IS removed by the organolithium reagent. The

acidfc nature o f t ha t proton was confrmed by 13c NHR a f t e r

deutertum exchange by treatment o f 5b w i t h LDA and quenching

w i t h D20. Inverse addition a t low temperature o f organo-

lithium reagents t o aminonitriles 5a.b avoided the competi-

tive acid-base reaction, leading t o high yields o f ketOneS 2,

which were tj-debenzylated by reaction w i t h phenyl chlorofor-

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2020 DELGADO ET AL.

CH2-Ph I

i ii - - .. R-

5a (piperidine) 2 a-c 5b (1.2.3.6-tetrahydropyridine)

0 II C-OPh

iv ___t _.__)

..- R

4 a-c 3 a-c

i: aryl lithium/THF/-70°C ?n ii: PhO-CO-Cl / CHC13

iv: KOH/EtOH-H20, rfx.

iii: NaBH4/MeOH, rfx.

R

threo-la-c - a: R=H (piperidine); b: R=3,4-(OCH3I2 (piperidine)

c: R=3,4-(OCH3)2 (1,2,3,6-tetrahydropyridine)

S C H E M E 2

mate. Treatment of the result ing carbamates 3 w i t h excess

NaBH4 in MeOH a f f o r d e d exclusively the t r a n s isomers of the

perhydrooxazolo[3,4-alpyridin-3-one der ivat ives 48-C, whose

stereochemistry was confirmed by IH NMR on the basis o f the

C(1)H chemical shift.'' Formation o f 4 is in agreement w i t h

t he above postulated mechanism f o r the reduction o f 3 w i t h

NaBHq. The alkoxide group o f t h e init ially f o rmed t h r e o

product can intramolecularly displace the phenoxide group t o

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THREO-ARYL-2-PIPERIDYLMETHANOL DERIVATIVES 2021

give the cyclic t rans carbamates 4. It is worth noting that,

aithough the open chain model f o r the reduction o f carbonyl

groups in a-acylaminocarbonyl derivatives predicts a maJor

th reo product, t he exclustve formation o f 4a confirms the

intramolecular hydride t r a n s f e r .

Alkaline hYdrOlYSiS o f 423-c a f f o r d e d In each case the

desired threo-la-c derivatives, whose s te reochemis t ry was

confirmed on the basis o f the C(1)H-C(a)H coupling constant

and by comparison t o re la ted structures.12 The above

reac t ion sequence leading t o threo-aminoalcohols 1 f rom

Ketones 2 can be also carr ied out in a **one-pot*’ procedure,

as described in the experimental section f o r threo-lc.

Experimental

Melting points were determined on a capillary tube and

a r e uncorrected. 1~ NMR spec t ra were recorded on a Perkin-

-Elmer R-24B spectrometer, while 13c NMR spectra were recorded on

a Varian XL-200 spectrometer. In all cases, CDCI3 solutions w i t h

TMS as internal standard were used. IR spectra were recorded on a

Perkin-Elmer 1430 spectrophotometer. Elemental analyses were

performed by lnst i tuto de QuFmica Btoorginlca (CSIC, Barcelona)

and agreed w i t h theoretical values Within f 0.4%. Flash chromato-

graphy r e f e r s t o the medium pressure technique described by

w.c.still e t a1.13 AII solvents were f resh ly disti l led b e f o r e

use. THF and ether were distilled f rom Na/benzophenone.

General procedure f o r the synthesis o f Ketones 2a-c

A solution of BuLi in hexane (20 ml, 24 mequiv.) was

added dropwise under nitrogen over an externally cooled solution

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2022 DELGADO ET AL.

o f the corresponding haloaryl derivative (32 mmol) in THF (200

ml). A f t e r stirring lh a t -7OG the resulting solution was solwly added over a solution o f a-aminonitrile 5a o r 5614 (20

mequiv.) in THF (100 ml) a t -7O.C. Stirring was continued f o r lh,

during which period the temperature was allowed t o rise. Water (10 ml) was added t o the reaction vessel and the solvent was evaporated in vacuo. The resulting residue was treated with Et20

and 2tj HCI (150 m1 each) and st i r red f o r lh a t room temperature.

The aqueous Phase was decanted, made alkaline with 5@ NaOH, and

extracted with CH2C12 t o give the corresponding aminoketone 2a-c,

Which were purified by f lash chromatography (hexane-ethyl

acetate, 85:15).

2a (75% yield, hydrochloride, mp: 200-203-C, acetone-

-Et2O); IR (CHC13): 1670 cm-l (C=O); lH NMR: 1.7 (m, 6H,

C(3,4,5)H2), 2.5 (m, lH, C(6)Ha)s 2.9 (m, IH, C(6)He)B 3.1,

3.7 (dd, J=12 HZ, 2H, N-Ctiz-Ph), 3.6 (m, IH, C(2)H), 7.0 (S,

5H, N-CH2-PJ, 7.2 (m, 3H, C(3,4,5)Ar-H), 7.9 (m, 2H, C(2,6)-

2b (75% yield, hydrochloride, mp: 19OG acetone); IR

(CHCIj): 1670 Cm-I (C=O); 'H NMR: 1.6 .(m, 6H, C(3,4,5)H2),

2.8 (m, lH, C(6)Ha)S 3.6 (m, lH, C(6)He), 3.1, 3.7 (dd, J=13

HZ, 2H, N-Ckiz-Ph), 3.8 (3, 6H, (OCH3)2), 6.6 (d, J=9 Hz, lH,

2c (78% yield, hydrochloride, mp: 190.C, Et$, EtOH); IR

Ar-H).

C(5)Ar-Hh 7.0 (5, 5H, N-CHz-B), 7.7 (m, 2H, C(2,6)Ar-H).

(CHC13): 1670 Cm- l (C=O); lH NMR: 2.4 (m, 2H, C(3)H2), 3.2

(m. 2H, C(6)H2), 3.4, 3.7 (dd, J=13 HZ, 2H, N-Cli2-Ph), 3.8

(S, 6H, (OCH3)2), 4.1 (t ap., J=J'=5 HZ, IH, C(2)H), 5.5 (m, 2H, C(4,5)H2), 6.6 (d, J=8 Hz, IH, C(5)Ar-H), 7.1 (s, 5H,

N-CH2-Ph), 7.5 (m, 2H, C(2.6)Ar-H).

General procedure f o r the synthesis o f chloroformates 3a-c

Phenyl chlorof Ormate (1.8 mmol) was added dropwise under

nitrogen over an ice-cooled solution o f the corresponding

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THREO-ARYL-2-PIPERIDYLMETHANOL DERIVATIVES 2023

tj-benzyl derivative 2a-c (0.9 mmol) in CHC13 (15 ml). A f t e r

s t i r r ing f o r 3h a t room temperature, the solvent was evapora-

ted in vacuo and the excess reagent was eliminated by bulb t o

bulb distillation. The result ing residue was purif ied by flash

chromatography (hexane-ethyl acetate 1:l) t o a f f o r d compounds

3a-c.

38 (85% yield, oil); IH NMR: 1.7 (m, 6H1 C(3,4,5)H2),

3,3 (m, lH, C(6)Hah 4.1 (m, lH, C(6)He)l 5.6 (m, IH, C(2)H),

7.1 (m, 8H, Ph-0 + C(3,4,5)Ar-H), 7,7 (m, 2H, C(2,6)Ar-H).

3b (88% yield); IH NMR: 1.8 (m, 6H, C(3,4,5)H2), 3,3 (m, lH, C(6)Ha)l 3.8 ( 5 , 6Hi (OCH3)2), 4.1 (m, IH, C(6)He), 515

(m, IH, C(2)H), 7.1 (m, 8H, Ar-H).

3c (94% yield, mp: 1 3 6 c hexane-ethyl acetate w); 1H

C(6)H2), 5,5 (bs, 2H, C(4,5)H2), 5.7 (m, IH, C(2)H), 6.6 (d,

J=8 Hz, IH, C(5)Ar-H), 6.9 (m, 5H, 0-Ph), 7.3 (m, 2H, C(2,6)ArH).

NMR: 2.6 (m, 2H, C(3)H2), 3.7 (5 , 3H, (OCH3)2), 4.1 (m, 2H,

General procedure f O r the Synthesis o f pyridooxazolones 4a-C

Sodium borohydride (4mmol) was added portionwise over a

s t i r r e d solution o f carbamate 3a-c (2 mmol) in MeOH (25 ml).

A f t e r s t i r r ing f o r 15 min a t re f l ux temperature, the mixture

was poured over ice-water, MeOH was removed in vacuo, and the

remaining aqueous solution was extracted w i t h Et20. The ethereal

extracts were washed w i t h 2tj NaOH, dried (Na2SOq), and evaporated

t o give compounds 4a-c.

4a (81% yield; oil); IR (CHC13): 1740 cm-1 (carbamate);

IH NMR: 1.5 (m, 6H, C(6,7,8)H2), 2.7 (m, lH, C(5)Ha)l 3.2 (m,

lH, C(Ba)H), 3.7 (m, IH, C(5)He)I 4.7 (d, J=8 HZ, lH, C(l)H),

7.1 (5 , 5H, Ar-H).

4b (85% yield, oil); IR (CHCI3): 1745 cm-1 (carbamate);

(H NMR: 1.6 (m, 6H, C(6,7,8)H2), 2.7 (m, lH, C(5)Ha)I 3.2 (m,

lH, C(Ba)H), 3.7 ( 5 , 6H, (OCH3)2), 3.8 (m, lH, C(5)He), 4.7

(d, J=8 Hz, lH, C(I)H), 6.6 (m, 3H, Ar-H).

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DELGADO ET AL. 2024

4 c (84% yield, mp:l36.C, hexane-ethyl acetate 1:2); IR

(CHC13): 1750 cm-I (carbamate); IH NMR: 2.3 (m, 2H, C(8)Ha+e),

3.6 (m, IH, C(Ba)H), 3.8 (m, lH, C(5)Ha)a 3.9 ( 5 , 6H, (OCH3)2),

4.1 (m, lH, C(5)He)v 5.1 (d, J=7.1 HZ, lH, C(l)H), 5.6 (m, 2H,

C(6,7)H2), 6.9 (m, 3H, Ar-H).

Compounds threo-la-c f r o m alkaline hydrolysis o f 4a-c

A solution o f KOH (10 mmol) and 4a-c (1 mmol) in EtOH:H20

(10:3 ml) was heated under nitrogen a t ref lux temperature. A f t e r

12 h, the reaction mixture was poured over ice-water and EtOH was

removed in vacuo. The aqueous phase was acidified w i t h 2N-HCI,

washed with Et20, made alKaline w i t h 5N NaOH, and extracted W i t h

CH2CI2. The organic ex t rac t was dried (Na2S04) and evaporated t o

give aminoalcohols threo-la-c.

th reo- la (72% yield, mp: 170-172.C, lit16 170-173.C).

th reo- lb (68% yield, hydrochloride mp: 204-206, e thy l

acetate), IR(K6r): 3400-3200 cm-l (OH, NH); IH NMR: 1.3 (m,

6H, C(3,4,5)H2), 2.6 (m, 3H, C(2)H, C(6)H2), 3.7 (S, 6H,

(OCH3)2), 4.1 (d, J=6 Hz, IH, C(a)H), 6.6 (bs, 3H, Ar-HI.

th reo- lc (70% yield, mp: 140-143.C, hexane-ethyl acetate

1:l); IR (KBr): 3320 cm-l (OH); lH NMR: 1.5 (m, 2H, C(3)H2lI

2.7 (5 , 6H, (OCH3)2), 4.1 (4, J=8 HZ, IH, C(a)H), 5.4 (m, 2H,

C(4,5)H), 6.6 (bs, 3H, Ar-HI.

One-Pot Procedure f o r the synthesis o f threo-lc f rom 2c

Phenyl chloroformate (490 mg, 3.2 mmol) was added dropwise

under nitrogen t o an ice-cooled solution o f Ketone 2c (530 mg,

1.6 mmol) in CHC13 (20 ml). The reaction mixture was s t i r red fo r

3h a t room temperature, the solvent was evaporated t o dryness,

the residue was dissolved in MeOH (35 ml), and NaBH4 (300 mg, 7.8

mmol) was added portionwise. A f t e r st irr ing f o r 15 m n a t ref lux

temperature, a solution o f KOH (600 mg, 15 mmol) in H20 (5 ml)

was added a t once and re f lux was continued f o r additional 12h.

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THREO-ARYL-2-PIPERIDYLMETHANOL DERIVATIVES 2025

The reaction mixture was poured over ice-water, made acidic with

2y HCI and washed w i t h Et20. The aqueous phase was alkalinized

w i t h 5tj NaOH and extracted w i t h CH2C12 t o a f f o r d 290 mg (74%

yield) o f threo-lc.

AcKnOwledgementS

The authors grateful ly acknowledge Cornisibn Asesora de

Investigacibn Cienti f ica y T8cnica (g ran t PR 84-0315) f o r

financial support .

References and notes

1.

2.

3.

4.

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10.

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Delgado, A., Maulebn, D., Rosell, G., Salas, w.L., and

Najar, J., An.Quim., 1907, 83,C, 90.

Delgado, A., and Maulebn, D., Synth.Commun., 1988, 18,

Cram, D.J., and Abd EIHafez, F.A., J.Am.Chf?m.SOC., 1952,

Cram, D.J., and Kopecky, K.R., J.Am.Chem.Soc., 1959,

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2026 DELGADO ET AL.

11. Treatment o f a sample o f erythro-la with dimethyl carbonate

afforded the cyclic carbamate erythro-4a: C(OH, 13 5.36,

J= 7 Hz. For lH NMR data o f threo-4aI see experimental

section.

12. Sankey, G.H., and Whiting, K.D.E., J.Heterocyct.Chem,

13. Still, W.C., Kahn, M., and Mitra, A., J.Org.Chem., 1978,

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43, 2923.

14. Bonin, M., Romero, J.R., Grierson, D.S., and Husson, H-P.,

J.Org.Chem., 1984, 49, 2392.

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