An improved and stereoselective route to all-cis-2,6-disubstituted 4-hydroxypiperidines from accessible 4-substituted 4-N-benzylaminobut-1-enes

PAPER

771

An Improved and Stereoselective Route to All-cis-2,6-Disubstituted

4-Hydroxypiperidines from Accessible 4-Substituted

4-N-Benzylaminobut-1-enes

A

Stereoselective

R

oute to

e

A

ll-cis-2,

x

6-Disubstitut

e

ed 4-Hydro

y

xypiperidines Varlamov,*^aVladimir Kouznetsov,*^bFedor Zubkov,*^aAlexey Chernyshev,^aOlga Shurupova,^aLeonor Y.

Vargas Méndez,^bAlirio Palma Rodríguez,^bJuliette Rivero Castro,^bAlfredo J. Rosas-Romero^c

a

Department of Organic Chemistry, Russian Peoples Friendship University, 3 Ordzhonikidze St., 117419, Moscow, Russia

Fax +7(95)9540336; E-mail: fzubkov@sci.pfu.edu.ru

b

Research Center for Biomolecules, Laboratory of Fine Organic Synthesis, School of Chemistry, Industrial University of Santander, A.A.

678, Bucaramanga, Colombia

Fax +57(76)349069; E-mail: kouznet@uis.edu.co

c

Department of Chemistry, Simon Bolivar University, Caracas 1080A,Venezuela

Received 9 June 2001; revised 19 February 2002

piperidines such as piperidine 214D (4) (cis,cis-4-

hydroxy-2-methyl-6-nonylpiperidine) has been dis-

covered⁶and synthesized^7–9(Figure). Special interest has

been generated by those hydroxypiperidines which dis-

Abstract: The reaction between allylmagnesium bromide and

imines 5a–l leads to the corresponding 4-substituted 4-N-benzy-

laminobut-1-enes 6a–l, which were oxidized in a regioselective

manner to the alkenylnitrones 7a–l. The intramolecular 1,3-dipolar

cycloaddition of these nitrones gave 2-spiroannulated or 2-substi- play important physiological properties such as cardioton-

ic,⁴tranquilizing (haloperidol analogues), and analgesic

tuted 6-exo-phenyl-1-aza-7-oxabicyclo[2.2.1]heptanes 8a–j. Re-

ductive cleavage of the N–O bond of the obtained bicycles afforded

the diverse substituted 4-hydroxypiperidines 9a–h in good yields.

(promedol derivatives) activities.¹⁰

Despite the development of general methods for the syn-

thesis of the above heterocycles, there are few examples

where the accessible substituted 4-aminobut-1-enes (ho-

moallylic amines) serve as starting materials to synthesize

diverse 2,6-disubstituted 4-hydroxypipepiridines, includ-

ing 2-spiropiperidine ring. Hoffman and coworkers¹¹dis-

closed that the conversion of N-(homoallyl)-

hydroxylamines to the N-(3-alkenyl)nitrones followed by

intramolecular cycloaddition reaction afforded the 1-aza-

7-oxabicyclo[2.2.1]heptanes,¹²principal precursors of

2,6-disubstituted 4-hydroxypiperidines. This methodol-

ogy allowed the synthesis of alkaloid 1.¹³It is also note-

worthy that this nitrone strategy was developed for the

preparation of all-cis-2,3,6-trisubstituted piperidines,

which in turn were used in the total synthesis of carpamic

acid.¹⁴

This stereoselective approach allowed the preparation of all-cis-4-

hydroxy-6-phenyl-2-nonylpiperidine (9i), a close analogue of den-

drobatid frog alkaloid 241D.

Key words: homoallylamines, nitrones, stereoselective intramo-

lecular 1,3-dipolar cycloadditions, 1-aza-7-oxabicyclo[2.2.1]hep-

tanes, 4-hydroxypiperidines, 4-hydroxy-2-spiropiperidines

Substituted piperidines play an important role in heterocy-

clic chemistry from the chemical, biological and medici-

nal points of view. The piperidine ring system occurs in

many alkaloids of both the plant and animal kingdom.^1,2

During the last 20–30 years, considerable effort has been

directed towards the study, isolation and total synthesis of

quinolizidines, indolizidines and piperidines such as epi-

lasubine II (1),³allopumiliotoxin 323B (2), and histrioni-

cotoxin 283A (3).^4,5The structures 1 and 2 contain a sub-

stituted 4-hydroxypiperidine nucleus and the latter

possesses a remarkable spiropiperidinecyclohexanol sys-

tem. Moreover, relatively simple monocyclic 4-hydroxy-

As part of our research program on the use of 4-N-ar-

yl(benzyl)aminobut-1-enes (homo-allylamines) in the

synthesis of diverse heterocycles of biological inter-

est,^15–21we decided to investigate the scope of the nitrone-

OH

N

CH₃

OH

CH₃

OH

H

N

HO

OH CH₃

N

2

H₃CO

OCH₃

OH

1

3

H₃C

N

H

4

Figure

Synthesis 2002, No. 6, 29 04 2002. Article Identifier:

1437-210X,E;2002,0,06,0771,0783,ftx,en;M13201SS.pdf.

ISSN 0039-7881

772

A. Varlamov et al.

PAPER

based methodology to the synthesis of dendrobate alka- amines.²²This reaction between allylmagnesium bromide

loid analogues. Here, we propose another approach to the and imines 5a–l in diethyl ether leads to the corresponding

key starting material, alkenyl nitrones by using the cata- 4-substituted 4-N-benzylaminobut-1-enes 6a–l in 61–

lytic oxidation reaction of 4-substituted 4-N-benzylami- 85% overall yields, except aminobutene 6a, which was

nobut-1-enes preformed from ket(ald)imines and obtained in 40% yield. The addition of allylmagnesium

allylmagnesium bromide. Moreover, we chose to examine bromide to N-pyridinylidenbenzylamines 5i–k in diethyl

the possibility of nitrone synthesis from amines, to deter- ether was ineffective, but the use of THF resulted in the

mine the size of the ring or the influence of the C-4-sub- desired products in good yields. The key intermediate ni-

stituent on the oxidation reaction of 4-N-benzylaminobut- trones in our research were prepared by oxidation of the

1-enes. Additionally we studied the stereoselectivity of in- aminobutenes 6a–l with 50% H₂O₂²²in the presence of a

tramolecular dipolar cycloaddition of these nitrones and catalytic amount of Na₂WO₄^23,24in a mixture of acetone–

to test the compatibility of different substituents (aryl, py- water (9:1) at room temperature (Scheme 1).

ridyl, furyl, alkyl) with this strategy. This paper describes

a simple, stereoselective approach for the preparation of

the 2,6-disubstituted 4-hydroxypiperidines, including the

all-cis-2-spiro-4-hydroxy-6-phenylpiperidine as well as

the all-cis-4-hydroxy-6-phenyl-2-nonylpiperidine, close

analogues of dendrobate alkaloid 241D, from accessible

and cheap ald- and ketimines.

It was established that the oxidation of 4-substituted 4-N-

aminobutenes 5f–l proceeds more easily than that of their

4,4-disubstituted analogues 5a–e, and that the size of cy-

cloalkane fragment in compounds 5a–d did not play con-

siderable influence on the reaction rate. The alkenyl

nitrones 7a–l were obtained in 42–87% yields as stable

compounds which could be purified by fractional crystal-

Our synthetic strategy contains two parts: i) effective lisation or by alumina column chromatography (Table 1).

preparation of diverse alkenylnitrones from 4-aryl(hetar-

yl, alkyl)-4-N-benzylaminobut-1-enes and 1-allyl-1-N-

benzylaminocycloalkanes starting from simple imines

(Scheme 1); ii) stereoselective synthesis of structurally

different 2,6-disubstituted (2,2,6-trisubstituted) 4-hydrox-

ypiperidines via the reductive cleavage of the N–O bond

In the ¹H NMR spectra of compounds 6a–l the character-

istic signals of allyl moiety were observed in the region

2.07–2.56 (3-CH₂) and 4.96–5.94 ppm (CH₂=CH) with

coupling constants ²J_1Hcis,2H= 9–11, ²J_1Htrans,2H= 16–17.6,

1

²J_1H,1H= 1.0–2.1 Hz. At the same time the H NMR data

of all synthesized nitrones 7a–l indicate the conservation

of the 2-(spiro)substituted 6-phenyl-1-aza-7-oxabicyc-

of the characteristic signals of allyl fragment which

lo[2.2.1]heptanes prepared by the intramolecular 1,3 di-

proves that an allyl fragment is intact during the oxidation

polar cycloaddition reaction of alkenylnitrones

reaction. The signal of the aldiminic proton (HC=N) of all

(Scheme 2).

nitrones appears at the region 7.26–7.66 ppm as singlet,

The required imines 5a–l were prepared according to lit- easily identified among the aromatic protons. It was found

erature procedure^15,18and were used in subsequent synthe- that these mild conditions guarantee a high regioselectiv-

sis without further purification. The nucleophilic addition ity; oxidation reaction occurs at the less steric bulky ben-

of organometallic compounds to the C=N bond of the zyl CH₂N group in the case of aminobutenes 6f–l

imines is one of the key methods for preparing various (Tables 2, 3).

O

O^-

R¹

R²

R¹

R²

H

ii

iii

+

N

NH₂

N

i

R¹

R²

R¹

R²

5a-l

6a-l

7a-l

R¹

R²

R¹

R²

Starting Compounds

Imine Amine Nitrone

Starting compounds

Imine Amine Nitrone

(CH₂)₄

(CH₂)₅

(CH₂)₆

(CH₂)₇

6g

5g

7g

4-CH₃OC₆H₄

α-furyl

5a

5b

5c

6a

7a

H

5h

6h

7h

6b

6c

7b

7c

α-pyridyl

β-pyridyl

γ-pyridyl

5i

5j

6i

6j

7i

7j

5d

6d

7d

(CH₂)₆CH₃CH₃

C₆H₅

5k

5l

5e

5f

6e

6f

7e

7f

6k

6l

7k

7l

H

(CH₂)₈CH₃

Scheme 1 Reagents and Conditions: i) benzene, reflux, 6–10 h; ii) CH₂=CHCH₂MgBr/Et₂O (THF for 5i–k), r.t., 2 h; aq sat. NH₄Cl solution;

iii) Na₂WO₄2H₂O, 50% H₂O₂, acetone–H₂O, r.t., 2–4 d.

Synthesis 2002, No. 6, 771–783 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER

A Stereoselective Route to All-cis-2,6-Disubstituted 4-Hydroxypiperidines

773

Table 1 4-Substituted 4-N-Benzylaminobut-1-enes 6a–l and N-Benzylidene-N-butenylamino-N-oxides 7a–l

Product^aMolecula Mass m/z

Bp (°C)/ Torr

or Mp (°C)^b

R_f

IR (cm^–1)

Yield (%)

(Silufol UV₂₅₄

)

Found M⁺Calcd

C=C

NH

N

C=N

6a

6b

6c

6d

6e

6f

215

229

202^d

216^d

232^d

237

267

227

238

197^d

238

246^d

229

215

229

243

257

273

237

267

227

238

287

229

115–118/2.0

120–125/2.0

121–126/1.5

148–150/1.0

oil^f

0.48^c

0.50^c

0.48^c

0.80^e

0.96^e

0.39^c

0.50^g

0.45^c

0.86^h

0.81^h

0.44^c

0.95^e

0.30^g

1645

3327

–

40

78

70

65

61

84

83

82

64

82

85

65

1640

1642

1638

1639

1640

1643

1645

1642

1640

1632

1640

1636

3330

3335

3330

3335

3333

3331

3330

3326

3308

3290

3325

–

124–130/1.5

165–172/1.5

115–118/1.5

oil^f

6g

6h

6i

6j

168–170/5.0

152–154/1.5

oil^f

6k

6l

7a

40–43

1156,

954

1576,

1560

7b

7c

7d

7e

7f

243

257

271

287

251

281

241

252

243

257

271

287

251

281

241

252

36–38

0.38^c

0.21^c

0.32^g

0.36^e

0.36^g

0.18^g

0.21^g

0.37^h

0.33^h

1643

1638

1640

1641

1644

1643

1644

1639

–

1140

1577,

1562

70

75

55

61

81

66

42

87

76

oil^f

1150,

935

1560

1557

1559

oil^f

1122,

921

oil^f

1127,

919

127.5–130.0

81.5–83.0

90.5–91.5

129–130

130–132

1152,

941

1591,

1576

7g

7h

7i

1153,

935

1587,

1615

1155,

930

1579,

1565

1138,

917

1586,

1577

7j

1115,

923

1583

7k

7l

252

301

252

301

0.44^h

0.27^g

1645

1643

–

1150

1598

1563

45

75

103–104

oil^f

1126,

919

^aAll compounds showed satisfactory elemental analysis: C 0.21, H 0.25, N 0.25.

^bRecrystallisation from hexane–Et₂O.

^cEtOAc–hexane, 1:10.

^d[M – CH₂=CHCH₂]⁺.

^eHeptane.

^fPurification by Al₂O₃(EtOAc–hexane, 1:40).

^gEtOAc–hexane, 1:5.

^hAcetone.

Synthesis 2002, No. 6, 771–783 ISSN 0039-7881 © Thieme Stuttgart · New York

774

A. Varlamov et al.

PAPER

Table 2 ¹H NMR Spectra [(CDCl₃/TMS), , J (Hz)] of 4-N-Benzylaminobut-1-enes 6a–l and N-Benzylidene-N-butenylamino-N-oxides

7a–l

H-cis

H₁-cis

H-trans

1

-

H

N

O

2

H-trans

4

3

N⁺

R²

4

3

R²

R¹

6a-l

7a-l

Prod-

uct

1-H_cis

1-H_trans

2-H

3-H_A,H_B

2.37 (d)

4-H

6a

6b

6c

6d

6e

6f

5.14 (dd, J_1,1= 2.0, J_1-Hcis,2

= 10.3)

5.16 (m, J_1-Htrans,2= 17.6)

5.10 (m, J_1-Htrans,2= 17.8)

5.16 (m, J_1-Htrans,2= 16.6)

5.10 (m, J_1-Htrans,2= 17.2)

5.11 (m, J_1-Htrans,2= 17.5)

5.92 (ddt, J_2,3A= J_2,3B

7.2)

=

–

5.18 (J_1,1= 1.4, J_1-Hcis,2

9.3)

=

5.92 (m, J_2,3A= J_2,3B= 7.4) 2.28 (d)

–

5.15 (m, J_1,1= 1.0, J_1-Hcis,2

= 9.1)

5.94 (m, J_2,3A= J_2,3B= 7.5) 2.30 (d)

–

5.09 (dd, J_1,1= 1.5, J_1-Hcis,2

= 10.2)

5.88 (m, J_2,3A= J_2,3B= 7.2) 2.22 (d)

–

5.08 (m, J_1,1= 1.0, J_1-Hcis,2

= 11.1)

5.85 (m, J_2,3A= J_2,3B= 7.4) ~2.21 (m, J_3A,3B= 13.6)

–

5.18 (dd, J_1,1= 1.5, J_1-Hcis,2

= 10.0)

5.22 (ddt,

J_1-Htrans,2= 16.9,

J_1-Htrans,3= 1.5)

5.84 (m, J_2,3A= 8.1, J_2,3B

6.5)

=

~2.56 (m, J_3A,4= 5.8, J_3B,4

= 7.9)

3.84 (dd)

6g

6h

5.16 (m, J_1,1= 1.5, J_1-Hcis,2

= 10.4)

5.20 (ddt,

J_1-Htrans,2= 17.3,

J_1-Htrans,3= 1.5)

5.82 (m, J_2,3A= 7.7, J_2,3B

6.4)

~2.52 (m, J_3A,4= J_3B,4

6.9)

=

3.77 (t)

4.99 (dd, J_1,1= 2.1, J_1-Hcis,2

5.05 (dd, J_1-Htrans,2= 17.2)

5.69 (ddt, J_2,3A= J_2,3B

=

2.49 (t, J_3A,4= J_3B,4= 7.0) 3.74 (t)

= 10.1)

7.0)

6i

6j

4.82 (dd)

4.76 (dd)

5.50 (m)

5.67 (m)

2.40–2.15 (m)

3.56 (t)

5.06 (dd, J_1,1= 1.5 J_1-Hcis,2

5.04 (dd, J_1-Htrans,2= 16.1)

2.40 (t, J_3A,4= J_3B,4= 7.0) 3.72 (t)

= 10.9)

6k

6l

5.06 (dd, J_1,1= 1.5, J_1-Hcis,2

= 11.0)

5.04 (dd, J_1-Htrans,2= 16.2)

4.98 (dd, J_1-Htrans,2= 17.4)

5.11 (dd, J_1-Htrans,2= 17.1)

5.08 (d, J_1-Htrans,2= 17.0)

5.08 (dd, J_1-Htrans,2= 17.1)

5.09 (dd, J_1-Htrans,2= 17.2)

5.12 (dd, J_1-Htrans,2= 18.0)

5.68 (m)

2.50–2.25 (m, J_3A,4= 6.1,

J_3B,4= 7.6)

3.69 (dd)

4.96 (dd, J_1,1= 1.4, J_1-Hcis,2

= 10.1)

5.70 (m, J_2,3A= 7.4, J_2,3B

6.7)

=

2.17–2.07 (m, J_3A,4= 5.7,

J_3B,4= 6.2)

2.54 (dd)

7a

7b

7c

7d

7e

7f

5.07 (dd, J_1,1= 2.1, J_1-Hcis,2

= 10.2)

5.71 (ddt, J_2,3A= J_2,3B

7.0)

=

2.66 (d)

–

5.06 (d, J_1-Hcis,2= 10.0)

5.66 (m, J_2,3A= J_2,3B= 7.6) 2.59 (d)

–

5.07 (dd, J_1,1= 2.4, J_1-Hcis,2

= 10.1)

5.63 (ddt, J_2,3A= J_2,3B

7.0)

=

2.60 (d)

2.58 (d)

–

5.02 (dd, J_1,1= 2.1, J_1-Hcis,2

= 10.1)

5.60 (ddt, J_2,3A= J_2,3B

7.3)

–

5.09 (dd, J_1,1= 1.0, J_1-Hcis,2

= 11.2)

5.67 (m, J_2,3A= 6.4, J_2,3B

8.4)

=

2.88 (dd), 2.38 (dd),

J_3A,3B= 13.8

–

5.10 (ddt, J_1,1= 1.5, J_1-Hcis,2

= 10.4)

5.23 (ddt,

J_1-Htrans,2= 17.1,

J_1-Htrans,3= 0.5)

5.80 (ddt, J_2,3A= J_2,3B

6.8)

=

3.35 (m), 2.78 (m),

J_3A,3B= 13.8, J_3A,4= 5.8,

J_3B,4= 9.2

4.97 (dd)

7g

5.06 (dd, J_1,1= 1.2, J_1-Hcis,2

= 10.1)

5.17 (dd, J_1-Htrans,2= 17.1)

5.75 (ddt, J_2,3A= J_2,3B

7.0)

3.29 (ddd), 2.74(ddd),

J_3A,3B= 14.4, J_3A,4= 8.5,

J_3B,4= 6.1

4.88 (dd)

Synthesis 2002, No. 6, 771–783 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER

A Stereoselective Route to All-cis-2,6-Disubstituted 4-Hydroxypiperidines

775

Table 2 ¹H NMR Spectra [(CDCl₃/TMS), , J (Hz)] of 4-N-Benzylaminobut-1-enes 6a–l and N-Benzylidene-N-butenylamino-N-oxides

7a–l (continued)

H-cis

H₁-cis

H-trans

1

-

H

N

O

2

H-trans

4

3

N⁺

R²

4

3

R²

R¹

6a-l

7a-l

Prod-

uct

1-H_cis

1-H_trans

2-H

3-H_A,H_B

4-H

7h^a

5.11 (dd, J_1,1= 1.5, J_1-Hcis,2

= 10.2)

5.23 (dd, J_1-Htrans,2= 17.2)

5.79 (ddt, J_2,3A= J_2,3B

6.8)

=

3.25 (ddd, J_3A,3B= 14.0,

J_3A,4= J_3B,4= 7.2)

5.05 (t)

7i

5.10 (d, J_1-Hcis,2= 10.3)

5.24 (dd, J_1-Htrans,2= 17.1, 5.82(m)

_1-Htrans,3= 1.4)

3.32 (ddd), 2.92 (ddd), 5.15 (dd)

J_3A,3B= 13.0, J_3A,4= 7.0,

J_3B,4= 5.6

J

7j

7k

7l

5.01 (dd, J_1-Hcis,2= 9.2, J_1,1

= 1.5)

5.10 (dt, J_1-Htrans,2= 17.1,

J_1-Htrans,3= 2.7)

5.70 (m)

3.22 (ddd), 2.64 (ddd),

J_3A,3B= 13.0, J_3A,4= 6.8,

J_3B,4= 5.9

4.88 (dd)

4.90 (dd)

3.70 (m)

5.13 (ddt, J_1,1= 1.5, J_1-Hcis,2

= 10.1)

5.23 (ddd,

J_1-Htrans,2= 17.1, J_1-Htrans,3=

1.5)

5.78 (m, J_2,3A= J_2,3B= 7.0) 3.31 (m), 2.73 (m), 3.35

(ddd), J_3A,3B= 13.7, J_3A,4

= 9.5, J_3B,4= 5.5

4.97 (dd, J_1,1= 1.5, J_1-Hcis,2

= 10.0)

5.06 (dddd,

J_1-Htrans,2= 17.1)

5.67 (m, J_2,3A= 6.5, J_2,3B

8.2)

=

2.70 (ddd), 2.27(ddd),

J_3A,3B= 14.5, J_3A,4= 9.4,

J_3B,4= 4.7

^aInternal reference: HMDS (hexamethyldisilane).

Table 3 ¹H NMR Spectra [CDCl₃/TMS, , J (Hz)] of 4-N-Benzylaminobut-1-enes 6a–l and N-Benzylidene-N-butenylamino-N-oxides

7a–l

H-cis

H₁-cis

H-trans

1

-

H

N

O

2

H-trans

4

3

N⁺

R²

4

3

R²

R¹

6a-l

7a-l

Product N–CH_AH_B(N=CH)

H_arom

Other Protons

(R¹, R²)

6a

6b

6c

6d

6e

3.71 (s)

3.69 (s)

3.71 (s)

3.63 (s)

3.59 (s)

7.39–7.19 (m)

7.46–7.21 (m)

7.21–7.07 (m)

7.37–7.20 (m)

7.39–7.19 (m)

1.80–1.48 (m)

1.67–1.28 (m)

1.76–1.40 (m)

1.68–1.44 (m)

1.55–1.10 [m, (CH₂)₆], 1.09 (s, 4-CH₃), 0.88 [t, CH₂CH₃,

J (CH₃,CH₂) = 6.8]

6f

3.82 (d), 3.66 (d), J (H_A,H_B) = 13.4

3.80 (d), 3.63 (d), J (H_A,H_B) = 13.4

3.32 (d), 3.56 (d), J (H_A,H_B) = 13.1

7.52–7.38 (m)

7.45–7.01 (m)

7-30–7.05 (m)

–

6g

6h

3.88 (s), OCH₃

7.32 (d, -H), 6.27 (dd, -H),

6.13 (d, -H), J = 1.8, J = 3.4

,

6i

6j

3.30 (d), 3.40 (d), J (H_A,H_B) = 13.3

3.64 (d), 3.53 (d), J (H_A,H_B) = 13.5

7.06–6.94 (m)

7.32–7.28 (m)

8.32 (d, -H), 7.38 (dt, -H), 7.10 (d, -H), 6.88 (dt, -H)

8.55(d, -H), 8.50 (dd, -H), 7.73 (dt, -H), 7.23 (t, -H),

J

=7.7, J =6.2, J =1.8, J =1.5

, , ,

,

6k

3.66 (d), 3.51 (d), J (H_A,H_B) = 13.4

7.40–7.15 (m)

8.56 (AA , -H),

7.44–7.15 (BB , -H)

Synthesis 2002, No. 6, 771–783 ISSN 0039-7881 © Thieme Stuttgart · New York

776

A. Varlamov et al.

PAPER

Table 3 ¹H NMR Spectra [CDCl₃/TMS, , J (Hz)] of 4-N-Benzylaminobut-1-enes 6a–l and N-Benzylidene-N-butenylamino-N-oxides

7a–l (continued)

H-cis

H₁-cis

H-trans

1

-

H

N

O

2

H-trans

4

3

N⁺

R²

4

3

R²

R¹

6a-l

7a-l

Product N–CH_AH_B(N=CH)

H_arom

Other Protons

(R¹, R²)

6l

3.68 (s)

7.22–7.13 (m)

1.23–1.18 [m, (CH₂)₈], 0.80 [t, CH₂CH₃, J (CH₃,CH₂) =

6.9]

7a

7b

7c

7d

7e

7.37 (s)

7.39 (s)

7.38 (s)

7.39 (s)

7.41 (s)

8.24, 7.45–7.35 (m)

8.30-7.45 (m)

2.53–1.54 [m, (CH₂)₄]

2.35–1.35 [m, (CH₂)₅]

2.56–1.38 [m, (CH₂)₆]

2.38, 1.84–1.48 [m, (CH₂)₇]

8.29, 7.45–7.30 (m)

8.34, 7.48–7.30 (m)

8.30, 7.52–7.40 (m)

2.20–1.20 [m, (CH₂)₆], 1.52

(s, 4-CH₃), 0.85 [t, CH₂CH₃,

J (CH₃,CH₂) = 6.7]

7f

7.54 (s)

7.46 (s)

7.41 (s)

8.24, 7.41–7.35 (m)

8.19, 7.40-7.30 (m)

8.22, 7.43–7.35 (m)

7.58 (H_m,o), 7.40–7.35 (H_p)

7g

7h^a

7.47 (H_o,o), 6.88 (H_m,m), 3.78 (s, OCH₃)

7.43 (d, -H), 6.55 (d, -H),

6.41(dd, -H), J =1.8, J =3.4

,

7i

7j

7.66 (s)

7.50 (s)

7.40–7.27 (m)

7.35–7.20 (m)

8.58 (d, -H), 8.24 (t, -H), 7.75 (d, -H), 7.72 (t, -H), J

= 4.8, J =3.9, J =1.2, J =1.7

,

8.60 (d, -H), 8.50 (dd, -H), 8.15 (t, -H), 7.98 (dt, -H),

=7.7, J =6.5, J =2.2, J =1.6

J

,

7k

7l

7.51 (s)

7.26 (s)

8.23, 7.43–7.41 (m)

8.18, 7.34–7.30 (m)

8.63 ( , -H), 7.49 ( , -H)

1.23–1.15 [m, (CH₂)₈], 0.78 [q, CH₃, J (CH₃,CH₂) = 6.7]

^aInternal reference: HMDS (hexamethyldisilane).

During the elaboration of our strategy, we mentioned that taining a pyridine ring possess a higher activity and that

nitrone precursors are not only versatile and excellent the replacement of the aromatic substituents at C-4 with

building blocks in the preparation of novel heterocyclic spiroalkylidene fragment resulted in a decrease in poten-

structures by use of 1,3-dipolar cycloaddition, both in in- cy.³⁴

ter- and intramolecular version^25,26or by use of the nu-

The heterobicyclic skeleton was then constructed by an

intramolecular thermal cyclisation of nitrones 7a–h and

7k,l which proceeded smoothly in benzene or toluene to

give the corresponding 2-substituted 6-exo-phenyl-1-aza-

7-oxabicyclo[2.2.1]heptanes 8a–j (Scheme 2). The in-

tramolecular 1,3 dipolar cycloaddition of alkenylnitrones

7a–d and 7f,g,l occurs with a high degree of stereoselec-

tivity with the formation of 2-spiroannulated 6-exo-phe-

nyl-1-aza-7-oxabicyclo[2.2.1]heptanes 8a–d or 2-exo-

aryl(n-nonyl)-6-exo-phenyl-1-aza-7-oxabicyclo-[2.2.1]-

heptanes 8f,g,j, respectively, as the major isomeric prod-

ucts with yields ranging from 48 to 83%. These major 2-

cleophilic addition reactions,²⁷but are also effective in

trapping short-lived free radical species and potent antiox-

idants.^28–30The effectiveness of radical scavengers in re-

ducing oxidative stress within a living biological

environment has not been established;³¹however, one

molecule under investigation as a therapeutic agent is phe-

nyl-tert-butylnitrone (PBN),³²which has shown promis-

ing activity as a neuroprotector in certain animal

models.³³The design and synthesis of analogues of PBN

are still needed. Moreover, their alicyclic analogues bear-

ing a quaternary carbon at a nitrogen atom, are not acces-

sible. Antioxidant activity of the obtained nitrones 7d–f

exo-, 6-exo-isomers were isolated and purified either by

and 7i–l showed that these compounds possess moderate

fractional crystallisation (8a–c,f,g) or by alumina column

potency (20–55% compared to BHT) as inhibitors of lipid

chromatography (8d,e,j)³⁵(Table 4).

peroxidation. It was established that nitrones 7i–k, con-

Synthesis 2002, No. 6, 771–783 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER

A Stereoselective Route to All-cis-2,6-Disubstituted 4-Hydroxypiperidines

777

Table 4 1-Aza-7-oxabicyclo[2.2.1]heptanes 8a–j and 2,6-Disubstituted 4-hydroxypiperidines 9a–i

Product^a

Molecular

Mp (°C)^b

R_f

IR (cm^–1)

Yield (%)

Mass (m/z)

(Silufol UV₂₅₄

)

/

NH OH

Found (M^+.)

Calcd

229

243

257

271

287

251

281

241

252

301

231

245

259

273

289

253

283

243

303

8a

8b

8c

8d

8e

8f

229

78–80

88–89

96–97

oil

0.64^c

0.53^d

0.63^e

0.65^e

0.59^e

0.50^c

0.57^c

0.45^f

0.53^d

0.60^c

0.64^g

0.51^h

0.54^g

0.60^g

0.53^g

0.57^g

0.44^h

0.40^h

0.53^g

–

50

83

48

75

60

56

34

36

73

75

76

78

75

72

75

66

45

73

243

–

257

–

271

–

287

oil

–

251

97–100

126–128

36–37

88–89

38–40

51–54

102.5–103.5

oil

–

8g

8h

8i

281

–

241

–

252

–

8j

301

–

9a

9b

9c

9d

9e

9f

231

3380/3240

3480/3280

3385

245

259

273

oil

3338

289

85–87

113–114

101–103

73.5–75.0

68–70

3259

253

3275/3210

3400

9g

9h

9i

283

243

3382

303

3285/3220

^aAll compounds showed satisfactory elemenatal analyses: C, 0.26; H, 0.18; N, 0.13.

^bSolvent for recrystallisation: EtOAc–hexane.

^cEtOAc–hexane (1:5).

^dEtOAc–acetone (2:1).

^eEtOAc–hexane (1:10).

^fEtOAc–hexane, (1:3).

^gEtOAc–hexane, (1:1).

^hEtOAc.

An intramolecular [3+2] cycloaddition reaction of ni- also successfully isolated by alumina column chromatog-

trones 7h and 7k proceeded more slowly than that of ni- raphy.

trones 7a–d and 7f,g and resulted in the formation of

considerable amounts of 2-endo-, 6-exo-substituted prod-

1

Due to the structural similarity, the mean signals in H

NMR spectra of dominant isomers of compounds 8a–j

ucts. The ratio of 2-exo-, 6-exo-/2-endo-, 6-exo-isomers

were assigned largely on the basis of correlation to the

1

found by H NMR in reaction mixtures is 5:1. In these

chemical shifts and vicinal coupling constants in spectra

cases, the individual exo-, exo-isomers of 2-hetaryl substi-

of previously investigated 2-phenyl-1-aza-7-oxabicyc-

tuted bicycles 8h,i were isolated in moderate yields (34

lo[2.2.1]heptane¹²and 6-substituted 2-methyl-3-trime-

and 36%) by fractional crystallisation of the reaction mix-

thylsilyl-1-aza-7-oxabicyclo[2.2.1]heptanes.³⁶

tures.

Chemical shifts in spectra of compounds 8a–j have been

measured by irradiation of the samples in CDCl₃and C₆D₆

solutions. Unfortunately, the results of irradiation in

CDCl₃were not clear enough to compare with those re-

An intramolecular [3+2] cycloaddition reaction of nitrone

7e proceeded with moderate stereoselectivity and led to

bicycloheptane 8e, which was characterized by GC-MS as

a mixture of two isomers in a 2.2:1 ratio. However, the

ported by Lumma¹²and Wuts.³⁶For this reason we used

major isomer, identified as 2-endo-methyl-2-exo-n-hep-

C₆D₆solution in order to determine the 4-H, 5-H , 5-H

tyl-6-exo-phenyl-1-aza-7-oxabicyclo[2.2.1]heptane, was

Synthesis 2002, No. 6, 771–783 ISSN 0039-7881 © Thieme Stuttgart · New York

778

A. Varlamov et al.

PAPER

O

OH

Ph

ii

N

Ph

( )_n

N

H

(

)

n

H

8a-d

8a,9a n= 1; 8b,9b n= 2;

8c,9c n= 3; 8d,9d n= 4

9a-d

O

N

OH

i

O^-

Ph

i

CH₃

ii

C₇H₁₅

CH₃

+

N

H

N

Ph

R¹

H

R²

7a-h,7k,l

8e

9e

i

OH

O

N

ii

Ph

+

R¹

Ph

N

H

N

Ph

N

H

α−furyl

Ph

R¹

2-endo, 6-exo

2-exo, 6-exo

8f-j

9f-i

9h´

8f,9f R¹= C₆H₅; 8g,9g R¹= 4-CH₃OC₆H₄; 8h,9h,9h´ R¹= α−furyl; 8i R¹= γ−pyridyl;

8j,9i R¹= (CH₂)₈CH₃

Scheme 2 Reagents and Conditions: i) benzene or toluene, reflux, 5–10 h; ii) 80% AcOH/Zn, 60–65 °C, 3–5 h.

and 6-H absorptions and their vicinal coupling constants agreed with those determined previously (J_{5 ,6}= 8.2–8.3

(Tables 5, 6). Our detailed explications for these NMR and J_{5 ,6}= 4.3–5.6 Hz).^12,36The exo-orientation of C-2

experiments have been recently described¹⁷taking the 1- substituents (phenyl, 4-methoxyphenyl, n-heptyl, -furyl,

aza-6-phenyl-2-spiro-7-oxabicyclo[2.2.1]heptane-2,1 -

-pyridyl) in bicycloheptanes 8f–j has been established in

cyclohexane 8b as a model molecule. Thus, the exo rela- the same manner (J_{2 ,3}= 7.3–8.3 and J_{2 ,3}= 4.3–4.6 Hz).

tive stereochemistry of C-6 phenyl group in major isomers

of all analysed bicycloheptanes was inferred by the values

of coupling constants J_5,6(7.0–8.3 and 4.3–5.5 Hz) which

Table 5 ¹H NMR Spectra [( , J (Hz)] of 1-Aza-7-oxabicyclo[2.2.1]heptanes 8a–j

O

β

5

4

Ph

3

2

R¹

N

1

6

R²

α

8a-j

Product

Solvent^a2 -H

3 -H

4-H

5a-H

b

8a

CDCl₃

–

1.47 (d)

–

4.97 (t,

2.14 (dd,

J_3a,3b= 11.3

J_4,3=5.2, J_4,5=5.2)

J₅= 11.3, J₅

,5

,6

= 8.2)

b

C₆D₆

–

0.87 (d, J₃= 11.3)

–

4.40 (t,

-

,3

J_4,3= 4.9, J_4,5= 4.9) (J₅= 7.9)

,6

8b

8c

CDCl₃

1.23 (d, J₃= 11.3)

1.82 (dd,

J_{3 ,4}= 5.3)

4.89 (dt,

~2.04 (m,

,3

J_4,5= 2.6,

J₅= 6.3)^c

,6

J_4,5= 2.6)^c

C₆D₆

–

0.58 (d, J₃= 11.3

1.34 (ddd,

J_{3 ,4}= 5.2,

4.31 (t,

1.41 (dd,

,3

J_4,3= 5.2, J_4,5= 5.2) J₅= 11.3,

,5

J₃= 2.4)

J₅= 8.2)

,5

,6

CDCl₃

1.36 (d,

1.77 (dd,

J_{3 ,4}= 5.2)

4.86 (dt,

~2.03 (m,

J₃= 11.3)

J_4,5= 2.6)^c

J₅= 6.3)^c

,3

,6

Synthesis 2002, No. 6, 771–783 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER

A Stereoselective Route to All-cis-2,6-Disubstituted 4-Hydroxypiperidines

779

Table 5 ¹H NMR Spectra [( , J (Hz)] of 1-Aza-7-oxabicyclo[2.2.1]heptanes 8a–j (continued)

O

β

5

4

Ph

3

2

R¹

N

1

6

R²

α

8a-j

Product

Solvent^a2 -H

3 -H

4-H

5a-H

C₆D₆

–

0.74 (d,

1.32 (ddd,

4.31 (t,

1.42 (dd,

J₃= 11.3)

J_{3 ,4}= 5.2, J₃= 2.2) J_4,5= 5.2)

J₅= 11.3,

,3

,5

J₅= 8.3)

,6

8d

CDCl₃

C₆D₆

–

1.34 (d,

1.75 (dd,

J_{3 ,4}= 5.2)

4.88 (dt,

~2.04 (m,

J₃= 11.3)

J_4,5= 2.6)^c

J₅= 6.3)^c

,3

,6

0.74 (d,

1.32 (ddd,

4.31 (t,

1.42 (dd,

J₃= 11.3)

J_{3 ,4}= 5.2, J₃= 2.2) J_4,5= 5.2)

J₅= 11.3,

,3

,5

J₅= 8.3)

,6

8e

8f

CDCl₃

C₆D₆

–

2.03 (m,

2.15 (dd,

4.83 (t,

J_4,5= 2.6)c

~2.03 (m,

J₃= 11.3)

J_{3 ,4}= 2.6)^c

J₅= 7.0)

,3

,6

b

0.88 (d,

–

4.34 (t,

J_4,5= 5.2)

1.49 (dd,

J₃= 11.3)

J_{3 ,4}= 5.2

J₅= 11.4,

,3

,5

J₅= 8.3)

,6

CDCl₃

C₆D₆

4.10 (dd,

J₂= 8.2, J₂

= 4.6)

2.27 (dd,

2.09 (ddd,

J_{3 ,4}= 4.9)

5.09 (t,

J_4,5= 4.9)

2.27 (dd,

J₃= 11.0)

J₅= 11.0,

,3

,5

J₅= 8.2)

,6

3.53 (dd,

1.48 (dd,

1.61 (ddd,

4.40 (t,

1.48 (dd,

J₂= 8.2,

J₃= 11.0)

J_{3 ,4}= 4.7)

J_4,5= 4.7)

J₅= 11.0,

,3

,5

J₂= 4.6)

J₅= 8.2)

,3

,6

8g

CDCl₃

C₆D₆

4.07 (dd,

2.25 (dd,

2.07 (ddd,

J_{3 ,4}= 4.9)

5.10 (t,

J_4,5= 4.9)

2.27 (dd,

J₂= 8.2, J₂

J₃= 11.2)

J₅= 11.2,

,3

,5

= 4.5)

J₅= 8.2)

,6

3.48 (dd,

1.45 (dd,

1.70–1.50^b

4.39 (t,

1.45 (dd,

J₂= 8.2,

J₃= 11.0)

(J_{3 ,4}= 4.6)

J_4,5= 4.6)

J₅= 11.0,

,3

,5

J₂= 4.3)

J₅= 8.2)

,3

,6

8h

8i

C₆D₆

3.60 (dd,

1.26 (dd,

1.79 (m,

J_{3 ,4}= 4.9, J₃

= 2.4)

4.34 (t,

J_4,5= 4.9)

1.33 (dd,

J₂= 8.2,

J₃= 11.6)

J₅= 11.6,

,3

,5

J₂= 4.6)

J₅= 8.2)

,3

,6

CDCl₃

C₆D₆

4.09 (dd,

2.32 (dd,

2.1–1.9^b

(J_{3 ,4}= 4.9)

5.09 (t,

J_4,5= 4.9)

2.29 (dd,

J₂= 8.3, J₂

J₃= 11.8)

J₅= 11.8,

,3

,5

= 4.6)

J₅= 8.3)

,6

3.21 (t,

1.30 (m)

4.27 (m)

1.38 (dd,

J₂= 6.5,

J₅= 11.6,

,3

,5

J₂= 6.5)^c

J₅= 8.2)

,3

,6

8j

CDCl₃

2.79 (m,

1.71 (dd,

1.48 (m,

4.84 (t,

1.88 (m,

J₂= 7.3,

J₃= 11.5)

J_{3 ,4}= 4.9)

J_4,5= 4.8)

J₅= 11.6,

,3

,5

J₂= 4.4)

J₅= 8.3)

,3

,6

^aInternal refernce: TMS.

^bOverlapped with other protons.

^cCoupling constants were measured using the first order NMR spectra approximation.

780

A. Varlamov et al.

PAPER

Table 6 ¹H NMR spectra [ , J (Hz)] of 1-Aza-7-oxabicyclo[2.2.1]heptanes 8a–j

O

β

5

4

Ph

3

2

R¹

N

1

6

R²

α

8a-j

Product Solvent^a

5 -H

6 -H

H_arom

Other Protons (R¹, R²)

b

8a

8b

8c

8d

8e

8f

CDCl₃

–

4.32 (dd,

7.42, 7.35–7.20 (m)

1.95–1.59

(m)

J₆= 5.2)

,5

b

C₆D₆

–

4.01 (dd,

7.40, 7.22-6.85 (m)

7.47–7.11 (m)

2.15–1.15 (m)

J₆= 5.2)

,5

CDCl₃

C₆D₆

2.04 (m,

4.50 (t,

1.96–1.17 (m)

J₅= 6.3)^c

J₅= 6.3,^cJ₅= 6.3)^c

,6

1.63 (dddd,

J₅= 4.3)

4.14 (dd,

7.44, 7.20–6.90 (m)

7.45, 7.35–7.10 (m)

7.48, 7.15–6.93 (m)

7.45, 7.35–7.15 (m)

7.48, 7.15–6.90 (m)

7.42, 7.35–7.10 (m)

7.43, 7.20–6.90 (m)

7.45, 7.41–7.08 (m)

7.45, 7.25–6.95 (m)

6.90, 7.49–7.15 (m)

6.76, 7.50–6.95 (m)

7.35, 7.15–6.90 (m)

7.50–7.15 (m)

1.25–0.95 (m)

J₆= 4.3, J₆= 8.2)

,6

,5

CDCl₃

C₆D₆

2.03 (m,

4.48 (t)

2.28–1.24 (m)

J₅= 6.3)^c

,6

1.62 (dddd,

J₅= 4.3)

4.14

(dd)

2.36 (dd), 1.78–0.93 (m)

2.30–1.25 (m)

,6

CDCl₃

C₆D₆

2.04 (m,

4.50

(t)

J₅= 6.3)^c

,6

1.62 (dd,

J₅= 4.3)

4.14

(dd)

2.36 (dd), 1.80–0.90 (m)

,6

CDCl₃

C₆D₆

2.03 (m,

J₅= 5.5)

4.44

(dd)

1.30 (s, 2-CH₃), 0.88 (t, CH₂CH₃), 2.04–

1.26 [m, (CH₂)₅]

,6

1.62 (dddd,

J₅= 4.3)

4.14

(dd)

0.87 (s, 2-CH₃), 0.78 (t, CH₂CH₃), 1.85–

0.76 [m, (CH₂)₅]

,6

CDCl₃

C₆D₆

2.09 (ddd,

J₅= 4.6)

4.10

(dd)

–

,6

1.61 (ddd,

J₅= 4.6)

3.53

(dd)

–

,6

8g

CDCl₃

C₆D₆

2.09 (ddd,

J₅= 4.5)

4.10

(dd)

3.80 (s, OCH₃)

3.22 (s, OCH₃)

,6

1.50–1.70^b(J₅

4.3)

=

3.50

(dd)

,6

8h

8i

C₆D₆

1.48 (ddt, J₅

4.9)

=

3.41

(dd)

7.01 (dd, -H), 6.22 (m, -H), 6.00 (dd,

,6

-H), J = 1.8, J = 0.9, J = 3.4

,

CDCl₃

C₆D₆

2.1–1.9,^b

J₅= 4.6)

4.07

(dd)

8.53 (AA , -Pyr)

,6

1.52 (m,

J₅= 4.9)

3.39

(dd)

7.38, 7.40–7.10 (m)

7.32, 7.25–7.10 (m)

8.49 (AA , -Pyr), 7.05 (BB - -Pyr)

,6

8j

CDCl₃

2.02 (dd,

J₅= 4.8)

3.79

(dd)

1.81 [m, CH₂(CH₂)₇], 1.64–1.61 (m, 2-

CH_2B), 1.37–1.34 (m, 2-CH_2A), 0.80 [t,

(CH₂)₈CH₃, J (CH₃,CH₂) = 6.7]

,6

^aInternal refernce: TMS.

^bOverlapped with other protons.

^aCoupling constants were measured using the first order NMR spectra approximation.

PAPER

A Stereoselective Route to All-cis-2,6-Disubstituted 4-Hydroxypiperidines

781

Finally, reductive cleavage of the N–O bond of heterocy- only major isomer 9h was successfully isolated by frac-

clic bicycles 8a–j was performed with a 5–6 fold excess tional crystallisation of the reaction mixture. New all-cis-

of zinc in the presence of 80% acetic acid at 60–65 °C. R-substituted 4-hydroxypiperidines 9a–i are fully charac-

Under these reaction conditions, all major individual iso- terized by physical and spectral methods (Table 4). Anal-

1

mers of the above mentioned bicycloheptanes have been ysis of the H NMR spectra of these piperidines showed

subjected to this reduction, except for the compound 8h that the C-4 hydroxyl (J_3a,4a= J_4a,5a= 11.3–12.3 Hz,

which has been treated as a mixture of isomers. The re-

J_3e,4a= J_4a,5e= 4.3–5.5 Hz), C-6 phenyl (J_5a,6a= 11.3–12.4

ductive cleavage of the N–O bridged bond proceeded Hz) and C-2 R¹(phenyl, 4-methoxyphenyl, furyl, n-non-

smoothly with the formation of all-R-cis-substituted 4-hy- yl) (J_2a,3a= 11.2-11.6 Hz) substituents are all oriented

droxypiperidines 9a–g and 9i (Scheme 2). Of all bicycles equatorially. Together, these facts were taken as evidence

underwent reductive cleavage, only the cleavage of 8i for the all-cis stereochemistry of obtained piperidines 9a–

with pyridyl substituent resulted in a complex mixture of i with the chair conformation (Tables 7, 8). The structure

products that is probably due to the formation of appropri- of all-cis-4-hydroxy-6-phenyl-2-(n-nonyl)piperidine (9i)

ate di- and tetrahydropyridines as final byproducts of par- was confirmed also by COSY and NOESY techniques. It

tial and total reduction of the pyridine ring. For this was also established by ¹H NMR spectrum of the mixture

reason, the nitrones 7i and 7j with - and -pyridyl sub- of isomers 9h and 9h , that the minor isomer 9h has the

stituents were not transformed to respective bicycles. Re- furyl and hydroxyl groups in trans configuration

ductive cleavage of the N–O bond of molecule 8h (as a (J_2e,3a= 5.8, J_2e,3e= 1.7 Hz).

mixture of isomers) also led to a mixture of isomers 9h

and 9h in 4:1 ratio (determined by ¹H NMR), from which

Table 7 ¹H NMR Spectra [CDCl₃/TMS, , J (Hz)] 2,6-Disubstituted 4-Hydroxypiperidines 9a–i

a

R²

4

e

HO

R¹

N

2

a

e

a

6

H

Ph

a

9a-i

Product 2a-H

3a-H

3e-H

4a-H

5a-H

9a

–

1.41 (t, J_3a,3e= 11.6,

1.88 (ddd, J_3e,4a= 4.3,

J_3e,5e= 2.4)

3.84 (tt, J_4a,5a= 11.6,

J_4a,5e= 4.3)

1.39 (q, J_5a,5e= 11.6,

J_5a,6a= 11.6)

J_3a,4a

=

11.6)

9b

9c

9d

9e

9f

–

1.14 (t, J_3a,3e= 11.6,

J_3a,4a= 11.6)

2.04 (ddd, J_3e,4a= 4.6,

J_3e,5e= 2.4)

4.00 (tt, J_4a,5a= 11.6,

J_4a,5e= 4.6)

1.39 (q, J_5a,5e= 11.6,

J_5a,6a= 11.6)

1.13 (t, J_3a,3e= 11.6,

J_3a,4a= 11.6)

2.00 (ddd, J_3e,4a= 4.6,

J_3e,5e= 2.4)

3.93 (tt, J_4a,5a= 11.6,

J_4a,5e= 4.6)

1.34 (q, J_5a,5e= 11.6,

J_5a,6a= 11.6)

1.08 (t, J_3a,3e= 11.6,

J_3a,4a= 11.6)

2.06 (ddd, J_3e,4a= 4.6,

J_3e,5e= 2.4)

3.98 (tt, J_4a,5a= 11.6,

J_4a,5e= 4.6)

1.34 (q, J_5a,5e= 11.6,

J_5a,6a= 11.6)

1.63 (dd, J_3a,3e= 12.1,

J_3a,4a= 11.4)

2.13 (dd, J_3e,4a= 4.6)

3.99 (ddd, J_4a,5a= 12.3, 1.51 (q, J_5a,5e= 12.1,

J_4a,5e= 5.5)

J_5a,6a= 12.4)

3.84 (dd, J_2a,3a= 11.3,

J_2a,3e= 2.1)

1.54 (ddd, J_3a,3e= 11.3, 2.16 (ddd, J_3e,4a= 4.6)

J_3a,4a= 11.3)

3.93 (tt, J_4a,5a= 11.3,

J_4a,5e= 4.6)

1.54 (ddd, J_5a,5e= 11.3,

J_5a,6a= 11.3)

9g

9h

3.84 (dd, J_2a,3a= 11.6,

J_2a,3e= 2.5)

1.56 (q, J_3a,3e= 11.6,

J_3a,4a= 11.6)

2.16 (m, J_3e,4a= 4.9)

3.93 (tt, J_4a,5a= 11.6,

J_4a,5e= 4.9)

1.56 (q, J_5a,5e= 11.6,

J_5a,6a= 11.6)

3.96 (br dd, J_2a,3a

=

1.68 (q, J_3a,3e= 11.6,

J_3a,4a= 11.6)

2.31 (ddt, J_3e,4a= 4.6,

J_3e,5e= 2.4)

3.91 (tt, J_4a,5a= 11.6,

J_4a,5e= 4.6)

1.58 (q, J_5a,5e= 11.6,

J_5a,6a= 11.6)

11.6, J_2a,3e

=

2.4)

9h

9i

4.51 (2e-H, br dd, J_2e,3a1.91 (ddd, J_3a,3e= 12.8, 2.46 (m, J_3e,4a= 4.6,

4.10 (tt, J_4a,5a= 11.6,

J_4a,5e= 4.6)

1.62 (q, J_5a,5e= 11.6,

J_5a,6a=11.6)

= 5.8, J_2e,3e= 1.7)

J_3a,4a= 11.6)

J_3e,5e= 2.4)

2.60 (m, J_2a,3a=11.2,

J_2a,3e=2.8)

1.06 (q, J_3a,3e= 11.6,

J_3a,4a= 11.3)

1.92 (ddd, J_3e,4a= 4.6,

J_3e,5e= 2.2)

3.68 (ddd, J_4a,5a= 11.0, 1.36 (q, J_5a,5e= 11.3,

J_4a,5e= 4.6) J_5a,6a= 11.3)

782

A. Varlamov et al.

PAPER

Table 8 ¹H NMR Spectra [CDCl₃/TMS, , J (Hz)] 2,6-Disubstituted 4-Hydroxypiperidines 9a–i

a

R²

4

e

HO

R¹

N

2

a

e

a

6

H

Ph

a

9a-i

Product

5e-H

6a-H

6-Ph

Other Protons (R¹, R²)

1.78–1.46 (m)

9a

2.09 (ddt,

3.75 (dd)

7.48–7.12 (m)

J_5e,6a= 2.4)

9b

9c

9d

9e

2.14 (ddt,

J_5e,6a= 2.4)

3.87

(dd)

7.35

(m)

1.79–1.20 (m)

1.90–1.35 (m)

2.15–1.23 (m)

2.11 (ddt,

J_5e,6a= 2.4)

3.82 (dd)

3.86 (dd)

3.92 (dd)

7.50–7.15 (m)

7.47–7.05 (m)

7.30–7.15 (m)

2.13 (ddt,

J

_5e,6a= 2.4)

2.16 (dd,

J_5e,6a= 2.4)

4.79 (s, 1 H, OH), 3. 45 (s, NH), 1.92

(s, CH₃), 1.30–1.20 [m, (CH₂)₆], 0.86

(t, CH₂CH₃)

9f

2.16 (ddd,

3.84 (dd)

3.82 (dd)

3.81 (dd)

7.50–7.15 (m)

J

_5e,6a= 2.1)

9g

9h

2.16 (m,

J_5e,6a= 2.5)

6.86, 7.48–7.19 (m)

7.45–7.23 (m)

6.86, 7.48–7.19 (m), 3.79 (s, OCH₃)

2.15 (ddt,

J_5e,6a= 2.4)

7.32 (dd, -H, J = 1.8, 0.8), 6.30 (dd,

-H, J = 3.1, 1.8),

6.20 (dd, -H, J = 3.1, 0.8)

9h

9i

2.08 (ddt,

J_5e,6a= 2.4)

3.77 (dd)

3.56 (dd)

7.45–7.23 (m)

7.30–7.15 (m)

7.32 (dd, -H, J = 1.8, 0.8), 6.35 (dd,

-H, J = 3.1, 1.8),

6.23 (dd, -H, J = 3.1, 0.8)

2.00 (ddd,

1.30–1.11 [m, (CH₂)₈],

J

_5e,6a= 2.3)

0.80 (t, CH₂CH₃)

and Kratos MS25 RF mass or Finnegan MAT95XL spectrometers.

Microanalyses were performed on a Perkin Elmer 2400 Series II an-

alyzer. The purity of the obtained substances and the composition

of the reaction mixtures were controlled by TLC Silufol UV₂₅₄

plates. The separation of the final products was carried out by col-

umn chromatography on Al₂O₃or by fractional crystallisation.

In summary, a family of the phenyl 4-hydroxypiperidine

derivatives at position C-6 with different substituents and

variable steric size spirocyclic fragments at position C-2

has been synthesized following the molecular modelling

of some relevant dendrobate alkaloids to study their phar-

macological properties. The results given here represent

an original approach using accessible homoallylic amines

as starting materials to prepare stereoselectively 2,6-dis-

ubstituted 4-hydroxypiperidines, including new all-cis-2-

spiro-4-hydroxy-6-phenylpiperidines as well as the all-

cis-4-hydroxy-6-phenyl-2-n-nonylpiperidine.

4-Substituted 4-N-Benzylaminobut-1-enes 6a–l; General

Procedure

The imine 5a–l (0.30 mol) was slowly added dropwise at reflux to

a stirred solution of allylmagnesium bromide, prepared from allyl

bromide (39 mL, 0.45 mol) and Mg turnings (22.0 g, 0.90 mol) in

Et₂O (300 mL) or THF (300 mL) (for 5i–k). After the addition of

the Schiff base, the reaction mixture was stirred for 1 h at r.t. The

cooled mixture was taken up in sat. aq NH₄Cl solution (300 mL) un-

der ice cooling and extracted with Et₂O (3 100 mL). The organic

layer was dried (Na₂SO₄) and concentrated. The residue was dis-

tilled in vacuo to give the product 6a–l as colourless oils.

Tables 1, 2 and 3 contain the yields and some physical and spectral

properties of these compounds.

All reagents were purchased from Merck-Schuchardt and Aldrich

Chemical Co. All solvents were used without further purification.

Melting points were determined using a Fisher-Johns melting point

apparatus and are uncorrected. IR spectra were obtained on a Per-

kin-Elmer 599B-FTIR and UR-20 spectrometers as KBr pellets for

1

solid or as thin film for oils. H NMR spectra were recorded on a

Bruker WP-200 or WH-400 spectrometers for solutions (2%) in

CDCl₃or C₆D₆at 30 °C and using TMS or HMDS (hexamethyldis-

ilane) as internal standard. Chemical shifts are reported in ppm

units, and coupling constants (J) are quoted in Hz. Mass spectra

were obtained by electron impact at 70 eV on a Varian MAT-112

N-Benzylidene-N-3-butenylamino-N-oxides 7a–l; General

Procedure

Aq H₂O₂(50%, 34 mL, 0.60 mol) was added dropwise at 20 °C³⁷to

a

solution of the homoallylamine 6a–l (0.20 mol) and

PAPER

A Stereoselective Route to All-cis-2,6-Disubstituted 4-Hydroxypiperidines

783

Na₂WO₄2H₂O (0.33 g, 0.01 mol) in a mixture of acetone–H₂O (9:1,

150 mL). The reaction mixture was stirred at r.t. for 2–4 d (TLC

control) and then diluted with H₂O (400 mL). The organic products

were extracted with Et₂O (5 70 mL). The combined organic layers

were washed with H₂O (2 100 mL), dried (MgSO₄) and concen-

trated. Evaporation of the solvent and column chromatography (3

7 cm) on alumina (EtOAc–hexane, 1:10, as eluent) gave the pure ni-

trones. For 7a–h,k the residue solidified on standing. Further crys-

tallisation from hexane–Et₂O gave the corresponding nitrones as

colourless crystals. Tables 1, 2 and 3 contain the yields and some

physical and spectral properties of these compounds.

(6) Edwards, M. W.; Daly, J. W.; Myers, C. W. J. Nat. Prod.

1988, 51, 1188.

(7) Edwards, M. W.; Garraffo, H. M.; Daly, J. W. Synthesis

1994, 1167.

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Abst. 1991, 115, 158846.

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(13) Hoffman, R. W.; Endesfelder, A. Liebigs Ann. Chem. 1986,

1823.

(14) Holmes, A. B.; Swithenbank, C.; Williams, S. F. J. Chem.

Soc., Chem. Commun. 1986, 265.

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F.; Varlamov, A.; Martínez, J. R. J. Heterocycl. Chem. 1997,

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Kouznetsov, V. J. Heterocycl. Chem. 1998, 35, 183.

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1-Aza-7-oxabicyclo[2.2.1]heptanes 8a–j; General Procedure

A solution of nitrones 7a–l (0.10 mol) and benzene or toluene (100

mL) was refluxed for 5–10 h (monitoring by TLC). Evaporation of

the solvent left crude products as viscous oils. In all cases the major

isomer could be easily separated by simple short column chroma-

tography on alumina (4 3 cm, EtOAc–hexane, 1:10, as eluent, for

8d,e,j), or by fractional crystallisation of the reaction mixture from

hexane–EtOAc (all other compounds). Tables 4, 5 and 6 contain the

yields and some physical and spectral properties of these com-

pounds.

2,6-Disubstituted 4-Hydroxypiperidines 9a–i; General Proce-

dure

(18) Kouznetsov, V.; Palma, A. R.; Aliev, A. E. An. Quím. Int.

Ed. 1998, 94, 132; Chem. Abstr. 1999, 130, 52317.

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Kouznetsov, V. V.; Palma, A. R. Khim. Geterotsikl. Soedin.

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To a solution of 8a–j (40 mmol) in 80% AcOH (150 mL) was added

Zn powder (15.7 g, 0.24 mol). After stirring for 3–5 h at 60–65 °C

the transparent reaction mixture was cooled to r.t. The precipitate of

Zn(AcO)₂was filtered. The residue after removal of AcOH in vacuo

was combined with the precipitate of Zn(AcO)₂and dissolved in

H₂O (150 mL). A solution of 25% NH₄OH was added until the so-

lution became clear (pH 10–11). The mixture was then extracted

with CHCl₃(3 100 mL). The combined extracts were washed

twice with 5% NH₄OH solution (100 mL), dried (MgSO₄) and con-

centrated. The residue was purified by column chromatography on

alumina (for 9c–e,i) or by fractional crystallisation from a mixture

of hexane–EtOAc (all other compounds). Tables 4 and 7, 8 contain

the yields and some physical and spectral properties of these com-

pounds

(21) Vargas, L. M.; Rozo, W.; Kouznetsov, V. Heterocycles

2000, 53, 785.

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Watanabe, S. J. Org. Chem. 1990, 55, 1736.

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Padwa, A., Ed.; Wiley-Interscience: New York, 1984, 83–

168.

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A., Ed.; Wiley-Interscience: New York, 1984, 277–406.

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Acknowledgements

The authors are grateful for the financial support by the Russian

Foundation for Basic Research (grant No.99-03-32942) and by the

Colombian Institute for Science and Research (COLCIENCIAS,

grant 1115-05-353-96). V.K. also thanks Dr. E. Stashenko (Labora-

tory of Chromatography, School of Chemistry, Industrial Universi-

ty of Santander) for providing GC-MS spectra and to Dr. Ali Bahsas

(NMR Laboratory, Department of Chemistry, University of Mérida,

Venezuela) for the NMR measurements.

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(34) The detailed results from these studies will be published

elsewhere.

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the homoallylamines.

Article Doi

An improved and stereoselective route to all-cis-2,6-disubstituted 4-hydroxypiperidines from accessible 4-substituted 4-N-benzylaminobut-1-enes

DOI: 10.1055/s-2002-25770

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Full text of DOI:10.1055/s-2002-25770

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