Stereospecific synthesis of secondary amines by the Mitsunobu reaction

Tetiti

Letten.Vol.31.No.24.pi 34173420.1590

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SMXBBMRTABIBBS BY TBB KCTSUNUBU REACTI~ Michael L. Edwards*, David U. Stemerick and James R. McCarthy Herrell

Dow Research Institute,

2110 E. Galbraith

Rd.,

Cincinnati,

Ohio, 45215

amines from alcohols is reported with N-methyltriA facile synthesis of secondary Abstract: The reaction was demonstrated to profluoromethanesulfonamide (2) in the Mitsunobu reaction. a convenient synthetic route to the (R,R)ceed with inversion of configuration and provided 1 by utilizing either (R)- or and (S,S)-enantiomers (24 and 25) of the antitumor polyamine (S)-3-(N-methyltrifluor~ethan~ulfonamido)butan-l-o1 (11 or 22) and 1,7-bis-(trifluoroReagents 21 and 12 were preparehfrom commercially available methanesulfonamido)heptane (2). (S)- and (R)-1,3-butanediol, respectively.

Polyamines are critical amine analogs increased

are antitumor

interest

centers

for

both

agents.lp2

in efficient

polyamine syntheses,6 synthesis

in the growth of

The

the enantiomers

biochemical

methods for

we have prepared of

for antitumor activity.

-1

normal and neoplastic

their

syntheses.3-5

compound 1,

was

desired

We report

a

importance

a

to

H

H

1

tiomers

(2

and

demonstrate Protected

2)

of

as

a

1

which

the generality

A convenient

the importance

of the chiral

method to the (R,R)-

component,

Reaction conditions

by

suggested

providing

a

4HCl

chiral

the

(TfNECE,, 2; that both 2

H

pKa 7.5)“’ and

amines in

3417

amines.

of alcohols

Mitsunobu reaction,7,8 component.g 2

4Hcl

route

(2)

in the

In addition,

to secondary

we

amines.

and a key to the suc-

Examination of the pKa values of and N-methyl-p-toluenesulfonamide

might serve as useful

new stereospecific secondary

secondary

the conversion

of TfNRCH, (1) with both primary and secondary gave the Tf protected

and (S,S)-enan-

N-methyltrifluoromethanesulfonamide these

is the pKa of the acidic

N-methyltrifluoromethanesulfonamide (TsNBCR,, 2; pKa 11.7)1’

to

of this method for

primary amines can be obtained

cess of these reactions

acidic

utilizes

new method

poly-

agent.

25 Hitsunobu reaction

certain

of these compounds led to

potent antitumor

high yield

and

As part of our program of

ascertain

N-N

cells

to

alcohols

70-86X yield

protected

synthons for the secondary

amines.

under Bitsunobu reaction (see Table 1).12

N-Methyl-

3418

p-toluenesulfonamide

(2) gave significantly

53%) when reacted not surprising tion

with

synthons report

the same alcohols

based on the pKa values

(TfNHPh, $I4

pRa

4.51°)

for the preparation describing

lower yields

and

as

1 under Hitsunobu

of 1 and 2.l’

Ts

of Ts protected

of N-substituted

conditions.

(TsNRPh,

anilines.

-

Ph AOH

are

both Tf activaprovide

useful

During

the course

of this

work, a

reaction

appeared.’

reaction.

PNRR PNRR

l.@J*Y(P

These results

pRa 9.Y1)

Table 1. Comparison oi Tf and Ts activated amines in the Minobu

PNHR

(33-

?;I5

in the Hitsunobu

PNHR + R’OH

amines

In the case of anilines,

activation

N-alkyl-p-toluenesulfonamides

secondary

~~04

Ph*NTl%(D

w@P)“c

70

22smmn

L

We used the Tf activating Scheme 1 for alcohol

2 (Table

utilized third alcohol

1) and both

Ts activated

Ts activated step

methylamine

In addition,

the alcohol enantiomer

1

Preliminary

derived

of 12, the

activating were

in low yield

Table

First, 1).

introduction coupling

of Tf activated

using racemic

of mono and bis

provided

gave

by the same sequence

only bis as outlined

adduct

in the

in 90% yield.

in Scheme 1 starting

adducts.

In contrast

2 (Table

1,7-bis-(trifluoromethanesulfonamido)heptane 21)

of the

of 3J> and the

of more reagents.

methylamine

in Scheme 1

the coupling

(instead

in

the racemic

the introduction

Second,

a mixture

by the addition

to completion

using

When the sequence

groups.

(12,

of A as illustrated

were performed

encountered.

CH,CH(NTsCE,)CH,CX,QE)gave

from 2 (i.e., of g.lg

Tf

studies

1,7-bis-(p-toluenesulfonamido)heptane

not be forced

251’ was prepared

the (R)-enantiomer

and

proceeded using

of the enantiomers

preparation

two problems

from 12 (i.e.,

could

to the preparation yield.

Ts

amines,

of Scheme

derived

The reaction

group in the

the (R,R)-enantiomer’g.16

1) in 86% (22) and The (S,S)with x,l*

3419

Scheme 1. Preparation of compound &

To

demonstrate

the (R,R)-enantiomer of compound 1.

that the Uitsunobu reaction

the reductive

removal of the Tf group

transformations

outlined

proceeded with inversion

did

not

result

in loss

Compound 21 was converted

in Scheme 2.

methyltrifluoromethanesulfonamido)butane

(z),

and the

compared in this manner was 27 reaction.

prepared

2

(c-1.07,

CHCl,),

and (S)-(+)-2-butanol

respectively.

(Na, N&, THP, t-BuOH) and converted The optical fi-2-aminobutane CBCl,),

rotation

of this

(28) These -* respectively.

to

the

samples

(c=1.09

(30)

t-Boc

derivative

prepared

(3).

Also

by the Hitsunobu

CECl,),

-lS.OO (cz1.00,

Compound 27 was deprotected

compound was

two

to (R)-(-)-2-(N-

of material

from (R)-(-)-2-aminobutane

Samples prepared by these methods gave [a]$O’ -13.1

CHCl,) and -14.5O

(~~1.04,

from

rotation

and that

we performed the

in two steps

optical

by this method was compared to 22 prepared in two steps

of configuration

of chirality,

reductively

for ease of isolation

to yield

compared to 32 prep&red in two steps

from (R)-

gave

[ar]i’J’

-16.0”

(c-1.04,

CIiCl,) and -15.1°

Scheme 2. Proof of stereochemistry

In a typical

procedure

(S)-(+)-2-butanol

(30)

(0.74

0.01 mol) and N-methyltrifluoromethanesulfonamide TEP (10 ml) under nitrogen.

A solution

(1 ml) was added dropwise

and the reaction

removed at atmospheric tilled (2)

at (1.84

reduced

pressure

pressure

of diethyl

through a to

obtain

g, 0.01 mol),

(2)

triphenylphosphine

vas stirred of

glass

(2.62

(1.74

g, 0.01 mol) in TAP

for 5-10 min. helices

The solvent

and the residue

-14.5’

(~11.04,

CECl,).

was

was dis-

(R)-(-)-2-(N-methyltrifluoromethanesulfonamido)butane

g, 84%); bp 67-69OC (12 mm); [o];o”

g,

g, 0.01 mol) were combined in dry

azodicarboxylate

mixture column

(1.63

3420

In a typical butanol

deprotection

procedure,

(30 ml) and freshly

blue color

persisted

remove the NH,.

distilled

for 30 min.

The residue

27 (1.32

The reaction

was

the

organic

pressure gave 32 (0.82gz1,

72%)

diluted layer as

0.006 mol) was combined with TiiF (30 ml),

NH, (60 ml)

a

was warmed to 60°C under a condenser

stirred was

for

dried

liquid,

t-

at -7OOC and sodium metal was added until

with water (30 ml),

0.008 mol) was added and the mixture was ether (100 ml) and

g,

bp

lh.

and

di-t-butyldicarbonate

(1.74 g,

The mixture was then diluted

evaporated.

65-70°C

(0.25

Distillation mm); [o]i””

a

for 2 h to with

at reduced

-16.0

(c-1.04,

CHCl,) . In summary, we report

a

chiral

synthesis

of

fluoromethanesulfonamides

by

the

Mitsunobu

utilized

of

the

(R,R)-

in the synthesis

polyamine (1) and represents thesesze6.

a

secondary reaction.

and

significant

for

the synthesis

of 24 and

improvement 21.

from alcohols

was investigated

In addition,

utilizing

methodology 24

and N-alkyltriwas successfully

and 25 of the antitumor

over standard chiral

, as recently

BuOli/TBF) for removal of the trifluoromethanesulfonamido N-alkylamines

This

(S,S)-enantiomers

Use of N-alkyl-p-toluenesulfonamides

unsatisfactory

amines from alcohols

reported

polyamine syn-

by Ueinreb,

we describe

et al’,

group and the synthesis

of N-phenyl-

both TfNEPh (4) and TsNEPh (5).

RRPRRRNCRS

:: 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

Weinstock, L.T.; Rost, W.J.; Cheng, C.C. J. Pharm. Sci., 1981, 70, 956. Bergeron, R.J.; Neims, A.B.; HcManis, J.S.; Hawthorne, T.R.; Vinson, J.R.T.; Bortell, R.; Ingeno, M.J. J. Med. Chem., 1988, 31, 1183. Nagarajan, S.; Ganem, B. J. Org.l;~~.~t9~~;.~ 4856 and 1987, 52, 5044. Bergeron, R.J. Act. Chem. Res., Casara, P.; Danzin, C.; Metcalf, B.; Jung, M. J. Chem. Sot. Perkin Trans. I, 1985, 2201. Edwards, M.L.; Prakash, N.J.; Stemerick, D.M.; Sunkara, S.P.; Bitonti, A.J.; Davis, G.P.; Dumont, J.A.; Bey, P. J. Ued. Chem., in press. Henry, J.R.; Narcin, L.R.; McIntosh, H.C.; Scala, P.M.; Harris, G.D. Jr.; Weinreb, S.M. Tet. Lett., 1989, 30, 5709. Hitsunobu, 0.; Wada, M.; Sane, T. J. Amer. Chem. Sot., 1972, 94, 679. Mitsunobu, 0. Synthesis, 1981, 1. Trepka, R.D.; Barrington, J.K.; Belisle, J.W. J. ;;;.,Ci;;:, 1974, 39, 1094. Dauphin, G.; Kergomand, A. Bull. Sot. Chim. Pr., Purchased from Aldrich Chemical Co. All new compounds gave satisfactory elemental analyses and spectral data consistent with the assigned structure. Halononitrile (pKa 11.2), but not diethyl malonate (pKa 13.3) undergoes the Witsunobu reaction: Wada, M.; Mitsunobu, 0. Tetrahedron Lett., 1972, 1279. Brice, T.J.; Trott, P.W. U.S. Patent 2,732,398, 1956. 1952, 5, N6grAdi, T.; Vajda, M. Magyar KernLapja, 1949, 4, 709; Chem. Abstr., 8028. mp 241-2OC. NNR (300 Mtiz, D,O) 6 3.36 (m, 28); 3.15 (m, 4B); 3.06 (m, 4A); s, 6R); 2.18 (m, 2H); 1.96 (m, 2E); J.68 (m, 4B); 1.38 (m, 6H); 1.34 (d, 6H, J=6.5 ?lz). MS (CI) m/z=301 (M+H). [ali +ll.l” (c-1.0, H,O).

18.

!% (:p %$;‘;Ci8 NMR (m, 2H); (300 MHz 1.9; D (:, 0) 2H); 6 3.36 1.68(mim28);48);3.15 1 38 (mim48).6fI);3.06 1.34(mid,4H); 68, J-6.5 Hz). MS (CI) m/z=301 (M+E). [a]goO -10.3: (c-0.62, H,Oj. The synthesis of 22 from 34 is outlined below:

19.

Seebach, D.; ZUger, M.

(Rccoived in USA 14 March 1990)

Helv. Chim. Acta 1982, 65, 495.

was

a method (Na/NE,/t-