Stereochemical observations on the Wittig reaction of oxido phosphonium ylides with aldehydes

Tetrahedron Letters,Vo1.24,No.24,pp Printed in Great Britain

STEREOCHEMICAL

2477-2480,1983

OBSERVATIONS

OF OXIDO PHOSPHONIUM Bruce E. Maryanoff,* Chemical

Allen

Research

ON THE WITTIG REACTION

YLIDES WITH ALDEHYDES?

8. Reitz,

Department,

Spring House,

oo40-4039/83 $3.00 + .OO 01983 Pergamon Press Ltd.

and Barbara A. Duhl-Emswiler McNeil Pharmaceutical

Pennsylvania

19477

USA

Abstract: The reaction of aldehydes with oxido ylides shows a dramatic dependence of alkene stereochemistry on the distance between oxygen and phosphorus atoms; ylides with proximal 0 and P atoms favor production of g alkenes. The high r stereoselectivity with r-oxido ylides is not mainly attributable to intramolecular proton-exchange in a Wittig intermediate. The stereochemistry

of alkene formation in the Wittig reaction has attracted widespread for many years. 192 Although non-stabilized phosphonium ylides generally react with

interest aldehydes

to afford

and r-oxido4

ylides,

largely 1. alkenes,' which exhibit

stereoselectivity

of r-oxido

tion of a Wittig

intermediate

which

requires

tane/betaine), although

alkenes

from carbon

only a weakly

give accentuated

amounts

abolished

of E alkene,7

1

2

and homoallylic

centers,

show a dramatic contradict

aldehydes,

intermediate

with a-carboxy

group, it gives anomalously and (2) the exaggerated

even though 8

aldehydes.

Also,

a seven-membered

(oxaphosphe-

ylide k:6 (1) large amounts

production

of r

c-oxido ylide $ does not

cyclic

transition

state is

03:(CH2)3CH3

Br-

03;(CH2)nOH

Br-

(0 = C6H5)

4 (n = 2-5,8,11)

3

of the usefulness

have now studied ylide

The high E

proton transfer.

03P=CH(CH2)40-M+

allylic

the Wittig

by our observations

for aliphatic

03P=CH(CH2)3COO-M+

Because

to oxygen within

basic carboxylate

with aromatic

for intramolecular

E stereoselectivity.

by internal, base-induced equilibra5 4a,4b Wittig" mechanism ). This mechanism,

("trans-selective

into question

in reactions

enhanced

such as s-oxido3

has been rationalized

proton transfer

with ,$ is virtually

suitable

unexpectedly

has been drawn

t possesses

of r alkenes

ylides

there are some special exceptions,

of B- and r-oxido ylides in the stereoselective synthesis of 394 alcohols, we have been investigating this area systematically. We

(1) oxido phosphonium

and (2) an a-deuterio dependency

an intrinsic

ylides

r-oxido

with different ylide

of alkene stereochemistry

"trans-selective

distances

as a mechanistic on ylide chain

Wittig" mechanism

between

probe. length

as a major

the oxido and

Notably,

our results

(viz. 4J, and

source of the exaggerated

!Z_stereoselectivity. A standard hydes.

procedure

Each hydroxy

t Dedicated

was employed

phosphonium

to Professor

to evaluate

bromide

the reaction

salt (1 mmol),

Kurt Mislow on the occasion

2477

42-K,

of phosphonium was treated

of his 60th birthday.

ylides

with

with alde-

lithium

2478

hexamethyldisilazide

(LHMD, 2.1 mol-equiv)

min).

Benzaldehyde

color,

and the reaction

products

or hexanal

and analyzed;

a reference

standard

conditions

hexanal

it was 82/18

present

gave -Z/E ratios

salt, analogous selectivity,

"trans-selective

aldehyde

Wittig"

enhancement

11

g stereoselectivity

applicability

with hexanal,

benzaldehyde

at -78°C to form a Wittig

products

(equally

distributed

wash-out

by H/D exchange.

ca. 70% D (GLC/MS).

have been realized

in the homocinnamyl

Anomalous nucleophilic) the anionic

mechanism

residues and ylide

intermediate.

(stirred

corresponding

centers. caused

length.

(entries

to benzaldehyde,

relative

8-10; the

to reference

1.0 mol-equiv),

ylides:

alcohols.

to a small amount

by GLC/MS

(ca. 15%) of deuteri; source, ylide

k

(Z/E -- = 12:88), each

with @, were to require

Since residual

with 5 mol-equiv

species

of proton

alcohols

of exchangeable

in THF from

to 60-C to liberate

ca. 85% deuterio

with 5 mol-equiv

to

reacted with

20 min), treated

of homocinnamyl

distribution

an internal

epimer-

H and D (ca. 17% D) should D content

greatly

for the high r stereoselectivity

exceeded

17%,

(88% E_).14

is associated

in the phosphonium

to be principally

trend is evident

for 45 min, and rapidly warmed

does not account

g stereoselectivity

from $,a-%

of short chain

with two o-deuterated

(1.6 M in hexane,

If L alkene formation

then a statistical

for ylides

for benz-

Significantly

for oxido ylides

(6,). As a model, ylide 1 was produced

to give a mixture

ization mechanism,

conditions,

nucleophilic

experiments

Using this procedure,

was reacted with benzaldehyde

from the Figure.

is comparable

(Z/E -- = 62:38) contained

for both isomers),

related

stereochemistry

groups could be attributed 4a,4b betaine/oxaphosphetane. To explore the

intermediate

(proton source)

The olefinic

an equilibration

such a lithium

as a base in a

and some special

is lower relative

bearing

we conducted

with -n-butyllithium

olefin.

but a similar

for both aldehydes

of an intermediate

of hexamethyldisilazane

containing

by acting

with benzaldehyde

with hexanal

(zi ;;d m3P=CD(CH2)20-Lit

03PCD2(CH2)2CH3 Br

lithium pentoxide Thus,

is unable to augment E stereo-

length on reaction

being greatest

with ylides

of this mechanism,

03;=CD(CH2)2CH3

under

(entry 11) and for with

12 and 13).

importantly,

appreciated

(~20%) was observed

of g stereoselectivity

an internal equilibration

reaction

of chain

but it can be more readily

g stereoselectivity

for each.

Abnormal

appear

or, more

from $, under the standard

The influence

were conducted

Although

reactions

salt in oxido ylides, effect

from 2 to 5), E stereoselectivity

Fewer experiments Figure).

(entries

reaction

or hexanal

reaction.

abnormal g stereoselectivity (n ranging

reference

from 53:47 to 63:37

with ylides

in the Table.

is obvious,

the -Z/E ratio was 50:50

The benzaldehyde

by a lithium-salt

obtained

are presented

ranging

by GLC.l'

$ was reacted with benzaldehyde

for benzaldehyde

(entry 14).

to the intramolecular

either

Results

the -Z/E isomer ratios were determined

for comparison,

(Table):

(THF) at 23'C (15-30

was added, immediately dissipating the ylide 9 for 30-60 min. After quenching with water, the alkene

was stirred

were isolated

To establish

in 3 ml of tetrahydrofuran

(0.8 mol-equiv)

not only with the presence of anionic (or 6a but also with the appropriate proximity ylide,

The anomalous

r stereoselectivity

by intramolecular

A mechanistic

discussion

base-promoted is reserved

with oxido ylides epimerization

of

does not

of a Wittig-

for a full account

of our work.

2479

Wittig Reactions

Table.

entry

of Oxido Ylidesa phosphonium salt

aldehyde

mol-equiv base

Z/E

r;tTo

lb

0CHO

4a (n = 2)

2.1

28172

2c

OCHO

4a (n = 2)

2.1

3197

isolated yield 14% --

3d

QCHO

$

(n = 3)

2.1

4/96

80

4

0CHO

s

(n = 4)

2.1

15185

--

5

0CHO

$$ (n = 5)

2.1

26174

--

6

0CHO

g

(n = 8)

2.1

59/41

50

OCHO

x

(n = 11)

2.1

62138

68

2.1

42158

82

8

hexanal

4$ (n = 3)

ge

hexanal

$j (n = 5)

2.1

83117

--

loe

hexanal

M

2.1

9218

--

1.1

50/50f

86

1.1

63137

87

1.1

53147

--

1.1

82118

--

11

OCHO

129

0CHO

13h

OCHO

14e

(n = 11) 3 'L 3 QJ 3 'L 3 s

hexanal

(a) Reactions were performed under standard conditions (23'C) with LHMD, unless yt,l;e;wi.;e n = number of carbon atoms separating the oxygen and phosphorus atoms. noted. was added to the phosphonium salt and benzaldeyde at O'C, because of ylide instability. (c) Conducted with 2.1 mol-equiv of n-butyllithium (1.6 M in hexane) according to (d) The r-oxido ylide was also generated from published procedure (ref 3a, 3b). (e) Analyzed by 03P=CH2 and ethylene oxide (ref 4); a 4/96 z/E ratio was obtained. GLC/MS as the mixture of epoxides (prepared with MCPBA). (f) Four experiments showed a (g) Standard reaction of 3 but 1.0 mol-equiv of lithium deviation of l2% in g/E ratio. pentoxide (from fi-pentanol and LHMD -in situ) was present $-ior to addition of benzaldehyde. (h) Similar to footnote 9; 5.0 mol-equiv of lithium pentoxide present.

Figure. Variation of Z/E alkene ratio with distance between Dznd P atoms in oxido ylides from ,$a-jJ. Symbols are assiqned as follows: l benzaldehvde The reaction, n hexanal reaction. brackets around a data point denote departure from the standard LHMD reaction conditions (see Table). Reference reactions with are indicated by the horizontal dotte $ lines (entries 11 and 14); reference reactions with and added lithium pentoxide 0CH0, are ini icated by the shaded area (entries 12 and 13). Lines connecting the data points are present only as an aid to the viewer.

0’

1

I

I

9

1

2

3

4

I

1

1

,

,

5 6 7 8 9 Spacing Value. n

,

1011

,

,

12

2480

References 1.

I.; Rowley, A. G., in "Organophosphorus

(a) Gosney,

Ed., Academic

3. I. G. Cadogan, Stereochem. 2.

(a) Bestmanny

3: Pure w.

(a) Corey,

E. 3.; Shirahama,

Lett. I$$&

(a) Salmond,

3,

M.; Christmann,

Am. Chem. a. R. 3.; Sorgi, K. L. 2. -104, 3511; (e) Wasserman,

M.; Tatsuoka,

The base-induced

T.; Nakatsuka,

"trans-selective

although 5 stereoselectivity

8.

(a) Bernasconi,

9.

Reactions

10. Alkene protons

monitored

were analyzed

by reaction

"Organophosphorus

Reagents

New York, 1979, pp 207-211 IH NMR data were obtained 13. Generated

salt was prepared

(Received

m,

c,

by

lb

SChlOSSer,

and

of metal

(b) It should ion (Li, Na, K),

5979. Chem. &.

Reactions,"

m,

Caldin,

104, 3459 and E.; Gold, V.,

course. of the vinyl

us higher E stereoselectivities

reports

with ;-propyl Synthesis,"

on methylated

phosphonium

Br- and 2 mol-equiv deuterium

in analogous

1983)

bromide;

than

r-oxido ylides.4

see: Smith, D. J. H., in

J. I. G. Cadogan,

(b) Satisfactory

for the deuterated

via base-induced

'H NMR integrations

in a full paper.

and ref 3f.

in USA 9 February

M. J.

3859.

in -E/Z ratio over the reaction

have afforded

of g3P=CD2

results were obtained

Y.;

with those from GLC analysis.

in Organic

from B,$CD,(CH,),OH

A. P.;

with Na and K.

with literature

of this point will appear

29.

23, 1067; (g)

Lett. ,#3,&, 22, 4185;

by GLC and GLC/MS.

substitution

from ,@, consistent

12. (a) Synthesized

$$$,

790; (b)

1975.

gave isomer ratios consistent

Discussion

m,

D. Synthesis

(d) Ohfune,

with 1 is independent

with time showed no change

with methyl

a.

or mechanism.

B., in "Proton-Transfer

and Hall, London,

11. r-Oxide ylides

14. Similar

is diminished

(b) Gabon,

isomer mixtures

has the ylide

process

A.; Hoover,

%.

R. J.; Pulwer,

was first described

C. F.; Hibdon, S. A.; McMurry, S. E. J. @.

ref cited therein; Eds., Chapman

g,

A.

(c) Kozikowski,

Lett. m,

B. A. Tetrahedron

E. W. Tetrahedron

Meyers, A. I.; Collington,

9,

$T$T, 102, 6577;

reaction

bias for r olefin

m,

H. H.; Gambale,

N. ibid. $+$2,

Wittig"

to as a "Schlossler-type"

be noted that the abnormal

J. 2. 5.

45, 3350;

(f) Wang, C.-L. Tetrahedron

B. E.; Duhl-Emswiler,

(a) Maryanoff,

w.

ibid. I$$,

M. ibid. m,

4059;

(d) Corey, E. J.; Marfat,

J. L. J. m.

Schmiesing,

D.; Ciabatti,

P.; Venkateswarlu,

K. F.; Piskala, A; Coffinet,

M. A.; Havens,

(d)

A.; Schaaf,

F.; Paul, K. G.; Favara,

E. J.; Niwa, H.; Knolle,

A. P.; Ishida, H.; Chen, Y.-Y.

37 ,@#&, _,

S.; Venkateswarlu,

E. J.; Ulrich,

3231 and ref cited therein; 1587; (e) Corey,

W. G.; Barta,

has been referred

7.

(c) Corey,

&!@$, 103, 2823;

Chem. ,Q,Q!& 45, 4262.

H.; Terashima,

Kozikowski,

Ishiguro,

6.

H.; Yamamoto,

104, 2190;

100, 1942; (f) Schlosser,

Tetrahedron

M. w.

H. J. ibid. $$$Q, 52, 771;

2. Am_. Chem. x.

Cnem. $c_. ,#Q., 93, 1490; (b) Johnson, U. ibid. $38&

D. J. ibid. m,

Tomita,

Synthesis,"

(b) Schlosser,

&979, 51, 515; (b) Bestmann,

E.; Meier, G. P.; Snoble, K. A. J.

Tetrahedron

5.

m.

C.; Darst, K. P.; Still, W. C. J. a.

R .; Guzzi,

in Organic

New York, 1979, pp 17-153;

Sreekumar,

T. K. J. @.

4.

Press,

Reagents

1970, 5, 1.

(c) Vedejs,

3.

and Notes

deuterium

Press,

and 360-MHz

salt (98+% D content).

of!-BuLi

exchange

Ed., Academic

microanalytical

at -78OC.

The phosphonium

of $?.12b exchange

experiments

with hexanal.