Polymeric Reagents and Catalysts - American Chemical Society

8 Wittig Reactions on Polymer Supports Warren T. Ford

Downloaded by UNIV OF CALIFORNIA IRVINE on November 3, 2014 | http://pubs.acs.org Publication Date: May 5, 1986 | doi: 10.1021/bk-1986-0308.ch008

Department of Chemistry, Oklahoma State University, Stillwater, OK 74078

Polymer-supported Wittig reagents give excellent yields of alkenes using a wide variety of bases and solvents. The polymer-supported reagents are preferred to soluble Wittig reagents when separation of triphenylphosphine oxide from the product alkene is difficult. The most useful support for laboratory scale syntheses is 1-2% crosslinked p-polystyryltriphenylphosphine prepared by bromination of polystyrene and replacement of the bromine by lithium diphenylphosphide. More highly cross-linked supports may be needed for large scale reactions because of greater ease of filtration and suitability for use in flow reactors. Stabilized carbanions from phosphonates can be prepared in anion exchange resins and give high yield modified Wittig reactions by a method readily adapted to continuous processes. The Wittig reaction is the most general method for regiospecific introduction of carbon-carbon double bonds in organic synthesis (Scheme 1). The starting materials are usually readily available alkyl halides and aldehydes or ketones. Alkylation of triphenylphosphine gives a phosphonium salt that can be used directly, but often is recrystallized. Treatment of the phosphonium salt with a strong base converts it to a phosphorane, also known as an ylide from its zwitterionic resonance structure. The phosphorane cycloadds [2+2] to the carbonyl compound to form an intermediate oxaphosphetane, which decomposes to the alkene and triphenylphosphine oxide. Reviews of the synthetic scope and the mechanism of the Wittig reaction are available Scheme 1 1

2

PhP + R R CHX 3

1

2

Ph PCHR R X" + base 3

1

2

3

4

Ph P=CR R + R R CO 3

1

2

1

2

> Ph PCHR R X' 3

> Ph P=CR R + base-HX 3

1

2

3

4

> PhPO + R R C=CR R 3

0097-6156/86/0308-O155S08.75/0 © 1986 American Chemical Society

In Polymeric Reagents and Catalysts; Ford, W.; ACS Symposium Series; American Chemical Society: Washington, DC, 1986.

POLYMERIC REAGENTS A N D CATALYSTS

156

Although not all Wittig reactions proceed by exactly the same mechanism, an oxaphosphetane intermediate is common to all of the mechanisms (Scheme 2). The overall rates of the reactions depend upon the rates of formation of the oxaphosphetane and of its conversion to alkene and phosphine oxide. The stereochemistry of alkene formation depends on the rates of formation and conversion to product of the stereoisomeric oxaphosphetanes, and upon equilibration of the oxaphosphetane with starting materials and with zwitterionic intermediates in some cases (3-5). Scheme 2

1

Ph P=CR R

2

3


+

,/>

0=Cr3r4

^

In spite of its wide use, there are still three major problems with the Wittig reaction. 1) The stereochemistry often cannot be controlled. 2) Ketones and hindered aldehydes fail to react with phosphoranes that are hindered or are stabilized by strongly electron withdrawing substituents. 3) The by-product triphenylphosphine oxide can be difficult to separate from the product alkene. Often the alkene and the triphenylphosphine oxide cannot be separated by extraction, distillation, or crystallization, and column chromatography is required. Polymer-supported Wittig reagents overcome the problem o f separation of the triphenylphosphine oxide from the alkene (6-11). With polystyryldiphenylphosphine in place of triphenylphosphine, the by-product triarylphosphine oxide is bound to an insoluble polymer and removed from a solution o f the alkene by filtration. Such a reagent could be used in a column i n a continuous process in place o f the conventional batch processes of small scale organic synthesis. The polymer-bound phosphine oxide can be reduced to the starting phosphine and recycled. The cost of polymersupported Wittig reagents is much higher than the cost of conventional soluble Wittig reagents. Polymer-supported Wittig reagents do not solve the remaining problems of stereochemical control and of low reactivity of ketones, hindered aldehydes, and stabilized ylides. The polymer may exert stereochemical effects, but there are too few results so far to allow prediction of the courses of new reactions. This chapter is a comprehensive review of alkene syntheses with polymer-supported Wittig reagents to produce soluble and polymer-bound alkenes. It does not i n clude polymerizations of difunctional phosphoranes with difunctional carbonyl compounds, polymer-bound ylides of elements other than phosphorus, or other synthetic and catalytic uses of polymer-bound phosphines.


8.

FORD

Wittig Reactions on Polymer

157

Supports


Reactions of Polymer-Bound Phosphonium Ions Phosphonium Ions from p-Polystyryldiphenylphosphine. These reagents are polymer-bound analogs of the classic Wittig reagents prepared from alkyl halides and triphenylphosphine. The results are in Table I. In some cases yields in the original papers were corrected for recovered starting materials. Table I reports yields on the basis of the limiting reagent, either polymer-bound phosphonium ion or carbonyl compound, and it reports, when known, the amounts of starting materials that could have reacted but failed to react. Most of the reactions have employed polystyrenes cross-linked with 0.5-2% divinylbenzene. The data available do not show consistently better results with any one level of cross-linking. Degrees of functionalization (DF, the mol fraction of functionalized repeat units) of the phosphine polymers from 0.06 to 0.81 have been used, and high yield syntheses have been found throughout the range. The major factors that affect the results of the Wittig reactions are the method of synthesis of the polymer support and the solvent and base employed to generate the ylide. The methods used for the reactions are in the footnotes of Table I. Reactions of (p-PoIystyrylmethyl)triphenylphosphonium Ions. In these reactions the polymer-bound phosphorane reacts with an aldehyde or ketone to produce an alkene substituent on the polymer and leave the by-product triphenylphosphine oxide in solution, where it can be washed away from the polymer. The results are in Table II. Many of the same methods of phosphorane generation used to produce soluble alkenes were used. The yields in Table II are less accurate than the yields of micromolecular alkenes in Table I because of the difficulty of analysis of insoluble polymers. The yields have been based on weight changes of the polymer, analysis of the polymer for an element introduced during the reaction, the yield of triphenylphosphine oxide, or the amount of bromine consumed by the modified polymer. Polymer Functionalization p-Polystyryldiphenylphosphine. Copolymers of styrene and p-styryldiphenylphosphine (1) (23) in a 3/1 mole ratio cross-linked with 2 wt % divinylbenzene were used for some of the first polymer-supported Wittig reagents (12.20). Modest yields of alkenes and frequently unreacted aldehyde or ketone were recovered, as shown in the entries in Table I where "monomer" is the source of phosphine. Copolymer reactivity ratios for styrene (M ) and p-styryldiphenylphosphine ( M , r = 0.46 and r = 1.11 (29) or rj = 0.52 and r = 1.43 (10)), indicate that the copolymer initially formed from the 75/25 monomer mixture has a 64/36 composition. The mixture of m- and p-divinylbenzene likewise is incorporated rapidly into copolymer (31) with 2 wt % in the monomer mixture giving 4 wt % in the initially formed polymer. Consequently the pstyryldiphenylphosphine is incorporated preferentially into the more highly crosslinked parts of the heterogeneous polymer matrix. Although most of these sites can be alkylated to phosphonium ions, the more sterically demanding Wittig reaction fails at some of the least accessible sites. {

2

x

2

2

1 The more effective methods of preparation of polymer-bound triarylphosphine for Wittig reactions are 1) lithiation of the polymer followed by reaction with chlorodiphenylphosphine, and 2) reaction of brominated polystyrene with lithium or sodium diphenylphosphide as shown in Scheme 3.


In Polymeric Reagents and Catalysts; Ford, W.; ACS Symposium Series; American Chemical Society: Washington, DC, 1986. A A

A A A

PhCH=CHCHO

Ph C0

Ph C0

0.25

0.35

0.70

0.25

0.35

0.25

0.35

monomer

monomer

monomer

2

LiPPh

monomer

2

LiPPh

LlPPh

LiPPh

Mel

Mel

Mel

Mel

Mel

Mel

Mel

Mel

2

2

0.35

0.35

LiPPh

Mel

2

0.25

monomer

H

C H 0

4

9

1 9

2

(n-C H ) C=0

2

2

PhCOMe

6

£-ClC H CHO

PhCHO

(CH^)Jj>0

C

-~ 5 11

a

A

A

B

A

A

method-

Mel

compound

DF

a

carbonyl

source °f phosphine

ft l i d

C

C H = C H

1.5

1.09

1.0

1.05

1.0

1.5

2

2

9

1 9

2

2

2

(n-C H ) C-CH

2

Ph C-CH

2

Ph C=CH

2

PhCH=CHCH=CH

Ph(Me>:=CH

4

2

2

2

£-ClC H CH=CH 6

PhCH=CH

1.0

2

(CH^C=CH

(CH^7pC=CH

H

-~ 5 11

product

1.0

1.05

1.0

+

mol ratio P /C=0

2

(96)

(94)

(72)

(95)

(14)

(0.4)

0

13

13

12

13

0 (23)

12

14

12

12

13

12

(82)

(39)

(50) 0

(30)

0

(3)

% recovered l i t . C=0

(63)

(99)

(56)

% yield isolated (gc)

T a b l e I . S o l u b l e A l k e n e s from S o l u b l e C a r b o n y l Compounds and Phosphonium Ions Bound t o 0 . 5 - 2 . 0 % C r o s s - l i n k e d Polystyrenes



2

2

LiPPh

LiPPh

LiPPh

LiPPh

LiPPh

MeOCH Cl

MeSCH Cl

MeSCH Cl

MeSCH Cl

Me0 CCH Br

2

2

2

2

2

2

2

PhCHO

0.81

2

LiPPh

MeOCH Cl

2

(CHp^CO

0.81

2

LiPPh

MeOCH Cl

2

2

2

(CH ) J:O

0.81

2

LiPPh

MeOCH Cl

2

(CH )^C0

0.25

monomer

4

2

F

6

p-C H (CHO)

0.19

E

Ph CO

0.60

2

PhCOMe

0.60 E

E

PhCHO

0.60

D

D

D

D

2

4

A

C

A

Ph C0

0.81

2

2

9-formylanthracene

EtI

b

2

NaPPh

EtBr

cholest-4-en-3-one

2

LiPPh

Mel

0.35

1.0

1.0

1.0

1.0

1.0

1.0

1.0

1.0

1.0

5

C=CHOMe

6

4

2

p-OHCC H CH=CHC0 Me

2

Ph C=CHSMe

PhMeC=CHSMe

PhCH=CHSMe

2

Ph C=CHOMe

PhCH=CHOMe

2

(CH )

(CHp^C=CHOMe

(CH^^C^CIIMe

32

(44)

17

16

16

16

16

16

16

16

12

C o n t i n u e d on next page

63

79

81

86

92

85

95

89

(50)



LiPPh

2

PhCH Cl

6

LiPPh

13

Me

n-C H Br

2

Et0 C

CH Br

LiPPh

NaPPh

n-BuBr

2

2

NaPPh

i.-PrBr

y

LiPPh

2

2

0

2

2

2

2

2

2

CH =CHCH Br

2

LiPPh

2

CK =CHCH Br

2

LiPPh

2

(continued)

Me0 CCH Br

2

Table I

0.81

0.70

0.35

0.43

b

0.70

0.70

0.24 4

2

2

HC0 Me

p-ClC.H, CHO — 6 4

PhCOMe

CHO

9-formylanthracene

OH 9-formylanthracene

—

p-ClC.H.CHO

6

p-C H (CH0)

C

B

1.0

d —

1.08

1.3

1.5

1.5

1.0 4

2

c

11

Me0CH=CHPh

H —p-ClC.H.CH=CHC OH _> l

^^^^^^y^y^O

PhMeC=CHPr

TO

CH=CMe.

COXOIO

i

0

CH=CHCH=CH

0

p-ClC.K.CH-CHCH=CH — 6 4 2

6

p-CHCC H CH=CHC0 Me

^Et


93

26

70

97

10

trace

78

80


0.70

2

2

2

2

2

2

2

LiPPh

LiPPh

LiPPh

LiPPh

LiPPh

LiPPh

LiPPh

LiPPh

LiPPh

PhCH Br

PhCH Cl

PhCH Br

PhCH Cl

PhCH Br

PhCH Br

PhCH Br

PhCH Cl

PhCH Cl

2

2

2

2

2

2

2

2

2

2

2

0.35

monomer

PhCH Br

5

CO

0.35

0.06

0.12

4

2

2

2

2

PhCH=C(Me)CHO

6

4

p-C H (CHO)

6

4

m-C H (CHO)

6

p-C H (CHO)

4

0.12

6

CHO

p-C H (CHO)

n-CjH

p-BrC,H,CHO — 6 4

PhCHO

PhCHO

PhCHO

PhCHO

PhCHO

2

(CH )

0.12

0.70

0.17

0.25

0.25

monomer

2

PhCH Cl

0.70

0.25

2

monomer

LiPPh

PhCH Cl

2

2

PhCH Cl

M

F

F

F

N

B

Q

B

M

A

L

K

B

1.0

1.0

1.0

1.0

1.0

1.5

1.2

1.5

0.97

1.0

1.0

1.0

1.5 5

C=CHPh

i5

4

PhCH=C(Me)CH=CHPh

6

4

p-0HCC H CH=CHPh

6

4

m-0HCC H CH=CHPh

6

4

p-0HCC H CH=CHPh

6

p-0HCC H CH=CHPh

?

4

n-C H CH=CHPh

6

p-BrC H CH=CHPh

PhCH=CHPh

PhCH=CHPh

PhCH=CHPh

PhCH=CHPh

PhCH=CHPh

2

(CH )

60

40

0

(6)

22

36

0

(51)

13

17

17

17

17

14

21

14

13

12

20

20

14

C o n t i n u e d on n e x t page

(89)

49

67

54

83

(93)

71

92

(93)

(35)



N

?

s

0

C H

s

/

0

2

B r

L i P P h

2

2

0

^ \ ^ s < ^ N ^ B r NaPPh

1 1

p-Me CC,H CH Cl 3 6 4 2

2

2

2

2

2

LiPPh

PhCH Br

LiPPh

LiPPh

PhCH Cl

2

LiPPh

(continued)

PhCH C I

Table I

0

,

3

5

b

0.70

0.17

0.70

0.70

CHO

CHO

2

OHC^s^V^/C0 Et

p-ClC^CHO

o

CH 0

©da

Fe -4-

-CHO

I

C

B

Q

Q

B

0.67

c

1.5

1.1

c

1.5

3

6

4

0^

O]CI

2

CH=CHPh

CH=CHPh

p-Me CC H CH=CH

Fe

CH=CHPh


50

48

95

57

94

62

18

15

14

21

19

19

H

^

m > O m 2! H

TS

o

2

o

13


F o o t n o t e s on n e x t page



164

Table I. (Footnotes)

a A.


B.

C. D. E. F. G. H. I. J. K. L. M. N. O. P. Q. R. S. T.

Add a solution of the sodium salt of D M S O in D M S O to polymer in tetxahydrofuran (THF). Add 50% aqueous NaOH and a phase transfer catalyst, either cetyltrimethylammonium bromide or tetra-n-butylammonium iodide, to polymer in dichloromethane. Add n-butyllithium in hexane to polymer in dioxane. Add phenyllithium in ether to polymer in ether. Add phenyllithium (solvent not specified) to polymer in T H F . Add excess ethylene oxide to preformed phosphonium ion polymer in benzene. Add excess ethylene oxide to the phosphine polymer in a solution of methyl bromoacetate in benzene. Add 50% aqueous NaOH to polymer in dichloromethane without any phase transfer catalyst. Add sodium ethoxide in ethanol to polymer in ethanol. Add sodium methoxide in methanol to polymer in methanol. Add potassium f—butoxide to polymer in T H F . Add sodium hydride to polymer in T H F . Add sodium methoxide in methanol to polymer in T H F . Add n-butyllithium in ether to polymer in T H F . Add 50% aqueous NaOH to polymer in aqueous 37% formaldehyde. Add n-butyllithium in hexane to polymer in benzene. Add solid potassium carbonate and dicyclohexyl-18-crown-6 ether to polymer in T H F and reflux. Add solid potassium carbonate to polymer in T H F and reflux. Add aqueous sodium hydroxide to polymer in methanolic formaldehyde. Add methyl bromoacetate and ethylene oxide to the phosphine polymer in THF.

k Not reported, but probably 0.3-0.5. £ Not reported, but probably cj|. 0.4. d Not reported specifically, but in the range 1.0-1.3.


8.

FORD

Wittig Reactions

on Polymer

165

Supports

T a b l e I I . Polymer-Bound A l k e n e s from Polymer-Bound B e n z y l Phosphonium Ions and S o l u b l e C a r b o n y l Compounds -


PPh„ C l ~ +

1 2 R R CO

1

I 2

2

R R CO

method—

CH=CR R

% yield

lit.

CH 0

13

22

CH 0

79

23

50

24

83

25

76

19

£-ClC H CHO

97

22

£-BrC H CHO

79

19

£-0 NC H CHO

49

25

£-BrC H C0Me

17

22

41

25

2

2

C1CH CH0 2

CHO

PhCHO

6

4

6

2

4

6

6

4

4

^CHO

25

Me C 0

-CHO

62

25

C o n t i n u e d on n e x t page



166


Table I I (continued)

- A l l r e a c t i o n s were c a r r i e d out on DF 0.18-0.55, 1-2% c r o s s - l i n k e d polymers w i t h 1.0-1.5 molar e q u i v o f c a r b o n y l compound, except f o r 17-50 molar e q u i v o f formaldehyde. - See T a b l e I .


8.

FORD

Wittig Reactions on Polymer

167

Supports

Scheme 3

H„C=CH

Br

.Br. n-BuLi TMEDA


Li

ClPPh

BuLi

OHC

Polymeric Reagents and Catalysts - American Chemical Society

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