Zinc Enolates: the Reformatsky and Blaise Reactions

1.8 Zinc Enolates: the Reformatsky and Blaise Reactions MICHAEL w. RATHKE and PAUL WEIPERT Michigan State University, East Lansing, MI, USA 1.8.1

INTRODUCTION

277

1.8.2 NATURE OF THE REFORMATSKY REAGENT 1.8.2.1 Isolation and Stability ofZinc Enolales 1.8.2.2 Structure of Zinc Enolates

278 278 280

1.8.3 REACTION WITH ALDEHYDE AND KETONE SUBSTRATES 1.8.3.1 Scope and Procedures 1.8.3.2 Chemoselectivity 1.8.3.3 Regioselectivity 1.8.3.3.1 Reaction of zinc ester enolates with conjugated enones 1.8.3.3.2 Reaction of zinc ester dienolates with simple aldehydes and ketones 1.8.3.3.3 Reaction of zinc ester dienolates with conjugated enones 1.8.3.4 Stereoselectivity 1.8.3.4.1 Introduction 1.8.3.4.2 Thermodynamic stereoselection 1.8.3.4.3 Kinetic stereoselection 1.8.3.5 Preparation of Unsaturated Esters

281 281 283 285

285 286 287

289

289 289 291

294

1.8.4 REACTION WITH IMINES

294

1.8.5 REACTION WITH ACYLATING AGENTS /.8.5.1 Reaction with Esters and Acid Chlorides / .8.5.2 Reaction with Nitriles, the Blaise Reaction

296 296 297

1.8.6 REFERENCES

298

1.8.1 INTRODUCTION The Refonnatsky reaction is the reaction of an a-halo ester with an aldehyde or ketone in the presence of zinc metal as shown in Scheme 1. The usual product of the reaction is a ~-hydroxy ester, which may be dehydrated in subsequent steps to give an unsaturated ester. A zinc ester enolate (1), the so-called Refonnatsky reagent, is an intennediate in the reaction and the sequence is thus classified as an aldol condensation. Compared to the usual base-promoted aldol procedures, the distinguishing features of the Refonnatsky reaction are the use of a metal-halogen redox reaction rather than an acid-base reaction to fonn the enolate, and the fact that the counterion of the enolate is zinc. Assuming ready availability of the a-halo ester component, the Reformatsky reaction is often a convenient and economical alternative to base-promoted aldol procedures. Since its discovery in 1887, lover 500 research articles and six reviews 2- 7 of the reaction have been published. Heathcock has recently reviewed the stereochemistry of the reaction of a variety of zinc enolates with aldehydes and ketones. 8

277

278

Uncatalyzed Additions ofNucleophilic Alkenes to C X

+

Zn

(1)

Scheme 1

This chapter summarizes studies on the nature of the Reformatsky reagent as well as other, related, zinc enolates and outlines the synthetic aspects of the reaction with aldehydes and ketones. In addition, reactions of the R.eformatsky reagent with imines and nitriles (the Blaise reaction) are described.

1.8.2 NATURE OF THE REFORMATSKY REAGENT

1.8.2.1 Isolation and Stability of Zinc Enolates The Reformatsky reaction is most commonly conducted in a single step by addition of a mixture of ahalo ester and carbonyl substrate to a suspension of zinc in a suitable solvent. This one-stage procedure clearly minimizes any problems due to instability of the Reformatsky reagent. Since 1953,9 solutions of the reagent have occasionally been prepared, with varying degrees of success, by reaction of the a-halo ester with zinc in an initial separate step of a two-stage procedure. The first detailed examination of a Reformatsky reagent was described in 1965 by Vaughan and coworkers,IO who prepared a solution of the reagent from ethyl a-bromoisobutyrate. Hydrolysis of the freshly prepared solution gave ethyl isobutyrate (from the Reformatsky reagent) and the so-called 'condensed ester', ethyl isobutrylisobutyrate (2; equation 1). Refluxing the reaction mixture for longer periods prior to hydrolysis gave a gradual decrease in ethyl isobutyrate and a corresponding increase in (2). Vaughan II proposed that the zinc ester enolate decomposed by loss of EtOZnBr to form a ketene intermediate, which subsequently formed condensed ester (Scheme 2). A similar formation of ketenes from 1: 1 ether-benzene 4 h, reflux

~COzEt

o + WOzEt

(1)

(2)

EtOZnBr

>=.=0

+

>=.=0

+

(2)

Scheme 2 Zn

Scheme 3

(2)

Zinc Enolates: the Reformatsky and Blaise Reactions

279

lithium ester enolates has been well documented. 12,13 It is also possible that at least some of the condensed ester is produced by a direct condensation as suggested earlier by Newman and Hussey (Scheme 3).14 According to Gaudemar and Cure,5,15 dimethoxymethane is an especially useful solvent for two-stage reactions and they report yields of 70-80% for the Reformatsky reagents derived from a variety of abromo esters (equation 2); however, the procedure was unsatisfactory with ethyl a-bromopropionate, methyl a-bromophenylacetate and phenyl a-bromoisobutyrate. The zinc enolates were generally used shortly after preparation and no data on their stability in this solvent were reported.

+

(2)

Zn 40°C, 24 h

Orsini and coworkers l6 ,17 obtained BrZnCH2C02But·THF in 80% yield as a colorless crystalline solid by reaction in THF at 25-35 °C. They described the reagent as mostly unchanged after 4-6 d in a number of solvents, with a slow hydrolysis to t-butyl acetate and a gradual formation of ButOZnBr. Using the same procedure, BrZnCHMeC02Bu t and BrZnCMe2C02But were isolated as THF complexes. They were described as stable in THF for a few hours and in pyridine and in DMSO for about 10-15 min, after which time an abundant precipitate of BrZnOBut was present. Orsini and coworkers 16 obtained primarily 'condensed ester' from the reaction of methyl a-bromopropionate with zinc in a variety of solvents; however, Johnson and Zitsman 18 evidently obtained the reagent from ethyl a-bromopropionate in good yield by conducting the reaction at a lower temperature in ether (equation 3). It seems likely that many simple a-bromo esters can be reacted with zinc to produce the Reformatsky reagent nearly quantitatively, and that the reagent forms condensed ester primarily in a subsequent step. A successful synthesis of a Reformatsky reagent should then depend strongly on the time and temperature required for the preparation. Recently, a number of methods, including ultrasound promotion 19 and the use of highly active forms of zinc,2o have allowed completion of the Reformatsky sequence in

+

Zn 10°C, 1 h reflux, 1 h

+ condensed ester

(3)

products derived from hydrolysis or alkylation of BrZnCH(Me)C0 2Et 85%

150/0 dioxane ultrasound (12, trace), 25-30 °C

5 min, 100%

(4) n-C7H 15 ~C02Et

OH

Br~C02Et

6 °

+

Zn/Ag-graphite

+

THF, -78°C

20 min, 92%

280

Uncatalyzed Additions ofNucleophilic Alkenes to C X MeC0 2Bu t

o II But~

(6)

ii, ZnCI 2, ether, -70°C

EtZnO +

But~

Pri2NZnEt

+

(7)

remarkably short times and at low temperatures. However, these methods have so far been applied only to one-stage procedures (equations 4 19 and 521 ). Zinc ester enolates may also be obtained by the addition of ZnX2 to lithium or sodium enolates as first described by Hauser and Puterbaugh (equation 6).22 This approach has so far received little attention but similar reactions have been used to obtain zinc ketone enolates. 22 ,23 In this regard, it should be noted that Heathcock and coworkers 24 have shown that deprotonation reactions of ketones with zinc dialkylamide bases reach equilibrium at only about 50% conversion (equation 7). This result implies that attempts to prepare zinc enolates from solutions of amide-generated lithium enolates will be successful only when the lithium enolate is made amine-free.

1.8.2.2 Structure of Zinc Enolates Metal enolates may have structures with either a metal-oxygen (3) or a metal-carbon (4) bond. Lithium enolates typically have oxygen-bonded structures,25 while mercury enolates are usually assumed to have carbon-bonded structures. 26

O-M

~

}=
From a crystallographic study of the Reformatsky reagent obtained from t-butyl a-bromoacetate, Boersma and coworkers 27 reported the carbon-bonded dimeric structure (5). Based on ebulliometric and cryoscopic molecular weight measurements, the dimeric structure persists in solvents of medium coordinating power (THF, DME, dioxane, dimethoxymethane and pyridine), but the reagent is monomeric in strongly coordinating solvents (HMPA and DMSO). Spectral data l6 are also consistent with a carbonbonded structure for the reagent in solution (Table 1). The spectral differences observed between the solvents THF and DMSO are consistent with the presence (THF solution) or absence (DMSO solution) of zinc coordination to the carbonyl oxygen of a carbon-bonded structure, as first suggested by Gaudemar and Martin. 28 In strongly coordinating solvents, the carbonyl frequency of a variety of Reformatsky reagents appears just below 1700 cm- I , close to the normal value for ester carbonyls.28 It is interesting to note that a dimeric structure (6) completely analogous to (5) was considered in 1970 for the Reformatsky reagent obtained from ethyl a-bromoisobutyrate and discarded, based on the failure of the reagent to react with Grignard reagents. II Clearly, with sufficient ionic character to the metal bonds, the reactivity of a carbon-bonded enolate to any reagent must approach that of the corresponding oxygen-bonded enolate. No crystallographic structure has been reported for zinc ketone enolates. Although carbon-bonded structures analogous to (5) have been proposed,27 spectral data obtained for the bromozinc and ethylzinc

But~

o

: Br, : Zn

Zn . . : Br :

~O

~OBUI

(5)

(6)

281

Zinc Enolates: the Reformatsky and Blaise Reactions Table 1 Spectral Data for BrZnCH2C02Bu1 Spectrum

Solvent

IHNMR BrZnCH2C0 2C(CH3)3 A B

THF

Signal (assignment) p.p.m. relative to Me4Si

1.88 (A), 1.40 (B)

1.04 (A), 1.30 (B)

DMSO

13CNMR BrZnCH2C02C(CH3)3 ABC D

p.p.m. relative to Me4Si

22.7 (A), 186.2 (B), 80.4 (C), 27.6 (D), J(CI-H o) 132 Hz 20.8 (A), 177.4 (B), 75.3 (C), 28.6 (D) J(CI-Ho:) 128.6 Hz

THF DMSO

cm- 1

IR

1580 (C==O) 1660 (C=O)

THF DMSO

o

M-O

BU

But~M

tQ (7)

(8)

Table 2 NMR Spectral Data for Enolates (7) and (8)

M

Solvent

CA

ZnEt ZnBr MgBr Li HgBr

THF-ds THF Ether Benzene Benzene

165.5 164.7 162.4 169 213

Chemical shifts (p.p.m.)

CB

Ha

93.0 96.6 95.5 84 51

J(Crr-Ha) (Hz)

Ref

4.41

155

4.54

154

24 29 30 31 31

140

/)=
~

(10)

enolates of 2,2-dimethyl-3-pentanone seem most consistent with oxygen-bonded (7) rather than carbonbonded (8) structures. The chemical shifts and C-H coupling constants are close to the oxygen-bonded lithium or magnesium enolates and not to the presumably carbon-bonded mercury enolates (Table 2).24 The preference of zinc ester enolates for carbon-bonded structures and zinc ketone enolates for oxygen-bonded structures is reminiscent of the situation with silicon. A carbon-bonded structure (9) is the thermodynamically more stable form for the trimethylsilyl derivatives of esters, while the oxygenbonded structure (10) is the more stable form for ketone derivatives. This has been attributed to the greater resonance stability of ester compared to ketone carbonyls.32

1.8.3 REACTION WITH ALDEHYDE AND KETONE SUBSTRATES

1.8.3.1 Scope and Procedures Reformatsky reactions of more than 500 different aldehydes and ketones have been tabulated. 2,5,7 One of the significant features of the Reformatsky reaction is that it succeeds even with highly hindered

282

Uncatalyzed Additions ofNucleophilic Alkenes to C X

ketones (equation 8).33 It is one of the few successful methods 34 for the addition of carbon nucleophiles to the readily enolized cyclopentanone ring system (equation 9).35 Because the Reformatsky sequence allows the generation of an ester enolate in the presence of an enolizable aldehyde or ketone, it is uniquely suited for intramolecular aldol reactions. 36-40 The transformation shown in equation (10) would be difficult to accomplish by conventional base-promoted aldol methods.4o Single-stage procedures are most commonly used for the Reformatsky reaction with aldehydes and ketones. A mixture of a-halo ester and carbonyl substrate is added to a suspension of zinc at a rate sufficient to maintain the reaction. In the original procedure of Reformatsky, 1 no solvent was used but modern practice is to use benzene or an ether solvent such as diethyl ether, THF, glyme or dimethoxymethane. The reaction is often conducted at reflux temperature, probably to avoid surges from the highly exothermic nature of the reaction. However, in a comparison with a number of aldehydes and ketones, much higher yields were obtained at room temperature than at reflux in benzene (equation 11 ).41 The zinc metal is typically activated before use and methods for accomplishing this have been reviewed. 2o The use of highly reactive forms of zinc (Reike powders), obtained by reduction of zinc salts with an alkali metal, detracts from the convenience of the classical procedure but much higher yields have been obtained, at least with the simple substrates that have so far been examined. One of the most convenient preparations of a Reike powder uses sodium naphthalide, as shown in Scheme 4. 42 Reactive zinc powders also allow the use of a-chloro esters which are unsatisfactory with the usual forms of zinc. 2o

°

LY

+

Zn,benzene reflux, 30 min

(8) 62%

0

+

HO

Zn, benzene reflux,4 h

Cz

C02Et

(9)

84%

Zn-Ag Et2AICI

0

THF, 35°C 4.5 h 62%

+

MeCHO

+

+

benzene

Zn

Zn powder

OJ ~

OH

0

(11 ) reflux, 2 h, 22% 25°C, 4 h, 65%

Na

(10)

~

THF

ZnCl2

2h

20°C

OH

BrCH 2C02Et PhCHO -10°C, 20 min 75%

Scheme 4

Ph

~C02Et

Zinc Enolates,· the Reformatsky and Blaise Reactions

283

1.8.3.2 Chemoselectivity In addition to aldehydes and ketones, organic compounds which are known to react with Reformatsky reagents include: esters,43 nitriles,44 acid chlorides,43 organic halides,17,45 epoxides,46 nitrones,47 azirenes48 and imines. 49 This section describes the selectivity reported for Reformatsky reactions with functionally substituted aldehydes or ketones. Symmetrical diketones react normally with either one (equation 12)50 or two (equation 13)51 equivalents of the Reformatsky reagent. There are no reports of selective reaction at a single carbonyl of an unsymmetrical substrate, although this has been accomplished by selective acetal protection (Scheme 5).52

o /"-.... Br

+

C0 2Et

Zn

BUtr( But

reflux, 2 h 39%

o

o

I(

( 13)

Br/"-..C0 2Et

OEt

E102C X O E l

benzene reflux, 4 h 34%

0

0

OEt

Zn/I2

P h 0 OEt

PhY'H

(12)

o

71%

o

0

But

2Zn benzene, reflux

Jl'Ph

Ph~

+

HO

BUI~C02El

ether/benzene

Ph

OH

Scheme 5 H I

+

BrZn/"-....C02Et

CH2(OMeh, benzene

PhOCH2cO:n~

r.t.,10min reflux,2 h

COMe

OH CH 2C0 2Et

HO CH 2C02Et 33%

67%

0

/"-....

C02Et

~CN

+

H BrZn

/"-....

C02Et

+

(14)

l-r~

l-r~

Br

42%

Ph

H'AC02El COMe C02Et

Zn/I2 benzene/toluene

H~CN

reflux, 2.5 h 20%

( 15)

H

THF r.t.,5 h

"",C0 2Et (16)

96%

Et0 2CCH 2

0

Uncatalyzed Additions ofNucleophilic Alkenes to C X

284

Ketoamides,53 ketonitriles 54 and keto esters55 may all be reacted selectively at the ketone function (equations 14--16). In fact, esterification was found to be the best of several hydroxy-protecting methods for the transformation shown in Scheme 6. 56 Ethyl acetoacetate gave only low yields in a Reformatsky reaction 57 but even this is remarkable considering its acidic nature (equation 17). J3-Keto esters that lack acidic hydrogens react in good yield (equation 18).58 Halogen can be tolerated either in the carbonyl substrate or in the bromo ester component of the Reformatsky reaction. It is noteworthy that the intermediate zinc aldolate (11) does not internally substitute halogen until HMPA is added (Scheme 7).39 For reactions with a-halo ketone substrates in a d I-buten-

o

o

~OH

Zn, ether

~OAC

reflux, 2 h 51%

Scheme 6 Zn benzene

0

Br

/"--..

COzEt

~C02Et

+

Br

COzEt

eY

+

( 17)

COzEt

~02Et

Zn/I2 ether benzene

o2Et

/"--..

H % C 02Et

reflux, 2 h 14%

HO

( 18) reflux, 6 h 88%

Br

o

r

~

OZnBr

o

Br Zn (Reike powder)

HMPA

THF O°C

0-

'_ _- .

BnN ",-""",

BnN

25°C,2 h

73%

(11)

Scheme 7

CI

o

Br

~OMe

II

o

~ ~ ~

+

. . . .". .

I

6

CI

BrZn~ OEt

+

OMe

---~

OEt

HO

N0

2

(19)

reflux, 14 h 67%

CHO

0

o

Zn/I2 ether, benzene

ether reflux, 1 h

42-50%

~

#

0

-NO

.z

(20)

285

Zinc Enolates: the Reformatsky and Blaise Reactions

olide synthesis,59 the use of a-chloro rather than a-bromo ketones was recommended to avoid formation of a zinc ketone enolate (equation 19). The two-stage Reformatsky procedure was originally devised to avoid the reduction of quinone substrates by zinc, which was observed in a single-stage sequence.9 A two-stage sequence also allows successful reaction with nitrobenzaldehydes (equation 20),60 although in this case the problem is a marked inhibition of the reaction of zinc with the bromo ester by nitro aromatics.

1.8.3.3 Regioselectivity

1.8.3.3.1 Reaction ofzinc ester enollltes with conjugated enones

Reaction of zinc ester enolates with a conjugated enone can give either ~-hydroxy esters (12) from 1,2-addition, or 8-keto esters (13) from 1,4-addition, as shown in Scheme 8. Cyclization of the 1,4-product to the corresponding 8-lactone (14) is occasionally observed.

Brzn'><1r°R+ ~

OH ~

o

+1x1 ,/ AA

0 OR

'OR

(12)

/

(13)

(14)

Scheme 8 Zn

ether (21 )

reflux 59 -73%

Rl

~OEt

Br

= H, Me, Et; R2 = H, Me; R3 = H, Me

+

R'yR

3

R2

0

R2

Zn, HgI 2 THF, reflux, I h

0

R1

R3 (22)

0-95%

0

0

OEt

(0) BrZn ~OEt

LSMe N

+

0 Ph

0

ether reflux, 4 h 65%

(0)

n N

Ph

0

(23)

0

Uncatalyzed Additions ofNucleophilic Alkenes to C X

286

Reaction of a variety of unsaturated methyl ketones with relatively unhindered bromo esters in refluxing ether gave only 1,2-addition products (equation 21).61 A similar study in refluxing THF with the more hindered ethyl a-bromoisobutyrate gave exclusively 1,4-addition products; however, the conditions of work-up were such that 1,2-addition products would not have been isolated (equation 22).62 There has been no systematic study of the Reformatsky reaction of conjugated enones under conditions where both 1,2- and 1,4-products could be determined. In general, only 1,2-addition products are obtained with a-bromoacetates. However, in one favorable case, exclusive 1,4-addition was observed (equation 23).63 Reactions with a-bromoisobutyrates commonly give 1,4-addition products. It is not known whether these are the result of a kinetically or thermodynamically controlled process. Low temperature reactions of conjugated enones with preformed Reformatsky reagents of a-bromoisobutyrates, conditions most favorable for a kinetically controlled process, have apparently never been reported.

1.8.3.3.2 Reaction ofzinc ester dienolates with simple aldehydes and ketones The Reformatsky reaction of 4-bromocrotonate esters can give either a- or ')'-products as shown in equation (24). Hudlicky and coworkers 64 have suggested that the high ,),-selectivity usually observed for the reaction may be due to the instability of the a-products to isolation procedures. They examined the reaction of ethyl 4-bromocrotonate with 10 carbonyl substrates and defined conditions for obtaining either a- or ')'-products with generally good selectivity (Scheme 9). In at least one case, these results were shown 34 to be the result of a selection between kinetic control, leading to a-product, and thermodynamic control, leading to ')'-product (equation 25). In a similar study of the reaction of trimethylsilyl esters of 4-bromocrotonic and 4-bromosenecioic acids with benzaldehyde, low temperatures favored a-products, while higher temperatures or longer reaction times favored ')'-products (equation 26).65 It seems reasonable to conclude that, as originally proposed by Gaudemar,66 one-stage Reformatsky reactions of zinc ester dienolates will produce mainly a-products in kinetically controlled processes, and

Br~ o

OR l

OH

Zn

+

+

:~C02RI (24)

a-product

y-product

o

Zn (dry), THF

100%y

Br

reflux, 1 h

+

~OEt

/'

II

o

6

Zn,

eu (AcOH) 100%

ether, reflux, 1 h

a

Scheme 9

o

Br

~OEt

II

/'

o

6

+

Zn, benzene reflux

60:40 (a.:y),

6 min

40:60 (a.:y), 45 min 0: 100 (a.:y),

(25)

2h

100:0 (a:y) (-40°C, 120 h)

CHO

~OSiMe3

Br

I

~ o

+

6

Zn, THF

92:8 (a:y) (reflux, 1 h)

42:58 (a:y) (reflux, 96 h)

(26)

287

Zinc Enolates: the Reformatsky and Blaise Reactions THF

-40 °C, 48 h 75% PhCHO

zinc enolate

0: 100 (a:y)

-40 °C, 48 h 53% overall

Scheme 10

(15)

PhCHO

y-product

~

(15)

a-product

(16)

Scheme 11

mainly ')'-products in thermodynamically controlled processes. Similar conclusions were reached for the corresponding reactions of lithium ester dienolates. 67 It is therefore surprising that two-stage Reformatsky reactions, completed under conditions where the a-product is stable, gave exclusively ')'-products (Scheme 10).65 The existence of two different zinc dienolates was proposed to explain these results, as shown in Scheme 11. In one-stage reactions, the initially formed enolate (15) is trapped to give a-products. In two-stage reactions, (15) rearranges to a second enolate (16), which then reacts to give ')'-products.

1.8.3.3.3 Reaction ofzinc ester dienolates with conjugated enones The Reformatsky reaction of 4-bromocrotonate esters with conjugated enones can conceivably give four regioisomers, as shown in equation (27). Several workers have applied such reactions to the synthesis of vitamin A and related compounds. 7 In most cases, 8-lactones derived from 1,2-,),-adducts were obtained, as exemplified by results with ~-cyclocitral (equation 28).68 In a study of the reaction of ethyl 4-bromocrotonate with a variety of conjugated enones, Hudlicky and coworkers 34 observed almost exclusive formation of 1,2-a-products at very short reaction times in

HOjj

CO')R

R

1

R3

I

1,2-a

I

R2

+

H05l?C0 R

1

1

R-

I

1,2-y

0

R-

R1

R1

I

2R

+

+

R3

R2

iJC0 0

C02R 1,4-a

2R

R3

R2 1,4-y

(27)

Uncatalyzed Additions ofNucleophilic Alkenes to C X

288

refluxing ether. Longer reaction times produced increasing amounts of 1,2-"1- and 1,4-'Y-products. Reaction for several hours in refluxing THF gave, with ketones, exclusively the 1,4-')'-product and, with the single aldehyde examined, exclusively the 1,2-'Y-product. Selected data are shown in Table 3. Interestingly, the lithium enolate of ethyl crotonate gave primarily the 1,4-a-product with cyclohexenone (entry 7), a regioisomer not observed with any of the Reformatsky reactions of Table 3.

Br~C02Me

+

CX

~

Zn, ether benzene

HO

0

0

(28)

reflux, 30 min 29%

Table 3 Regioselectivity in the Reformatsky Reaction (equation 27) Unsaturated carbonyl compound

Reaction conditions

Product distrihution (%) 1,2a

-?

1,2y

1,4a

1,4"1

0

6 0

Zn/Cu (HOAc)!Et20, 3 min Zn/Cu (HOAc)!Et20, 1 h Zn, THF,4h

>95 28 10

Zn/Cu (HOAc)!Et20, <1 min Zn/Cu (HOAc)!Et20, 45 min Zn, THF, 6 h LDA, -78°C, THF, MeCHCHC02Et

>90 53

Zn/Cu (HOAc)!Et20, 1 min Zn/Cu (HOAc)!Et20, 1 h Zn, THF,4 h

100 16

Zn/Cu (HOAc)!Et20, 3 min Zn, THF, 2 h

>96 15

Zn/Cu (HOAc)!Et20, 30 s Zn/Cu (HOAc)!Et20, 1 h Zn, THF, 2 h

100 41

Zn/Cu (HOAc)!Et20

35

46 90

26

17 75

<10 30 >90 25

0

~Ph

26

58 >90

0

6

85

0

~

59 100

0

~

55

<10

Zinc Enolates: the Reformatsky and Blaise Reactions

289

1.8.3.4 Stereoselectivity

1.8.3.4.1 Introduction Reaction of an a-substituted enolate with an aldehyde or ketone can give two pairs of aldol diastereomers, which are conveniently designated as the syn form (17) and the anti form (18), where R2 is part of the parent chain'in IUPAC nomenclature (equation 29). For simplicity, only one enantiomer of each pair will usually be shown throughout this section. The syn/anti notation for aldol diastereomers has been described in detail by Heathcock. 8

RI~X

R2

+

Y

R3 2

0

0

R3

OH 0

. RX(X

R3

+

OH 0

Ry X 2

(29)

R

1

R1 (17) syn-aldol

(18) anti-aldol

1.8.3.4.2 Thermodynamic stereoselection Aldol condensations of zinc enolates under conditions of thermodynamic control are reasonably discussed in terms of the relative stability of the two chelated aldolates; (19), which leads to the syn aldol, and (20), which leads to the anti aldol. If R2 is larger than R3, the anti chelate, with R 1 and R2 trans in a six-atom ring, is expected to be the more stable form. Heathcock8 has noted that the most common mechanism for equilibration of aldolate stereochemistry is reverse aldolization (reversal of equation 29). Aldolates obtained by reaction of an enolate with ketone substrates are expected to undergo reverse aldolization at a faster rate than those obtained with aldehyde substrates, in part for steric reasons. Similarly, aldolates derived from ketone enolates are expected to undergo reverse aldolization at a faster rate than those derived from the more basic ester or amide enolates. Chelated structures analogous to (19) and (20) were first proposed by House and coworkers 23 to explain the increased anti selectivity observed for lithium ketone enolates following addition of ZnCl2 (equation 30). Heathcock and coworkers69 determined the rate of equilibration as well as the equilibrium composition for a number of aldolates derived from benzaldehyde and zinc ketone enolates (equation 31). Again, the preference for anti aldolates is in accord with zinc-chelated structures. Jacques and coworkers 7o examined the Reformatsky reaction of a series of a-alkyl-substituted bromo esters. In refluxing benzene, the zinc aldolates derived from aromatic ketones, but not from aromatic 0"

Zn

"0

R3~)lX R2 I 1 R

(20) anti-chelate

(19) syn-chelate

6 OLi

DME

-20°C, 5 min

Ph~

Ph~

syn

anti

50%

50%

(25%)

(75%)

(30)

Uncatalyzed Additions ofNucleophilic Alkenes to C X

290

THF

25% 9%

TI /2 = 4 min, -10°C

75%

T I /2 = 0.5 min, -78°C

91 %

>-Br

+

Me02C

Zn benzene

°

Ph

A

"

reflux, 1h

R=Ph R = mesityl

R=But

TI /2 = 210 min, 25°C

R

(31)

anti

syn

Ph

OH

+

'XyC02Me

"

OH

Ph

::

R

30-87%

Br AC02Et+

if X

~ I

anti

OH

Zn

IIIIIIII

~

X

OH C02Et

~

benzene reflux

~

X=OMe, H, CI

(32)

R

syn

°

~C02Me

IIIIIIII

+

C02Et (33)

~

X

~

syn

anti

Zn

+

benzene reflux, 1.5 h 64%

(21)

"

10%

(22)

0%

(24)

15%

(34)

OH

Ph0C02Me

(23)

BriC02Et

75%

+

°

0

Ph

Zn benzene

H

toluene

c : : f t hC0 Et 2 OH

85°C

(25)

(35)

Zinc Enolates: the Reformatsky and Blaise Reactions

291

H

~OEt 0,

... 0

Zn I

Br (26)

aldehydes, were found to equilibrate. Syn:anti ratios increased with increasing size of R and ranged from 30:67 (R = Me) to 17:83 (R =Pri ) (equation 32). Balsamo and coworkers7l observed a similar equilibration in the reaction 'of ethyl a-bromopropionate with substituted acetophenones in refluxing benzene (equation 33). Equilibration of stereochemistry was fastest with X = OMe (complete equilibration in 1 h) and slowest with X = CI (complete equilibration in 5 h). All three substrates gave approximately the same equilibrium syn:anti ratio of 30:70. Other studies of the Reformatsky reaction in refluxing benzene with ketone substrates are readily explained in terms of equilibrated zinc aldolates, although direct evidence for equilibration was not obtained. Matsumoto and coworkers72 examined the reaction of 3-phenyl-2-butanone with methyl a-bromopropionate and observed a net syn:anti ratio [(21 + 22):(23 + 24)] of 10:90, in harmony with equilibrated zinc aldolates (equation 34). Thomas and coworkers 73 examined the reaction of 2-phenylcyclohexanone with a number of nucleophiles. The highest stereoselectivity was observed with a Reformatsky reaction of ethyl a-bromopropionate (equation 35). The exclusive product (25) corresponds to that expected from the most stable zinc aldolate (26) with the a-methyl away from the phenyl group.

1.8.3.4.3 Kinetic stereoselection Because of conflicting reports or inadequate controls, the question of kinetic or thermodynamic control of stereochemistry for reported Reformatsky reactions often has no satisfactory answer. Jacques and coworkers70 have concluded that Reformatsky reactions of benzaldehyde in refluxing benzene can be completed with kinetic stereoselection. The relatively high syn:anti ratios they observed, at least with small R groups (equation 36 and Table 4), are not those expected for equilibrated zinc chelates. Matsumoto and coworkers74 observed a similar high syn:anti ratio for the Reformatsky reaction of a chiral aldehyde in refluxing benzene [syn:anti = (27 + 28):(29 + 30) =71:29] (equation 37). The optimum approach to kinetic stereoselection in the Reformatsky reaction would appear to be the use of two-stage procedures, which allows the zinc aldolates to be formed at the lowest possible temperature. Gaudemar-Bardone and Gaudemar75 prepared a variety of zinc ester enolates in dimethoxymethane at 40°C which were then reacted at lower temperatures with benzaldehyde or with acetophenone (equation 38). Selected data from their study are shown in Table 5. If these data are the result of total kinetic control, as concluded by the authors, it is clear that the reactions exhibit only a modest kinetic stereoselectivity.

BryCOzMe R

+

PhyH

Zn, benzene

0

reflux, 1 h 80-87%

H Ph

H

OH

>Z(COzMe

+

Ph

OH

~C02Me ~

R

R syn

anti

Table 4 Syn:Anti Ratios (equation 36) R

Syn:anti

Me

63:37 54:46 47:53

Et

pri

R

Syn:anti 50:50 31:69 24:76

(36)

292

Uncatalyzed Additions ofNucleophilic Alkenes to C X

Gaudemar and Cure76 examined a two-stage procedure for condensing a-bromoamides with aldehydes and ketones. Again, no significant stereoselectivity was observed (syn:anti ratios ranged from 52:48, R = Me, to 72:28, R = Pri; Scheme 12). Ito and Terashima77 obtained good syn selectivity for a two-stage condensation of 3-(2-bromopropionyl)-2-oxazolidone derivatives and zinc dust with aldehydes (Scheme 13). Syn:anti ratios as high as 98:2 were obtained. Although zinc--carbon bonded structures have been established for zinc ester enolates, it is conceivable that the alternate zinc-oxygen bonded structure is the reactive form in aldol condensations. Two research groups78,79 have observed a modest degree of optical activity in the products from reaction of benzalde-

o

Ph~ ::

+

Zn benzene

H

reflux, 1.5 h 90%

(27)

16%

(37)

55%

(28)

OH

Ph Y i C 02Me

(29)

5%

24%

(30)

solvent

+

Toe, time

(38)

R\

RI.::.

OH

r

X--~CO R2 Ph2

+

OH

~/--- CO

Ph~

Et

Et

syn

anti

R2 2

Table 5 Syn:Anti Ratios (equation 38)

R1

R2

Dimethoxymetha,!e (-75 CC, 24 h)

Syn:anti Dimethoxymethane (-10°C, 0.5 h)

DMSO (-10 °C, 0.5 h)

Me Me Me Me

Me Et

62:38 50:50 30:70 15:85 50:50 44:56 38:62 47:53

29:71 25:75 21:79 15:85 50:50 51:49 42:58 44:56

60:40 52:48 50:50 40:60 68:32 66:34 68:32 68:32

H H H H

Pt

But Me E~

Pr

But

Zinc Enolates: the Reformatsky and Blaise Reactions

293

hyde with optically active methyl a-bromopropionate (equation 39), and this result is most simply explained by reaction of a zinc-carbon bonded enolate.

Br

y

Zn, 40 °c

CONR2

Brzn

dimethoxymethane

Et

y

CONR2

Et

(31)

OH

(31)

+

Ph ~CONR2

5°C

PhyH

30 min

0

OH

Ph

Et

67-73%

~CONR2 =

Et

syn

anti

Scheme 12

Zn, THF 25 °C, 10 min

enolate

-78°C, I h 75-98%

+

syn

anti

Scheme 13

PhCHO

Zn benzene reflux,2h 89%

22%

32%

Ph

=

~C02Me OH

27% syn,59%

19% anti, 41 %

(39)

294

Uncatalyzed Additions ofNucleophilic Alkenes to C X

1.8.3.5 Preparation of Unsaturated Esters Dehydration of the aldol products of a Reformatsky reaction does not normally occur under the usual reaction conditions but is often accomplished in a separate step to prepare unsaturated esters. Acidpromoted dehydration of J3-hydroxy esters can give significant amounts of nonconjugated unsaturated esters by either kinetic or thermodynamic control. 2 Mirrington and coworkers 80 found that acetates can be prepared directly from Reformatsky reaction mixtures by addition of acetyl chloride. Base-promoted elimination of the acetates produced conjugated esters in high yield. For the reaction shown in Scheme 14, the thermodynamic ratio of products (32):(33) is 40:60 and four different acid-promoted dehydration procedures gave at best a 68:32 ratio of products. 2

o

)l Et Et

+

MeCOCI

~

PhNMe2 80-85%

NaOEt (1.0 equiv.) EtOH, 25°C 45 s >90%

(32) 97%

(33) 3%

Scheme 14

°

6

Zn/Ag-graphite

(40)

THF, -78°C, 35 min 88%

Reformatsky reactions of
1.8.4 REACTION WITH IMINES The reaction of imines with Reformatsky reagents was first examined by Gilman and Speeter8 2 in 1943 with benzalaniline. The product of the reaction was a J3-lactam, formed by cyclization of an intermediate zinc salt (Scheme 15). The stereoselectivity of the reaction of
Br

~

C0 2Et

+

F

~

Ph

N

Ph

ZnBr I

PhyN'Ph

-BrZnOEt

Zn,12 toluene reflux, 30 min 56%

Ph

Lt

Ph

0

CH 2C02 Et

Scheme 15

295

Zinc Enolates: the Reformatsky and Blaise Reactions

BT +

RIAc02R

r

AT

I

Ar)=tAr N'

Zn benzene

AT

N reflux, 2 h 70-100%

R1

(41)

0

cis and trans

BTZn

R1AC02R2

+

r AT

AT I N

dimethoxymethane -10 °C,48 h 50-91%

ATNH

AT ~C02R2

H3O+ ~

Af)=tAf N'

EtMgB~

R1

R1 (34)

0

-100% cis Scheme 16

AT, ,ZnBT N

AT ~C02R2 RI

.

~

AT N I

r AT +

RI

(35)

BTZn A

.

AT, ,ZnBT N AT

~C02R2 ~

RI (36)

C02R2

cis

trans Scheme 17

~OMe

+

AT

N

)1

AJ

Zn, (12) ultrasound -5°C,2 h

dioxane 25°C,5 h 95%

60%

Af~ o Scheme 18

Uncatalyzed Additions ofNucleophilic Alkenes to C X

296

Me R,I S' Me" 1, N ~C02Et I

i, LDA; ii, ZnCl2

I

Me

RI ~e Me I 'Si I. .-R .- , SI. Me N' Me

ether, -78°C, 15 min

. . . SL

lIMe

R

J

EtO

:Zn-CI 0

(37)

-78°C, 1h to r.t

(37)

+

70-98%

70-100% trans

- - - - SiMe3 Scheme 19

Condensations conducted at low temperatures using preformed Reformatsky reagents gave r3-amino esters that have almost exclusively the syn configuration (34; Scheme 16). These may be cyclized by forming the magnesium salt to give the pure cis-r3-lactam. It was concluded that the first step of the reaction is reversible at reflux temperature and equilibration of syn and anti zinc salts, (35) and (36), is competitive with irreversible cyclization, as shown in Scheme 17. 84 Bose and coworkers 85 have reported that the condensation of ethyl bromoacetate with a variety of imines can be completed in a few hours at room temperature by means of ultrasound activation. Oxidative removal of a N-(p-methoxyphenyl) group gave N-unsubstituted r3-lactams, which are useful intermediates in the preparation of r3-lactam antibiotics (Scheme 18). Van Koten and coworkers 86 prepared zinc ester enolates of N-protected a-amino esters from the corresponding lithium enolates and allowed them to react with imines at low temperature to obtain trans-3amino-r3-lactams, often with high stereoselectivity as shown in Scheme 19. Interestingly, the authors interpreted their results in terms of an internally chelated zinc-oxygen bonded enolate (37).

1.8.5 REACTION WITH ACYLATING AGENTS 1.8.5.1 Reaction with Esters and Acid Chlorides Reactions of Reformatsky reagents with esters or with acid chlorides generally give only low yields of r3-keto esters. 2 Hauser reported that ethyl a-bromoisobutyrate could be acylated in reasonable yields with either the acid chlorides43 or the phenyl esters87 of aromatic acids, but the reaction fails with acylating 0

Br7c02El

+

Zn

Ar)lCI

ether, reflux

57-72%

0

Br7c02El

+

Ar)lOPh

0

Ar~

(42)

. C02Et

0

Zn benzene-toluene reflux 35-59%

Ar~

C0 2Et

(43)

297

Zinc Enolates: the Reformatsky and Blaise Reactions Zn Me3SiCI (5-10%) ether

+

(44) O°C,1 h 25°C, 1 h 91%

(38)

agents or with bromo esters which possess a-hydrogens (equations 42 and 43). It is interesting to note that Reformatsky himself8 8 reported a reasonably successful synthesis (41 % yield) of the tandem aldol product (38) by reaction of ethyl formate with two equivalents of ethyl a-bromopropionate. Recently, with zinc metal activated with Me3SiCI,89 the same product was obtained in 91 % yield (equation 44).

1.8.5.2 Reaction with Nitriles, the Blaise Reaction The most successful acylations of Refonnatsky reagents have been obtained with nitriles. This reaction, first reported in 1901 by Blaise,9o was little used until Kagan and Suen91 reported that slow addition of a benzene solution of a-bromo esters to a refluxing mixture of zinc and the nitrile gave good yields (70-83%) of a,a-disubstituted ~-keto esters. Hannick and Kishi 92 reported that a similar proce-

Zn, THF

+

reflux 0.5-1 h

(40)

(39)

Scheme 20 Table 6

Yield of Enamino Esters (39) or J3-Keto Esters (40) (Scheme 20)

R1

R2

R3

(38) (%)

(39) (%)

Me But Me Me Me Me

H H H H

(CH2)4CI (CH2)4CI C(CH3)2(CH2)2CI

95 87 70 88 84 54

85 83 62 82 79 84

Ph Ph

Me Me

Br

~

(CH2)4CI

rl

C02 Me

+

S

S

MeoycN

+

THF reflux

Zn (5 equiv.)

55 min 79%

OMe

C02Me

C02Me

:J

BrZnN MeO

H,

N

SJ S

OMe

OMe

(42)

(41) Scheme 21

Uncatalyzed Additions ofNucleophilic Alkenes to C X

298

><

R1

R2

Br

C02Et

+

ZnCu,12

R4

R3

N

THF

NCXoSiMe3

Me3SiobC02Et

reflux, 2 h

R

21-72%

n

,ZnBr

3

4R 1 R

R2

R1

R3 R4

0

R2

R:}i R4 0 0

Rl=H

0

(44)

(43)

Scheme 22 RCN

o

Me

) l OBut

ether,O°C

O°C 25-86%

Scheme 23

dure using activated zinc dust in refluxing THF was substantially better for the preparation of both amonosubstituted or a-unsubstituted J3-keto esters (Scheme 20 and Table 6). Hannick and Kishi 92 cyclized an intermediate bromozinc enamino ester (41; Scheme 21) to obtain the heterocycle (42), used for the synthesis of saxitoxins. The Kishi procedure for the Blaise reaction has been applied44 to a facile synthesis of J3-keto-8-butyrolactones (43), or tetronic acids (44; Scheme 22). It is useful to note that Hiyama and Kobayashi93 have reported successful reactions of nitriles with a magnesium ester enolate (Scheme 23), whereas the corresponding lithium ester enolate failed to react.

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