Preparation and reactions of polyfunctional organozinc reagents in

Chem. Rev. 1993, 93, 2117-2188

2117

Preparation and Reactions of Polyfunctional Organozinc Reagents in Organic Synthesis Paul Knochel' and Robert D. Singer Fachberelch Chemle dor Phillpps-Unlvorsitat, Hans-Meerweinstrasse, W-35043 Marburg, Germany

Received April 5, 1993 (Revised Manuscript Received June

11, 1993)

Contents I. Introduction II. Preparation of Functionalized Organozinc

III.

Reagents A. Preparation by a Direct Insertion of Zinc Metal B. Preparation of Functionalized Dialkylzincs by an Iodine-Zinc Exchange Reaction C. Preparation of Functionalized Organozinc-Copper Reagents by Using Insertion Reactions D. Preparation of Functionalized Organozinc Reagents Obtained from Reactive Organolithlums by a Lithium-Zinc Transmetalation E. Diverse Preparations of Organozinc Reagents 1. Via a Boron-Zinc Exchange Reaction 2. Via a Mercury-Zinc Exchange Reaction Reactions of Functionalized Organozincs Mediated by Copper(I) Salts A. General B. Substitution Reactions 1. Coupling with

Reactive Halides

2. Coupling with Alkynyl, Alkenyl, and

Alkyl Halides 3. Coupling with Acid Chlorides C. Addition Reactions

to Aldehydes and Related Reagents 2. 1,4-Additions to a,^-Unsaturated Carbonyl Compounds 3. Michael Additions to Nitro Olefins and Related Reagents 4. Carbocupratlon Reactions Reactions of Functionalized Organozincs Catalyzed by Palladium(O) Compounds A. Cross-Coupling Reactions with Alkenyl and Aryl Halides B. Acylation Reactions Asymmetric Addition of Functionalized Organozincs to Aldehydes Catalyzed by Chiral Titanlum{ IV) Complexes Conclusions and Perspectives Acknowledgments References 1. Additions

IV.

2117 2119

2119 2121

2122

2125

2126

2126 2127 2127 2127 2128 2128 2138

Paul Knochel, born in 1965 in Strasbourg, France, completed his Ph.D. under the supervision of Professor Dieter Seebach In 1962 (ETH Zurich, Switzerland). He joined the CNRS in Paris and worked in the laboratory of Professor Jean Francois Normant until 1986.

After a year of post-doctoral research at the Princeton University with Professor Martin F. Semmelhack, he became assistant professor atthe University of Michigan In Ann Arbor and fuS professor in 1991. He was awarded an Alfred P. Sloan fellowship and received the Berthelot Medal of the Academie des Sciences, Paris, France, In 1992. He then moved back to Europe and accepted a 04professor position at the Philipps-Unlverstty in Marburg, Germany. His research is focused on the use of organometallic reagents for the development of new synthetic methodologies.

2143 2143 2143

2158 2167

2167 2173 2173 2179 2179

2185 2185 2185

I. Introduction

Robert Douglas Singer was born at Halifax, Canada, on September 16, 1964. He received his B.Sc. Honours from Saint Mary's University, Halifax, Nova Scotia, and hts Ph.D. from Simon Fraser University, Burnaby, British Columbia, in 1992 under Professor A. C. Oehlschlager. His thesis work Involved spectroscopic and chemical investigations of alkyl-, (trialkylsilyl)-, and (trlalkylstannyl)cuprates. He Is currently an Alexander von Humboldt Fellow engaged in postdoctoral research in the laboratory of Professor Paul Knochel at Phillpps-Universtty In Marburg, Germany. His research Interests Include the development of new organometallic methods in organic synthesis.

Most organic target molecules are polyfunctional compounds requiring, in a retrosynthetic analysis,1 the reaction between a functionalized carbon electrophile

and a functionalized carbon nucleophile. Many carbon nucleophiles are organometallic reagents, and the highly reactive nature of the carbon-metal bond often pre-

V.

VI. VII. VIII.

0009-2665/93/0793-2117S12.00/0

©

1993 American Chemical Society

2118

Knochel and Singer

Chemical Reviews, 1993, Vol. 93, No. 6

eludes having functional groups present in these reagents. Thus, the development of methods allowing

the preparation of functionalized organometallic compounds is of great importance. These reagents will be very useful in the preparation of complex organic molecules since they will allow shorter synthetic routes by avoiding, for example, the use of protectiondeprotection steps as well as functional group interconversions. The use of functionalized organometallics may also lead to the discovery of new reactivity patterns, especially if the carbon-metal bond can interact with an organic functionality in close proximity. This type of interaction may change both the chemical behavior of the functional group and of the carbon-metal bond leading to new synthetic applications. If the carbon chain linking the carbon-metal bond to the functional group has the appropriate length, then new ring closure reactions can be performed. Finally, if the functional group contains a chiral moiety, then new types of asymmetric synthesis will become possible. A reactivity problem may, however, occur if functionalized organometallics are used. As a general rule, an organometallic reagent which tolerates the presence of a broad range of functional groups will display a low reactivity toward these organic functions and, in general, will also be relatively unreactive toward many organic electrophiles. The apparent contradiction of having a reactive organometallic bearing functionalities can be realized if two metals, M1 and M2, are used instead of one. The role of the first metal, M1, will be to convert a highly functionalized organic substrate FG-RX into a relatively stable (and unreactive) organometallic FGRM1. This reagent is then transmetalated by the second metal, M2, to a more reactive organometallic reagent, FG-RM2, which can then react efficiently with an electrophile. A large part of this review will be devoted to the demonstration of the synthetic utility of this approach using Zn as M1 and Cu, Pd, or Ti as M2. Thus, after a section describing the various preparations of functionalized organozinc reagents, we will examine their reactivity toward electrophiles after transmetalation or in the presence of other metallic salts. Applications of the use of functionalized zinc-copper organometallics in natural product synthesis will be presented. Only the preparation and reactivity of organometallics bearing relatively reactive functionalities will be discussed. The chemistry of organometallic species bearing an ether, acetal, or ketal functionality will generally not be covered in this review. Only reactions in which organozinc compounds are clearly reaction intermediates will be discussed in detail. Organozinc compounds (R2Zn and RZnX) are one of the first classes of main-group organometallic compounds prepared.2 Frankland discovered, in 1849 at Marburg, that the heating of ethyl iodide with zinc produces highly pyrophoric diethylzinc. Amazingly, hydrogen gas was used as protective atmosphere in this preparation.3'4 A systematic study of the carboncarbon-bond-forming ability of these reagents with typical organic electrophiles such as acid chlorides,5 aldehydes, ketones,6’7 or esters had been completed before 1880.® These popular organometallic reagents were, however, replaced at the turn of the century by the more reactive organomagnesium compounds. Only the Reformatsky reaction9 (addition of zinc ester

enolates to aldehydes) has remained in use by organic chemists. The reasons for this lack of interest were due to the very low reactivity of dialkylzincs toward most organic electrophiles and to the moderate yields obtained.2 This low reactivity presents a potential advantage for the preparation of functionalized zinc reagents. This was first recognized in 1936 by Hunsdiecker who prepared several organozinc iodides 1 bearing an ester functionality by the direct insertion of zinc into the corresponding alkyl iodides in boiling ethyl acetate.10 More than 30 years later, Wittig and Jautelat

reported the preparation of [(benzoyloxy)methyl]zinc iodide 2 in ether (reflux, 4 h, 82% yield) and [3-(benzoyloxy)propyl]zinc iodide 3 in dioxane (90 °C, 2.5 h, 65% yield).11 PhC02CH2Znl

R02C(CH2)„Znl 1

:n>5

PhC02(CH2)3Znl 3

2

In these reports, no reactivity studies of these reagents

made. The reagent 211’12 as well as ICH2ZnI12-15 used as precursors of a carbene in cyclopropanation reactions. Only a few other reactions using ICH2ZnI for forming new carbon-carbon bonds have been reported.16’17 The low reactivity of organozincs is a result of were were

the high covalent character of the carbon-zinc bond (comparable to the carbon-tin bond).18 Also, the Lewis acidity of Zn(II) is not sufficient to activate carbonyl groups toward addition reactions (eq 1). On the other

slow

R—Zn-X

R^-OZnX

0)

hand, the empty low-lying p orbitals of zinc allow many transmetalation reactions with metallic salts to proceed as long as they are thermodynamically favored (eq 2). This excellent transmetalation ability permits the conversion of organozinc reagents 4 into a variety of new organometallics 5. ,R

R—Zn-Y

+

Y—Zn"'

X-MU,

""X

4

:ml*

Y = R, halide... M = Ti, Mo, Ta, Nb, V, Pd, Ni, Pt, Cu...

RML„

+

ZnXY

(2)

5

Especially interesting for synthetic applications are compounds 5 in which M is a transition metal, since these metals can mediate reaction pathways not available for main-group metals. Thus it has been shown, first by Negishi, that intermediate organopalladium(II) 6 can readily be formed from organozinc compounds 4, and after reductive elimination, various crosscoupling products are obtained20-25 (eq 3). PdL2

R1—X

-

f

R-ZnY 4

R1—Pd-L

-»-

l1

ZnXY

R

R1—Pd-L I

L

R—R1

--

(3)

Pdl-j

6

The process is catalytic in palladium and allows efficient cross-coupling reactions of various unsaturated


Organozinc Reagents in Organic Synthesis

halides or acid chlorides with organozinc reagents.20-25 Similarly, a transmetalation of 4 to copper organometallics using CuBr*SMe226-27 in ether/HMPA, CuCN,28 or CuCN-2LiCl29 in THF are also possible (eq 4). The THF soluble copper salt CuCN-2LiCl is especially convenient, leading to functionalized copper reagents which react with various classes of electrophiles. R—Zn-Y

CuX

E+

R-Cu

.--

+

R-Cu-E

-

_qu

+

R—E

(4)

4

Some of these reactions (allylation, acylation) can be performed using catalytic amounts of copper (I) salts.28,29 Finally, the reactivity of the carbon-zinc bond toward aldehydes can be improved by the presence of various Lewis acids, and efficient asymmetric catalysis can be developed if chiral Lewis acid complexes are used.30

II. Preparation of Functionalized Organozinc Reagents A. Preparation by a Direct Insertion of Zinc

Metal

The rate of zinc insertion into the carbon-halide bond of organic halides depends strongly on the nature of the organic moiety, the halide, the reaction conditions (solvent, concentration, temperature), and the zinc activation. In 1962, Gaudemar reported that alkyl iodides insert zinc rapidly using zinc foil (electrolytic quality >99.9% purity) in THF under relatively mild conditions31 (50 °C, for primary iodides, 25 °C for secondary iodides). This procedure proved to be very general. Zinc foil can be replaced by zinc dust from various sources (Aldrich, Fluka, Riedel-de Haen).32 If the zinc dust is activated successively with 1,2-dibromoethane (4-5 mol % )29,33 and chlorotrimethylsilane (1 mol %)29,33,34 prior to the addition of the organic halide, then fast reaction rates are observed. Thus if the alkyl iodide (i.e. butyl iodide) is added as a 2.5-3.0 M THF solution, the zinc insertion is complete within 2-3 h between 35 and 40 °C. Secondary iodides react even faster, and a complete conversion to the alkylzinc iodide is usually observed after 0.5-1 h at 25 °C.29 The zinc insertion shows a remarkable functional group tolerance and most common organic functional groups (i.e. ester,29,35-52 ketone,29,35 cyanide,29,35-43,47,49-52,54 haiV^V-bis(trimethylsilyl)amino group,55 primary and secondary amino groups,56 amide and phthalimide,25,56,57 trialkoxysilyl group,58 sulfoxide,59 sulfide,59 sulfone,59,60 thioester,60 boronic ester,46,48,50 enone,40,53 and phosphate39,61) can be present during the organozinc formation (eq 5). Only hydroxyl groups (deprotonation) or nitro and azide functionalities (inhibition of the zinc insertion) cannot be present in lide,29,35,43,48,50,52

the alkyl iodide.

THF FG-RX

+

Zn

-

5-45 ’C

FG-RZnX

(5)

>85%

X = I, Br; FG = C02R, enoate, CN, enone, halide, (RCO)2N, (TMSfeSi, RNH, NH2, RCONH, (RO)3Si, (ROfePfO), RS, RS(O), RS02, PhCOS; R = alkyl, aryl, benzyl, allyl.

benzylic groups considerably facilitate the formation of the zinc reagent and these reactions occur between 5 and 10 °C allowing the less active organic bromides31 (or even chlorides36,37) to be used. The presence of a polar functional group in the a or j3 position to the halide in an alkyl chain also strongly enhances the zinc insertion rate. Thus, whereas butyl iodide reacts in THF at 40 °C, the presence of a cyano group54,55 at the /3 position to the halide allows zinc insertion at 25-30 °C. The presence of a polar phosphonate moiety in the organic halide enables successful zinc insertion under very mild conditions. Thus, diethyl 2-iromoethylphosphonate61 is converted to the corresponding zinc reagent at 30 °C (10 h; >85 % yield). The exact reason for such a rate enhancement is not clear. Since the addition of equimolar quantities of acetonitrile to butyl iodide does not enhance the rate of zinc insertion in this reaction, the observed rate enhancement mentioned above cannot only be due to more efficient solvation of the zinc reagent or more efficient displacement of the newly formed organometallic from the zinc surface. The close proximity of the polar group to the carbon-iodine bond is also important. Hence, the rate of the zinc insertion to the iodides of type NC(CH2)nI decreases as n increases and reaches a comparable rate to the zinc insertion into butyl iodide when n = 4. Thus, the polar group may facilitate the zinc insertion by accepting an electron from the zinc surface. This electron may then be transferred in a second step into the 90% yield).46 The presence of a phenylthio group, which is also a good electron acceptor,63 allows smooth zinc insertion into the carbonchlorine bond in chloromethyl phenyl thioether (THF, 25 °C, 1 h).59,60 Alkenyl and aryl iodides having a stronger Csp2-! bond (compared to Csp3-I) do not insert zinc in THF and react only in polar solvents at elevated temperatures with zinc metal (DMF, 70 °C, 14 h).35 However, a vinylic iodide conjugated with a carbonyl group such as 3-iodo-2-cyclohexen-l-one is converted to (3-oxo-l-cyclohexenyl)zinc iodide in THF under quite mild conditions (25-50 °C, 0.5 h; >85% yield).53 Some typical reaction conditions for the preparation of organozinc halides are summarized in Table 1. The preparation of alkylzinc halides can also be performed in mixtures of benzene and DMA or HMPA using a zinc-copper couple.21-25,28b,c It is possible to generate in situ very reactive zinc metal by the reduction of zinc chloride with lithium naphthalenide in THF (eq 6) .64-67 This type of zinc reacts with alkyl bromides FG-RX ZnCI2

The structure of the alkyl halide is very important for predicting the zinc insertion rate. Thus, allylic and

2119

+

Li-Naphthalene-» zn *

-»-

THF, 25-60 -C

X

=

Cl, Br,

I

FG-RZnX

(6)

2120


Knochel and Singer

Table 1. Reaction Conditions for the Preparation of Organozinc Halides from the Corresponding Organic Halides (Added as 2.5-3.0 M Solution) T (°C) solvent t( h) organic halide n-BuI 3-4 45-50 THF 2 c-HexI 25-30 THF 20 2 THF NC(CH2)2I 30 10 THF (Et0)2(0)P(CH2)2Br 20 0.1 THF Me MeAÔ

T

BCH

catalytic amount of Lil allows the use of primary alkyl chlorides, sulfonates, phosphates, or bromides as precursors for the formation of organozinc compounds 7 (eq 9).76 Zn, Ml (0.2 equiv.), MBr (1.0 equiv.)

R— X

DMA or DMPU, 40-80 ’C, 2-12h

R—ZnX

103 Thus, alkynylcopper reagents like 73 selectively insert, in the absence of an electrophile, four methylene units leading to dienylcopper-zinc reagents 74 which after allylation give the unsaturated esters 7 5a-c in 74-50 % yield (Scheme 4) .103 84b:

Scheme 4

R

=

Pent; 58%

R—C=C-Cu 73 ICHaZnl

R—C=C—CH2Cu 76

CH2

77

ICHgZnl

ICHaZnl

95%

R

=ch2 CuCH

78

Scheme 6 OMe 1) BuLi, THF, -30 ‘C

The first methylene insertion converts the alkynyl copper 73 into a propargylic organometallic 76 which is in equilibrium with the allenic from 77. The insertion of a new methylene unit leads to the allylic reagent 78 which is in equilibrium with the dienic organocopper 79. The methylene homologation of 79 by ICH2ZnI furnishes the relatively reactive allylic reagent 80 which readily inserts another molecule of ICH2ZnI, providing the alkylzinc-copper 74 which under the reaction conditions does not insert another methylene group and can be allylated cleanly (Scheme 4). Alkynylcoppers, bearing an alkoxy group in the propargylic position, display a reactivity pattern which depends on the nature of the electrophile. Thus the tetrahydropyranyl ether 81 is readily homologated by ICH2ZnI in the presence of a carbonyl compound, giving the chelation stabilized allenic copper compounds 82. In the presence of a reactive electrophile such as benzaldehyde, the polar addition reaction proceeds and the homopropargylic alcohol 83 is isolated as the only product. In the presence of a less reactive electrophile such as cyclopentanone, further homologation of 82 is faster than the addition to the electrophile and it is only when the homologation process produces a reactive allylic intermediate (of type 80, Scheme 4) that the reaction with cyclopentanone occurs. The hydroxydienes 84a,b are then obtained in 58-70% yields (Scheme 5). The same type of reactivity is observed with the propargylic ether 85 (eq 35).101'103 The functionalized allenic copper reagent 86, obtained by the metalation of methoxyallene, is also an excellent precursor for a selective double methylene homologation. Its reaction with ICH2ZnI in the presence of an aldehyde or a ketone provides functionalized dienols of type 87 in fair to good yields (Scheme 6).103

h9c=*=^ 2

\H

--r** 2) Cul*2LiCI, -30 C

.OMe

PMe ICHjZnl, RCHO

H2C=*^^ 2 86

---

H2C='

>û

iHgCu

II

no RCHO

CuCH2

M

OMe

•3>c

iCH^nl

Cu

Ofc

^>r

The insertion reaction described in this section allow unique and very efficient preparations of various types of functionalized zinc and copper organometallic reagents. The novel aspects of this chemistry certainly increases the synthetic potential of carbenoic reagents15-116 and should lead to useful applications in synthesis. D. Preparation of Functionalized Organozlnc

Reagents Obtained from Reactive Organolithlums by a Lithium-Zinc Transmetalatlon Organolithium reagents are considered to be too reactive to tolerate most functionalities.18-117-118 However, the polar character and the reactivity of a carbonmetal bond depends not only on the nature of the metal, but also on the hybridization of the carbon atom attached to this metal and on the structure and aggregation of this organometallic.18-117-118 Alkenyl- and aryllithiums are known to be less reactive than their alkyl counterparts and several electrophilic functions can be present in these organometallics [i.e. a halide (eq 36),119 a sulfone (eq 37),120 an epoxide (eq 38),121a or in the case of aryl126 and acetylenic123 lithiums, an

even

2126


Knochel and Singer

ester, a nitro or a cyano group (eqs 39 and 40)]. However, most of these organometallics are very unstable and react only with selected electrophiles. The stability of these polyfunctional lithium derivatives can be greatly improved by performing a transmetalation

with zinc(II) salts. Me3Sn

MeLi, THF

«

«361"

Me

Me

ToI02S.

A^-Cl

-70 'C

ToI02S.^^ss>.A

MeLi, THF

MeO OMe MeOOl

Me

'I

-20 'C

(37)120

Me

provides the corresponding functionalized lithium derivatives 92. The iodine-lithium exchange is complete within 3 min at -100 °C.128 After the addition of Znl2 (-100 °C), the zinc reagents 93 are obtained. They can be handled at 25 °C without decomposition. This method allows access to functionalized organozincs which cannot be prepared by direct zinc insertion. Although the presence of an azide or nitro group both inhibit direct zinc insertion, the iodine-lithium exchange reaction can be performed on the unsaturated azide 94 or on the aromatic nitro compound 95122ij furnishing the desired lithium compounds 96 and 97 which can subsequently be cleanly transmetalated to the corresponding zinc (or copper) reagent (eqs 44 and 45).122ij,125

(38)1

2) and that in the complex 100 the cyanide ligand is still attached to the copper center.138 These reagents should be considered as being mixed clusters of copper and zinc. It was noted that the addition of increasing amounts of zinc salts to the reagent 100 considerably decreases its reactivity, suggesting that even in 100 some of the FG-R groups could still be attached to a zinc center. The use of lithium halides to solubilize CuCN was found to facilitate the transmetalation (i.e. to form the copper reagents 105 rapidly and under mild conditions). The new copper compounds 100 and 105 present a significant advantage compared to classical copper reagents since most organic functional groups can be contained in these copper derivatives. Their reactivity is somewhat reduced compared to lithium or magnesium-based reagents, and for example, epoxides do not react with 100 or 105. Also the substitution reactions with alkyl halides proceed well only with primary alkyl iodides and need to be performed in polar solvents. Nevertheless, they react with a wide range of electrophiles as shown in Scheme 7 and display a remarkable thermal stability. Thus primary alkyl zinc-copper compounds 100 can be heated in refluxing 1,2-dimethoxyethane for several

2128


Knochel and Singer

hours without appreciable decomposition (eq 57).139 The Et02C(CH2)3Cu(CN)Znl DME, 85'C, 6 days

A^r

R-M

cat. Cu(l)

Hex^97:3

88

39

>97:3

85

39

>97:3

76

39

>97:3

90

39

>97:3

89

39

>97:3

89

39

>97:3

88

39

>97:3

80

39

92

61

79

61

94

64

ch3

ch3

yield (%) ref(s)

H^VvVv1 Bu

3C02Et

Cl

(CH2)3CN

E/Z (21:79) SPh

J^CI

SPh

NC(CH2)3^l^/(CH2)3CN

Cl

E/Z (8:92) SPh

SPh

(CH2)6OAc

|AC|

AcO(CH2)6

(CH2)6OAc

BZ (45:55)

Cl

SPh

(CH2)2P(0)(0Et)2

SPh

(Et0)2P(0)(CH2)2vA^(CH2)2P(0)(0Et)2 Cl

BZ (8:92) SPh

SPh

(CH2)3C02Et

!^YCI

Cl

EtO2C(CH2)3ViiSsiv^,(CH2)3C02Et

ch3

ch3

BZ (11:89) (CH2)3C02Et

SePh

^Cl

SePh

Et02C(CH2)3v^N_^(CH2)3C02Et

Cl

(CH2)3CN

BZ (20:80)

1,3-dichloropropene

NC(CH2)3^\(CH2)iCN

BZ (CH2)6OAc

(CH2)2P(0)(0Et)2

1,3-dichloropropene

C02Et

(87:13)

AcO(CH2)6vj^\(ChÔAo BZ (70:30) "

(EtO) P*(0)

^j^C02Et

2

(CH2)2P(0)(0Et)2

t-Bu02S

—

(EtO)2P(0)^

S02t-Bu

(CH2)eCl

1-chloro-2-butene

ch3

CI(CH2)6A^ H

98:2

2134


Table

5.

Knochel and Singer

(Continued) Sn2/Sn2

RCu(CN)ZnX (R)

product

allylic electrophile

ratio

yield (%)

ref(s)

83

46b

74

101

t-Bu02C

70

101

t-Bu02C

50

80d

65

80d

48

80d

48

80d

55

80d

56

80d

51

80d

62

49b

70

49b

81

49b

C02Et

68

49b

C02Et

67

49b

59

49b

64

49b

74

49b

75

49b

C02Et

A^Br

-(CHa)4_ H

C02Et

Hex

t-BuC^C

A^

A^Br

A.*

|-CH2n-NHBoc h'’"C02Bu

|-ch2v,nhboc

Br

COjBu

j_{

I-CH: n.NHBoc C02BU

l-j

Ph

C02Bu

j-CHss^NHBoc Cl

CO2BU

l~l

Me

j-CH2^NHBoc

A^0Ts

'C02Bu

Yt

|-CH2-,NHBoc Yf

Me02Cx^\^.Br

”'C02Bu

IZnO

CH,

C02Et

A^Br

c-Hex

C02Et

A^

A^

A^Br Bu

OSiMe3

A^Br

'(CH2)6-

a CA x'/^(CH2)7

C02Et

no2 Ph

TBDMSO

OTBDMS

.OZnl (Et02C)2CH ____^

Chemical Reviews, 1993, Vo). 93, No. 6

Organozlnc Reagents in Organic Synthesis

2135

Products Obtained by the Reaction of Functionalized Benzylic Zinc-Copper Reagents with Allylic Halides FG-RCu(CN)ZnX (FG-R) allylic halide product ref(s) yield (%)

Table

6.

C02t-Bu

95

36

98

36

97

37

96

37

87

37

82

37

92

37,54b

86

55

84

55

81

55

93

55

OAc

91

45

OAc

89

45

71

45

96

99

74

99

COjt-Bu

I

A^Sr

oI

CH2

x^^s^-OCHa

XX.

C02t-Bu

.och3 OAc

C02t-Bu

-CH2N^p^CN

C02t-Bu

A^8r

CCM-Bu

C-

.CN

Cl

-CH(CH2)2CN Ph

N(SiMe3)2

-ch2

COot'Bu

N(SIMe3)2

A^r

N(SiMe3)2

A-^

-ch2

-ch2

OCH2OCH3

C02t-Bu

N(SiMe3)2

A-

CH3OCH2^0

N(SiMe3)2

OPh

N(SiMe3)2

N(SiMe3)2

-ch2

OAc i

OAc i

C02t-Bu

t-Bu02C

C02t-Bu

t-Bu02C

A^r A^

C02t-Bu

A^r Bu

-CH

A

AAi u

A A-ÔAc

U

t-Bu02C

OAc

ArV

u

A^Br

-CH2

-CH

2136


Table

6

Knochel and Singer

(Continued) allylic halide

FG-RCu(CN)ZnX (FG-R) Br

kJ

C02Et

Table

ref(s)

86

76

82

76

A

l!

C02Et

A

A^Br

Aoac

Br

A

A^Br

'CHzyS

yield (%)

product C02Et

C02Et

'A^0Ac

Products Obtained by the Reaction of Functionalized Alkenyl and Aromatic Zinc-Copper Reagents with

7.

Allylic Halides

FG-RCu(CN)ZnX (FG-R)

allylic halide

product

Sn27Sn2

yield (%)

ref

C02Et

83

53

C02Et

71

53

C02Et

81

125a

C02Et

59

46b

C02Et

69

46b

72

35

91

35

72

35

80:20

86

64

100:0

93

64

83

35

Ck ^,Ph

83

35

O-^c-Hex

72

35

79

125

A^ V

A^ VY V

'Cl

V

./bV9rI

o-L

Me Me

Me

Ab-

Me

Me

Me

Me

9VS O-B

Bu

CN

CN

OCH2OCH3

*0

A^1

A"

A^1

OCH2OCH3

/7v^^C02Et

A

CH30CH20

OCH2OCH3

A^1

l-chloro-2-butene C02Et

A,

aaS

ch3och2o

CH30CH20

ch3

aa

C02Et

3-chloro-1-butene CH.

C02Et C02Et

/>

xx Ck-Ph

OOot-Bu

A^

YY1

t-BuQ2C

C02t-Bu

A-Br

t-Bu02C o-Hex

C02t-Bu

A-Br

t-Bu02C

no2

N02

C02t-Bu

A/Br

t-BuOjC

Organozlnc Reagents

Table

7

In

2137


Organic Synthesis

(Continued)


/TX

*Cl ^XOMe Table 8. Preparation of Dienes Organozinc-Copper Reagents FG-RCu(CN)ZnX (FG-R)

allylic halide allyl chloride

Sn2'/Sn2

product

yield (%)

ref

41

144

63

144

^*X02Me allyl chloride

^X30Me or

Allenes by the Reaction of Propargylic Halides

Tosylates with

HC^CCHjOTs

—

=/

ref

yield (%)

product

propargylic electrophile

(CH2)3C02Et

or

28b

^—C02Et

ch3 R

R R R R R R

C1CH20=CCH2C1 C1CH2C=CCH2C1 C1CH2C=CCH2C1

(CH2)3CN (CH2)3C02Et (CH2)eCl CH2-C6H4-P-CN

CeH^p-COMe C„H4-p-CN

TsOCH2C^CCH2OTs TsOCH2C=CCH2OTs TsOCH2C^CCH2OTs

^^s^,NHBoc

HC=CCH2Br

=

(CH2)3CN (CH2)3C02Et (CH2)eCl

* =

=

CHa-Cs^-p-CN

=

CeH4-p-COMe C6H4-p-CN

=

^yv^NHBoc

84 95 92 93 93 97

65 65 65 65 65 65

55

80d

C02Bn

C02Bn

Table 9. Functionalized Iron and Molybdenum Diene Complexes Obtained by the Reaction of Cationic Iron Molybdenum Complexes with Functionalized Zinc-Copper Reagents FG-R2Cu(CN)ZnX (FG-R2)

cationic complex

R1

+F8(CO)3

bf4

yield (%)

product R1^

or

ref

R2

Fe(CO)3

Ri

(CH2)2CN (CH2)3CN (CH2)3C02Et (CH2)3CN

R1 R1 R1

(CO)3Fe

PFe-

Me

= = =

H; R2 = (CH2)2CN H; R2 = (CH2)3CN H; R2 = (CH2)3C02Et Me; R2 = (CH2)3CN

84 90 97 75

51a 51a 51a 51a

78 75 83 60 76

51a 51a 51a 51a 51a

R’ix

(CO)Fe

R1 R1 R1 R1 R1

(CH2)2CN (CH2)3CN (CH2)3C02Et (CH2)4OAc (CH2)3C02Et

=

= = = = =

H; R2 H; R2 H; R2 H; R2

=

(CH2)2CN (CH2)3CN = (CH2)3C02Et = (CH2)4OAc OMe; R2 = (CH2)3C02Et =

^ +

Mb^Xr'

M®

r1

M8y#V^r2 Me

+Fe(CO)4

A

(CH2)3C02Et (CH2)4OAc (CH2)3CN

R1

=

Ri

=

(CHj)2CN

R1 R1

(CH2)3C02Et (CH2)4OAc (CH2)2CN

R1 R1

ri

Q +:

= =

s = =

H; R2 = H; R2 = H; R2 = H; R2 = Me; R2 Me; R2 Me; R2

R1

B

(CH2)3C02Et (CH2)4OAc (CH2)3CN (CH2)2CN (CH2)3C02Et = (CH2)4OAc = (CH2)2CN —

A:B 57:0 68:0 65:0 45:0 28:23 15:43 20:36

51b 51b 51b 51b 51b 51b 51b

90 90 33 58

51c 51c 51c 51c 51c 51c

€>-r2

Cp(CO)Mo'

Mo(CO)2Cp PFe-

(CHahCOaEt (CH2)3C02Et (CH2)2C02Et (CH2)4CN (CH2)3CN (CH2)4OAc

R2 R2 R2 R2 R2 R2

= = = =

= =

(CH2)4C02Et (CH2)3C02Et (CH2)2C02Et (CH2)4CN (CH2)3CN (CH2)4OAc

41 51

2138


Table

9

Knochel and Singer

(Continued) product

yield (%)

ref

(CH2)4OCOPh

57

51c

68

80f

59

80f

57

80f

64

80f

52

80f

31

80f

cationic complex

FG-R2Cu(CN)ZnX (FG-R2)

R2

(CH2)4OCOPh CH2n^ NHBoc

=

^

NHBoc

(CO)3Fe-j—

C02Bn (CO)3Fe

PF6'

Me

CH2,___.NHBoc

(CO)3Fe-j

C02Bn (CO)3Fe' PF6‘

Me

-Me

Me^

CH2 ___.NHBoc

W

C02Bn

(CO)3Fe

PF6'

MeO.

CH2.___NHBoc

C02Bn (CO)3Fe

PFe-

CH2n^, NHBoc C02Bd

CH2n^NHBoc C02Bn (CO)3Fe

BF4

2. Coupling with Alkynyl, Alkenyl, and Alkyl Halides

C02Et

Organocopper reagents are well known to undergo coupling reactions with alkenyl halides.136 The copper reagents derived from organozinc halides, RCu(CN)Znl, react only under harsh conditions with alkenyl halides139 (several days, reflux in DME); however, the reactions produce functionalized olefins in a stereocontrolled fashion (eqs 57 and 69).

/=\ Hex'

DME, 85 'C +

(Et0)2P(0)(CH2)2Cu(CN)ZnBr

-C02Et

k^5yC02Et

/=\

>-'

P(0)(OEt)2

nitro olefin 114 in good yields (eq 72).45b The addition of FG-RCu(CN)ZnX to 3-iodocyclohexenone usually proceeds very well and leads to highly functionalized

(69)138

e,so2^n°2

Piv0

,Cu(CN)ZnBr ,7goC 74% OAc

PivOfCH^^s^NOa (72)',45b

82%; E/Z: 17/83

OAc

The presence of an electron-withdrawing substituent at the /3-position considerably facilitates the substitution reaction since an addition-elimination mechanism can take place. Various reagents of type 113 react with zinc-copper organometallics in high yields (eq 70 and Table 10). FG-RCu(CN)ZnX

(71)«

C02Et

E/Z : 17/83

Hex'

90%

3-substituted cyclohexanones (eqs 73 and 74 and Table

-

6 days

I

PhS02^C02Et

-30°C, 1h

Et02C^^---Cu(CN)Znl

(70) FG-R

113

e=no2,co2r,cor

The reaction can be used to prepare a variety of /3-substituted alkylidenemalonates by the addition of various zinc-copper reagents FG-RCu(CN)ZnX to a

[(phenylsulfonyl)methylidene]malonate (eq 71).43 A unique access to y-acetoxy nitro olefins 114 is also possible by this approach. Thus, the addition of an a-acetoxyalkylzinc-copper reagent to (E)-2-(ethylsulfonyl)-l-nitroethylene provides the pure (E)-acetoxy

114 (TMS)2N



2139

Table 10. Reaction of Alkenyl Halides and Related Compounds with Zinc-Copper Organometallics Leading to Functionalized Olefins alkenyl iodide

FG-RCu(CN)ZnI

(CH2)3CN (CH2)3C02Et

(CH2)2P(0)(OEt)2

CHsOPiv

(E)-octenyl iodide (E)-octenyl iodide (£/Z)-l-octenyl iodide E/Z(17:83) 0

product

R H R

= =

=

O

(CH2)3CN (100% E) (CH2)3C02Et (100% E)

(CH2)2P(0)(0Et)2

E/Z( 17:83)

yield (%)

ref(s)

85 76 82 97 97

139 139 139 44 44

90

43

88

43

83

43

84

43

74

43

40

43

88

43

82

43

74

43

86

61

95

61

CHjOPiv

(CH2hC02Et

C02Et

C02Et

Et02C(CH2)3

C02Et

'fc02Et

(CH2)sOAc

C02Et

C02Et

AcO(CH2)3

\—^ C02Et C02Et

(CH2)3CN

C02Et NC(CH2)3

C02Et

\—/

^C02Et

(CH^Cl

C02Et

C02Et C02Et

CI(CH2)4

C02Et

C02Et

(CH2)3SPh

C02Et

PhS(CH2)3

C02Et

SiMe2Ph

C02Et

C02Et

K C02Et

PhMe2Si

C02Et

\ C02Et

C02Et

(CH2)3OAc

C02Et

\

AcO(CH2)6^_^C02Et C02Et

C02Et

(CH2)3C02Et

C02i-Pr

Et02C(CH2)3

C02i-Pr

Et02C(CH2)3

C02c-Hex

C02i-Pr

(CH2)3C02Et

C02c-Hex

C02i*Pr

C02c-Hex

CH2CH2P(0)(0Et)2

C02c-Hex

3-iodo-2-cyclohexenone

P(OEt)2

0

CH(Pr)CH2P(0)(0Me)2


CH(Pr)SPh


CH(SPh)CH2CN


(CH2)3SPh


S02t-Bu

o


(CH2)2^ S02t*Bu

2140

Knochel and Singer


Table

(Continued) FG-RCu(CN)ZnI 10

(CH2)6C02Me

Me

alkenyl iodide 3-iodo-2-cyclohexenone


Me^Me CH(OAc)CH(CH3)2


(CH2)3—C=C—H



3-iodo- 2-cyclohexenone

ch-ch2cn

3-iodo- 2-cyclohexenone

Ph

(CHjfcCl


(CH2)3OAc


(CHjhCN






pioduct 0

yield (%) 86

ref(s) 76



Table

10

2141

(Continued) alkenyl iodide

FG-RCu(CN)ZnI NO,

yield (%)

ref(s)

70

125a

74

45b

x^-no2

80

45b

^°2

74

45b

72

45b

79

146

89

146

83

146

83

146

72

146

74

146

67

146

65

146

57

146

81

146

77

146

64

49b

product


CH(OAc)-CH(CH3)2

CH(OAc)Pent CH(OAc)(CH2)3OPiv

PhS02

EtSO.

PhS02'^^^

AcO

3-iodo-2-cyclohexenone ;n-ch2 O

CO (CH2)eOAc

(CH2)3C02Et

y y y y y y y

CI^CI

cr

(CH2)3CN

ci

Cr

(CH2)3OAc

c-Hex

c/C-Hex (CH2)3CN

°Yf°

0.

y y

CV

(CH2)3CN

Cl/ OS1M83

C-Hex

,0

Cf

Cr

(CH2)3CC02Et

N(CH2)3CN

PhOC(CH2)j

V(CH2)3COPh

Et02C(CH2);f

C-Hex

.0

Cf

C-Hex

NC(CH2)C

y

CI(CH2)4/

C-Hex

Ov

C-Bu

C-Bu


C-Hex

C-Hex

AcO(CH2)5/

0.

c/ (CH2)4C1

y y y y y

Et02C(CH2)/CcH2)3C02Et

NC(CH2)/

CI^CI (CHa^COaEt

CcH2)5OAc

AcO(CH2)5/

Cl'ci (CH2)3COPh

.0

Ov

.0

ct

Et02C(CH2)f

y

NC(CH2)C

C-Bu

C-Bu

2142


Table

11.

Knochel and Singer

Functionalized Alkynes Obtained by the Reaction of Zinc-Copper Organometallics with 1-Haloalkynes alkynyl halide

FG-RCu(CN)ZnX (FG-R) CH2OPiv (CH2)3C02Et (CH2)3C02Et (CH2)3C02Et (CH2)3C02Et

1-bromooctyne

BrC=CCH2OTHP 1-bromooctyne l-bromo-2-phenylacetylene

6 9 6

O III o

CD

(CH2)3CN (CH2)3CN

1-bromooctyne

(CH2)3CH(OPiv)CH3

l-iodooctyne

L

(CH2)4Cl CD

(CH2)3CssCPent CH2CH2P (0) (OEt) CH2SPh

O HI o

7 O III o

BrC^CPh 2

(CH=CH)Hex-(E)

1-bromooctyne 1-bromooctyne 1-iodohexyne

product PivOCH2C^CHex Et02C(CH2)3C^CCH20THP Et02C(CH2)3C=CHex Et02C(CH2)3C=CPh Et02C(CH2)3

-CEC

yield (%)

ref(s)

72 74 78 71

74

44 147e 41 41 41

81 79

41 41

75 81

41 41

73 89 70 77

41 61

86

45

)

HexO=C(CH2)3CN nc(Ch2)3—cec

CH3CH(OPiv)(CH2)3C=CHex ci(ch2)4—cec

yyy

PentC=C(CH2)3C=CPh (Et0)2P(0)CH2CH2C=CHex PhSCH2C=CHex

(E)-BuC=CCH=CHHex

59,60 50

(100% E) CHOAo

1-bromooctyne

AcO

>—CEC-Hex

v (CH2)3C=CH CH2OPiv (H)C=C(H)(CH2)3OPiv-(E)

F± 'o"9

1-iodohexyne 1-iodohexyne 1-iodohexyne 1-iodohexyne

BuC^C(CH2)30=CH BuC=CCH2OPiv (E)-BuC^CCH=CH(CH2)3OPiv PentCOC^CBu

60 74 66 86

56 45 125a 46b

1-iodohexyne

Cl(CH2)4COC=CBu

87

46b

92

53

81

53

61

148

56

148

56

148

Bu(H)C=C-b'

Hr '0“X

CI(CH2)3(H)C=C-B

1-iodohexyne

cX

*C'Bu

(H)C=(H)C02Et

1-iodohexyne

Bu

9

C

C02Et

\=/

CH2C(CH3)2CH2C=CMe

CT V

O-CEC-I

aPh

0-C=C^Me

Me-C=C—'

(CH2)3C02Et

Cf ^

O-CEC-I

Me

or

O-CBC—k Et02C—'

CH2C(CH3)2CH2C=CMe

Hex

V-cec-i ch/

Hex

MeX-CEC-^

Me

Me-C=C—'Me

10). A selective double addition-elimination on 3,4dichlorocyclobutene-l,2-dione (115) provides a range of functionalized 3,4-disubstituted cyclobutene-1,2-

diones 116 (eq 75).146 Lithium- and magnesium-derived organocopper reagents are known to react under mild conditions with 1-halogenoalkynes.147 Similarly, it was found that the functionalized copper-zinc reagents FG-RCu(CN)ZnX (100) undergo a smooth coupling reaction with 1-iodo or 1-bromoalkynes. This provides an excellent synthesis of functionalized alkynes (Table 11) and has been used

to prepare functionalized acetylenic ethers 117 (eq 76).148

Et02Cx''' ^vCu(CN)Znl

-80°C to -55“C, 1h

.Ph

o>— 117

(76)

‘

Chemical Reviews, 1993, Vd. 93, No. 6

Organozlnc Reagents In Organic Synthesis

Table

12.

DMPU14*

2143

Coupling Reaction between Functionalized Alkylzinc Reagents and Polyfunctional Electrophiles in alkyl halide OctI

(FG-R)2Cu(MgX)-Me2Zn (FG-R) AcO(CH2)g AcO(CH2)6 AcO(CH2)6

EtU2C (CH2) 31 NC(CH2)3I

OctI I(CH2)3C=CH

Et02C (CH2) 3 Et02C(CH2)3

yield (%)

product

80 74

AcO(CH2)i2CH3

Ac0(CH2)8C02Et AcO(CH2)8CN Et02C (C H2) ioC H3

k^C02Et

81 72 71

H

83

AcO(CH2)4

PhXâ AcO(CH2)4

so2cf

PhCH2N(S02CF3)(CH2)3 NC(CH2)6

y^n°2 Ph 87

PhCH2N(CH2)3l

PhCH2-N(CH2)7OAc S02CF 3

NC(CH2)3I PhCH2Br

PhCH2N(S02CF3)(CH2)gCN NC(CH2)7Ph

3

The lower reactivity of copper-zinc reagents compared to the corresponding lithium or magnesium copper derivatives becomes especially apparent in alkylation reactions. However, it was found that the treatment of dialkylzincs with 1 equiv of a lithium or magnesium dimethylcuprate provides a reagent which is able to alkylate primary alkyl iodides and benzylic bromides in polar solvents such as DMPU or NMP under relatively mild conditions (0 °C, 2 h).149 Less than 5 % of methyl transfer was observed under these conditions. This reaction shows a remarkable functional group tolerance, and an iodide bearing a primary nitroalkane (118) or a terminal acetylene functionality (119) reacts to provide the expected mixed coupling product (Table 12 and eqs 77-79). This is one of the few methods allowing cross-coupling reactions between functionalized substrates to be performed.

3. Coupling with

77 93

Acid Chlorides

Acid chlorides react only slowly with alkylzinc halides, and the reaction is further complicated by zinc(II)catalyzed THF ring opening. In contrast, the corresponding organocopper reagents 100 react smoothly with acid chlorides at 0 °C (2-12 h) and provide polyfunctional ketones in excellent yields. Alkyl, aryl, or benzylic zinc-copper reagents can be used with equal success (eqs 80-83 and Table 13). In the case of a-oxygenated organometallics, it was shown that the corresponding copper-cadmium organometallics react with acid chlorides in better yields.46

Me2Cu(CN)(MgCI)2 (AoO(CH2)4)2Zn

+

DMPU 0°C, 2 h

118

Ph

83%

90%

(E.O)2(0)P^.Cu(CN)ZnBr

Me2Cu(CN)(MgCI)2

(Et02C(CH2)3)2Zn

+

l(CH2)3-C=C-H-:-1 11 9

PentCOCI

Pent

0°C

DMPU 0°C, 2 h

(82)61

1)

CuCN'2LiBr

2) MeCOCI

Ac

Ac (S3)64

76% 67%

(NC(CH2)6)2Zn

+

PhCH2Br

C. Addition Reactions 1. Additions to Aldehydes and Related Reagents

Me2Cli(CN)(M9cl)2 DMPU 0°C, 2 h Ph(CH2)7CN

93%

(79)149

The direct addition of alkyl, aryl, or alkenyl zinc reagents to aldehydes is usually relatively inefficient.2 However, it has been shown that alkenylzinc chlorides which seem to be more reactive than their alkyl

2144


Table

13.

Knochei and Singer

Preparation of Polyfunctional Ketones by the Addition of Zinc-Copper Reagents to Acid Chlorides


RCOC1 (R)

product 0

Ph

PivOCHa

y

yield (%)

ref(s)

81

44,45

90

44,45

66 42 82

44,45 44,45 45

93

45

76

27a

89

27a

93

59,60

79

59,60

85

60

87

59,60

83

54a

77

54a

79

54a

87

29

93

29

93 74

46a

74

57

68

56

67

56

96 86 84 87

61 61 61 48

PhÔHjOPiv PivOCHa

Qy c-Hex

PivOCH2 PivOCHa

Cl(CHa)3

Ph

|

N(yV'OPiv 0

PivOCHaCOc-Hex CKCHalsCOCHaOPiv OAc

Me^Jv^Ph

Me^CHIOCOChy Me

0

Me

PhsAr°'cH2

0

Ph

0

0

EtOaCCHaCHa

Ph

EtOaCCHaCHa

Ph(CH2)2

PrCH(SPh)

Ph

0

Ph-^-^COjEt 0

Ph^—'^'•^v'C02Et 0

Ph'JVph Pr

NCCHaCH(SPh)

0

Ph

-SPh

Ph

CN

PhCOSCHa

Ph

PhA-yPh 0 PhS(CHa)3

Ph

Ph

"

PhS

O

NC(CH2)a

Ph

NC(CH2)a

C1(CH2)3

NC(CH2)a

c-Hex

0

Ph'^v----'"CN 0

CI(CH2)3'^/V'CN 0 c-Hex"^ EtC>2C(CH2)3 Me

PivO^

I

o 0

Me

PivO^-^^^Ph

""'VCH2

Ph Ph

Me

Me-Ô' Me

Et02C'^x/sY'Ph

Ph

NC(CH2)3

Me-V-0.

Ph

’"''CN

NC(CH2)3COPh

HeptCOPh

29

B-CH h8x

Ph ,N(CH2)3

yN(CH2)3COPh

[|

0

HC=C—(CH2)3

Ph

HC=C—(CHa)s

c-Hex

(EtO)a(0)P(CH3)a (Et0)a(0)P(CH2)a (EtO)a(0)P(CH2)a AcO(CHa)3

Ph c-Hex Pent Ph

O

r.H

pA—-*

PhCO(CHa)aP(0)(OEt)a c-HexCO(CHa)3P(0)(OEt)a PentCO(CHa)aP(0)(OEt)2 OhCO(CH2)6OAc


Organozlnc Reagents In Organic Synthesis

Table

13

(Continued)


RCOC1 (R)

Ph

product

Yy"CN

yield (%)

ref(s)

*39

54b

67

54b

68

54b

81

54b

^—^*COPh ds/trans (1:4)

Ph t-Bu''

cr

''COPh

ds/trans (99)

Ph

CCl

»CN

Xû.

M9'Y'~'CHO Me

Fe(CO)3

OCH2Ph

PhCHO Bn0^

OCH2Ph

yk

,OCH2Ph

PhCOMe

.OCH2Ph

0

,OCH2Ph

6 6

J3CH2Ph

Ph^N'Me

Bn°>

OH

OH

BnO^

0

BnCN

NHMe

^kAph

In

Organozinc Reagents

Table


Organic Synthesis

14

(Continued) FG-RM-

M

=

Cu(CN)ZnI

product

carbonyl compound

.oc .OCH2Ph

Me

Bn0>

NHBu

2149

yield (%)

ref

91

157c

88

105b

33

105b

87

105b

89

105b

76

106

78

106

75

106

76

106

85

106

68

106

82

106

86

106

Me'^Ssj?'N'Bu

M

Me

C02Et

PhCHO

C02Et

PhCHO

Ph-^^*0

PhCHO

c

C02Et

M

Ph.

Mey/ PhA.Q/^0

Me

PhCHO

C02t-Bu

M

"°yj

PhAQ/^0

Me

c-HexCHO

C02Et

Bw

H

c-Hex*’k0'^sO

Bu

cis/trans (80:20)

PhCHO

C02Et

H^^M

PhA/

—1

Ph-^koÔ

CH2Ph

dsArans (92:8)

PhCHO

C02Et

/,

NC(CH2)3

H^sk.M Ph^kQ/k-o

NC(CH2)3

dsArans (90:10) C02Et

PhCHO

H^k^M

Bu„

C—\_J

BuCSC(CH2)2

Ph-^0^=0 Ph

dsArans (95:5)

PhCHO

C02Et

H>^sk^M

EtO,C^-A //

Ph-kô

(CH2)3C02Et

dsArans (95:5) C02Et

Et02C"

(CH2)3C02Et

PhCOMe

C02Et

H^k^M

ci-^-A, // Ph

°

(CH2)4CI

cisArans( 100:0) C02Et

Et02C^

M

(CH2)3C02Et

O

aAh

Ph'

2150


Table

14

Knochel and Singer

(Continued) FG-RM0

M

=

Cu(CN)ZnI

product

carbonyl compound c-HexCHO

yield (%)

ref

93

106

60

106

67

106

78

106

85

106

85

156a

77

156a

78

76

PhCHO

95

76

.Me

PentCOSiMe3

78

155

c

Ph

70

156b

85

156b

78

156b

75

156b

COjEt

EtOzC

t.

Et02C^^\ .M c-Hex"'S,-'*!tO (CH2)3CN

cis/trans (95:5)

PhCHO

C02Et

/

c-Hex

0

PI^CT

c-Hex

cis/trans (75:25)

PhCHO

C02Et

c-Hex

c-Hex

Ph-^-oÔ

Bu

cis/trans (98:2)

PhCHO

C02Et

p

Bu

„a_(

Ph^0^0

Ph

cis/irans (60:40)

PhCHO

C02Et

Ph^SQ/Ô

Bu

cis/trans (98:2)

Ph^N^H

:02t-Bu M

t-Bu02C

Ph

t-Bu02C

Ph

Ph

Ph

H C

C02t-Bu

Ph^N'YÔH Me

Me

Me^

AAnAôh

c-HexCHO c-Hex

.M

\

i

OH Me

Me

(dr .Me

Me^

=

9:1)

S___M

Me

Me

C02Me

s^-C02Me

iS^^ZhBr

C02Et

Ph

c

Ph

^nvco2ei

2C(CH2)2M

PhCHO PhCHO

Et02C(CH2)2M

BuCHO

100

158

Et02C(CH2)3M

PhCHO

78

158

EtOiACH^Jd

PhCHO

80

158

Et02C(CH2)6M

PhCHO

95

158

88

158

95

158

76

158

PhSCHjM

PhSCH2CH(OH)Ph 0

95

Et02C(CH2)2M

t-Bu

Et02C(CH2)2M

I(CH2)4COPh

O' Ph

PhC0(CH2)3M

0

PhCHO

OH

Ph'

Ph

PhCO(CH2)6M

BuCHO

75

158

Me

PhCHO

94

158

95

158

95

160

40

160

97

160

Y^C02Et M

dsArans (>99:1) Me

v|^^C02Et

0

Ph^\, CHO

M

Me

Ph'

ds/trans (83:17)

Et02C(CH2)2M

PhCHO

Et02C(CH2)3M

t-BuCHO

0

1 Et02C—

OH

t-Bu

Et02C(CH2)3M

CHO

OH

2152


Table

15

Knochel and Singer

(Continued) FG-RM0

yield (%)

product

carbonyl compound

ref(s)

ii

160

68

160

22

160

80

160

70

160

32

159

96

61

88

61

PhCHO

81

61

PhCHO

75

56

65

57

80

40

84

40

77

40

77

40

91

40

93

40

79

40

-CX>

CHO

Et02C(CH2)3M

F

Et02C(CH2)sM

Et02C(CH2)4M

Ph^CHO

Ph^

PentCHO EtOj.C"'

Et02C(CH2)4M

OH

PhCHO

Ph

Et02C'

M8Y^C02Et

OH

PhCHO

Me

Ph'^v^vC02Et Et02C(CH2)2M

OH

H

N

h\N Y

BocNH

O

Bu

0

.Ot-Bu

Y^^~C02Et Bu

PhCHO Ph

(EtO)2P.^. M

(E10)2Pv_/nv^ OH

HexCHO

(EtO)2Pv-^^ Hex

rv^yf

(EtO)2P.______

OH

0

Me

(MeO)2P—60

150

CHO

Ph-^Ô'

u

mo

Ph^ô^^Y^Ph

Ph^CHj

OH

(R ,R /R S

NC(CH2)3M

PhCHO

=

85:15)

,Ph

NC

OH

Et02C(CH2)sM

H_*0

Me

Me-Y-0„

MeY-o Me

BCH2M

0

Et02C(CH2)sM

Et02C(CH2)8M

Et02C(CH2)ev^!^Ph

Ph^T^n

OH

0

OH

AcO./^X'*|_| AcO^Pent

AcO^^^k^H^^QjEt AcO^Pent

Me

o-Tol-CH(OH)C2F6

CaF^M

(0-CHO Cr(CO)3 Me

1-CgF 7M

CFa

o-TolCH(OH)CFs

cf3

98% E)

16). However, under these conditions (i-disubstituted

enones or unsaturated esters do not react. The use of a polar solvent such as HMPA circumvents this problem

and allows the addition of organozinc reagents to both /3-mono and 3-disubstituted enones as well as to ethyl acrylate to proceed (eqs 102 and 103).28b Another way o

CuCN (0.35 equiv.) HMPA (1.5 equiv.)

79%

tageously in Michael additions, and their transmetalation with CuCN-2LiCl affords a copper species which reacts readily with enones (eq 107).48 It should be noted

0°C, 15h

(102)285

IZn^~^^CN

54% +

^C02Me

CuCN(a35equiVj HMPA (1.5 equiv.) 0°C, 16 h

o

59%

to extend the scope of the reaction is to use a Lewis acid or MesSiX180 to activate the unsaturated carbonyl moiety. The reaction of fi-disubstituted enones with various functionalized zinc-copper reagents occurs well under these conditions (eqs 104 and 105 and Table 17).38 Interestingly, if a cyano substituent is present or introduced on the side chain at the appropriate position, as in 136, a ring closure occurs affording a stable difluoroboron enolate 137 which can be purified by flash-chromatography and was characterized by its X-ray structure.38 The Michael addition can also be performed with functionalized arylzinc reagents prepared by an electroreduction of the corresponding chloride or bromide using a sacrificial zinc electrode (eq 106).144 Dialkylzincs like 138 can be used advan-

1) Me3SiCI

-78°C to 25°C

C02Me C^Cu(CN)Znl

139

2) 1N HCI, 0°C

OTBS O

'C02Me

(106)185

.^Pent

TBSO'

OTBS

140 66%

that unfunctionalized dialkylzincs (Et^Zn)

can also be added enantioselectively in a 1,4-fashion to chalcone in the presence of Ni(II) salts and chiral ligands181-182 or

Knochel and Singer


2166

Table 17. Michael Additions of Functionalized Zinc-Copper Reagents to 0-Disubstituted Enones in the Presence of BFj*OEt2 FG-RM-

a,/3-unsaturated carbonyl compound O

PivOCH2M

C1(CH2)4M

C1(CH2)4M

c-Hex

O

C1(CH2)4M

Me

O Ph

0(CH2)3M Me

o

AcO(CH2)2M

Me

Et02C(CH2)3M

0

Me Me

Me'

0

Me

r T

Ph^tAo(CH2)3M

Ms

Me

0

Et02C (CH2)3M

>1

Me

Ph

0(CH2)3M

OPiv

>

Me Me

OPiv

Me

0

O

Et02C(CH2)3M

0

Cl(CH2)eM Me'

Me

C02Et

«M

=

Cu(CN)ZnI.

Organozinc Reagents

In

Chemical Reviews, 1993, Vd. 93, No. 6

Organic Synthesis

by using a chiral copper(I) catalyst.183-184 The Michael addition of functionalized zinc-copper organometallics has been extensively applied to the synthesis of prostacyclins, prostaglandins, and related molecules.185-186 Thus, the a-methylenecyclopentanone 139 reacts in excellent yields with various types of polyfunctional reagents (FG-R)Cu(CN)ZnI providing the desired prostaglandin 140 (eq 108). 3. Michael Additions to Nitro Olefins and Related Reagents

may be due to electron-transfer side reactions and to the fact that the magnesium and lithium nitronates obtained after addition can themselves add to nitro olefins and hence lead to polymerization products.188-189 In strong contrast, copper reagents derived from organozinc compounds add cleanly and in high yields to various types of nitro olefins.42-47-52 The reaction proceeds at -20 °C for aliphatic nitro olefins, whereas conjugated aromatic nitro olefins, such as nitrostyrene, react only at 0 °C (eq 109 and Table 18). Unsaturated nitro compounds bearing a leaving group in the ^-position,190 such as 2-nitro-l-acetoxy-2-propene, (141), react under milder conditions (-55 °C, 10 min) and provide new nitro olefins which are susceptible to addition of a second different nucleophile (multicoupling reagent)190 (eq 110). The intermediate nitronates ''Cu(CN)Znl

+

-78°C to -20°C, 2 h

Pf^N02

THF

94% N02

Et02C'

Cu(CN)Znl

olefins bearing a leaving group in the /3-position (SR or SO2R) produces pure (E)-nitro olefins.47-52 The reaction has been applied to the preparation of the nitro triene 142 which undergoes a highly stereoselective DielsAlder reaction on silica gel191 leading to the nitro compound 143 (eq 112)47-52-192 The addition of RCu(CN)Znl to 2,2-bis(methylthio)-l-nitroethylene (144) provides the exo-(nitromethylidene)cyclopentane (145) in 85% yield. No migration of the double bond is observed under the mild reaction conditions used (eq 113).52

Nitro olefins are excellent Michael acceptors and add a wide range of nucleophiles providing functionalized nitroalkanes which are important intermediates in synthesis. They can be readily converted to amines by reduction or carbonyl compounds by a Nef reaction.187 Interestingly, the addition of lithium or magnesium cuprates to nitrostyrene does not occur cleanly. This

NC

2167

-55°C, 10 min

THF

141

?h3

PhS02^N°2 (CH2)3Cu(CN)Znl CH3

Me

N02

Si02, hexane

»N02 (112)52

»H

25°C, 4 h H

85%

142

143

MeS MeS ^55^N02

+

IZn(CN)Cu/Ss^'

1—-Cu(CN)Znl

144 THF

-30°C, 4 h*

/sN^Cu(CN)Znl

1) 0°C, 4h 2) 03, CH2CI2

+

NO, C02Me

25°C, 3.5 *

(114)

195

ch2

-78°C, 3 h 3) Me2S, -78°C to 25°C

148 84%

Me

O

Et02C

h

Pd(PPh3)4 cat.

C02Mg

(111 )52

Me

87%

interesting addition-elimination reaction of 100 to nitro

Table 19).195 Several classes of mixed zinc-copper organometallics are able to add to activated and some nonactivated alkynes. Ethyl propiolate reacts at -60 to -50 °C with FG-RCu(CN)ZnI and provides the syn-addition product 149 with high stereoselectivity. By performing the reaction at higher temperature and

2168


Knochel and Singer

Table 18. Preparation of Polyfunctional Nitroalkanes by the Addition of Polyfunctional Zinc-Copper Reagents to Nitro Olefins FG-RM0 nitro olefin product ref(s) yield (%) OAc

ph'^N°2

Me.

Me

Ph

72

45

68

45b

83

60

81

61

91

61

82

48

90

42,52,56

77

42.52

84

42.52

80

61

94

42.52

76

42.52

94

42.52

Me

OAc

Hex

Ph^N°*

A.

M

ph'^'N02

PhS

56 and propiolamide (152)66 react in satisfactory yield with FG-

esters the addition proceeds only at -30 to -20 °C resulting in a partial isomerization of the intermediate alkenylcopper leading to a mixture of (E)- and (Z)acrylic esters 153 (eq 118).41 If the addition is performed Hex-C=C-C02Me

MeO^—C=C—C02Me

+

NC(CH2)3Cu(CN)Znl

-

Hex

151

W

NC(CH2)/

(0.7 equiv.)

C02Me (118)4’

h

153

-60°C, 2 h

82%

O PhCH2NH

(116)* CO2MO

M8O2C

71% (100% Z)

in HMPA using (2-carbethoxyethyl)zinc chloride (154), cyclization reaction occurs leading to a highly functionalized cyclopentenone 155 (eq 119).196 The zinc-copper reagents FG-RCu(CN)ZnI (100) do not add to unactivated alkynes; however, the treatment a

2170


Table

19.

Additions of Zinc

FG-RM

or

Knochel and Singer

Zinc-Copper Reagents to Alkynes

HC=€C02Et

E/Z ratio

product

alkyne

yield (%)

ref(s)

C02Et

97:3

83

41

SiMeg

>99:1

QO Tl*

41

>99:1

99

41,76

H99:1

91°

41

HC=CC02Et

>99:1

00

96:4

91

45

>97:3

93

45

Me02CC=CC02Me

>98:2

77

45b

HOCC02Et

98:2

69

45b

100:0

87

60

100:0

95

60

100:0

85

61

100:0

91

61

>95.5:0.5

92

56

NC H

HC=CC02Et

NC

C02Et

HC=CC02Et

Et02CN^x\x^55^'C02Et

12:88

AcO(CH2)3M

Me

Me

MeC^CC02Me

XOsMe

AcO(CH2)6

AoO(CH2)e'

SiMe3

C02Me

H

17:83 Me

HC==CC02Et Me

.OAc OAc H Me

Me02CC=CC02Me ,OAc

co2Me

Me^\/^^C02Me

C02Et

NCHoM

PhS(CH2)3M

Et02CC^CC02Et

PhS(CH2)3M

HC==CC02Et

PhS

C02Et

HC=CC02Et (EtO)2P^^

(EtO)2Pv^^c Me02CC=CC02Me

(EtO)2P.------

(EtO)2Pv

HC=CC02Et

(

o C02Me C02Me

==

(130)2

100% Me

alkenyl triflates such as 158 can also be used under the same reaction conditions (eq 128).24 The use of

^Bu OTf 158

4 mol% Pd(PPh3)4

40°C,

1

h

||

Znl

1

Me

mol% Pd(dba)2 4(1mol% PPh3

||

*1Ph^'-^V'-'^Bu

Mev.,A.,.Me N N

N

Cl

45'°C, 24 h

67% (128)24b

functionalized aromatic zinc halides allows easy access to polyfunctional aromatic and heteroaromatic compounds (eqs 129-131).64’203’95 The remarkable aspect of this cross-coupling reaction is its high functional group tolerance.204 Hence, a wide range of amino acids

'0

(131

f

Organozinc Reagents

In


Organic Synthesis

Table 21. Palladium-Catalyzed Cross-Coupling Reaction between Alkenyl and Aryl Halides Functionalized Organozincs FG-RZnX

organic halide

|Zn^NHBoc

Ar

Triflates and yield (%)

ref(s)

Ph 1-naphthyl

55 64

80,81 80,81

product r

COjBn

or

2175

.NHBoc

002Bn

Phi

Ar Ar

i

= =

kAX

cc' ^ÔAc cc'

Ar

=

2-AcOC6H4

13

80,81

At

=

2-MeOC6H4

50

80,81

Ar

=

AcOC3H4

53

80,81

Ar

=

4-BrCeH4

67

80,81

Ar

=

4-FC6H4

36

80,81

Ar

=

4-MeC6H4

50

80,81

Ar

=

4-N02C6H4

61

80,81

99 67

24b 24b

74

24b

Bu/^(CH2)3COPh

77

24b

Me ^

77

46b

86

46a

86

64

93

64

90

64

80

64

jS^vOMe

> o

JO1

jcr1 .-a1 pm

PhCO(CH2)3ZnI PhCO(CH2)sZnI

PhCO(CH2)aPh OTf

x x

Abj

Bu^(CH2)3COPh

OTf

PhCO(CH2)gZnI

Abu

Bo

'^'Bu

PhCO(CH2)3ZnI Znl

BuAB'XMe

'"^"'Hex

Me

(CH2)6COPh

v>

H

Hex Me Me

Me

X.Me

Me-V-O, 1

MevÔ

BCHjZnl

O^^-Me Bu'^y'B_°

Me

Me MeOv 7

Me M

Is™ \

Me Me

°'B'° oA

w,

1

Bu

Et02C(CH2)3ZnBr

.COAB' Et02C(CH2)3ZnBr

jCr*

Et02C(CH2)3ZnBr

$ 0

EtQ2C(CH2)3—COMe

EtO20(CH2)3—-CN

Et02C(CH2)3—^^>-N02

o z Et02C

—^ ^—Zn

1

zo

ffi

^cOOcn

2176

Table

Knochel and Singer


(Continued)

21

FG-RZnX Et02C

organic halide

—^ ^—ZnBr UJ

o o

X

Et02C

o— NC—^ ^—ZnBr

NC—^ ^—ZnBr

nc{K>cn

JCT Br

u

CN

COjEt

95

64

82

64

93

64

95 93 90 90 90

64 64 24a,27a 24a 24a

95

24a

96

24a

75

24a

95

24a

100

24a

67

24a

75

24a

78

24a

80

24a

74

24a

87

24a

C02Et

C02Et

R R Et02C(CH2)2Ph Et02C(CH2)3Ph

Phi Phi

=

H

=

Me

MeO

CC

Et02C(CH2)2ZnI

64

q^B

r^Br

Et02C(CH2)3ZnI

82

R

a—ZnBr

Et02C(CH2)2ZnI Et02C(CH2)3ZnI Et02C (CH2) 2ZnI

64

Nc“O~O~c02Et

Et02C>s^,,^._____NHBoc

O

EtCOCl

Et

C02Bn IZn

NHBoc

C02Bn IZn

s^NHBoc

C02Bn IZn

s^NHBoc

NHBoc

C02Bn

YY 0

NHBoc

C02Bn

Me.

)— CH2COCI

Me

t-BuCHsCOCl

C02Bn

|Zn^NHB0C

y"y

Me

rrr 0 Me

NHBoc

C02Bn

t-Bu'^^^' 0

NHBoc

C02Bn

PhCHjCOCl

Ph/YVNHB0C O

0

COzBn

C02Bn

C02Bn IZn ^v^NHBoc

C02Bn

2181

2182


Table

22

Knochel and Singer

(Continued) FG-RZnI ,

IZn

acid chloride

product AcO.

NHBoc

AcO—k

/>—COCI

yield (%)

ref(s)

63

80,81

39

80,81

64

80,81

53

80,81

61

80e

41

80e

10

80e

10

80e

45

80e

87°

207

85°

207

85°

207

100“

207

100“

207

35“

207

44“

207

28“

207

78“

207

C02Bn

IZn

NHBoc

^

CI^YYC02Bn

C1CH2C0C1

O

C02Bn IZn

NHBoc

^

AcOCH2COC1

C02Bn IZn

o

v

C02Bn

IZn

v^NHBoc

nYYY 0

COCI

o

0

0

0

eoV

C02Bn

NHBoc

EtO' O

C02Bn

CICOOPh

|Zn^^C°2Bn

ClC02Et

|Zn^NHB0C

YY 0

EtO.

G02Bn ,

NHBoc

C02Bn

0

IZn

NHBoc

C02Bn

NHBoc

^

AcO^YV O

NHBoc

C02Bn

NHBoc

0

i-PrCHaOCOCl Me

C02Bn

C02Bn NHBoc

Me IZn

_

NHBoc

PhOCOCl

C02Bn

BocNH

rY^0

Bn02C

NHBoc

C02Bn

Et02C(CH2)3ZnI

Et02C(CH2)3ZnI

^ÔCOPh Me

Me

Et02C(CH2)3ZnI

Me

0

^Y°COPh

Me^^^

Et02C(CH2)3ZnI

ÔCOPh

C02Et

0

Me

OCOPh

Et02C(CH2)3ZnI Me

Me

Me^ÔCOPh

Et02C (CH2)2ZnI

^x Me

Et02C(CH2)2ZnI

OCOPh Me

Et02C(CH2)3ZnI

Ph^ÔCOPh

Et02C(CH2)3ZnI

“

Reaction performed under

a

CO atmosphere.

Organozinc Reagents

In


Organic Synthesis

2183

Table 23. Enantioselective Addition of Functionalized Dialkylzinc Reagents to Aldehydes in the Presence of Catalytic Amounts of l(i2)^(R)-Bis(trifluoromethanesulfonamido)cyclohexane enantiomeric (FG-R)2Zn (FG-R) AcO(CH2)6

aldehyde PhCHO

AcO(CH2)6

PentCHO

AcO(CH2)s

c-HexCHO

ckch2)4

PhCHO

AcO

AcO'

AcO'' Cl

0

C1(CH2)4

product

excess

(% ee)

yield (%)

ref

93

79

48

97

62

48

97

83

48

93

95

48

97

95

48

ch3

AcO(CH2)4

PhCHO

92

72

48

AcO(CH2)3

PhCHO

86

75

48

PivO(CH2)3

PhCHO

92

90

48

Et02C(CH2)3

PhCHO

60

75

48

98

70

48

93

85

211

92

81

211

95

79

211

91

75

211

95

69

211

90

67

211

92

90

210

75

83

210

80

78

210

86

56

210

94

95

210

0

AcO(CH2)6

Me

0

AcO(CH2)4

H^^SnBu3 O

AcO(CH2)j

'^vSnBu3

0

C1(CH2)4

H'^/v'SnBu3 0

AcO(CH2)s

H'^N^s'SnBu3 0

ckch2)4

H'^v^SnBu3 0

PivO(CH2>3

H'^N^SnBu3 PivO(CH2)6

AcO(CH2)6

AcO(CH2)6

0

h-^ôtips 0

H^^Pr 0

^ H

^

C02Et

Me

PhCH2(Tf)N(CH2)8

0

H^y^Pr Br AcO(CH2)fi

0

H^f^Pr Br

2184


Knochel and Singer

Table 23 (Continued) enantiomeric (FG-R)2Zn (FG-R)

product

aldehyde 0

C1(CH2)4

OH

AcO(CH2)6

0

ref

95

68

210

95

68

210

68

68

210

80

77

210

82

62

210

96

70

210

96

70

214

91

71

214

91

72

214

99

62

214

40

55

214

66

59

214

Br

Br

0

yield (%)

(% ee)

pr^>jA/\â

H'^'y^Pr PivO(CH2)3

excess

OH

Br Me

'^y^'Ue Br

H

0

AcO(CH2)3

Br

Br

0

PhCH2(Tf)N(CH2)3

OH

Tf

H''^Y#!S'SnBu3 1

AcO(CH2)6

0

H^^'SiMejPh 0

C1(CH2)4

H^—' AcO(CH2)5

SiMe2Ph

0

H"^^—^

PivO(CH2)6

OSi(iPr)3

0

H^ÔSKiPrJj AcO(CH2)4

0

H^ PivO(CH2)3

ÔSi(iPr)3

0

H'^s

1

"OSi(iPr)3

0

C1(CH2)3

H'^v-—"vOSi(iPr)3

of functionalizied dialkylzincs to /3-(silyloxy)propionaldehyde 165 provides 1,3-diol derivatives which can be converted to aldol products of type 166 (eq 141).214 The

TIPSO^^H

Ti(0-iPr)4

(AcO(CH2)5)2Zn

0

rT

165

TIPSO

—

OH

1) 1-BuPh2SiCI 2) CF3C02H

3) PCC

71%, 91%ee

(1

---

equiv.)

Vi(Oi-Pr)2 '"N Tf

(8 mol%) O

OSiPh2(t-Bu)

(142)214

*

H'J^Jv'(CH2)5OAc 166 70% (141)214

enantioselective addition of a diorganozinc to these carbonyl compounds selectively provides syn- or anti1,3-diols 167, depending on the configuration of the catalyst used (eq 142).214>215 Functionalized mixed alkenyl(alkyl)zincs can be readily prepared from the corresponding boranes.131 Their addition to aldehydes

in the presence of a chiral catalyst proceeds with high enantioselectivity.131b It should be noted that the alkenyl group is transferred preferentially to the alkyl group. This method has been elegantly applied to a synthesis of CR)-(-)-muscone (eq 143).217 Clearly, this approach will allow the preparation of a wide range of chiral polyfunctionalized building blocks with a high enantioselectivity.


Organozinc Reagents In Organic Synthesis O H

C

H

1) HB(c-Hex)2, hexane, 0°C

2) add 1% (+)-DAIB in

Et^n '

3) aq. NH4CI 75%

(CH2)r

92% ee (R)-(-)-Muscone

(143)217

218S

(9) (a) Reformatsky Chem. Ber. 1887, 20, 1210; 1895, 28, 2842. (b) Furstner, A. Synthesis 1989, 571. (10) Hunsdiecker, H.; Erlbach, H.; Vogt, E. German Patent 722467, 1942; Chem. Abstr. 1943, 37, P 5080. (11) Wittig, G.; Jautelat, M. Liebigs Ann. Chem. 1967, 702, 24. (12) (a) Wittig, G.; Schwarzenbach, K. Angew. Chem. 1959,71,652. (b) Wittig, G.; Schwarzenbach, K. Liebigs Ann. Chem. 1961, 650, 1. (c) Wittig, G.; Wingler, F. Liebigs Ann. Chem. 1962,656,18. (d) Wittig, G.; Wingler, F. Chem. Ber. 1964, 97, 2139, 2146. (13) (a) Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958,80,5323. (b) Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1959,81,4256. (c) Blanchard, E. P.; Simmons, H. E. J. Am. Chem. Soc. 1964,86,

1337,1347. Me2N HO,

Me

(+)-DAIB

VI. Conclusions and Perspectives Organozinc compounds have been considered for a long time as unreactive organometallics with limited applications in organic synthesis. It has become clear within recent years that this opinion has to be revised. In fact, the low reactivity of the carbon-zinc bond can be exploited for the preparation of a wide range of polyfunctionalized zinc reagents. The good transmetalation ability of organozinc derivatives with soluble copper salts such as CuCN*2LiX29 or palladium(II) complexes20 allows the in situ preparation of highly reactive organometallic species. The reaction pathways which are now available for these transition-metal intermediates allow reactions with numerous carbon electrophiles in excellent yields. The addition of functionalized dialkylzincs to aldehydes in the presence of chiral titanium catalysts provides a general enantioselective preparation to polyfunctional secondary alcohols and considerably extends the synthetic utility of diorganozincs. Their excellent functional group tolerance, their high chemoselectivity and excellent stereoselectivity in many reactions makes organozincs ideal organometallic intermediates for the construction of complex polyfunctional molecules.

VII. Acknowledgments I would like to thank all my co-workers for their dedication, intellectual contribution, and hard work. I would also like to thank Mrs. Alice Fortney from the University of Michigan for typing part of this manuscript. Finally, I thank the Alfred P. Sloan Foundation for a Fellowship (1992-1993), the Alexander von Humboldt Foundation for a fellowship to R.D.S., the donors of the Petroleum Research Found, administered by the American Chemical Society, the Fonds der Chemischen Industrie, and the Deutsche Forschungsgemeinschaft (SFB 260) for generous support of this research.

VIII. References (1) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis;

Wiley: New York, 1989.

(2) NQtzel, K. Methoden der Organischen Chemie; Metallorganische Verbindungen Be, Mg, Ca, Sr, Ba, Zn, Cd; Thieme: Stuttgart, 1973; Vol. 13/2a, p 552. (3) Frankland, E. Liebigs Ann. Chem. 1849, 71, 171; 213. (4) Elschenbroich, C.; Salzer, A. Organometallics: a concise introduction; VCH: Weinheim, 1989. (5) Freund, A. Liebigs Ann. Chem. 1861,118, 1. (6) Rieth, R.; Beilstein, F. Liebigs Ann. Chem. 1863,126, 248. (7) Pawlow, D. Liebigs Ann. Chem. 1877,188, 130. (8) Wagner, G.; Saytzeff, A. Liebigs Ann. Chem. 1875,175, 361.

(14) Reviews on (iodomethyl)zinc iodide and related reagents as organic reagents have been published: (a) Simmons, H. E., Cairns, T. L.; Vladuchick, A.; Hoiness, C. M. Org. React. 1972, 20, 1. (b) Furukawa, J.; Kawabata, N. Adv. Organomet. Chem. 1974,12,83. (c) Zeller, K.-P.; Gugel, H.; Houben-Weyl Methoden der Organischen Chemie; Regitz, M., Ed.; Band EXIXb; Thieme: Stuttgart, 1989; p 195. (15) For recent applications of ICH2ZnI in cyclopropanation reactions, see: (a) Staroscik, J. A.; Rickbom, B. J. Org. Chem. 1972,37,738. (b) Kawabata, N.; Nakagawa, T.; Nakao, T.; Yamashita, S. J. Org. Chem. 1977,42,3031. (c) Johnson, C. R.; Barbachyn, M. R.

Preparation and reactions of polyfunctional organozinc reagents in

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