CHAPTER-1

Preparation and applications of organozinc compounds: A

literature survey

1

Introduction

Enantioselective addition of organometallic reagents to aldehydes is one of

the fundamental asymmetric reactions and it is a powerful tool for the construction of

chiral carbon-carbon bond. This method provides enantiorich secondary alcohols,

which are building blocks for the synthesis of natural products and pharmaceuticals.1

Asymmetric addition of alkyllithium and Grignard reagents is a straightforward

approach for the synthesis of optically active alcohols. Although several examples

involving organolithium and Grignard reagents have been reported, these usually

require stoichiometric amounts of valuable chiral ligands.2 Due to the high

background reactivity of these reagents, catalytic version remained unexplored until

the recent report of Harada and co-workers.3 Furthermore, these reagents preclude

the presence of many functional groups due to their high reactivity which reduces

their attractiveness in organic synthesis. In contrast, organozinc reagents show very

mild reactivity and excellent chemoselectivity.4 In addition to the Reformatsky

reaction5 and the Simmons−Smith6 reaction, a number of carbon-carbon bond

forming reactions using organozinc reagents have been reported.4 Organozinc

reagents can be classified as four types,

(I) Organozinc halides (R-Zn-X, X = Cl, Br, I)

(II) Diorganozincs (R-Zn-R)

(III) Organozincates R3ZnM (M= MgX, Li) or R4ZnLi2

(IV) Reformatsky reagentOR

OZnX

Despite their discovery in 1849 by Frankland,7 organozinc reagents were

unexplored in asymmetric synthesis for a long period of time due to their poor

reactivity. After the report of Oguni and Omi in 1984,8a the enantioselective addition

of diorganozinc reagents to carbonyl compounds emerged as one of the attractive

tools for the preparation of optically active alcohols.1c,8 However lack of wide

commercial availability, high cost and pyrophoric nature limits their use to only

lower homologues.9 Therefore a search for the other alternatives is desirable. The

reagents of type RZnX (X = Cl, Br, I) which are easily accessible, are good

2

alternatives to diorganozincs. Organozinc halides have very less reactivity towards

most class of organic electrophiles due to high covalent character of carbon-zinc

bond and less Lewis acidity of Zn(II) metal centre. However, transmetallation with

transition metals such as Pd, Ni, Cu etc. generates reactive complex which shows

excellent reactivity.4b Their use has been mainly in Ni and Pd-catalyzed cross-

coupling reactions.10

Organozincates11 is another class of organozinc compounds which are more

reactive as compared to organozinc halides and diorganozincs. These reagents were

found to be attractive by synthetic organic chemists due to their unique reactivity and

excellent chemoselectivity.4a Organozincates have shown their usefulness in many

chemoselective organic transformations.4a,11c,d,g As compared to diorganozinc

reagents, reagent of type I and III are not much explored in asymmetric synthesis.

The present chapter will focus on reviewing the literature on preparation and

applications of organozinc halides and triorganozincates in asymmetric synthesis.

1. Preparation of organozinc halides

There are three general methods for the preparation of organozinc halides;

(i) Oxidative insertion (direct insertion of metallic zinc into carbon-halogen bond)

(ii) Transmetallation (the reaction of RM (M = Li or MgX) with zinc salt) and

(iii) Ligand exchange (the exchange of ligands between R2Zn and zinc salt)

1.1. Preparation of organozinc halides by oxidative insertion

The oxidative insertion is the most general and attractive protocol for the

preparation of organozinc halides. This method shows very broad scope and it is

applicable to the preparation of a number of simple as well as functionalized

organozinc reagents. In 1942 Hunsdiecker12a reported the preparation of number of

functionalized alkylzinc iodides 1 by the reaction of zinc with corresponding alkyl

iodide in ethyl acetate (Scheme 1).

RO2C(CH2)nI + ZnEtOAc

refluxn > 5

RO2C(CH2)nZnI

1

Scheme 1. Oxidative insertion of zinc into alkyl iodide in EtOAc

3

After this report, various other procedures have been reported. Some of the

important ones are described below.

In 1962, Gaudemar et al.12b reported that the primary alkyl iodide reacts with

zinc foil in THF at 50 oC in few hours to give corresponding alkylzinc iodide

whereas secondary iodide reacts at ambient temperature (Scheme 2).

RI + Zn RZnITHF, 25−50 oC

RI = primary or secondary alkyl iodide

Scheme 2. Preparation of alkylzinc iodides in THF

In 1964 Paleeva et al.12c reported the preparation of ethylzinc iodide by the

reaction of zinc-copper couple13 (8% copper) with ethyl iodide under reflux

condition (Scheme 3).

EtI + Zn-Cureflux

EtZnI

68%

Scheme 3. Preparation of ethylzinc iodide using Zn-Cu couple

In 1988 Knochel et al.14a observed fast reaction rates when zinc was

activated successively with a catalytic amount of 1,2-dibromoethane and TMSCl.

Thus, in the case of primary alkyl iodides insertion is complete in 2−3 h in THF at 40 oC, whereas secondary iodides react at room temperature. Under the optimized

conditions, various simple as well as functionalized alkylzinc iodides (RZnI) were

prepared in good yield (Scheme 4).

RI + Zn RZnITHF, 25−40 oC

Up to 90% yield

(CH2Br)2 (4 mol%)TMSCl (3 mol%)

R = alkyl, FG-alkyl; FG = CN, CO2R'

Scheme 4. Preparation of alkylzinc iodides using in situ activated zinc

4

In the same year Knochel′s group observed that the presence of cyano group

at β-carbon greatly accelerates the rate of the insertion reaction.14b The reaction of 2-

cyano iodides 2 with in situ activated zinc14c (cut foil or dust) in THF provided

corresponding zinc reagents 3 in good yield14d (Scheme 5).

R

CNI

R

CNIZn

80-90% yieldR = H, Pr

+ Zn

2 3

THF

5−30 oC, 3−5 h

Scheme 5. Preparation of 2-cyanozinc iodides

Knochel et al. also observed the presence of oxygen at α-carbon accelerates

the rate of the insertion reaction.15a,b For example, treatment of iodomethyl pivalate 4

with activated zinc foil14c in THF at 12 oC furnished PivOCH2ZnI 5 in excellent

yield15a (Scheme 6).

O

O

I

4

THF, 12 oC, 1 h+ Zn PivOCH2ZnI

5>85% yield

Scheme 6. Preparation of iodomethylzinc pivalate 5

Later in 2004 Kimura and Seki15c reported the preparation of alkylzinc iodide

7 by the treatment of zinc dust (activated with bromine) with corresponding alkyl

iodide 6 in excellent yield (Scheme 7). In comparison with other activators such as

TMSCl or 1,2-dibromoethane, use of bromine proved better for the large scale

preparation.

EtO2CI + Zn

Br2 (0.5 equiv)

THF:toluene50-60 oC, 1 h

EtO2CZnI

6 794% yield

Scheme 7. Preparation of ethyl iodovalerate

5

Simple alkyl bromides and chlorides usually cannot be converted to the

corresponding organozinc compounds in THF under the normal reaction conditions.

In 1990 Knochel et al.15d reported that the presence of phosphate group

considerably accelerates the rate of formation of organozinc bromides. Thus, the

treatment of primary bromophosphonates 8a with activated zinc dust14c in THF at 30 oC for 12 h gave the corresponding alkylzinc bromide 9a in excellent yield.

Secondary bromophosphonates 8b-d requires only 0.5 h for completion of the

reaction (Scheme 8).

PO Br

R1R2OR2O

THF, 25−30 oCPO ZnBr

R1R2OR2O

8a = R1 = H, R2 = Et8b = R1 = Me, R2 = Me8c = R1 = Pr, R2 = Me8d = R1 = Pr, R2 = Et

+ Zn

9a-d

0.5−12 h

upto 90% yield

Scheme 8. Oxidative insertion of zinc into bromophosphonates 8a-d

In the same year, Knochel et al. reported that the presence of sulfur allows

smooth insertion of zinc into carbon-chlorine bond.15e,f Thus, the reaction of α-

chloroalkyl phenyl sulfides 10a-e with activated zinc dust14c in THF at room

temperature for 2 h provided corresponding organozinc chlorides 11a-e in good

yield15e (Scheme 9).

PhS Cl

R+ Zn

THF, 25 oC, 2 h

PhS ZnCl

R

10a R = H10b R = CH310c R = Pr10d R = CH2CN10e R = (CH2)2CO2Et

11a-e

>85% yield

Scheme 9. Oxidative insertion of zinc into α-chloroalkyl phenyl sulfide 10a-e

6

In 1992 Knochel et al.16a reported that the use of polar solvents such as N,N-

dimethylacetamide (DMA) or N,N-dimethylpropyleneurea (DMPU) allows the

preparation of functionalized alkylzinc bromides 13 by the reaction of activated zinc

dust14c with corresponding primary alkyl bromides 12 using catalytic amount of

alkali iodide (Scheme 10). The insertion is reported to be complete in few hours at

70−80 oC.

FG Brn

FG ZnBr+ ZnMI (0.2 equiv)

DMA or DMPU70−80 oC, 2.5 h

n = 3, 4M = Li or CsFG = Cl, CO2Et

12 13

n

Scheme 10. Preparation of alkylzinc bromides in polar solvent

This reaction was extended for the preparation of functionalized alkylzinc

chlorides, tosylates, mesylates and diphenylphosphates using additional equivalent of

LiBr (or NaBr) (Scheme 11).

+ Zn

MI (0.2 equiv)MBr (1.0 equiv)

DMA or DMPU40−80 oC, 6−12 h

n = 3 to 8FG = Cl, CO2RX = Cl, OMs, OTs, OP(O)(OPh)2M = Li, Na, Cs

FG Xn

FG ZnXn

Scheme 11. Preparation of RZnX (X = Cl, OMs, OTs, OP(O)(OPh)2)

Later in 2003 Huo et al.16b reported a very efficient method for the

preparation of alkylzinc bromides in DMA. The treatment of zinc metal (activated by

5 mol % iodine) with primary alkyl bromide 14a in polar solvent such as DMA at 80 oC afforded the corresponding alkylzinc bromide 15a in excellent yield (Scheme 12).

Number of simple as well as functionalized alkyl bromides 14b-i (Figure 1) were

reacted with zinc under the optimized conditions to obtain corresponding zinc

reagent in >90% yield. However, the reaction of secondary alkyl bromides was

sluggish whereas, tertiary alkyl bromide did not even require iodine for activation.

7

On the other hand, no zinc reagent was formed when less polar solvents such as

diethyl ether, THF, dioxane, DME and acetonitrile were used.

n-OctBr + ZnDMA, 80 oC, 3 h

n-OctZnBrI2 (5 mol%)

14a 15a

Scheme 12. Preparation of n-Octylzinc bromide in DMA

Cl Br6

O Br5

O

NC Br4

Br3

EtO

O

Br Br Br Br

14b 14c 14d 14e

14f 14g 14h 14i

Figure 1

Use of other polar solvents such as DMF, DMSO, DMPU or NMP, and also

the various forms of zinc metal provided comparable results (Table 1).

8

Table 1. Direct insertion of zinc into n-Octyl bromide under various conditions

n-Oct-Br + Zncat. I2

80 oCn-OctZnBr

14a 15a

Entry Zn I2 (mol %) Solvent Time (h) Conversion (%)

1 dust 5 DMA 3 >99

2 dust 1 DMA 9 >98

3 dust 5 DMF 4.5 >99

4 dust 5 DMSO 3 >99

5 dust 5 DMPU 3 >99

6 dust 5 NMP 6 >98

7 powder 5 DMA 3 >99

8 granule 5 DMA 3 >98

9 shot 5 DMA 12 >98

Using this methodology alkylzinc chlorides 17a,b were also prepared from

the corresponding alkyl chlorides 16a,b in very good yield. The presence of

stoichiometric amount of salts like LiBr or R4NBr is required to achieve efficient

conversion (Scheme 13).

RCl + Zn

I2 (5 mol%) LiBr or Bu4NBr (1 equiv)

DMA, 80 oC, 12 hRZnCl

RCl = Cl7

Cl3EtO

O

16a,b 17a,b

16a 16b

Scheme 13. Preparation of alkylzinc chlorides in DMA

Later in 2006 Knochel et al.16c described LiCl-accelerated preparation of

alkylzinc bromides in THF. This method allows the preparation of alkylzinc

bromides from simple as well as functionalized alkyl bromides. Thus, the treatment

of zinc powder in situ activated by catalytic 1,2-dibromoethane and TMSCl, with

9

primary or secondary alkyl bromides (14a-c and 14j-o) in the presence of

stoichiometric amount of LiCl furnished the corresponding alkylzinc bromides in

excellent yield (Scheme 14). Author proposed that LiCl rapidly removes the formed

organozinc reagent from the metal surface by generating highly soluble RZnX⋅LiCl

complex, and freshly activated metal surface gets exposed to further insertion

process.

RBr + Zn 50 oC, 1−50 h

LiCl, THFRZnBr LiCl

Cl Br5

O Br4

O

Br

5

Br Br

Br

14k

14m 14n 14o

14j 14l

14a-c, 14j-o >92% yield

Scheme 14. LiCl-accelerated preparation of alkylzinc bromides

Unlike alkyl iodides, vinyl or aryl iodides do not undergo insertion in THF

under normal conditions and requires higher temperature or polar solvents such as

DMF, DMA.

In 1990 Knochel et al.17a reported the preparation of arylzinc iodides by the

reaction of commercial zinc with aryl iodides. The treatment of aryl iodides 18 with

zinc dust (in situ activated using 1,2-dibrmoethane) in DMF or DMA at 25 to 55 oC

afforded the corresponding arylzinc iodides 19 in good yield (Scheme 15). It was

observed that the substituent on the aromatic ring strongly influence the rate of the

zinc insertion. For example, iodobenzene requires 22 h at 55 oC for 80% conversion

whereas 2-iodobenzonitrile undergoes complete insertion within 2 h at 35 oC. A

comparison between the zinc insertion rates of o-, m- and p-iodobenzonitrile

indicated that o-iodobenzonitrile reacts significantly faster.

10

I

FG

+ Zn25−55 oC, 2−22 h

DMF or DMA ZnI

FG

FG = CN, Cl, COR, CO2Et

18 19

65-85% yield

Scheme 15. Preparation of arylzinc iodides in polar solvent

Author has also reported the preparation of alkenylzinc iodide 20 under these

conditions. The (E)-1-iodo-1-octene reacts with zinc in 14 h at 70 oC (Scheme 16).

H

Hex

I + Zn70 oC, 14 h H

Hex

E :Z(1:1 to 1 :1.5)

DMF

ZnI20

Scheme 16. Preparation of alkenylzinc iodide

In 1993 Takagi et al.17b reported the ultrasound-promoted insertion of zinc

into functionalized aryl iodides. Various functionalized aryl iodides were reacted

under different reaction conditions to obtain the corresponding arylzinc iodides in

good yield. One representative example is described below. Under ultrasound-

irradiation, the reaction of methyl 2-iodobenzoate with zinc powder in TMU (1,1,3,3-

tetramethyl urea) at 30 oC for 5 h gave arylzinc iodide 21 in good yield (Scheme 17).

Same reaction without irradiation of ultrasound requires 15 h for the completion.

CO2Me

I+ Zn

TMU, 30 oC

CO2Me

ZnI

ultrasound-irradiation 5 hwithout ultrasound-irradiation 15 h 87% yield

21

Scheme 17. Ultrasound-promoted preparation of arylzinc iodide

11

Later in 2003 the same author17c reported the preparation of functionalized

arylzinc iodides in ethereal solvents such as THF, diglyme or triglyme. The reaction

of zinc powder with functionalized aryl iodides 18 provided corresponding arylzinc

iodides 19 in good yield (Scheme 18).

I

FG

+ ZnZnI

FG

FG = H, CN, Cl, Br, CO2R', CH3, OCH3

18 19

TMSCl (3 mol%)

THF or diglymeor triglyme70−180 oC

Up to 95% yield

Scheme 18. Preparation of arylzinc iodides in ethereal solvents

It was observed that the aryl iodides containing EWG at the ortho-position

smoothly reacts in THF at 70 oC (Table 2), whereas those containing EWG at the

meta- and para-position or electron-rich aryl iodides were less reactive and requires

elevated temperature as well as solvents such as diglyme or triglyme.

Table 2. Preparation of various arylzinc iodides in etheral solvents

I

FG

+ ZnZnI

FG18 19

TMSCl (3 mol%)

24 h

Entry R Solvent Temp (oC) Yield (%)

1 o-CO2Me THF 70 87

2 m-CO2Me THF 70 20

3 m-CO2Me diglyme 100 84

4 p-CO2Me diglyme 100 89

5 p-CH3 diglyme 130 87

6a p-CH3 triglyme 180 83 a The reaction time was 1.5 h.

12

In the same year Gosmini et al.18a reported a new method for the preparation

of arylzinc bromides and iodides. In this method the treatment of aryl halide 22a-c

with zinc dust in the presence of catalytic amounts of PhBr, CoBr2, ZnBr2 and TFA

in acetonitrile furnished corresponding arylzinc halide 23 in moderate to excellent

yield (Scheme 19). In their initial study, they observed the formation of byproducts

such as reduction product (ArH) and the homocoupling product Ar-Ar. The addition

of catalytic amount of phenyl bromide prior to the addition of aryl halide (the

substrate) allows this side reaction to proceed on PhBr rather than on aryl halide

which results in increased yield of the desired product. Number of simple as well as

functionalized aryl and hetero arylzinc halides were prepared under mild reaction

conditions in good yield. The role of TFA was to activate the zinc metal. Author

proposed that the activated zinc reduces the Co(II) to Co(I) species which initiates

the insertion process.

ArX + Zn

TFA (cat.)PhBr (0.1 equiv.)CoBr2 (0.1 equiv.)

ZnBr2 (0.1 equiv.)Acetonitrile, RT, 30 min.

ArZnX

ArX =X

FG

X = Br, IFG = H, Cl, CN, OCH3, NR2, OCOR, COR, SO2Me

SBr

Up to 100% yield

S

Br

22a-c 23

22a 22b 22c

Scheme 19. CoBr2 catalyzed preparation of arylzinc halides

Aromatic chlorides are generally inexpensive and readily available substrates

as compared to the corresponding bromides and iodides. Later in 2005 the same

group18b extended the above reaction for the preparation of functionalized aryl and

hetero arylzinc chlorides using optimized reaction conditions.18c In this protocol the

reaction of aryl chlorides 24a-c with zinc dust in the presence of catalytic amount of

TFA, CoBr2, allyl chloride and use of pyridine as co-solvent furnished the

corresponding arylzinc chlorides 25 in moderate to excellent yield (Scheme 20).

13

ArCl + Zn

24a-c

TFA (cat.)allyl chloride (0.33 equiv.)CoBr2 (0.33 equiv.)

25Acetonitrile:PyridineRT, 2−31 h

ArZnCl

ArCl =Cl

FG

FG = H, CN, CF3, COMe, SO2Me

SCl

S

Cl

24a 24b 24c

45-95% yield

Scheme 20. CoBr2 catalyzed insertion of zinc into aryl chlorides

In 2006 Knochel et al.16c reported LiCl-accelerated preparation of arylzinc

iodides from activated zinc powder and corresponding aryl iodides in THF. Various

simple as well as functionalized aryl iodides 18 were converted to the corresponding

zinc reagent in excellent yield (Scheme 21).

I

FG

+ Zn50 oC, 1−90 h

LiCl, THF ZnI LiCl

FG

FG = H, CF3, CN, OMe, CHO, COR, CO2Et, CONR2

Up to 98% yield18

Scheme 21. LiCl-accelerated insertion of zinc into aryl iodides

This method was successfully extended for the preparation of vinyl and

arylzinc bromides. The treatment of aryl bromide 26a,c or vinyl bromide 26b

(containing electron withdrawing substituent) with activated zinc powder furnished

corresponding organozinc bromides 27 in very good yield (Scheme 22).

14

ArBr + Zn

26a-c

LiCl, THF

2725 oC, 24 h

ArZnBr LiCl

ArBr = BrCO2Et

EtO2C

Br

O BrEtO2C

26a 26b 26c

>90% yield

Scheme 22. LiCl-accelerated insertion of zinc into activated aryl bromides

In contrast to alkyl and aryl halides, allyl and benzyl halides are highly

reactive towards oxidative insertion of zinc. In 1962 Gaudemar et al.12b reported the

preparation of allylic and benzyliczinc bromides. The reaction of cinnamyl bromide

with zinc in THF at −15 to −5 oC gave corresponding zinc reagent in good yield

(Scheme 23). Benzyl bromide was also reacted under the similar reaction conditions

to obtain benzylzinc bromide.

Ph + ZnTHF, −15 to −5 oC

Br Ph ZnBr

Scheme 23. Preparation of cinnamylzinc bromide

Later in 1978 Bellassoued and Frangin19a reported the preparation of allylzinc

bromide by the reaction of allyl bromide and zinc in THF at ambient temperature

(Scheme 24).

Br + ZnTHF, 20 oC, 1 h

ZnBr

Scheme 24. Preparation of allylzinc bromide

15

The zinc insertion to substituted allylic halides is less satisfactory due to the

formation of substantial amount of homocoupling product. Knochel et al.19b in 2007

described the preparation of substituted allyliczinc chlorides 29 by the reaction of

allylic chloride 28a-d with zinc dust in the presence of LiCl in THF with moderate to

good yield (Scheme 25).

+ ZnLiCl, THF

0 oC to RTClR ZnClR

28a-d 29

ClR =

Cl

Me

Cl Cl

Ph Cl

55-84% yield

28a 28b 28c 28d

Scheme 25. Preparation of substituted allyliczinc chlorides

In 1988 Knochel et al.20a reported the preparation of various benzyliczinc

bromides. The reaction of benzylic halides 30 with zinc foil activated with 1,2-

dibromoethane in THF at 5 oC for 2−3 h gave corresponding benzylzinc bromides 31

in >90% yield along with the formation of homocoupling product in <5% yield

(Scheme 26). In the case of secondary benzyl bromides addition was done at −15 oC

to obtain good yield while corresponding chloride requires higher temperature (30 oC) for smooth conversion.

R

Br

+ Zn(CH2Br)2 (cat.)

THF, 5 oC, 2−3 hFG

R = H, CH3 FG = Cl, I, CN, OMe, COR', OAc

R

ZnBr

FG3031

> 90% yield

Scheme 26. Preparation of benzyliczinc bromides

16

Recently, Knochel et al.20b reported excellent method for the preparation of

benzyliczinc chlorides. Various functionalized benzylic chlorides 32 were converted

to the corresponding zinc organometallics 33 at room temperature in excellent yields

using activated zinc dust14c and stoichiometric amount of LiCl (Scheme 27). In the

absence of LiCl the reaction was incomplete and proceeds at slow rate.

R

Cl

+ ZnTHF, 25 oC, 3 h

FG

32a R = H32b R = Me

FG = Cl, Br, I, F, CN, COR', CO2R'.

R

ZnCl LiCl

FG

LiCl

32 33

Up to 99% yield

Scheme 27. Preparation of various benzyliczinc chlorides

1.1.1. Preparation of organozinc halide using highly reactive zinc (Zn*)

In 1973 Rieke et al.21a reported that the metallic zinc can be generated in situ

by the reduction of zinc halide with alkali metals. The zinc prepared by the reduction

of ZnCl2 with alkali metals such as Li, Na or K using electron carriers like

naphthalene shows higher reactivity than the commercial zinc powder and reacts

with unreactive alkyl as well as aryl bromides in less polar solvents like THF to give

corresponding organozinc bromides in excellent yield21b-f (Scheme 28).

ZnCl2 + 2 Li +THF or DME

(cat.)

Zn* + 2 LiClRT

RX + Zn*THF or DME

RZnXRT to reflux

Zn* = Highly reactive zincRX = 1o, 2o or 3o alkyl bromides, simple or functionalized aryl bromides and iodides

Scheme 28. Preparation of RZnX (R = alkyl, aryl, X= Br, I) using Rieke zinc (Zn*)

17

However alkyl chlorides are unreactive under these conditions and requires

Zn* prepared by the reduction of Zn(CN)2 with lithium using catalytic amount of

naphthalene.21g The zinc obtained by this method smoothly reacts with alkyl

chlorides 16a,c-f in THF at room temperature to provide corresponding alkylzinc

chlorides in good yield (Scheme 29).

Zn(CN)2 + 2 Li +

(cat.)

Zn* + 2 Li(CN)2RT, 5 h

RCl + Zn* RZnClRT, 12 h

RCl = Cl5

NC Cl4

Cl7

NC Cl6

OClN

N

THF

THF

16a 16c 16d 16e 16f

16a, c-f

Scheme 29. Preparation of alkylzinc chlorides using Rieke zinc

Later in 1999 Rieke's group21h has done a detailed study on oxidative addition

of highly reactive zinc to organic bromides. On the basis of kinetic and linear free

energy relationship studies (LFERs) they have suggested a mechanism in which the

insertion reaction proceeds through electron transfer (ET) and it is the rate

determining step. It was observed that the rate of insertion of zinc into organic

bromides follows the order allyl > benzyl > 3o alkyl > 2o alkyl > 1o alkyl > aryl >

vinyl. Authors proposed that zinc transfers the electron to alkyl halide and reaction

proceeds through intermediate I which upon transfer of second electron gives

alkylzinc halide (Scheme 30).

Zn + Br-R Zn Br R Zn-Br R RZnBrET ETδ

I

Scheme 30. Proposed mechanism for the oxidative insertion of zinc into R-Br

18

1.2. Preparation of organozinc halides by transmetallation

The second method for the preparation of organozinc halides is

transmetallation that is the reaction of highly reactive organometallics like RLi or

RMgX with zinc halide (Scheme 31). In this method, there is always formation of

lithium / magnesium salts in stoichiometric amount along with the zinc reagent. Due

to the high reactivity of alkyl lithium and Grignard reagent, this method cannot be

applied for the preparation of functionalized organozinc halides. There are several

reports on preparation of organozinc halides by transmetallation method.22,23 Few

important reports where the preparation and characterization of organozinc halides

have been done are described below.

RMX + ZnX2Transmetallation

R = Alkyl, Aryl, benzyl etcM = Li, MgX X = Cl, Br, I

RZnX MX2

Scheme 31. Preparation of organozinc halides by transmetallation

In 2009, Marder and Aiwen23e reported the preparation of PhZnCl⋅MgCl2 34

by the stoichiometric reaction of PhMgCl with ZnCl2 in THF (Scheme 32). The

complex was shown by single crystal X-ray analysis to be the novel dichloro-bridged

Zn/Mg complex (Figure 2).

PhMgCl + ZnCl2THF

0 oC to RT, 2 hPhZnCl MgCl2

34 Scheme 32. Preparation of phenylzinc chloride

Cl

Zn

Cl

Mg

Ph

Cl

THF

THF

THF

THF

Figure 2

19

Recently, Hevia et al.23f reported the preparation of complex t-BuZnCl⋅MgCl2

35 by the stoichiometric reaction of t-BuMgCl with ZnCl2 in THF (Scheme 33).

tBuMgCl + ZnCl2THF

tBuZnCl MgCl2 4THF35

Scheme 33. Preparation of tbutylzinc chloride complex

The complex 35 was characterized by X-ray crystallography. The structure of

the complex is depicted in figure 3, where zinc and magnesium are connected

through two chlorine bridges. Zinc forms distorted tetrahedral geometry whereas

magnesium achieves distorted octahedral geometry through bonding with four THF

molecules.

Cl

Zn

Cl

Mg

But

Cl

THF

THF

THF

THF

Figure 3

1.3. Preparation of organozinc halides by ligand exchange

The third method is ligand exchange,24 that is the exchange of ligands

between diorganozinc reagent and zinc halide. The reaction of R2Zn with ZnX2 gives

corresponding RZnX (Scheme 34). This method provides organozinc halides which

are free of magnesium or lithium salts.

R2Zn + ZnX2 2 RZnX

R = alkyl, aryl etc.X = Cl, Br, I

Scheme 34. Preparation of organozinc halides by ligand exchange

Important contributions made by different research groups for the preparation

of organozinc halides by ligand exchange method are described below.

20

In 1966, Boersma and Noltes24a prepared EtZnX (X = Cl, Br, I) by heating

the ZnX2 with diethylzinc at 70 oC (Scheme 35). These compounds were found to be

colorless, crystalline solids.

Et2Zn + ZnX270 oC, 10-20 min.

2 EtZnX

X = Cl, Br, I

Scheme 35. Preparation of salt-free ethylzinc halide

On the basis of cryoscopic molecular weight determination it was suggested

that ethylzinc chloride and bromide forms tetramer in benzene and have cubic

arrangement of Zn and halogen (Figure 4).

X

Zn X

Zn

Zn

X Zn

X

Et

Et

Et

Et

X = Cl, Br

Figure 4

Later in 1973, Shearer et al.24b crystallized EtZnI from ethyl iodide solution.

The X-ray crystallographic studies showed that ethylzinc iodide forms polymeric

structure which is consistent with the results obtained by Boersma and Noltes.24a

In 2006 Bochmann et al.24d prepared EtZnCl by heating the mixture of

diethylzinc and ZnCl2 in toluene for 72 h (Scheme 36). The X-ray crystallographic

studies showed that ethylzinc chloride forms infinite sheets [EtZnCl]∞ in which each

zinc atom is tetrahedrally coordinated to one ethyl and three chloride ligands.

Et2Zn + ZnCl270 oC, 72 h

2 EtZnCltoluene

Scheme 36. Preparation of salt-free ethylzinc chloride

21

In 2007 Woodward et al.24e reported the preparation of ethylzinc chloride in

THF by the treatment of diethylzinc with ZnCl2 at ambient temperature (Scheme 37).

Et2Zn + ZnCl225 oC, 1 h

2 EtZnClTHF

Scheme 37. Preparation of salt-free ethylzinc chloride

1.4. Miscellaneous methods

1.4.1. From diethylzinc and alkyl iodide

Higher homologues of alkylzinc halides can be prepared from Et2Zn and

alkyl halide in the presence of transition metal catalyst such as palladium or nickel.

In 1993 Knochel et al.25a reported the preparation of higher alkylzinc halides

for e.g. n-octylzinc iodide by the treatment of 1-iodooctane with Et2Zn in the

presence of catalytic PdCl2(dppf)2 in THF with good yield (Scheme 38).

n-OctI + 2 Et2ZnPdCl2(dppf)2 (1.5 mol%)

THF, 25 oC, 1.5 hn-OctZnI

78% yield

Scheme 38. Preparation of salt-free octylzinc iodide

A tentative mechanism25b was proposed for the above transformation. The in

situ generated L2Pd (L2 = dppf) inserts into OctI to give Pd(II) intermediate, which

undergoes transmetallation with Et2Zn to give OctZnI and L2Pd(Et)2 complex. This

complex rapidly decomposes to ethylene and ethane regenerating Pd(0) catalyst.

In 1994 Knochel and Cahiez25c reported Mn/Cu catalyzed preparation of

alkylzinc bromides using alkyl bromide and Et2Zn. The treatment of n-octyl bromide

14a with Et2Zn in the presence of MnBr2 (5 mol %) and CuCl (3 mol %) in DMPU

under mild reaction conditions provided n-octylzinc bromide 15a in good yield

(Scheme 39). Other functionalized alkylzinc halides were also prepared in good

yield.

22

n-OctBr + Et2Zn

MnBr2 (5 mol%)CuCl (3 mol%)

DMPU, 25 oC, 4−10 hn-OctZnBr

80-90% yield-(CH2=CH2, H3C-CH3)14a 15a

Scheme 39. Preparation of alkylzinc bromide from RBr and Et2Zn

Later in 1996, the same author25d reported Ni-catalyzed preparation of

alkylzinc halides from diethylzinc and alkyl halide without use of solvent. The

reaction of primary alkyl bromide or chloride (14a or 16a) with Et2Zn in the

presence of catalytic Ni(acac)2 afforded the corresponding alkylzinc halide in 70-

80% yield along with protonated product RH (~10%) and elimination product

(~10%) (Scheme 40).

RX + Et2Zn

70-80% yield14a or 16a

X = Cl, Br

Ni(acac)2 (5 mol%)

neat, 50−60 oCRZnX

Scheme 40. Ni-catalyzed preparation of alkylzinc halides from Et2Zn and RX

Author proposed the mechanism in which the in situ formed Ni(0) from

Ni(acac)2 and Et2Zn undergoes insertion reaction with alkyl halide to form RNiXLn

complex. This complex on transmetallation with Et2Zn gives RZnX and diethyl

nickel complex, which decomposes to give Ni(0), ethylene and ethane.

In 2008 Knochel et al.26a reported one pot procedure for the preparation of

benzyliczinc chlorides by using magnesium, ZnCl2 and LiCl. In this method

magnesium metal was reacted with benzylic chlorides 32a,b in the presence of ZnCl2

and LiCl in THF at room temperature to provide corresponding benzyliczinc

chlorides in excellent yield (Scheme 41). The formation of homocoupling product

was observed in <5% amount.

23

R

Cl

FG

32a R = H32b R = Me

FG = Cl, F, CN, CF3, CO2Et, OMe, SMe

32

+ Mg + ZnCl2 + LiCl R

FG25 oC, 2 h

THF

ZnCl

Scheme 41. One pot preparation of benzyliczinc chlorides using Mg, ZnCl2 and LiCl

Later, using this methodology various alkylzinc bromides, arylzinc chlorides,

bromides and iodides were prepared from corresponding halides in excellent yield

under the mild reaction conditions.26b-d Various functional groups like cyano, esters,

amides etc. were tolerated.

24

2. Applications of organozinc halides

2.1. Enantioselective 1,2-addition

In 2007 Woodward et al.27a reported the Me3Al promoted addition of arylzinc

bromides and iodides to aromatic aldehydes. In this protocol PhZnBr was first

converted to PhZnMe by stoichiometric amount of Me3Al. 13C NMR studies of the

mixture indicated rapid ligand exchange takes place between zinc and aluminum. In

situ formed PhZnMe was then treated with the 4-chlorobenzaldehyde in the presence

of catalytic amount of chiral β-aminoalcohols 36a-d, 37 and 38 (Scheme 42).

H

O

+

THF:Toluene RT, 16 h

OHPh

Me NBu2

PhZnX + AlMe3 PhZnMe + Me2AlX

AlMe336- 38 (10 mol%)

36b

OHPh

Me NMe2

OHPh

Me N

OHPh

Me N

OHPh

Ph NBu2

OHPh

Ph N

Ph

Ph

Ph

36a 36c 36d

37 38

Cl

PhZnX

Cl

Ph

OH

S

63% yieldup to 83 % ee

Scheme 42. Me3Al promoted addition of PhZnBr to 4-chloro benzaldehyde

The ligand 36b was found to be the most efficient ligand and therefore used

for the addition of ArZnX to various aldehydes (Table 3). Authors proposed that the

addition of Ph group takes place from Si face as shown in Figure 5.

25

Table 3. Enantioselective addition of ArZnMe to aromatic aldehydes using 36b

Entry Aldehyde ArZnX Yield (%) ee (%) Config.

1 4-ClC6H4CHO PhZnBr 67 83 S

2 4-ClC6H4CHO PhZnI 50 89 S

3 4-FC6H4CHO PhZnBr 76 90 S

4 4-MeC6H4CHO PhZnBr 61 89 S

5 4-MeOC6H4CHO PhZnBr 70 86 S

6 3-MeC6H4CHO PhZnBr 58 91 S

7 2-MeC6H4CHO PhZnBr 51 86 S

8 C6H5CHO 4-MeOC6H4ZnI 73 84 R

MePh

Bu2NO

ZnPh

Al

XO

HArSi

Me

Me

Figure 5. Proposed transition state

Later in 2010, the same research group27b studied the scope of the above

reaction in detail. They have examined number of other promoters such as ZnR2 (R =

Me, Et, Bu), AlR3 (R = Et, i-Bu), methylaluminooxane (MAO) and BR3 (R = Et,

OMe, F). However Me3Al proved to be the best. Under optimized conditions, the

addition of ArZnBr to various aromatic as well as aliphatic aldehydes afforded good

to excellent enantioselectivities. Few important examples of aliphatic aldehydes are

given in (Table 4).

26

Table 4. Enantioselective addition of ArZnMe to aliphatic aldehydes

R H

O+

CH3CN:Toluene RT, 16 h

AlMe3 36b (10 mol%)

ArZnBrAr

OH

R

Entry Aldehyde Ar Yield (%) ee (%)

1 n-BuCHO 4-MeOC6H4 87 82

2 t-BuCHO 4-MeOC6H4 96 93

3 t-BuCHO 4-EtO2CC6H4 76 96

4 i-PrCHO 4-EtO2CC6H4 48 93

5 c-C6H11CHO 4-EtO2CC6H4 53 97

In 2009 Walsh et al.27c used EtZnCl for the preparation of mixed

phenylethylzinc (PhZnEt) by treatment with PhLi in methyl tert-butyl ether (MTBE).

This reagent was then reacted with 2-benzofurancarbaldehyde 39 in the presence of

isoborneol based ligand (−)-MIB 40 (5 mol %) to obtain arylated product 41 in 92%

yield with 90% ee (Scheme 43). The role of N,N,N,N-tertaethylethylenediamine

(TEEDA) was to reduce the Lewis acidic effect of lithium halide generated during

the preparation of PhZnEt. In the absence of TEEDA poor enantioselectivity was

realized. The alcohol 41 was further converted to (S)-1-(benzofuran-3-

yl(phenyl)methyl)-1H-imidazole, a potential anticancer compound.

2 PhBr

i) n-BuLi (2 equiv) MTBE

ii) EtZnCl (2 equiv) −78 oC

PhZnEt

iii) TEEDA (0.8 equiv) toluene, 0 oC

iv) 40 (5 mol%)v) 39, 0 oC, 12 h

O

PhHO

92% yield90% ee

OHN

O

40

41

O

HO

39

Scheme 43. Enantioselective addition of PhZnEt to aldehyde

27

2.2. Diastereoselective 1,2-addition

2.2.1. Diastereoselective addition to keto esters

In 1991 Basavaiah et al.28a described cyclohexyl based chiral auxiliary

mediated preparation of various optically active α-hydroxy acids by the

diastereoselective addition of RZnCl to (1R,2S)-2-phenylcyclohex-1-yl

phenylglyoxalate 42. The treatment of 42 with alkylzinc chlorides, prepared from

RMgBr and ZnCl2, afforded corresponding α-hydroxy ester 43 which on hydrolysis

gave the desired α-hydroxy acid 44 in moderate to good yield with high optical

purity (Scheme 44).

Ph

O

OPh

O+ RZnCl

ether

−78 to 0 oC

Ph

O

OPh

HO R43

KOH

MeOH PhHOOC

HO R

50- 80% yield84- 99% ee

44R = Et, n-Bu, n-Hex i-Pr, i-Bu

42(R)

Scheme 44. Diastereoselective addition of RZnCl to α-keto esters

Encouraged by these result, the same group28b,c later examined various

cyclohexyl based chiral auxiliaries 45a-d (Figure 6) to study the steric effect. The

result showed that introduction of more bulky group on cyclohexyl ring does not

have significant variation on the diastereoselectivity.

OH

ONO2

OH

O

tBu

OH

O

OH

O

Ph

45a 45b 45c 45d

Figure 6

28

Later in 2002, Monteux et al.28d used the protected isomannide and isosorbide

as chiral auxiliaries in diastereoselective addition of various alkylzinc halides to

corresponding glyoxalate. The outcome of study was described below with one

representative example. Treatment of phenyl glyoxylate 46a (Figure 7) with i-PrZnX

(prepared from i-PrMgX and ZnCl2) in the presence of stoichiometric amount of

ZnCl2 gave corresponding α-hydroxy ester 47a in 78% yield with 88% de (Table 5,

entry 1). On the basis of outcome of the stereoselectivity, it was suggested that the

addition takes place in accordance with Whitesell′s model.28e However dramatic

decrease in selectivity was observed by interchanging the positions of α-ketoester

and protecting group. Thus, addition of i-PrZnX to 46b furnished the desired α-

hydroxy ester 47b with only 12% de whereas 46c afforded the ester 47c with >99%

de (Table 5, entry 2 and 3). In the case of 46c conformational arrangement allows the

л-stacking between the dicarbonyl moiety and phenyl ring of protecting group, which

is responsible for high stereoselectivity. Lack of such interactions in the case of 46b

explains the low selectivity. Saponification of 47a provided the corresponding α-

hydroxy acid with good enantioselectivity.

O

O

H

H

BnO

O

46b

O

O

H

H

O

OBn

O

O

Ph

46a

O

Ph

OO

O

H

H

BnO

O

O

Ph

O

46c

Figure 7

29

Table 5. Diastereoselective addition of RZnX to 46a-c

46a-ci) ZnCl2

ii) RZnX

O

O

H

H

BnO

O

O

Ph

OH

47a-cR

*MeOH/H2O

KOHO

OHR OH

Ph *

82% ee

Entry Substrate R 47, Yield (%) de (%)

1 46a i-Pr 78 88

2 46b i-Pr 51 12

3 46c i-Pr 53 >99

In 2006 Gaertner et al.28f reported the diastereoselective addition of RZnX to

α-ketoesters containing chiral m-hydrobenzoin auxiliaries. This reaction was studied

in solution as well as on solid support. Addition of alkylzinc chlorides to α-

ketoesters 48 afforded corresponding α-hydroxy esters 50a-c with moderate to

excellent diastereoselectivity (Table 6, entries 1−3). The larger nucleophiles like n-

BuZnCl and i-PrZnCl gave excellent diastereoselectivity, whereas the reaction with

small nucleophile like MeZnCl resulted in only moderate diastereoselectivity. Under

similar reaction conditions the keto ester 49 containing polymer supported chiral

auxiliary showed similar results affording the hydroxyl esters 51a-c (Table 6, entries

4−6). Author proposed that chelation of Zn2+ cation forces the two carbonyls of the

keto carboxylic ester into syn-conformation29 which effectively shields one face of

the elcetrophile (Figure 8). This methodology was employed for the preparation of

frontalin which is an aggregation pheromone of a pine beetle population in the

Dendroctonus family.

30

Table 6. Diastereoselective addition of RZnCl to 48 and 49

O

O

O

Ph

Ph

OR'

48 R' = O

O = Wang resin49 R' =

RZnCl

O

O

Ph

Ph

OR'R OH

50a-c51a-c

Up to 98% yield30-98% de

THF, -78 to -20 oC

Entry Substrate R Product de (%)

1 48 n-Bu 50a >98

2 48 i-Pr 50b 94

3 48 Me 50c 45

4 49 n-Bu 51a 90

5 49 i-Pr 51b 84

6 49 Me 51c 30

HO

Ph

O

PhH

O

Ph

O

OR'

Zn

X

Nure-attack

Figure 8. Proposed model for the diastereoselective addition

2.2.2. Diastereoselective addition to imino esters

The reaction of α-imino esters with organometallic reagents is an interesting

and potentially useful reaction for the synthesis of optically active amino acids and

amino alcohols.

In 1988 Yamamoto et al.30a reported the diastereoselective addition of

benzylzinc bromide to imino esters. The reaction of iminoester 52 with PhCH2ZnBr

in THF gave the desired product 53 (C-alkylation at imino carbon) in moderate yield

31

with 48% de (Scheme 45). Other organometallic reagents such as RMgX, R3Al,

RTi(O-i-Pr)3 provide the N-alkylated product.

NPh

Me

H CO2Bu

+ PhCH2ZnBrTHF

RT, overnight NPh

Me

CO2Bu

H

Ph

NPh

Me

CO2Bu

H

Ph

+

52 53a (major) 53b (minor)

S

R

S

S

50% yield48% de

Scheme 45. Diastereoselective addition of PhCH2ZnBr to 52

Later in 2002, Roland et al.30b studied this reaction in detail. In their

preliminary investigation they found that the presence of a chelating atom such as

oxygen in amine part or chiral alcohol in ester moiety and use of ZnBr2 is necessary

to achieve excellent diastereoselectivity in the addition of t-BuZnBr to α-imino ester.

Under the optimized conditions various organozinc bromides were reacted with α-

imino ester 54 to obtain desired product 55 in moderate to good yield with good

diastereoselectivity (Scheme 46).

NPh

OMe

OEt

O

i) ZnBr2, Et2Oii) RZnBr, 0 oC to RT

iii) NH4ClNH

Ph

OMe

OEt

O

R

54 55

Up to 68% yieldUp to 92% deR = t-Bu, sec-Bu, c-Hex, Bn

Scheme 46. Diastereoselective addition of RZnBr to 54

The stereochemical outcome of the reaction was explained by the proposed

chelate models A and B (Figure 9). Both the models lead to (R)-product. In chelate

A, ZnBr2 coordinates to imine nitrogen and two oxygen atoms (from the ester and

OMe) to form rigid five-membered rings and the zinc reagent attacks from less

hindered re face. In chelate B, zinc reagent may coordinate with oxygen atom of

methoxy group leading to preferential attack from re face.

32

N

O

O

OEtPh

H

ZnBr2

re face

N

O

O

OEtPh

H

Zn

Br

Br

Zn

R

X

chelate A chelate B

re face

Figure 9

Very recently Ellman et al.30c reported highly diastereoselective addition of

benzylzinc reagents to N-tert-butanesulfinyl aldimines. The treatment of benzylzinc

chloride with imine 56a gave the corresponding addition product 57a in good yield

and diastereoselectivity (Scheme 47). Under the optimized conditions, various

benzyliczinc chlorides were reacted with number of substituted imines. Few

representative examples are given in table 7.

H

N

MeO

SO

tBu

+ Ph ZnCl

THF, RTHN

MeO

SO

tBu

Ph

57a56a70% yield86% de

Scheme 47. Diastereoselective addition of PhCH2ZnCl to imine 56a

33

Table 7. Diastereoselective addition of benzyliczinc chlorides to various imines

R H

NS

O

tBu

THF, RTR

HNS

O

tBu

ZnCl

X

+

X56 57

Entry R X Yield (%) de (%)

1 4-CO2MeC6H4 H 86 84

2 4-ClC6H4 H 87 84

3 3-ClC6H4 H 86 84

4 2-ClC6H4 H 79 >98

5 3-Py H 98 92

6 4-CO2MeC6H4 4-OMe 69 88

7 4-CO2MeC6H4 4-F 86 88

8 t-Bu 4-F 77 52

2.3. Enantioselective 1,4-addition

In 2004 Hayashi et al.31a reported Rh-catalyzed enantioselective 1,4-

addition31b,c of arylzinc chlorides to protected 2,3-dihydro-4-pyridone to prepare

synthetically useful 2-aryl-4-piperidones 60a-f. In their initial study, they found that

PhZnCl was superior to other organometallics such as PhB(OH)2 or PhTi(O-i-Pr)3.

The addition of Phenylzinc chloride to 2,3-dihydro-4-pyridone 58 in the presence of

catalytic amount of [RhCl((R)-BINAP)]2 in THF afforded the desired product 60a in

excellent yield with high enantioselectivity (Scheme 48). This reaction showed broad

scope and the addition of various functionalized arylzinc reagents afforded excellent

enantioselectivities (Table 8). The methodology was successfully applied in the

preparation of a key intermediate for tachykinin antagonists B.

34

N

O

CO2Bn

+ ArZnCl

3 mol%[RhCl ((R)-BINAP)]2

THF, 20 oC, 2 h N

O

CO2BnAr

95% yield> 99.5% ee

58 60a Ar = Ph

PPh2

PPh2

(R)-BINAP =

59

Scheme 48. Enantioselective 1,4-addition of PhZnCl to 58

Table 8. Enantioselective 1,4-addition of various ArZnCl to 58

Entry Ar Product Yield (%) ee (%)

1 4-PhC6H4 60b 97 >99.5

2 4-MeOC6H4 60c 90 99

3 4-FC6H4 60d 91 >99.5

4 3,5-Me2C6H3 60e 87 99

5 2-MeC6H4 60f 100 99

The same author in 200531d described the preparation of 2-aryl-2,3-dihydro-4-

quinolones which are antimitotic antitumor agents. Initially the treatment of PhZnCl

with 4-quinolone 61 under the above reported conditions31a resulted in very low

yield. However, the addition of TMSCl (as a Lewis acid) gave smooth conversion

under mild conditions and expected product 62 was obtained with excellent

enantioselectivity (Scheme 49). The outcome of the stereoselectivity in Rh/(R)-

BINAP catalyzed 1,4-addition was rationalized by the re face approach of the

substrate to avoid the steric repulsion between the phenyl ring on the phosphorus

atom of (R)-BINAP and fused benzene ring of the substrate.

35

N

O

CO2Bn

+ PhZnClTMSClTHF, 20 oC, 20 hthen 10% aq. HCl

88% yield98% ee

61 62

[RhCl (C2H4)2]2 (7.5 mol% Rh)59 (8.2 mol%)

N

O

CO2BnPh

Scheme 49. Enantioselective 1,4-addition of PhZnCl to 61

In the same year Hayashi′s group31e reported the use of above methodology35d

in enantioselective 1,4-addition of phenylzinc chloride to α,β-unsaturated ketones

catalyzed by [Rh((1R,5R)-Ph-cod)((R)-1,1′-binaphthyl-2,2′-diamine)] 64. Treatment

of α,β-unsaturated ketones or esters 63a-d with phenylzinc chloride in the presence

of catalytic amount of 64 provided the expected product 65a-d in excellent yield with

high enantioselectivity (Scheme 50). The reaction was very fast and completes in 20

minutes at 0 oC.

X

O

63a-d

+ PhZnClTMSCl (1.5 equiv)

64 (3 mol%)THF, 0 oC, 20 min.

X

O

(R)-65a-dPh

O O

O

O

O

O

63a 63b 63c 63d

RhN

N

Ph

BF4

H

H

H

HPh

64

86-99% yield90-98% ee

X = CH2, O

Scheme 50. Enantioselective 1,4-addition of PhZnCl to 63

Later in 2006, Hayashi et al.31f described the enantioselective 1,4-addition of

arylzinc halides to α,β-unsaturated aldehydes. The reaction of various (E)-3-

arylpropenal 66 with ArZnCl in the presence of TMSCl and catalytic amount of

36

Rhodium catalyst (coordinated with (R)-BINAP 59) in THF at 20 oC furnished

corresponding 3,3-diarylpropanal 67 with excellent enantioselectivity (Scheme 51).

Ar1 H

O

+ ArZnCl

[RhCl((R)-BINAP)]2 (3 mol% of Rh)

TMSCl, THF20 oC 1 h

K2CO3

MeOH/H2ORT, 1 h

Ar1 H

OAr

55-80% yield98-99% ee

66 67

Ar1 = 4-MeOC6H4, 2-MeOC6H4, 2-FC6H4, C6H5

Ar = C6H5, 4-MeOC6H4, 3-MeOC6H4, 3,5-Me2C6H3 2-naphthyl, 4-ClC6H4, 3-ClC6H4

Scheme 51. Rh-catalyzed enantioselective 1,4-addition to enal 66

In 2008 Frost et al.31g reported the enantioselective 1,4-addition of substituted

thienylzinc and 2-furanylzinc bromides to α,β-unsaturated ketones and esters using

catalyst prepared from [Rh(C2H4)2Cl]2 and chiral phosphorous ligand. Initial

investigations showed (R,R)-Me-DUPHOS 69 gave excellent results as compared to

other phosphorus ligands. Excellent enantioselectivities were obtained in 1,4-

addition of 68a and 68b to α,β-unsaturated ketones (63a and 63b) and ester 63c

using catalytic amount of 69 (Scheme 52).

X

O

63a-c

+

TMSCl, THF, 20 oC

X

O

38-91% yieldUp to 98% ee

O ZnBr

R1

S ZnBr

[Rh(C2H4)2Cl]2 (cat.) 69 (cat.)

(R)

(R,R)-Me-DUPHOS

P P

69

X = CH2, O

68a 68bR1 = Br, Me,

68a,bY

R1Y = O, S

Scheme 52. Enantioselective 1,4-addition to 63 using ligand 69

In 2009 Martin et al.31h reported Rhodium-catalyzed enantioselective 1,4-

addition of 2-heteroarylzinc chlorides to cyclic enones, unsaturated lactones, and

unsaturated lactams using (R)-MeO-BIPHEP ligand 71. The addition of benzofuran-

37

2-ylzinc chloride 70a or benzothiophene-2-ylzinc chloride 70b to Michael acceptors

63a-e in the presence of TMSCl and catalytic amount of 71 afforded the

corresponding 1,4-addition product in moderate to good yield with high

enantioselectivity (Scheme 53).

63a-e

N

OMe

63e

TMSCl, THF−78 to 0 oC

[Rh(cod)acac] (cat.) 71 (cat.)

Ar1ZnCl X

O

Ar1

47-93% yield91- 98% ee

OS

70a 70b

P(Ph)2P(Ph)2

MeOMeO

(R)-MeO-BIPHEP

71

+

70a,b

Ar1 =

Scheme 53. Enantioselective 1,4-addition of 70 using ligand 71

2.4. Asymmetric cross-coupling reactions

In 1983 Kumada et al.32a reported Pd-catalyzed cross-coupling of organozinc

halides with vinyl bromide. The reaction of secondary alkylzinc halides 72 with vinyl

bromide in the presence of Palladium catalyst 73 afforded olefin 74a-c in good yield

with up to 86% enantioselectivity (Scheme 54).

Ar

RZnX + CH2=CHBr

THF, -78 to 0 oC

73 (cat.)

73 PdCl2[(R)-(S)-PPFA]

Ar

HR

7274a-c

X = Cl, Br, I72a Ar = Ph, R = Me72b Ar = p-Tol, R = Me72c Ar = Ph, R = Et

(s) FePPh2

NMe2

PdCl

Cl

H

Scheme 54. Pd-catalyzed enantioselective cross-coupling

Later in 1989, Hayashi and Ito32b reported Pd-catalyzed enantioselective

cross-coupling of l-phenylethylzinc chloride 72a with vinyl bromide using catalytic

amount of ferrocenylphosphine ligand 75. The expected product was obtained in

quantitative yield with excellent enantioselectivity (Scheme 55).

38

93% ee

Ph

MeZnCl + CH2=CHBr

THF, 0 oC

75 (0.5 mol%) Ph

MeH

74a(R)

72a

NMe2H

Me

NMe2Me

H

Ph2P

PPh2

PdCl2Fe

75

Scheme 55. Pd-catalyzed enantioselective cross-coupling catalyzed by 75

In 2005 Fu et al.33a reported first example of Ni-catalyzed asymmetric

Negishi cross-coupling33b of alkylzinc bromides with secondary α-bromo amides.

The treatment of various secondary α-bromo amides 76 with simple as well as

functionalized alkylzinc bromides in DMI/THF (DMI = 1,3-dimethyl-2-

imidazolidinone) using catalytic amount of NiCl2⋅glyme and (R)-i-Pr-Pybox ligand

77 provided desired product 78 in moderate to good yield with excellent

enantioselectivity (Scheme 56).

NN

OO

NPri iPr

+

NiCl2.glyme (10 mol%) ligand 77(13 mol%)

DMI/THF, 0 oC

51-90% yield87 to >98% ee

R1ZnBrN

ORBn

Ph BrN

ORBn

Ph R1

77

76

R = Me, Et, n-Bu, i-BuR1 = alkyl, functionalized alkyl

(R)-i-Pr-Pybox

(Recemic)

78

Scheme 56. Nickel-catalyzed asymmetric Negishi coupling of R1ZnBr with 76

The same year Fu′s group33c described Ni-catalyzed cross-coupling of

alkylzinc bromides with secondary benzylic halides. Thus, the reaction of 1-bromo or

1-chloro indanes 79 with various alkylzinc bromides in the presence of NiBr2⋅glyme

and (R)-i-Pr-Pybox ligand 77 in DMA gave desired product 80 in moderate to good

yield with moderate to excellent enantioselectivity (Scheme 57). Author

39

demonstrated that this methodology can be used in the synthesis of bioactive

molecules such as LG 121071.

+

NiBr2.glyme (10 mol%) ligand 77 (13 mol%)

DMA, 0 oC, 24 h

41-89% yield75-99% ee

X

R2

R1

R2

X = Cl, BrR1 = alkyl, functionalized alkylR2 = Cl, CN, Me, OMe

R1ZnBr

79(Racemic)

80

ferentially occurs at less hindered carbon with the regioselectivity

>20:1. The addition of NaCl accelerates the rate of cross-coupling, but has little

effect on ee. Author applied this methodology for the formal synthesis of

fluvirucinine A1.

Scheme 57. Nickel-catalyzed asymmetric Negishi coupling of R1ZnBr with 79

Later in 2008, the same author33d reported the Ni-catalyzed asymmetric cross-

coupling of allylic chlorides with various alkylzinc bromides. The reaction of various

symmetrical as well as unsymmetrical allylic chlorides 81 with alkylzinc bromides in

the presence of excess NaCl and catalytic amount of (S)-BnCH2-Pybox ligand 82

gave the corresponding coupling product 83 in good yield with excellent

enantioselectivity (Scheme 58). In the case of unsymmetrical allylic chlorides the

cross-coupling pre

R2 R3

Cl

+

NiCl2.glyme (5 mol%)ligand 82 (5.5 mol%)NaCl (4 equiv)

DMA/DMF, −10 oC, 24 hR2 R3

R1

Up to 95% yieldUp to 98% ee

R1 = alkyl, functionalized alkylR2 = n-Bu, i-Pr, t-Bu, COOEt, CONEt2, CON(OMe)Me, PO(OEt)2R3 = Me, n-Pr, i-Pr

R1ZnBr8381

NO

N N

O

82Bn Bn(S)-BnCH2-Pybox

Scheme 58. Nickel-catalyzed asymmetric Negishi coupling of R1ZnBr with 81

40

In 2009 Fu et al.33e reported the asymmetric cross-coupling of arylzinc

iodides with α-bromoketones. After extensive optimization of the reaction

conditions, they found that this reaction proceeds smoothly in the presence of

NiCl2⋅glyme (5 mol%), Pybox ligand 85 (6.5 mol%) in glyme/THF. Under optimized

conditions, treatment of α-bromoketones 84 with various arylzinc iodides provided

corresponding cross coupled product in good yield and good enantioselectivity

(Scheme 59). Decreased yield as well as ee was observed when Ar1 and R were the

bulky substituent.

NN

OO

N

+

NiCl2.glyme (5 mol%) ligand 85(6.5 mol%)

glyme/THF, −30 oCArZnI

OR

Br

8584

O

A

r = Ph, 2-MeOC6H4, 3-MeOC6H4, 4-MeOC6H4, 4-FC6H4, 4-Me2NC6H4, 4-MeSC6H4.

H , 4-F CC H , 2-thienyl

Ar1

Ar1 = Ph, 2-FC H , 3-EtC H , 4-Me6 4 6 4 OC6 4 3 6 4

(Recemic)

R

Ar

Ar1

Ph Ph

MeOOMe

Up to 93 % yield

In 1997 Knochel et al.34a reported the preparation of various chiral ferrocenes

by the reaction of ferrocenyl acetate with various organozinc reagents. The treatment

of chiral ferrocenyl acetate 86 with RZnX in the presence of BF3⋅OEt2 provided the

expected product 87 in good yield with >95% retention of stereochemistry (Scheme

60).

Up to 96 % ee

Scheme 59. Nickel-catalyzed asymmetric Negishi coupling of ArZnI with 84

2.5. Miscellaneous reactions

FeR1

OAc

+ RZnX

R

64-98% yield95-98% ee

THF

-78 oC to RT, 1.5 h FeR1

86 87X = Br, IR = i-Pr, (E)-PhCH=CH, allyl, 3-MeC6H4CH2R1 = Me, Ph

Scheme 60. Substitution of ferrocenyl acetate 86 with RZnX

41

Later in 2003, Xue et al.34b reported the preparation of C-Glycosides by

. Treatment of 88 (prepared by

Danishefsky′s protocol35) with organozinc halides, prepared from RLi and ZnCl2,

provided α-glycoside 89a as major product (Table 9). However, low

diastereoselectivity was observed when RZnX was prepared from RMgX and ZnCl2.

Table 9. Addition of various RZnX to epoxide 88

addition of organozinc halides to glycal epoxide 88

RR OOO

BnOOBn

BnO+ RZnX

Et2O

0 oC to RT

OBnO

BnOOBn

BnO

BnO+

OBnOHOH

88 89a 89b Entry RZnXa Yie ) 8 ld (% 9a:89b

1 n-BuZnCl 69 >95:5

2 PhZnCl 78 >95:5

3 O 72 >95:5 ZnCl

4 Ph-C C-ZnCl 86 100:0

5 C-ZnClC3H7 - 80 100:0

6 n-BuZnClb 41 66:34 a prepared from RLi and ZnCl2. b Prepared from RMgX and ZnCl2.

In 2004 Ready et al.36 found that alkylzinc chlorides prepared from Grignard

reagent and ZnCl2 undergo efficient cross-coupling with α-halo ketones in the

presence of copper catalyst. Using this methodology optically pure α-chloroketone

90 was reacted with iso-propylzinc chloride to obtain desired product 91 in good

enantioselectivity with 100% inversion of stereochemistry (Scheme 61).

OOCH3

Cl

i-PrZnCl MgCl2

Cu(acac)2 (5 mol%)Et2O/THF, 25 oC, 14 h

CH3

MeMe

90 9195% ee 77% yield

95% ee Scheme 61. Cu-catalyzed coupling of α-haloketones

42

3. Preparation of organozincates

The organometallic reagent having Lewis acidic metal centre possess ability

to react with anionic fragment. Due to the presence of vacant orbitals on the metal

centre these reagents when reacted with Lewis base, form a new organometallic

species which is termed as an ‘ate’ complex.11c,37 The outer shell of zinc atom in

dialkylzinc (e. g. Me2Zn) is filled with 14 electrons and there are two empty orbitals

which can occupy two pairs of electrons. Therefore it can react with one or two

Lewis basic reagent (e.g. MeLi) which results in the formation of organozincate

mple

incates. The

following literature survey therefore is mainly focused on preparation and

applications of triorganozincates in asymmetric reactions.

Triorganozincates are generally prepared by the reaction of zinc halide with

three equivalents of alkyllithium or Grignard reagent or from stoichiometric reaction

of organolithium or Grignard reagent with diorganozinc4a (Scheme 62).

co x Me3ZnLi or Me3ZnLi2 respectively. Organozincates are further classified

into two classes: i) Triorganozincates [R3Zn]M and ii) Tetraorganozincates

[R4Zn]M2. We were particularly interested in the chemistry of triorganoz

ZnX2 + 3 RM [R3Zn]M

ZnR2 + RM [R3Zn]M

M = Li, MgX

Schemer 62. Methods for the preparation of triorganozincates

These reagents have very old history and are known since the report of

Wanklyn in 1858.38 Author prepared [Et3Zn]M (M = Na, K) from the reaction of

Et2Zn and alkali metals (Na or K). However very little information was known about

such complexes at that time. There are several reports on the preparation of

iorganozincates. Some of the important methods are discussed below.

On the basis of spectroscopic evidence, Waack and Doran39a reported in 1963

that the 1:1 mixture of Et2Zn and 1,1-diphenyl-n-hexyllithium forms triorganozincate

species (Scheme 63).

tr

43

Et2Zn + RLi [Et2ZnR]Li

R = 1,1-diphenyl-n-hexyllithium

Scheme 63. Preparation of lithium triorganozincate

In 1986 Kjonaas et al.39b reported the preparation of magnesium

trialkylzincate [R3Zn]MgBr by the reaction of ZnCl2⋅TMEDA complex with 3

equivalent of Grignard reagent in THF (Scheme 64). Authors have observed that this

complex reacts chemoselectively with α,β-unsaturated ketones to give 1,4-addition

as the major product.

ZnCl2 TMEDA + 3 RMgX [R3Zn]MgXTHF

R = alkyl, aryl X = Cl, Br, I

Scheme 64. Preparation of magnesium triorganozincates

In 1991 Richey Jr. et al.40 reported the preparation of heteroleptic

triorganozincate 92. The reaction of stoichiometric amount of diethylzinc with

potassium tert-butoxide in toluene provided the zincate 92 (Scheme 65). NMR

plex exists in spectroscopy and X-ray crystallographic studies showed that the com

dimeric form.

Et2Zn + t-BuOKtoluene

[Et2ZnO-t-Bu]K

92

Scheme 65. Preparation of potassium triorganozincates

In 1992 Purdy et al.41 prepared the trialkylzincates 93a-c using the method of

Wanklyn (Scheme 66). These complexes were characterized using NMR

spectroscopy and X-ray crystallography. The alkyl groups on zinc adopt trigonal-

planar geometry.

44

3 R2Zn + 2 M 2 [ZnR3]M benzene, RT, 24 h

93a M = Na, R = CH2CMe393b M = K, R = CH2CMe393c M = K, R = CH2SiMe3

93a-c

Scheme 66. Preparation of trialkylzincates 93 from R2Zn and alkali metals

In 1993 Weiss et al.11b e crystal structure of potassium

imethylzincate 94 in which methyl groups exhibit trigonal-planar coordination

reported th

tr

(Figure 10). No details of preparation method were reported.

Zn K

Me

Me

Me

94

Figure 10

In 1994 Purdy et al.42 reported the preparation of tri-tert-butoxyzincates 95a

f t-BuOM (M = Na, K) in THF

or ether (Scheme 67). These complexes were purified by sublimation under reduced

roscopic and X-ray crystallographic studies showed that both the

comple

and 95b by the reaction of ZnCl2 with 3 equivalent o

pressure. Spect

x exists in dimeric form.

ZnCl2 + 3 t-BuOMTHF or Et2O

4 days[(t-BuO)3Zn]M

95a M = Na95b M = K

Scheme 67. Preparation of tri-tert-butoxyzincates 95

Later in 1996, Uchiyama et al.43a prepared Lithium trimethylzincate

(Me3ZnLi) and dilithium tetramethylzincate (Me4ZnLi2) by the reaction of ZnCl2

tively (Scheme 68). The 1H NMR

studies clearly indicated the upfield shift of methyl protons in Me3ZnLi and

with 3 and 4 equivalent of MeLi in THF respec

45

Me4ZnLi2 c to that Table 10), which indicates more anionic

ch cter of th tes.

ompared of Me2Zn (

ara e zinca

ZnCl2 + 3 MeLiTHF

[Me3Zn]Li

+ 4 MeLiZnCl2THF

[Me4Zn]Li2

Scheme 68. Lithium tri- and tetraorganozincates

Table 10. 1H NMR of zincates in THF

Entry Reagent δMe (ppm)a

1 MeLi −1.96

2 Me2Zn 0.84 −

3 Me3ZnLi 1.08 −

4 Me4ZnLi2 1.44 −a The δ values are relative to β methylene proton (1.85 ppm) of THF.

In 1998 Krieger et al.43b isolated the magnesium triphenylzincate

[Mg2Br3(THF)6][ZnPh3] 96 from the reaction of phosphoraneiminato complex

[ZnBr(NPMe3)]4 with excess PhMgBr (Scheme 69). The structure of the complex

was established by X-ray crystallographic studies.

[ZnBr(NPMe3)]4 + PhMgBrexcess

THF[MgBr(NPMe3)]4 + 96

Mg

Br

Mg

Br

Zn

Ph

Ph THFTHFTHF THFPh Br

THFTHF

96

cheme 69. Preparation of magnesium triphenylzincate 96

S

46

Recently in 2010, Hevia et al.23f reported the preparation of magnesium tri-

tert-butylzincate [t-Bu3Zn][Mg2Cl3⋅(THF)6] 97 by the reaction of ZnCl2 with 3

equivalent of t-BuMgCl in THF (Scheme 70).

ZnCl2 + 3 t-BuMgClTHF

[t-Bu3Zn][Mg2Cl3(THF)6]

97

Scheme 70. Preparation of tri-(tert-butyl)zincate complex

X-ray crystallographic studies of 97 showed that in the anionic moiety, the

inc centre is bonded to three tert-butyl groups with trigonal planar geometry

hereas cationic moiety consists of two distorted octahedral magnesium atoms

haring three chlorines and with three molecules of THF completing the coordination

phere of magnesium (Figure 11).

z

w

s

s

Mg

Cl

Mg

Cl THFTHF

THF

THFTHF

THFClZn

tBu

tBu

But

Figure 11

47

4. Applications of organozincates

Triorganozincates have been used in many organic reactions such as 1,2-

addition to carbonyl compounds,44 1,4-conjugated addition to α,β-unsaturated

carbonyl compounds,39b,45 addition to imines,44d,46 metalation of aromatic

halides,11c,43a,47 epoxide opening43a and Pd-catalyzed cross coupling23f,47b, (Fig. 12).

[R3Zn]M

R1

R2

OO

R1 R2

NR3

O

R1 ArI

ArI

Pd(II)

R1 R2

OH

R O

R

R

Ar-R

R3RHN1 R2R

[R2ZnAr]M

OHR1

and α,β-unsaturated ketones.

4.1. Asymmetric 1,2-addition

In 1979 Seebach et al.48a reported the enantioselective addition of lithium

tributylzincate (prepared from ZnCl2 and 3 equivalent of BuLi) to benzaldehyde

using (+)-DBB 98 as a chiral cosolvent (Scheme 71). Although good yield was

obtained, the enantioselectivities was very low.

Figure 12

However, these reagents have been used in a only few asymmetric reactions

such as addition to carbonyl compounds, imines

48

Me2NNMe2

OMe

OMe

[Bu3Zn]Li + PhCHOEt2O:(+)-DBB

Ph Bu

OH

(R)

85% yield15% ee

(+)-DBB 98

Scheme 71. Asymmetric addition of lithium tributylzincate to benzaldehyde

48b ition of

chiral organozincate 99 to Ethyl 2,2,2-trifluoropyruvate 100. Initial investigation

showed that (R)-BINOL was superior to other chiral modifiers. The chiral zincate 99

was prepared in situ by first treatment of the (R)-BINOL with stoichiometric amount

of Et2Zn followed by addition of Grignard reagent. The reaction of resulting chiral-

zincate complex with keto ester 100 in 1,2-dichloroethane:THF followed by

hydrolysis provided enantiomerically enriched α-hydroxy acids 101 with moderate to

good enantioselectivities (Table 11). Later in 2010, the same author48c used this

methodology in the preparation o iologic ta oxygenase inhibitor

MK-0633.

Table 11. Enantioselec e addit hiral-org zincates to 100

Later in 2007, Gosselin et al. reported the enantioselective add

f b ally impor nt 5-lip

tiv ion of c ano

Oi) Et2Zn i) CF3 OEt

(R)-BINOL

DCE:THF−40 oC to RT

[(R1O)2Zn(R)]MgClii) RMgCl −40 oC to RT

O O

-40 C, 18 ho

ROH

CF3HO

Up to 74% yieldUp to 83% ee

ii) KOH, H2OR1 = (R)-BINOL-ate

99101

Entry R Yield (%) ee (%)

100

1 Me 29 50 2 Et 74 74 3 Bu 35 83 4 vinyl 29 13 5 phenyl 38 69 6 allyl 37 4 7 benzyl 36 <5

49

4.2. Asymmetric 1,4-addition

In 1979 Seebach et al.49a reported the enantioselective addition of lithium

tributylzincate to 2-cyclohexenone using (+)-DBB 98 as chiral cosolvent. Moderate

yield of expected product was realized with poor enantioselectivity (Scheme 72).

Other Michael acceptors such as 2-cyclpentenone, crotonaldehyde and 1-nitro-1-

propene gave similar results.

O

+ [Bu

O

3Zn]LiEt2O:(+)-DBB

Bu*

62% yield16% ee

−78 oC

Scheme 72. Asymmetric 1,4-addition of lithium tributylzincate

In 1988 Feringa et al.49b found that the use of alkoxide as non-transferable

ligand in 1,4-addition of triorganozincates to 2-cyclohexenone. Encouraged by these

results, they examined chiral menthoxide as non-transferable ligand. Thus, chiral

zincate complex 102 was prepared in situ by the treatment of ZnCl2⋅TMEDA

complex with one equivalent of 1-menthyloxymagnesium bromide followed by the

addition of 2 equivalent of i-PrMgBr in THF. The reaction of resulting zincate

complex with 2-cyclohexenone provided the desired product with only 9% ee

(Scheme 73). Examination of triorganozincates obtained from chiral TMEDA⋅ZnCl2

analogue 103 provided similar results.

O

THF, 0 oC

O

iPr*

OR* = menthyloxy

TMEDA [(iPr)2Zn(OR*)]MgBr

80%9%

yield ee

102

N N

H H

Zn

ClCl

103

Scheme 73. Enantioselective 1,4-addition of chiral-zincate 102

50

In further study, Feringa′s group found that catalytic amount of ClZnOR can

be used in 1,4-addition.49c Later in 1990, they examined chiral-zinc alkoxides 104a

and 104b in enantioselective addition of Grignard reagent to 2-cyclohexenone.49d

The chiral zinc-alkoxide (prepared by the reaction of ZnCl2 with lithium alkoxides

derived from corresponding aminoalcohols) was first reacted with Grignard reagent

to form chiral organozincate species which on further treatment with to 2-

cyclohexenone afforded desired product in excellent yield with moderate

enantioselectivity (Scheme 74). Authors examined a library of various type of

ligands for this reaction but couldn’t achieve better results.

O

+ R*OZnCl

O

5 mol%

i-PrMgBr

THF, −90 oC, 15 min iPr

Up to 92% yieldUp to 33% eeR*OZnCl

N N

ZnOCl

NNMe

MeMe

OZn

Me Me

PhCl

104a 104b

Scheme 74. Catalytic enantioselective 1,4-addition of triorganozincates

4.3. Diastereoselective addition to imines

In 1997 Savoia et al.50a reported diastereoselective addition of

triorganozincates to imines. Initial study showed that valine-derived imine 105 was

better as compared to other imines. The reaction of imine 105 with various lithium

and magnesium triorganozincates provided corresponding amines 106a-h in

oderate to excellent diastereoselectivity (Table 12). It was also found that the

zincates derived from Grignard reagents were more effective than the corresponding

′ = Me),

selective transfer of R group was observed rather than R′. The diastereoselectivity

was slightly affected by the nature of R group and decreased in the order vinyl > i-Pr,

n-Bu > Me > Bn > allyl > t-Bu.

m

lithium zincates. In the case of mixed organozincates [R′2ZnR]M (R

51

Table 12. Diastereoselective addition of triorganozincates to imine 105

NN COOEt THF, −78 oC

NN COOEt

R

H

Up to 90% yieldUp to 98% de

+ [R'2ZnR]M

105M = Li, MgXR' = Me, t-BuR = alkyl, vinyl, allyl, benzyl

(S) (S)

106a-h

E y Yield (%) Product de (%) ntr [R'2ZnR]M

1 [Me3Zn]MgCl 50 106a 84

2 [Me3Zn]Li 50 106b 54

3 [Me2Zn-n-Bu]MgCl 86 106c 88

4 [Me2Zn-i-Pr]MgCl 90 106d 90

5 [Me2Zn-t-Bu]MgCl 80 106e 14

6 [Me2ZnBn]MgCl 88 106f 76

7 [Me2Zn(allyl)]MgBr 91 106g 46

8 [Me2Zn(vinyl)]MgBr 95 106h 98

On the basis of these results, the outcome of stereoselectivity was explained

through the formation of six-membered cyclic transition state (Figure 13).

Mg

N R

ZnMe

N

X Me

HEtO2C

iPr

f these zincates with (R)-N-

(tert-butanesulfinyl)benzaldimine 107 furnished corresponding chiral amines 108

with moderate to good diastereoselectivity (Scheme 75).

Figure 13

In 2008 Guijarro and Yus50b prepared various mixed trialkylzincates by the

treatment of Me2Zn with Grignard reagent. The reaction o

52

+ [Me2ZnR]MgBrPh H

NS

O

tBu THF, −78 oC

Ph R

HNS

O

tBu

107(Rs,R)-108

R = Et, i-Pr, n-C5H11, vinyl 85-93% yield88-96% de

1−3 h

Scheme 75. Diastereoselective addition of triorganozincates to 107

Later in 2009, the same author50c reported the catalytic version of the above

method. After extensive study they found that the use of 0.15 equivalent of Me2Zn

gave optimum results. Under the optimized conditions various Grignard reagents

were reacted with imine 107 to obtain corresponding chiral amine 108 with excellent

diastereoselectivity (Scheme 76). Author proposed that the reaction of RMgX with

Me2Zn generates triorganozincate [Me2ZnR]MgX, which transfers the R group

selectively to the imine and Me2Zn gets recycled to continue the reaction. This

methodology was later used for the preparation of various optically active α- and β-

amino acids.50d,e

+ Me2Zn + RMgBrPh H

NS

O

tBu THF, −78 oC

Ph R

HNS

O

tBu

107 (Rs,R)-108

R = Et, i-Pr, n-C5H11, vinyl83-99% yield86-96% de

(cat.)

Scheme 76. Catalytic diastereoselective addition of triorganozincates to 107

53

4.4. Miscellaneous reactions

4.4.1. Diastereoselective addition to vinylic sulfoxides

In 1997 Houpis and Molina51a reported the addition of triphenylzincates

[Ph3Zn]M (M = Li, MgBr) to optically active vinyl sulfoxide 109. Treatment of

[Ph3Zn]M (M = Li or MgBr) with 109 in the presence of catalytic amount of

Ni(acac)2 gave the sulfoxide 110 in good yield. Compound 110 upon desulfurization

provided the phosphodiesterase IV inhibitor 111 with good enantioselectivity

(Scheme 77).

NS

tolyl

O

MeO

CpO

[Ph3Zn]M

Ni(acac)2 (cat.)THF, −25 oC

NS

tolyl

O

MeO

CpO Ph

ZnTHF:AcOH 23 oC

N

MeO

CpO Ph

109 110 111M = Li, MgBrCp = cyclopentyl >90% yield 70-75% yield

82-92% ee

Scheme 77. Diastereoselective addition of triphenylzincates to sulfoxide 109

4.4.2. Enantiospecific cross-coupling

In 2008 Briet et al.51b reported ZnCl2-catalyzed enantiospecific cross

coupling of α-hydroxy ester triflates 112 with Grignard reagents. Under optimized

conditions, various RMgX (X = Cl, Br) provided the coupling product 113 in good

yield with 100% transfer of chirality (Scheme 78). In the absence of ZnCl2, low yield

of expected product was observed.

ButO

OR1

OTf

ZnCl2 (5 mol%)RMgX

THF, 0 oCButO

OR1

R112113

R1 = Me, n-Bu, i-Bu, i-Pr, Bn, CH2OR, CH2CORR = Me, Et, n-Bu, i-Bu, i-Pr, Oct, Bn, lauryl

(97 to >99% ee) 72 to >99% yield97 to >99% ee

Scheme 78. Zn-catalyzed cross-coupling of Grignard reagents with 112

This methodology was later used for the synthesis of

(Oligo)deoxypropionates which are common motifs in a large number of biologically

54

relevant natural products of polyketide origin. In this report, the author proposed a

catalytic cycle (originally postulated by Ishihara et al.44d) as shown in figure 14. The

addition of RMgX to zinc chloride generates diorganozinc species (R2Zn) which then

reacts with a third molecule of Grignard reagent to give a triorganozincate species

(R3ZnMgX). Lewis acid activation of the triflate with magnesium ion followed by

SN2 attack of triorganozincate gives the expected product with very high

stereoselectivity.51c cat. ZnCl2 + 2 RMgX

RMgX

[R3Zn]MgXZn(II)-ate complex

OButO

O

R1

SO2CF3

MgX

ZnR3

Product (R2Zn)

112

Figure 14. Proposed catalytic cycle

Summary and Outlook

It is evident from the above account that efficient methodologies now exist

for the preparation of organozinc halides.12-26 However, there is still need to develop

simple methods for their preparation, for example using zinc dust in THF as solvent.

Moreover, less reactive alkyl chlorides and aryl bromides are still useless substrates

for the reaction with zinc. These reagents have found applications mainly in Pd- or

Ni-catalyzed enantioselective cross coupling and Rh-catalyzed 1,4-additions. Unlike

diorganozincs, organozinc halides could not gain popularity for the enantioselective

addition to carbonyl group.

Organozincates are reactive species and have proved their utility in

asymmetric synthesis. However there are no catalytic protocols for their use in

enantioselective transformations.

To sum up, the oldest organometallic reagent still remains significantly

unexplored, and promises rich dividend for researchers.

55

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