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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