chem

1. Fan Liu, Michael
Furrow
1
Hursthouse, M. B.; Motewaili, M.; O'Brien, P.; Walsh, J. R.; Jones, A. C. J. Mater.
Chem.
1991, 1, 139–140.
Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc. 1986, 108, 6071-
6072.
Zn—C
1.98 Å
n-C6H13 Et 81 61
3
H C
Zn—C
1.95 Å
80
Et 90
PhCH2CH2
N
81
Et 96
(E)-PhC(H)=CH
180 ° N CH3
N
CH3 96
Et 93
145 ° Zn
H3C
p-CH3OC6H4
H3C Zn CH3
CH3
2 H3C H3C N 3 86
N N Et 93
N CH p-ClC6H4
59
Me 91
Ph
H3C
N
H3C
CH3
N
97
Et 98
Ph
R R' % yield % ee
R H toluene, 0
°C
R R'
 X-Ray structures of dimethylzinc and its adduct with 1,3,5-trimethylhexahydro-1,3,5-
triazine show that upon bis-complexation, dimethylzinc shifts from a linear geometry to a
tetrahedral geometry and that the carbon-zinc bond length increases from 1.95 Å to 1.98
Å. This is proposed to increase the nucleophilicity of the methyl groups, accelerating
addition to carbonyl compounds.
+ R'2Zn
O 2 mol % (–)-
DAIB
OH
Soai, K.; Watanabe, M.; Koyano, M. Bull. Chem. Soc. Jpn. 1989, 25, 2124–
2125.
(–)-DAIB
H3C
racemic
Bz Bz
toluene, 23°C, 14
h 93%
H (C2H5)2Zn
+ CH3
5 mol %
TMEDA
O OH
 In 1986, Noyori et al. published the first highly selective procedure for the asymmetric addition of
diethyl- and dimethylzinc to aldehydes employing (–)-3-exo-(dimethylamino)isoborneol (DAIB) as
a chiral catalyst.
H3C CH3
N(CH3)3
OH
 The addition of a catalytic amount of TMEDA will promote the addition of diethylzinc at
room temperature to 4-benzoylbenzaldehyde in 93% yield.
Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823–
2824.
 The reactivity of dialkylzinc reagents towards ketones and aldehydes is low; the rate of addition
of Et2Zn to benzaldehyde is negligible at room temperature.
96% yield, 49%
ee
Background:
H + (C2H5)2Zn
CH3
O OH
OH
H3C
2 mol % CH3 NH2
toluene, 20 °C, 43 h
Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757–824.
Lemire, A.; Cote, A.; Janes, M. K.; Charette, A. B. Aldrichimica Acta 2009, 42, 71–
83. Lumbroso, A.; Cooke, M. L.; Breit, B. Angew. Chem. Int. Ed. 2013, 52, 1890–
1932.
Recent Reviews:  In 1984, Oguni and Omi found that a small amount of (S)-leucinol catalyzed the
enantioselective addition (49% ee) of diethylzinc to benzaldehyde.
Chem
115
Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds
Myer
s

2. Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc. 1989, 111, 4028-4036. Oguni, N.;
Matsuda, Y.; Kaneko, T. J. Am. Chem. Soc. 1988, 110, 7877.
Fan Liu, Michael
Furrow
2
Itsuno, S.; Fréchet, J. M. J. J. Org. Chem. 1987, 52, 4142–4143.
Corey, E. J.; Hannon, F. J. Tetrahedron Lett. 1987, 28, 5237–
5240. Evans, D. A. Science 1988, 240, 420–426.
homochiral dimer,
less stable,
dissociates
Et Et Ar
Zn
H
3
O
Et
Ar
3
3 3 H
H C H C
O
CH
Zn
Et
O
CH O
H3C CH3
3
H C
N N 3
Zn
Et
Zn
Et H C
slow
3 3
CH CH
3 3 3 3 3
H C CH H C CH H C
CH3 R Zn
CH3
O
N
CH3
H
Ar
Et Ar Zn R
O
N
3
EtZnO H O H H
CH3 CH
heterochiral dimer,
more stable, does not
readily dissociate
H3C Zn
Et
Et
+
O 3
3
H C
O
CH
Zn Et CH3
3
3 H C
CH
N
Zn Et
CH3
H
N H3C
H3C CH3
N
CH3
R Zn
H3C CH3
R Zn O
O N
H3C H3C
CH3
CH3
H H H3C CH3
H
H3C H3C
3 O O
H C
Et2Zn H3C
N
Zn R
N
Zn R
3
N(CH3)3
OH
CH3
3
CH
CH3
H3C CH3 CH H3C CH3
H3C CH3
 This observation is consistent with a mechanistic proposal involving two Zn atoms per
aldehyde:
(–)-DAIB (+)-DAIB
Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc. 1989, 111, 4028–
4036.
H H3C CH3
3
3 H C
H3C 3
O
CH
H C
Zn Et +
N
R Zn
O
N
3
CH CH3
1 : 1 : 0 0 —
1 : 1 : 1 1 0
50 : 50 : 1 97 98
H3C CH3 H
aldehyde : Et2Zn : DAIB % yield % ee
92% yield, 95%
ee
toluene, 0 °C, 6
h
2 5 2
H (C H ) Zn
+
H + (C2H5)2Zn
CH3
CH3
cat. (–)-
DAIB
O
O OH
8 mol % (–)-DAIB
15 % ee
OH
 A non-linear dependence of product ee on catalyst ee was observed. Heterochiral dimerization
to form an unreactive species was invoked to account for in situ amplification of product ee:
Mechanism:
 The stoichiometry of aldehyde, diethylzinc, and DAIB ligand determines reactivity: alkylation
occurs only when the ratio of Et2Zn : DAIB is greater than 1:
Chem
115
Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds
Myer
s

3. Reeder, M. R.; Gleaves, H. E.; Hoover, S. A.; Imbordino, R. J.; Pangborn, J. J. Org. Process
Res.
Dev. 2003, 7, 696–
699.
Kim, J. G.; Walsh, P. J. Angew. Chem. Int. Ed. 2006, 45, 4175–
4178.
Fan Liu, Michael
Furrow
3
TEEDA
H3C CH3
SO2CH3
3 3 (5 mol%)
H C CH
H3C
unstable
above –50
ºC
stable N N TEEDA
(equiv) yield ee
0 –
2
0.8 99
92
SO2CH3
90% N
OH
H Li ZnCl Br
THF, –60
ºC
O
H3C CH3
ZnCl2 N MTBE
hexane
s
N O 1. n-BuLi N O O
N O
Pd(PPh 3)4
(5 mol%)
60 ºC
 Transmetallation with a Zinc Salt:
 Substrates that are less readily prepared by direct reduction can be prepared by treatment of
a Zinc(II) halide with two equivalents of alkyllithium or alkylmagnesium halide:
Cote, A.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 2771–2773.
• N,N,N,N-tetraethylethylenediamine (TEEDA) can be used to scavenge salts and the resulting in situ
formed zinc reagents function in catalytic asymmetric addition reactions to aldehydes:
3. O
H OH
Br1. n-BuLi 2. ZnCl2
Choi, B. S.; Chang, J. H.; Choi, H.-W.; Kim, Y. K.; Lee, K. K.; Lee, K. W.; Lee, J. H.; Heo, T.;
Nam,
D. H.; Shin, H. Org. Process Res. Dev. 2005, 9, 311–313.
0 → 23 ºC
> 95%
H3C H3C
MgCl Zn
2 x + Zn(OCH3)2 + 2 CH3OMgCl
CH3 CH3 CH3
CH3
2
Et O
11.5
kg
10.6 kg
THF, 70
ºC
Cl Cl
2 2 10.0
kg
2. 6N HCl
72%
EtO C Br EtO C ZnBr
Cl  Zn(OCH3)2 can also be used. The byproduct, CH3OMgCl, precipitates from the reaction mixture
and salt-free ethereal solutions of diorganozinc can be obtained after filtration or centrifugation:
Cl EtO2C F
1. Zn
MsOH (5
mol%)
O
NC F
von dem bussche-Hünnefeld, J. L.; Seebach, D. Tetrahedron 1992, 48, 5719–
5730. Brubaker, J. D.; Myers, A. G. Org. Lett. 2007, 9, 3523–3525.
O
 methanesulfonic acid can be used to activate zinc
metal:
N
>80%
93%
ee
CH3
OBn OBn
200 ºC
<30 mmHg
89 %
Et2Zn
EtI EtBr
+
Zn-Cu
neat, reflux
distillation
2
+
BrZnI
H N N
[EtZnI]
+
[EtZnBr]
Et Zn THF, –75 ºC
OLi
O O
Schlenk
Equilibrium
O OH
3.
filtration
Zn
ZnCl2
(1.0 M in Et2O)
2.
dioxane
(1.0 M in Et2O)
(salt free)
MgBr
1.
 Metallic Zinc Insertion:
 One of the early methods involves treatment of an alkyliodide or bromide with zinc dust or an
activated form of Zn, such as zinc-copper couple (Zn(Cu)). The method requires rather harsh
conditions and is limited to low molecular weight dialkylzinc species due to the need to distill
the products while avoiding competitive Wurtz coupling:
 1,4-Dioxane forms insoluble complexes with magnesium halides and allows the synthesis of
diorganozinc reagents that were not commercially available to subsequently be used in
asymmetric additions to carbonyl compounds:
Lemire, A.; Cote, A.; Janes, M. K.; Charette, A. B. Aldrichimica Acta 2009, 42, 71–
83. Knochel, P.; Perea, J. J. A.; Jones, P. Tetrahedron 1998, 54, 8275–8319.
 In many cases, lithium or magnesium halide byproducts must be removed to avoid salt
complexation with chiral additives in subsequent enantioselective processes.
Myers
Preparation of Organozinc Reagents:
Chem
115
Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds

4. Kneisel, F. F.; Dochnahl, M.; Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 1017–
1021.
Wipf, P.; Xu, W. Org. Synth. 1997, 74, 205–
211. Fan Liu, Michael
Furrow
4
CH3
Li(acac)2
H O O H H O
Cp2ZrHCl ZnMe2
CH2Cl2
0 → 23 ºC
toluene
–60 → 0 ºC
ZrCp2Cl > 86% Zn
OTBDPS OTBDPS OTBDPS 3
H O
H3CO Zn OCH3 H3CO Zn
O CH
i-Pr
Li+
OAc OAc AcO O
 organozirconium
:
CH3
H3CO I
Vettel, S.; Vaupel, A.; Knochel, P. J. Org. Chem. 1996, 61, 7473–
7481.
OAc
H O H O
OPiv OPiv
COD (2 mol%), neat, 50–60
°C
> 40%
2 x
Li(acac)2
Et2Zn (0.6 equiv), Ni(acac)2 (1 mol%) i-Pr
2
) Zn H3CO I H3CO Zn
i-Pr2Zn
Li(acac) 2 (10 mol%)
Et2O, NMP 25
ºC, 12 h
>90%
OAc OAc
 organonickel
:
 Aryl and alkenyl iodides can undergo halogen-zinc exchange with i-P2rZn. Li(acac)2 activates
the intermediate mixed diorganozinc as an ate complex and promotes the second exchange:
Langer, F.; Schwink, L.; Devasagayaraj, A.; Chavant, P.-Y.; Knochel, P. J. Org. Chem. 1996,
61, 8229–8243.
Powell, N. A.; Rychnovsky, S. D. J. Org. Chem. 1999, 64, 2026–
2037.
> 86%
2 2
EtO C 2. Et Zn, neat, 0 °C t-Bu
EtO2C 2
) Zn TMSOTf, CH2Cl2
–78 ºC, 67%
0.1 mm
Hg 50
°C
2
I OEt EtO ) Zn
CO2Et O O
1. Et2BH, Et2O, 0 °C CO2Et
OEt
O O
n-Hex
O O
t-Bu
O
Et2Zn CuI
(3 mol%)
neat, 50
°C
 organoboron
:
Milgram, B. C.; Liau, B. B.; Shair, M. D. Org. Lett. 2011, 13, 6436–
6439.
Substrate decomposition occurred in the absence of
ZnEt2.
Rozema, M. J.; Eisenberg, C.; Lütjens, H.; Ostwald, R.; Belyk, K.; Knochel, P. Tetrahedron
Lett.
1993, 34, 3115–3118.
Rozema, M. J.; Sidduri, A.; Knochel, P. J. Org. Chem. 1992, 57, 1956–1958.
n-Hex OAc
3 3
82% CH
3
H
OTBS
H C
OBn MoOPH OBn
H
OTBS
OBn
H
OTBS
Ph
Si
Ph
Si
H3C
CH
0.1 mm Hg, 50
°C
> 95%
OPiv
OPiv Me2PhSiLi,
ZnEt2;
AcOCH2(CH2)3CH2I (AcOCH2(CH2)3CH2)2Zn
HO
O O
OZn–Et2Li+
OPiv
Et2Zn, CuI (0.1 mol%)
neat, 50 °C;
 organolithium
:
 Halogen-Diorganozinc Exchange:
 Iodine-zinc exchange reactions have been used to prepare dialkylzinc species containing
esters, nitriles, chlorides, sulfonamides, and boronic acids. CuI or UV light were found to
accelerate the reaction. Removal of excess Et2Zn and EtI was necessary to drive the reaction:
Chem
115
Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds
Myers
 Transmetallation with a Diorganozinc Reagent:
 Functionalized diorganozinc reagents can be prepared via transmetallation of
organolithium, organoboron, organonickel, and organozirconium with dimethyl-, diethyl-, or
diisopropylzinc:

5. Nugent, W. A. Org. Lett. 2002, 4, 2133–
2136.
Fan Liu, Michael
Furrow
5
Berger, S.; Langer, F.; Lutz, C.; Knochel, P.; Mobley, T. A.; Reddy, C. K. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1496–1498.
H3C H3C
86%, > 94%
ee
hexanes,
toluene 0 ºC,
91%
99% ee
H3C H H3C Et
Cl
3 (5 mol%) 2
Et O, –20 °C
O OH
2
Et Zn H
OH
6 (8 mol%)
Ti(Oi-Pr)4
O
Watanabe, M.; Soai, K. J. Chem. Soc., Perkin Trans. 1, 1994, 3125–
3128.
(Cl(CH2)4)2Zn + (TMSCH2)2Zn (Cl(CH2)4)Zn(CH2TMS)
neat, 25
°C
O OH
H toluene, 0 ºC
82%, 96%
ee
Et
Ph Ph
 Unsymmetrical dialkyl zinc containing a trimethylsilylmethyl group as a non-transferable group
can be prepared to avoid losing one equivalent of valuable alkyl zinc precursor:
Et2Zn
n-BuLi, 2 (8 mol%)
O O
 Chemoselective addition to aldehydes can be achieved in the presence of
ketones:
Yoshioka, M.; Kawakita, T.; Ohno, M. Tetrahedron Lett. 1989, 30, 1657–1660.
Takahashi, H.; Kawakita, T.; Yoshioka, M.; Kobayashi, S.; Ohno, M. Tetrahedron Lett. 1989,
30, 7095–7098.
Hayasaka, T.; Yokoyama, S.; Soai, K. J. Org. Chem. 1991, 56, 4264–
4268.
toluene, –30
ºC
99%, 98% ee
Ph H Ph n-Bu
O OH
Ph H Ph Et
hexanes, 0
ºC
94%, 95% ee
n-Bu2Zn, Ti(Oi-Pr)4
6 (2 mol%)
O OH
Schmidt, B.; Seebach, D. Angew. Chem. Int. Ed. 1991, 30, 99–
101.
Et2Zn
1 (6 mol%)
5 6
 Ligand 1 extends the scope of the initial DAIB reaction to include aliphatic
aldehydes:
7 H3CO H3CO
toluene
0 → 23 ºC, 89%
98% ee
toluene
–75 → 23 ºC, 86% H3CO
94% ee
NHTf Et H Et
Ph
Ph N (1.2 equiv)
O
O 3
3 4
OH OH
CH
H C Et2Zn O Ti(Oi-Pr) 5 (2 equiv)
NHTf
CH3
H3C
OH
OH
O
O O O
Ti
O O
Ph
Ph
Ph Ph Ph Ph N
 Using 5 as a chiral additive, either enantiomer of the product can be obtained by changing
the reaction conditions:
Et2Zn
5 (10 mol%)
1 2 3 4
Nugent, W. A. Chem. Commun. 1999, 1369–
1370.
HO N(n-Bu)2 H3C
N
CH3
3
Ph CH
N
OH
CH3 CH3
Ph
Ph
OH
hexanes,
toluene 0 ºC,
94%
99% ee
O
HO N H3C CH3 H Et
H3C H3C
O OH
Et2Zn
ent-4 (5 mol%)
O
shown
here:
 3-exo-morpholinoisoborneol (MIB), 4, more stable and easier to prepare than DAIB, catalyzes
enantioselective additions to aldehydes with similar selectivity and efficiency. It also shows
improved selectivity with α-branched, aliphatic aldehydes:
Chem
115
Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds
Myers
Alkylzinc Addition to Aldehydes:
 A variety of chiral catalysts and ligands have been developed that promote the addition of
dialkylzinc reagents to give enantiomerically enriched secondary alcohols. Only a few
representative ones are

6. Wipf, P.; Ribe, S. J. Org. Chem. 1998, 63, 6454–
6455. Fan Liu, Michael
Furrow
6
Cl
toluene, –30 ºC
83%, 97%
ee
H
Langer, F.; Schwink, L.; Devasagayaraj, A.; Chavant, P.-Y.; Knochel, P. J. Org. Chem. 1996,
61, 8229–8243.
Cl
O
Ginnol
3 n-Bu
n-Bu
n-Bu H 3 2
Zn
CH
3 3 SH N(CH )
CH H C
THF, –60 → 0 °C
95%
OH
CH3
1.Cp2ZrHCl
CH2Cl2, 23 ºC
2.Me2Zn
toluene, –65 ºC
Bu2Cu(CN)Li2
(10 mol%)
OH
69%, 92%
ee
Oppolzer, W.; Radinov, R. N. Helv. Chim. Acta. 1992, 75, 170–173.
Oppolzer, W.; Radinov, R. N.; De Brabander, J. Tetrahedron Lett. 1995, 36, 2607–
2610.
CH3 CH3
H
Br
60%, 82%
de
O OH H3C
3
H C
(Br(CH2)5)2Zn
Ti(Oi-Pr)4
6 (8 mol%)
toluene
–60 → –20 °C
O O
O O
2. Et2Zn
(–)-DAIB (1 mol%)
H
1. (Cy)2BH•S(CH3)2
hexanes
–20 → 23 °C
HO
O
Fürstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119, 9130–
9136.
(–)-
Gloeosporone
 Mixed organozinc reagents, formed via transmetallation of organoboron or organozirconium with
dialkylzinc, can be used to form enantiomerically enriched allylic alcohols in the presence of a
chiral amino alcohol catalyst:
CH3
Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1988, 29, 5645–
5648.
H
O
O OH O
hexanes, 0
ºC
90%, 96%
ee
O
Zn
H n-Bu
n-Bu
88% yield, >98%
ee
3 OH
H C (20 mol%)
O
H3CO H H3CO CH3
N N(CH3)2
3 3
OCH O OCH OH
OH
(n-C5H11)2Zn
Ti(Oi-Pr)4
6 (20 mol%)
toluene
–78 → –20 °C
 The first example of catalytic asymmetric vinylzinc additions to aldehydes was reported using
a
chiral diaminoalcohol ligand:
H3C CH3
Alkenylzinc Addition to Aldehydes:
Myers
Dialkylzinc Reagents in Synthesis:
Chem
115
Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds

7. Kerrigan, M. H.; Jeon, S.-J.; Chen, Y. K.; Salvi, L.; Carroll, P. J.; Walsh, P. J. J. Am. Chem.
Soc.
2009, 131, 8434–
8445.
Fan Liu, Michael
Furrow
7
O
50%, 95%
ee
H OHC
(–)-Longithorone A CH3
Layton, M. E.; Morales, C. A.; Shair, M. D. J. Am. Chem. Soc. 2002, 124, 773–775.
H O
Cy
Et Et Cy
Zn B
O
3
CH
n-Bu n-Bu O
H
2
Et Zn
Cy Cy
OH n-Bu O
H H
H3C
TMEDA
4 (5 mol%)
toluene, 0
ºC
97% yield, 90%
ee
0 → 23 °C 2. TBAF, THF
0 → 23 °C
Br Br OH
TBSO I
Br n-Bu n-Bu 1. as above
n-Bu HO OCH3
–78 → 0 °C
Cy2B
2 +
2. Et Zn
1. (Cy)2BH
toluene
H H
Cy
Cy B
Et
HO
O
OCH3
CH3
H
 Tri-substituted Z-allylic alcohol can also be
prepared:
TBSO
TIPS CH3
91% yield, 95%
ee
TMS CH3 OH
+
Salvi, L.; Jeon, S.-J.; Fisher, E. L.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2007, 129,
16119– 16125.
OCH3
3. H3C NMe2
Ph OLi
(2.5 equiv)
toluene, 0°C
TMS CH3
I TBSO
2. ZnBr2,
Et2O, 0 ºC
H
69%, 93%
ee
S 3
2
BCy2 TIPS CH
Et O, –78°C
–78 °C
O OTBDPS 1. t-BuLi
S H
OH OTBDPS H
Et2Zn
TEEDA
4 (5 mol%)
–78 → 23 °C
Alkenylzinc Reagents in Synthesis:
DeBerardinis, A. M.; Turlington, M.; Pu, L. Angew. Chem. Int. Ed. 2011, 50, 2368–
2370.
Cl
OTBDPS
H3C
O
94%, >99%
ee
3
H C H O
H
Cy B
Cy
3
Li H H CO n-Bu
CH2Cl2
H3CO
–20 → 23 °C Cl
Cl (26 mol%)
n-Bu NMP, 0 ºC
7 (10 mol%) H CH3
OTBDPS 2
OTBDPS
Cy2B HO
MTBE I 3
O CH
Et2Zn
Li(acac)
2. t-BuLi
–78 → 23 °C
2 H
1. (Cy) BH
H3C CH3
 Hydride migration from a boron ate complex provides access to enantiomerically enriched Z-
allylic alcohols:
 Direct transmetallations from vinyl iodides provide alkenylzinc reagents not accessible
through hydroboration or hydrozirconation:
Chem
115
Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds
Myer
s

8. Ishizaki, M.; Hoshino, O. Tetrahedron: Asymmetry 1994, 5,
1901.
Magnus, N. A.; Anzeveno, P. B.; Coffey, D. S.; Hay, D. A.; Laurila, M. E.; Schkeryantz, J. M.; Shaw,
B. W.; Staszak, M. A. Org. Process Res. Dev. 2007, 11, 560–
567.
Fan Liu, Michael
Furrow
8
OTBS
17.6 kg
–5 → –10 ºC
47.6 kg
88%, >94%
ee
H
60 ºC CN  The low yields in these reactions was attributed in part to competitive addition of ethyl groups to
the aldehydes.
toluene O TBSO
B
O O
Et2Zn (20 mol%)
OH
O
B
B
Ph OH
Ph
Ph
N
OTBS OTBS
DiMPEG = dimethoxy
poly(ethyleneglycol)
Bolm, C.; Rudolph, J. J. Am. Chem. Soc. 2002, 124, 14850–
14851.
R1 R2 T (°C) % yield % ee
C6H5 C6H5 0 64 90
C6H5 c-Hx 0 88 91
C6H5 t-Bu 0 61 95
Ph3Si c-Hx 23 55 91
C6H13 t-Bu 23 67 87
CN
C6H13 C6H5 23 41 78
Cl 8
toluene, –10 ºC
O
H p-ClC6H4
toluene
60 ºC,
>95%
Ph
Ph ZnEt
Ph B(OH)2
Et2Zn OH N
OH
N
OH
Fe Ph Ph
(S)-cat.
t-Bu
8 (10 mol%)
DiMPEG
(10 mol%)
O O
H3C CH3
CH3
 Widely available aryl boronic acids and boroxines can be directly transformed into arylzinc
reagents and undergo enantioselective arylation of aldehydes with excellent selectivity:
R1
THF,
reflux
THF
DeBerardinis, A. M.; Turlington, M.; Ko, J.; Sole, L.; Pu, L. J. Org. Chem. 2010, 75, 2836–
2850.
R2
R1 ZnEt
R1
Et2Zn
OH
R2 H
10 mol % (S)-cat.
OCH3 OCH3
NMP, 0
ºC
THF, 0
ºC
23 ºC
O
7 (10 mol%)
I H
Et2Zn
Li(acac)2
(26 mol%)
OH
O
 Mixed alkylalkynylzinc reagents can be prepared directly from terminal acetylenes and have
been shown to undergo catalyzed 1,2-additions to aldehydes with good enantioselectivities.
 Ligand 7 (see page 5) has been found to promote highly enantioselective additions of
diphenylzinc and functionalized diaryl zinc to aromatic and aliphatic aldehydes:
Wu, X.-F.; Neumann, H. Adv. Synth. Catal. 2012, 354, 3141–
3160. Trost, B. M.; Weiss, A. Adv. Synth. Catal. 2009, 351, 963–
983.
Pu, L. Tetrahedron 2003, 59, 9873–9886.
 Unlike dialkylzinc additions, diphenylzinc additions to aldehydes take place smoothly even without
a catalyst. This background reaction has made it more difficult to develop enantioselective
variants.
Schmidt, F.; Stemmler, R. T.; Rudolph, J.; Bolm, C. Chem. Soc. Rev. 2006, 35, 454–470.
Recent Reviews:
Alkynylzinc Additions to Aldehydes
Chem
115
Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds
Myers
Arylzinc Addition to Aldehydes:

9. 77%, 98%
ee
Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687–
9688.
Fan Liu, Michael
Furrow
9
Diez, S. R.; Adger, B.; Carreira, E. M. Tetrahedron. 2002, 58, 8341–
8344.
3
Et N, toluene, 60 °C
3
CH
Zn(OTf)2 (20 mol%) CH3
H OTMS
CH3
CH3
3
H CH
CH3
+
H3C 3
H C
OTMS
O
OH
(+)-N-methyl
ephedrine (22
mol%)
OH
O 3
H CH
Zn(OTf)2, Et3N
toluene, 60 °C
72%, 99% ee, dr = 92 : 8
CH3
H
+
CH3
(–)-N-methyl ephedrine
3
CH
 The system is less effective for aromatic aldehydes because of a competitive Cannizzaro
reaction.
OBz OBz
 It was shown that by raising the reaction temperature to 60 °C, the in situ zinc acetylide
formation and addition reaction can be made catalytic in both zinc and chiral ligand.
 The resulting terminal acetylene can be used to prepare enantiomerically enriched 1,4 -
diols:
Boyall, D.; Lopez, F.;Sasaki, H.; Frantz, D.; Carreira, E. M. Org. Lett. 2000, 2, 4233–
4236.
Frantz, D. E.; Fassler, R.; Tomooka, C. S.; Carreira, E. M. Acc. Chem. Res. 2000, 33, 373–381.
Boyall, D.; Frantz, D.; Carreira, E. M. Org. Lett. 2002, 4, 2605–2606.
For an investigation on the reaction mechanism, see: Fässler, R.; Tomooka, C. S.; Frantz, D.
E.; Carreira, E. M. Proc. Natl. Acad. Sci. 2004, 101, 5843–5845.
Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122, 1806–1807.
R1 R2 yield (%) ee (%)
n-C5H11 CH2CH2Ph 94 97
n-C5H11 Ph 90 97
i-Pr Ph 96 92
Ph Ph 82 93
2 3
toluene, 23 °C;
benzoyl
chloride
Zn(OTf) , Et N
Ph OH
(+)-N-
methylephedrine
R2 toluene, 110
ºC
1
H3C CH3
H
R % overall yield % ee
n-C3H7 68 99
n-C5H11 71 98
t-Bu 65 98
c-C6H11 73 99
TIPSO(CH2)2 71 97
R H R H (–)-N-methyl ephedrine R
R1
OH
H R2
(+)-N-methyl ephedrine
Zn(OTf)2, Et3N
toluene, 23 °C
2 3
3 2 K CO
O H C NMe R
O OBz
OH cat. 18-cr-
6
H OBz
OH
CH3
CH3
 All reagents are stoichiometric or
superstoichiometric.
 Protection of the 2° propargylic alcohol prior to cleavage of acetone from the adducts leads
to improved yields.
 The reactions can be carried out without rigorous exclusion of oxygen or moisture using
reagent- grade toluene (84–1000 ppm H2O).
 Enantioselective additions of 2-methyl-3-butyn-2-ol to aldehydes provide access to optically
active terminal acetylenes after cleavage of acetone from the products.
 In 2000, Carreira et al. published an in situ preparation of alkynylzinc reagents and their addition
to aldehydes with excellent enantioselectivities and yields.
Chem
115
Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds
Myer
s

10. 1
Topic, D.; Aschwanden, P.; Fässler, R.; Carreira, E. M. Org. Lett. 2005, 7, 5329–
5330.
Fan Liu, Michael
Furrow
10
R O 3
CH
H H
H
O
N 1
O CH3
Li, X.; Lu, G.; Kwok, W. H.; Chan. A. S. C. J. Am. Chem. Soc. 2002, 124, 12636–12637.
85%, 99%
ee
3 2
Zn(CH ) , THF, 0 °C
R2
Ph OH
Ligand
R Ph
toluene, 23 °C
92%, dr = 96 : 4
–O +
6 4
p-BrC H H
H
+ p-BrC6H4 H3C NHTs
ZnCl2, Et3N HO
N
Xc* O H Ph
(S)-BINOL (10 mol%)
Ligand (10 mol%)
OH
H3C CH3
O O
 A highly effective two-catalyst system was reported for the addition of zinc acetylide to aromatic
aldehydes. The stereochemistry of BINOL determines the stereochemistry of the products, while
the second ligand improves catalytic activity and enantioselectivity:
 The use of ZnCl2 homogenizes the reaction mixture and obviates the need for N,N-
dimethylethanolamine:
Fassler, R.; Frantz, D. E.; Oetiker, J.; Carreira, E. M. Angew. Chem., Int. Ed. Engl. 2002,
41, 3054–3056.
 Lowering the loading of Zn(OTf)2 to 20 mol% resulted in lower selectivites and isolated
yields.
Knöpfel, T. F.; Boyall, D.; Carreira, E. M. Org. Lett. 2004, 6, 2281–2283.
O
R
HO O R
6 11
>98% ee
R = c-C H , 83%,
O
>98% ee
1. KOH, PrOH, 97 ºC H3C
1. DMSO, 100 ºC Ph
R = i-Pr, 97%, O
H3C
N
CH3 Ph 88 95:5
i-Pr C(OH)Me2 98 96:4
t-Bu Ph 91 97:3
Ph SiMe3 88 95:5
Ph Ph
R2 overall yield
(%)
dr
R1
O O
O O 2
Et3N, CH2Cl2, 23 ºC
Ph Ph R
O Zn(OTf) (60 mol%)
CH3
2
R
3
H O H
CH
HOHN H R , TiCl4
pyridine, THF
–78 → 23 ºC
O
MeOH, H2O, 60 ºC H3C H3C H
O O
+ Ph
H3C
N
H3C
N
O
2
H NOH•HCl, NaOAc
OH
HN
R1
H3C CH3
O O
 The oxazepanedione shown below, prepared in 3 steps from ephedrine and dimethyl malonate,
undergoes condensation with aldehydes mediated by TiCl4. Conjugate addition of zinc
alkynylides followed by hydrolysis and decarboxylation give β-alkynyl acids in good yields and
selectivities:
O 3 2 2
3 Et N, CH Cl , 23 °C;
CH R2
H H
R1 H
Pinet, S.; Pandya, S. U.; Chavant, P. Y.; Ayling, A.; Vallee, Y. Org. Lett. 2002, 4, 1463–
1466.
O CH3
O R1
–O +
N
N
c
HO X *
O O Bn
H R2
Zn(OTf)2 (0.5 equiv)
Me2NCH2CH2OH (0.5 equiv)
81% H3C
H3C
NHBn
N
3 3
H C CH OH
Zn, AcOH, H2O
Ph
Ph
 Hydroxylamines are readily reduced to free
amines:
 A mannose-derived auxiliary was employed to promote diastereoselective alkynylzinc additions
to nitrones. The nitrone auxiliary was prepared from mannose, acetone and N-hydroxylamine.
Chem
115
Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds
Myer
s

11. Lehr, K.; Mariz, R.; Leseurre, L.; Gabor, B. Fürstner, A. Angew. Chem. Int. Ed. 2011, 50,
11373–
11377. Fan Liu, Michael
Furrow
11
(–)-Tulearin
C
CH3
OH
H3C
Scheerer, J. R.; Lawrence, J. F.; Wang, G. C.; Evans, D. A. J. Am. Chem. Soc. 2007, 129,
8968– 8969.
O O CH3
OH HO
7 steps
C5H11
CH3
3 3
3 3
CH CH
OH CH OH CH
(–)-Salvinorin
A
2. I2, –20 ºC, 99%
(CH3O)2HC H3CO2C
CH3
3
CH
OH I
7 steps 1. Red-Al, Et2O
3Å MS, 0 → 23 ºC C5H11
Me
O C5H11
O
BOMO
AcO
H
O O
O
H
O
H
Me
toluene, 23 ºC
91%, dr > 95 : 5
CH3
O CH3
2 2
Zn(OTf) , i-Pr NEt
+
5 11
C H
O H
O (+)-N-Me-ephedrine
Kleinbeck, F.; Carreira, E. M. Angew. Chem. Int. Ed. 2009, 48, 578–
581.
–78 → 5 ºC, 99%
single
diastereomer
TBAF, DMF,
THF
(–)-Bafilomycin A1 CH3 CH3 OH
(CH3O)2HC
H3C CH3
O
CH3 CH3 OCH3 CH3
HO 13
steps
TBDPS
O
HO
10
steps
CH3 O
O
BOMO H3C
H3C
O OH O
Ph CH3 OTBS
CO2CH3
OH CH(OMe)2
H3C
O CH3
OTE
S
H3CO2C
H3C CH 3
O O
OH
i-Pr
O
H3CO CH3 CH3 O CH3 CH3
H3CO
Zn(OTf)2, Et3N
toluene, 23 ºC
90%, dr = 6 : 1
CH3
H + H 3 3
(–)-N-Me-ephedrine CH CH O
Ph 3
H C
CH3 OTBS
CO2CH3
O CH(OMe)2
Zn(OTf)2, i-Pr2NEt
toluene, 23 ºC
91%, dr > 95 : 5
H3C
H +
H3CO2C (+)-N-Me-ephedrine
OTES
TBDPS
O
3 3
3
H CO CH CH
H3C CH 3
O O
Alkynylzinc Reagents in Synthesis:
Chem
115
Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds
Myer
s

12. Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 8355–
8361. Fan Liu, Michael
Furrow
12
Chen, C.; Hong, L.; Xu, Z.-Q.; Liu, L.; Wang, R. Org. Lett. 2006, 8, 2277–
2280.
92%, 92%
ee
 This method is only effective for aromatic
ketones.
Zn(CH3)2, Ti (Oi-Pr)4
toluene, 23 ºC
9 (5 mol%)
CH3
H3C H3C
O H3C OH
Ph
hexanes, –18 ºC
83%, 94% ee
CH3 Ph
+
HO CH3
F
F O
11 (1 mol%)
Et2Zn
3
Zn
H C
1.Cp2ZrHCl
CH2Cl2, 23 ºC
2. Zn(CH3)2
toluene, –78 ºC
Saito, B.; Katsuki, T. Synlett. 2004, 1557–
1560.
Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 6538–
6539.
90%, 95%
ee
toluene, –78
ºC
3 2
2. Zn(CH ) Ph
CH2Cl2
toluene, 23 ºC
61%, 87% ee
3
Ph n-Pr Ph
Zn
H C
Ph
Ph CH3
9 (10 mol%)
Zn(CH3)2, Ti(Oi-Pr)4
toluene, 23 ºC
H3C OH
Ph
+
1. Cp2ZrHCl
CH2Cl2, 23 ºC
HO n-Pr
O
3. O 10 (8 mol%)
(CH3)2Zn
Garcia, C.; Larochelle, L K.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 10970–
10971. Yus, M.; Ramon, D. J.; Prieto, O. Tetrahedron: Asymmetry 2002, 13, 2291–
2293.
CH2Cl2
toluene, 23 ºC
53%, 93% ee
t-Bu CH3 t-Bu
CH3 CH3
+
hexanes
toluene, 23
ºC
78%, 99%
ee
HO CH3
O
10 (8 mol%)
(CH3)2Zn
CH3
9 (2 mol%)
Et2Zn, Ti(Oi-Pr)4
O OH
CH3
Et
10 11
HO CH3
H3C OH 9
OH
N
CH3
Ph
Ph
H3C O O
O S NH HN S O
Ph
N N
OH HO
Ph Ph
Using Ti(Oi-Pr)4 as a Lewis acid, ligand 9 catalyzes the formation of tertiary alcohols with high
selectivity:
 Salen ligand 10 and Schiff base ligand 11 were found to promote efficient addition of zinc
acetylides to ketones:
Chem
115
Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds
Myers
Asymmetric Addition to Ketones:
Ketones are less reactive than aldehydes and often give 1,2-addition products in lower
yields because of competitve enolization or reduction of the carbonyl group.