Bidentate ligand-catalyzed enantioselective addition of RZnX to benzaldehyde

Article abstract of DOI:10.1016/j.tetlet.2011.09.120

Enantioselective addition of RZnX (R = alkyl, X = Cl, OAc) was studied using chiral chelating agents, particularly metal-alkoxides. Moderate enantioselectivity was achieved in the presence of magnesium-TADDOLate using RZnOAcMg(OAc)Br as the alkylating agent.

Full text of DOI:10.1016/j.tetlet.2011.09.120

Tetrahedron Letters 52 (2011) 6501–6503
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Bidentate ligand-catalyzed enantioselective addition of RZnX to benzaldehyde
⇑
R.S. Jagtap, N.N. Joshi
Division of Organic Chemistry, National Chemical Laboratory, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantioselective addition of RZnX (R = alkyl, X = Cl, OAc) was studied using chiral chelating agents, par-
ticularly metal-alkoxides. Moderate enantioselectivity was achieved in the presence of magnesium-
TADDOLate using RZnOAcMg(OAc)Br as the alkylating agent.
Received 8 September 2011
Revised 22 September 2011
Accepted 24 September 2011
Available online 29 September 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric synthesis
Organozinc
Chelating ligands
1,2-Addition
Enantioselective addition of organometallic reagents to alde-
hydes is one of the fundamental asymmetric reactions and pro-
vides enantiorich secondary alcohols, which are building blocks
for the synthesis of natural products and pharmaceuticals.1 Asym-
metric addition of alkyllithium and Grignard reagents is a straight-
forward approach to synthesize optically active alcohols. However
due to their high reactivity, catalytic version remained unexplored
for a long period of time.2 Recently Harada and co-workers have re-
ported that high enantioselectivity can be achieved by adding the
Grignard reagent to aldehydes in the presence of catalytic amount
of (R)-DPP-BINOL.3 In this method, the reactivity of Grignard re-
agent was quenched by the use of titanium tetraisopropoxide to
achieve excellent enantioselectivity. But this method suffers from
drawbacks like the need to use large amount of titanium reagent,
transmetallation at low temperature, and slow addition. In con-
trast, organozinc reagents became most popular during last three
decades owing to their mild reactivity and excellent chemoselec-
tivity.4 Among different approaches, catalytic enantioselective
addition of diorganozincs to aldehydes is the most studied reac-
tion.1b,c,5 However lack of wide commercial availability, high cost,
and their pyrophoric nature demands an easy in situ preparation of
these reagents. Significant efforts have been made by various re-
search groups to circumvent these difficulties,6 which include
preparation of diorganozincs by boron–zinc7 or iodine–zinc8 ex-
change and transmetallation of alkyllithium or Grignard reagents
with zinc salts.9 One of the major drawbacks in the case of
in situ preparation of diorganozincs from alkyllithium or Grignard
and ZnX2 is the inherent formation of lithium and magnesium
salts, which affects the enantioselectivity.9c,e To overcome this dif-
ficulty, additional tasks like centrifugation/filtration9a–c or the use
of complexing agent like N,N,N,N-tertaethylethylenediamine have
been explored.9d,e The reagents of type RZnX (X = Cl, Br, I) which
are easily accessible, are good potential alternatives to diorgano-
zincs. Organozinc halides have been used as alkyl-source in a few
asymmetric reactions like catalytic enantioselective 1,4-addition10
and asymmetric Negishi coupling.11 Recently Woodward and co-
workers have shown that arylzinc halides can be used in catalytic
enantioselective arylation of aldehydes.12 In this method ArZnX
was first converted in situ to ArZnMe by treatment with stoichiom-
etric AlMe3, which was then treated with the aldehyde in the pres-
ence of catalytic amount of chiral b-aminoalcohol to achieve
excellent enantioselectivity. To our knowledge, the direct catalytic
enantioselective addition of alkylzinc halides or alkylzinc carboxyl-
ates to aldehydes is not known.
Alkylzinc halides (RZnX) are known to be weakly active nucle-
ophiles.4b,13 It should be possible to enhance the reactivity of these
reagents by activation with Lewis bases. It was thought that a chi-
ral bidentate chelating agent could coordinate with the zinc center
and form reactive tetrahedral complex14 (Fig. 1), which may react
with aldehyde enantioselectively.
THF
EtMgBr + ZnCl2
EtZnCl Mg(Br)Cl
ð1Þ
0 oC to rt, 1 h
A
THF
EtMgBr + Zn(OAc)2
Et2Zn + Zn(OAc)2
EtZnOAc Mg(OAc)Br
ð2Þ
ð3Þ
0 oC to rt, 1 h
THF:hexane
rt, 1 h
B
EtZnOAc
C
In our initial study, EtZnClꢀMg(Br)Cl (A) prepared by the trans-
metallation15 of EtMgBr with ZnCl2 (Eq. 1), was reacted with benz-
⇑
Corresponding author. Tel.: +91 20 25902055; fax: +91 20 25902629.
E-mail address: nn.joshi@ncl.res.in (N.N. Joshi).
aldehyde. In the absence of any additive,
A reacted with
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.120

6502
R. S. Jagtap, N. N. Joshi / Tetrahedron Letters 52 (2011) 6501–6503
Y
Z
X
Zn
R
Figure 1. A reactive tetrahedral complex.
Table 1
benzaldehyde to give 1-phenyl-1-propanol in 11% yield along with
propiophenone (25%) and benzyl alcohol (25%) in 4 h at room tem-
perature (Scheme 1). The formation of byproducts can be explained
by Oppenauer oxidation16 of the intermediate zinc-alkoxide. We
then examined the reaction in the presence of various chiral addi-
tives (1–6). The metal-alkoxides17 2 and 4 were prepared sepa-
rately by the reaction of the corresponding diol with 2 equiv of
BuLi, whereas the alkoxides 3, 5, and 6 were obtained by treatment
with EtMgBr in THF. The catalyst (10 mol %) was mixed with a
solution of reagent A prior to the addition of benzaldehyde.
Although good yields were obtained, negligible enantioselectivity
was realized in all the cases.
One of the difficulties in handling the zinc halides is their hygro-
scopic nature. We decided to use zinc acetate which is nonhygro-
scopic and can be a good alternative to zinc halides. The reagent
EtZnOAcꢀMg(OAc)Br (B) was prepared by the transmetallation of
EtMgBr with zinc acetate18 (Eq. 2) in THF. The reagent B was first re-
acted with benzaldehyde without any additive. It revealed a reactiv-
ity pattern similar to that of A. In the presence of chiral chelating
agent 1, racemic 1-phenyl-1-propanol was obtained in 18% yield
(Table 1, entry 2). Interestingly, the reaction of B in the presence
of lithium-TADDOLate 4 provided 31% yield with 13% ee. The corre-
sponding magnesium-TADDOLate 5 furnished 34% yield with 28%
ee. Our attempts to isolate the reagent B were unsuccessful. To ver-
ify the formation of EtZnOAc from EtMgBr and Zn(OAc)2, we pre-
pared magnesium-free EtZnOAc (C) from diethylzinc and zinc
acetate following the literature procedure19 (Eq. 3). The reagent C
was then reacted with benzaldehyde in the presence of stoichiom-
etric amount of Mg(OAc)Br20 (Eq. 4).
Enantioselective addition of EtZnOAcꢀMg(OAc)Br to benzaldehyde
OH
catalyst (10 mol%)
EtZnOAc.Mg(OAc)Br + PhCHO
Ph
(S)
7a
eec (%)
Entry
Catalyst
Solventa
Temp (°C)
Time (h)
Yieldb (%)
1
2
3
4
None
THF
THF
THF
THF
THF
THF
MTBE
MTBE
Et2O
MTBE
MTBE
0
0
0
0
0
0
0
25
25
25
25
4
8
8
8
8
8
8
24
24
24
24
29
18
31
34
37
22
44
60
54
45
49
—
—
1
4
5
5
5
5
5
5
3
6
13
28
18
21
50
39
38
<5
<1
5d
6e
7
8
9
10
11
a
b
c
The reactions were carried out at 0.4–0.5 molar concentrations.
Isolated yields of the product.
Determined by comparison of optical rotation with known literature value or
chiral GC/HPLC analysis.
d
One equivalent of 1,4-dioxane was added.
One equivalent of TMEDA was added.
e
attributed to MgX2-promoted background reaction.21 To overcome
this problem, we added complexing agents like 1,4-dioxane or
TMEDA. However, this modification proved inconsequential (en-
tries 5 and 6). By changing the solvent from THF to methyl tert-bu-
tyl ether (MTBE), enantioselectivity increased to 50% (entry 7).
When the reaction was carried out at room temperature, the prod-
uct was isolated in 60% yield but the enantioselectivity was
dropped to 39% (entry 8). Similar results were obtained when
diethyl ether was used as the solvent (entry 9). Other dimagne-
sium-alkoxides (3 and 6) proved inferior to TADDOL (entries 10
and 11).
At this stage we are unable to provide a precise model which
explains the outcome of stereoselectivity using reagent B. However
we presume that the oxygen atoms of the metal alkoxide, EtZ-
n(OAc), BrMg(OAc), and PhCHO bind as depicted in Figure 2. The
resulting cyclic transition state could be responsible for stereose-
lection. This would also explain the lack of enantioselectivity with
the reagent A, which proceeds through MgX2-catalyzed acyclic
pathway.
i) Mg(OAc)Br (1 equiv)
OH
C
Ph
ii) 5 (10 mol%)
iii) PhCHO, THF
(S)
ð4Þ
ð5Þ
7a
33% yield, 25% ee
i) 5 (10 mol%)
C
no reaction
ii) PhCHO, THF
These results were comparable to the ones realized with the re-
agent B. We also found that the presence of MgX2 was crucial. For
example, C in the presence of 10 mol % of 5 failed to provide the
product (Eq. 5). One of the reasons for moderate selectivity was
Heterogeneous reaction mixtures result in the use of solvents
other than THF. After extensive optimization, it was found that
by adding the Grignard reagent to a suspension of zinc acetate
and (ꢁ)-TADDOL in THF, a homogenous solution was obtained at
OH
catalyst (10 mol%)
THF, 0 oC, 8 h
EtZnCl Mg(Br)Cl
catalysts:
PhCHO
+
Ph
O
Br
M
O
Ph
Ph
Ph
Ph
OAc
Ph
Ph
O
Ph
Ph
OM
OM
O
Mg
O
O
O
OM
OM
Ph Ph
OMgBr
OMgBr
Zn
N
Me
O
O
O
M
H
Et
Ph
Ph
Ph
M = Li
2
M = Li
4
5
6
1
M = MgBr
Figure 2. Proposed mechanism for enantioselective alkylation.
= MgBr 3
= MgBr
Scheme 1. Addition of EtZnClꢀMg(Br)Cl to benzaldehyde.

R. S. Jagtap, N. N. Joshi / Tetrahedron Letters 52 (2011) 6501–6503
6503
Table 2
Org. Chem. 2002, 3221; (d) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B.
Chem. Rev. 2003, 103, 977; (e) Cozzi, P. G.; Mignogna, A.; Zoli, L. Pure Appl. Chem.
2008, 80, 891.
Enantioselective addition of various RZnOAcꢀMg(OAc)X to benzaldehyde
OH
(S)
5. (a) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757; (b) Binder, C. M.; Singaram, B.
Org. Prep. Proced. Int. 2011, 43, 139.
6. Review: Lemire, A.; Cote, A.; Janes, M. K.; Charette, A. B. Aldrichim. Acta 2009,
42, 71.
PhCHO, THF
RMgX
+
Zn(OAc)2
+
(-)-TADDOL
Ph
R
7. (a) Srebnik, M. Tetrahedron Lett. 1991, 32, 2449; (b) Oppolzer, W.; Radinov, R. N.
Helv. Chim. Acta 1992, 75, 170; (c) Oppolzer, W.; Radinov, R. N. J. Am. Chem. Soc.
1993, 115, 1593; (d) Schwink, L.; Knochel, P. Tetrahedron Lett. 1994, 35, 9007;
(e) Langer, F.; Schwink, L.; Devasagayaraj, A.; Chavant, P.-Y.; Knochel, P. J. Org.
Chem. 1996, 61, 8229; (f) Chen, Y. K.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc.
2002, 124, 12225; (g) Hupe, E.; Calaza, M. I.; Knochel, P. J. Organomet. Chem.
2003, 680, 136; (h) Bolm, C.; Rudolph, J. J. Am. Chem. Soc. 2002, 124, 14850; (i)
Paixao, M. W.; Braga, A. L.; Ludtke, D. S. J. Braz. Chem. Soc. 2008, 19, 813.
8. (a) Rozema, M. J.; Sidduri, A.; Knochel, P. J. Org. Chem. 1992, 57, 1956; (b)
Rozema, M. J.; Eisenberg, C.; Lutjens, H.; Ostwald, R.; Belyk, K.; Knochel, P.
Tetrahedron Lett. 1993, 34, 3115; (c) Kneisel, F. F.; Dochnahl, M.; Knochel, P.
Angew. Chem., Int. Ed. 2004, 43, 1017; (d) DeBerardinis, A. M.; Turlington, M.;
Pu, L. Org. Lett. 2008, 10, 2709.
9. (a) Seebach, D.; Behrendt, L.; Felix, D. Angew. Chem., Int. Ed. Engl. 1991, 30, 1008;
(b) Bussche-hunnefeld, J. L. V. D.; Seebach, D. Tetrahedron 1992, 48, 5719; (c)
Cote, A.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 2771; (d) Kim, J. G.; Walsh,
P. J. Angew. Chem., Int. Ed. 2006, 45, 4175; (e) Salvi, L.; Kim, J. G.; Walsh, P. J. J.
Am. Chem. Soc. 2009, 131, 12483.
10. Review: Hargrave, J. D.; Allen, J. C.; Frost, C. G. Chem. Asian J. 2010, 5, 386.
11. (a) Glorius, F. Angew. Chem., Int. Ed. 2008, 47, 8347; (b) Son, S.; Fu, G. C. J. Am.
Chem. Soc. 2008, 130, 2756; (c) Lundin, P. M.; Esquivias, J.; Fu, G. C. Angew.
Chem., Int. Ed. 2009, 48, 154.
7a, R = Et
7b, R = Bu
7c, R = iBu
Entry
RMgXa
Temp (°C)
Time (h)
Product
Yieldb (%)
eec (%)
1
EtMgBr
EtMgBr
EtMgBr
BuMgCl
BuMgBr
BuMgI
0
0
0
0
0
0
0
8
24
4
8
4
7a
7a
7a
7b
7b
7b
7c
30
18
60
5
17
44
5
40
36
8
2d
3e
4
0
5
13
50
16
6f
7
4
8
iBuMgBr
a
The stoichiometric ratio of RMgX/Zn(OAc)2:(ꢁ)-TADDOL/PhCHO was
1.7:1.5:0.1:1.0, respectively, unless otherwise noted.
b
Isolated yields of the desired product.
Ee was determined by chiral GC or HPLC analysis.
0.8 equiv EtMgBr was added with respect to Zn(OAc)2.
1.2 equiv EtMgBr was added with respect to Zn(OAc)2.
c
d
e
f
The reaction was carried out in THF/Et2O.
12. (a) Shannon, J.; Bernier, D.; Rawson, D.; Woodward, S. Chem. Commun. 2007,
3945; (b) Glynn, D.; Shannon, J.; Woodward, S. Chem. Eur. J. 2010, 16, 1053.
13. (a) Tamaru, Y.; Nakamura, T.; Sakaguchi, M.; Ochiai, H.; Yoshida, Z. J. Chem. Soc.,
Chem. Commun. 1988, 610; (b) Kondo, Y.; Takazawa, N.; Yamazaki, C.;
Sakamoto, T. J. Org. Chem. 1994, 59, 4717; (c) Ito, T.; Ishino, Y.; Mizuno, T.;
Ishikawa, A.; Kobayashi, J. Synlett 2002, 2116.
14. The complexes of RZnX with bidentate ligands: (a) Boersma, J.; Noltes, J. G.
Tetrahedron Lett. 1966, 1521; (b) Andrews, P. C.; Raston, C. L.; Skelton, B. W.;
White, A. H. Organometallics 1998, 17, 779; (c) Cheng, M.-L.; Li, H.-X.; Liu, L.-L.;
Wang, H.-H.; Zhang, Y.; Lang, J.-P. Dalton Trans. 2009, 2012.
15. (a) Nutzel, K. In Methoden der Organischen Chemie; Muller, E., Ed.; Georg Thieme
Velag: Stutgart, 1973; Vol. 13/2a, p 552; (b) Berman, A. M.; Johnson, J. S. J. Am.
Chem. Soc. 2004, 126, 5680; (c) Malosh, C. F.; Ready, J. M. J. Am. Chem. Soc. 2004,
126, 10240; (d) Hevia, E.; Chua, J. Z.; Garcia-Alvarez, P.; Kennedy, A. R.; McCall,
M. D. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 5294.
0 °C. This reagent was then reacted with benzaldehyde to obtain
30% yield of the product with 40% ee (Table 2, entry 1). We also
studied the effect of stoichiometry of Grignard with respect to zinc
acetate. It was found that the rate of the reaction as well as enanti-
oselectivity varied with the change in stiochiometry. Best results
were obtained when the ratio was 1:1 (entries 1–3). In terms of ha-
lide effect in RMgX, bromide and iodide were found to be better
than chloride (entries 4–6). We also examined other Grignard re-
agents under these conditions. n-Butyl and iso-butyl magnesium
bromide provided 13% and 16% enantioselectivity, respectively,
16. (a) Byrne, B.; Karras, M. Tetrahedron Lett. 1987, 28, 769; (b) Kloetzing, R. J.;
Krasovskiy, A.; Knochel, P. Chem. Eur. J. 2007, 13, 215.
t
(entries 5 and 7). In the case of BuMgCl, no reaction took place
at all.
17. Use of chiral metal-alkoxides in asymmetric synthesis: (a) Noyori, R.; Suga, S.;
Kawai, K.; Okada, S.; Kitamura, M. Pure Appl. Chem. 1988, 60, 1597; (b) Sasai, H.;
Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1992, 114, 4418; (c)
Belokon, Y. N.; Kochetkov, K. A.; Churkina, T. D.; Ikonnikov, N. S.; Orlova, S. A.;
Smirnov, V. V.; Chesnokov, A. A. Mendeleev Commun. 1997, 7, 137; (d) Ward, D.
E.; Souweha, M. S. Org. Lett. 2005, 7, 3533; (e) Ichibakase, T.; Orito, Y.;
Nakajima, M. Tetrahedron Lett. 2008, 49, 4427; (f) Prasad, K. R. K.; Joshi, N. N.
Tetrahedron: Asymmetry 1996, 7, 1957; (g) Weber, B.; Seebach, D. Tetrahedron
1994, 50, 6117; (h) Hatano, M.; Horibe, T.; Ishihara, K. Org. Lett. 2010, 12, 3502.
18. Transmetallation of RMgX with ZnX2 (X = OMe, OAc, etc.) is reported; for
example, see Ref. 9c.
In conclusion, we have found that alkylzinc carboxylates can be
used as alkylating agent in enantioselective 1,2-addition to benzal-
dehyde.22 These reagents can be attractive alternates to diorgano-
zinc. Detailed study is underway to broaden the scope of the
finding.
Acknowledgments
19. Orchard, K. L.; Harris, J. E.; White, A. J. P.; Shaffer, M. S. P.; Williams, C. K.
Organometallics 2011, 30, 2223.
20. Mg(OAc)Br was prepared by the reaction of EtMgBr with AcOH.
21. Metzger, A.; Bernhardt, S.; Manolikakes, G.; Knochel, P. Angew. Chem., Int. Ed.
2010, 49, 4665.
Financial support for this work was provided by Department of
Science and Technology, New Delhi. One of us (R.S.J.) thanks CSIR,
New Delhi, for a research scholarship. We are thankful to Dr. S.
Borikar for chiral GC-analysis.
22. General procedure for enantioselective addition of RZnOAcꢀMg(OAc)Br to
benzaldehyde: Anhydrous Zn(OAc)2 1.1 g (6 mmol) and (ꢁ)-TADDOL 0.186 g
(0.4 mmol) were suspended in anhydrous THF (5 mL). The mixture was cooled
to 0 °C and treated dropwise with RMgBr (6.8 mmol, 6.8 mL of 1 M solution in
THF). The reaction mixture was stirred for the next 1 h resulting in a clear
solution. Benzaldehyde 0.4 mL (4 mmol) was then added, and the mixture
stirred for the time indicated in Table 2. The reaction was cautiously quenched
with MeOH (1 mL), diluted with EtOAc (20 mL), washed with saturated NH4Cl
solution, and dried over anhydrous Na2SO4. Evaporation of the solvent
followed by Kugelrohr distillation provided the product contaminated with
benzyl alcohol and unreacted benzaldehyde. It was purified by ‘flash
chromatography’ to obtain the desired compound. The residue in the
distillation flask was triturated with hexane and crystallized from MeOH to
recover TADDOL.
References and notes
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