Enantioselective additions of diphenylzinc to aldehydes using chiral pyrrolidinylmethanol derivatives as catalysts

Article abstract of DOI:10.1016/S0957-4166(01)00074-X

The enantioselective addition of diphenylzinc to aldehydes using a series of chiral ligands derived from (S)-proline afforded secondary alcohols in high yields and with high enantiomeric excesses of up to 92.6%. The configuration of the secondary alcohol enantiomer obtained was found to be dependent on the catalyst used.

Full text of DOI:10.1016/S0957-4166(01)00074-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 399–403
Enantioselective additions of diphenylzinc to aldehydes using
chiral pyrrolidinylmethanol derivatives as catalysts
Gang Zhao,a,* Xiang-Guo Lib and Xiu-Ran Wangb
aShanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 FengLin Lu, 200032 Shanghai, China
bAnhui Normal University, Institute of Organic Chemistry, Anhui, China
Received 15 December 2000; accepted 5 February 2001
Abstract—The enantioselective addition of diphenylzinc to aldehydes using a series of chiral ligands derived from (S)-proline
afforded secondary alcohols in high yields and with high enantiomeric excesses of up to 92.6%. The configuration of the secondary
alcohol enantiomer obtained was found to be dependent on the catalyst used. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
using 1a as a chiral catalyst.12 We recently investigated
the use of sulfonyl (S)-prolinols as chiral catalysts to
reduce aromatic ketones to the corresponding alcohols
in high yields and with good enantioselectivities.7
Herein, we report the use of the prolinol derivatives
1a–1l (Scheme 1) as catalysts in the enantioselective
addition of diphenylzinc to aldehydes.
The catalytic enantioselective addition of dialkylzinc
reagents (ZnR2, where R=methyl, ethyl and isopropyl)
to aldehydes has been studied extensively in recent
years1 and dialkylzinc reagents have been used employ-
ing a variety of chiral ligands to yield the corresponding
secondary alcohols with high enantioselectivity.1,2 Few
asymmetric diarylzinc additions to aldehydes have been
reported,3–5 because the uncatalysed diphenylzinc addi-
tion can compete with the catalysed reaction. The
development of an enantioselective catalyst for diaryl-
zinc addition is therefore much more challenging than
the equivalent dialkylzinc reactions.
2. Results and discussion
2.1. Effect of solvent and temperature on the
asymmetric reaction
Soai et al. initially developed the enantioselective
phenylation of prochiral aldehydes using a kinetically
formed chiral complex between a phenyl Grignard
reagent, a zinc halide and N,N-dibutylnorephedrine.6 In
1997, Fu et al. reported the first enantioselective pheny-
lation of aldehydes using a catalyst based on a planar
chiral ligand.3 Recently, Pu et al. presented the highly
enantioselective phenylation reaction with chiral 1,1%-
binaphthol based monomeric and polymeric catalysts.4
Bolm et al. also reported good enantioselectivity in a
reaction using a chiral ferrocenyl hydroxyoxazoline cat-
alyst,5 while Soai et al. recently reported the enantio-
selective addition of dialkylzinc reagents to aldehydes
We first investigated the effect of solvent and reaction
temperature on the catalytic addition of ZnPh2 to p-
chlorobenzaldehyde using 10 mol% of catalyst 1a. The
results are summarised in Table 1. In this study, obvi-
ous solvent effects were observed. The highest enan-
tioselectivity of 89.1% was obtained by employing
toluene solvent at −30°C (entry 4). When reactions were
carried out in hexane, ether, THF or CH2Cl2, the
enantioselectivity was poor. This could be a result of
the strong coordinating ability of THF and Et2O to the
active catalyst complex. It is unclear why poor enantio-
selectivity is seen in the hexane and CH2Cl2 solvated
reactions.
The best result was achieved at a reaction temperature
of −30°C. Using the same conditions but at room
temperature, the reaction was complete within 30 min-
utes but afforded a product with lower e.e. (entry 6).
* Corresponding author. Fax: 86 21 64166128; e-mail: zhaog@
pub.sioc.ac.cn
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00074-X

400
G. Zhao et al. / Tetrahedron: Asymmetry 12 (2001) 399–403
Scheme 1.
2.2. Chiral catalysts and the amount of catalysts
We investigated the effect of catalyst loading on the
reaction. From this it was found that the optimum
amount was 15–20 mol%.
Based on the above optimum reaction conditions, we
chose p-chlorobenzaldehyde as the substrate to examine
the effect of various catalysts. The results are listed in
Table 2. All catalysts gave good yields. However, the
e.e. varied from 92.6 to 6.1%. Moreover, the absolute
configuration of the product was found to change on
employing different catalysts. The sulfonyl (S)-prolinols
It is noteworthy that the catalyst is very stable and was
recovered from the reactions in more than 90% yield
and re-used in the same reaction without any loss of
1
yield or e.e. The H NMR spectra and specific rotation
of the recovered catalyst proved that it was unchanged
after the reaction. Of the catalysts examined, catalysts
1a, 1e and 1h gave the highest enantioselectivities
(entries 3, 8 and 14).
1h–1l
gave
(R)-(p-chlorophenyl)phenylmethanols
(entries 11–19) and, interestingly, though chiral ligands
1a–1g have similar structures, they afforded products
with different absolute configuration. A similar trend
was observed by Wang8 using b-amino alcohols with
different a-substituents as chiral catalysts in the reac-
tion of diethylzinc additions to aldehydes. A tentative
mechanism proposed by Soai et al. could explain the
stereochemical course of the addition reaction.12
2.3. Enantioselective addition of various aldehydes using
catalysts 1a, 1e or 1h
We applied catalysts 1a, 1e and 1h to the additions of
various aldehydes, and the results are shown in Table 3.

G. Zhao et al. / Tetrahedron: Asymmetry 12 (2001) 399–403
401
Table 1. The effect of solvents and temperature on asymmetric addition of ZnPh2 to p-chlorobenzaldehyde
Entry
Solvent
Temp. (°C)
Time (h)
Yield (%)a
E.e. (%)b
Config.c
1
2
3
4
5
6
7
8
9
Hexane
Hexane
Toluene
Toluene
Toluene
Toluene
Toluene:hexane (v/v=1:1)
Ether
THF
−78 to 0
−30
−78 to 0
−30
0
15
9
16
8
4
0.5
8
7.5
9
7
92
98
99
95
96
92
98
94
96
97
5.0
24.3
81.4
89.1
83.1
11.2
72.5
0.9
S
S
S
S
S
S
S
S
–
Rt
−30
−30
−30
−30
0.0
3.1
10
CH2Cl2
S
a Yield of isolated pure product.
b E.e. was determined by HPLC with Chiralcel AD, with 10% 2-propanol in hexane as eluent.
c Configuration of products was established on the basis of the sign of the specific rotation.4b
Table 2. Chiral catalysts and the amount of catalysts
Entry
Catalysts
Mol %a
Time (h)
Yield (%)b
E.e. (%)c
Config.d
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1c
1d
1e
1f
1g
1h
1h
1h
1h
1h
1i
5
10
15
20
15
20
20
20
20
20
5
10
15
20
25
20
20
20
20
8
8
10
9
10
9
8
8
13
8
9
8
10
9
8
8
8
91
95
96
93
97
95
91
93
93
97
93
92
95
95
93
93
91
92
93
87.8
89.1
92.6
92.1
70.3
64.4
36.6
70.6
6.1
S
S
S
S
S
S
S
R
R
R
R
R
R
R
R
R
R
R
R
9
10
11
12
13
14
15
16
17
18
19
9.5
39.0
46.2
71.2
83.5
68.1
21.8
11.3
65.7
32.9
1j
1k
1l
7
9
a Molar ratio to p-chlorobenzaldehyde.
b Isolated yields.
c E.e. was determined by HPLC with a Chiralcel AD column, with 10% 2-propanol in hexane as eluent.
d Configuration of products was established on the basis of the sign of the specific rotation.4b
For the examined aryl aldehydes, the catalysts 1a, 1e
and 1h gave moderate to good e.e. and high chemical
yields. Generally, higher selectivities were seen with
para-substituted aryl aldehydes rather than their ortho-
and meta-substituted analogues, which is probably a
result of steric hindrance effects.
diphenylzinc to various benzaldehydes. Other ligands
have been developed in our group and will be reported
in detail soon.
3. Experimental
The absolute configuration of the product varied with
the catalyst employed. The (S)-configured products
resulted from reactions catalysed by 1a. In contrast, the
absolute configuration of products from reactions
catalysed by 1e and 1h was found to be (R). The
exception to this was the substrate m-Cl-C6H4CHO,
where the same absolute configuration of product was
observed irrespective of the catalyst used (runs 8, 19
and 30).
3.1. General methods
All reactions were carried out under a nitrogen atmo-
sphere with dry, freshly distilled solvents under anhy-
drous conditions. All solvents were purified according
to standard methods. Aldehydes were purchased from
Aldrich Ltd.
Catalysts 1h–1l were synthesised by our method.7 Cata-
lysts 1a and 1e were synthesised according to the litera-
ture.12,13 The synthesis of the other catalysts was similar
to the reported methods.12,13 Diphenylzinc was pre-
In conclusion, we have applied a series of chiral ligands
derived from (S)-proline to the asymmetric addition of

402
G. Zhao et al. / Tetrahedron: Asymmetry 12 (2001) 399–403
Table 3. Asymmetric addition of aldehydes using catalysts
1a, 1e and 1h
pared according to the literature,14 as a 0.5 M solution
in toluene as determined by titration.15
R1
R1
3.1.1. Preparation of 1b. PhMgBr (1 mmol) in ether
(11 mL) was added dropwise to a solution of (S)-1-
(2,4,6-trimethyl)benzenemethyl-proline ethyl ester (5
mmol) in ether (10 mL) at room temperature. The
mixture was stirred under reflux for 4 h and cooled to
0°C. The reaction was quenched with saturated
aqueous ammonium chloride, the organic layer was
separated and the aqueous extracted with ether (3×5
mL). The combined organic extract was dried over
Na2SO4, and the solvent was removed under reduced
pressure. The residue was purified by flash chromatog-
raphy over silica gel to provide 1b as a white solid (1.6
OH
N
OH
O
R2
*
+
Ph2Zn
R
Ph
R
H
Run
R
Yield (%)a
% E.e. (config.)b
Cat. 1a (15 mol%)
1
2
3
4
5
6
7
8
4-Cl-C6H4
4-Br-C6H4
2-Naphthyl
4-Me-C6H4
2-Cl-C6H4
trans-PhCHꢀCH 93
i-Pr
3-Cl-C6H4
4-CH3O-C6H4
4-F-C6H4
4-NO2-C6H4
96
94
93
94
99
92.6 (S)c
50.2 (S)c
60.5 (S)d
79.8 (S)e
15.2 (S)f
7.4 (R)d
56.8 (R)g
53.7 (R)h
92.2 (S)e
90.5 (S)i
81.8 (S)j
1
g, 84%): [h]2D0=−7.1 (c=1.39, CHCl3). H NMR (300
MHz, CDCl3): l 1.5–2.0 (4H, m), 2.1 (6H, s), 2.2 (3H,
s), 2.4 (m, 1H), 2.6 (m, 1H), 3.1, 3.4 (2H, AB-system,
J=12.2 Hz), 4.0 (1H, m), 4.9 (1H, br s), 6.7 (2H, s),
7.1–7.9 (10H, m). IR (KBr): 3401, 1613, 1491, 1368
cm−1. Anal. calcd for C27H31NO: C, 84.11; H, 8.10; N,
3.63. Found: C, 83.63; H, 8.45; N, 3.66%. MS (m/z):
384 (M+−1, 3), 368 (1), 202 (47), 133 (100), 77 (11).
94
92
95
93
94
9
10
11
Cat. 1e (20 mol%)
12
13
14
15
16
17
18
19
20
21
22
4-Cl-C6H4
4-Br-C6H4
2-Naphthyl
4-Me-C6H4
2-Cl-C6H4
trans-PhCHꢀCH 90
i-Pr
3-Cl-C6H4
4-CH3O-C6H4
4-F-C6H4
4-NO2-C6H4
95
96
91
91
97
70.6 (R)c
71.5 (R)c
43.9 (R)d
87.6 (R)e
13.2 (R)f
4.2 (S)d
3.1.2. Preparation of 1c. Prepared analogously to 1b
in 70% yield: white solid, [h]2D0=+47.6 (c 0.98,
1
CHCl3). H NMR (300 MHz, CDCl3): l 1.5 (2H, m),
1.7 (1H, m), 2.0 (1H, m), 2.2 (1H, m), 2.6 (1H, m),
4.1, 4.5 (2H, AB-system, J=12.5 Hz), 4.3 (1H, q,
J=4.9), 4.9 (1H, br s), 7.0–8.2 (18H, m), 8.3 (1H, s); IR
(KBr): 3371, 1624, 1523, 1490, 1340 cm−1. Anal. calcd
for C32H29NO: C, 86.64; H, 6.59; N, 3.16. Found: C,
86.42; H, 6.39; N, 3.20%. MS (m/z): 443 (M+, 0.35),
260 (15), 191 (100), 77 (6).
92
91
98
96
94
6.5 (S)g
7.9 (R)h
19.6 (R)e
71.8 (R)i
71.3 (R)j
Cat. 1h (20 mol%)
23
24
25
26
27
28
29
30
31
32
33
4-Cl-C6H4
4-Br-C6H4
2-Naphthyl
4-Me-C6H4
2-Cl-C6H4
trans-PhCHꢀCH 91
i-Pr
3-Cl-C6H4
4-CH3O-C6H4
4-F-C6H4
4-NO2-C6H4
95
97
90
91
93
83.5 (R)c
75.1 (R)c
45.9 (R)d
69.1 (R)e
8.5 (R)f
3.1.3. Preparation of 1d. Prepared by
a similar
method to the literature,12 yield 80%, white solid,
[h]2D0=+41.0 (c 1.75, CHCl3). 1H NMR (300 MHz,
CDCl3): l 1.6–1.8 (4H, m), 1.7 (3H, s) 2.4 (1H, m),
3.1 (1H, m), 3.5 (1H, m), 4.8 (1H, br s), 6.9–7.6 (8H,
m). 19F NMR (300 MHz, CDCl3): l –40.2 (1F, s),
−39.8 (1F, s). IR (KBr): 3315, 1601, 1502, 1373, 1156
cm−1. Anal. calcd for C18H19F2NO: C, 71.27; H, 6.31;
N, 4.62. Found: C, 71.22; H, 6.36; N, 4.60%. MS
(m/z): 304 (M++1, 14), 286 (10), 201 (1), 123 (6), 84
(100).
2.6 (S)d
93
92
91
95
93
6.9 (S)g
10.9 (R)h
48.2 (R)e
55.4 (R)i
65.0 (R)j
a Isolated yields.
b The absolute configuration was determined on the basis of the sign
of the specific rotation.4b,9–11
c Determined by Chiralcel AD column, 10% 2-propanol in hexane as
3.1.4. Preparation of 1f. Similar to the preparation of
1b, yield 72%, colourless oil, [h]2D0=−3.0 (c 1.40,
CHCl3). 1H NMR (300 MHz, CDCl3): l 1.1 (3H, s), 1.2
(3H, s), 1.6–1.9 (4H, m), 2.2 (3H, s), 2.4 (6H, s), 2.4–2.7
(4H, m), 3.7, 3.9 (2H, AB-system, J=12.5 Hz), 6.8 (2H,
s). IR (KBr): 3457, 1614, 1579, 1463, 1375 cm−1. Anal.
calcd for C17H27NO: C, 78.11; H, 10.41; N, 5.36.
Found: C, 77.92; H, 10.60; N, 5.22%. MS (m/z): 260
(M+−1, 34), 244 (5), 202 (79), 133 (100), 59 (7).
eluent.
d Determined by Chiralcel OD column, 10% 2-propanol in hexane as
eluent.
e Determined by Chiralcel OJ column, 20% 2-propanol in hexane as
eluent.
f Determined by Chiralcel OD column, 20% 2-propanol in hexane as
eluent.
g Determined by Chiralcel AS column, 5% 2-propanol in hexane as
eluent.
h Determined by Chiralcel OD column, 9% 2-propanol in hexane as
eluent.
i Determined by Chiralcel OB-H column, 20% 2-propanol in hexane
3.1.5. Preparation of 1g. A solution of (S)-1-(2,4,6-
trimethyl)benzenemethyl-proline ethyl ester (2 mmol)
in THF (4 mL) was dropped carefully into a mixture
as eluent.
j Determined by Chiralcel AD column, 20% 2-propanol in hexane as
eluent.

G. Zhao et al. / Tetrahedron: Asymmetry 12 (2001) 399–403
403
of LiAlH4 (2.5 mmol) in THF (4 mL) at room temper-
Acknowledgements
ature. After addition, the mixture was stirred under
reflux until the reaction was complete, then cooled to
0°C. Ethyl acetate (2 mL) and water (2 mL) were added
to the mixture slowly. The mixture was extracted with
ether (3×3 mL). The combined organic layer was dried
and evaporated. The residue was purified by flash chro-
matography to provide 1g as a white solid (350 mg,
75%): [h]2D0=−12.3 (c 1.68, CHCl3). 1H NMR (300
MHz, CDCl3): l 1.5–2.1 (4H, m), 2.2 (3H, s), 2.3 (6H,
s), 2.4–2.6 (2H, m), 2.7 (1H, m), 2.9 (1H, m), 3.4, 3.9
(2H, AB-system, J=11.6 Hz), 3.55 (2H, m), 6.85 (2H,
s); IR (KBr): 3431, 1612, 1578, 1461, 1374 cm−1. Anal.
calcd for C15H23NO: C, 77.21; H, 9.93; N, 6.00. Found:
C, 77.00; H, 10.04; N, 5.81%. MS (m/z): 233 (M+,
0.35), 202 (35), 133 (100), 117 (7), 91 (6).
We thank Mrs. Zuo-ding Ding for carrying out the
chiral HPLC analysis for us.
References
1. Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833.
2. Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl.
1991, 30, 49.
3. Dosa, P. I.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1997,
62, 444.
4. (a) Huang, W. S.; Pu, L. J. Org. Chem. 1999, 64, 4222;
(b) Huang, W. S.; Hu, Q. S.; Pu, L. J. Org. Chem. 1999,
64, 7940; (c) Huang, W. S.; Pu, L. Tetrahedron Lett.
2000, 41, 145.
5. Bolm, C.; Muniz, K. Chem. Commun. 1999, 1295.
6. Soai, K.; Kawase, Y.; Oshio, A. J. Chem. Soc., Perkin
Trans. 1 1991, 1613.
3.2. Typical procedure for asymmetric addition of Ph2Zn
to aldehyde
7. Yang, G. S.; Hu, J. B.; Zhao, G.; Ding, Y.; Tang, M. H.
To a solution of chiral ligand 1a (0.15 mmol) in toluene
(7.5 mL) was added dropwise a solution of Ph2Zn (0.5
M in toluene, 4 mL) at −30°C. After stirring for 1 h,
p-chlorobenzaldehyde (140.5 mg, 1 mmol) in toluene (2
mL) was added at a rate of 5 mL/h by syringe pump at
−30°C. The reaction was monitored by TLC. When the
reaction was complete, the mixture was quenched by
addition of 1N aqueous HCl and the mixture was
extracted with ethyl acetate (3×3 mL), the combined
organic extracts were washed with brine (5 mL), dried
over Na2SO4 and evaporated under reduced pressure.
The residue was purified by flash column chromatogra-
phy to give (p-chlorophenyl)phenylmethanol (210 mg,
96%) as a white solid. The e.e. was 92.6% (chiral AD
column, 10% 2-propanol in hexane as eluent). Catalyst
was recovered (36.4 mg, 91%).
Tetrahedron: Asymmetry 1999, 10, 4307.
8. Yang, X.; Shen, J.; Da, C.; Wang, R.; Choi, M. C. K.;
Yang, L. W.; Wong, K. Y. Tetrahedron: Asymmetry 1999,
10, 133.
9. Weber, B.; Seebach, D. Tetrahedron 1994, 50, 7473.
10. Wu, B.; Mosher, H. S. J. Org. Chem. 1986, 51, 1904.
11. Wang, J. T.; Fan, X.; Feng, X.; Li, Y. Chem. Res. Chin.
Univ. 1993, 9, 28.
12. Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J. Am.
Chem. Soc. 1987, 109, 7111.
13. Enders, D.; Kipphardt, H.; Gerdes, P.; Brenavalle, L. J.
Bull. Soc. Chim. Belg. 1988, 97, 691.
14. Synthetic Methods of Organometallic and Inorganic
Chemistry; Herrmann, W. A., Ed.; Georg Thieme Verlag:
Stuttgart, New York, 1999; Vol. 5, pp. 150–153.
15. Studlar, K.; Janousek, I. Talanta 1961, 8, 203.
.