Enantioselective addition of diethylzinc to aromatic aldehydes catalyzed by Ti(IV) complexes of C2-symmetrical chiral BINOL derivatives

Article abstract of DOI:10.1016/j.tetlet.2008.10.149

Enantioselective addition of diethylzinc to a series of aromatic aldehydes is developed using new chiral C₂-symmetric ligand (S)-2,2′-(1,1′-binaphthyl-2,2′-diylbis(oxy))bis(methyl ene)bis(4-nitrophenol) (S)-2b. The catalytic system employing 10 mol % of (S)-2b and 120 mol % of Ti(OiPr)₄ was found to promote the addition of diethylzinc to a wide range of aromatic aldehydes with electron-donating and electron-withdrawing substituents, giving up to 89% ee and up to 95% yield of the corresponding secondary alcohol under mild conditions.

Full text of DOI:10.1016/j.tetlet.2008.10.149

Tetrahedron Letters 50 (2009) 281–283
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Tetrahedron Letters
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Enantioselective addition of diethylzinc to aromatic aldehydes catalyzed
by Ti(IV) complexes of C2-symmetrical chiral BINOL derivatives
*
Shaohua Gou, Zaher M. A. Judeh
School of Chemical and Biomedical Engineering, Nanyang Technological University, 62 Nanyang Drive, N1.2 B1-14, Singapore 637459, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantioselective addition of diethylzinc to a series of aromatic aldehydes is developed using new chiral
C2-symmetric ligand (S)-2,20-(1,10-binaphthyl-2,20-diylbis(oxy))bis(methylene)bis(4-nitrophenol) (S)-2b.
The catalytic system employing 10 mol % of (S)-2b and 120 mol % of Ti(OiPr)4 was found to promote
the addition of diethylzinc to a wide range of aromatic aldehydes with electron-donating and electron-
withdrawing substituents, giving up to 89% ee and up to 95% yield of the corresponding secondary alco-
hol under mild conditions.
Received 24 September 2008
Revised 20 October 2008
Accepted 30 October 2008
Available online 5 November 2008
Keywords:
Aldehyde
Ó 2008 Elsevier Ltd. All rights reserved.
Alkylation
BINOL
Diethylzinc
Secondary alcohol
Ti(OiPr)4
Chiral core
Chiral C2-symmetric ligand
R1
Catalytic enantioselective carbon–carbon bond forming reac-
tions are extensively studied reactions in asymmetric synthesis1
The enantioselective alkylation of aldehydes with organozinc re-
agents has attracted much attention because of its simplicity and
utility for the preparation of chiral secondary alcohols, which are
key building blocks in the fine chemical and pharmaceutical indus-
tries.2 Various chiral catalysts based on amino alcohols, diols,
thiols, disulfides, diselenides, diamines, oxazaborolidines, bisoxaz-
olidines, sulfinamides, BINOLs, H4-BINOLs and H8-BINOLs have
been used successfully for the asymmetric addition of dialkylzinc
to aldehydes.3–8 However, studies on BINOLs have focused primar-
ily on the 3-monosubstituted- and the 3,30-disubstituted deriva-
tives. The rationale behind this design is to keep the 2- and
20-OH groups free for effective complexation with the dialkylzinc
and Ti(OiPr)4.6–8
R2
Br
R2
R2
2.2 equiv
R1
OH
OH
O
O
K2CO3, CH3CN, rt, 48 h
R1
S)-2a,b
(S)-1
2a: R1 = R2 = H
(
2b: R1 = NO2, R2 = OH
Scheme 1. Synthesis of chiral ligands (S)-2a,b from (S)-BINOL.
(2.2 equiv) in the presence of K2CO3 (4.4 equiv) in CH3CN at room
temperature for 48 h. These ligands are designed intentionally to
investigate the effect of expansion of the chirality and to determine
the significance of the hydrogens of the 2- and 20-OH groups. The
catalytic activity of these ligands was examined under typical con-
ditions10 for the addition of diethylzinc to aldehydes in the pres-
ence of Ti(OiPr)4 (Table 1). Titanium(IV) complexes with various
chiral ligands have been reported extensively as effective promot-
ers for the addition of diethylzinc to aldehydes. Preliminary studies
on the alkylation of benzaldehyde 3a using 10 mol % of (S)-2a and
120 mol % of Ti(OiPr)4 in dry toluene gave only traces of the corre-
sponding alcohol 4a (Table 1, entry 1). Fortunately, when the same
reaction was repeated using (S)-2b, secondary alcohol 4a was ob-
tained in 90% yield and in 67% ee. The complex (S)-2a–Ti(OiPr)4,
Herein, we report on the synthesis of new 2,20-disubstituted BI-
NOL ligands (Scheme 1), and examine their effectiveness and appli-
cation in the asymmetric additions of diethylzinc to various
aldehydes. The effect of expansion of the chirality of BINOL on
the enantioselectivity will be examined by incorporating substitu-
tion at the 2- and 20-positions.
Chiral ligands (S)-2a and (S)-2b were synthesized9 in good
yields by reacting (S)-BINOL with the appropriate benzyl bromide
* Corresponding author. Fax: +65 67947553.
E-mail address: zaher@ntu.edu.sg (Z. M. A. Judeh).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.149

282
S. Gou, Z. M. A. Judeh / Tetrahedron Letters 50 (2009) 281–283
Table 1
Table 2
Enantioselective addition of diethylzinc to benzaldehyde
Enantioselective addition of diethylzinc to various aromatic aldehydes catalyzed by
(S)-2b
OH
O
(
S
)-2b, Ti(O
i
Pr)4
10 mol% (
120 mol% Ti(O
CH2Cl2, 0 oC, 5 h
S
)-2b
Pr)4
OH
O
H
+
Et2Zn
i
H
solvent
+
Et2Zn
X
X
3a
4a
4a-s
Entrya
(S)-2
(mol %)
Ti(OiPr)4
(mol %)
Solvent
Temp
(°C)
Yieldb
(%)
eec
(%)
3a-s
Entrya
Aldehyde
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
2a (10)
2b (10)
2b (10)
2b (10)
2b (10)
2b (10)
2b (10)
2b (10)
2b (20)
2b (10)
2b (10)
120
120
140
100
120
120
120
120
120
120
120
PhCH3
PhCH3
PhCH3
PhCH3
CH2Cl2
THF
22
22
22
22
22
22
22
22
22
0
Trace
90
87
93
91
86
87
88
93
—
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
X = H (3a)
X = o-CH3 (3b)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4p
4n
90
84
88
92
87
89
77
73
80
71
70
93
88
92
76
87
84
76
81
77 (S)
73 (S)
67 (S)
68 (S)
83g
67
61
59
71
68
64
67
70
77d
74e
X = m-CH3 (3c)
X = p-CH3 (3d)
X = p-C2H5 (3e)
X = p-Ph (3f)
X = o-MeO (3g)
X = m-MeO (3h)
X = p-MeO (3i)
X = m-BnO (3j)
X = p-F (3k)
X = p-Cl (3l)
X = p-Br (3m)
X = p-I (3n)
X = p-F3C (3o)
X = o-I (3p)
X = m-I (3q)
67 (S)d
78 (S)
61 (S)e
79 (S)e
83 (S)e
79 (S)
84 (S)
69 (S)
82 (S)
64 (S)d
72g
Et2O
O
Hexane
CH2Cl2
CH2Cl2
CH2Cl2
H
X
10
11
90
81
ꢀ20
a
Reaction conditions: 0.25 M benzaldehyde, 3.0 equiv Et2Zn, 2–3 h.
Isolated yields.
Determined using a chiral GC G-TA column; the (S)-configuration was con-
b
c
firmed by comparison with the reported configuration.6f
d
Reaction time was 5 h.
Reaction time was 10 h.
82g
e
X = o-I (3p)
X = p-I (3n)
81f,g
89 (S)f
in which the ligand does not bear OH groups, did not catalyze the
reaction (Table 1, entry 1), whereas an excellent yield and moder-
ate enantioselectivity were obtained when the (S)-2b–Ti(OiPr)4
complex was employed (Table 1, entry 2). These results indicate
that the presence of a free OH, as in (S)-2b, is indispensable for cat-
alytic activity. Therefore, further reactions were performed using
ligand (S)-2b. Encouraged by the result in entry 2, we employed
(S)-2b to investigate the effect of various solvents and (S)-2b/
Ti(OiPr)4 loading on the yield and enantioselectivity of the prod-
ucts. An increase in the Ti(OiPr)4 loading from 120 to 140 mol % re-
sulted in a slight decrease in both the yield (to 87%) and the ee (to
61%) of 4a (Table 1, entry 3). A decrease in the Ti(OiPr)4 loading to
100 mol % resulted in a slight increase in the yield to 93% accompa-
nied by a drop in the ee to 59% (Table 1, entry 4). Next, a variety of
polar (THF, CH2Cl2 and Et2O) and non-polar (toluene, hexane) sol-
vents were screened. The reaction proceeded well in both polar
and non-polar solvents to give comparable yields and enantiose-
lectivities (Table 1, entries 2 and 5–8). The best yield and ee (91%
and 71%, respectively) were obtained when CH2Cl2 was used as sol-
vent (Table 1, entry 5). Subsequent reactions were carried out in
CH2Cl2 using 120 mol % of Ti(OiPr)4. An increase in (S)-2b loading
to 20 mol % had no significant effect on the yield or ee of 4a (Table
1, entry 9). A reduction in reaction temperature from 22 °C to 0 °C
led to an increase in both the yield and the ee (90% and 77%,
respectively) of 4a (Table 1, entry 10). A further reduction in tem-
perature from 0 °C to ꢀ20 °C gave a slight decrease in the yield and
the ee of 4a (Table 1, entry 11). Based on the above-mentioned re-
sults, the optimum conditions are 10 mol % of (S)-2b and 120 mol %
of Ti(OiPr)4 in CH2Cl2 at 0 °C.
To study the generality of the ligand (S)-2b for the enantioselec-
tive addition of diethylzinc to various aldehydes, a number of aro-
matic aldehydes having electron-donating (3b–j, 3r, and 3s) and
electron-withdrawing (3k–q) groups were examined under the
optimized conditions reported in Table 1. In comparison to the re-
sults obtained with 3a, the poor electron-donating substituents,
Me and Ph, led to a slight decrease in the ees of the products 3b–
d and 3f (Table 2, entries 2–4 and 6 vs entry 1), whereas the p-ethyl
group in 3e resulted in an increase in the ee of the product to 83%
(Table 2, entry 5 vs entry 1). Interestingly, the position of the sub-
stituent on the aromatic ring of 3b–d (Table 2, entries 2–4) had lit-
tle effect on the ee of 4b–d. In the case of stronger electron-
O
20
(3r)
(3s)
4r
4s
92
95
72 (S)e
75 (S)e
O
21
a
Reaction conditions: 10 mol % (S)-2b, 120 mol % Ti(OiPr)4, 3.0 equiv Et2Zn, 5 h,
0 °C.
b
c
Isolated yields.
The ee was determined using a chiral GC G-TA column. The configuration was
confirmed by comparison with literature data.4d,6f,k
d
The ee was determined by using a Chiral OJ-H column (Hex/IPA = 95/5).6f
The ee was determined by using a Chiral OD-H column (Hex/IPA = 95/5).4d,6f
e
f
Reaction performed at ꢀ20 °C for 10 h.
g
Configuration not determined.
donating substituents, X = MeO and BnO, lower yields but compa-
rable ees of 4g, 4h, and 4j (Table 2, entries 7–10 vs entry 1) were
observed, whereas the m-MeO substituent in 3h led to a decrease
in the ee of 4h to 61% (Table 2, entry 8). Electron-withdrawing
groups (F, Cl, Br, I, and CF3, Table 2, entries 11–17) showed varia-
tion in the yields, but no major differences in the ees of 4k–n
and 4p–q except for the strongly electron-withdrawing CF3 group
which led to a lower 64% ee for product 4o. When the reactions
in entries 14 and 15 (Table 2) were attempted at ꢀ20 °C, an in-
crease in the ee of 4p (81%) and 4n (89%) (Table 2, entries 18
and 19) was observed. Reaction of
a- and b-naphthaldehydes 3r
and 3s, respectively, resulted in excellent yields and good ees (Ta-
ble 2, entries 20 and 21). In general, very good yields and enanti-
oselectivities of the secondary alcohols 4a–s were obtained
(Table 2).
In summary, the substituted BINOL ligand (S)-2b, readily pre-
pared in one step from commercially available starting materials,
showed excellent catalytic activities and very good enantioselec-
tivities (up to 89%) in the asymmetric additions of diethylzinc to
various aldehydes in the presence of Ti(OiPr)4. The presence of free
OH groups on the chiral ligand is essential in delivering good cat-
alytic activity and high enantioselectivities. Further investigation
on the applications of these ligands for other asymmetric reactions
is ongoing.

S. Gou, Z. M. A. Judeh / Tetrahedron Letters 50 (2009) 281–283
283
7. (a) Brunel, J. M. Chem. Rev. 2005, 105, 857; (b) Chen, Y.; Yekta, S.; Yudin, A. K.
Chem. Rev. 2003, 103, 3155.
Acknowledgment
8. (a) Burguete, M. I.; Collado, M.; Escorihuela, J.; Luis, S. V. Angew. Chem., Int. Ed.
2007, 46, 9002; (b) Schmidt, B.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1991, 30,
1321.
We gratefully acknowledge the Nanyang Technological Univer-
sity for financial support (Grant No. RG27/07).
9. Synthesis of chiral ligand (S)-2b: 2-Bromomethyl-4-nitrophenol (508 mg,
2.2 mmol) was added to a stirred mixture of (S)-BINOL (286 mg, 1.0 mmol)
and K2CO3 (607 mg, 4.4 mmol) in CH3CN (10 mL) at room temperature, and the
resulting mixture was stirred for 48 h. The reaction mixture was diluted with
ethyl acetate (200 mL), washed with H2O (3 ꢁ 50 mL) and brine (2 ꢁ 30 mL).
The organic phase was dried over MgSO4, and evaporated to dryness under
vacuum pressure. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate, 1/1, v/v) to afford (S)-2b as a white
References and notes
1. Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New York, 1994.
2. Soai, K.; Shibata, T.. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, Germany, 1999; Vol. 2, pp 911–
922.
3. For comprehensive reviews, see: (a) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757;
(b) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833; (c) Noyori, R.; Kitamura, M.
Angew. Chem., Int. Ed. Engl 1991, 30, 49.
4. (a) Mori, M.; Nakai, T. Tetrahedron Lett. 1997, 38, 6233; (b) Zhang, F. Y.; Yip, C.
W.; Cao, R.; Chan, A. S. C. Tetrahedron: Asymmetry 1997, 8, 585; (c) Shen, X.;
Guo, H.; Ding, K. L. Tetrahedron: Asymmetry 2000, 11, 4321; (d) Zhang, F. Y.;
Chan, A. S. C. Tetrahedron: Asymmetry 1997, 8, 3651.
5. (a) Matsui, K.; Takizawa, S.; Sasai, H. J. Am. Chem. Soc. 2005, 127, 3680; (b)
Matsui, K.; Tanaka, K.; Horii, A.; Takizawa, S.; Sasai, H. Tetrahedron: Asymmetry
2006, 17, 578.
6. (a) Huang, Z.; Lai, H.; Qin, Y. J. Org. Chem. 2007, 72, 1373; (b) Xiao, F. Y.; Takuji,
H.; Guang, Y. Z. Tetrahedron: Asymmetry 2008, 19, 1670; (c) Yan, Q. C.; Zheng, B.;
Chuan, Q. K.; Hai, Q. G.; Lian, X. G. Tetrahedron: Asymmetry 2008, 19, 1572; (d)
José, E. D.; Martins, M. W. Tetrahedron: Asymmetry 2008, 19, 1250; (e) Jiang, F.
Y.; Liu, B.; Dong, Z. B.; Li, J. S. J. Organomet. Chem. 2007, 692, 4377; (f) Manabu,
H.; Takashi, M.; Kazuaki, I. J. Org. Chem. 2006, 71, 6474; (g) Tanaka, T.; Yasuda,
Y.; Hayashi, M. J. Org. Chem. 2006, 71, 7091; (h) Liu, S.; Wolf, C. Org. Lett. 2007, 9,
2965; (i) Blay, G.; Fernández, I.; Olmos, V. H.; Marco-Aleixandre, A.; Pedro, J. R.
J. Mol. Catal. A: Chem. 2007, 276, 235; (j) Bisai, A.; Singh, P. K.; Singh, V. K.
Tetrahedron 2007, 63, 598; (k) Shi, M.; Sui, W. S. Tetrahedron: Asymmetry 1999,
10, 3319.
amorphous solid in 87% yield; mp 197–199 °C; ½a D22
ꢂ
ꢀ24.36 (c 0.2, CH2Cl2); 1
H
NMR (300 MHz, CDCl3) d (ppm) 5.01 (s, 2H), 5.15 (s, 2H), 5.25 (s, 2H), 7.10–7.16
(m, 3H), 7.19–7.43 (m, 6H), 7.91–8.02 (m, 5H), 8.26–8.35 (m, 4H). 13C NMR
(75 MHz, CDCl3) d (ppm) 162.8, 152.8, 133.4, 131.4, 129.5, 128.4, 127.5, 127.1,
124.9, 124.2, 124.1, 117.8, 113.2, 110.9, 68.4. HRMS(ESI): calcd for (M++1)
C34H25N2O8: 589.1611, found: 589.1624.
10.
A
typical procedure for the catalytic addition of diethylzinc to aromatic
aldehydes: To a solution of (S)-2 (14.7 mg, 0.025 mmol) in CH2Cl2 (1.0 mL),
Ti(OiPr)4 (89.3 L, 0.3 mmol) was added under a nitrogen atmosphere, and the
l
reaction mixture was stirred for 30 min at room temperature. A solution of
diethylzinc (1.0 M in hexane, 0.75 mL, 0.75 mmol) was added dropwise to the
above reaction mixture, and stirring was continued for another 10 min. The
reaction mixture was then cooled to 0 °C, and the aldehyde (0.25 mmol) was
added and stirring was continued for 5 h. The reaction mixture was quenched
with HCl (1.0 M, 2.0 mL), and the product was extracted with (3 ꢁ 2 mL) ethyl
acetate. The combined ethyl acetate extracts were dried over Na2SO4 and
evaporated to dryness under vacuum pressure. The residue was purified by
silica gel column chromatography (hexane/ethyl acetate, 10/1, v/v) to afford
the secondary alcohol products. The enantioselectivities of the reactions were
determined by Chiral GC G-TA using OJ-H or OD-H columns.