Asymmetric pinacol coupling of aromatic aldehydes catalyzed by a new titanium-Schiff base complex

Article abstract of DOI:10.1016/j.tetasy.2004.04.012

A new Schiff-base with two stereogenic centers has been prepared and its titanium complex applied to catalyze the pinacol coupling of aldehydes, which afforded pinacols in high yield, excellent diastereoselectivities, and high enantioselectivities.

Full text of DOI:10.1016/j.tetasy.2004.04.012

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1707–1710
Asymmetric pinacol coupling of aromatic aldehydes catalyzed by a
new titanium–Schiff base complex
You-Gui Li, Qing-Shan Tian, Jun Zhao, Yan Feng, Min-Jie Li and Tian-Pa You*
Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, PR China
Received 4 March 2004; accepted 9 April 2004
Available online
Abstract—A new Schiff-base with two stereogenic centers has been prepared and its titanium complex applied to catalyze the pinacol
coupling of aldehydes, which afforded pinacols in high yield, excellent diastereoselectivities, and high enantioselectivities.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Pinacol coupling of a carbonyl compound is one of the
most effective routes for the formation of C–C bonds
and the generation of vicinal diols in one step.1 It has
been employed in the key steps of several total syntheses
of natural products.2 Asymmetric pinacol coupling,
which is one of the most promising methods for pre-
paring chiral vicinal diols that are versatile chiral auxi-
liaries in various asymmetric reactions, has attracted
increasing attention.3 Since the first report by Muka-
yama of pinacol coupling reactions mediated with a
titanium reagent in 1973,4 a number of effective reduc-
tive systems have been developed to carry out this
reaction.5 Nevertheless, they all suffer from the principal
drawback of having to be employed in stoichiometric
amounts. Bandini et al.6 achieved pinacol coupling of an
aldehyde using a catalytic amount of a titanium–(Schiff-
base) complex, while other groups7 introduced various
chiral ligands to conduct this reaction enantioselectively:
however, only poor to moderate enantioselectivities
were obtained. Bensari et al.8 first developed a series of
easily available chiral Schiff bases to improve the
enantioselectivity. More recently, Joshi et al.9 have
enhanced the enantioselectivity with a tetradentate
Schiff base. Based on Bensari’s work, we have prepared
a new chiral Schiff-base and applied it to the pinacol
coupling of aldehydes; the corresponding pinacols were
obtained in high yield, excellent diastereoselectivities,
and high enantioselectivities under the mild condition.
The chiral tetradentate Schiff-base L was prepared from
(S,S)-())-1,2-diphenylethylenediamine and 2-pyridine-
carboxaldehyde. Its chiral titanium complex was
obtained by an exchange reaction between commercially
TiCl4(THF)2 and the chiral Schiff-base in a ratio of 1:2.
Ph
N
Ph
N
N
N
L
Initially, the chiral Schiff-base with TiCl4(THF)2 was
applied to catalyze the pinacol coupling of benzaldehyde
under different conditions. The results are listed in
Table 1.
In order to optimize the reaction conditions, the cata-
lytic reaction with ligand L was investigated by varying
solvent, reductant metal, reaction temperature, reaction
time, and the amount of ligand L. The best results were
achieved in CH2CN at 0 °C for 12 h in the presence of
15% mol of ligand L, 1.5 equiv of Me3SiCl, and 3 equiv
of Mn power. The diastereoselectivity and enantio-
selectivity notably increased when the catalyst concen-
tration was increased from 5 to 15 mol % (entries 5, 14,
and 15); there was no significant improvement when the
catalyst concentration was higher than 15% (entries 16
and 17).
* Corresponding author. Tel.: +86-551-3606944; fax: +86-551-36061-
81; e-mail: ytp@ustc.edu.cn
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.04.012

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Y.-G. Li et al. / Tetrahedron: Asymmetry 15 (2004) 1707–1710
Table 1. Pinacol coupling of benzaldehyde under various conditionsa
HO
TiCl4(THF)2/ L
Ph
2PhCHO
Ph
TMSCl, [M]
OH
Entry
Cat. (mol %)
Solvent (reductant)
T (°C)
Yield (%)b
Dl/mesoc
Ee (%)c (S,S)
1
15
15d
15
15d
15
15
15d
15
15d
15
15
15
15
5
CH3CN(Mn)
CH3CN(Mn)
CH3CN(Mn)
CH3CN(Mn)
CH3CN(Mn)
CH3CN(Mn)
CH3CN(Mn)
CH3CN(Mn)
CH3CN(Mn)
CH2Cl2(Mn)
THF(Mn)
50
50
25
25
0
56
25
78
41
95
76
92
65
89
76
73
76
86
93
92
95
96
85/15
86/14
91/9
39
38
64
63
88
82
87
78
86
67
64
55
73
16
61
89
90
2
3
4
91/9
93/7
5
6
)10
)10
)25
)25
0
92/8
94/6
7
8
90/10
93/7
91/9
9
10
11
12
13
14
15
16
17
0
87/13
83/17
89/11
60/40
88/12
94/6
CH3CN(Zn)
CH3CN(Mg)
CH3CN(Mn)
CH3CN(Mn)
CH3CN(Mn)
CH3CN(Mn)
0
0
0
10
25
50
0
0
0
95/5
a The reaction was carried out in acetonitrile at 0 °C with 15% mol of chiral Schiff-base, 1.5 equiv of Me3SiCl, and 3 equiv of Mn power (99.9%,
50 mesh) for 12 h.
b Isolated yield.
c Measured by chiral HPLC column: chiralcel-OJ-H; hexane/2-propanol ¼ 9:1, flow rate ¼ 0.5 mL/min, tr (S,S)¼27.3, tr (R,R)¼30.2, tr (meso)¼37.5.
d The reaction was carried out for 24 h.
Under the optimized conditions, pinacol couplings of
various aldehydes were investigated with the results
summarized in Table 2. It seems an electron-donating
group at the para-position of –CHO group slightly im-
proves the diastereoselectivity and enantioselectivity
(entries 3 and 4), while an electron-withdrawing group
had the opposite effect (entries 5, 6, and 7). The diol
resulting from the coupling of 2-thiophenecarboxalde-
hyde only showed a moderate enantioselectivity (entry 8).
For isobutyraldehyde (entry 9), no diol could be ob-
tained.
The mechanism of the previous reports7;9 may be in-
voked to explain the results we obtained.
3. Conclusion
In conclusion, the titanium complex of ligand L is an
effective catalyst for the asymmetric pinacol coupling of
aromatic aldehydes. These results provide useful infor-
mation for designing more efficient catalyst systems for
Table 2. Pinacol coupling of aromatic aldehydes in the presence of La
HO
Ar
TiCl (THF) /L
4
2
2ArCHO
TMSCl, Mn
Ar
OH
2a-h
1a-h
Entry
1 ArCHO(Ar)
2 Yieldb (%)
Dl/mesoc
Eec (%) (S,S)
1
2
3
4
5
6
7
8
9
Phenyl
95 (a)
82 (b)
92 (c)
90 (d)
86 (e)
84 (f)
87 (g)
80 (h)
0
93/7
95/5
98/2
95/5
92/8
87/13
93/7
89/11
––
88
80
91
90
60
68
74
53
––
1-Naphthaldehyde
4-Methoxybenzaldehyde
4-Tolualdehyde
2-Chlorobenzaldehyde
4-Chlorobenzaldehyde
2,4-Dichlorobenzaldehyde
2-Thiophenecarboxaldehyde
Isobutyraldehyde
a The reaction was carried out in acetonitrile at 0 °C with 15% mol of chiral Schiff-base, 1.5 equiv of Me3SiCl, and 3 equiv of Mn power (99.9%,
50 mesh) for 12 h.
b Isolated yield.
c Measured by chiral-HPLC column.10;7b

Y.-G. Li et al. / Tetrahedron: Asymmetry 15 (2004) 1707–1710
1709
enantioselective pinacol coupling reactions of aldehydes,
ketones or imines.
temperature then cooled to 0 °C. The Mn power
(6 mmol) was added followed by the addition of
Me3SiCl (0.28 mL, 3 mmol) with the suspension turning
green-blue. After a few minutes, the benzaldehyde
(2 mmol) was added and the suspension stirred at 0 °C
for 12 h. The suspension was quenched with a solution
of 10% Na2CO3 and extracted with EtOAc. The organic
solvent was evaporated under reduced pressure. The
resulting brown-red oil was dissolved in THF solution
of 1 M HCl (5 mL) and stirred at room temperature until
the pinacol product had completely desilylated. The
reaction was diluted with water and extracted twice with
EtOAc. The organic phases were collected and dried
over Na2SO4 and the residue purified by chromato-
graphy.
4. Experimental
4.1. General
All reactions were carried out under argon atmosphere.
Commercial reagents were used without further purifi-
cation. All solvents were dried using standard methods
and were freshly distilled before use. Melting points
were determined using hot-stage apparatus and are
uncorrected. Optical rotations were measured on a
WZZ-1 rotation spectrometer. NMR spectra were
measured on a Bruker av300 spectrometer (300 Hz) by
using a CDCl3 as solvent and TMS as internal standard.
IR spectra were recorded on a Bruker VECTOR-22
(KBr) spectrometer. Element analyses were performed
on a Vari E spectrometer. HPLC analyses were per-
formed using AGILENT1100 SERIES spectrometer.
The diastereomeric excesses (dl/meso) and the enantio-
meric excesses were determined by HPLC using chiral
Compound 2a, 1,2-diphenylethane-1,2-diol: Colorless
20
crystals; mp 142–144 °C; ½aꢀ ¼ ꢁ82:5 (c 1.0, CHCl3);
D
1H NMR: d (ppm) 2.03 (s, 2H, OH), 4.73 (s, H, dl), 4.83
(s, H, meso), 7.12–7.30 (m, 10H, Ph); enantiomeric
excess by HPLC: chiralcel-OJ-H (hexane/2-propa-
nol ¼ 90:10, flow rate ¼ 0.5 mL/min): tr (S,S)¼27.3 min,
tr (R,R)¼31.1 min, tr (meso)¼38.8 min.
1
stationary phases or H NMR analysis.
Compound 2b, 1,2-di(1-naphthyl)ethane-1,2-diol: Col-
20
D
orless crystals; mp 122–124 °C; ½aꢀ ¼ ꢁ41:0 (c 1.0,
1
C2H5OH); H NMR: d (ppm) 1.71 (s, 2H, OH), 5.79 (s,
4.2. Preparation of (S,S)-1,2-diphenylethylenediamine
(1S,2S)-1,2-Diphenylethylenediamine was prepared
2H, dl), 5.81 (s, 2H, meso), 7.58–7.02 (m, 6H, Ph), 7.96–
7.60 (m, 8H); enantiomeric excess by HPLC: chiralcel-
AD (hexane/2-propanol ¼ 85:15, flow rate ¼ 1.0 mL/
min): tr (S,S)¼21.2 min, tr (R,R)¼22.4 min, tr (meso) ¼
25.2 min.
according to the literature11 with slight modification.
20
D
Mp 83–84 °C, ½aꢀ ¼ ꢁ106:5 (c 1.0, CH3OH); {lit.11, mp
20
82–84 °C; ½aꢀ ¼ ꢁ105:2 (c 1.0, CH3OH)}.
D
Compound 2c, 1,2-di(4-methoxylphenyl)ethane-1,2-
20
D
diol: Colorless crystals; mp 130–132 °C; ½aꢀ ¼ ꢁ105:0
4.3. Preparation of (1S,2S)-N,N0-Bis(pyridylmethene)-
1,2-diphenylethylenediimine
(c 1.0, C2H5OH); H NMR: d (ppm) 1.68 (s, 2H), 3.75
1
(s, 6H), 4.63 (s, H, dl), 4.74 (s, H, meso), 6.74–7.22 (m,
10H); enantiomeric excess by HPLC: chiralcel-
AD (hexane/2-propanol ¼ 95:5, flow rate ¼ 1.0 mL/
min): tr (S,S)¼9.3 min, tr (R,R)¼11.1 min, tr (meso) ¼
15.4 min.
(1S,2S)-1,2-Diphenylethylenediamine (0.416 g, 2 mmol)
and 2-pyridincarboxaldehyde (0.214 g, 1 mmol) were
dissolved in 30 mL dry benzene. The mixture was gently
refluxed under an inert atmosphere of argon. The water
from the reaction was released by a Dean–Stark trap.
After approximately 2 h, all of the water had been sep-
arated. The mixture was cooled to room temperature
and concentrated under reduced pressure. The Schiff
Compound 2d, 1,2-di(4-methylphenyl)ethane-1,2-diol:
20
D
Colorless crystals; mp 109–111 °C; ½aꢀ ¼ ꢁ91:5 (c 1.0,
1
C2H5OH); H NMR: d (ppm) 2.30 (s, 6H), 2.75 (s, 2H,
OH), 4.67 (s, H, dl), 4.74 (s, H, meso), 7.04–7.23 (m, 8H);
enantiomeric excess by HPLC chiralcel-WH (hexane/
2-propanol ¼ 9:1, flow rate ¼ 1.0 mL/min): tr (S,S)¼
11.2 min, tr (R,R)¼12.4 min, tr (meso)¼15.2 min.
base was then obtained as a yellow solid in quantitative
20
yield. Mp 164–166 °C; ½aꢀ ¼ ꢁ12:7 (c 1.0, C2H5OH);
D
1H NMR (300 MHz, CDCl3) d (ppm): 4.73 (s, 2H, CH),
6.77 (d, 2H, Ar), 6.92 (d, 2H, ArH), 7.13–7.96 (m, 12H,
Ar), 8.30 (s, 2H, N@CH), 8.81 (d, 2H, Ar); 13C NMR d
(ppm): 81.08, 117.02, 118.76, 127.73, 127.87, 128.28,
131.25, 132.48, 139.45, 161.11, 162.02. IR (KBr) m
(cmꢁ1): 1350, 1650; Anal. Calcd for C26H22N4: C 80.78,
H 5.95, N 14.08. Found: C 80.62, H 5.63, N 14.35.
Compound 2e, 1,2-di(2-chlorophenyl)ethane-1,2-diol:
20
D
Colorless crystals; mp 130–132 °C; ½aꢀ ¼ ꢁ38 (c 0.5,
1
CHCl3); H NMR: d (ppm) 1.64 (s, 2H), 5.32 (s, H, dl),
5.45 (s, H, meso), 7.25–7.32 (m, 8H, Ar); nantiomeric
excess by HPLC: chiralcel-WH (hexane/2-propa-
nol ¼ 9:1, flow rate ¼ 0.8 mL/min): tr (S,S)¼8.6 min, tr
(R,R)¼10.2 min, tr (meso)¼14.1 min.
4.4. Typical procedure for the pinacol coupling of
aldehydes catalyzed by Schiff base
Compound 2f, 1,2-di(4-chlorophenyl)ethane-1,2-diol:
20
D
Colorless crystals; mp 189–191 °C; ½aꢀ ¼ ꢁ42:5 (c 0.5,
1
To a solution of L (0.3 mmol) in CH3CN (2 mL),
TiCl4(THF)2 (0.15 mmol) was added under argon. The
resulting red solution was stirred for 30 min at room
CHCl3); H NMR: d (ppm) 2.53 (s, 2H), 5.36 (s, H, dl),
5.60 (s, H, meso), 7.14–7.65 (m, 8H); enantiomeric excess
by HPLC: chiralcel-WH (hexane/2-propanol ¼ 95:5,

1710
Y.-G. Li et al. / Tetrahedron: Asymmetry 15 (2004) 1707–1710
Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; 3, p 563; (d) McMurry,
J. E. Chem. Rev. 1989, 89, 1513.
flow rate ¼ 1.0 mL/min): tr (S,S)¼7.4 min, tr (R,R)¼
9.1 min, tr (meso)¼12.3 min.
2. (a) Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S.;
Siret, P.; Keck, G. E.; Gras, J. J. Am. Chem. Soc. 1978,
100, 8031; (b) Swindell, C. S.; Fan, W.; Klimko, P. G.
Tetrahedron Lett. 1994, 53, 4959.
3. (a) Whitesell, J. K. Chem. Rev. 1989, 89, 1581; (b) Ray, C.
A.; Wallace, T. W.; Ward, R. A. Tetrahedron Lett. 2000,
41, 3501; (c) Andrus, M. B.; Somasekhar, B. B. V.;
Meredith, E. L.; Dalley, N. K. Org. Lett. 2000, 2, 2035.
4. Mukaiyama, T.; Sato, T.; Hanna, J. Chem. Lett. 1973,
1041.
5. (a) Clerici, A.; Clerici, L.; Porta, O. Tetrahedron Lett.
1996, 37, 3035; (b) Li, T.; Cui, W.; Liu, J.; Zhao, J.; Wang,
Z. Chem. Commun. 2000, 139; (c) Mukaiyama, T.;
Yoshimura, N.; Igarashi, K.; Kagayama, A. Tetrahedron
2001, 57, 2499.
Compound 2g, 1,2-di(2,4-dichlorophenyl)ethane-1,2-
20
diol: Colorless crystals; mp 135–137 °C; ½aꢀ ¼ ꢁ58:0 (c
D
1.0, CHCl3); 1H NMR: d (ppm) 1.57 (s, 2H), 5.43 (s, H,
dl), 5.55 (s, H, meso), 7.13–7.32 (m, 6H); enantiomeric
excess by HPLC: chiralcel-WH (hexane/2-propa-
nol ¼ 9:1, flow rate ¼ 0.8 mL/min): tr (S,S)¼15.1 min, tr
(R,R)¼17.2 min, tr (meso)¼21.1 min.
Compound 2h, 1,2-di(2-thiophenyl)ethane-1,2-diol:
20
D
Colorless crystals; mp 102–104 °C; ½aꢀ ¼ ꢁ26:0 (c 1.0,
1
C2H5OH); H NMR: d (ppm) 3.74 (s, 2H), 5.22 (s, H,
dl), 5.37 (s, H, meso), 6.68–7.22 (m, 6H); enantiomeric
excess by HPLC: chiralcel-OB (hexane/2-propa-
nol ¼ 85:15, flow rate ¼ 0.5 mL/min): tr (S,S)¼10.5 min,
tr (R,R)¼11.5 min, tr (meso)¼14.1 min.
6. Bandini, M.; Cozzi, P. G.; Morganti, S.; Ronchi, A. U.
Tetrahedron Lett. 1999, 40, 1997.
7. (a) Matsubara, S.; Hashimoto, Y.; Okano, T.; Utimoto,
K. Synlett 1999, 9, 1411; (b) Enders, D.; Ullrich, E. C.
Tetrahedron: Asymmetry 2000, 11, 3861; (c) Bandini, M.;
Cozzi, P. G.; Morganti, S.; Ronchi, A. U. Tetrahedron
Lett. 1999, 40, 1997; (d) Panlap, M. S.; Nicholas, K. M.,
et al. Synth. Commun. 1999, 29, 1097; (e) Melinda, S. et al.
J. Organomet. Chem. 2001, 63, 125.
Acknowledgements
This work was supported by National Science Foun-
dation of China.
8. Bensari, A.; Renaud, J. L.; Riant, O. Org. Lett. 2001,
3863.
9. Chatterjee, A.; Bennur, T. H.; Joshi, N. N. J. Org. Chem.
2003, 68, 5668.
References and notes
10. Li, Y.-G.; Jiang, C.-S.; Tian, Q.-S.; Ke, Y.-P.; You, T.-P.
Chin. J. Chem. 2003, 21, 1369.
11. Pikul, S.; Corey, E. J. Org. Synth. 1993, 71, 22.
1. (a) Gansaner, A. Chem. Commun. 1997, 5, 457; (b) Wirth,
T. Angew. Chem., Int. Ed. Engl. 1996, 35, 61; (c)