Asymmetric pinacol coupling of aromatic aldehydes with TiCl2/enantiopure amine or hydrazine reagents

Article abstract of DOI:10.1016/S0957-4166(00)00379-7

Asymmetric pinacol coupling of aromatic aldehydes under homogeneous conditions with TiCl₂ in the presence of enantiopure amines or hydrazines afforded 1,2-diols in moderate to excellent yields with good dl-diastereoselectivities and enantioselectivities in the range of 6-65% ee. A non-linear temperature effect ('principle of isoinversion') has been examined. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00379-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3861–3865
Asymmetric pinacol coupling of aromatic aldehydes with
TiCl2/enantiopure amine or hydrazine reagents
Dieter Enders* and Elke C. Ullrich
Institut fu¨r Organische Chemie, Rheinisch-Westfa¨lische Technische Hochschule Aachen, Professor-Pirlet-Str. 1,
52074 Aachen, Germany
Received 29 August 2000; accepted 19 September 2000
Abstract
Asymmetric pinacol coupling of aromatic aldehydes under homogeneous conditions with TiCl2 in the
presence of enantiopure amines or hydrazines afforded 1,2-diols in moderate to excellent yields with good
dl-diastereoselectivities and enantioselectivities in the range of 6–65% ee. A non-linear temperature effect
(‘principle of isoinversion’) has been examined. © 2000 Elsevier Science Ltd. All rights reserved.
One of the most straight forward and efficient methods for the synthesis of vicinal diols is the
pinacol coupling reaction of carbonyl compounds.1 Since the pioneering contributions in this
field by Mukaiyama et al.2 and McMurry et al.,3 low valent titanium compounds are most
prominent for this CꢀC bond coupling. One general method involves the reduction of titanium-
(IV) compounds, for instance with Zn, LiAlH4, etc., usually under heterogeneous conditions.3,4
Recently, the dl-diastereoselectivity of the pinacol coupling reaction has been controlled
efficiently by low valent titanium species under homogeneous conditions.5 Another protocol is
based on titanium(II) chloride, easily prepared from titanium(IV) chloride and hexamethyldi-
silane,6 in the presence of zinc7a or titanium(II) bromide/copper.7b
Very recently, Matsubara et al.8 developed an enantioselective version of the pinacol coupling
with titanium(II) chloride and enantiopure tertiary amines or vicinal diamines as additives. In
the case of hydrobenzoin enantiomeric excesses of 0–41% were reached.
We now wish to report our independent results9 on the asymmetric pinacol coupling reaction
of aromatic aldehydes with titanium(II) chloride in the presence of enantiopure secondary
amines or hydrazines.
As is described in Scheme 1, aromatic aldehydes 1 were treated with a brown black to blue
tetrahydrofuran solution generated from titanium(II) chloride and two equivalents of the
enantiopure secondary amines and hydrazines 3–9, respectively. In the case of benzaldehyde, the
* Corresponding author. Fax: +49(0)241-8888-127; e-mail: enders@rwth-aachen.de
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00379-7

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D. Enders, E. C. Ullrich / Tetrahedron: Asymmetry 11 (2000) 3861–3865
resulting 1,2-diol 2a was obtained in moderate to excellent yields (33–100%) with good
diastereoselectivities (dl:meso=71:29–94:6) and enantiomeric excesses in the range 6–65% (Table
1).
Scheme 1. Diastereo- and enantioselective pinacol coupling of aromatic aldehydes by TiCl2/enantiopure amine or
hydrazine reagents18
Table 1
Enantioselective pinacol coupling of benzaldehyde by TiCl2/2*R2NH or 2*R2NNH2, THF
Chiral amine
T (°C)
t (h)
Yield (%)
dl:meso
ee (%)a (S,S)
3
3
3
3
3
3
3
4
4
5
5
6
7
8
9
rt
0
8
8
8
23
8
48
8
7
8
8
8
42
35
35
31
31
100
25
60
100
40
100
33
83:17
79:21
79:21
81:19
81:19
56:44
72:28
65:35
78:22
70:30
74:26
94:6
36
31
42
65
48
37
31
30
29
31
29
6
−50
−78
−78
−78
−100
rt
−78
rt
−78
rt
7
7
7
7
rt
rt
rt
100
60
90
71:29
75:25
89:11
24
21
23
a Determined by HPLC on chiral stationary phases.
1
The diastereomeric excesses (dl/meso) were determined by H NMR analysis, the enan-
tiomeric excesses by HPLC using chiral stationary phases. In the cases of the hydrazines SAMP
4 and RAMBO 5 as chiral additives the yield of hydrobenzoin 2a was higher at −78°C than at
room temperature. This may be explained by the competing formation of the corresponding
hydrazones as a side reaction at room temperature.

D. Enders, E. C. Ullrich / Tetrahedron: Asymmetry 11 (2000) 3861–3865
3863
The pinacol coupling reaction of benzaldehyde 1a in the presence of two equivalents of the
enantiopure secondary amine (S)-2-methoxymethyl-pyrrolidine 3 (SMP) in THF generates the
dl-1,2-diol 2a at 78°C with an enantiomeric excess of 65% and at 100°C with an ee value of 31%.
In the case of a decreasing enantioselectivity in combination with a decreasing reaction
temperature the principle of isoinversion introduced by Scharf et al.10 can be applied. The
Eyring plot ln [S]/[R] against 1/T of this system showed two linear regions intersecting at an
inversion point Tinv (Fig. 1).11,19 The activation parameters DDHc and DDSc are accessible from
the Eyring plot. From these parameters the isoinversion temperature was calculated to be
Tinv=194 K. For this temperature the best enantioselectivity is expected.
Figure 1. Eyring plot and calculation of the inversion temperature Tinv
In addition we varied the aldehydes 1 under the optimum pinacol coupling conditions with
SMP as the auxiliary ligand at −78°C and established that the yields are in the range of 15–100%
reaching enantioselectivities of 26–65% ee. The absolute configurations of the dl-1,2-diols given
Table 2
Enantioselective pinacol coupling of aromatic aldehydes by TiCl2/2SMP, THF12

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D. Enders, E. C. Ullrich / Tetrahedron: Asymmetry 11 (2000) 3861–3865
were determined by comparison of the specific rotations with compounds of known configura-
tion (Table 2).
Additionally, we tried the asymmetric pinacol coupling reaction with three heteroaromatic
aldehydes, namely 2-pyridinecarbaldehyde, 1H-2-pyrrolecarbaldehyde and 2-furaldehyde. With
the two nitrogen-containing aldehydes no reaction was observed and no starting material was
recovered. With 2-furaldehyde a good dl:meso selectivity of 91:9 and a remarkable enantiomeric
excess of 45% of the (R,R)-diol was obtained, however only in low yield.
In conclusion, the new variant of the asymmetric pinacol coupling of aromatic aldehydes with
TiCl2 in the presence of two equivalents of SMP leads to 1,2-diols in moderate to excellent
yields, good dl-diastereoselectivities and enantiomeric excesses of up to 65%.
Acknowledgements
This work was supported by the Fonds der Chemischen Industrie. We are grateful to BASF
AG, Degussa AG, Bayer AG and Roche Diagnostics for the donation of chemicals.
References
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12. Typical procedure for asymmetric pinacol coupling: To a solution of TiCl2 (2.0 mmol) in THF (10 ml) was added
the amine (4.0 mmol) at 0°C. The mixture was stirred for 15 min at room temperature. In the case of amine 3
the solution of the coupling reagent TiCl2/2SMP in THF was homogeneous and dark blue. The solution was
cooled to the desired temperature, the aldehyde (1.0 mmol) was added and the resulting mixture was stirred. The
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gave the corresponding 1,2-diols.
1
(S,S)-1,2-Diphenyl-1,2-ethanediol (S,S)-2a mp 99°C; [h]2D5=−7.90 (c=0.12, CHCl3); H NMR (300 MHz, CDCl3)
l 3.21 (2H, s, OH), 4.63 (2H, s, CH, dl), 4.84 (2H, s, CH, meso), 7.03–7.25 (m, 10H, arom. H). Enantiomeric

D. Enders, E. C. Ullrich / Tetrahedron: Asymmetry 11 (2000) 3861–3865
3865
excess by HPLC: (S,S)-Whelk-01 (hexane:2-propanol 95:5, flow rate=1.0 mL/min): tr(S,S)=9.4 min, tr(R,R)=
11.4 min. All other data were identical with those given in lit.13
(S,S)-1,2-Di(4-chlorophenyl)-1,2-ethanediol (S,S)-2b mp 142°C; [h]2D5=+9.73 (c=0.18, CHCl3); 1H NMR (400
MHz, CD3OD) l 4.64 (2H, s, OH), 4.73 (2H, s, CH, meso), 4.86 (2H, s, CH, dl), 6.95–7.35 (8H, m, arom. H).
Enantiomeric excess by HPLC: (S,S)-Whelk-01 (hexane:2-propanol 95:5, flow rate=1.0 mL/min): tr(S,S)=9.1
min, tr(R,R)=10.8 min. All other data were identical with those given in lit.13,14
(S,S)-1,2-Di(4-methylphenyl)-1,2-ethanediol (S,S)-2c mp 156°C; [h]2D5=−1.55 (c=0.52, EtOH); 1H NMR (400
MHz, CD3OD) l 2.16 (6H, s, CH3), 3.24 (2H, s, CH, meso), 4.48 (2H, s, CH, dl), 6.87 (8H, m, arom. H).
Enantiomeric excess by HPLC: (S,S)-Whelk-01 (hexane:2-propanol 95:5, flow rate=1.0 mL/min): tr(S,S)=10.9
min, tr(R,R)=14.2 min. All other data were identical with those given in lit.13,15
(R,R)-1,2-Di(2-thienyl)-1,2-ethanediol (R,R)-2d mp 69°C; [h]2D5=+3.70 (c=0.41, EtOH); 1H NMR (400 MHz,
CDCl3) l 4.00 (2H, s, OH), 4.84 (2H, s, CH, dl), 5.00 (2H, s, CH, meso), 6.64–7.11 (6H, m, arom. H).
Enantiomeric excess by HPLC: Chiralcel OD2 (hexane:2-propanol 95:5, flow rate=1.0 mL/min): tr(S,S)=26.4
min, tr(R,R)=30.3 min. All other data were identical with those given in lit.16
(S,S)-1,2-Di(2-bromophenyl)-1,2-ethanediol (S,S)-2e mp 97°C; [h]2D5=+2.74 (c=0.73, EtOH); 1H NMR (400 MHz,
CD3OD) l 4.72 (2H, s, OH), 5.19 (2H, s, CH, dl), 5.41 (2H, s, CH, meso), 6.85–7.66 (8H, m, arom. H).
Enantiomeric excess by HPLC: (S,S)-Whelk-01 (hexane:2-propanol 90:10, flow rate=1.0 mL/min): tr(S,S)=5.4
min, tr(R,R)=6.4 min. All other data were identical with those given in lit.17
1
(S,S)-1,2-Di(2-naphthyl)-1,2-ethanediol (S,S)-2f mp 209°C; [h]2D5=+4.62 (c=0.26, d4-THF); H NMR (400 MHz,
THF) l 2.50 (2H, s, OH), 4.84 (2H, s, CH, dl), (2H, s, CH, meso), 7.16–7.72 (14H, m, arom. H). Enantiomeric
excess by HPLC: (S,S)-Whelk-01 (hexane:2-propanol 90:10, flow rate=1.0 mL/min): tr(S,S)=20.8 min, tr(R,R)=
29.2 min. All other data were identical with those given in lit.16
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.