Asymmetric reduction of ortho-multisubstituted benzophenones catalyzed by diamine-Zn-diol complexes

Article abstract of DOI:10.1016/j.tetlet.2005.02.135

The asymmetric reduction of benzophenones multisubstituted at the ortho-positions was achieved via hydrosilylation catalyzed by in situ generated chiral diamine-Zn-diol complexes under mild conditions, wherein polymethylhydrosiloxane (PMHS) served as a sa

Full text of DOI:10.1016/j.tetlet.2005.02.135

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2903–2906
Asymmetric reduction of ortho-multisubstituted
benzophenones catalyzed by diamine–Zn–diol complexes
Hiroyuki Ushioꢀ and Koichi Mikami*
Department of Applied Chemistry, Tokyo Institute of Technology, Meguro-ku, Tokyo 152-8552, Japan
Received 7 January 2005; revised 9 February 2005; accepted 18 February 2005
Abstract—The asymmetric reduction of benzophenones multisubstituted at the ortho-positions was achieved via hydrosilylation
catalyzed by in situ generated chiral diamine–Zn–diol complexes under mild conditions, wherein polymethylhydrosiloxane
(PMHS) served as a safe and inexpensive source of hydride.
Ó 2005 Elsevier Ltd. All rights reserved.
The development of chiral catalysts, which transform
prochiral molecules into optically active ones by propa-
gation of chirality, has been recognized as one of the
most important subjects in modern synthetic organic
chemistry. Highly promising candidates for use as chiral
catalysts are generally metal complexes that bear chiral
and nonracemic organic ligands. The chiral metal cata-
lysts are known to exhibit ligand-acceleration or asym-
metric-activation catalysis.1 Herein, we reporton hte
asymmetric-activation approach to the asymmetric
reduction of sterically demanding benzophenones cata-
lyzed by Zn complexes composed of chiral diamines
and achiral diols.
ation using silanes or siloxanes. In general, reduction
by silanes is achieved in the presence of a hard acid such
as CF3CO2H or BF3OEt2.7 In the presence of a nucleo-
phile, on the other hand, reduction with siloxanes pro-
ceeds under mild conditions.8 Among the siloxanes
which are generally stable and hence less reactive than
silanes,9 polymethylhydrosiloxane (PMHS) is one of
the most attractive reducing reagents, as it is inexpen-
sive, nontoxic, and stable in air and moisture.10,11
Asymmetric hydrosilylation using a chiral zinc com-
plex12 prepared from chiral diamine 3a and Et2Zn has
been reported by Mimoun and co-workers,12a,b who,
however, did notreportreduction of any benzophenone,
particularly of the hindered 1. When we used a stoichio-
metric amount of this complex for hydrosilylation of 1
at room temperature, a high yield was obtained (Table
1, entry 1). Using a stoichiometric amount of the zinc
complex, moderate enantioselectivity (up to 84% ee)
was achieved at ꢀ10 °C (entry 2). Lewis acidic ZnF2
(entry 5) and Zn(OTf)2 (entry 6) were unsuccessful.
Although Mimoun postulated the involvement of ZnH
in his catalytic hydrosilylation, the ZnH complex13 was
not effective in this hydrosilylation (entry 7). Toluene
was the best solvent for these stoichiometric reactions
(entries 1, 2, 8–12). However, the decrease in the amount
of the diamine (3a)–Et2Zn complex resulted in the
decrease in enantioselectivity (entries 3 and 4).
Benzhydrol is known as a basic skeleton for bioactive
pharmaceuticals and the intermediates used in commer-
cial drug synthesis.2 While several trials of asymmetric
reduction of monosubstituted benzophenones have been
reported,3 there has been no report on asymmetric
reduction of benzophenones multisubstituted at the
ortho-positions, that is, the 2, 6, and 20 positions. We
first attempted asymmetric reduction of 2,6-dimethyl-
benzophenone and 2,20,4,6-tetramethylbenzophenone
(1) through chiral borane or aluminate reagents,4 enzy-
matic reduction,5 and catalytic hydrogenation,6 without
success, apparently due to the steric shielding effect of
the ortho-substituents. We then examined hydrosilyl-
We therefore searched for another Zn catalyst system
in which an anion was notfreely released, namely
Zn-dialkoxide catalysts. In the context of asymmetric
activation,1c,14 we have already reported that BINOL–
Zn–diamine catalysts are effective for alkylation of
*
Corresponding author. Tel.: +81 3 5734 2142; fax: +81 3 5734
2776; e-mail: kmikami@o.cc.titech.ac.jp
ꢀ On leave from Pharmaceutical Development Laboratories, Produc-
tion Unit, Technology & Production Division, Mitsubishi Pharma
Corporation.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.135

2904
H. Ushio, K. Mikami / Tetrahedron Letters 46 (2005) 2903–2906
Table 1. Reduction of 1 by PMHS in the presence of diamine (3a)–zinc catalyst
Me
Me
NH HN
3a
MeMe
Me
MeMe
*
Me
1) 3a, Et2Zn, PMHS
/ solvent
2) OH-/ MeOH
O
Me
OH
Me
2
1
Entry
Catalyst
Zn source
Reaction conditions
Selectivitya
Conv. (%)
mol %
SolventTemp (
°C)
Time (h)
>99
ee (%)
84
1
Et2Zn
Et2Zn
Et2Zn
Et2Zn
ZnF2
100
100
20
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
rt3.5
ꢀ10
rt28
rt10
rt24
rt24
rt48
0
77
2
9
>99
>99
0
>99
37
3
4
10
5
—
5
100
100
100
100
100
100
100
100
6
Zn(OTf)2
ZnH2
0
—
—
7
0
8
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
6
>99
89
49
51
9
CH2Cl2
DMSO
CH3CN
Hexane
0
9
10
11
12
rt3.5
0
92
6
67
>99
>99
1
71
0
6
a By chiral HPLC analysis: CHIRALCEL OJ (Daicel Chemical Ind., Ltd., Japan): UV at 231 nm; hexane/2-PrOH = 9/1; 0.6 mL/min).
aldehydes and that reduction of aldehydes proceeds as a
side reaction. Therefore, we examined the addition of
diols to the diamine–Zn complex (Table 2), as several
alkoxides had been employed as activators for silanes/sil-
Table 2. Reduction by chiral diamine–zinc–diol catalysts
: diamine
Me
Me
3a: X = H
NH HN
3b: X = Br
3c: X = Cl
3d: X = F
X
X
1) diamine, diol,
Et2Zn, additive,
PMHS/ THF
Me
Me
Me
Me
Me
Me
2) OH-/ MeOH
*
O
Me
OH
Me
2: 2'-Me, 2': 4'-Me
1: 2'-Me, 1': 4'-Me
Entry Substrate
Catalyst
PMHS (equiv mol) Additive
Reaction conditions
Selectivitya
Diamine Zn source Diol
mol %
SolventTemp
(°C)
Time Conv. ee
(h)
97
45
>99
(%)
74
77
76
(%)
1
2
1
1
3a
3a
Et2Zn
Et2Zn
(S)-BINOL
(R)-BINOL
10
10
6
6
MS3A
MS3A
THF
THF
rt48
rt48
3
1
1
1
1
1
1
10
1
1
1
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
10
10
10
10
10
2
6
MS3A
MS3A
MS3A
MS3A
—
THF
Toluene
THF
THF
THF
THF
THF
THF
THF
THF
rt9
0
HO
HO
HO
OH
4
6
6
6
17
21
74
54
84
OH
OH
5
6
0
OH
6
6
rt24
rt8
rt48
5
74
1
HO
HO
HO
HO
HO
HO
HO
OH
OH
OH
OH
OH
OH
7
6
—
8
2
MS3A
MS3A
MS3A
MS3A
MS3A
70
77
68
85
90
96
9
2
2
24
83
10
11
12
10
10
10
6
rt24
rt24
rt24
68
98
97
2.5
2.5
a By chiral HPLC analysis (DAICEL CHIRALCEL OJ: UV at 231 nm; hexane/2-PrOH = 9/1; 0.6 mL/min). Detection of 2: TR 11.6 min (major
enantiomer), 18.4 min (minor enantiomer) and substrate 1 was detected at 15.5 min. Detection of 20: TR 15.5 min (major enantiomer), 24.1 min
(minor enantiomer) and substrate 10 was detected at 13.9 min.

H. Ushio, K. Mikami / Tetrahedron Letters 46 (2005) 2903–2906
2905
anions, would release hydrides for reduction of the sub-
strate in a concerted fashion (B). In the final step, the
new alkoxide anion, derived from the substrate, would
attack the silylether (C) to afford the initial cyclic dialk-
oxide catalyst (A) and the silylether of the reduction
product.
Diamine,
Diol
Et2Zn
Ph
HN
Zn
Me
O
O
Ar'
Ar
H
Catalyst
A
(CH2)n
Si
Representative procedure for asymmetric hydrosilylation
of benzophenone 1 catalyzed by the diamine (3a)–
Et2Zn–ethylene glycol (1:1:1) complex: In an argon
atmosphere, Et2Zn (1 mol/L in hexane, 0.1 mL,
0.1 mmol) was added to a solution of diamine 3a
(26.8 g, 0.1 mmol) and ethylene glycol (6.2 mg,
0.1 mmol) in THF (2 mL) in the coexistence of dried
MS3A (10 mg) and stirred for 10 min at 0 °C. To the
solution, benzophenone 1 (238.6 mg, 1 mmol) and
PMHS (390 mg, 6 mmol) were added successively with
THF (1 mL), and the reaction mixture was warmed to
room temperature with stirring. The stirring was contin-
ued for 24 h and quenched by the addition of 1 mol/L
NaOH (ca. 1 mL) and MeOH (ca. 1 mL). The mixture
was then extracted with AcOEt. The organic layers were
then washed with brine and dried over Na2SO4. Evapo-
ration of the organic solvent gave the reduction product
2. Both the enantiomeric excess and the conversion were
measured using chiral HPLC analysis.20
Ar
Ar'
O
HN
(n = 2, 3)
O
Ph
Me
PMHS
Ar
Ar'
H
Ar
Si
O
Si
H
O
Ar'
Ph
Ph
O
O
Me
(CH2)n
(n = 2, 3)
Zn
Me
HN
(CH2)n
Zn
HN
O
O
(n = 2, 3)
HN
HN
Ph
Ph
Me
Me
C
B
Scheme 1. Proposed catalytic cycle.
oxanes.15 Interestingly, the configuration of (S)/(R)-BI-
NOL had little effect on the degree of enantioselectivity
(entries 1 and 2). Furthermore, achiral diols such as
1,3-propanediol16 (entries 3–5) and ethylene glycol
(entries 6–12) gave almost the same degree of enantio-
selectivity. In these catalytic reactions, THF was the best
solvent rather than toluene, which was the best in the
stoichiometric reactions. The addition of MS3A also
increased the conversion (entries 6 vs 7), as previously
suggested17 that MS3A could be effective for the ligand
exchange or catalyst turnover. In sharp contrast to the
Zn–diamine (3a) complex, essentially no change was seen
in the degree of enantioselectivity (77% ee vs 74% ee)
even by the decrease in the amount of the diamine–Zn–
diol complex (entries 8 vs 6). Catalytic asymmetric reduc-
tion of 2,4,40,6-tetramethylbenzophenone (10) also gave a
high degree of enantioselectivity (83% ee) (entry 9).
Through derivation of diamines (Br: entry 10, Cl: entry
11, and F: entry 12), the p-F-diamine (3d)–Zn–diol com-
plex gave the highest enantioselectivity (96% ee, 97%).
References and notes
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Et2Zn is reported to form a number of oligomeric struc-
tures.18 In a combination of bidentate ligands such as
diamines and aminoalcohols, a monomeric species
forms.12f,g Mimoun has demonstrated by X-ray crystal-
lography that an intermediate composed of diamine 3a
and benzaldehyde forms a dimer in aprotic solvent.12a
Carpentier has also reported that a dimeric Et2Zn–
dibenzylethylenediamine complex is changed to the
monomeric complex by the addition of alcohol.12c In
our diamine–Zn–diol complex (Scheme 1), Et2Zn reacts
with diol and diamine to give the diamine–Zn–diol com-
plex (A).19 As reported, Et2Zn with diols immediately
forms cyclic Zn-dialkoxide with the generation of eth-
ane.17f Zn(II) has a d10 electron system and, according
to the 18-electron rule, the coordination sites of Zn(II)
are limited to a maximum number of four. Therefore,
after the addition of ketones and PMHS, one Zn(II)-diol
bond may be cleaved via the reduction of ketones with
PMHS. PMHS, activated by one of the dialkoxide
5. After screening a total of 450 reducing enzymes, yeasts,
and bacteria, we found that one bacterium called Cory-
nespora cassicola reduced 2% of 2-methylbenzophenone to
the correspondent benzhydrol. However, there was no
means of reducing 2,6-dimethylbenzophenone or 1.

2906
H. Ushio, K. Mikami / Tetrahedron Letters 46 (2005) 2903–2906
6. The asymmetric hydrogenation of 2,6-dimethyl-benzophen-
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1.45 (4H, m), 1.51–1.57 (2H, m), 2.0 (2H, br), 3.43–3.52
(4H, m), 3.44 (1H, d, J = 6.9 Hz), 3.50 (1H, d, J = 6.9 Hz),
6.94–7.12 (10H, m).
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19. We obtained almost the same enantioselectivity, irrespec-
tive of the order of addition of diamine, diol, and Et2Zn.
Case 1: addition of ethylene glycol to diamine–Et2Zn
complex; case 2: addition of Et2Zn to ethylene glycol and
diamine 3a solution; case 3: addition of diamine to Zn–
ethylene glycol complex. In all contacts of Et2Zn with
ethylene glycol, evolution of ethane gas was observed.
20. HPLC analysis condition, see: footnote in Table 2.