Zn(salen)-catalyzed enantioselective phenyl transfer to aldehydes and ketones with organozinc reagent

Article abstract of DOI:10.1055/s-0034-1380461

Abstract A chiral zinc complex of salen was found to be an efficient catalyst for the phenyl transfer of organozinc reagent to aromatic aldehydes and ketones. High enantioselectivities were obtained in reactions of both aromatic aldehydes and ketones (up to 97% and 92% ee, respectively).

Full text of DOI:10.1055/s-0034-1380461

SYNLETT
0
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3
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0
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6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1238–1242
letter
1238
K. Shimizu et al.
Letter
Synlett
Zn(salen)-Catalyzed Enantioselective Phenyl Transfer to Alde-
hydes and Ketones with Organozinc Reagent
Keisuke Shimizu
Hidenori Uetsu
Takashi Gotanda
Katsuji Ito*
Ph2Zn (1.0 equiv)
Et2Zn (2.0 equiv)
R2
HO
R1
O
R1
R2
salen 1 (10 mol%)
R1 = aryl, R2 = H; up to 97% ee
R
2 = aryl, R2 = Me; up to 92% ee
Department of Chemistry, Fukuoka University of Education,
Akama, Munakata, Fukuoka, 811-4192, Japan
itokat@fukuoka-edu.ac.jp
Received: 26.01.2015
Accepted after revision: 27.02.2015
Published online: 20.03.2015
transfer to both aldehyde and ketones with arylzinc reagent
without the use of a titanium complex.10 Thus, a new cata-
lyst is still required for aryl transfer to both aldehydes and
ketones.
DOI: 10.1055/s-0034-1380461; Art ID: st-2015-u0055-l
Abstract A chiral zinc complex of salen was found to be an efficient
catalyst for the phenyl transfer of organozinc reagent to aromatic alde-
hydes and ketones. High enantioselectivities were obtained in reactions
of both aromatic aldehydes and ketones (up to 97% and 92% ee, respec-
tively).
The catalytic behaviors of Zn(salen) complexes with or-
ganozinc reagent have attracted our attention, because
Zn(salen)-catalyzed enantioselective alkyl transfer to alde-
hyde and enantioselective alkynyl transfer to ketones have
been reported, whereas enantioselective aryl transfer to al-
dehydes or ketones has not been reported. Cozzi et al. re-
ported the first Zn(salen)-catalyzed ethyl transfer to alde-
hydes with diethylzinc using salen 1 (Figure 1) bearing tert-
butyl groups at C3(3′) and C5(5′).11a This reaction was
thought to proceed through a Lewis acid–Lewis base dual
activation mode: The Lewis acidic central zinc ion captures
the carbonyl oxygen of aldehyde, and the Lewis basic phe-
nolic oxygen captures the diethylzinc. Later, a zinc complex
of 1 was successfully utilized in an enantioselective alkynyl
transfer with an alkynylzinc reagent to ketones.11b,c Kozlo-
wski et al. developed the modified salen 2, which bears
more Lewis basic alkyl amino groups at C3(3′) on a salen li-
gand. The zinc complex of 2 exhibited high catalytic activity
in the ethyl transfer to aldehydes or α-ketoesters and high
enantioselectivities were obtained.12 On the other hand,
Katsuki et al. reported highly enantioselective alkynyl
transfer to ketones using the zinc complex of 3 bearing a 2-
substituted naphthyl group at C3(3′) on a salen ligand.13 Al-
though its precise reaction mechanism is unclear, they stat-
ed that the coordination of organozinc with the phenolic
oxygen is unlikely due to the steric hindrance caused by a
bulky 2-phenylnaphthyl group at C3(3′), and that the 2-
phenylnaphthyl group makes it possible to discrimination
of the enantioface of ketone coordinated with the central
zinc ion.
Key words Zn(salen) complex, asymmetric catalysis, phenyl transfer,
aldehydes, ketones, diarylmethanol
Enantioselective aryl transfer to aromatic aldehydes or
ketones is a current topic in synthetic organic chemistry.
These reactions provide a useful method for the synthesis
of chiral secondary or tertiary diarylmethanols, which are
useful chiral building blocks for synthesizing pharmacolog-
ically active compounds.1 Since Bolm et al. reported using
an arylzinc reagent prepared from Ph2Zn/Et2Zn2a,b or
ArB(OH)2/Et2Zn2c,d as a nucleophile, various chiral ligands
have been developed that exhibit high enantioselectivity in
aryl transfer to aldehydes.3,4 However, a relatively small
number of chiral ligands are effective for aryl transfer to ke-
tones due to their lower reactivity and their difficulty in
discriminating lone pairs of carbonyl oxygen.5
In 1998, Fu et al. reported the first enantioselective phe-
nyl transfer to ketones using diphenylzinc with methanol as
an additive.6 Subsequently, Walsh et al.7 and Yus et al.8 in-
dependently reported that the use of titanium tetraiso-
propoxide greatly improves the effect of the addition of or-
ganozinc reagent to ketones and high enantioselectivities
were obtained. However, to the best of our knowledge, only
the zinc complex of a chiral phosphoramide ligand, a class
of Lewis acid–Lewis base catalyst, developed by Ishihara et
al.4c,d,9 could efficiently catalyze the enantioselective phenyl
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1238–1242

1239
K. Shimizu et al.
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Synlett
N
N
N
N
N
N
t-Bu
OH HO
t-Bu
OH HO
Ph
Y
OH HO
Y
Ph
R
R
N
X
X
4a: X = t-Bu, Y = H
4b: X = H, Y = t-Bu
4c: X = t-Bu, Y = OMe
4d: X = t-Bu, Y = Br
1: R = t-Bu
2: R =
3
X
Figure 1
These reports suggested that the Lewis acidic zinc ion of
a Zn(salen) complex could discriminate between the lone
pairs of the carbonyl oxygen and efficiently activate not
only aldehydes but also ketones. It is well-known that dia-
rylzinc and alkylarylzinc reagents are more nucleophilic
than dialkylzinc. Thus we expected that chiral Zn(salen)
complexes bearing appropriate substituents at least at
C3(3′) on a salen ligand would be an effective catalyst for
phenyl transfer to both aldehydes and ketones with zinc re-
agent. Moreover, salen ligands have the advantage of high
availability (some are commercially available) and modifi-
ability.
On this basis, we first examined phenyl transfer using p-
chlorobenzaldehyde as the test substrate at 0 °C with ethyl-
phenylzinc in the presence of 10 mol% of Zn(salen) com-
plexes prepared in situ from salen 1, 4a–d (Table 1). An eth-
ylphenylzinc solution was prepared from phenylboronic
acid and a hexane solution of diethylzinc according to
Bolm’s procedure.2c,14 As expected, the reaction with a zinc
complex of 1 proceeded smoothly, and the product was ob-
tained with a good enantioselectivity of 83% ee (Table 1, en-
try 1). Reaction with a zinc complex of 4a bearing the tert-
butyl group only at C3(3′) also proceeded smoothly al-
though the enantioselectivity was slightly diminished,
while that with a zinc complex of 4b bearing the tert-butyl
group only at C5(5′) proceeded more slowly and poor enan-
tioselectivity was obtained (Table 1, entries 2 and 3). Next,
we examined the electronic nature of the C5(5′) substitu-
ents but the catalytic activity and enantioselectivity were
not greatly affected (Table 1, entries 4 and 5). With a zinc
complex of 1, we also examined the effect of temperature,
and a high enantioselectivity of 93% with a high chemical
yield was obtained when the reaction was carried out at
–40 °C (Table 1, entry 6). When we used an ethylphenylzinc
reagent obtained by mixing diphenylzinc and diethylz-
inc,2a,b,14 we could significantly increase the reaction rate
without any deterioration in the enantioselectivity or the
chemical yield (Table 1, entry 7).
Table 1 Enantioselective Phenyl Transfer to p-Chlorobenzaldehyde
with a Zinc Complex of Salen Ligandsa,19
O
OH
zinc reagent
H
salen (10 mol%)
Cl
Cl
Entry
Salen
Time (h)
Yield (%)
ee (%)b
1
1
1
95
95
96
98
93
94
95
83
71
8
2
4a
4b
4c
4d
1
1
3
3.5
1
4
80
71
93
94
5
1
6c
7c,d
5.5
1
1
a All reactions were carried out with molar ratio of p-chlorobenzalde-
hyde/PhB(OH)2/Et2Zn/salen = 1:2.5:7.5:0.1 at 0 °C, unless otherwise indi-
cated.
b Determined by HPLC analysis using chiral stationary-phase column (Daicel
Chiralpak AD-H; hexane–i-PrOH, 90:10).
c Reaction was carried out at –40 °C.
d Reaction was carried out with molar ratio of p-chlorobenzalde-
hyde/Ph2Zn/Et2Zn/salen = 1.0:1.0:2.0:0.1.
To explore the scope of the present reaction, we next
examined the reactions of various aldehydes under opti-
mized reaction conditions (Table 2). The reactions of substi-
tuted aromatic aldehydes exhibited high enantioselectivi-
ties, irrespective of the electronic nature of the aryl substit-
uent (Table 2, entries 1–8). The reaction of heteroaromatic
aldehydes, such as 2-thiophenecarboxaldehyde, also exhib-
ited high enantioselectivity while that of furfural showed
some drop in enantioselectivity (Table 2, entries 9 and 10).
In particular, poor enantioselectivity was obtained for the
reaction of 2-pyridinecarboxaldehyde (Table 2, entry 11).
This tendency is probably attributable to the fact that the
nitrogen atom coordinates strongly with the Lewis acidic
central zinc atom, which leads to the reaction having an un-
desired transition state (vide infra). In contrast, the reac-
tions of aliphatic aldehydes showed moderate enantio-
selectivities (Table 2, entries 12–14).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1238–1242

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K. Shimizu et al.
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Table 2 Enantioselective Phenyl Transfer to Aldehydes with a Zinc
Complex of 1a,19
Table 3 Enantioselective Phenyl Transfer to Ketones with a Zinc Com-
plex of 1a,19
HO
R
Ph2Zn (1.0 equiv)
Et2Zn (2.0 equiv)
Ph2Zn (1.0 equiv)
Et2Zn (2.0 equiv)
HO
R
O
O
H
R
R
H
1 (10 mol%)
1 (10 mol%)
ee (%)b
Entry R in ketone
Temp
Time (h)
Yield (%)
ee (%)b
Entry
R in aldehyde
Time (h)
Yield (%)
1
2
4-ClC6H4
4-ClC6H4
2-naphthyl
2-naphthyl
4-MeC6H4
4-MeOC6H4
4-BrC6H4
4-BrC6H4
2-thienyl
2-furyl
r.t.
0 °C
r.t.
0 °C
r.t.
r.t.
r.t.
0 °C
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
24
96
30
144
48
60
20
96
42
30
81
82
80
75
74
52
77
80
72
60
87
74
59
87
88
1
2
2-naphthyl
2-MeC6H4
2-MeOC6H4
2-BrC6H4
4-PhC6H4
4-MeC6H4
4-MeOC6H4
4-BrC6H4
2-thienyl
2-furyl
1
94
95
95
89
91
87
95
92
96
93
71
64
61
71
95
97
89
90
94
90
95
95
92
83
6
92
1
3
85
3
1
4
90
4
1.5
1
5
85
5
6
87
6
2
7
86
7
1.5
1
8
92
8
9
90c
71
9
1
10
11
12
13
14
10
11
12
13
14
1
2-pyridyl
c-Hex
3.5
rac.
–44
–42
rac.
2-pyridyl
c-Hex
1
65
48
24
1
76
59
54
i-Pr
i-Pr
1
n-Hex
n-Hex
1
a All reactions were carried out with molar ratio of ke-
tone/Ph2Zn/Et2Zn/salen = 1.0:1.0:2.0:0.1.
a All reactions were carried out at –40 °C with molar ratio of alde-
hyde/Ph2Zn/Et2Zn/salen = 1.0:1.0:2.0:0.1, unless otherwise indicated.
b Determined by HPLC analysis using chiral stationary-phase column ac-
cording to the literature (ref. 4 and 10).
b Determined by HPLC analysis using chiral stationary-phase column ac-
cording to the literature (ref. 4c, 6–10, and 15).
c Absolute configuration was not determined.
We further examined the reactions of several ketones
with a zinc complex of 1 as a catalyst using an ethyl-
phenylzinc reagent derived from diphenylzinc and diethylz-
inc (Table 3). Due to the lower reactivity of ketones, all the
reactions were carried out without the addition of toluene
at room temperature. As expected, the reactions of the aro-
matic aldehydes exhibited good to high enantioselectivities
(Table 3, entries 1–8). In these reactions, some ketones
bearing electron-withdrawing groups proceeded smoothly,
which enabled the reactions to be carried out at 0 °C, and
high enantioselectivities were obtained (Table 3, entries 2,
4, and 8). The reactions of heteroaromatic aldehydes also
showed good to high enantioselectivities except for the re-
action of 2-acetylpyridine (Table 3, entries 9–11). Interest-
ingly, the reactions of α-substituted aliphatic ketones gave
opposite enantiomers with low enantioselectivities, and
no asymmetric induction was observed in the reaction of
2-octanone (Table 3, entries 12–14).
ing to the transition-state model reported by Cozzi et al.,11a
the observed stereochemistry can be explained by the tran-
sition-state model depicted in Figure 2, in which the si face
of aldehyde (R1 = Ar or Alk, R2 = H) or ketone (R1 = Ar, R2 =
Me) was preferentially attacked by the zinc reagent.16 How-
ever, in the reaction of dialkyl ketone, the orientation of the
zinc-bonded ketone was mainly dictated by the steric factor
of the alkyl substituents, and the opposite enantiomer was
produced as the result of a re-face attack by the zinc reagent
(R1 = Me, R2 = α-substituted Alk).18 Furthermore, the lone
pairs of carbonyl oxygen of 2-octanone are difficult to dis-
criminate, which meant there was no asymmetric induc-
tion of the reaction. However, further study is required to
fully understand the mechanism of asymmetric induction.
O
HO
Ph2Zn (1.0 equiv)
Et2Zn (2.0 equiv)
We also examined the reactions of cyclic aromatic ke-
tones and good enantioselectivities were obtained (Scheme
1). The absolute configurations of the products from the re-
actions of aromatic aldehydes or aromatic ketones were de-
termined as S by comparison of their specific rotation or
elution order of HPLC with reported values.4,6–10,15 Accord-
n
n
1 (10 mol%)
r.t.
n = 1: 24 h, 77% yield, 88% ee
n = 2: 120 h, 62% yield, 86% ee
Scheme 1 Enantioselective phenyl transfer to cyclic ketones using
Zn(salen) complex
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R1
O
R2
Ph
N
HO R2
R1
O
Zn
N
Zn
Et
O
Figure 2 Possible mechanism for enantioselective phenyl transfer to
aldehydes or ketones using a zinc complex of salen 1
In conclusion, we have demonstrated that a zinc com-
plex of salen 1 is an efficient catalyst for enantioselective
phenyl transfer to both aromatic aldehydes and aromatic
ketones. Further studies on the scope of the reaction and
clarification of the reaction mechanism are under way in
our laboratory.
Acknowledgment
This work was partially supported by JSPS KAKENHI Grant Number
24650532 and by the Cooperative Research Program of the ‘Network
Joint Research Center for Materials and Devices (IMCE, Kyushu Uni-
versity)’.
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nitrogen, and diethylzinc (0.38 mL, 1.06 mol·dm–3 in hexane)
was added at r.t. and stirred for 30 min at the temperature. This
suspension was added to a solution of salen 1 (10.9 mg, 0.02
mmol) in toluene (0.25 mL) and further stirred at the tempera-
ture for 30 min. After the mixture was cooled to –40 °C, p-chlo-
robenzaldehyde (28.1 mg, 0.2 mmol) was added. After being
stirred for 1 h at the same temperature, the mixture was
quenched with sat. aq NH4Cl, allowed to warm to r.t., and
extracted with Et2O and then washed with sat. aq NaCl. The
organic extract was dried over anhydrous Na2SO4 and concen-
trated. Silica gel chromatography of the residue (hexane–EtOAc,
19:1 to 9:1) gave the desired product (41.4 mg, 95%) as an oil.
The ee of the product was determined to be 94% by HPLC using
chiral stationary-phase column as described in the footnote b of
(13) Saito, B.; Katsuki, T. Synlett 2004, 1557.
(14) Although the structure of the actual zinc species is still unclear,
it is believed that the formation of PhZnEt is occurred, based on
the theoretical studies. For recent study, see: Rudolph, J.; Bolm,
C.; Norrby, P.-O. J. Am. Chem. Soc. 2005, 127, 1548; and refer-
ences cited therein.
(15) For enantioselective conversion of secondary alcohols into ter-
tiary alcohols, see: (a) Bagutski, V.; French, R. M.; Aggarwal, V.
K. Angew. Chem. Int. Ed. 2010, 49, 5142. (b) Stymiest, J. L.;
Bagutski, V.; French, R. M.; Aggarwal, V. K. Nature (London, U.K.)
2008, 456, 778.
(16) Cozzi presumed that the absolute configurations of the tertiary
propargylic alcohols from the alkynyl transfer to ketones in the
presence of (R, R)-Zn(salen) are S.11c However, some of these
alcohols seems to be R according to the recent study on the
determination of the absolute configurations of the tertiary
propargylic alcohols.17 Abdi et al. reported that the addition of
phenylacetylene to arylmethylketones in the presence of (R,R)-
Table 1. [α]D +20.2 (c 0.45, CHCl3) [lit.10d [α]D +19.1 (c 0.83,
CHCl3) for 83% ee, (S)].
13
23
All spectral data of products in Tables 1–3 were in accordance
with those reported in the literature.
Specific Rotation of some Compounds
(R)-Cyclohexylphenylmethanol
[α]D +33.9 (c 0.2, CHCl3) for 76% ee [lit.10d [α]D +38.0 (c 0.4,
CHCl3) for 96% ee, (R)].
26
23
Zn(salen) gave
R alcohols through the si-face attack of
ketones.11d
(S)-1-(4-Chlorophenyl)-1-phenylethanol
13
22
(17) Kotani, S.; Kukita, K.; Tanaka, K.; Ichibakase, T.; Nakajima, M.
J. Org. Chem. 2014, 79, 4817.
[α]D +13.2 (c 0.2, CHCl3) for 92% ee [lit.15b [α]D +14.8 (c 6.5,
CHCl3) for 98% ee, (S)].
(18) At present, we do not have any evidence to explain the change-
over of the stereoselectivity in the reactions of aliphatic
ketones.
(S)-Phenylindan-1-ol
[α]D17 +36.9 (c 1.6, CHCl3) for 88% ee [lit.15b [α]D24 –33.3 (c 1.05,
CHCl3) for 88% ee, (R)].
(19) Typical Experimental Procedure is Exemplified by Enantio-
selective Phenyl Transfer to p-Chlorobenzaldehyde
Diphenylzinc (43.9 mg, 0.2 mmol) was placed in a flask under
(S)-1-Cyclohexyl-1-phenylethanol
13
24
[α]D –7.1 (c 0.75, CH2Cl2) for 44% ee [lit.15a [α]D +17.9 (c 3.4,
CH2Cl2) for 99% ee, (R)].
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1238–1242

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