Instantaneous room-temperature and highly enantioselective ArTi(O-i-Pr)3 additions to aldehydes

Article abstract of DOI:10.1039/c1cc15059f

Direct asymmetric additions of ArTi(O-i-Pr)₃ to aldehydes catalyzed by a titanium catalyst of (R)-H₈-BINOL are reported. The reactions proceed instantaneously at room temperature, affording alcohols in ≥90% ee. Importantly, the ArTi(O-i-Pr)₃ reagent differentiates the ligand effectiveness in an order of H₈-BINOL > BINOL > TADDOL > diol 3 > disulfonamide 2.

Full text of DOI:10.1039/c1cc15059f

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COMMUNICATION
Instantaneous room-temperature and highly enantioselective
ArTi(O-i-Pr) additions to aldehydesw
3
a
ab
a
a
a
Kuo-Hui Wu, Shuangliu Zhou, Chien-An Chen, Mao-Chi Yang, Ruei-Tang Chiang,
a
a
Chi-Ren Chen and Han-Mou Gau*
Received 15th August 2011, Accepted 19th September 2011
DOI: 10.1039/c1cc15059f
Direct asymmetric additions of ArTi(O-i-Pr) to aldehydes catalyzed
3
demonstrated only in a couple of catalytic systems with the reactions
3a,14
1
by a titanium catalyst of (R)-H
proceed instantaneously at room temperature, affording alcohols in
Z90% ee. Importantly, the ArTi(O-i-Pr) reagent differentiates the
ligand effectiveness in an order of H -BINOL 4 BINOL 4
TADDOL 4 diol 3 4 disulfonamide 2.
8
-BINOL are reported. The reactions
being conducted at an initial low temperature of ꢀ78 1C
15
or at temperatures rꢀ15 1C. In contrast, our recent study
found that the 3-furyl addition of (3-furyl)Ti(O-i-Pr) to
ketones could be conducted at a mild reaction temperature
3
3
8
1
6
of 0 1C. The above study prompted us to explore direct
addition reactions of ArTi(O-i-Pr) (Ar = Ph (1a); p-tolyl (1b);
-MeOC (1c); 2-naphthyl (1d); 4-ClC (1e); 4-TMSC
1f)) which are effective reagents in late-transition metal-
3
4
6
H
4
H
6 4
6 4
H
The highly enantioselective addition reactions of arylzinc
reagents to aldehydes have been extensively explored in the
1
past decade for the synthesis of diarylmethanols, which are
(
1
7
18
catalyzed asymmetric reactions and coupling reactions.
Addition reactions of PhTi(O-i-Pr)3 to 2-naphthaldehyde
0
(8g) were first screened using chiral ligands of (1R,2R)-N,N -
key intermediates leading to bioactive compounds such as
2
3
neobenodine and cetirizine hydrochloride. A variety of
19
4
arylzinc sources, such as ZnPh , mixtures of ZnR /ZnPh ,
5
bis(trifluoromethylsulfonyl)-1,2-cyclohexanediamine (2), 1,2:5,
2
2
2
2
0
0 0
-di-O-isopropylidene-D-mannitol (3), a,a,a ,a -tetraphenyl-
21
6
2
arylzinc reagents from transmetallation of arylboronic acid or
6
,2-dimethyl-1,3-dioxolane-4,5-dimethanol (4, TADDOL),
arylboron with ZnEt
nucleophile with dialkylzinc or zinc halides, have been introduced
for this purpose. The commercially available ZnPh and the
mixed ZnPh /ZnR (R = Me or Et) reagents produce the
2
, and arylzinc from reactions of aryl
2
2
23
24
7
(
S)-BINOL (5), and (R)-H
8
-BINOL (6) and complex (R)-7
(eqn (1)); the results are summarized in Table 1. Compounds 2–6
2
are known as highly enantioselective ligands for titanium-
catalyzed organozinc addition reactions of aldehydes.
2
2
phenyl addition products only. Later, the in situ-prepared
arylzinc compounds have extended the reaction scope to
addition reactions of various aryl nucleophiles.
Recent studies have demonstrated that AlAr Et (THF)
x
3ꢀx
8
,9
10
11
(
x = 3 or 1), ArMgX and ArLi compounds are efficient
aryl sources for titanium-catalyzed asymmetric aryl addition
reactions of organic carbonyls, and excess amounts of Ti(OR)
are required to ensure the high stereocontrol of the addition
4
1
2
products. Roles of excess Ti(OR)
4
have been suggested as to
generate the dititanium active species bearing a chiral ligand
1
3
and to facilitate a removal of the product. It has been
suggested that the reactions involve the additions of organo-
titanium species, which are in situ-generated from reactions of
In the absence of Ti(O-i-Pr)4 and at 0 1C, the titanium
catalyst of disulfonamide 2 or diol 3 produced 2-naphthyl-
phenylmethanol (9g) in 100% conversions over 10 min, but racemic
or a low enantioselectivity of 24% ee of 9g were obtained (entries
1 and 2). The TADDOL 4 yielded 9g in a 47% ee (entry 3). The
catalytic system of (S)-BINOL ((S)-5) produced (S)-9g in a
organometallic compounds with Ti(OR) . However, direct
4
asymmetric additions of organotitanium reagents have been
a
Department of Chemistry, National Chung Hsing University,
Taichung 402, Taiwan, Republic of China.
E-mail: hmgau@dragon.nchu.edu.tw; Tel: +886 4 2287 8615;
Fax: +886 4 2286 2547
Anhui Key Laboratory of Functional Molecular Solids, College of
Chemistry and Materials Science, Anhui Normal University, Wuhu,
Anhui 241000, China
7
7% ee (entry 4), while a catalyst of (R)-H
afforded (R)-9g in an excellent 92% ee (entry 5). The preformed
titanium catalyst of (R)-7 along with 1.2 equiv. PhTi(O-i-Pr)
8
-BINOL ((R)-6)
b
3
also afforded (R)-9g in a similar 93% ee (entry 6). The above
results reveal that both the in situ-formed titanium catalyst of
w Electronic supplementary information (ESI) available: General pro-
cedures, HPLC conditions and chromatograms, and H and C NMR
spectroscopic data of addition products. See DOI: 10.1039/c1cc15059f
1
13
(R)-H -BINOL and the preformed (R)-7 afford the product in
8
1
1668 Chem. Commun., 2011, 47, 11668–11670
This journal is c The Royal Society of Chemistry 2011

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Table 1 Optimizations of asymmetric PhTi(O-i-Pr)
2-naphthylaldehyde
3
addition to
Table 2 ArTi(O-i-Pr) addition reactions of aldehydes catalyzed by
the catalytic system of (R)-7
3
a
a
b
c
b
c
(R)-7
(mol%) Product (%)
Yield
Ee
(%)
Entry Compound 1a (equiv.) T/1C Time/min Conv (%) Ee (%)
Entry RCHO
1
Ar
Ph
1
2
3
4
5
6
7
8
9
1
1
2
3
4
1.4
1.4
1.4
1.4
1.4
1.2
1.2
1.2
1.2
1.2
1.2
0
0
0
0
0
0
0
0
10
10
10
10
10
10
10
10
10
1
100
100
100
100
100
100
100
100
100
100
100
rac
24 (R)
47 (R)
77 (S)
92 (R)
93 (R)
92 (R)
93 (R)
93 (R)
93 (R)
94 (R)
10
10
(R)-9a 94
(R)-9b 95
99
(S)-5
(R)-6
(R)-7
(R)-7
(R)-7
(R)-7
(R)-7
(R)-7
2
Ph
94
d
e
rt
rt
rt
3
4
Ph
Ph
10
10
(R)-9c
92
90
95
0
1
f
—
a
2
-Naphthylaldehyde/2–7 = 0.50/0.050 mmol; equiv. of PhTi(O-i-Pr)
b
3
is
relative to 2-naphthylaldehyde. Conversions were determined based on
(R)-9d 95
1
c
H NMR spectra. ee values were determined by HPLC using suitable
d
e
4 4
columns. 0. 25 equiv. Ti(O-i-Pr) was added. 0.50 equiv. Ti(O-i-Pr)
5
Ph
3
(R)-9e
(R)-9f
91
94
90
f
was added. The reaction was quenched immediately.
4
the best enantioselectivities. The effect of Ti(O-i-Pr) was also
6
7
8
9
Ph
Ph
Ph
Ph
5
5
95
91
94
94
studied, and additions of 0.25 or 0.50 equiv. of Ti(O-i-Pr) did
4
not improve the stereoselectivity of the product (entries 7 and
8
). To our surprise, the reactions could be carried out at room
(R)-9g 94
(R)-9h 94
temperature (entries 9–11) and completed instantaneously,
producing (R)-9g in 94% ee (entry 11). In terms of stereo-
chemistry, the catalyst of (S)-BINOL catalyzed the phenyl
addition of 8g from a Si-face to yield (S)-9g (entry 4) pre-
dominantly as compared to (R)-9g obtained from a Re-face
10
10
(R)-9i
(R)-9j
92
95
addition by the catalyst of (R)-H
In terms of reactivity and enantioselectivity, this study
clearly reveals that the titanium catalyst of the H -BINOL is
8
-BINOL (entries 5 and 6).
8
1
1
1
0
1
2
Ph
Ph
Ph
10
10
10
98
97
90
currently the most efficient system. In contrast, catalysts of
ligand 2–4 are not good enough to attain high enantio-
selectivities for the PhTi(O-i-Pr) addition reaction. The low
3
(R)-9k 96
enantioselectivities are attributed to higher levels of back-
ground reaction of PhTi(O-i-Pr)
entiates the ligand effectiveness in an order of H
BINOLs (5) 4 TADDOL (4) 4 diol 3 4 disulfonamide 2
Table 1, entries 1–5).
3
. Thus PhTi(O-i-Pr)
3
differ-
8
-BINOLs (6) 4
(S)-9l
93
(
Addition reactions of aromatic, vinylic, heterocyclic and
aliphatic aldehydes were subsequently studied with the reaction
time kept at 1 min (eqn (2)); the results are listed in Table 2.
For aromatic aldehydes with either an electron-donating or an
electron-withdrawing substituent at 2-, 3-, or 4-position,
PhTi(O-i-Pr)3 addition reactions employing 3–10 mol% of
1
1
1
3
4
5
Ph
Ph
Ph
10
10
10
(R)-9m 94
93
92
95
(S)-9n
(S)-9o
90
88
(
R)-7 afforded chiral secondary diarylmethanols 9a–9k in
4
that 3 mol% of (R)-7 was effective enough for 4-methoxy-
90% yields and Z 90% ee (entries 1–11). It is worth noting
16
Ph
10
10
(S)-9p
90
96
93
1
7
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
p-Tolyl
6
4-MeOC H 10
2-Naphthyl 10
4-ClC
(S)-9b
(S)-9e
(S)-9g 86
(S)-9l
(S)-9q
95
95
94
90
benzaldehyde (entry 5), and 5 mol% of (R)-7 was used for
18
19
94
4
d
1
- or 2-naphthaldehyde (entries 6 and 7). The catalytic system
applied equally well to (E)-cinnamaldehyde or 2-furaldehyde
entries 12 and 13), affording products 9l and 9m in 90 and
3% ee. Regardless of the steric bulk of aliphatic aldehydes,
the addition reactions of linear pentanal or of bulkier
-methylpropanal or 2,2-dimethylpropanal furnished secondary
2
2
a
0
1
6
H
4
10
10
92
95
e
94
4-TMSC
6
H
4
(
b
3
Aldehyde/(R)-7/ArTi(O-i-Pr) = 0.50/0.015–0.050/0.60 mmol. Isolated
9
c
yield. Determined by HPLC using appropriate chiral columns.
d
e
1% conversion. (S)-9q was converted to (4-BrC
9
a determination of the ee value.
6 4
H )CH(OH)Ph for
2
alcohols 9n–p in good to excellent yields and excellent
This journal is c The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 11668–11670 11669

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5
6
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Fig. 1 Linear plot of ee of (R)-9g vs. ee of (R)-H -BINOL.
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of aryl nucleophiles of ArTi(O-i-Pr)3 (Ar p-tolyl,
-MeOC H , 2-naphthyl, 4-ClC H , or 4-TMSC H ) to
=
4
6
4
6
4
6
4
benzaldehyde were also studied, affording aryl addition products
in Z 90% ee (entries 17–21) but in opposite absolute structure
as compared to products from additions of the phenyl nucleo-
phile to aryl aldehydes.
To explore the mechanistic insight, PhTi(O-i-Pr)
to 8g in the presence of 0, 20, 40, 60, 80, or 100% ee of
R)-H -BINOL were conducted, producing (R)-9g in 1.3, 18.1,
6.8, 56.3, 74.5, and 91.6% ee, respectively. A linear plot of ee
of (R)-9g vs. ee of (R)-H -BINOL (Fig. 1) suggests that the
3
additions
(
2
b) C.-A. Chen, K.-H. Wu and H.-M. Gau, Adv. Synth. Catal.,
008, 350, 1626; (c) S. Zhou, K.-H. Wu, C.-A. Chen and
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(
8
3
10 Y. Muramatsu and T. Harada, Chem.–Eur. J., 2008, 14, 10560.
1
1 Y. Nakagawa, Y. Muramatsu and T. Harada, Eur. J. Org. Chem.,
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13 (a) B. Weber and D. Seebach, Tetrahedron, 1994, 50, 7473;
8
2
2
5
metallic active species involves only one H -BINOL. To
8
´
n and M. Yus, Chem. Rev., 2006, 106, 2126.
study the autocatalysis, 0.60 mmol of PhTi(O-i-Pr)3 and
(
(
(
b) M. Mori and T. Nakai, Tetrahedron Lett., 1997, 35, 6233;
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d) J. Balsells, T. J. Davis, P. Carroll and P. J. Walsh, J. Am.
5
0% of (R)-9g (0.25 mmol, 91.6% ee) were mixed in the
absence of (R)-H -BINOL followed by an addition of 50%
substrate of 8g (0.25 mmol). The reaction over 2 h furnished
R)-9g in a 96% conversion with an 84.7% ee. The result did
´
8
Chem. Soc., 2002, 124, 10336; (e) K.-H. Wu and H.-M. Gau,
Organometallics, 2004, 23, 580.
4 (a) Y. N. Ito, X. Azira, A. K. Beck, A. Bohac, C. Ganter,
´ ˇ
(
1
show autocatalysis with an improvement of 38.9% ee relative
to the 45.8% ee of the pre-added (R)-9g in the case of no
autocatalysis. However, the slower reaction and the linear
effect of the catalytic system indicate that the autocatalysis
of the chiral alcohol product is negligible as compared to the
catalytic reaction.
R. E. Gawley, F. N. M. Kuhnle, J. Tuleja, Y. M. Wang and
¨
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1
1
1
In summary, the most efficient and direct aryl additions of
ArTi(O-i-Pr) to aldehydes catalyzed by the titanium catalyst
3
1
8 (a) J. W. Han, N. Tokunaga and T. Hayashi, Synlett, 2002, 871;
(
of (R)-H
several important features. First, the ArTi(O-i-Pr)
reactions complete instantaneously at room temperature.
Second, excess amounts of Ti(O-i-Pr) are not necessary along
with 0.2 equiv. excess of ArTi(O-i-Pr) used, revealing the
atomic efficiency of the Ti–H -BINOLate catalytic system.
8
-BINOL are reported. This study demonstrates
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3
addition
(
d) H.-T. Yang, S. Zhou, F.-S. Chang, C.-R. Chen and H.-M. Gau,
4
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3
8
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the order of H -BINOLs 4 BINOLs 4 TADDOL 4 4 diol 3 4
disulfonamide 2.
8
Financial support from the National Science Council of
Taiwan, ROC, under the grant number of NSC99-2113-
M-005-005-MY3 is appreciated.
1
9, 3368.
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2
1
2
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1670 Chem. Commun., 2011, 47, 11668–11670
This journal is c The Royal Society of Chemistry 2011