Novel Lewis acid-assisted chiral Lewis acid (LLA) system: Development of boroxin-Ti-BINOL-catalyzed asymmetric allylation of aldehydes

Article abstract of DOI:10.1055/s-2004-832830

The formation of hetero multimetallic complex having B-O-Ti bond could increase the Lewis acidity of titanium. A novel LLA system made up of Ti-BINOL and 4-(trifluoromethyl)phenyl-boroxin dramatically accelerated the allylation reaction of aldehyde with h

Full text of DOI:10.1055/s-2004-832830

CLUSTER
2437
Novel Lewis Acid-Assisted Chiral Lewis Acid (LLA) System: Development of
Boroxin–Ti–BINOL-Catalyzed Asymmetric Allylation of Aldehydes
Development of
B
u
oroxin–Ti–B
o
IN
O
L
-Cataly
y
ze
d
A
symm
a
etric
A
llyla
o
tion of Aldehydes Xia, Kazutaka Shibatomi, Hisashi Yamamoto*
Department of Chemistry, University of Chicago, 5735 South Ellis Avenue, Chicago, IL 60637, USA
Fax +1(773)7020805; E-mail: yamamoto@uchicago.edu
Received 16 March 2004
was far superior to the control (5% yield, 51% ee: entry
Abstract: The formation of hetero multimetallic complex having
B-O-Ti bond could increase the Lewis acidity of titanium. A novel
LLA system made up of Ti–BINOL and 4-(trifluoromethyl)phenyl-
boroxin dramatically accelerated the allylation reaction of aldehyde
with high enantioselectivity.
1).8 It was surprising that aryl boroxin 2 also accelerated
the reaction although aryl boroxin itself is generally
known to have weak Lewis acidity. Increasing the amount
of 1 decreased the % ee value significantly (entries 6–8),
because 1 itself was able to catalyze the reaction under the
present reaction conditions to generate the racemic prod-
uct. On the other hand, the use of 5 mol% (based on B) of
2 afforded excellent yield while retaining a high% ee val-
ue (entry 10: 92% yield, 93% ee) because aryl boroxin it-
self did not catalyze the reaction at all. However, the use
of 10 mol% of 2 again decreased the chemical yield (entry
11). As might be expected, the use of boroxin having elec-
tron-withdrawing group showed higher reactivity (entries
11–13). The optimized reaction system was applied to a
variety of aldehydes and the results are summarized in
Table 2. In all cases the reaction proceeded in high yield
and high asymmetric induction up to 97% ee (entry 4,
Table 2) was achieved.
Key words: aldehydes, allylations, asymmetric catalysis, titanium,
Lewis acid assisted chiral Lewis acid catalysts
It is obvious that Lewis acid catalysis has played an im-
portant role in synthetic organic chemistry.1 During the
last decade, our research interest has been focused on the
design of combined acid catalyst2–5 examples of which are
classified into three categories: Brønsted acid assisted
chiral Lewis acid catalysts (BLA),2 Lewis acid assisted
chiral Brønsted acid catalysts (LBA)3,4 and Lewis acid as-
sisted chiral Lewis acid catalysts (LLA).5 BLA and LBA
are capable of dramatic acceleration of the reaction rate
and/or quite unique selectivity which is totally unattain-
able by the use of Lewis acid or Brønsted acid alone. In
contrast, the development of an efficient LLA system has
not yet been well established because of the difficulty in
fixing a reaction site between more than two acidic cen-
ters. Nonetheless, the combination of different Lewis
acids in enhancing reactivity and/or selectivity will surely
break new ground in Lewis acid catalysis if a suitable
catalyst system is designed.
The exact activation mechanism of this LLA system has
not been clarified yet. A plausible interpretation is the for-
mation of hetero multimetallic complex having B-O-Ti
bond shown in Figure 2.9 Thus, Lewis acidity of boron
atom would enhance the Lewis acidity of titanium atom.10
In conclusion, the results reported herein provide addi-
tional evidence of the utility of the concept of combined
acid catalysis. We believe that the mechanistic model im-
plied by the complex in Figure 2 has useful predictive
power. The application of such a LLA system to other
types of reaction will be reported in due course.
In this context, we designed a novel LLA system made up
of Ti–BINOL6 and the various achiral Lewis acids shown
in Figure 1. Achiral Lewis acid is expected to coordinate
with oxygen atom on Ti–BINOL complex to enhance the
Lewis acidity of the titanium metal center. Ti–BINOL-
catalyzed asymmetric allylation7 of benzaldehyde by al-
lyltributyltin was examined with several Lewis acids as
co-catalyst to afford chiral homoallyl alcohol (Table 1).
Although Ti–BINOL catalyst and allyltributyltin is one of
the best methods to generate chiral homoallylic alcohols,
there still remain several problems to be solved: catalyst
loading, reaction time, reproducible results, and others.
The reaction was therefore dramatically accelerated by
the use of only 1 mol% tris(pentafluorophenyl)borane (1)
or 4-(trifluoromethyl)phenylboroxin (2) which retained a
significantly high% ee value (entries 6 and 9). This result
δ–
LA
OiPr
O
Ti
OiPr
O
O
H
R
Figure 1 Design of Lewis acid-assisted chiral Lewis acid
General Experimental Procedure.
All manipulations were carried out under dry nitrogen using stan-
dard Schlenk or vacuum line techniques. Solvents were dried over
appropriate drying agents and freshly distilled prior to use. CDCl3
SYNLETT 2004, No. 13, pp 2437–2439
Advanced online publication: 24.09.2004
DOI: 10.1055/s-2004-832830; Art ID: Y03104ST
© Georg Thieme Verlag Stuttgart · New York
0
3
.1
1
.2
0
0
4
1
was dried by MS 4 Å. H NMR spectra were measured on a 400
MHz spectrometer. Chemical shifts of 1H NMR spectra were

2438
G. Xia et al.
CLUSTER
Ar
Table 2 Boroxin–Ti–(S)-BINOL-Catalyzed Asymmetric Allyla-
tion of Aldehydesa
B
OiPr
O
O
O
Ti-(S)-BINOL (10 mol%)
[4-(CF3)C6H4BO]3 (5 mol%)
n
Ti
O
OH
OiPr
Sn(Bu)3
m
+
m = 1, n = 1 or m = 0, n = 2
CH2Cl2, –20 °C, 4 h
R
H
R
Entry R-CHO
1
Time (h) Yield (%) % ee
(config.)b
Figure 2 Plausible structure of active catalyst
4
93
94 (R)
CHO
CHO
Table 1 LLA-Catalyzed Asymmetric Allylation of Benzaldehydea
Ti-(S)-BINOL (10 mol%)
O
OH
Lewis acid
Sn(Bu)3
+
2
3
8
8
3
83
87
95
88 (S)
92 (S)
97 (S)
CH2Cl2, –20 °C, 4 h
Ph
H
Ph
Entry Lewis acid
mol%
Yield (%) % ee
(config.)b
CHO
CHO
1
2
None
–
1
5
6
51 (S)
4
O
Al(OPh)3
Sc(OTf)3
Yb(OTf)3
In(OTf)3
(C6F5)3B
(C6F5)3B
(C6F5)3B
66 (S)
53 (S)
74 (S)
71 (S)
89 (S)
67 (S)
48 (S)
89 (S)
93 (S)
92 (S)
91 (S)
89 (S)
3
1
21
22
51
77
76
74
82
92
66
56
75
a The reactions were carried out in CH2Cl2 at –20 °C in the presence
of 10 mol% of LLA catalyst.
4
1
b The ee values were determined by HPLC analysis. Absolute config-
urations were determined by the comparison of optical rotations with
reported values. See ref.11
5
1
6
1
7
5
Typical Experimental Procedure for Asymmetric Allylation of
Aldehydes with Allyltri-n-butylstannane Reagents Catalyzed
by BINOL, Ti(Oi-Pr)4 and 4-(Trifluoromethyl)phenylboroxin.
Synthesis of (S)-(–)-1-Phenyl-3-buten-1-ol.
8
10
1
9c
10c
11c
12c
13c
[4-(CF3)C6H4BO]3
[4-(CF3)C6H4BO]3
[4-(CF3)C6H4BO]3
[C6H5BO]3
5
Ti(Oi-Pr)4 (56.8 mg, 0.200 mmol) was added to a solution of (S)-
(–)-1,1¢-bi-2-naphthol (57.2 mg, 0.199 mmol) and 4-(trifluoro-
methyl)phenylboroxin (17.2 mg, 0.0333 mmol) in CH2Cl2 (6 mL).
The red-dark mixture was stirred for 6 h and benzaldehyde (212 mg,
1.99 mmol) was added. After being stirred for 10 min, the contents
were cooled to –20 °C, and allyltri-n-butylstannane (726 mg, 2.19
mmol) was added. The reaction mixture was stirred for 4 h. Sat.
NaHCO3 (1 mL) was added, and the contents were stirred for 1 h
and then poured over Na2SO4 and filtered through a plug of Celite.
The crude material was purified by flash chromatography, eluting
with 10:1 (v/v) hexanes–EtOAc to give (S)-(–)-1-phenyl-3-buten-1-
ol as a clear oil (282 mg, 92%). The enantioselectivity was deter-
mined to be 93% ee by HPLC analysis using a chiral column
(Chiralcel OD-H, hexane–i-PrOH = 97.5:2.5, flow rate = 1.0 mL/
10
10
[3,5-(CF3)2C6H3BO]3 10
a The reactions were carried out in CH2Cl2 at –20 °C for 4 h in the
presence of LLA catalyst. LLAs were prepared by stirring the mixture
of Ti(Oi-Pr)4 and (S)-BINOL (1 equiv) in CH2Cl2 at r.t. for 30 min,
followed by the treatment of present mol% Lewis acid at r.t. for 30
min.
b The ee values were determined by HPLC analysis. Absolute config-
urations were determined by the comparison of optical rotations with
reported values. See ref.11,
1
min): tminor = 10.6 min (R), tmajor = 12.7 (S). H NMR (400 MHz,
c LLA was prepared by stirring the mixture of Ti–(S)-BINOL and
present mol% [B] of aryl boroxin at r.t. for 6 h.
CDCl3): d = 2.01 (d, 1 H, J = 2.5 Hz), 2.52 (m, 2 H), 4.75 (dt, 1 H,
J = 6.9, 2.5 Hz), 5.14–5.20 (m, 2 H,), 5.82 (m, 1 H), 7.25–7.37 (m,
5 H).
(R)-1-Phenyl-5-hexen-3-ol. 1H NMR (400 MHz, CDCl3): d = 1.60
(d, 1 H, J = 1.9 Hz), 1.80 (m, 2 H), 2.16–2.23 (m, 1 H), 2.29–2.36
(m, 1 H), 2.64–2.84 (m, 2 H), 3.68 (m, 1 H), 5.15 (d, 2 H, J = 11.8
Hz), 5.75–5.86 (m, 1 H), 7.16–7.31 (m, 5 H). The enantioselectivity
was determined to be 94% ee by HPLC analysis using a chiral col-
umn (Chiralcel OD-H, hexane–i-PrOH = 95.3:4.7, flow rate = 0.5
mL/min): tminor = 17.0 min (S), tmajor = 24.8 min (R).
reported relative to tetramethylsilane (d = 0 ppm) or CHCl3 (d =
7.26 ppm). Unless otherwise specified, all reagents were purchased
from Aldrich Chemical Co. Titanium isopropoxide, allyltri-n-butyl-
stannane and aldehydes were purified by distillation before use.
Preparation of 4-(Trifluoromethyl)phenylboroxin.
Heating commercially available 4-(trifluoromethyl)phenylboronic
acid at 110 °C under vacuum for 24 h afforded 4-(trifluorometh-
yl)phenylboroxin. H NMR (400 MHz, CDCl3): d = 7.78 (d, 6 H,
(S),(E)-1-Phenyl-1,5-hexadien-3-ol. 1H NMR (400 MHz, CDCl3):
d = 1.78 (br, 1 H), 2.39 (m, 2 H), 4.37 (dd, 1 H, J = 12.3, 6.1 Hz),
5.16–5.22 (m, 2 H), 5.87 (m, 1 H), 6.25 (dd, 1 H, J = 15.9, 6.3 Hz),
6.62 (d, 1 H, J = 15.7 Hz), 7.22–7.40 (m, 5 H). The enantioselectiv-
ity was determined to be 88% ee by HPLC analysis using a chiral
column (Chiralcel OD-H, hexane–i-PrOH = 95.0:5.0, flow
rate = 1.0 mL/min): tminor = 11.0 min (R), tmajor = 17.9 min (S).
1
J = 7.7 Hz), 8.35 (d, 6 H, J = 7.7 Hz).
Synlett 2004, No. 13, 2437–2439 © Thieme Stuttgart · New York

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Development of Boroxin–Ti–BINOL-Catalyzed Asymmetric Allylation of Aldehydes
2439
1
(S)-1-(2-Furyl)-3-buten-1-ol. H NMR (400 MHz, CDCl3): d =
2.00 (br, 1 H), 2.61–2.66 (m, 2 H), 4.76 (m, 1 H), 5.14–5.23 (m, 2
H), 5.82 (m, 1 H), 6.26 (d, 1 H, J = 3.2 Hz), 6.34 (dd, 1 H, J = 3.1,
1.6 Hz), 7.39 (d, 1 H, J = 1.8 Hz). The enantioselectivity was deter-
mined to be 97% ee by HPLC analysis using a chiral column
(Chiralcel OJ, hexane–i-PrOH = 98.0:2.0, flow rate = 1.0 mL/min):
(4) LBA-catalyzed enantioselective cyclizations: (a) Ishihara,
K.; Nakamura, S.; Yamamoto, H. J. Am. Chem. Soc. 1999,
121, 4906. (b) Nakamura, S.; Ishihara, K.; Yamamoto, H. J.
Am. Chem. Soc. 2000, 122, 8131. (c) Ishihara, K.; Ishibashi,
H.; Yamamoto, H. J. Am. Chem. Soc. 2001, 123, 1505.
(d) Ishihara, K.; Ishibashi, H.; Yamamoto, H. J. Am. Chem.
Soc. 2002, 124, 3647.
t
major = 16.7 min (S), tminor = 18.0 min (R).
(5) Ishihara, K.; Kobayashi, J.; Inanaga, K.; Yamamoto, H.
Synlett 2001, 394.
(6) Recent review of BINOL ligands for asymmetric catalysis:
Chen, Y.; Yekta, S.; Yudin, A. K. Chem. Rev. 2003, 103,
3155.
(S)-1-Cyclohexyl-3-buten-1-ol. 1H NMR (400 MHz, CDCl3): d =
0.80–1.40 (m, 5 H), 1.54 (d, 1 H, J = 6.9 Hz), 1.60–1.92 (m, 6 H),
2.07–2.18 (m, 1 H), 2.29–2.38 (m, 1 H), 3.40 (m, 1 H), 5.15 (m, 2
H), 5.87 (m, 1 H). The enantioselectivity was determined to be 92%
ee by HPLC analysis of the 3,5-dinitrobenzoate of the product pre-
pared by esterification (3,5-dinitrobenzoyl chloride, triethylamine–
1,2-dichloroethane) using a chiral column (Chiralcel OD-H, hex-
ane–i-PrOH = 98.5:1.5, flow rate = 1.0 mL/min): tminor = 13.6 min
(R), tmajor = 14.4 min (S).
(7) Catalytic asymmetric allylations with Ti–BINOL complex:
(a) Aoki, S.; Mikami, K.; Terada, M.; Nakai, T. Tetrahedron
1993, 49, 1783. (b) Costa, A. L.; Piazza, M. G.; Tagliavini,
E.; Trombini, C.; Umani-Ronchi, A. J. Am. Chem. Soc.
1993, 115, 7001. (c) Keck, G. E.; Tarbet, K. H.; Geraci, L. S.
J. Am. Chem. Soc. 1993, 115, 8467. (d) Keck, G. E.; Geraci,
L. S. Tetrahedron Lett. 1993, 34, 7827. (e) Keck, G. E.;
Krishnamurthy, D.; Grier, M. C. J. Org. Chem. 1993, 58,
6543. (f) Keck, G. E.; Krishnamurthy, D.; Chen, X.
Tetrahedron Lett. 1994, 35, 8323. (g) Faller, J. W.; Sams,
D. W.; Liu, X. J. Am. Chem. Soc. 1996, 118, 1217.
(h) Gauthier, D. R. Jr.; Carreira, E. M. Angew. Chem., Int.
Ed. Engl. 1996, 35, 2363. (i) Weigand, S.; Brückner, R.
Chem.–Eur. J. 1996, 2, 1077. (j) Yu, C.-M.; Choi, H.-S.;
Jung, W.-H.; Lee, S.-S. Tetrahedron Lett. 1996, 37, 7095.
(k) Yu, C.-M.; Choi, H.-S.; Jung, W.-H.; Kim, H.-J.; Shin, J.
Chem. Commun. 1997, 761. (l) Yu, C.-M.; Choi, H.-S.;
Yoon, S.-K.; Jung, W.-H. Synlett 1997, 889. (m) Marshall,
J. A. Chemtracts 1997, 10, 649. (n) Keck, G. E.; Yu, T. Org.
Lett. 1999, 1, 289. (o) Brenna, E.; Scaramelli, L.; Serra, S.
Synlett 2000, 357. (p) Kii, S.; Maruoka, K. Tetrahedron
Lett. 2001, 42, 1935. (q) Hanawa, H.; Kii, S.; Maruoka, K.
Adv. Synth. Catal. 2001, 343, 57. (r) Maruoka, K. Pure
Appl. Chem. 2002, 74, 123. (s) Hanawa, H.; Hashimoto, T.;
Maruoka, K. J. Am. Chem. Soc. 2003, 125, 1708. (t) Kii, S.;
Maruoka, K. Chirality 2003, 15, 68. (u) Hanawa, H.;
Uraguchi, D.; Konishi, S.; Hashimoto, T.; Maruoka, K.
Chem.–Eur. J. 2003, 9, 4405.
(8) Keck has also reported that the use of Ti(Oi-Pr)4 and BINOL
(1:1) catalyze the allylation of benzaldehyde very slowly at
–20 °C even in the presence of activated molecular sieves
[10 mol% (Ti), 70 h, 88% yield, 95% ee]. See ref.7c
(9) A referee has argued that an ionic complex made up of
borane–isopropoxide ate complex and cationic titanium(IV)
triisopropoxide could be formed and act as catalyst.
(10) Maruoka has reported bis[binaphthoxy(isopropoxy)tita-
nium] oxide having Ti-O-Ti bond. In this paper, they
assumed this type activation system (LLA) as one of the
possible intermediates for the reaction. See ref.7s. Another
possibility in our system is that the monomer of aryl boroxin
would coordinate to an oxygen atom on Ti–BINOL complex
and enhance the Lewis acidity of titanium in the same
fashion, which seem to be also an example of LLA
activation.
Acknowledgment
Support of this research was provided by SORST project of Japan
Science and Technology Agency (JST), National Institute of Health
(NIH) GM068433-01, and starter grant from the University of
Chicago.
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Synlett 2004, No. 13, 2437–2439 © Thieme Stuttgart · New York