Catalytic enantioselective aryl transfer: Asymmetric addition of boronic acids to aldehydes using pyrrolidinylmethanols as ligands

Article abstract of DOI:10.1016/j.tetlet.2005.09.026

Pyrrolidinylmethanols, easily accessible from readily available (S)-proline, were applied in zinc-catalyzed addition of arylboronic acids to aromatic aldehydes; the reaction was found to proceed in excellent yields and high enantioselectivities (up to 98% ee).

Full text of DOI:10.1016/j.tetlet.2005.09.026

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7827–7830
Catalytic enantioselective aryl transfer: asymmetric addition
of boronic acids to aldehydes using pyrrolidinylmethanols as ligands
a,
a
a
a
*
Antonio L. Braga, Diogo S. L u¨ dtke, Paulo H. Schneider, Fabricio Vargas,
b
b
a
Alex Schneider, Ludger A. Wessjohann and M a´ rcio W. Paix a˜ o
a
Departamento de Qu ı´ mica, Universidade Federal de Santa Maria, 97105-900, Santa Maria, RS, Brazil
b
Leibniz-Institute of Plant Biochemistry, Weinberg 3, D-06120 Halle (Saale), Germany
Received 15 June 2005; revised 5 September 2005; accepted 6 September 2005
Abstract—Pyrrolidinylmethanols, easily accessible from readily available (S)-proline, were applied in zinc-catalyzed addition of aryl-
boronic acids to aromatic aldehydes; the reaction was found to proceed in excellent yields and high enantioselectivities (up to 98%
ee).
ꢀ
2005 Elsevier Ltd. All rights reserved.
Due to the high biological activity of various deriva-
tives, enantiopure diarylmethanols are important com-
pounds for the pharmaceutical industry. For example,
neobenodine, orphenadrine, and carbinoxamine show
effectively catalyze the phenyl transfer reactions to alde-
hydes using boronic acids as the aryl source with high ee
values are relatively rare. Thus, the development of
easily prepared and effective chiral ligands is an impor-
tant challenge for the practical applications of phenyl
transfer using boronic acids.
6
,7
1
strong antihistaminic properties. More recently, enantio-
merically pure diarylmethanols have been used as key
intermediates for the synthesis of diarylalkylmethanes,
which are antimuscarinics, antidepressants, and endo-
In connection with our current interests in the asymmet-
2
8
thelin antagonists.
ric addition of organozinc reagents to aldehydes, we
recently described the highly enantioselective addition
of an arylzinc reagent to aldehydes, generated from
readily accessible aryl boronic acids. The major advan-
tage of this protocol is that almost any aryl group can
be transferred to aromatic aldehydes with excellent
Besides the reduction of appropriate diarylketones,
where the achievement of high enantioselectivities can
become problematic when the two aryl groups are simi-
3
lar in volume or electronic nature, the enantioselective
9
arylation of aldehyde substrates appears to be the most
promising alternative for the preparation of these mole-
enantioselectivities.
4
cular systems. Since the pioneering work of Fu, several
In this letter, we wish to report our successful endeavor
in this area by using readily accessible chiral proline-
based amino alcohols 2a–c as ligands.
reports concerning the preparation of chiral diarylmeth-
anols by arylzinc addition to aldehydes have been pub-
5
lished. In this context, the recently introduced
6
procedure, which takes advantage of the readily avail-
A series of chiral and modular pyrrolidinylmethanols
were obtained starting from readily available (S)-proline
as shown in Scheme 1. Ligands 2a–c were obtained in
good yields from N-Boc proline methyl ester 1 by reac-
tion with ArMgBr and subsequent reduction with lith-
ium aluminum hydride in THF under reflux to afford
the corresponding N-methyl derivatives in 82–87% over-
able aryl boronic acids appears to be very promising
for effecting this transformation, since it allows the easy
preparation of several substituted arylzinc reagents and
therefore the synthesis of a wide range of substituted
chiral diaryl methanols. Unfortunately, ligands which
1
0,11
all yields.
Keywords: Diarylmethanols; Asymmetric catalysis; Zinc; Boronic acids;
Proline.
*
Corresponding author. Tel.: +55 55 3220 8761; fax: +55 55 3220
998; e-mail: albraga@quimica.ufsm.br
With the target ligands in hand, we focused our atten-
tion to investigating the enantioselective arylation of
8
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.026

7828
A. L. Braga et al. / Tetrahedron Letters 46 (2005) 7827–7830
O
Table 2. Catalytic arylation of aldehydes with aryl boronic acids using
ligand 2a
Ar
Ar
(i), (ii)
OMe
OH
1
2
) Toluene, 60˚C, 12 h
OH
N
N
) 2a (20 mol%)
1
Boc
Me
Ar B(OH)2
Et Zn
2
Ar1
Ar2
2
3
) Ar CHO, 0˚C, 12 h
1
2 a-c
1
2
a
b,c
Entry Ar
Ar
Yield ee (%)
(%)
Scheme 1. General synthesis of chiral ligands 2a–c. Reagents and
conditions: (i) 2.5 equiv ArMgBr, THF, rt; (ii) LiAlH , THF, reflux.
4
1
2
3
4
5
6
7
8
9
Phenyl
4-Methylphenyl
2-Methylphenyl
4-Methoxyphenyl 97
2-Methoxyphenyl 92
4-Chlorophenyl
2-Chlorophenyl
2-Bromophenyl
Phenyl
95
98
94 (S)
98 (S)
93 (S)
84 (S)
98 (S)
90 (S)
80 (S)
93 (R)
86 (R)
86 (R)
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
4-Methylphenyl
4-Methoxyphenyl Phenyl
4-Chlorophenyl Phenyl
p-tolualdehyde with phenylboronic acid. The results of
this study are depicted in Table 1.
90
88
91
90
98
91
In order to optimize the reaction conditions, effects of
catalyst loading, temperature, and amount of Et Zn
were first investigated in some detail for ligand 2a (Table
, entries 1–8). The arylation of p-tolualdehyde in the
2
1
10
a
b
c
presence of 20 mol % of ligand 2a gave the correspond-
ing product in a high yield (96%) and an enantiomeric
excess of 87% (entry 1). Carrying out reaction at 0 ꢁC,
the ee was increased to 94% (entry 2). No changes in
ee values were observed when the temperature of the
reaction was decreased from 0 to ꢀ20 ꢁC (entry 3).
Decrease in the catalyst loading resulted in the forma-
tion of products with slightly or significantly lower
enantiomeric excesses (entries 4, 5, and 6). We then
examined the effect of the Et Zn–PhB(OH) ratio on
Isolated yield of the corresponding product.
Enantiomeric excesses were determined by chiral HPLC.
Configuration determined by comparison with the literature data.
5e,6
With ligand 2a identified as the most effective, next we
examined the scope of our system in reactions with
several aromatic aldehydes with diverse electronic and
steric properties. The presence of electron-donating
groups in the aldehyde, such as methyl and methoxy,
furnished the corresponding products in high levels of
stereoselectivity (see Table 2, entries 1–4).
2
2
the reaction, and we found that decreasing the ratio of
Et Zn 3:1 to 2:1 resulted in a decrease in the enantio-
2
selectivity. Further decrease in the amount of Et Zn–
2
PhB(OH)2 ratio to 1:1 and no product of arylation
was observed (compare entries 7 and 8).
The presence of groups at the ortho-position at the alde-
hyde shows some differences in the enantioselection
event. For example, p-chlorobenzaldehyde undergoes
smooth aryl addition, delivering the corresponding
diarylmethanol in 98% ee, while the o-chloro derivative
resulted in much lower enantioselectivity (entries 5 and
6). This fact can be explained by the influence of steric
effects, since when the chlorine atom is replaced by the
more encumbered bromine, even lower ee was achieved
(compare entries 6 and 7).
Under the best conditions,12 we evaluated the electronic
effect based on the different structures of ligand 2. The
study of the electronic effects of substituents on ligands
2
b and 2c showed that neither electron-donating nor
electron-withdrawing group on the para-position of
the phenyl group could decrease the enantiomeric excess
(
entries 9 and 10).
a
Table 1. Catalytic arylation of p-tolualdehyde with phenylboronic acid
OH
B(OH)
2
1) Toluene, 60˚C, 12 h
2
) Ligand 2
Et Zn
2
3
) p-tolualdehyde, 12 h
Me
a
b
c,d
ee (%)
Entry
Ligand (mol %)
Ar
T (ꢁC)
Et
2
Zn/PhB(OH)
2
ratio
Yield (%)
1
2
3
4
5
6
7
8
9
2a (20)
2a (20)
2a (20)
2a (15)
2a (10)
2a (5)
2a (20)
2a (20)
2b (20)
2c (20)
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
rt
0
3:1
3:1
3:1
3:1
3:1
3:1
2:1
1:1
3:1
3:1
96
95
93
93
92
91
87
—
96
98
87 (S)
94 (S)
94 (S)
84 (S)
35 (S)
30 (S)
77 (S)
—
ꢀ20
0
0
0
0
0
0
0
4-Methylphenyl
4-Chlorophenyl
90 (S)
91 (S)
10
a
2 2
Reactions were performed on a 0.5 mmol scale with PhB(OH) (2.4 equiv), Et Zn (7.2 equiv) in toluene (first at 60 ꢁC for 12 h, then at room
temperature for 12 h).
Isolated yield of the corresponding product.
Enantiomeric excesses were determined by chiral HPLC on a Chiralcel OD column.
Configuration determined by comparison with the literature data.
b
c
d
5e,6

A. L. Braga et al. / Tetrahedron Letters 46 (2005) 7827–7830
7829
In order to examine if different aryl groups could be
transferred to aldehydes with the same stereoselectivity,
the aryl transfer reaction of some substituted aryl boro-
nic acids with benzaldehyde was studied, and to our de-
light, high yields and enantiomeric excesses were
obtained (entries 8–10). For example, aryl transfer reac-
tion from 4-methylphenyl boronic acid to benzaldehyde
occurred with 93% ee (entry 8).
5. (a) Huang, W.-S.; Hu, Q.-S.; Pu, L. J. Org. Chem. 1999,
6
2, 7940; (b) Bolm, C.; Mu n˜ iz, K. Chem. Commun. 1999,
1
295; (c) Bolm, C.; Hermanns, N.; Hildebrand, J. P.;
Nu n˜ iz, K. Angew. Chem., Int. Ed. 2000, 39, 3465; (d)
Zhao, G.; Li, X.-G.; Wang, X.-R. Tetrahedron: Asymme-
try 2001, 12, 399; (e) Rudolph, J.; Hermanns, N.; Bolm, C.
J. Org. Chem. 2004, 69, 3997; (f) Fontes, M.; Verdaguer,
X.; Sol a` , L.; Peric a` s, M. A.; Riera, A. J. Org. Chem. 2004,
6
9, 2532; (g) Bolm, C.; Schmidt, F.; Zani, L. Tetrahedron:
Asymmetry 2005, 16, 1367; (h) Rudolph, J.; Schmidt, F.;
Bolm, C. Adv. Synth. Catal. 2004, 346, 867; (i) Bolm, C.;
Zani, L.; Rudolph, J.; Schiffers, I. Synthesis 2004, 2173; (j)
Park, J. K.; Lee, H. G.; Bolm, C.; Kim, B. M. Chem. Eur.
J. 2005, 11, 945; (k) Huang, W.-S.; Pu, L. Tetrahedron
Lett. 2000, 41, 145.
This is one of the most interesting features of this meth-
odology, since both enantiomers of a given product can
be easily prepared in excellent yields and high enantio-
meric excesses with the same catalyst, just by appropri-
ate choice of both reaction partners; aryl boronic acid
and aldehyde.
6
. Bolm, C.; Rudolph, J. J. Am. Chem. Soc. 2002, 124,
1
4850.
7
. (a) Prieto, O.; Ram o´ n, D. J.; Yus, M. Tetrahedron:
Asymmetry 2003, 14, 1955; (b) Ji, J.-X.; Wu, J.; Au-Yeung,
T. T.-L.; Yip, C. W.; Haynes, K. R.; Chan, A. S. C. J.
Org. Chem. 2005, 70, 1093; (c) Rudolph, J.; Schmidt, F.;
Bolm, C. Synthesis 2005, 840.
8. For some representative examples, see: (a) Braga, A. L.;
Appelt, H. R.; Schneider, P. H.; Silveira, C. C.; Wessjo-
hann, L. A. Tetrahedron: Asymmetry 1999, 10, 1733; (b)
Braga, A. L.; Paix a˜ o, M. W.; L u¨ dtke, D. S.; Silveira, C.
C.; Rodrigues, O. E. D. Org. Lett. 2003, 5, 2635; (c) Braga,
A. L.; Milani, P.; Paix a˜ o, M. W.; Zeni, G.; Rodrigues, O.
E. D.; Alves, E. F. Chem. Commun. 2004, 2488.
In conclusion, we have described herein the catalytic
asymmetric arylation of aldehydes in the presence of
proline-based chiral ligands. The reactive arylzinc
species are generated in situ from a boron–zinc exchange
instead of employing the more expensive diphenyl-
5
d,j
zinc.
The reaction of these arylzinc species with alde-
hydes gives access to both enantiomers of the chiral
diaryl methanols in high yields and enantiomeric
excesses. These results are similar or even superior to
6
,7b
those obtained by BolmÕs or ChanÕs.
Further work
is in progress in our laboratory with the aim of expand-
ing applications of these inexpensive chiral ligands to
other enantioselective catalytic processes.
9
. Braga, A. L.; L u¨ dtke, D. S.; Vargas, F.; Paix a˜ o, M. W.
Chem. Commun. 2005, 2512.
10. For other applications, see: (a) Soai, K.; Ookawa, A.;
Kaba, T.; Ogawa, K. J. Am. Chem. Soc. 1987, 109, 7111;
(
b) Liu, G.; Ellman, J. A. J. Org. Chem. 1995, 60, 7712; (c)
Gibson, C. L. Tetrahedron: Asymmetry 1999, 10, 1551.
1. General procedure for the preparation of ligands (2a–c):
ArMgBr (40 mmol) in THF (40 mL, 1 M solution) was
added to a THF (20 mL) solution of N-Boc methyl ester
Acknowledgements
1
We are grateful to the CAPES, CNPq, and FAPERGS,
for financial support. CAPES is also acknowledged for
providing Ph.D. fellowships for M.W.P. and D.S.L.,
and CNPq for a Ph.D. fellowship to F.V. We are also
grateful to Dr. J. Schmidt and C. R. B. Rhoden (IPB,
Germany), for HPLC and HRMS analyses.
(
10 mmol) at 0 ꢁC, and the mixture was stirred for
additional 4 h, before being quenched by pouring into
M NaOH. The heterogeneous mixture was filtered
2
through a pad of Celite and washed with dichloromethane
(3 · 50 mL). The combined organic phases were dried with
MgSO , filtered, and the solvent removed under vacuum.
4
The resulting product was used without further purifica-
tion. The product was dissolved in THF (30 mL) and was
cooled to 0 ꢁC. Lithium aluminum hydride (0.759 g,
20 mmol) was added to the solution in several portions,
and the mixture was refluxed for 2 h. After the mixture
was cooled to 0 ꢁC, water was added. The mixture was
acidified to pH 3 with 1 M HCl, washed with dichloro-
methane, and made alkaline with concentrated aqueous
NaOH. The precipitate was filtered off and washed with
ethyl acetate. The organic layer was separated, and the
filtrate was extracted with dichloromethane. The com-
References and notes
1
. (a) Meguro, K.; Aizawa, M.; Sohda, T.; Kawamatsu, A.;
Nagaoka, A. Chem. Pharm. Bull. 1985, 33, 3787; (b) Toda,
F.; Tanaka, K.; Koshiro, K. Tetrahedron: Asymmetry
1
991, 2, 873; (c) Stanev, S.; Rakovska, R.; Berova, N.;
Snatzke, G. Tetrahedron: Asymmetry 1995, 6, 183; (d)
Botta, M.; Summa, V.; Corelli, F.; Di Pietro, G.;
Lombardi, P. Tetrahedron: Asymmetry 1996, 7, 1263.
. For leading references, see: Bolshan, K.; Chen, C.-Y.;
Chilenski, J. R.; Gosselin, F.; Mathre, D. J.; OÕShea, P.
D.; Roy, A.; Tillyer, R. D. Org. Lett. 2004, 6, 111, and
references cited therein.
. For asymmetric hydrogenation and oxazaborolidine
reduction of benzophenones, see: (a) Ohkuma, T.; Koi-
zume, M.; Ikehira, H.; Yokozawa, T.; Noyori, R. Org.
Lett. 2000, 2, 659; (b) Corey, E. J.; Helal, C. J. Angew.
Chem., Int. Ed. 1998, 37, 1986; (c) Noyori, R.; Ohkuma, T.
Angew. Chem., Int. Ed. 2001, 40, 40; (d) Noyori, R. Angew.
Chem., Int. Ed. 2002, 41, 2008; (e) Chen, C.-Y.; Reamer,
R. A.; Chilenski, J. R.; McWilliams, C. J. Org. Lett. 2003,
2
3
4
bined extract was dried under MgSO and filtered. The
solvent was removed under vacuum and the crude product
was purified by flash chromatography in hexanes/ethyl
acetate (90:10).
Selected spectral and analytical data for 2a: Yield: 83%; mp
2
D
0
1
68.5–68.9; ½aꢁ +19 (c 1.2, CH
2 2
Cl ). H NMR (400 MHz,
CDCl ): d 7.63–7.61 (m, 2H); 7.53–7.51 (m, 2H); 7.25–7.21
3
(m, 4H); 7.10–7.09 (m, 2H); 4.54 (br s, 1H); 3.61–3.58 (m,
1H); 3.09–3.07 (m, 1H); 2.43–2.37 (m, 1H); 1.87–1.79 (m,
1
3
3
4H); 1.68–1.57 (m, 3H). C NMR (100 MHz, CDCl ): d
148.20; 146.68; 127.92; 126.05; 125.44; 125.38; 77.36;
5
, 5039.
. Dosa, P. I.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1997, 62,
44.
71.94; 59.07; 42.90; 29.81; 23.94. HRMS-ESI: m/z calcd
+
+
4
for C18
H21NO + H : 268.1701; found: C18H21NO + H :
4
268.1696.

7830
A. L. Braga et al. / Tetrahedron Letters 46 (2005) 7827–7830
1
2. General procedure for the asymmetric arylation of aldehydes:
and the aqueous layer was extracted with dichloromethane.
4
The combined organic layers were dried with MgSO ,
Diethylzinc (3.6 mmol, toluene solution) was dropwise
added to a solution of boronic acid (1.2 mmol) in toluene
filtered, and the solvents evaporated. Purification by flash
chromatography eluting with a mixture of hexanes/ethyl
acetate (90:10) afforded the pure diarylmethanols. HPLC-
analyses: All measurements were performed at a 20 ꢁC
column temperature using a UV detector at 254 nm.
Phenyl(p-tolyl)methanol (4a): Chiralcel OD, hexane/
i-PrOH (90:10), 0.5 mL/min, (S): 19.1 min, (R): 21.1 min.
(
2 mL) under an argon atmosphere. After stirring for 12 h
at 60 ꢁC, the mixture is cooled to 0 ꢁC and a toluene
solution of chiral amino alcohol (20 mol %) was intro-
duced. The reaction is stirred for additional 15 min and the
aldehyde (0.5 mmol) was subsequently added. After stir-
ring for 12 h at 0 ꢁC the reaction was quenched with water