TABLE 3. Microwave-Assisted Aryl Transfer to Aldehydes Using
Ligand 3aa
While utilizing ligands 1 and 2, the resulting diarylmethanols
were obtained in lower yields and ee’s compared to ligand 3a
(entries 10, 11 vs entry 7). Aziridine ligand 3a also led to high
levels of enantiocontrol. In comparison, catalysts 3b and 3c
(entries 12, 13) promote the reaction less efficiently and with
lower enantioselectivity than ligands 1 and 2. Under the
optimized microwave conditions no ethyl transfer was detected;
since phenyl transfer is some orders of magnitude faster, as
observed previously by others12,13 for the addition of Ph2Zn/
Et2Zn in a conventional experiment.
With reaction time, yield, ee, and catalyst optimized, the scope
of the reaction system with various aromatic boronic acids and
aldehydes of diverse electronic and steric properties was
examined.
Phenylboronate underwent smooth aryl addition to o- and
p-tolaldehyde in almost quantitative yields and with very high
ee (Table 3, entries 1 and 2).
entry
Ar1
Ph
Ph
Ph
Ph
p-ClPh
p-MePh
Ar2
yieldb (%)
eec,d (%)
1
2
3
4
5
6
p-MePh
o-MePh
p-ClPh
o-ClPh
Ph
97
98
93
88
90
96
98 (S)
93 (S)
93 (S)
98 (S)
89 (R)
70 (R)
Ph
a Reactions were performed on a 0.25 mmol scale with PhB(OH)2 (2.4
equiv) and Et2Zn (7.2 equiv) in toluene with 300 W µw irradiation of to 60
°C for 10 min, subsequent addition of ligand and carbonyl compound under
the same conditions for 5 min. b Isolated yield. c Enantiomeric excesses were
determined by chiral HPLC (Chiralcel OD-H). d Absolute configuration
assigned by comparison with literature data.2
Changing to electron-withdrawing substituents in the carbonyl
compound did not result in a different behavior; the enantiose-
lectivities remained high (Table 3, entries 3 and 4). In order to
examine some substituent effects of the aryl groups to be
transferred, substituted aryl boronic acids were studied. Also
with these, high yields and good enantiomeric excesses were
obtained (entries 5, 6). For example, aryl transfer reaction from
p-chlorophenyl boronic acid to benzaldehyde occurred with 89%
ee (Table 3, entry 5); however, the tolyl derivative reacted less
selectively (entry 6)
In summary, we have demonstrated an efficient and very fast
catalytic enantioselective arylation of aromatic aldehydes under
microwave “flash-heating” using rigid chiral ligands readily
available from common amino acids. The major advantage of
microwave irradiation is the considerable reduction in reaction
time without loss of enantioselectivity.
The postive thermal effects of microwave heating can be
explained by the different heating kinetics similar to a microre-
actor thermal exchange and possibly a different reaction vessel
wall involvement rather than by a doubtful special microwave
effect.6
Reactions were performed with a single-mode cavity in
sealed, heavy-walled Pyrex tubes. In preliminary experiments,
the reaction time required for the arylzinc additon to the
aldehyde (time 2) was varied using 10 mol % of the catalyst
3a, microwave irradiation at 300 W, and temperatures up to 60
°C (method A). A reaction time of 10 min furnished the desired
product in high yield and high enantioselectivity (Table 2, entry
1). Reduction of the reaction time from 10 to 5 min did not
alter the degree of enantioselectivity of the reaction (entry 2).
Further shortening the reaction time (time 2) to 2.5 or 2 min
resulted in incomplete conversion, while the enantiomeric excess
of the product remained unaffected (entries 3 and 4). By using
ligand 2, the chiral diarylmethanol was obtained in lower yield
and enantioselectivity (entry 5).
More interestingly, though, is the fact that the reactive arylzinc
species also can be effectively generated under microwave
irradiation. Consequently, the desired diarylmethanols can be
obtainded in high yields and ee’s (method B). Thus, the best
reaction conditions established for this particular reaction consist
of 10 min (Table 2, time 1) for the generation of the arylzinc
species, followed by the addition of the catalyst and the
appropriate aldehyde and an additional irradiation time of only
5 min (Table 2, time 2). This afforded the chiral diarylmethanol
in 98% ee (entry 7). This is a significant improvement over
previously reported protocols. Increasing the arylzinc formation
time (time 1) to 20 min or decreasing it to 5 or 2.5 min led to
a slight reduction of both ee and yield (Table 2, entries 6, 8,
and 9). We hypothesized that ZnPh2 can be formed under
microwave irradiation by using 20 min as a reaction time (time
1), and this species likely promotes the addition faster than the
amino alcohol based catalyst promotes the asymmetric addition.
A similar proposal was advanced by Bolm11 in reactions that
began with ZnPh2.
Experimental Section
General Procedure for the Asymmetric Arylation of Alde-
hydes. (1) Typical Experimental Procedure for Reactions
Performed without Microwave Irradiation (Table 1, Entry 6).
Diethylzinc (3.6 mL, 3.6 mmol, toluene solution) was added
dropwise to a solution of phenylboronic acid (146.2 mg, 1.2 mmol)
in toluene (2 mL) under an argon atmosphere. After being stirred
for 12 h (time 1) at 60 °C, the mixture was cooled to room
temperature and a solution of the chiral amino alcohol 3a (23.4
mg, 0.05 mmol, 10 mol %) in 1 mL of toluene was added. The
reaction was stirred for 15 min, and a solution of p-tolualdehyde
(60 mg, 0.5 mmol) in toluene was subsequently added. After being
stirred overnight (time 2) the reaction was quenched with water
and the aqueous layer was extracted with dichloromethane. The
organic phase was dried over MgSO4 and filtered, and the solvents
were evaporated under reduced pressure. Purification by flash
chromatography on silica, eluting with a mixture of hexane/ethyl
acetate (90:10), gave 96.1 mg (0.49 mmol, 97% yield, 96% ee) of
(S)-(4-methyphenyl)phenylmethanol as a white solid. NMR 1H
(CDCl3, 400 MHz): δ ) 7.31-7.08 (m, 9H), 5.68 (s, 1H), 2.55
(s, 1H), 2,29 (s, 3H). NMR 13C (CDCl3, 100 MHz): δ ) 143.9,
140.9, 137.1, 129.0, 128.3, 127.3, 126.4, 126.4, 75.9, 21.0. HRMS
calcd for C14H14O (M)+: 198.1045, found 198.1046. HPLC
separation conditions: Chiralcel OD, hexane/i-PrOH 90:10, 0,5 mL/
min, λ ) 254 nm, tR(R): 19.1 min, tR(S): 21.1 min.
(10) (a) Hosseini, M.; Stiasni, N.; Barbieri, V.; Kappe, C. O. J. Org.
Chem. 2007, 72, 1417. (b) Perreux, L.; Loupy, A. Tetrahedron 2001, 57,
9199. (c) De la Hoz, A.; D´ıaz-Ortiz, A.; Moreno, A. Chem. Soc. ReV. 2005,
34, 164.
(12) Fontes, M.; Verdaguer, X.; Sola`, L.; Perica`s, M. A.; Riera, A. J.
Org. Chem. 2004, 69, 2532.
(11) (a) Bolm, C.; Hermanns, N.; Hildebrand, J. P.; Mun˜iz, K. Angew.
Chem., Int. Ed. 2000, 39, 3465. (b) Bolm, C.; Kesselgruber, M.; Hermanns,
N.; Hildebrand, J. P. Angew. Chem., Int. Ed. 2001, 40, 1488.
(13) (a) Rudolph, J.; Bolm, C.; Norrby, P.-O. J. Am. Chem. Soc. 2005,
127, 1548. (b) Rudolph, J.; Rasmussen, T.; Bolm, C.; Norrby, P.-O. Angew.
Chem., Int. Ed. 2003, 40, 3002.
J. Org. Chem, Vol. 73, No. 7, 2008 2881