Highly enantioselective arylation of aldehydes and ketones using AlArEt2(THF) as aryl sources

Article abstract of DOI:10.1021/jo900348p

A series of AlArEt₂(THF) (Ar = Ph (la), 4-MeC₆H ₄ (1b), 4-MeOC₆H ₄ (1c), 4-Me ₃SiC₆H₄ (1d), 2-naphthyl (le)) were synthesized from reactions of AlEt₂Br(THF) with ArMgBr. In CDC1₃ solution, the ¹H NMR spectra showed that AlArEt₂(THF) compounds exist as a mixture of four species of formulas of AlAr _xEt_3-x (THF) (x = 0, 1, 2, or 3). AlArEt₂(THF) compounds were found to be superior and atom-economic reagents for asymmetric aryl additions to organic carbonyls. Aryl additions of AlArEt₂(THF) to aldehydes catalyzed by the titanium(IV) complex of (R)-H₈-BINOL were efficient with a short reaction time of 1 h, affording aryl addition products as exclusive or main products in high yields and excellent enantioselectivities of up to 98% ee. Although ethyl additions to aldehydes occurred in minor extent, this study demonstrates that increasing the amount of AlArEt₂(THF) from 1.2 to 1.4 or to 1.6 equiv significantly improved the aryl addition products of up to >99%. On the other hand, asymmetric arylations of AlArEt₂(THF) to ketones employing a titanium(IV) catalyst of (S)-BINOL produced optically active tertiary alcohols exclusively in excellent enantioselectivities of up to 94% ee.

Full text of DOI:10.1021/jo900348p

Highly Enantioselective Arylation of Aldehydes and Ketones Using
AlArEt2(THF) as Aryl Sources
Shuangliu Zhou,†,‡ Kuo-Hui Wu,† Chien-An Chen,† and Han-Mou Gau*,†
Department of Chemistry, National Chung Hsing UniVersity, Taichung 402, Taiwan, and Anhui Key
Laboratory of Functional Molecular Solids, College of Chemistry and Materials Science, Anhui Normal
UniVersity, Wuhu, Anhui 241000, China
hmgau@dragon.nchu.edu.tw
ReceiVed February 17, 2009
A series of AlArEt2(THF) (Ar ) Ph (1a), 4-MeC6H4 (1b), 4-MeOC6H4 (1c), 4-Me3SiC6H4 (1d), 2-naphthyl
1
(1e)) were synthesized from reactions of AlEt2Br(THF) with ArMgBr. In CDCl3 solution, the H NMR
spectra showed that AlArEt2(THF) compounds exist as a mixture of four species of formulas of AlArxEt3-x
(THF) (x ) 0, 1, 2, or 3). AlArEt2(THF) compounds were found to be superior and atom-economic
reagents for asymmetric aryl additions to organic carbonyls. Aryl additions of AlArEt2(THF) to aldehydes
catalyzed by the titanium(IV) complex of (R)-H8-BINOL were efficient with a short reaction time of
1 h, affording aryl addition products as exclusive or main products in high yields and excellent
enantioselectivities of up to 98% ee. Although ethyl additions to aldehydes occurred in minor extent,
this study demonstrates that increasing the amount of AlArEt2(THF) from 1.2 to 1.4 or to 1.6 equiv
significantly improved the aryl addition products of up to >99%. On the other hand, asymmetric arylations
of AlArEt2(THF) to ketones employing a titanium(IV) catalyst of (S)-BINOL produced optically active
tertiary alcohols exclusively in excellent enantioselectivities of up to 94% ee.
Introduction
a highly reactive PhTi(O-i-Pr)3 reagent,3 chemists have shown
a continuous interest in developing highly enantioselective
The catalytic asymmetric synthesis of chiral secondary and
tertiary diaryl alcohols has attracted extensive attention in the
past few years because chiral diaryl alcohols are important
precursors that lead to many biologically active compounds.1
The enantioselective addition of organometallic reagents to
carbonyl compounds is a straightforward strategy for the
construction of optically active secondary and tertiary alcohols.2
After the pioneering work by Seebach and a co-worker on the
asymmetric catalytic phenyl additions to aldehydes employing
(1) (a) Ramo´n, D. J.; Yus, M. Curr. Org. Chem. 2004, 8, 149–183. (b)
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* To whom correspondence should be addressed. Fax: (886)4-22862547. Tel:
(886)4-22878615.
† National Chung Hsing University.
‡ Anhui Normal University.
3500 J. Org. Chem. 2009, 74, 3500–3505
10.1021/jo900348p CCC: $40.75 2009 American Chemical Society
Published on Web 04/01/2009

Arylation of Aldehydes and Ketones Using AlArEt2(THF)
catalysts for the asymmetric aryl transfer to aldehydes. Fu and
co-workers4 reported the first diphenylzinc addition to 4-chlo-
robenzaldehyde by using a chiral azaferrocene as a catalyst, and
subsequently, chiral catalysts have been developed by Pu5 and
Bolm6 for direct diphenylzinc additions to aldehydes affording
phenyl addition products in high enantioselectivities. To improve
the atomic-efficiency of phenyl transfer and to compensate for
the competitive noncatalytic pathway, mixed zinc reagents of
Ph2Zn/Et2Zn7 as a phenyl source were developed for the
enantioselective phenyl additions to aldehydes. Bolm and co-
workers8 later developed systems for the enantioselective
synthesis of diarylmethanols through the use of arylboronic acids
or arylboranes in combination with Et2Zn in situ to generate
various arylzinc compounds for the asymmetric addition reac-
tions. The studies extended the reaction scope from the phenyl
addition to aryl addition reactions, and this strategy has been
further demonstrated by Dagmen,9 Chan,10 Zhao,11 Braga,12 and
Jin.13 The enantioselective aryl transfer to aldehydes has also
been reported employing a zinc reagent prepared in situ from
ZnCl2 and phenylmagnesium bromide by Soai et al.14 or
aryllithium by Walsh and a co-worker.15 Recently, Knochel16
and Pu17 reported that arylzinc compounds generated in situ
from a reaction of aryliodide with dialkylzinc reacted with
aldehydes to give the desired secondary alcohols in high yields
and enantioselectivities.
excellent enantioselectivities. Yus and co-workers20 have de-
veloped catalytic systems for asymmetric aryl additions to
ketones employing in situ generated arylzinc reagents by heating
ZnEt2 and ArB(OH)2 or Ph3B compounds. Recently Ishihara
and co-workers21 also reported mixed zinc reagents of Ph2Zn/
Et2Zn as a phenyl source for enantioselective phenyl additions
to ketones employing an in situ prepared chiral phosphoramides-
Zn(II) complex.
In contrast, organoaluminum reagents are more reactive than
the zinc or boron reagents and have been applied to a variety
of asymmetric addition reactions.22 Recently, we have demon-
strated that AlAr3(THF) compounds are effective reagents in
asymmetric aryl additions to aldehydes.23 The addition reactions
catalyzed by the titanium catalyst of 10 mol% commercially
available (R)-H8-BINOL are complete in only 10 min at 0 °C,
and afford a wide variety of secondary alcohols including
diarylmethanols in excellent enantioselectivities of >90% ee.
Furthermore, the AlAr3(THF) compounds have been proven to
be highly efficient aryl transfer reagents for ketones, affording
tertiary alcohols in excellent stereocontrol.24 Subsequently, the
asymmetric 1,2 or 1,4 additions of arylaluminum reagents to
cyclic enones using in situ prepared AlPhMe2 were demonstrated
by Zezschwitz25 et al. and by Hoveyda26 et al. A copper-
catalyzed asymmetric conjugate addition of AlArEt2 reagents
to enones was also reported by Alexakis and co-workers.27
To further explore and to improve the atomic-efficiency of
arylaluminum reagents for asymmetric catalytic aryl additions
to organic carbonyls, we herein report the catalytic asymmetric
AlArEt2(THF) addition to aldehydes employing a titanium(IV)
complex of (R)-H8-BINOL or to ketones using a titanium
catalyst of (S)-BINOL. The AlArEt2(THF) compounds are
superior and atomic-efficient reagents for additions to organic
carbonyls, affording secondary and tertiary alcohols in excellent
enantioselectivities of up to 98% ee.
In sharp contrast to aldehydes, there are few examples of
catalytic enantioselective aryl additions to ketones due to the
attenuated reactivities of ketones. An early example was reported
by Fu and a co-worker,18 who employed a catalytic system of
ZnPh2 and 15 mol% (+)-DAIB (3-exo-(dimethylamino)-
isoborneol) to afford tertiary alcohols with enantioselectivities
of up to 91% ee. Walsh and co-workers19 demonstrated that
titanium complexes of trans-1,2-bis(hydroxycamphorsulfonyl-
amino)cyclohexane were excellent catalysts for asymmetric
ZnPh2 additions to ketones or R,ꢀ-unsaturated ketones with
Results and Discussion
Syntheses and 1H NMR Studies of the Aluminum
Reagents. A series of AlArEt2(THF) (Ar ) Ph (1a), 4-MeC6H4
(1b), 4-MeOC6H4 (1c), 4-Me3SiC6H4 (1d), 2-naphthyl (1e))
(Scheme 1) were prepared easily from the reaction of
AlEt2Br(THF) with 1 equiv of ArMgBr in THF. Compounds 1
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J. Org. Chem. Vol. 74, No. 9, 2009 3501

Zhou et al.
TABLE 1. Optimizations of Asymmetric Addition of AlPhEt2(THF)
SCHEME 1. Synthesis of AlArEt2(THF)
to 1-Naphthylaldehyde Catalyzed by 2/Ti(O-i-Pr)4 Catalysta b
,
1
were obtained as colorless liquids. The H NMR spectrum of
Ti(O-i-Pr)4 AlPhEt2(THF) time conv. 4a/5a
ee
entry
equiv
equiv
(h)
(%)c
(%)d
(%)e
1a revealed only one set of signals belonging to the coordinated
THF. To our surprise, three sets of ethyl resonances and three
sets of phenyl signals were observed, indicating that 1a in CDCl3
solution contained a mixture of four species. By comparing the
spectra of AlEt3(THF) and AlPh3(THF) with that of 1a and
examining the integrals of ethyl and phenyl 1H resonances, the
four species were assigned as AlPhxEt3-x(THF) (x ) 0, 1, 2, or
1
2
3
4
1.5
1.5
1.25
1.75
1.5
1.2
1.2
1.2
1.2
1.4
1.6
1.2
0.5
1
1
1
1
75
100
79
81:19 87/80f
83:17 97
83:17 87
86:14 83
>99
>99
96
5
100
100
71
98
96
6
1.5
1.5
1
1
7g
85:15 97
1
3) with relative percentages of 19:54:24:3%. Similarly, the H
a 1-Naphthyladehyde/2 ) 0.50/0.050 mmol; toluene, 4 mL; 0 °C.
b Equivalents of Ti(O-i-Pr)4 and AlPhEt2(THF) are relative to
1-naphthyladehyde. c Conversions are based on 1H NMR. d Ratios of 4a
and 5a are based on 1H NMR spectra. e ee values were determined by
HPLC using chiral OJ column. f The ee value of ethylation product 5a.
g In situ-prepared (R)-H8-BINOL/Ti(O-i-Pr)4 catalyst was used.
NMR spectra of 1b-1e also showed four species assigned as
AlArxEt3-x(THF) (x ) 0, 1, 2, or 3). Though 1a-1e exist as a
mixture of four species in solution, they are represented as a
general formula of AlArEt2(THF) for simplification. Variable-
1
temperature H NMR spectra of 1a in toluene-d8 showed that
the equilibrium of the four species was almost temperature
independent. An attempt to purify compound 1a via distillation
under reduced pressures was conducted. However, the distilla-
tion afforded a colorless liquid of AlEt3(THF) and a residue
that could crystallize from toluene as colorless crystals of
AlPh3(THF). The mole ratio of AlEt3(THF) and AlPh3(THF)
was close to 2:1. It was interesting to find that mixing 1 equiv
of AlPh3(THF) and 2 equiv of AlEt3(THF) in THF also produced
compound 1a.
TABLE 2. Asymmetric Addition of AlArEt2(THF) to Aldehydes
Catalyzed by 2/Ti(O-i-Pr)4Catalysta
4/5
yield
ee
entry
R
Ar
(%)b product (%)
(%)c
1
2
3
4
5
6
7
8
1-naphthyl
2-naphthyl
2-ClC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
>99
87:13
>99
>99
>99
90:10
>99
>99
92:8
>99
91:9
>99
>99
>99
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4f′
93
85
91
93
90
86
93
94
89
92
86
93
90
91
85
98 (R)
83 (R)d
90 (R)d
92 (R)d
74 (R)d
87 (R)d
90 (R)d
96 (R)
91 (R)d
86 (R)
80 (R)d
91 (S)
Asymmetric Addition of AlArEt2(THF) to Aldehydes Cata-
lyzed by a Titanium(IV) Complex of (R)-H8-BINOL. It has
been established by us that AlAr3(THF) compounds are excellent
arylation reagents of aldehydes in THF employing [{(R)-
H8-BINOLate}Ti(O-i-Pr)2]n (2)28 as a catalyst precursor.23b In
order to improve the atomic efficiency, asymmetric aryl addi-
tions of AlArEt2(THF) to aldehydes were studied using the
above-reported system. Asymmetric reactions were first opti-
mized on phenyl additions to 1-naphthylaldehyde and the results
are listed in Table 1. It was found that the addition of 1.2 equiv
of AlPhEt2(THF) to 1-naphthylaldehyde in a reaction time of
0.5 h gave a mixture of phenyl addition product 4a and ethyl
addition product 5a in a 75% combined yield. The ratio of 4a/
5a was found to be 81:19, and the enantioselectivities of 4a
and 5a were 87 and 80% ee (Table 1, Entry 1), respectively.
Further extending the reaction time to 1 h improved the
combined yield of 4a and 5a to 100% with a ratio of 83:17.
The enantioselectivity of 4a also improved to an excellent 97%
ee (Table 1, Entry 2). This observation is in accordance with
the fact that the transfer of sp2-hybridized carbon-based sub-
stituents of aluminum reagents is more facile than that of sp3-
hybridized carbon-based substituents.26,27,29-32 Decreasing the
amount of Ti(O-i-Pr)4 to 1.25 equiv or increasing to 1.75 equiv
did not improve the ratio of 4a and 5a. However, the enanti-
oselectivities of 4a decreased to 87 and 83% ee (Table 1, Entries
4-ClC6H4
2-MeOC6H4
4-MeOC6H4
4-F3CC6H4
2-MeC6H4
4-MeC6H4
2-BrC6H4
4-BrC6H4
9
10
11
12
13
14
15
(E)-PhCHdCH Ph
t-Bu
i-Pr
Ph
Ph
Ph
94 (S)
95 (S)
4-MeOC6H4 90:10
62 (S)d
a Substrate/AlArEt2(THF)/Ti(O-i-Pr)4 ) 0.50/0.70/0.75 mmol, toluene,
4 mL; 0 °C. b Ratios of 4 and 5 are based on 1H NMR spectra. c ee
values of compound 4 were determined by HPLC using chiral columns.
Absolute configurations were obtained by comparison with the HPLC
data of known compounds. d AlArEt2(THF) (1.6 equiv, 0.80 mmol).
3 and 4). While keeping Ti(O-i-Pr)4 at 1.5 equiv and increasing
the amount of AlPhEt2(THF) to 1.4 and 1.6 equiv, diarylmetha-
nol 4a was formed exclusively with excellent enantioselectivities
of 98 and 96% ee (Table 1, Entries 5 and 6). It was found that
the in situ-prepared (R)-H8-BINOL/Ti(O-i-Pr)4 catalytic system
also catalyzed the reactions (Entry 7), giving both 4a and 5a in
a similar ratio of 85:15 relative to the results employing 2 (Entry
3). The same enantioselectivity of 97% ee was obtained for 4a.
However, the reaction was slower with a conversion of 71%.
Next we examined aryl transfer reactions of a wide variety
of aldehydes by employing 1.4 or 1.6 equiv AlArEt2(THF)
(Table 2). The results showed that the phenyl transfer to aromatic
aldehydes afforded nearly 100% yields of diarylmethanols 4 as
sole products, except for 2-naphthylaldehyde (3b, 87%, Entry
2), 4-methoxybenzaldehyde (3f, 90%, Entry 6), 4-methylben-
zaldehyde (3i, 92%, Entry 9), and 4-bromobenzaldehyde (3k,
(28) (a) Waltz, K. M.; Carroll, P. J.; Walsh, P. J. Organometallics 2004, 23,
127–134. (b) Terada, M.; Matsumoto, Y.; Nakamura, Y.; Mikami, K. Inorg.
Chim. Acta 1999, 296, 267–272.
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A. H. J. Am. Chem. Soc. 2008, 130, 446–447.
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Int. Ed. 2003, 42, 3002–3005. (b) Rudolph, J.; Bolm, C.; Norrby, P.-O. J. Am.
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3502 J. Org. Chem. Vol. 74, No. 9, 2009

Arylation of Aldehydes and Ketones Using AlArEt2(THF)
TABLE 3. Optimizations of Asymmetric Addition of
AlPhEt2(THF) to 2′-Acetonaphthone Catalyzed by the (S)-BINOL/
Ti(O-i-Pr)4 Catalysta,b
conducted at 25 °C, 7a was obtained in the highest yield of
98% but with a lower enantioselectivity of 70% ee (Table 3,
Entry 6).
A variety of ketones were then evaluated under the optimized
reaction conditions of 3.5 equiv of Ti(O-i-Pr)4 and 2.5 equiv of
AlArEt2(THF). The results are presented in Table 4. This study
shows that the optimized catalytic system worked excellently
in terms of stereocontrol for a wide range of aromatic ketones,
regardless of the electronic nature or the steric effect of the
substituents on the aryl groups, affording 7 as the sole products
with enantioselectivities of g90% ee (Table 4, Entries 1-14)
except for the substrates of 1′-acetonaphthone (88% ee, Entry
2), 2′-methoxyacetophenone (29% ee, Entry 7), 3′-methoxyac-
etophenone (72% ee, Entry 8), 4′-methoxyacetophenone (89%
ee, Entry 8), 3′-(trifluoromethyl)acetophenone (85% ee, Entry
12), and R-bromo-2′-acetonaphthone (77% ee, Entry 14).
entry Ti(O-i-Pr)4 equiv AlPhEt2(THF) equiv conv. (%)c ee (%)d
1
2
3
4
2.5
3.5
5.0
3.5
3.5
3.5
2.5
2.5
2.5
3.0
2.0
2.5
67
89
90
92
86
98
81
90
89
80
90
70
5
6e
a 2′-Acetonaphthone/(S)-BINOL ) 0.50/0.050 mmol; toluene, 4 mL; 0
°C, 18 h. b Equivalents of Ti(O-i-Pr)4 and AlPhEt2(THF) are relative to
2′-acetonaphthone. c Conversions are based on 1H NMR. d ee values
were determined by HPLC using chiral OJ column. e At 25 °C.
It was found that the steric hindrance of the substrates had
an effect on the reactivity of phenyl transfer to ketones. The
phenyl addition to hindered ketones required longer reaction
times to produce desired products in higher yields. For examples,
the phenyl addition to 1′-acetonaphthone over 36 h afforded
the product 7b in only a 39% yield (Table 4, Entry 2), the
addition to 2′-bromoacetophenone gave 7e in a 49% yield (Table
4, Entry 5), and the addition to 2′-methylacetophenone gave 7j
in a 35% yield (Table 4, Entry 10). However, the addition to
2′-methoxyacetophenone afforded 7g in an excellent yield of
96% over 18 h, but with a low enantioselectivity of 29% ee
(Table 4, Entry 7). The high yield of 7g can be attributed to the
chelate effect of the substrate, which facilitated the coordination
of 2′-methoxyacetophenone to the active metal center. But small
differentiations in terms of both orientations chelated to the
metal center reduced the enantioselectivity. A similar result was
also observed in the addition reaction of AlPh3(THF) to
2′-methoxyacetophenone catalyzed by the titanium complex of
(S)-BINOL. For R,ꢀ-unsaturated 1-acetylcyclohexene and
2-acetylfuran, the alcohol 7o and the tertiary 2-furyl alcohol
7p were obtained in good yields with good enantioselectivities
of 85% ee (Table 3, Entry 15) and 83% ee (Table 4, Entry 16).
It is worth noting that a series of chiral tertiary 2-furyl alcohols
could also be obtained by (2-furyl)aluminum addition to ketones
employing a titanium catalyst of 10-20 mol% (S)-BINOL.31
However, for aliphatic ketones of 3-methyl-2-butanone and
2-hexanone, the phenyl additions afforded products 7q and 7r
in low yields and poor enantioselectivities of 48 and 15% ee
(Table 4, Entries 17 and 18). Additions of different arylalumi-
num reagents, such as 4-tolyl, 4-methoxyphenyl, 4-(trimethyl-
silyl)phenyl, or 2-naphthyl to aromatic ketones were carried out
and produced the desired products in good yields with excellent
enantioselectivities of 87 to 93% ee (Table 4, entries 19-22).
The aryl additions to acetophenone (Table 4, entries 20 and
22) afforded products in an opposite absolute configuration
relative to products derived from the phenyl addition to aryl
ketones.
91%, Entry 11). For substrates 3b, 3f, 3i, and 3k, ethylation
products were also observed and yields of the secondary alcohols
range from 8 to 13%. The enantioselectivities were found to be
somewhat lower for arylation products 4b (83% ee, entry 2),
4f (87% ee, entry 6), and 4k (80%, entry 11). Except for 3b,
3e, 3f, 3j, and 3k, it can be seen from Table 2 that asymmetric
AlPhEt2(THF) additions to aromatic aldehydes, regardless of
the electronic nature or the steric effect of the substituent on
the aryl groups, afforded diarylmethanols 4 with excellent
enantioselectivities of 90% ee or greater. For aliphatic aldehydes
and vinyl aldehydes, the sole products 4l, 4m and 4n were
obtained in high yields with excellent enantioselectivities of
91-95% ee (Entries 12-14). However, the addition of the
substituted arylaluminum reagent Al(4-MeOC6H4)Et2(THF) to
benzaldehyde afforded a 90% of the Ar-transfer product 4f′ with
moderate enantioselectivity of 62% ee (Entry 15). In the
Al(4-MeOC6H4)Et2(THF) addition reaction, the ethyl group also
competed for the addition to benzaldehyde, giving the ethylation
product in a 10% yield.
Asymmetric Addition of AlArEt2(THF) to Ketones
Catalyzed by a Titanium Catalyst of (S)-BINOL. We have
demonstrated that asymmetric aryl additions of AlAr3(THF) to
ketones employing a titanium catalyst of (S)-BINOL affords
optically active tertiary alcohols in high yields with excellent
enantioselectivities.24b In this study, we also examined asym-
metric aryl additions of the atomic-efficient AlArEt2(THF)
reagents to the more inert ketones. Asymmetric addition
reactions were first optimized on 2′-acetonaphthone and the
results are listed in Table 3. In the presence of 10 mol% (S)-
BINOL and 2.5 equiv of both Ti(O-i-Pr)4 and AlPhEt2(THF) at
0 °C, the reaction over 18 h afforded the tertiary alcohol 7a in
a 67% yield with an enantioselectivity of 81% ee (Table 3, Entry
1). Unlike addition reactions to aldehydes, the addition of
AlPhEt2(THF) to 2′-acetonaphthone afforded the phenyl addition
product 7a exclusively. Increasing the amount of Ti(O-i-Pr)4
to 3.5 and 5.0 equiv afforded 7a in higher yields and excellent
enantioselectivities of 90 and 89% ee (Table 3, Entries 2 and
3). While keeping Ti(O-i-Pr)4 at 3.5 equiv and increasing the
amount of AlPhEt2(THF) to 3.0 equiv, the enantioselectivity
decreased to 80% ee (Table 3, Entry 4). Decreasing the amount
of AlPhEt2(THF) to 2.0 equiv afforded the product in an 86%
yield and a 90% ee (Table 3, Entry 5). When the reaction was
For the AlAr3(THF) additions to ketones reported previously
by us, the optimized conditions were 10 mol% (S)-BINOL, 2.5
equiv of AlAr3(THF), and 5.0 equiv of Ti(O-i-Pr)4 in a reaction
time of 12-36 h conducted at 0 °C. AlAr3(THF) (2.5 equiv)
required for the addition reaction meant that only one aryl group
out of 7.5 aryls was consumed in addition to ketones. In contrast,
this study used the same 10 mol% of (S)-BINOL ligand along
with 2.5 equiv of AlArEt2(THF) and 3.5 equiv of Ti(O-i-Pr)4
for the aryl addition reactions. The reaction temperature
J. Org. Chem. Vol. 74, No. 9, 2009 3503

Zhou et al.
TABLE 4. Asymmetric Addition of AlArEt2(THF) to Ketones
remained at 0 °C with a reaction time from 18-36 h. In the
AlArEt2(THF) addition reactions, one out of the 2.5 aryl groups
was transferred to ketones, giving desired tertiary alcohols in
similar yields and enantioselectivities. In terms of the aryl group
consumed, the atomic-efficiency of the AlArEt2(THF) reagent
was 3-times that of the AlAr3(THF) reagents in asymmetric aryl
transfer reactions to ketones. In addition, the amount of Ti(O-
i-Pr)4 required in the AlArEt2(THF) addition reactions was also
less by 1.5 equiv.
Catalyzed by (S)-BINOL/Ti(O-i-Pr)4 Catalysta
Conclusion
We here demonstrate an easy preparation of a series of
AlArEt2(THF) reagents (Ar ) Ph (1a), 4-MeC6H4 (1b),
4-MeOC6H4 (1c), 4-Me3SiC6H4 (1d), 2-naphthyl (1e)). In CDCl3
solution, the 1H NMR spectra showed that AlArEt2(THF)
compounds exist as a mixture of four species of formulas of
AlArxEt3-x(THF) (x ) 0, 1, 2, or 3). Despite the existence of a
mixture of four species in solution, the AlArEt2(THF) com-
pounds were still excellent reagents for asymmetric additions
to organic carbonyls in comparison to the AlAr3(THF) reagents.
Asymmetric aryl additions of AlArEt2(THF) to aldehydes
employing a titanium(IV) complex of (R)-H8-BINOL afforded
optically active secondary alcohols 4 as exclusive products in
high yields and excellent enantioselectivities of up to 98% ee
except for aldehydes 3b, 3f, 3i, and 3k for which minor
ethylation products 5 were obtained with yields from 8 to 13%.
For asymmetric aryl addition of AlArEt2(THF) to ketones
employing a titanium(IV) catalyst of (S)-BINOL, optically active
tertiary alcohols 7 were obtained as sole products with excellent
enantioselectivities of up to 94% ee. This study demonstrates
that AlArEt2(THF) compounds are the atom-economical alu-
minum reagents for the aryl addition reactions to both aldehydes
and ketones.
Experimental Section
Synthesis of AlPhEt2(THF) (1a).
A THF solution of
AlEt2Br(THF)33 (30.0 mmol) was added to a THF solution of
phenylmagnesium bromide (30.0 mmol) at 0 °C. The mixture was
stirred at room temperature for 12 h and the solvent was removed
under reduced pressures to afford a residue which was extracted
with n-hexane (3 × 50 mL). The extracts were combined and
concentrated to furnish a colorless liquid of 1a which is a mixture
of four species assigned as AlPhxEt3-x(THF) (x ) 0, 1, 2, or 3). 1H
NMR (CDCl3, 400 MHz): AlEt3(THF) (19%), δ 4.05 (m, 4H), 2.03
(m, 4H), 1.02 (t, J ) 8.2 Hz, 9H), -0.21 (q, J ) 7.8 Hz, 6H);
AlPhEt2(THF) (54%), δ 7.64 (m, 2H), 7.38-7.24 (m, 3H), 4.05
(m, 4H), 2.03 (m, 4H), 1.13 (t, J ) 8.0 Hz, 6H), 0.10 (q, J ) 8.0
Hz, 4H); AlPh2Et(THF) (24%), δ 7.74 (m, 4H), 7.38-7.24 (m,
6H), 4.05 (m, 4H), 2.03 (m, 4H), 1.21 (t, J ) 8.2 Hz, 3H), 0.34 (q,
J ) 8.0 Hz, 2H); AlPh3(THF) (3%), δ 7.80 (m, 6H), 7.38-7.24
(m, 9H), 4.05 (m, 4H), 2.03 (m, 4H). Distillation of compound 1a
afforded AlEt3(THF), and recrystallization of the residue from
toluene afforded AlPh3(THF).
1b-1e were synthesized by similar procedures as those used
1
for the preparation of 1a. Their H NMR data can be obtained in
the Supporting Information.
General Procedures for the Asymmetric Aryl Addition of
Aldehydes. Synthesis of (R)-Naphthalen-1-yl-phenyl-methanol (4a).
Under a dry nitrogen atmosphere, [{(R)-H8-BINOLate}Ti(O-i-
28
Pr)2]n (0.023 g, 0.050 mmol) and Ti(O-i-Pr)4 (0.22 mL, 0.75
mmol) were mixed in 4.0 mL of dry toluene at room temperature.
After stirring for 30 min, AlPhEt2(THF) (0.70 mmol) was added
a Ketone/(S)-BINOL/AlArEt2(THF)/Ti(O-i-Pr)4 ) 0.50/0.050/1.25/2.5
mmol; toluene, 4 mL; 0 °C. b ee values were determined by HPLC
using chiral columns. c (S)-BINOL (0.06 mmol).
(33) Grosse, A. V.; Mavity, J. M. J. Org. Chem. 1940, 5, 106–121.
3504 J. Org. Chem. Vol. 74, No. 9, 2009

Arylation of Aldehydes and Ketones Using AlArEt2(THF)
at 0 °C. The mixture was stirred for another 10 min, and the
resulting solution was treated with 1-naphaldehyde (0.068 mL, 0.50
mmol) at 0 °C. The mixture was allowed to react at this temperature
and then quenched with 2 M NaOH. The aqueous phase was
extracted with diethyl ether (3 × 10 mL), dried over MgSO4,
filtered, and concentrated. The residue was purified by column
HCl (2 mL). The aqueous phase was then extracted with CH2Cl2
(3 × 10 mL). The combined organic phase was dried over MgSO4,
filtered, and concentrated to dryness. The residue was purified by
1
column chromatography to give the tertiary alcohol 7a. H NMR
(400 MHz, CDCl3): δ 7.97 (d, J ) 1.6 Hz, 1H), 7.85-7.74 (m,
3H), 7.49-7.25 (m, 8H), 2.30 (s, 1H), 2.05 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ 147.7, 145.2, 132.9, 132.3, 128.2, 128.1,
127.9, 127.4, 126.9, 126.0, 125.89, 125.86, 124.9, 123.7, 76.3, 30.6.
The enantiomeric excess of the product was determined by HPLC
using suitable chiral columns.
1
chromatography to give the secondary alcohol 4a. H NMR (400
MHz, CDCl3): δ 8.06-7.25 (m, 12H), 6.55 (d, J ) 4.0 Hz, 1H),
2.32 (d, J ) 4.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 143.1,
138.7, 133.9, 130.6, 128.7, 128.5, 128.4, 127.6, 127.0, 126.1, 125.5,
125.3, 124.6, 123.9, 73.5. Enantiomeric excesses of products were
determined by HPLC using suitable chiral columns.
General Procedures for the Asymmetric Aryl Addition of
Ketones. Synthesis of 1-Naphthalen-2-yl-1-phenyl-ethanol (7a).
Under a dry nitrogen atmosphere, (S)-BINOL (0.0500 mmol, 0.0143
g), Ti(O-i-Pr)4 (1.75 mmol, 0.52 mL) were mixed in dry toluene
(4 mL) at room temperature. After stirring the mixture for 1 h,
AlPhEt2(THF) (1.25 mmol) was added at 0 °C. The mixture was
stirred for 30 min and the resulting solution was treated with 2′-
acetonaphone (0.085 g, 0.50 mmol) at 0 °C. The mixture was
allowed to react at this temperature and quenched with 1 M aqueous
Acknowledgment. Financial support under the grant number
of NSC 96-2113-M-005-007-MY3 from the National Science
Council of Taiwan, Republic of China is appreciated.
Supporting Information Available: 1H NMR data and
spectra of compounds 1 and HPLC conditions and spectra of
the secondary and tertiary alcohols. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO900348P
J. Org. Chem. Vol. 74, No. 9, 2009 3505