From aryl bromides to enantioenriched benzylic alcohols in a single flask: Catalytic asymmetric arylation of aldehydes

Article abstract of DOI:10.1002/anie.200600741

(Chemical Equation Presented) Stop that achiral catalyst! Chiral Lewis acid catalyzed aryl additions to aldehydes that originate from aryl halides generate products with very low ee values (see scheme, left), because the achiral metal halide by-products are much more efficient catalysts than those derived from chiral amino alcohols. A LiCl-selective inhibitor is introduced that enables a highly enantioselective one-pot arylation of aldehydes that begins with aryl bromides (right).

Full text of DOI:10.1002/anie.200600741

Angewandte
Chemie
biologically active compounds, such as clemastine,[2] orphena-
drine,[3,4] neobenodine,[3,4] chloropheniramine,[5,6] cizolir-
tine,[7] and carbinoxamine.[8] Although the majority of enan-
tioselective aldehyde arylation reactions rely on the use of
costly diphenylzinc ($55–75 gÀ1), important advances in the
use of other aryl transfer reagents, such as arylboronic
acids[9,10] and Ph2Si(OMe)2,[11] have been reported. Although
a limited number of aryl boronic acids are commercially
available, they are quite expensive as well (e.g., PhB(OH)2
$225.00 molÀ1 from Aldrich). A more practical and versatile
method would begin with aryl bromides, many of which are
commercially available and inexpensive (compare PhBr
$2.50 molÀ1 from Aldrich). There are no reports, however,
of successful catalytic asymmetric aryl additions to aldehydes
that begin with aryl bromides.[12,13] Herein, we disclose a one-
pot method that begins with aryl bromides for the in situ
generation of aryl zinc intermediates and their catalytic
asymmetric addition to aldehydes to afford highly enantioen-
riched diarylmethanols and benzylic alcohols.
We chose to examine the amino alcohol ligand MIB
developed by Nugent[14,15] in the asymmetric addition of
commercial ZnPh2 to 2-naphthylaldehyde [Eq. (1)]. We were
Asymmetric Catalysis
DOI: 10.1002/anie.200600741
pleased to find that phenylation proceeded in toluene with
94% enantioselectivity (Table 1, entry 1). Unfortunately,
transmetalation of phenyllithium with ZnCl2 in toluene was
From Aryl Bromides to Enantioenriched Benzylic
Alcohols in a Single Flask: Catalytic Asymmetric
Arylation of Aldehydes**
Table 1: Commercially available ZnPh2 versus ZnPh2 formedin situ.
Jeung Gon Kim and Patrick J. Walsh*
Dedicated to Professor Madeleine JoulliØ
Entry
ZnPh2
Solvent
ee [%]
1
2
3
4
5
commercial
commercial
commercial
commercial
in situ
toluene
Et2O
tBuOMe
tBuOMe/Hex (1:3)
tBuOMe/Hex (1:3)
94
60
88
89
2
The catalytic asymmetric addition of aryl groups to aldehydes
has generated an enormous amount of attention.[1] The
resulting diarylmethanols are important constituents of
unsuccessful because of the insolubility of ZnCl2 in this
medium. In contrast, ethereal solvents are known to promote
transmetalation reactions. The asymmetric addition in diethyl
ether, however, gave a low enantioselectivity (60%; Table 1,
entry 2). In an attempt to balance both the solvating proper-
ties of diethyl ether, needed for the transmetalation, and the
low polarity of toluene, we examined tert-butyl methyl ether
(tBuOMe). A reaction mixture of commercial ZnPh2, (À)-
MIB, and 2-naphthylaldehyde in tBuOMe furnished the
product in 88% ee (Table 1, entry 3). A solvent system of
tBuOMe and hexanes (1:3) exhibited about the same
[*] Dr. J. G. Kim, Prof. P. J. Walsh
P. Roy andDiana T. Vagelos Laboratories
University of Pennsylvania
Department of Chemistry
231 South 34th Street, Philadelphia, PA 19104-6323 (USA)
Fax: (+1)215-573-6743
E-mail: pwalsh@sas.upenn.edu
[**] We thank the National Institutes of Health (National Institute of
General Medical Sciences) and the National Science Foundation for
support of this research.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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enantioselectivity as tBuOMe alone (89%; Table 1, entry 4).
and yields (78–99%). trans-Cinnamaldehyde and cyclohex-
anecarboxaldehyde underwent addition with 84 and 85%
enantioselectivities (Table 2, entries 12 and 13, respectively).
Having identified a suitable solvent for the asymmetric
addition, we focused on the in situ generation of diphenylzinc.
The preparation of ZnPh2 was performed by metalation of
4.5 equivalents bromobenzene in tBuOMe with 4 equivalents
of a freshly titrated solution of nBuLi (2.5m in hexanes),
transmetalation of the resultant PhLi with 2.1 equivalents of
ZnCl2, and the addition of hexanes to precipitate LiCl. The
use of solutions prepared as described in the asymmetric
addition to 2-naphthylaldehyde in the presence of 5 mol% of
(À)-MIB resulted in the formation of the product with 2%
enantioselectivity (Table 1, entry 5). We hypothesized that
the LiCl, generated en route to ZnPh2, likely promoted the
addition faster than the amino alcohol based catalyst pro-
motes the asymmetric addition. Similar proposals were
advanced by Seebach[12] and Bolm[16] in reactions that began
with Grignard reagents or PhLi. Based on their observations,
we set out to design an inhibitor to reduce the undesired LiCl
promoted addition.
To develop a selective inhibitor for lithium chloride we
took advantage of the differences in coordination chemistry
between the lithium salts and the zinc-based catalyst. It is
proposed that three coordinate amino alcohol based catalysts
possess a single open coordination site [Eq. (1)].[17] In
contrast, the lithium salts likely have at least two available
coordination sites. Structures of [tmeda·LiCl]n (TMEDA =
N,N,N’,N’-tetramethylethylene diamine) contain four-coordi-
nate lithium centers with bridging chlorides.[18,19] Further-
more, we expected that the zinc catalyst is more sterically
saturated than the lithium salts. Based on these points, we
chose to examine bulky multidentate diamines as inhibitors
that would chelate to lithium, but bind to the zinc catalyst in a
monodentate fashion.
Table 2: Catalytic asymmetric aryl additions to aldehydes from Ar2Zn.
Entry
ArBr
Aldehyde
ee [%]
Yield[%]
1
2
phenyl
2-tolyl
92
92
99
90
3
2-naphthyl
89
96
4
5
phenyl
2-tolyl
84
80
89
92
6
7
8
phenyl
2-tolyl
2-naphthyl
90
80
87
85 (S)[a]
86
96
9
10
11
phenyl
2-tolyl
2-naphthyl
90
87
91
90 (S)[a]
78
99
12
phenyl
84
91
13
14
phenyl
2-naphthyl
85
82
92
92
[a] Absolute configuration.
A series of chelating diamines was evaluated as LiCl
inhibitors in the asymmetric addition with ZnPh2 prepared in
situ under the conditions employed in Table 1, entry 5. In this
study, it was found that addition of toluene (or hexanes) after
transmetalation aided the precipitation of the lithium salts.
Subsequent injection of tetraethylethylene diamine (TEEDA,
0.8 equiv) resulted in addition with 89% enantioselectivity,
the same value obtained under salt-free conditions with
commercially available diphenylzinc [Eq. (2) and Table 1,
During early investigations of phenyl additions with
ZnPh2, it was realized that the uncatalyzed addition was fast
and competitive with the catalyzed reaction pathway, thus
resulting in low enantioselectivity.[20–22] To circumvent this
problem, Bolm and co-workers introduced the mixed zinc
reagent Et/Zn/Ph formed from combination of ZnEt2 and
ZnPh2.[22–28] Enantioselectivities with Et/Zn/Ph and planar
chiral catalyst were up to 38% higher than those that
employed the same catalyst with ZnPh2 alone.
Based on the successful application by Bolm of mixed
alkyl aryl zinc reagents,[9] we wished to develop an in situ
route to these species to increase the levels of enantioselec-
tivity in the aryl addition reactions. In our strategy to prepare
the mixed alkyl aryl zinc intermediates in situ, we chose to
avoid the use of dialkyl zinc reagents and focused on the more
readily available alkyl lithium reagents instead. Thus,
2.0 equivalents of aryl bromide and 2.1 equivalents of ZnCl2
were employed. Metalation of PhBr with nBuLi and addition
to ZnCl2 resulted in the generation of Ph/Zn/Cl. A second
equivalent of nBuLi was then added to produce Ph/Zn/Bu,
which was used in situ in the asymmetric addition reaction
after the addition of 0.8 equivalents of TEEDA [Eq. (3)]. We
were pleased to find that the enantioselectivity observed with
entry 4]. Achieving of the same enantioselectivity in the
absence or presence of LiCl indicates that the diamine
effectively inhibits the LiCl-promoted addition pathway.
Under the conditions outlined above, unfunctionalized
aryl bromides (bromobenzene, 2-bromotoluene, and 2-bro-
monaphthalene) were employed to prepare diarylzinc
reagents [Eq. (2)]. TEEDA was then added followed by
MIB and the aldehyde. In this fashion, aryl aldehydes gave
addition products with high enantioselectivities (80–92%)
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the Ph/Zn/Bu generated in situ was higher than that with
Ph2Zn and equal to that of Ph/Zn/Et (generated from
commercial Ph2Zn and Et2Zn), despite the 4 equivalents of
LiCl formed in the preparation of Ph/Zn/Bu.
Scheme 1. Formal synthesis of (S)-BMS184394.
A variety of substituted and functionalized aryl bromides
underwent enantioselective addition to benzaldehyde deriv-
atives under the conditions in Equation (3) with enantiose-
lectivities around 95% (Table 3, entries 2–9). These include 2-
bromotoluene, 2-bromonaphthylene, 4-bromoanisole, 4-bro-
both (R)- and (S)-BMS184394 are RAR g-selective, the
S enantiomer is significantly more potent than the R enan-
tiomer.[30] Enantioselective synthesis of this compound
proved difficult. Currently, the only enantioselective route
to this drug candidate employed two sequential enzymatic
kinetic resolutions that required 2 and 3.5 days (43% yield
and 95% ee).[30] As with any kinetic resolution, the maximum
yield is 50% and the desired compound must be separated
from the undesired derivatized product. In principle, secon-
dary diarylmethanols could be prepared enantioselectively by
asymmetric reduction of diaryl ketones. This approach has
proven quite challenging, however, because it is difficult for
catalysts to differentiate between the lone pairs on the
carbonyl oxygen atom when the aryl groups are similar in size,
thus resulting in low enantioselectivities.[32–36]
Using our method, 3.0 equivalents aryl bromide (2,
Scheme 1) were combined with nBuLi followed by ZnCl2 to
generate the mixed aryl butyl zinc reagent. TEEDA
(1.5 equiv) in hexanes was added followed by (+)-MIB
(5 mol%) and the aldehyde 3. The addition product 4 was
produced with 87% enantioselectivity in 88% yield
(Scheme 1). Conversion into (S)-BMS184394 can be accom-
plished by saponification of the ester.[30] The one-pot enan-
tioselective arylation of 3 demonstrates the potential utility of
our method for the synthesis of enantioenriched biologically
active benzylic alcohols.
Table 3: Catalytic asymmetric aryl additions to aldehydes with ArZnBu.
Entry
ArBr
Aldehyde
ee [%]
Yield[%]
1
2
3
Ph2Zn + Et2Zn
phenyl
4-methoxyphenyl
97
97
93
98
90
96
4
5
4-fluorophenyl
4-chlorophenyl
97
95
75
78
6
7
phenyl
4-methoxyphenyl
96
93
80
84
8
9
2-tolyl
2-naphthyl
95
96
73
79
10
11
12
13
14
15
4-methoxyphenyl
4-fluorophenyl
4-chlorophenyl
phenyl
4-fluorophenyl
4-chlorophenyl
83
88
87
88
84
81
82
64
55
95
74
68
In summary, we have developed a versatile method to
generate secondary benzylic alcohols with high levels of
enantioselectivity and yields. The importance of this method
is that one can now begin the asymmetric arylation of
aldehydes with aryl bromides, many of which are readily
available. In contrast, previous methods employed preformed
aryl boron reagents to generate salt-free aryl zinc intermedi-
ates or began with diphenylzinc. The introduction of a
diamine, such as TEEDA, was the key to the success of this
method. In the absence of TEEDA, the addition reaction is
promoted by LiCl, thus generating racemic products. TEEDA
prohibits the LiCl by-product from promoting the addition
reaction, thus allowing the addition to proceed through the
chiral zinc catalyst. Importantly, it is not necessary to filter,[16]
centrifuge,[13] or isolate the pyrophoric aryl zinc reagents, as
required with previous methods, in the presence of the
diamine, thus increasing the attractiveness of our method for
large-scale applications. This method enables the synthesis of
a variety of benzylic alcohols that were previously difficult to
access in enantioenriched form.
16
17
2-naphthyl
4-methoxyphenyl
82
78
76
84
mofluorobenzene, and 4-bromochlorobenzene. a,b-Unsatu-
rated aldehydes underwent addition with enantioselectivities
between 81 and 88%, whereas cyclohexanecarboxaldehyde
again gave slightly lower enantioselectivities (78 and 82%).
The results in Table 3 indicate that various aryl bromides can
now be employed as starting materials in the catalytic
asymmetric arylation of aldehydes.
To demonstrate the utility of our method, we chose to
prepare the precursor to BMS184394 (1, Scheme 1), an
retinoic acid receptor (RAR) g-selective retinoid with activity
against various skin diseases and cancers, in particular breast
cancer and acute promyelocytic leukemia.[29–31] Although
Angew. Chem. Int. Ed. 2006, 45, 4175 –4178
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4177

Communications
[16] Generation of ZnPh2 from PhLi and ZnBr2 followed by
filtration through Celite and addition of dimethoxy poly(ethy-
lene glycol) (to inhibit traces of remaining LiBr) and addition to
4-chlorobenzaldehyde afforded the diaryl methanol in up to
93% enantioselectivity in 8–31% yield; see: J. Rudolph, N.
Hermanns, C. Bolm, J. Org. Chem. 2004, 69, 3997.
[17] M. Kitamura, S. Okada, S. Suga, R. Noyori, J. Am. Chem. Soc.
1989, 111, 4028.
[18] D. Hoffmann, A. Dorigo, P. von R. Schleyer, H. Reif, D. Stalke,
G. M. Sheldrick, E. Weiss, M. Geissler, Inorg. Chem. 1995, 34,
262.
[19] S. Chitsaz, J. Pauls, B. Neumüller, Z. Naturforsch. B 2001, 56,
245.
[20] P. I. Dosa, J. C. Ruble, G. C. Fu, J. Org. Chem. 1997, 62, 444.
[21] W.-S. Huang, L. Pu, J. Org. Chem. 1999, 64, 4222.
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Experimental Section
Preparation of (4-fluorophenyl-4-methoxyphenyl)methanol (Table 3,
entry 7): A nitrogen-purged Schlenk flask was charged with 4-
bromoanisole (100.1 mL, 0.8 mmol) and tBuOMe (1 mL) and cooled
to À788C. Freshly titrated nBuLi (0.32 mL, 2.5m in hexanes,
0.8 mmol) was added dropwise, and the solution was stirred for 1 h.
The dry-ice bath was replaced with an ice bath, ZnCl2 (114.5 mg,
0.84 mmol) was added, and the reaction mixture was stirred for
30 min. Additional nBuLi (0.32 mL, 2.5m in hexanes, 0.8 mmol) was
added to the reaction mixture, which was then stirred for 4.5 h at
room temperature. Toluene (5 mL) and TEEDA (68 mL, 0.32 mmol)
were added, and the solution was stirred for 1 h. After the addition of
(À)-MIB (4.8 mg, 0.02 mmol, 5 mol%), the reaction cooled to 08C for
30 min, and p-fluorobenzaldehyde (43 mL, 0.4 mmol) was added. The
reaction was stirred at 08C and monitored by TLC. After completion
(18 h), the reaction mixture was quenched with H2O (20 mL) and
extracted with ethyl acetate (3 ” 20 mL). The organic layer was dried
over MgSO4, filtered, and the solvent was removed under reduced
pressure. The crude product was purified by column chromatography
on silica gel (hexanes/EtOAc, 95:5) to give the product (77.7 mg, 84%
yield, 93% ee) as a white solid. M.p. 528C; [a]2D0 = (+)13.846( c =
0.195, THF); 1H NMR (C6D6, 300 MHz): d = 2.17 (s, 1H), 3.38 (s,
3H), 5.50 (s, 1H), 6.81–6.95 (m, 4H), 7.17–7.29 (m, 4H) ppm; 13C{1H}
NMR (C6D6, 75 MHz): 55.0, 75.3, 114.3, 115.4 (d, J = 21.2 Hz), 128.4,
128.7 (d, J = 8.0 Hz), 136.9, 141.0 (d, J = 3.0 Hz), 159.7, 162.6 ppm (d,
J = 243 Hz); IR (neat): n˜ = 3421, 2957, 2837, 1609, 1504, 1248, 1033,
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831 cmÀ1
;
HRMS calcd for C13H13FO2 [M]+: 232.0900, found:
232.0900; determination conditions for the ee: Chiralpak AS-H,
hexanes/isopropylamine (95:5), flow rate = 0.5 mLminÀ1
,
t =
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20.0 min, 22.1 min.
Received: February 26, 2006
Published online: May 24, 2006
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Keywords: addition reactions · alcohols · aldehydes ·
asymmetric catalysis · zinc reagents
.
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