COMMUNICATION
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Highly Enantioselective Arylation of N-Tosylalkylaldimines Catalyzed
by Rhodium-Diene Complexes
Zhe Cui,†,‡ Hong-Jie Yu,† Rui-Feng Yang,† Wen-Yun Gao,‡ Chen-Guo Feng,*,† and Guo-Qiang Lin*,†
†Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P.R. China
‡College of Life Sciences, Northwest University, Xi’an, Shaanxi 710069, P.R. China
S Supporting Information
b
efficient arylation of N-tosylalkylaldimines with chiral bicyclo-
[3.3.0]octadiene ligands.10
ABSTRACT: A highly enantioselective rhodium-catalyzed
arylation of aliphatic N-tosylaldimines has been developed.
The combination of chiral bicyclo[3.3.0]octadiene ligands,
an active rhodium hydroxide complex, and neutral reaction
conditions is the key to achieving high yield and enantios-
electivity. The application of this method is demonstrated
by the enantioselective synthesis of chiral 2-aryl pyrrolidines
and piperidines in a one-pot procedure. Furthermore,
excellent results are also obtained for the imine substrates
with the more readily cleavable N-nosyl protecting group.
Our investigation commenced with the use of N-tosylimine 1a
as a model substrate.11 Under the standard reaction conditions
previously developed for N-tosylarylimines, the addition of phenyl-
boronic acid to 1a, with bicyclo[3.3.0]octadienes 4aÀ4d as ligands
for screening, gave the desired product 3aa in excellent enantios-
electivities (98À99% ee). However, the yields were unsatisfac-
tory (22À40%; Table 1, entries 1À4). Attempts to improve the
reaction yield by employing KHF2 as an additive7c (entry 5) or
Ellman’s reaction conditions proved to be fruitless (entry 6).9
We postulated that the low yields were due to the rapid
decomposition of N-tosylimine 1a. To verify this speculation,
several control experiments were performed. It was found that
∼75% of imine 1a was destroyed in hot aqueous dioxane (70 °C)
in 3.5 h. This process was accelerated in the presence of a given
base. For example, no imine 1a was observed after 3.5 h when
K3PO4 was added. According to this stability information, there
are two possible options to improve the reaction yield: (1) use a
more active catalyst to accelerate the imine transforming process
or (2) use a base/acid-free reaction condition to slow the de-
composition process.
In the following optimization studies, the reaction was carried
out with [RhCl(4a)]2 as catalyst without any base additive.
Though only 29% yield was obtained, the result was promising,
as this arylation could occur under a neutral condition (Table 2,
entry 1). When more active [Rh(OH)(4a)]2 was tested,12
the desired adduct was obtained in almost quantitative yield
(99%) with excellent enantioselectivity (>99% ee, entry 2). High
enantioselectivities and slightly lower yields were observed when
the reactions were conducted at lower temperatures (entries 3 and
4). Dropping the catalyst to 1 mol % did not affect the high
selectivity (entry 5). The presence of 4 Å MS was also helpful for
achieving high reaction yield (entry 6).
hiral R-arylamines are a common structural motif in natural
C
products as well as in pharmaceutical molecules. Some ex-
amples are the naturally occurring cytokine modulator (À)-cyto-
xazone,1 the third-generation antihistamine levocetirizine,2 and
the selective Kv1.5 blocker BMS-394136.3 Among the methods
to synthesize these structures, asymmetric rhodium-catalyzed
arylation of imines represents an attractive approach. Since the
first example reported by Tomioka in 2004,4 significant efforts
have been devoted to this rhodium-catalyzed transformation by
various research groups.5À8 In spite of the considerable advance-
ments, the imine substrates are usually limited to aromatic imines.
The major challenge in the addition of aliphatic imines is their
tendency to undergo imineÀenamine tautomerization, decom-
position, and self-condensation under common reaction condi-
tions. The only example with aliphatic imines was reported by
Ellman and co-workers in 2008, utilizing a chiral bisphosphine
ligand.9 The resulting chiral R-aryl alkylamines were prepared in
68À96% yield with 81À98% ee. Therefore, a more efficient
catalytic system is still highly desirable for the preparation of
these interesting substructures in higher yield and with improved
enantioselectivity.
With the optimal reaction conditions in hand (Table 2, entry 2),
the reaction scope was examined. Varying the substituent at the
4- or 3-position of the phenyl ring of the boronic acid with either
an electron-donating or -withdrawing group gave the product in
high yields (91À99%) with excellent enantioselectivities (98 to
>99% ee; Table 3, entries 1À7). Slight decreases in the reaction
selectivity were observed when the more sterically hindered
2-methoxyphenylboronic acid and 1-napthylboronic acid were
used (entries 8 and 9). However, the enantioselectivity could be
In 2004, Hayashi reported a rhodium-catalyzed arylation of
N-tosylarylaldimines with chiral bicyclo[2.2.2]octadiene ligands.8a
Since then, a wide variety of chiral diene ligands have been suc-
cessfully applied in this transformation.7,8 Compared with chiral
phosphine ligands, chiral diene ligands have provided higher
enantioselectivity in many cases, especially the chiral bicyclo-
[3.3.0]octadiene ligands, which were first introduced by our
group in 2007.7a They can readily be prepared in both enantio-
meric forms and were found to be superior ligands for enantio-
selective arylation of N-tosyl- or N-nosylarylaldimines, providing
chiral diaryl amines in extremely high enantioselectivity (98À
99% ee). Herein, we report our recent success in the highly
Received: May 23, 2011
Published: July 19, 2011
r
2011 American Chemical Society
12394
dx.doi.org/10.1021/ja2046217 J. Am. Chem. Soc. 2011, 133, 12394–12397
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