Asymmetric synthesis of (Triaryl)methylamines by rhodium-catalyzed addition of arylboroxines to cyclic N-sulfonyl ketimines

Article abstract of DOI:10.1021/ja300697c

Asymmetric addition of arylboroxines to cyclic N-sulfonyl ketimines proceeded in the presence of a rhodium catalyst coordinated with a chiral diene ligand to give high yields of benzosultams, where a triaryl-substituted stereogenic carbon center was created with high enantioselectivity (93-99% ee). The chiral benzosultams were transformed into the chiral (triaryl)methylamines by breaking the cyclic structure.

Full text of DOI:10.1021/ja300697c

Communication
pubs.acs.org/JACS
Asymmetric Synthesis of (Triaryl)methylamines by Rhodium-
Catalyzed Addition of Arylboroxines to Cyclic N-Sulfonyl Ketimines
Takahiro Nishimura,* Akira Noishiki, Gavin Chit Tsui, and Tamio Hayashi*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
S
* Supporting Information
Scheme 1. Asymmetric Arylation of Cyclic N-Sulfonyl
Ketimines
ABSTRACT: Asymmetric addition of arylboroxines to
cyclic N-sulfonyl ketimines proceeded in the presence of a
rhodium catalyst coordinated with a chiral diene ligand to
give high yields of benzosultams, where a triaryl-
substituted stereogenic carbon center was created with
high enantioselectivity (93−99% ee). The chiral benzo-
sultams were transformed into the chiral (triaryl)-
methylamines by breaking the cyclic structure.
biologically active compounds.16 Enantioselective synthesis of
benzosultams possessing an α-trisubstituted carbon center has
been reported in the metal-catalyzed intramolecular C−H
amination17 and asymmetric reduction of cyclic N-sulfonyl
ketimines.15a,16b,18 As an example of constructing an α-
tetrasubstituted carbon center of benzosultams, the chiral
NHC-catalyzed enantioselective annulation of a cyclic N-
sulfonyl ketimine with cinnamaldehyde has been reported by
Bode et al.19 Here we report the rhodium-catalyzed asymmetric
addition of arylboroxines to cyclic N-sulfonyl ketimines to give
high yields of benzosultams with high enantioselectivity.
he transition-metal-catalyzed asymmetric addition of
T
organometallic reagents to imines offers one of the
most reliable methods available for the synthesis of
enantioenriched α-chiral amines.1 A variety of useful catalytic
systems based on copper,2 zirconium,3 rhodium,4 and
palladium5 complexes have been reported in the asymmetric
alkylation and arylation of imines derived from aldehydes. In
contrast, the asymmetric addition of organometallic reagents to
ketimines, which provides chiral amines bearing an α-
tetrasubstituted carbon stereocenter, remains significantly
underdeveloped,6 and there have been only a few reports to
date.7−10 Copper-catalyzed asymmetric addition of allylboro-
nates have been reported by Kanai and Shibasaki.7 The
asymmetric addition of dialkylzinc has been reported by
Charette (Cu),8 and Snapper and Hoveyda (Zr).9 In this
context, we recently reported the rhodium-catalyzed asym-
metric addition of arylboron reagents to N-sulfonyl ketimines
derived from alkyl aryl ketones giving α-diaryl alkyl amines with
high enantioselectivity.11 In the rhodium-catalyzed arylation of
imines, the enantioface of the CN bond is differentiated by
the steric interactions between a substituent on the chiral ligand
and a sulfonyl moiety on the nitrogen atom of the imine.4 Thus,
the geometry (E or Z) of the imine greatly affects the
enantioselectivity. It follows that the arylation of ketimines
derived from diaryl ketones has inherent difficulty in
controlling the enantioselectivity due to the lack of sufficient
steric difference between the two aryl rings.12 To the best of
our knowledge, there have been no examples to date that report
the catalytic asymmetric arylation of diaryl-substituted
keimines.13 We focused on the cyclic N-sulfonyl ketimines
bearing the diaryl-substituted azomethine carbon toward the
synthesis of benzosultams bearing a triaryl-substituted stereo-
genic carbon center, which can lead to chiral (triaryl)-
methylamines (Scheme 1).14
We found that cyclic N-sulfonyl ketimine 1a, which is readily
derived from saccharin,16b,20 is a good substrate for
constructing a triaryl-substituted stereogenic carbon center
enantioselectively in the rhodium-catalyzed addition of
arylboroxines. Thus, treatment of 1a with p-tolylboroxine
(2m) (2 equiv of B) in the presence of a rhodium/
21
bisphosphine catalyst [RhCl((R)-binap)]2 (5 mol % of Rh),
K3PO4 (1 equiv), and tert-amyl alcohol (3 equiv) in 1,4-dioxane
at 60 °C for 12 h gave benzosultam 3am in 93% yield, whose
enantiomeric purity was 39% (Table 1, entry 1). A higher
enantioselectivity (71% ee) for 3am was observed by use of
(R)-segphos (entry 2), but the bulky ligand DTBM-segphos
decreased both the catalytic activity and enantioselectivity (10%
yield, 9% ee; entry 3). Chiral diene ligands22 were effectively
applied to the present arylation. Thus, the reaction by use of
[RhCl((S,S)-Fc-tfb*)]223 (Fc = ferrocenyl), which is one of the
most active catalysts displaying high enantioselectivity in the
rhodium-catalyzed arylation, gave 3am in 96% yield with 90%
ee (entry 4). Chiral diene ligands L1−L3,4c,l,24 which are
readily prepared from a natural product in enantiopure form,
also displayed high catalytic activity (entries 5−7), and the use
of ligand L3 bearing a bulky (2,6-diisopropyl)phenyl ester
moiety gave 3am in 99% yield with 98% ee (entry 7).25 The
absolute configuration of 3am was assigned to be R by analogy
Enantiopure sultams are an important class of compounds in
organic and medicinal chemistry, which have been used as
chiral auxiliaries15 and as key intermediates for the synthesis of
Received: January 21, 2012
Published: March 6, 2012
© 2012 American Chemical Society
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Table 1. Rhodium-Catalyzed Asymmetric Addition of p-
Tolylboroxine (2m) to Ketimine 1a
Table 2. Rhodium-Catalyzed Asymmetric Addition of
a
a
Arylboroxines 2 to Ketimine 1
a
a
Reaction conditions: ketimine 1a (0.20 mmol), 2m (0.13 mmol),
Reaction conditions: ketimine 1 (0.20 mmol), arylboroxine 2 (0.13
mmol), [RhCl((R)-L3)]2 (5 mol % of Rh), K3PO4 (0.20 mmol), tert-
amyl alcohol (0.60 mmol), 1,4-dioxane (0.8 mL) at 60 °C for 12 h.
[RhCl(L*)]2 (5 mol % of Rh), K3PO4 (0.20 mmol), tert-amyl alcohol
b
(0.60 mmol), 1,4-dioxane (0.8 mL) at 60 °C for 12 h. Isolated yields.
c
b
c
Determined by chiral HPLC analysis.
Determined by chiral HPLC analysis. At 80 °C for 24 h using 0.33
d
mmol of 2m with tert-amyl alcohol (1.50 mmol). For 24 h using 0.20
e
with (R)-3au, which was determined by X-ray crystallography
(vide infra).
mmol of 2 with tert-amyl alcohol (0.90 mmol). Performed using 0.20
mmol of 2 with tert-amyl alcohol (0.90 mmol).
The present catalytic system can be applied to the
asymmetric addition of several arylboroxines 2 to cyclic N-
sulfonyl ketimines 1 with high enantioselectivity (Table 2). Aryl
groups having a variety of substituents at the ortho, meta, and
para position of phenyl were successfully introduced to the
azomethine carbon of 1a to give the corresponding
benzosultams 3am−3aw in high yields with over 94% ee
(entries 1−11). The addition of phenylboroxine (2x) to
ketimine 1b substituted with a p-tolyl group, which is a reverse
combination of the reaction of 1a with 2m, gave an opposite
enantiomer ((S)-3bx) of 3am in 94% yield with 97% ee (entry
12). A benzosultam 3bn substituted with a meta- and a para-
tolyl group was also synthesized with 97% ee (entry 13). The
addition of p-tolylboroxine to ketimines 1c−1g possessing
several aromatic rings substituted with both an electron-
donating (MeO) and -withdrawing groups (F, Cl, CF3)
proceeded to give the corresponding benzosultams 3cm−
3gm in high yields with high enantioselectivity (entries 14−18).
Ketimines bearing heteroaromatic rings, 2-furyl (1h) and 2-
thienyl (1i), are also good substrates to give the corresponding
benzosultams 3hm and 3im with 99% and 93% ee, respectively
(entries 19 and 20).
The reaction of the cyclic ketimine 4 with p-tolylboroxine
(2m) in the presence of the Rh/(R)-L3 catalytic system also
proceeded to give the sulfamidate 5 in 71% yield with 99% ee
(Scheme 2).
Scheme 2. Asymmetric Arylation of Ketimine 4
The absolute configuration of the benzosultam 3au was
determined to be R by X-ray crystallographic analysis (Figure
1). The absolute configuration is in good agreement with the
stereochemical model shown in Scheme 3. Thus, imine 1a
coordinates to a rhodium with its re-face avoiding the steric
interaction between the sulfonyl moiety of 1a and the ester
group on the ligand, which is similar to the arylation of imines
that we previously reported.4c
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and compound characterization data
(PDF and CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
tnishi@kuchem.kyoto-u.ac.jp; thayashi@kuchem.kyoto-u.ac.jp
Notes
The authors declare no competing financial interest.
Figure 1. ORTEP illustration of 3au with thermal ellipsoids drawn at
50% probability level (hydrogens are omitted for clarity).
ACKNOWLEDGMENTS
■
This work has been supported by a Grant-in-Aid for Scientific
Research from the MEXT, Japan.
Scheme 3. Stereochemical Model
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