Rhodium-catalyzed highly enantioselective arylation of cyclic diketimines: Efficient synthesis of chiral tetrasubstituted 1,2,5-thiadiazoline 1,1-dioxides

Article abstract of DOI:10.1021/ol501770q

A highly enantioselective rhodium-catalyzed arylation of cyclic diketimines with arylboronic acids was achieved under mild conditions by employing a simple, sulfinamide-based branched olefin ligand. This protocol provides an efficient access to valuable chiral tetrasubstituted 1,2,5-thiadiazoline 1,1-dioxides in high yields with excellent enantioselectivities of up to 99% ee.

Full text of DOI:10.1021/ol501770q

Letter
pubs.acs.org/OrgLett
Rhodium-Catalyzed Highly Enantioselective Arylation of Cyclic
Diketimines: Efficient Synthesis of Chiral Tetrasubstituted 1,2,5-
Thiadiazoline 1,1-Dioxides
Hui Wang,† Yi Li,† and Ming-Hua Xu*
State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road,
Shanghai 201203, China
S
* Supporting Information
ABSTRACT: A highly enantioselective rhodium-catalyzed
arylation of cyclic diketimines with arylboronic acids was
achieved under mild conditions by employing a simple,
sulfinamide-based branched olefin ligand. This protocol
provides an efficient access to valuable chiral tetrasubstituted
1,2,5-thiadiazoline 1,1-dioxides in high yields with excellent
enantioselectivities of up to 99% ee.
1,2,5-Thiadiazoline 1,1-dioxide derivatives are versatile building
blocks for the synthesis of wide ranges of biologically active
natural products and pharmaceutical compounds.1 Moreover,
as key precursors, they also provide efficient access to valuable
cyclic sulfamides,2 1,2-diamines,3 and α-amino acids.4 Despite
their great synthetic importance, however, stereoselective
methods for preparing chiral thiadiazoline structures have
been surprisingly limited.5,6 Zezschwitz and co-workers recently
reported a Ru-catalyzed asymmetric transfer hydrogenation
approach in which one imine function of 3,4-disubstituted
1,2,5-thiadiazole 1,1-dioxides was selectively reduced to afford
highly enantiomerically enriched thiadiazoline derivates, but it
cannot be used for the construction of quaternary carbon
stereocenters.5 Accordingly, catalytic asymmetric 1,2-addition is
robust and applicable for chiral tetrasubstituted thiadiazolines
syntheses. However, there appears to be a significant challenge
for the control of stereochemistry of additions to ketimi-
ne.2d,3b,6−9 Until now there have been only several reports with
specific thiadiazole substrates describing the successful use of
transition-metal catalysts for this attractive transformation.6 In
2012, Lam succeeded in the highly enantioselective addition of
allyltrifluoroborates to simple 3-methyl-4-phenyl-1,2,5-thiadia-
zole 1,1-dioxide by use of a chiral Rh/diene catalyst.6a More
recently, in another work by the Zhang group dealing with Pd-
catalyzed enantioselective arylation of cyclic ketimines, a sole
example of addition of 3,4-dimethyl-1,2,5-thiadiazole 1,1-
dioxide with phenylboronic acid was described, giving the
product with moderate enantioselectivity (84% ee).6b Thus,
there is an unmet need for highly efficient asymmetric
approaches that could enable easy access to versatile thiadiazo-
line derivatives in a stereospecific manner.
asymmetric 1,2-addition of stable, commercially available
arylboronic acids to cyclic ketimines enables access to various
α-quaternary benzosultams and benzosulfamidates with ex-
cellent enantioselectivities (up to 99% ee) under mild
conditions.11h,i On the basis of these findings, we envisioned
that these rhodium/sulfur−olefin complexes might also act as
effective catalysts for the asymmetric addition to 3,4-
disubstituted 1,2,5-thiadiazole 1,1-dioxides. Herein, we wish
to disclose results of our efforts on the development of a mild
catalytic asymmetric addition of 3,4-disubstituted 1,2,5-
thiadiazole 1,1-dioxides for synthesis of various highly
enantioenriched thiadiazolines (Scheme 1).
Scheme 1. Asymmetric Arylation of Cyclic Diketimines
Our initial investigation was carried out by evaluating the
reaction of 3,4-diphenylthiadiazole13 (1a) with p-tolylboronic
acid (2a) under conditions similar to those previously reported
for the asymmetric arylation of cyclic N-sulfonyl α-iminoester
in the presence of optimal sulfur−olefin ligand.11h To our
delight, the reaction proceeded very well and gave the expected
α-quaternary thiadiazoline product 3a in good yield (93%) with
high enantioselectivity (94% ee) (Table 1, entry 1). Following
up on this encouraging result, effects related to the reaction
solvent, base, and temperature were carefully examined (entries
2−8). As summarized, of the solvents tested, CH2Cl2 exhibited
the greatest preference in terms of enantiocontrol without loss
of reactivity (92% yield, 97% ee) (entry 4). Employing other
Previously, we have reported the design of a new and
promising class of chiral sulfur-based olefin ligands and their
successful applications in a series of Rh-catalyzed asymmetric
reactions.10−12 In particular, by employing a structurally simple
chiral sulfinamide-based branched olefin as the ligand, the
Received: June 19, 2014
Published: July 16, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions for
Asymmetric 1,2-Addition of 1a with 2a
Table 2. Rh/L-Catalyzed Asymmetric Arylation of 1
a
b
c
entry
R
Ar
3
yield (%) ee (%)
b
c
1
C6H5 (1a)
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
4-CF3C6H4
3-MeOC6H4
3-ClC6H4
2-naphthyl
1-naphthyl
3-thienyl
3a
3b
3c
3d
3e
3f
92
98
91
89
91
88
89
92
94
96
87
84
88
85
88
85
91
99
95
79
70
97
97
99
97
99
98
99
98
99
98
98
99
99
99
94
99
98
96
99
88
96
entry
solvent
toluene
base
KF
yield (%)
ee (%)
2
C6H5 (1a)
1
2
3
4
5
6
7
93
72
23
92
93
33
15
80
94
94
95
97
95
96
97
97
3
C6H5 (1a)
THF
KF
4
C6H5 (1a)
CH3OH
CH2Cl2
ClCH2CH2Cl
CH2Cl2
CH2Cl2
CH2Cl2
KF
5
C6H5 (1a)
KF
6
C6H5 (1a)
KF
7
C6H5 (1a)
3g
3h
3i
K3PO4
KOH
KF
8
C6H5 (1a)
9
C6H5 (1a)
d
8
10
11
12
13
14
15
16
17
18
19
20
21
C6H5 (1a)
3j
a
The reaction was performed with 1a (0.25 mmol), 2a (0.5 mmol),
[Rh(COE)2Cl]2 (1.5 mol %), L (3.3 mol %), and 1.0 equiv of base
(1.5 M) in 1 mL of solvent at 40 °C for 6 h. COE = cyclooctene.
Isolated yields. Determined by HPLC analysis using a chiral
stationary phase. The reaction was performed at room temperature.
4-BrC6H4 (1b)
4-BrC6H4 (1b)
4-BrC6H4 (1b)
4-BrC6H4 (1b)
4-MeC6H4 (1c)
4-MeC6H4 (1c)
4-FC6H4 (1d)
4-FC6H4 (1d)
4-FC6H4 (1d)
Me (1e)
4-MeC6H4
4-ClC6H4
4-FC6H4
3k
3l
b
c
3m
3n
3o
3p
3q
3r
3s
3t
d
1-naphthyl
4-MeOC6H4
4-ClC6H4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-MeOC6H4
4-ClC6H4
bases, such as KOH or K3PO4, led to a dramatic decrease in the
yield, which was due to competitive hydrolysis of the substrate
(entries 6−7). In addition, performing the reaction at room
temperature did not bring any noticeable change in the
enantioselectivity, but a small erosion of yield was observed
(entry 8).
Me (1e)
3u
a
The reaction was performed with 1 (0.25 mmol), 2 (0.5 mmol),
[Rh(COE)2Cl]2 (1.5 mol %), L (3.3 mol %), and 1.0 equiv of KF (1.5
M) in 1 mL of CH2Cl2 at 40 °C for 6 h. Isolated yields. Determined
by HPLC analysis using a chiral stationary phase; see the Supporting
Information for details.
Having identified the optimal reaction conditions, we sought
to evaluate the scope and generality of the reaction. As revealed
in Table 2, reactions involving various thiadiazoles 1 with a
wide range of arylboronic acids 2 bearing diverse steric and
electronic properties were all found to be successful, affording
the corresponding thiadiazoline products 3 in high yields and
excellent enantioselectivities (up to 99% ee). Generally, when R
is aryl group, the electronic nature of the para and meta
substituent on the phenyl ring of boronic acids did not appear
to affect the reactivity and enantioselectivity (entries 1−19).
With respect to sterically hindered arylboronic acids, such as 1-
naphthylboronic acid or 3-thiopheneboronic acid, the reactions
proceeded equally smoothly and gave products in up to 96%
yield with outstanding stereocontrol (entries 9, 10, and 14).
However, with the more hindered 2-methylphenylboronic acid,
almost no reaction occurred. Furthermore, the electronically
different para-substituted 3,4-diarylthiadiazole species 1b−d
and the less sterically hindered 3,4-dimethylthiadiazole 1e are
also proved to be suitable substrates, as they exhibited high
reactivity and led to the formation of highly optically active C3
tetrasubstituted 1,2,5-thiadiazoline 1,1-dioxides 3k−u (entries
11−21). Notably, in all the examined reactions, no diarylation
occurs.
b
c
standard column chromatography and obtained in moderate
yields (up to 94% overall conversion). To our delight, the
enantioselectivities remain essentially high (up to 97% ee).
Gratifyingly, the stereochemistry of the newly formed chiral
center of product 3p was determined to be R by X-ray
crystallographic analysis. Assuming an analogous reaction
mechanism, the same absolute configurations of the obtained
thiadiazoline derivatives were assigned. Although the exact
intermediate in catalytic process remains unclear at this time, an
empirical transition-state model14,15 is proposed. As depicted in
Figure 1, the tert-butyl group provides an excellent stereo-
environment, so the arylrhodium species formed by trans-
metalation adopt a favorable conformation with the aryl group
positioned trans to the olefin moiety of ligand. To avoid the
steric interaction with the bulky R substituent, the thiadiazole
substrate could coordinate only from the re-face of the imine
CN to form the major (R)-product, in accordance with the
observed reaction stereochemical outcome.
Finally, the synthetic utility of the current method to prepare
α-amino ketones containing a quaternary stereogenic center is
shown in Scheme 3. Facile removal of the sulfonyl group by
treatment of 3a with hydrazine monohydrate at 110 °C gave
the corresponding product 7 in 81% yield without loss of
optical purity (96% ee). This protocol offers an efficient process
for the synthesis of interesting optically active tertiary α-amino
ketone derivatives.
Further broadening of the substrate scope indicated that the
reaction of arylboronic acids 2 with unsymmetrical thiadiazoles
4 could also proceed smoothly to provide the corresponding
adducts 5 and 6 under the same reaction conditions (Scheme
2). Unlike the case of unsymmetrical α-diketones, regardless of
differences in the steric and electronic properties of each imine
moiety, the addition reaction performed with relatively low
regioselectivity. Fortunately, in all cases, both regioisomers of
the products could be readily separated from each other by
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Organic Letters
Letter
a,b,c
Scheme 2. Rh/L-Catalyzed Asymmetric Arylation of 4
Scheme 3. Synthesis of the Tertiary α-Amino Ketones
Derivative 7
ally mild conditions. Following completion of the reaction, the
arylation products could be easily converted to tertiary α-amino
ketone compounds, which can be utilized as versatile chiral
synthons in synthetic organic chemistry.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, product characterization, and crys-
tallographic data for 3p (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xumh@simm.ac.cn.
Author Contributions
†These authors contributed equally.
Notes
a
The reaction was performed with 4 (0.25 mmol), 2 (0.5 mmol),
[Rh(COE)2Cl]2 (1.5 mol %), L (3.3 mol %), and 1.0 equiv of KF (1.5
b
c
M) in 1 mL of CH2Cl2 at 40 °C for 6 h. Isolated yields. Determined
by HPLC analysis a chiral stationary phase; see the Supporting
Information for details.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (21325209) and the Shanghai
Municipal Committee of Science and Technology
(14XD1404400).
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