Enantioselective metal/organo-catalyzed aerobic oxidative sp3C-H olefination of tertiary amines using molecular oxygen as the sole oxidant

Article abstract of DOI:10.1021/ja303333k

An organocatalysis/copper-catalyzed asymmetric oxidative sp³ C-H olefination reaction of tertiary amines with olefins using molecular oxygen as the sole oxidant under mild conditions was realized for the first time. This novel strategy provides

Full text of DOI:10.1021/ja303333k

Communication
pubs.acs.org/JACS
Enantioselective Metal/Organo-Catalyzed Aerobic Oxidative sp3
C−H Olefination of Tertiary Amines Using Molecular Oxygen
as the Sole Oxidant
Gen Zhang, Yunxia Ma, Shoulei Wang, Yaohu Zhang, and Rui Wang*
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, and State
Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
S
* Supporting Information
Oxone, BQ, DDQ, IBX, PhI(OAc)2, etc. Nevertheless, more
ABSTRACT: An organocatalysis/copper-catalyzed
economical and green oxidantdioxygen with water as the
only byproduct has not been widely employed in these
reactions.10 To the best of our knowledge, there have been no
examples to date that report on the transition-metal or Lewis
acid-catalyzed asymmetric oxidative coupling of amines under
molecular oxygen. As our continuous interest in amines
functionalization,11 we recently reported the first example on
copper-catalyzed asymmetric oxidative cross-coupling reactions
of amines with activated methylenes for Csp3−H alkylation of
amines (eq 1).11a,b Encouraged by these successful efforts and
asymmetric oxidative sp3 C−H olefination reaction of
tertiary amines with olefins using molecular oxygen as
the sole oxidant under mild conditions was realized
for the first time. This novel strategy provides an effi-
cient and environmentally friendly way to access diver-
sify optically active C1-alkene tetrahydroisoquinoline
derivatives.
he transition-metal-catalyzed C−H olefination reactions,
T
which replace simple C−H bonds with readily derivatizable
alkene functional groups, are uniquely powerful transformations
available for forging new C−C bonds and play a fundamentally
important role in modern organic synthesis.1 Significant
advances have been made in Pd-2 and Rh-catalyzed3 olefination
of aromatic C−H bonds through C−H activation generally using
a neighboring directing group (DG) in recent years. In contrast,
the similar process at unactivated alkyl C−H sites remains
undeveloped. To date, the only examples on sp3 C−H olefination
were disclosed by the groups of Yu4 and Sanford5 using a
palladium catalysis and employing N-arylamide or pyridine as
DG by means of metal insertion. However, a prominent
challenge remaining in sp3 C−H olefination is control of the
enantioselectivity as regioselectivity must also be controlled
simultaneously, which cannot be overcome via the existing
DG-directed C−H activation due to the harsh reaction
conditions;6 therefore, the development of a complementary
method is highly desired.
aiming to develop other unprecedented transformations, herein
we describe our contribution on enantioselective oxidative
Csp3−H olefination of amines using cooperative catalysts and
utilizing dioxygen as a stoichiometric oxidant under mild
conditions (eq 2).
The oxidative coupling reaction has evolved to be one of the
most efficient and atom-economical approaches to construct
new bonds through direct coupling of two C−H or
heteroatom−H bonds.7 The prospect of concise synthesis of
complex molecules from simple starting materials under mild
conditions makes this reaction particularly attractive. Among
this reaction, the oxidative coupling of amines with various
nucleophile-catalyzed simple metal salts has received consid-
erable attention,8 and tremendous progress has been made in
this fascinating field since the pioneering studies of Murahashi
and Li.9 However, the development of this transformation into a
general, catalytic and enantioselective process still remains a
great challenge and has never been achieved, especially for
the coupling between amines and olefins. On the other hand,
the current oxidative coupling reactions are usually environ-
mentally unfriendly, using excess oxidant such as TBHP,
As increasing attention has been given to this new topic, the
combination of the transition metal/Lewis acid catalysis and
organocatalysis in one process has emerged as a highly attractive
strategy for developing new and valuable reactions, as it could
potentially achieve unparalleled transformations not currently
possible by use of the transition-metal/Lewis acid complex or the
organocatalyst alone.12 Since this concept was first introduced by
Krische in 2003,13 various transition metals/Lewis acid and
several types of organocatalysts (including aminocatalysts,14a,b
Bronsted acid,14c,d Lewis base14e,f and phase transfer catalyst14g,h
)
Received: April 6, 2012
Published: July 17, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
a
have been combined successfully for promoting a variety of
unprecedented transformations. However, the combining
transition metal/Lewis acid with bifunctional cinchona alkaloids
has not been successfully developed. Thus, the design and dis-
covery of this novel type of cooperative catalytic system to
promote some undeveloped transformations, such as asymmetric
oxidative cross-coupling reaction of amines and olefins, is partic-
ularly challenging.
Table 1. Optimization of Reaction Condition
Considering tetrahydroisoquinolines, especially C1-alkene
tetrahydroisoquinolines with a stereocenter at the C1
position, are active determining building blocks with wide
utility in organic synthesis and pharmaceutical chemistry,15
we chose N-aryl tetrahydroisoquinolines as the tertiary amines
to oxidative couple with olefins in the presence of a metal salt
and an organocatalyst under the oxidizing conditions at room
temperature. An initial survey of oxidant indicated that O2 is a
good oxidant, and the yield and enantioselectivity could be
improved when molecular sieve was added to the reaction
(Table 1, entries 1−5). The investigation of metals salts and
organocatalysts 4a−n showed that Cu(OTf)2 and quinine
(4b) were the best cooperative catalysts (Table 1, entries 6−
20 and see the Supporting Information). Solvent optimization
results showed that DCM was a better solvent with regard to
the enantioselectivity (see the Supporting Information). The
results of optimization of N-protecting groups of tetrahy-
droisoquinolines showed that PMP- is the best choice (for the
detial, see the Supporting Information). To our delight, the
best outcome for conversion and enantioselectivity could be
achieved when anhydrous Na2SO4 was added to the reaction
(up to72% yield and 90% ee; Table 1, entry 21). The reaction
became slower and yield was decreased without molecular
sieves, although little influence on stereoselectivity (Table 1,
entry 22).
With the best reaction conditions established, the scope of
substrates for the asymmetric copper/quinine-catalyzed oxida-
tive coupling reactions was then studied. In general, the reaction
proceeded well to afford the desired products in good yields
and good to excellent enantioselectivities. For the reaction
with acrylaldehyde (2a), a wide range of aromatic-substituted
tetrahydroisoquinolines 1a− q were examined, and it was
observed that with both electron-withdrawing and electron-
donating groups on the para, meta and ortho position of the
phenyl ring of 1 the desired oxidative coupling products were
obtained in satisfactory yields of 47−73% and excellent
enantioselectivities of 85−99% (Table 2, entries 1−11). The
coupling products of 2a and aromatic-substituted tetrahydroiso-
quinolines 1 with double substituents on the N-aryl ring,
respectively, were also isolated in good yield and high
enantioselectivity (49−81% yields and 80−93% ee; Table 2,
entries 12−15). The substituents with methoxy on the 6,7-
position or chlorine on the 7-position of tetrahydroisoquinoline
ring did not influence the reaction outcomes (Table 2, entries
16−17). After testing the generality of this novel oxidative
coupling reaction with regard to the series of N-aryl
tetrahydroisoquinolines with acrylaldehyde (2a), various olefins
were then investigated for the synthesis of diverse optically active
C1-alkene tetrahydroisoquinoline derivatives. When methylvi-
nylketone (2b), ethylvinylketone (2c) and acrylonitrile (2d)
were used to react with 1a and 1b, the reaction proceeded readily
to give coupling products 3r−u in good yield (48−77%) and
good to excellent enantioselectivity (69−99% ee; Table 2, entries
18−21). However, the result was frustrated by using N-
benzylaniline 1r to couple with 2a due to the weak reaction
yield
b
ee
c
entry
metal
L*
oxidative
O2
tBuOOH
PhI(OAc)2
DDQ
O2
additive
(%)
(%)
1
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
AgOTf
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
4e
4f
68
<10
80
73
71
55
36
70
54
52
59
<10
61
64
n.d.
n.d.
67
59
75
62
72
56
28
d
2
n.d.
20
3
4
12
5
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
Ph3P
51
6
O2
−47
24
7
Pd(OAc)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
O2
8
O2
81
9
O2
−53
−51
−55
10
11
12
13
14
15
16
17
18
19
20
21
22
O2
O2
d
O2
n.d.
4g
4h
4i
O2
50
O2
63
d
d
O2
n.d.
n.d.
50
4j
O2
4k
4l
O2
O2
−13
−45
42
4m
4n
4b
4b
O2
4 Å MS
4 Å MS
4 Å MS
Na2SO4
O2
e
O2
90
O2
88
a
Unless otherwise specified, the reaction was performed on a 0.1 mmol
b
scale at room temperature (see the Supporting Information). Isolated
c
d
yield. Determined by HPLC on chiral stationary phase. Not deter-
e
mined. Na2SO4 (0.3 mmol) was added to the reaction.
(Table 2, entry 22). The absolute configuration of products were
determined to be S by using a single-crystal X-ray diffraction of
3q (Figure 1).16
In summary, we have described a novel asymmetric oxidative
cross-coupling reaction between simple amines and olefins for
constructing Csp2−Csp3 bonds catalyzed by organo/metal
cooperative catalysis under mild conditions using molecular
oxygen as the terminal oxidant and with moderate to good
yields (47−82%) and excellent enantioselectivities (up to 99%
ee). This method provided an alternative approach to current
DG-directed sp3 C−H activation olefinations and allowed
the rapid construction of diverse optically active C1-alkene
tetrahydroisoquinoline derivatives in one step from basic
starting materials and under a direct, efficient, mild and atom-
economical process. The development of this novel cooperative
catalysis system in other asymmetric oxidative coupling
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Journal of the American Chemical Society
Communication
a
Table 2. Investigating the Scope of the Procedure
a
Unless otherwise specified, the reaction was carried out with 1a (0.1 mmol) and 2a (0.2 mmol) in the presence of Cu(OTf)2 (0.01 mmol) and 4b
(0.02 mmol), 4 A molecular sieve (100 mg), anhydrous Na2SO4 (0.3 mmol), and DCM (1.0 mL) under 1 atm molecular oxygen at room
b
c
temperature for 24−72 h. Isolated yield. Determined by HPLC on chiral stationary phase and the configuration was assigned by comparison of
d
HPLC data and X-ray crystal data of 3q. Not determined.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details including product characterization and
NMR-experiments. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
wangrui@lzu.edu.cn
■
Notes
Figure 1. X-ray crystal data of compound 3q.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for the grants from the National Natural Science
Foundation of China (nos. 20932003 and 90813012) and the
■
reactions and the mechanism study of this process are being
pursued.
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Journal of the American Chemical Society
Communication
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