Rhodium(III)-catalyzed C-C coupling of arenes with 2-vinyloxiranes: Synthesis of allylic alcohols

Article abstract of DOI:10.1021/ol5000764

A rhodium(III)-catalyzed C-C coupling between 2-vinyloxiranes and arenes directed by different chelating groups has been realized via a C-H activation pathway. This reaction proceeded under conditions with a low catalyst loading, and allylic alcohols were isolated as the coupling products. A series of benzoazepanes has been synthesized by following this coupling.

Full text of DOI:10.1021/ol5000764

Letter
pubs.acs.org/OrgLett
Rhodium(III)-Catalyzed C−C Coupling of Arenes with 2‑Vinyloxiranes:
Synthesis of Allylic Alcohols
Songjie Yu and Xingwei Li*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
S
* Supporting Information
ABSTRACT: A rhodium(III)-catalyzed C−C coupling be-
tween 2-vinyloxiranes and arenes directed by different
chelating groups has been realized via a C−H activation
pathway. This reaction proceeded under conditions with a low
catalyst loading, and allylic alcohols were isolated as the
coupling products. A series of benzoazepanes has been synthesized by following this coupling.
unctionalized allylic alcohols are well-known as biologically
active small molecules and are also key building blocks in
might be ascribable to the lower ligating ability of epoxide
oxygen. To address this issue and to take advantage of the
strain-induced reactivity of epoxides, we designed 2-vinyl-
oxiranes as the substrate. The CC bond in 2-vinyloxirane
should readily undergo insertion to a Rh−C bond to give a
rhodium alkyl intermediate, which may induce the epoxide
opening via β-oxygen elimination. We noted that a related
allylic alcohol formation via nucleophilic addition of lithium
dialkylcuperate to 2-vinyloxiranes has been reported.10
However, using this reactive organometallic reagent may pose
an issue of functional group compatibility. It will be highly
desirable to take advantage of the ready availability of arenes via
a C−H activation pathway. We now report our findings in the
coupling of arenes and 2-vinyloxiranes under mild conditions
and in high catalytic activity.
We initiated our investigation with the optimization studies
of the coupling of N-(2-pyrimidyl)indole and 2-vinyloxirane
(2a, Table 1). Using a cationic [RhCp*(MeCN)3](SbF6)2
complex (3 mol %) as a catalyst, a coupling occurred and
product 3aa was isolated in 65% yield as a result of olefin
insertion and epoxide opening. Product 3aa was characterized
as a mixture of allylic alcohols in 1.8:1 E/Z ratio (1H NMR
analysis). Introduction of PivOH further improved the isolated
yield. Thus product 3aa was isolated in 94% even at room
temperature,11 where DCE was identified as the optimal
solvent. Using a combination of [RhCp*Cl2]2 and AgSbF6
afforded comparable results, but for operational simplicity
[RhCp*(MeCN)3](SbF6)2 was retained for further studies.
By following the optimized conditions, the scope and
limitations of this system were next explored (Scheme 2). N-
(2-Pyrimidyl)indoles bearing a large variety of electron-
donating (Me, OMe, OBn) and -withdrawing (Cl, Br,
COOMe) groups in the benzene ring coupled smoothly with
2-vinyloxirane. Introduction of a substituent at the 3-position of
the indole ring has minimal influence (3ba and 3ca), indicative
of tolerance of steric effects. In this case, the products were
F
the synthesis of natural and pharmaceutical compounds.1
Therefore, the synthesis of compounds with an allylic alcohol
fragment has attracted the attention of synthetic chemists. Over
the past decades, transition-metal-catalyzed C−H bond
activation has emerged as a powerful tool for the formation
of functionally diverse and structurally complex aromatics.2
From a step- and atom-economic standpoint, synthesis via C−
H bond functionalization would be a more straightforward and
attractive alternative.
Recently, Rh(III)-catalyzed C−H bond functionalization3 has
allowed effective construction of various C−C bonds. The
oxidative C−H olefination4 of arenes and alkenes has been
particularly well studied. However the direct C−H insertion
into olefins under redox-neutral conditions has been rarely
realized.5 To achieve this insertion, two strategies with
additional driving forces have been employed (Scheme 1).
Scheme 1. Rhodium(III)-Catalyzed Redox-Neutral Coupling
of Arenes
Glorius, Loh, and others independently applied allyl esters to
coupling with arenes under Rh(III)-catalysis, leading to
allylation of C−H bonds.6 In this process, the olefin insertion
is coupled with subsequent β-elimination of an acetate or
carbonate leaving group. This strategy has also been extended
to the coupling of allenyl carbinol carbonate.7 Alternatively,
olefin insertion can be streamlined with subsequent opening of
a strained cyclobutane.8 We recently reported the rhodium-
catalyzed insertion of aryl C−H bonds into N-Ts aziridines,
leading to the synthesis of β-branched amines (Scheme 1).9
The analogous reaction for epoxides, however, failed even after
extensive screenings. We reasoned that the poor reactivity
Received: January 9, 2014
Published: February 7, 2014
© 2014 American Chemical Society
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Letter
a
Table 1. Optimization Studies
Scheme 3. C−H Allylation of Benzene and Thiophene
a
,b
Rings
b
entry
1
catalyst (mol %)
solvent
yield
−
DCE
0
65
c
2
[Cp*Rh(MeCN)3](SbF6)2 (3)
[Cp*Rh(MeCN)3](SbF6)2 (3)
[Cp*RhCl2]2 (1.5)/AgSbF6 (6)
[Cp*Rh(MeCN)3](SbF6)2 (3)
[Cp*Rh(MeCN)3](SbF6)2 (3)
[Cp*Rh(MeCN)3](SbF6)2 (3)
[Cp*Rh(MeCN)3](SbF6)2 (3)
[Cp*Rh(MeCN)3](SbF6)2 (3)
DCE
3
4
5
6
7
8
9
DCE
94
DCE
92
DCM
acetone
THF
91
15
45
MeCN
dioxane
<10
26
a
Reactions conditions: 1a (0.3 mmol), 2a (0.36 mmol), PivOH (0.3
b
c
mmol), 25 °C, 16 h, sealed tube under argon. Isolated yield. No
PivOH was used.
a
,b
Scheme 2. C−H Allylation of Heterocycles
a
Reaction conditions: arene (0.3 mmol), 2-vinyloxirane (0.36 mmol),
PivOH (0.3 mmol), [Cp*Rh(MeCN)3](SbF6c)2 (3 mol %), 25 °C, 16
b
h, sealed tube under argon. Isolated yield. [RhCp*Cl2]2 (2.5 mol
%) and AgSbF6 (10 mol %) were used.
coupled with 2a with an additional issue of mono- and
diallylation selectivity, installation of a substituent at the ortho
or meta position ensures monoallylation. These blocking
groups can vary significantly from electron-donating to
-withdrawing groups and can be halogen groups. Variation of
the directing group has been demonstrated. Other heterocycles
such as quinoline and pyrazole are equally competent. N-
Methoxy oximes functioned to some extent as a directing
group; reasonably high yields were isolated for oximes of
acetophenones bearing EDGs in the benzene ring. However,
introduction of EWGs such as p-Cl dramatically decreased the
reaction yield. Installation of substituents at both the olefin and
the epoxide units is also well-tolerated. Thus 2-vinyloxiranes
with a di- or trisubstituted olefin unit, including epoxides of
cyclic dienes of different ring sizes, all coupled smoothly
although a lower yield tends to be reached for an epoxide fused
to a larger ring, probably due to steric effects. This coupling is
not limited to an epoxide moiety, and the same reaction pattern
was followed for the N-Ts aziridine derived from 1,3-
cyclohexadiene. This observed reaction pattern is in contrast
to our recently reported ring-opening coupling between N-Ts
aziridine and 2-phenylpyridines (Scheme 1).9 In the current
reaction, the organorhodium species interacts preferentially
with the olefin unit instead of with the aziridine ring (Scheme
1).
a
Reaction conditions: arene (0.3 mmol), 2-vinyloxirane (0.36 mmol),
PivOH (0.3 mmol), [Cp*Rh(MeCN)3](SbF6)2 (3 mol %), 25 °C, 16
h, sealed tube under argon. Isolated yield.
b
isolated in a slightly higher trans/cis ratio. In all cases, the
coupled products were isolated in high yield (81−97%). In
addition to the simple 2-vinyloxirane, high efficiency was also
observed for the coupling of 1,3-cyclohexadiene monoxide,
where product 3ac was obtained as a single diastereomer with
the aryl and the OH being cis disposed. When 2-methyl-2-
vinyloxirane was used, a slightly reduced yield but an improved
selectivity was obtained (3ab, 6.1:1). Extensions of the indole
ring to thiophene proved to be successful, as in the isolation of
3oa in 91% yield.
N-Nitrosoanilines have shown to be viable susbtrates that
may allow diversified postcoupling transformations.12 Here
extension to N-nitrosoaniline substrates allowed the synthesis
of useful heterocycles. Subjection of substituted N-alkylnitroso-
The arene substrate was successfully extended to 2-
phenylpyridines (Scheme 3). While simple 2-phenylpyridine
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Letter
anilines to the standard conditions afforded the expected
allylation products (Scheme 4, isolated but not characterized).
Scheme 6. Mechanistic Studies
a
,b
Scheme 4. Synthesis of Benzoazepane
allylation product from the intermolecular competition of 2-
PhPy and 2-PhPy-d5 in an equimolar ratio gave KIE = 2.3,
indicating that the C−H cleavage is probably involved in the
rate-limiting step. We attempted the isolation of a reaction
intermediate by reacting complex 11 with 2-vinyloxiranes or N-
Ts aziridine derived from 1,3-cyclohexadiene, but failed to
obtain any clean reaction. A proposed catalytic cycle is given in
Scheme 7 to account for this transformation. C−H activation of
a
Reaction conditions: arene (0.4 mmol), 2-vinyloxirane (0.48 mmol),
PivOH (0.4 mmol), [Cp*Rh(MeCN)3](SbF6)2 (3 mol %), 25 °C, 16
h, sealed tube under argon. The product was isolated without further
characterization and was subjected to Raney-Ni (50 wt %), H2
b
(balloon pressure), MeOH (10 mL), rt, 12 h. Isolated yield for
two steps.
Subsequent Raney-Ni catalyzed hydrogenation did not afford
the denitrosylated alcohol. Instead, benzoazepanes were
isolated in high total yields,13 possibly as a result of
isomerization of the allylic alcohol to aldehyde, followed by
reductive amination (Scheme 4). Here the 2-vinyloxirane
functions as a four-carbon synthon. The benzoazepane is an
important structure motif in natural products,14 and this
method allowed ready synthesis of benzoazepanes using simple
substrates. In contrast, applying the same sequence to N-
phenylnitrosoaniline and 2-vinyloxirane only afforded the
denitrosylated alcohol, likely due to the lower nucleophilicity
of the diarylamine.
Scheme 7. Proposed Mechanism
To demonstrate the synthetic applications, further trans-
formations of the coupled products have been performed
(Scheme 5). Hydrogenation of 3aa and 4aa affords the
Scheme 5. Derivatization of Some Coupled Products
the arene substrate gives a rhodacyclic intermediate. Migratory
insertion of the aryl group to the olefin unit generates a Rh(III)
alkyl with a proximal epoxide. Subsequent β-oxygen elimi-
nation17 leads to the ring opening of the epoxide to give a
rhodium(III) alkoxide. Here the β-oxygen elimination takes
preference over β-hydrogen elimination owing to the release of
the ring strain. The final product was released, and the catalytic
cycle was completed when an incoming 2-PhPy substrate
underwent coordination and cyclometalation. This mechanism
can also account for the observed cis orientation of the coupled
products obtained from the epoxide of cyclic dienes.
Alternatively, the Rh(III) alkoxide intermediate may undergo
protonolysis to release the product by PivOH, which may also
facilitate the catalysis by carboxylate-assisted C−H activation.2g
In summary, we have realized a highly efficient rhodium(III)-
catalyzed C−C coupling between 2-vinyloxiranes and arenes
directed by different chelating groups. This reaction proceeded
under conditions with a low catalyst loading, and allylic alcohols
were isolated as the coupling products. A broad scope of the
reaction substrate has been demonstrated, and further
derivatizations of the products have been performed. This
catalytic system expanded the synthetic utility of rhodium
catalyzed C−H activation. Given the mild conditions, broad
scope, and high catalytic activity, this method may find
applications in the synthesis of complex structures.
corresponding saturated alcohols 8 and 7, respectively, in high
yields. Treatment of 8 with EtONa led to removal of the
pyrimidyl group, and the protic indole 9 was isolated in 71%
yield. This indole is known to undergo oxidative dearomative
cyclization to give a spiral indolinone 10,15 and this structural
motif is represented in a variety of natural products.16
Several experiments have been performed to probe the
reaction mechanism (Scheme 6). When cyclometalated Rh(III)
complex 11 (3 mol %) was designated as a catalyst precursor,
the coupling of 2-phenylpyridine (2-PhPy) and 2a afforded
product 4aa in 69% yield together with a small amount of the
diallylation product, which closely parallels the actual catalytic
system. This indicates that a cationic cyclometalated rhodium
species originating from C−H activation is a likely
intermediate. To probe the C−H activation process, the kinetic
isotope effect has been measured. Analysis of the mono-
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Letter
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ASSOCIATED CONTENT
* Supporting Information
Experimental details, characterization data, and copies of NMR
spectra of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xwli@dicp.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, and the NSFC (No. 21272231) for
financial supports.
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