Rhodium(III)-catalyzed olefinic C-H alkynylation of acrylamides using tosyl-imide as directing group

Article abstract of DOI:10.1021/ol502984g

The Rh(III)-catalyzed C-H alkynylation of acrylamide derivative is realized using a hypervalent alkynyl iodine reagent. The use of a weakly coordinating directing group proved to be of critical importance. This reaction displays broad functional group tolerance and high efficiency, which opens a new synthetic pathway to access functionalized 1,3-enyne skeletons.

Full text of DOI:10.1021/ol502984g

Letter
pubs.acs.org/OrgLett
Rhodium(III)-Catalyzed Olefinic C−H Alkynylation of Acrylamides
Using Tosyl-Imide as Directing Group
Chao Feng,† Daming Feng,† Yang Luo,† and Teck-Peng Loh*,†,‡
†Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
637371, Singapore
‡Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, P. R. China
S
* Supporting Information
ABSTRACT: The Rh(III)-catalyzed C−H alkynylation of
acrylamide derivative is realized using a hypervalent alkynyl
iodine reagent. The use of a weakly coordinating directing
group proved to be of critical importance. This reaction
displays broad functional group tolerance and high efficiency,
which opens a new synthetic pathway to access functionalized 1,3-enyne skeletons.
irecting-group assisted transition-metal-catalyzed C−H
Dactivation reactions, which allow site-selective manipu-
lation of otherwise inert C−H bonds beyond their intrinsic
electronic properties, offer an alternative to the traditional
method for the construction of C−C and C−X bonds.1 From the
viewpoint of atom-economy and sustainability, transition-metal-
catalyzed C−H activation reactions have been attracting
increasing attention from the synthetic community. In this
context, the past decade has witnessed an explosive advancement
in this arena with a wide variety of chelating auxiliaries devised as
effective directing groups. Specifically, hypervalent Rh(III) salt
has recently been recognized as catalyst of choice for a large
variety of C−H bond functionalizations.2 Elegant works from the
groups of Miura, Fagnou, Glorius, Rovis, Ellman, Ma, Shi, Li, and
Chang among others not only substantially expanded this area
but also demonstrated the high potential of Rh(III) catalyst in
the process of C−H bond activation, thus drawing much
attention from organic chemists.3
1,3-Enynes constitute a class of prevalent subunits widely
found in naturally occurring compounds and pharmaceuticals
and represent a key structural motif in synthetic chemistry
because of their dense functionality, amenable to a diverse range
of synthetic transformations.4 Although considerable efforts have
been made, the reported methods suffer from either a necessity of
substrate preactivation or reliance on harsh reaction conditions;
therefore the development of a mild and step-economical
pathway for the synthesis of a 1,3-enyne framework is still
required.5
ment of weakly coordinating directing group proved to be critical
for the accomplishment of this transformation (Scheme 1).
Scheme 1. Rh-Catalyzed C−H Alkynylation of Electron-
Deficient Alkenes
At the very beginning, we commenced our study by exploring
effective directing groups in the olefinic alkynylation of 2-phenyl
acrylamide derivatives with the hypervalent alkynyl iodine
reagent 1.8 Using [Cp*RhCl2]2, NaOAc, and DCE as catalyst,
additive, and reaction solvent, a series of different N-substituents
was examined, and the results are shown in Table 1. It was found
that the nature of amide directing group is critical for the
initiation of alkynylation reaction. When N-alkyl substituted or
aniline derived substrates were employed, no reaction occurred
(Table 1, entries 1−4). It needs to be pointed out that 4-
trifluoromethyl-2,3,5,6-tetrafluoroaniline based amide auxiliary,
which is frequently employed by Yu as an effective weakly
coordinating directing group in palladium catalysis, proved to be
ineffective in this reaction (Table 1, entry 3).9 Pleasingly, by
changing alkyl- or aryl-substituted amide to O-pivaloyl
hydroxylamide as directing group, the C−H alkynylation product
could be obtained in 35% yield (Table 1, entry 5). Further
Quite recently, Loh, Glorius and Li have developed rhodium-
catalyzed alkynylation of arenes as well as alkenes through C−H
activation, independently.6 While much progress has been
achieved, the realization of alkynylation of alkenes, which
operate under milder reaction condition and accommodate a
broad range of functionalities, are still highly desirable. With our
ongoing interest in alkene functionalization,7 we would like to
report our recent achievement in the rhodium-catalyzed C−H
alkynylation of electron-deficient alkenes, wherein the employ-
Received: October 10, 2014
Published: November 10, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
a
ab
,
Table 1. Optimization of Directing Group
Scheme 2. Substrate Scope of Acrylamides
b
entry
R
yield (%)
1
2
3
4
5
6
7
Bn
Ph
NR
NR
NR
NR
35
C6F4CF3
Me
OPiv
OMe
Ts
68
96
c
8
d
Ts
67
9
Ts
NR
a
Unless otherwise noted, the reactions were carried out at room
temperature using 2a (0.1 mmol), hypervalent alkynyl iodine reagent 1
(0.11 mmol), NaOAc (0.1 mmol), and [Cp*RhCl2]2 (0.002 mmol) in
b
c
d
DCE (0.5 mL) for 16 h. Isolated yields. No NaOAc was added. No
rhodium catalyst was added.
improvement was attained with O-methyl hydroxylamide as
directing group, which afforded the desired enyne product in
68% yield (Table 1, entry 6).10 Much to our surprise, the reaction
efficiency was extremely enhanced with the desired product
being formed in 96% yield when Ts-imide was adopted as the
directing group (2a, Table 1, entry 7). It is evident that the
directing group with certain pKa value had a critical impact on
this reaction process. The remarkable effect of Ts-imide as
directing group was assumed to be due to its weakly coordinating
ability, which rendered the formation of highly active ligated
catalyst because of its weak σ-donation and the generation of
thermodynamically labile metalacycle, making it more suscep-
tible to the ensuing reaction steps. It is worth mentioning that the
reaction still proceeded to a decent extent even in the absence of
NaOAc, which is in sharp contrast with our previous finding in
the alkynylation of arenes, thus further illustrating the
competence of Ts-imide as directing group in this reaction
(Table 1, entry 8).6,10 As expected, the rhodium catalyst was
found to be indispensable and the starting material 2a remained
intact with its absence (Table 1, entry 9). It needs to be
emphasized that when 2a was reacted with reagent 1-C13, no
silyl-migration product was observed.11
With Ts-imide as the optimal directing group, the reaction
generality with respect to electron-deficient alkene was thus
investigated and presented in Scheme 2. The α-aryl amides were
first examined, showing that the electronic property of the aryl
substituent exerted negligible effect on the reaction, with both
electron rich and deficient ones being converted into the desired
products in high to excellent yield. What needs to be pointed out
is that halogen substituents, such as Cl and F were well tolerated,
furnishing the opportunity for further synthetic manipulation.
Furthermore, biphenyl and naphthalyl derived substrates were
also amenable to this reaction condition, thus generating the
products 3f and 3g in 98% and 87% yields, respectively. It is
noteworthy that the present reaction was not limited to α-aryl
amide derivatives, α-alkyl amides with a diverse range of
functional groups were all nicely accommodated, highlighting
the synthetic potential of this protocol. Specifically, linear alkyl
based substrates such as 2h and 2i reacted smoothly with alkynyl
reagent 1 to afford products 3h and 3i in 99% and 96% yields. In
the case of acrylamides 2j and 2k, the reactions occurred
a
Unless otherwise noted, the reactions were carried out at room
temperature using 2 (0.1 mmol), hypervalent alkynyl iodine reagent 1
(0.11 mmol), NaOAc (0.1 mmol), and [Cp*RhCl2]2 (0.002 mmol) in
b
DCE (0.5 mL) for 16 h. Isolated yields.
selectively to produce 1,3-enyne products in excellent yield
without the formation of alkene shift products, despite the
presence of π-conjugation of aryl units.
In addition, carbocycle containing starting materials also
engaged well in this transformation without any compromise in
yield, among which the result when using α-cyclopropylacryla-
mide 2m is more meaningful as it precludes the possibility of the
involvement of radical pathway in the reaction process. When α-
trimethylsilyl-methyl acrylamide 2n was subjected to the
standard reaction condition, the product 3n was obtained in
quantitative yield, with the silyl group remaining intact
throughout the reaction, which indicated the C−H activation
for the formation of metallacycle intermediate did not follow an
electrophilic-metalation/deprotonation pathway. The tolerance
of alcohol and amine derived functionalities, such as those of in
2o and 2p, further expanded the reaction scope and indicated the
synthetic potential of this reaction in the course of complicated
molecule synthesis. Last but not least, the present reaction was
found to be highly stereoselective, with the alkynyl group
incorporated into the cis-position with respect to the Ts-imide
substituent. The structure of 3c was unambiguously confirmed
through a single-crystal X-ray diffraction analysis.12
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Organic Letters
Letter
In order to further extend the reaction scope, α,β-disubstituted
Scheme 4. Synthetic Transformation of 3q
acrylamide derivatives were subsequently examined (Scheme 3).
a b
,
Scheme 3. Substrate Scope of Acrylamide Derivatives
methylation, desilylation, and copper-catalyzed azide alkyne
cycloaddition, triazole 8q could be isolated in 83% yield.
In conclusion, the rhodium(III)-catalyzed olefinic C−H
alkynylation of electron-deficient alkenes was developed. The
weakly coordinating directing group Ts-imide proved to be
critical and responsible for the occurrence of C−H alkynylation
in a highly efficient and stereospecific manner. By taking
advantage of C−H activation and high functional group
tolerance, mild reaction conditions, and operational simplicity,
this protocol represents a straightforward and expedient method
to access the functionalized 1,3-enyne structural motif. Further
transformations into a series of pyridinone and triazole were also
attempted to showcase the synthetic potential of alkynylation
products obtained from this reaction.
a
Unless otherwise noted, the reactions were carried out at room
temperature using 2 (0.1 mmol), hypervalent alkynyl iodine reagent 1
(0.11 mmol), NaOAc (0.1 mmol), and [Cp*RhCl2]2 (0.002 mmol) in
b
MeOH (0.5 mL) for 16 h. Isolated yields.
After several attempts, it was revealed that using methanol as
reaction solvent in place of DCE was proved to be beneficial.
With such slight alteration, the introduction of alkynyl group to a
diverse range of α,β-disubstituted acrylamides, either cyclic or
acylic ones, could be successfully accomplished, thus generating
the alkynylation products in moderate to good yields. To be
more specific, 1-cyclohexenyl derived substrate 2q reacted
smoothly to furnish product 3q in 79% yield. Furthermore, the
reaction of acyclic substrates (2r−2u) either containing alkyl/
aryl or aryl/aryl substituents worked without any difficult to
afford related products in the yields ranging from 42% to 61%. It
is noteworthy that heterocycle derived acrylamides such as 2v,
2w, and 2x, which possess Lewis basic heteroatoms, also nicely
engaged in this reaction to furnish desired products in good yield,
thus further demonstrating the synthetic potential of this
reaction.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization data, and 1H and 13
C
NMR spectra for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: teckpeng@ntu.edu.sg.
Notes
To showcase the synthetic utility of the structural motif
obtained with this method, a set of synthetic derivatizations were
conducted with 3q as a representation (Scheme 4); the TIPS
group could be readily removed with TBAF to afford the terminal
alkyne, which, however, was unstable and simultaneously
underwent intramolecular cyclization to generate the pyridinone
4q in 97% yield. In addition, the palladium-catalyzed desilylative
Sonogashira reaction/intramolecular cyclization could be
successfully applied without any compromise, thus delivering
products 5q and 6q in 78% and 76% yields, respectively, when 4-
cyanophenyl iodide and 4-acetylphenyl iodide were employed.
When 3q was reacted with NBS in acetonitrile, bromonium-
induced electrophilic cyclization occurred nicely, giving rise to
the product 7q in 99% yield. Furthermore, with a sequence of
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge USTC Research Fund, the Nanyang
Technological University, Singapore Ministry of Education
Academic Research Fund (ETRP 1002 111, MOE2010-T2-2-
067, MOE 2011-T2-1-013) for the funding of this research. We
also thank Dr. Li, Y.-X. for X-ray support.
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