Rhodium(III)-catalyzed cross-coupling of alkenylboronic acids and N -pivaloyloxylamides

Article abstract of DOI:10.1021/ol501309e

Rh(III)-catalyzed umpolung amidation of alkenylboronic acids for the synthesis of enamides is reported. This reaction proceeds readily at room temperature and displays an extremely wide spectrum of functional group tolerance. With cooperation of hydrobora

Full text of DOI:10.1021/ol501309e

Letter
pubs.acs.org/OrgLett
Rhodium(III)-Catalyzed Cross-Coupling of Alkenylboronic Acids and
N‑Pivaloyloxylamides
Chao Feng† and Teck-Peng Loh*,†,‡
†Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371
‡Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, P. R. China
S
* Supporting Information
ABSTRACT: Rh(III)-catalyzed umpolung amidation of
alkenylboronic acids for the synthesis of enamides is reported.
This reaction proceeds readily at room temperature and
displays an extremely wide spectrum of functional group
tolerance. With cooperation of hydroboration, it enables the
formal anti-Markovnikov hydroamidation of terminal alkynes,
stereospecifically affording the trans-enamides in excellent
yields.
he umpolung C−N bond formation, which operates
Tbetween electrophilic amino reagents and a diversity of
nucleophiles, such as organomagnesium, zinc or boron
derivatives, has been gaining increasing attention from the
synthetic organic community in the past two decades.1 By
taking advantage of the electrophilic amination, it not only
offers an alternative to the conventional C−N bond formation
reactions, such as Buchwald-Hartwig amination,2 but more
importantly opens a new synthetic route for the retrosynthetic
disconnection of these skeletons. In this context, transition-
metal (TM)-catalyzed protocols prove to be particularly
attractive because of their high efficiency, mild reaction
conditions, and broad functional group tolerance. The elegant
works by Narasaka,3 Miura,4 Lalic,5 Jarvo,6 Johnson,7
Liebeskind,8 and other groups nicely demonstrate the utility
and potential of the TM-catalyzed umpolung amination in
Figure 1. Biologically active natural products containing enamide
structural motifs.
diverse C−N bond formation reactions.9 In the realm of TM-
catalyzed umpolung C−N bond formation, while much
advancement has been attained with respect to the construction
of aryl C−N and alkyl C−N bonds, relatively less attention has
been paid toward the formation of alkenyl C−N analogues,
such as those of enamides.
in developing TM-catalyzed enamide synthesis in the past
decades, several shortcomings still remain, such as high
stoichiometric amounts of coupling reagents used, intolerance
of halogen functional groups, inapplicability to the formation of
multisubstituted enamides. Therefore, it is still highly desirable
to discover new synthetic methods of enamide formation that
display broad functional group tolerance and high efficiency
and, more importantly, are applicable in the late-stage
transformation in natural products synthesis.
With our continuing interests in enamide chemistry and
rhodium catalysis,13,14 we report herein a highly efficient and
reliable method for the synthesis of enamides via rhodium-
catalyzed umpolung amidation between O-pivaloyl hydroxamic
Enamides constitute a class of useful intermediate in
synthetic organic chemistry and represent key structural motifs
in various naturally occurring products, biologically active
compounds, and pharmaceuticals (Figure 1).10 Accordingly,
much effort has been paid toward the discovery of new
synthetic methods for the ease of realization of enamide
construction.11 Probably, the most widely applicable approach
for the synthesis of such a motif relies on the copper-catalyzed
cross-coupling between alkenyl halides and amides.12 This
method, while effective, often shows limited substrate scope;
for example, halide functional groups could not be tolerated,
owing to the harsh reaction conditions and low-valent copper
catalyst employed. While substantial progress has been attained
Received: May 7, 2014
© XXXX American Chemical Society
A
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Letter
acids and alkenylboronic acids, which could be easily accessed
through hydroboration of alkynes. Thus, the total trans-
formation could be regarded as a formal anti-Markovnikov
hydroamidation of terminal alkynes.15 It is also important to
note that unlike most of the reported examples of TM-
catalyzed umpolung amidation reactions employing low-valent
(or in situ generated) metal catalysts, which enable the
activation of electrophilic amino reagents through oxidative
addition, this protocol relies on a high-valent rhodium catalyst
and 1,2-alkenyl migration to accomplish the C−N bond
formation.
At the very beginning, we endeavored to optimize the
reaction conditions by cross-coupling of N-pivaloyloxyl
benzamide 1a and trans-2-phenylvinylboronic acid 2a with
copper as catalysts. However, after considerable attempts, no
positive results were obtained. It was found that benzamide
could be detected as the byproduct in many cases of copper
catalysis, which results from the oxidative addition of 1a to the
copper catalyst followed by protiodemetalation. To prevent
such an unproductive pathway, we turned our attention to the
high-valent TM catalysts, envisioning that oxidative addition
was much less favorable and the ensuing protiodemetalation
would thus be inhibited in these cases. Much to our pleasure,
when [RhCp*Cl2]2 was used, the reaction proceeded smoothly
even at room temperature to deliver the desired product 3aa in
quantitative yield (Table 1). Meanwhile, the formation of
used in place of [RhCp*Cl2]2, no desired product 3aa could be
detected. What needs to be further highlighted is that a Rh(I)
catalyst, in sharp contrast with its Rh(III) analogue, did not
display any catalytic reactivity in this reaction. Further
examinations showed that both NaOAc and [RhCp*Cl2]2
were indispensable, since no reaction occurred in the absence
of either of these two species. Furthermore, 0.1 mol % of
catalyst loading enabled the reaction to occur on gram scale to
afford 3aa in comparable yield.
With the optimized reaction conditions in hand, we moved
on to investigate the reaction scope of N-pivaloyloxylamides. As
clearly shown in Scheme 1, this reaction tolerated a large variety
a
Scheme 1. Substrate Scope of N-Pivaloyloxyl Amides
a
Table 1. Optimization of Reaction Conditions
b
entry
catalyst
Cu(OAc)2
solvent
MeOH
yield (%)
1
2
CuCl2
MeOH
MeOH
THF
3
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Rh(cod)Cl]2
[RuCl2−cymene]2
Pd(OAc)2
99
4
trace
82
5
MeCN
toluene
ClCH2CH2Cl
DME
6
76
7
24
8
trace
9
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
a
Unless otherwise noted, the reactions were carried out at room
10
11
12
13
temperature using 1 (0.2 mmol), 2a (0.3 mmol), [RhCp*Cl2]2
(0.0025 mmol), and NaOAc (0.3 mmol) in MeOH (1 mL) for 12
FeCl2
b
h. Isolated yields.
[Cp*IrCl2]2
[Cp*RhCl2]2
c
14
of functional groups regardless of the electronic proprieties and
substitution patterns, such as OMe, Ac, NO2, and CF3, and the
products were formed in excellent to quantitative yield.
Halogen substituents, such as Br and F, were nicely compatible
with these reaction conditions. Notably, this reaction was also
applicable to heterocyclic N-pivaloyloxyl amide, and when 1l
and 1m were employed, the products 3la and 3ma were
isolated in quantitative yield. With such excellent results using
aromatic amide derivatives, we envisioned expanding the
reaction scope further to nonaromatic substrates. Gratifyingly,
both alkyl- and alkenyl-derived substrates worked smoothly to
deliver the enamide products in excellent yield. In particular,
when a 3-bromopropanamide derivative was subjected to the
optimized reaction conditions, 3oa was readily obtained in 94%
yield, leaving the sp3 C−Br bond untouched. Remarkably, the
amino acid derived analogue 3pa also successfully engaged in
15
NR
a
Unless otherwise noted, the reactions were carried out at room
temperature using 1a (0.2 mmol), 2a (0.3 mmol), and catalyst (0.0025
mmol) in solvent (1 mL) for 12 h. Isolated yields. NaOAc was
omitted.
b
c
benzamide was totally suppressed. With such an exciting
preliminary result in hand, a systematic screening of reaction
solvents was carried out. Among all the solvents examined,
methanol proved to be the best choice, affording the desired
product in quantitative yield. While ethereal or chlorinated
solvents, such as THF, DME and ClCH2CH2Cl, turned out to
be inappropriate, toluene and acetonitrile were found to
mediate the reaction with moderate to good efficiency. It is
worth mentioning that when other TM catalysts, such as
[RuCl2-p-Cymene]2, Pd(OAc)2, FeCl3, and [Cp*IrCl2]2 were
B
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Letter
such a transformation, which further demonstrates the potential
and utility of this reaction in the elaboration of amino acid
derivatives. Furthermore, when α,β-unsaturated hydroxamic
acid derivatives 1q and 1r were employed, the reactions
proceeded smoothly to afford the desired products in 97% and
92% yield, respectively. It also needs to be pointed out that in
these two cases products arising from 1,4-addition were not
detected.
With the aim of extending the reaction scope further and
evaluating the applicability of this method, the following
experiments were conducted (eqs 1−4). It needs to be noted
The reaction generality with respect to alkenylboronic acids
was subsequently probed, and the results were summarized in
Scheme 2. Initial examinations with β-aryl-substituted vinyl-
a
Scheme 2. Substrate Scope of Alkenylboronic Acids
that not only boronic acids but also a pinacol boronate
derivative could be successfully engaged in such trans-
formations. Furthermore, it was demonstrated that this reaction
was not limited to the terminal alkenylboronic acids, and when
1-cyclohexenylboronic acid 2m was employed, the desired
product 3am was isolated in quantitative yield. Moreover, the
reaction between 1a and (Z)-pent-1-en-1-ylboronic acid (Z)-2f
worked fairly well to produce the cis-enamide (Z)-3af in 77%
yield. For a further showcase of the applicability of this method
to the modification of naturally occurring or related
compounds, estrone derived N-pivaloyloxyl amide 1s was
synthesized and subjected to the optimized reaction condition
with 2a, which worked nicely and afforded the desired enamide
3sa in 94% yield.
a
Unless otherwise noted, the reactions were carried out at room
temperature using 1a (0.2 mmol), 2 (0.3 mmol), [RhCp*Cl2]2
(0.0025 mmol), NaOAc (0.3 mmol) in MeOH (1 mL) for 12 h.
b
Isolated yields.
Based on the documented precedents and results of our
examination, the reaction mechanism is tentatively proposed as
shown in Scheme 3. The reaction is initiated through the
transmetalation between Rh(III) catalyst and vinylboronic acid
to form intermediate I,16 which further undergoes base-induced
association with N-pivaloyloxyl amide to produce intermediate
II. As an alternative pathway to reach intermediate II, the
coordination of N-pivaloyloxyl amide to the Rh(III) catalyst
boronic acids showed that the electronic nature of aryl
substituents had little influence on the reaction efficiency
with both electron-donating and electron-withdrawing ones,
affording the desired products in excellent yields. Pleasingly,
this reaction was also applicable to β-alkyl-substituted vinyl-
boronic acids without any complication, and the desired
enamides were obtained in excellent yield. In the case of 2g, the
desired product 3ag was isolated in 90% yield, with the chlorine
substituent being left untouched. This reaction also worked
nicely with sterically more bulky alkenylboronic acids, for
example, when using β-cyclohexyl and β-tert-butyl vinylboronic
acids, the coupling products were formed in 99% and 94%,
respectively. To investigate the reaction scope further and shed
some light on the applicability of this method to natural
products synthesis, several more complex alkenylboronic acids
were synthesized and subjected to the optimized reaction
conditions. It turned out to be rather noteworthy that reactions
with alkenylboronic acids containing ester, heterocycle based
ester as well as phthaloyl protected amino functional groups
proceeded well without any difficulty, thus producing the
corresponding functionalized enamides in high yield. What also
needs to be pointed out is that in all these reactions examined
in Scheme 2 only trans-enamides were formed.
Scheme 3. Proposed Reaction Mechanism
C
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may happen first followed by ensuing transmetalation with
boronic acid. Once the intermediate II is formed, 1,2-migration
of the vinyl group from rhodium to nitrogen, which is
accompanied by the release of the pivaloyloxyl group, results in
the C−N bond formation and affords the intermediate III.17
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Rh(III) catalyst.
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method for enamide synthesis using Rh(III)-catalyzed
umpolung amidation between N-pivaloyloxyl amides and
alkenylboronic acids. By taking advantage of hydroboration
reaction, this protocol enables the formal anti-Markovnikov
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mild reaction conditions, and broad functional group tolerance
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization data, and 1H and 13
■
S
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
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the USTC Research Fund, the
Nanyang Technological University, and the 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.
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