Palladium-catalyzed direct C-H arylation of enamides with simple arenes

Article abstract of DOI:10.1002/anie.201109247

Z only: An atom-economical synthetic route towards arylated Z-enamides through double C-H functionalization is described. The Z/E selectivity of the palladium-catalyzed monoarylation is absolute (step A in scheme), and the molecular complexity of the products can be further endowed by a sequential second arylation, which requires the use of trifluoracetic acid (TFA; step B). Copyright

Full text of DOI:10.1002/anie.201109247

Angewandte
Chemie
DOI: 10.1002/anie.201109247
À
C H Arylation
À
Palladium-Catalyzed Direct C H Arylation of Enamides with Simple
Arenes**
Sreekumar Pankajakshan, Yun-He Xu, Jun Kee Cheng, Man Ting Low, and Teck-Peng Loh*
Table 1: Effect of various nitrogen-protecting groups on the reactivity of
The realm of transition-metal-catalyzed cross-coupling reac-
tions[1] has traditionally depended on prefunctionalized sub-
strates for both reactivity and selectivity. The quest for
improved atom economy and efficiency has brought forward
enamides towards direct arylation.[a]
revolutionary changes and important advances especially in
[2,3]
À
the palladium-catalyzed direct C H functionalization
where one or ideally both coupling partners could be replaced
with simple arenes/alkenes.[3,4] A vast majority of these
À
tandem C H activation reactions are devoted on the syn-
Entry Enamide
R
X
t [h] Product
Yield [%]
thesis of biaryl motifs. Direct oxidative coupling of unac-
tivated arenes with olefins,[3a,5] the Fujiwara–Moritani reac-
tions[6,7] are comparatively under-explored in terms of the
olefinic substrate scope and selectivity.[8] Given the synthetic
and economic potential of these reactions, development of
new olefin functionalities that could be coupled with simple
arenes is much warranted. Enamides are stable enamine
surrogates and important synthetic intermediates having
tunable reactivity and potential usage in various transforma-
tions.[9] Development of effective and direct olefin function-
alization[10,11] of these compounds is highly desirable, because
it provides access to multisubstituted amines and olefins,
which are scaffolds that are pivotal in natural products as well
as in molecular materials.[12] Absolute stereocontrol of the
double bond in these type of transformations is quite
challenging, particularly when Z-enamides are required.[13]
Herein we present our results on the palladium-catalyzed
direct arylation of enamides by using unactivated arenes
1
1
2
3
Me
Me
Me
Me
Me
H
24
36
24
26
decomposed
2a
decomposed
4a
5a
–
59
–
91
90
2[b]
3
Me
Ac
Bn
4[b]
5[b]
4[d]
5
PMB 26
6[c]
6
Bn 30
6a
78
[a] Unless otherwise specified, the reaction conditions are as follows:
enamide 1–6 (0.1 mmol), benzene (0.5 mL), Pd(OAc)2 (1 equiv),
Na(OAc) (2 equiv) at 808C. [b] Z configuration of the product was
confirmed by NMR spectroscopy. [c] E/Z mixture (60:40). [d] Enamide 4
in this scheme is the p-methoxyphenyl derivative of the general enamide
4 in Scheme 1. PMB=p-methoxybenzyl.
acetate was employed as a base and a stoichiometric amount
of palladium acetate was used for the initial studies to avoid
any side reactions that may happen with a terminal oxidant.
Enamide 1 decomposed to the corresponding ketone under
the reaction temperature of 808C (no reaction was observed
at room temperature). We assumed that protecting the
nitrogen atom of the enamide would increase the chemical
stability of the enamide under the reaction conditions, and
accordingly the N-methylated substrate 2 (Table 1, entry 2)
was tested next. Significantly the substrate underwent a clean
conversion and 59% of the desired arylated product 2a was
isolated as a single stereoisomer (Z configuration as evi-
denced by NOESY, see the Supporting Information). The
doubly acylated enimide 3 responded poorly under the
reaction conditions (Table 1, entry 3). We reasoned that the
electron density of the double bond is crucial for the coupling
reaction and switched to the benzyl-protected substrate 4.
Gratifyingly the product 4a was isolated in 91% yield in 26 h
solely as the Z isomer (Table 1, entry 4, see the Supporting
Information for the NMR proof for the Z configuration).
Further increase of the electron density through a p-methoxy
benzyl protection (enamide 5) did not alter the reaction
profile (Table 1, entry 5). The carbonyl ligand on the nitrogen
atom was also modified (enamide 6), but an E/Z mixture of
the product 6a was isolated in a yield of 78% (Table 1,
entry 6).
À
through double C H functionalization. To our knowledge,
this is the first report[14] on the catalytic direct arylation of
enamides and provides cost-effective and efficient access to
highly substituted enamides with perfect Z selectivity.
The initial screening studies were carried out using the
enamide substrate 1 (Table 1, entry 1). Benzene was chosen as
the model arene partner and used as the solvent, too. Sodium
[*] Dr. Y. H. Xu, Prof. Dr. T. P. Loh
Department of Chemistry
University of Science and Technology of China
Hefei, 230026 (P. R. China)
Dr. S. Pankajakshan, J. K. Cheng, M. T. Low, Prof. Dr. T. P. Loh
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
Singapore 637371 (Singapore)
E-mail: teckpeng@ntu.edu.sg
[**] We gratefully acknowledge Nanyang Technological University and
the Singapore Ministry of Education Academic Research Fund
(MOE2011-T2-1-013) for the funding support for this research. We
thank Prof. S. Chiba for the helpful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201109247.
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Having found the right substitution (enamide 4), we went
on to develop the catalytic variant of this transformation.
Several palladium catalysts, oxidants, and acid/base additives
were screened (see the Supporting Information for details),
and finally one equivalent of copper acetate was found to be
the best terminal oxidant for a catalytic loading of 10 mol%
palladium acetate at a reaction temperature of 1108C. Acid
additives were imperative, and five equivalents of acetic acid
were found to be optimal (notably zero conversion was
observed in the absence of the palladium catalyst). The
product 4a was isolated in 72% yield under the optimized
catalytic conditions (Scheme 1).
compounds 4a, 4b, 4c, 4g, 4j, and 4k). The results demon-
strated that the electronic nature of the substituents on the
enamide moiety played a negligible role in the reaction
kinetics as both electron-rich and electron-poor substrates
underwent the coupling with comparable ease (Scheme 1,
compare 4a, 4b, 4c, and 4g with 4j and 4k). Steric effects
adjacent to the reaction center had a significant influence on
the reaction profile as evidenced by the lower reactivity of
enamides having substituents in the ortho positions
(Scheme 1, compounds 4b, 4h, 4l, and 4m). The lower
reactivity of o-xylene compared to benzene (Scheme 1,
compare 4a’, 4e’, 4 f’, 4g’ and 4j’ with their benzene
analogues) could also be attributed to the increased steric
bulk of the former. The Z configuration of the alkenes were
confirmed from the NOESY spectra (see the Supporting
Information for details) of the representative product 4g
(Scheme 1). Further proof was obtained by comparing the
1H NMR spectra of the product 4e (Scheme 1) with its
authentic E isomer (see the Supporting Information for
details).
For practical purposes, the reaction could be conducted
with the arene (40 equiv) in dioxane as the solvent with
a slightly longer reaction time (Scheme 1).
Having the optimized conditions in hand, we investigated
the scope of various enamides for the arylation using benzene
and o-xylene as the arene partners. Pleasingly enamides that
display a variety of functional motifs could be selectively
arylated (Scheme 1, compounds 4a–m). The alkenes were
formed with absolute regio- and stereoselectivity (Z configu-
ration, see below) and functional groups like methoxy and
carbonyl groups as well as fluorine were tolerated (Scheme 1,
The generality of this arylation protocol with respect to
the arene partner was tested for a range of electronically
different arenes with the benzyl-protected p-methoxyphenyl-
substituted enamide 4 as the model sub-
strate. Pleasingly electronically different
arenes could be accommodated under this
procedure (Scheme 2, compounds 4n–u),
although regioisomers were observed when
monosubstituted arenes were employed.
Homocoupling of the arenes was not
observed, and the reactions exclusively
furnished Z-alkenes (see above). The
para- and meta-xylenes were equally effec-
tive (Scheme 2, compounds 4n, 4o),
though the later produced a regioisomeric
mixture. Toluene furnished the coupling
product in 83% yield (Scheme 2, com-
pound 4p). Diphenyl ether, an electron-
rich arene gave the arylation product in
69% yield (Scheme 2, compound 4q). Sig-
nificantly the electron-poor fluorobenzene
could also be coupled, and the product was
isolated in 81% yield (Scheme 2, com-
pound 4r). More-electron-deficient arenes
like methyl benzoate, (Scheme 2, com-
pound 4s), trifluoromethyl benzene
(Scheme 2, compound 4t), and 1,2-dichlo-
robenzene (Scheme 2, compound 4u) were
also suitable partners under the reaction
conditions, though the efficiency of aryla-
tion decreased with increasing electron
deficiency of the arenes. Monosubstituted
electron-deficient arenes preferentially
Scheme 1. Exploration of the scope of various enamides in the direct arylation. Unless noted
otherwise, the reactions were carried out as follows: enamide 4 (0.1 mmol), arene (0.5 mL),
Pd(OAc)2 (10 mol%), Cu(OAc)2 (1 equiv), and AcOH (5 equiv) at 1108C. [a] 70% (30 h) with
arene (0.36 mL, 40 equiv) in dioxane (0.5 mL ), 69% (32 h) with catalyst (5 mol%) in arene
(1 mL, 110 equiv) and AcOH (10 equiv). [b] 70% (48 h) with arene (0.36 mL, 40 equiv) in
dioxane (0.5 mL). [c] 80% (48 h) with arene (0.36 mL, 40 equiv) in dioxane (0.5 mL).
[d] 20 mol% of Pd(OAc)2 was used.
formed meta isomers (Scheme 2, com-
pounds 4s, 4t), whereas their electron-
rich analogues (Scheme 2, compounds 4p,
4q) and fluorobenzene (Scheme 2, com-
pound 4r) did not have any appreciable
regioselectivity.
2
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Scheme 2. Scope of various arenes in the direct arylation of the model
enamide 4. Unless noted otherwise, the typical reaction was done as
follows: enamide 4 (0.1 mmol), arene (0.5 mL), Pd(OAc)2 (10 mol%),
Cu(OAc)2 (1 equiv), AcOH (5 equiv) at 1108C till the starting material
was consumed. [a] 20% of the ortho isomer was also formed as
determined by NMR spectroscopy. [b] Ratio of regioisomers, which
could not be assigned and are thus given in no particular order
(determined by NMR spectroscopy). [c] 75% (36 h) with arene
(0.36 mL, 40 equiv) in dioxane (0.5 mL). [d] p/m/o ratio of isomers
determined by NMR spectroscopy. [e] 20 mol% of Pd(OAc)2 was used.
[f] Enamide 4 in this scheme is the p-methoxyphenyl derivative of the
general enamide 4 in Scheme 1.
Scheme 4. Intermolecular kinetic isotopic effect (KIE) studies.
cleavage[16] (Scheme 4, Eq. (1)). The absence of a KIE (KH/
1
KD = 1.20, calculated from H NMR spectra) in the competi-
tion reaction of the deuterated and the protonated enamides
towards direct arylation with benzene (Scheme 4, Eq. (2))
further serves to discard the possibility of a cyclopalladation[17]
mechanism directed by the N-acetyl fragment.[11] Supplemen-
tary proof in favor of the oxidative pathway can be found in
the Supporting Information on page 11.
We have sought to extend the scope of this methodology
further by performing a sequential double arylation. The
monoarylated product was unreactive under the proposed
reaction conditions. But when acetic acid was replaced with
the more acidic trifluoroacetic acid (TFA) the tetrasubsti-
tuted enamide products were obtained in good yields
(Scheme 5, Eq. (1), (2)).
The key to this double arylation strategy lies in exploiting
the robustness of the monoarylation product in TFA (the
terminal enamide decomposes in TFA, see the optimization
studies in the Supporting Information), an acid that is known
to generate a highly electrophilic palladium cation,[7a] thereby
The finite mechanistic possibilities for this transformation
warrant detailed investigation. Based on the preliminary
studies and observations, an electrophilic palladation pathway
involving a s-aryl Pd complex is postulated (Scheme 3). The
formation of this species under acidic conditions is well-
known from the arylation reactions described by Fujiwara
Scheme 3. Plausible mechanism for the palladium-catalyzed direct
arylation of enamides.
and co-workers.[6,7a,15] Insertion of this aryl–palladium species
on the enamide double bond and subsequent b-hydride
elimination furnish the arylated product. The terminal
oxidation of the resulting palladium hydride or palladium(0)
by the sacrificial oxidant (copper acetate) complete the
catalytic cycle. The fact that the reaction is slowed down in the
absence of acetic acid and the diminished reactivity of
electron-deficient arenes support this carbopalladation mech-
anism.
To gain further mechanistic insights, isotope effect studies
were conducted on both the enamide and the arene partners
(Scheme 4). The significant primary kinetic isotope effect
(KH/KD = 4, calculated from 1H NMR spectra) that was
observed in the intermolecular competition reaction between
Scheme 5. Synthesis of tetrasubstituted enamides through second
arylation of monoarylation products. Product 4aa was obtained in
55% yield (72 h) and 4ii was obtained in 62% yield (72 h) when the
reactions were carried out in a one-pot manner starting from the
respective terminal enamides.
À
benzene and [D6] benzene hints at a rate-limiting C H bond
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pursuing the less reactive monoarylated enamide towards
further arylation. The double arylation could be done in
a sequential manner in the same pot by adding a fresh batch of
catalyst, oxidant, and TFA once the monoarylation is
completed (albeit with a slight decrease in yield; see
Scheme 5).
In summary, we have developed an efficient and environ-
mentally benign synthetic route towards arylated enamides
À
through double C H functionalization. The Z/E selectivity of
the monoarylation is absolute, and the molecular complexity
of the products can be further endowed by a sequential
second arylation. Investigation on the origin of Z selectivity
and possible functional transformations of these products are
currently underway and will be reported in due course.
Experimental Section
General procedure for the direct monoarylation of enamides: The
terminal enamide (0.1 mmol, 1 equiv) was dissolved in the arene
(0.50 mL) in a screw cap vial. Palladium acetate (2.30 mg, 0.01 mmol,
10 mol%), copper acetate (18 mg, 0.1 mmol, 1 equiv), and acetic acid
(31 mg, 0.5 mmol, 5 equiv) were added to the solution, and the vial
was heated at 1108C till the starting material was consumed. The
solution was concentrated in vacuum, and the product was isolated
through flash column chromatography (n-hexane/ethyl acetate) to
furnish the monoarylated product.
Received: December 30, 2011
Revised: February 28, 2012
Published online: && &&, &&&&
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À
group has reported the aliphatic C H oxidation of amines and
À
Keywords: arylation · C H functionalization · enamides ·
palladium · synthetic methods
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À
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3
À
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4
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Communications
À
C H Arylation
Z only: An atom-economical synthetic
route towards arylated Z-enamides
À
S. Pankajakshan, Y. H. Xu, J. K. Cheng,
through double C H functionalization is
M. T. Low, T. P. Loh*
&&&& — &&&&
described. The Z/E selectivity of the
palladium-catalyzed monoarylation is
absolute (step A in scheme), and the
molecular complexity of the products can
be further endowed by a sequential
second arylation, which requires the use
of trifluoracetic acid (TFA; step B).
À
Palladium-Catalyzed Direct C H
Arylation of Enamides with Simple Arenes
6
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Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!