Rh catalyzed olefination and vinylation of unactivated acetanilides

Article abstract of DOI:10.1021/ja103834b

In the catalyzed oxidative olefination of acetanilides (oxidative-Heck coupling), Rh offers great advantages over more common Pd catalysts. Lower catalyst loadings, large functional group tolerance (in particular to halides), and higher reactivity of elec

Full text of DOI:10.1021/ja103834b

Published on Web 07/02/2010
Rh Catalyzed Olefination and Vinylation of Unactivated Acetanilides
Frederic W. Patureau and Frank Glorius*
Organisch-Chemisches Institut der Westfa¨lischen Wilhelms-UniVersita¨t Mu¨nster, Corrensstrasse 40,
48149 Mu¨nster, Germany
Received May 5, 2010; E-mail: glorius@uni-muenster.de
Scheme 1. Rh Catalyzed Olefination and Vinylation of
Acetanilides, Conditions, and Isolated Yields
Abstract: In the catalyzed oxidative olefination of acetanilides
(oxidative-Heck coupling), Rh offers great advantages over more
common Pd catalysts. Lower catalyst loadings, large functional group
tolerance (in particular to halides), and higher reactivity of electron-
neutral olefins (styrenes) are some of the attractive features. Most
interestingly, even ethylene reacts to yield the corresponding ac-
etanilido-styrene. Moreover, the CuII oxidant can also be utilized in
catalytic amounts with air serving as the terminal oxidant.
Arguably, the Heck reaction is one of the most popular and distinct
cross-coupling reactions.1 The oxidatiVe Heck reaction, utilizing a C-H
instead of a C-X bond, as pioneered by Fujiwara and Moritani,2
obviates the need for prior functionalization steps and is thus even
more atom economic and versatile.3 Recently, mostly using Pd
catalysts, a number of spectacular advances have been made by Yu et
al.4 and others.5-7 Among these, van Leeuwen et al. showed that
acetanilides were very effective in directing Pd catalyzed C-H bond
activation and oxidative olefination.6 Nevertheless, in these cases the
substrate scope is often limited to acrylates as coupling partners, which
limits applications of these methods. Miura, Satoh et al. recently
reported the Rh catalyzed oxidative mono- and bis-olefination of
phenylpyrazoles and pyridines with styrene derivatives.7 The applica-
tion of substrates bearing synthetically more versatile functional groups
and their selective coupling with different classes of olefins, especially
electron-neutral ones, would be highly desirable. Herein we report the
selective Rh catalyzed oxidative olefination of acetanilides8 with
different classes of olefins, most notably styrenes and ethylene. This
represents a general method of broad utility for the ortho-olefination
of aniline derivatives.
a Reaction temperature: 140 °C. b 2.5 mol % of [RhCp*Cl2]2 and 9 mmol
of styrene. c 2.5 mol % of [RhCp*Cl2]2 and 2 bar of ethylene in dioxane.
Gratifyingly, the C-H bond activation of acetanilide (1a) and
subsequent coupling to styrene was found to proceed smoothly at 0.2
M in tert-amyl alcohol as solvent employing only 0.5 mol% of
[RhCp*Cl2]2 catalyst precursor (120 °C, 16 h, Scheme 1).9 The
resulting trans product 3a was isolated in 80% yield.10 In contrast,
neither the unprotected aniline nor the electronically related phenyl
acetate nor nitrobenzene afforded any conversion under these condi-
tions. Using electron-rich para-methoxyacetanilide (1b) or meta-
methyl-acetanilide (1c) afforded the corresponding stilbene derivatives
3b and 3c in high isolated yield.9 Furthermore, products 3c-f,h-m,p,q
were all obtained with very high regioselectivities. In these cases, the
olefination occurs selectively in para-position to the functional group
R2, whether it is electron-donating (R2 ) CH3 or OAc) or electron-
withdrawing (R2 ) CF3 or Cl). This is consistent with mechanistic
experiments of Fagnou et al. on meta-substituted acetanilides, dem-
onstrating that, while a reversible hydrorhodation occurs on both
positions ortho to the directing group, only the less sterically hindered
site allows the new C-C bond to form.8a Importantly, halide functional
groups were tolerated, both in the acetanilide (3e) and in the styrene
substrate (3h,i). Even valuable brominated products can be formed
efficiently, with no proto-debromination or Heck coupling products
being detectable, showing one advantage of this Rh catalyzed
transformation compared to many Pd catalyzed ones. These latter
products allow further functionalization through other cross-coupling
reactions.1b Interestingly, 2-methyl-acetanilide 1g led to product 3g
in only 51% isolated yield, quite below our expectation, considering
that the electronically analogous product 3c was obtained in high yield
(88%). We attribute this decrease to the steric hindrance between the
amide directing group and the CH3 in the ortho-position, thus disturbing
the planarity of the substrate. Similarly, when N-methyl-acetanilide
was engaged as a substrate in the reaction, only 13% conversion to
the expected product was observed (3r, conversion determined by 1H
NMR).11 This ortho-steric effect may also account for the fact that
the transformation virtually stops at the mono-olefination stage. In other
words, the second C-H activation is disfavored compared to the first
one due to the loss of planarity induced by steric hindrance with the
stilbene functional group on the other ortho position. Thus, a planar
conformation of the acetanilide seems important for effective direction
of the metal and successive C-H bond activation. Interestingly, it was
found possible to achieve further olefination to the bis-olefinated
product by increasing the catalyst loading (2.5 mol%) and the styrene
9
9982 J. AM. CHEM. SOC. 2010, 132, 9982–9983
10.1021/ja103834b  2010 American Chemical Society

C O M M U N I C A T I O N S
concentration (cosolvent). The bis-olefinated product (3n) was obtained
in 75% isolated yield (Scheme 1).
References
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(9) See Supporting Information for further information.
Additionally, this method was found applicable to the olefination
of biologically relevant acetyl-indole, bearing a tertiary amide directing
group, resulting in the selective coupling at the 2-position, although
in modest yield under standard conditions (Scheme 1, 3o).12
Our preliminary investigation indicates that the initial rate of the
reaction is high but tends to decrease dramatically. Indeed, product
3a is already obtained in 77% conversion after only 3 h (80% after
16 h, Scheme 1). Furthermore, our investigation shows that in all cases
it is difficult to reach full conversion. This indicates that the product
is a strong competitor for coordination to the active sites of the catalyst
due to bidentate binding through the acetyl and the olefin functional-
ities.13 Thus, the product seems to be a poison to its own formation.
In the case of activated olefins such as butyl-acrylate, however, a
quantitative yield of the coupling product could be obtained (3p, 98%,
Scheme 1). In this case the reaction is so fast that 90% conversion
(1H NMR) is obtained after only 5 min.9 Thus, the average TOF is
∼1080 h-1, a high value for C-C bond formation catalysis.14
Moreover, preliminary experiments show that air can serve as an
oxidant in this reaction when using a catalytic amount of Cu(OAc)2
(10 mol %). This afforded 3c and 3p in 61% and 97% isolated yields,
respectively (no reaction was obtained without Cu salt).9 While Liu,
Guo et al. reported the use of O2 as an oxidant in a related Pd catalyzed
C-H activation,6b arguably, the use of air or O2 as terminal oxidants
in homogeneous rhodium catalysis is less common.
Importantly, submitting the catalytic system to a mild pressure of
ethylene (2 bar) selectively yielded styrene 3q in 48% yield, although
a higher catalytic loading is required in this case to achieve a
satisfactory conversion (2.5 mol%, Scheme 1).9,15 Neither diolefination
nor multiple step coupling products were observed. The preparation
of styrenes by direct catalytic oxidative-Heck coupling with ethylene
is usually acknowledged to be difficult, poorly selective, and only
feasible under harsh conditions.16 The implications of this discovery
are therefore tremendous due to the synthetic versatility of the vinyl
group.17 Furthermore, the high tolerance of this transformation (e.g.,
halides, esters) leads to the assumption that this reaction could be
incorporated in late stage total synthesis.
(10) The transformation is highly selective for the formation of the trans-olefin
product. The cis-isomer was not detected, neither by GC-MS nor by 1H
NMR of the crude products.
(11) Steric congestion near the acetanilide directing group slows down the
reaction and deteriorates the yield:
In conclusion, we have developed a novel methodology to
achieve the direct ortho olefination and vinylation of acetanilides.
This methodology is attractive since the catalytic loadings are very
low and since acetanilides are easily prepared and hydrolyzed to
the corresponding anilines. It also allows electron-withdrawing (R2
) CF3, 3d) as well as -donating groups (R3 ) OMe, 3b) and
provides the products in yields of up to 98% (3p). Furthermore
this method affords the direct and selective vinylation of acetanilides
from ethylene (product 3q), a powerful method for the preparation
of styrenes. The versatility of the produced olefins, the general
attractiveness of the method, and the high levels of regio- and
chemoselectivity obtained should lead to many applications,
especially in natural product total synthesis.
(12) Increasing the temperature or the catalytic loading did not significantly
improve the yield in this case. However, no side products were observed.
(13) For the application of a structurally related olefin-oxazoline ligand in Rh
catalysis, see: Hahn, B. T.; Tewes, F.; Fro¨hlich, R.; Glorius, F. Angew.
Chem., Int. Ed. 2010, 49, 1143.
(14) The high value of the TOF for the acrylate substrate is in accordance with
previous reports on related transformations; see refs 2 and 3.
(15) It should be noted that when 1-octene was engaged as a substrate, only
trace amounts of product could be detected.
(16) For styrene preparation through prior activation, see: (a) Lindh, J.;
Sa¨vmarker, J.; Nilsson, P.; Sjo¨berg, P. J. R.; Larhed, M. Chem.sEur. J.
2009, 15, 4630. (b) Smith, C. R.; RajanBabu, T. V. Tetrahedron 2010, 66,
1102. For direct catalytic C-H oxidative Heck coupling to ethylene, see:
(c) Fujiwara, Y.; Moritani, I.; Danno, S.; Asano, R.; Teranishi, S. J. Am.
Chem. Soc. 1969, 91, 7166. (d) Moritani, I.; Fujiwara, Y. Synthesis 1973,
524. (e) Yamada, T.; Sakakura, A.; Sakaguchi, S.; Obora, Y.; Ishii, Y.
New J. Chem. 2008, 32, 738. For the vinylation of preformed palladacycles,
see: (f) Horino, H.; Inoue, N. J. Org. Chem. 1981, 46, 4416.
Acknowledgment. We thank the Alexander von Humboldt
Foundation (F.P.) and AstraZeneca for generous support as well
as Souvik Rakshit (1o) and Dr. Tatiana Besset (2j, 2l) for
discussions and substrate preparation. The research of F.G. has been
supported by the Alfried Krupp Prize for Young University
Teachers of the Alfried Krupp von Bohlen und Halbach Foundation.
(17) For two of the many types of transformations of terminal olefins, see reviews
on Ru catalyzed olefin metathesis: (a) Fu¨rstner, A. Angew. Chem., Int. Ed.
2000, 39, 3012. (b) Grubbs, R. H. Tetrahedron 2004, 60, 7117. For an
overview on Rh catalyzed hydroformylation, see: (c) van Leeuwen,
P. W. N. M. Homogeneous Catalysis: Understanding the Art; Kluwer:
Dordrecht, the Netherlands, 2004.
Supporting Information Available: Experimental and characteriza-
tion details. This material is available free of charge via the Internet at
http://pubs.acs.org.
JA103834B
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