Rh(III)-catalyzed Directed C-H Olefination using an oxidizing directing group: Mild, efficient, and versatile

Article abstract of DOI:10.1021/ja109676d

An efficient Rh(III)-catalyzed oxidative olefination by directed C-H bond activation of N-methoxybenzamides is reported. In this mild, practical, selective, and high-yielding process, the N-O bond acts as an internal oxidant. In addition, simply changing the substituent of the directing/oxidizing group results in the selective formation of valuable tetrahydroisoquinolinone products.

Full text of DOI:10.1021/ja109676d

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pubs.acs.org/JACS
Rh(III)-Catalyzed Directed C-H Olefination Using an Oxidizing
Directing Group: Mild, Efficient, and Versatile
Souvik Rakshit, Christoph Grohmann, Tatiana Besset, and Frank Glorius*
Organisch-Chemisches Institut, Westf€alische Wilhelms-Universit€at M€unster, Corrensstrasse 40, 48149 M€unster, Germany
S Supporting Information
b
Scheme 1. Improving Oxidative C-H Olefination Reactions
by Using Internal Oxidants
ABSTRACT: An efficient Rh(III)-catalyzed oxidative ole-
fination by directed C-H bond activation of N-methoxy-
benzamides is reported. In this mild, practical, selective, and
high-yielding process, the N-O bond acts as an internal
oxidant. In addition, simply changing the substituent of the
directing/oxidizing group results in the selective formation
of valuable tetrahydroisoquinolinone products.
Herein we report a uniquely efficient Rh(III)-catalyzed C-H
olefination reaction of N-methoxybenzamides 1, enabled by the
use of CONH(OMe) as DG as well as internal oxidant (DGOx,
Scheme 1). This results in numerous advantages: the reaction
proceeds under mild conditions, is very practical and completely
regio- and monoselective, and, most importantly, results in
improved yields and substrate scope. Moreover, a slight structur-
al variation of this DGOx group allowed the switching of the
reaction to yield valuable cyclized lactam products, providing
mechanistic insight into these processes.
Benzoic acid derivatives are of great importance; thus, for
maximum relevance of our study, we selected a valuable car-
boxylic acid derivative as DGOx. We commenced our study with
the coupling of N-methoxybenzamide (1a) and styrene (2a,
Table 1). The use of [Cp*RhCl2]2 (1.0 mol %) as catalyst
together with CsOAc (30 mol %) as additive11 at 60 °C in
MeOH resulted in the formation of the desired trans-olefinated
benzamide 3aa. Spectroscopically pure product was obtained in
90% yield by simply washing the crude reaction mixture with
chilled MeOH.12 Diolefinated or cis-olefin side products were
not observed by GC-MS nor by 1H NMR of the crude reaction
mixture.13
This high level of reactivity allows an impressively low reaction
temperature and, as a consequence, high yields and a remarkably
broad substrate scope (Table 1). The reaction does not require
an inert atmosphere and can conveniently be run on a 10 mmol
scale.13 Many important functional groups like iodides, bro-
mides, methoxy, nitro, ester, and acetyl were well tolerated.14,15
In addition, alkenes bearing organometallic (2l) and heterocyclic
groups (2m) also reacted well. Moreover, acrylates smoothly
react to the Heck-type product at even lower temperature (40 °C),
largely avoiding the overreaction to a five-membered lactam.16
Naturally, in all cases the reactions were completely ortho-
selective. Moreover, as a direct consequence of the use of an
internal oxidant, in each case the reactions nicely stopped after
ver the past decades, the Mizoroki-Heck reaction1 has
O
become one of the most important and distinct metal-
catalyzed C-C bond-forming processes. However, the activa-
tion of normally unreactive C-H bonds allows access to new
products, the use of cheaper, more readily available starting mate-
rials, and, thus, increased sustainability.2 Consequently, an attrac-
tive alternative to the Heck reaction is the oxidative coupling of
unactivated aryl C-H bonds with olefins, the Fujiwara-Moritani
reaction.3 One of the most popular strategies to obtain a selective
C-H activation is the use of a neighboring directing group (DG)
that precomplexes the metal and directs it to the desired posi-
tion.4-6 Mostly Pd-4 and Rh-catalyzed6 directed olefinations of
aromatic C-H bonds have been reported. Generally, the use of
external oxidants requires rather harsh oxidative reaction condi-
tions and high reaction temperatures and provides stoichiometric
amounts of the reduced external oxidant as waste. In addition, the
scope and yield of these transformations are limited. For exam-
ple, in the only reported olefination using primary benzamides as
DGs, the reaction conditions are quite harsh, resulting in limited
substrate scope and yields and, depending on the substitution
pattern, the formation of diolefination side products (Scheme 1).6g
Thus, application of innovative DGs with improved directing
qualities, representing useful functional groups, that are tunable
and show increased levels of reactivity and selectivity should
be beneficial.
One emerging strategy in the area of C-H activation chemistry is
the use of entities that at the same time act as both DG and (internal)
oxidant (DGOx).7 Recently, the groups of Cui and Wu,8 Hartwig,9
and Yu10 applied DGs bearing an N-O bond as oxidant in different
Pd-catalyzed C-H activation reactions. Very recently, Fagnou et al.
reported on the Rh(III)-catalyzed isoquinoline synthesis by using the
N-O bond of N-methoxybenzamides 1 as oxidant and coupling it
with internal alkynes.11 The only olefination reaction among these, the
olefination of quinoline-N-oxides by Cui and Wu,8 still requires a
high reaction temperature (110 °C) and, like most Pd-catalyzed
oxidative olefinations, is largely limited to acrylates as coupling partner.
Received: October 27, 2010
Published: January 28, 2011
r
2011 American Chemical Society
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Table 1. Scope on the Rhodium-Catalyzed Olefinationa
3-nitrostyrene (2i), vinylferrocene (2l), 4-vinylpyridine (2m),
ethylene (2o), and allylbenzene (2p)).
Furthermore, we conducted a series of experiments to probe
the reaction mechanism. Fagnou et al. showed that the ortho-
rhodation step in their alkynylation of 1a is reversible under their
reaction conditions.11 When our reaction was conducted in
MeOH for 1a and in CD3OD for D5-1a under standard reaction
conditions for 5 min in parallel, 32% of the desired product was
observed (by 1H NMR) in both cases.13 This observation of an
intermolecular kinetic isotope effect (kH/kD) of 1.0 supports that
the ortho-rhodation (C-H activation) step is fast relative to the
other steps of the catalytic cycle. A competition experiment
carried out by coupling the electronically different para-substi-
tuted benzhydroxamic acid derivatives 1c and 1j (equimolar
amounts) with styrene (2a) for 7 min showed that the rate of the
reaction increased ∼3.1 times in the order 1j (4-OMe) < 1c (4-
Ac). The substituents on the aromatic ring influence the DG
properties, thus indicating that the electronic nature of the DG
plays a prominent role in the rate-determining step.18 The fact
that N-methyl-N-methoxybenzamide (1a0) did not give any pro-
duct implies that the N-H bond is essential for this reaction. In
order to elucidate the role of the N-OMe group, two separate
reactions of N-unsubstituted and N-methoxy-substituted benza-
mides using stoichiometric amounts of [Cp*RhCl2]2 were run at
60 °C. Under these conditions, N-methoxybenzamide (1a)
provided around 90% of the desired product 3aa, together with
a small amount of the diolefination product, whereas benzamide
largely remained unreacted, and only less than 10% of the mono-
olefination product formed.13 This clearly shows that the N-
methoxy amide group not only acts as an internal oxidant but also
is a better DG than the N-unsubstituted primary amide.
a Reaction conditions: 1a (1.0 mmol), alkenes 2 (1.5 mmol),
[Cp*RhCl2]2 (1.0 mol %), CsOAc (30 mol %), dry MeOH (0.2 M),
60 °C, 3-16 h, Ar atmosphere. Isolated yields are given. Unless
otherwise mentioned, product was purified by column chromatog-
raphy. b Product was purified by simply washing with MeOH.14
c Reaction run at 80 °C. d Reaction run at 40 °C for 0.7 h. e Run under
5 bar of ethylene. f Ratio of olefin regioisomers = 10:1. g Reaction run
at 110 °C. h Reaction run at 80 °C for 60 h, then 8 h at 100 °C.
To learn about the subsequent steps of the catalytic cycle, we
carried out competition experiments between equimolar amounts
of electron-rich p-methoxystyrene (2f) and electron-deficient
pentafluorostyrene (2j) with 1a as coupling partner, affording
2 times more 3af than 3aj at the initial stage of the reaction. This
seems to render the insertion of alkene into the Rh-Car bond a
likely rate-limiting step.19
mono-olefination. This is in contrast to the common use of DGs
together with an external oxidant in Rh-catalyzed olefinations.6
In these latter reactions, double olefination can only be sup-
pressed by steric shielding expressed by a carefully chosen sub-
stitution pattern. Thus, the mono-olefination selectivity of our
oxidizing DG presents a distinct and important advantage over
established methods.
No olefinated product was observed when 1a and 2a were
treated with catalytic amounts of Rh(I) under reaction con-
ditions. Instead, a considerable amount of demethoxylated ben-
zamide and starting material was obtained.13 To further examine
whether the alkenylated 1 oxidizes the Rh catalyst by an intra-
molecular redox reaction, another insightful competition experi-
ment was performed (Scheme 2). Equimolar amounts of 1i and
1q were added to 5 equiv of 2d under the standard reaction
conditions. The observed 93% recovery of 1q suggested that the
N-OMe bond of alkenylated 1l acts as a truly internal oxidant to
convert Rh(I) into Rh(III), completing the catalytic cycle.20
However, at present, the exact timing and mode of action of the
N-O bond cleavage and oxidation of the metal are unclear.21
The potential intermediacy of the seven-membered rhoda-
cycle A led us to explore the possibility of a different pathway,
namely a reductive elimination of A, leading to the formation of
lactam 5aa after oxidation of the Rh catalyst (Figure 1). The
successful execution would not only represent a synthetically
exciting and efficient entry to these compounds but also be an
indication for the intermediacy of A. The coordinative saturation
of the metal center represents one established strategy to
suppress β-hydride elimination.22 Thus, key to success was the
use of an O-pivaloyl group on the benzamide N, which can
potentially chelate the Rh.23 In addition, small amounts of pivalic
Intriguingly,17 using gaseous ethylene (5 bar) as an alkene
coupling partner, under standard reaction conditions, we were
pleased to get the terminal olefin (3ao, 3ho) in good—and com-
pared to the use of benzamide as the DG,6g dramatically imp-
roved—yield of up to 84%. No further arylation of the terminal
olefin of these products was observed.
It should be noted that some other terminal alkenes (1-octene,
1,4-hexadiene) gave only trace amounts of product under stan-
dard conditions. However, allylbenzene (2p) and 3-phenyl-1-
butene (2q) can also be smoothly transformed to the desired
product (3ap and 3aq, respectively) in good yield, presumably
due to π-interaction of the phenyl group with the metal. When
the meta-substituted 1k and 1l or the β-naphthyl derivative 1m
was used, ortho-rhodation took place regioselectively at the less
hindered site, providing 3ka and 3la.11 Interestingly, R-naphthyl
derivative 1n did not provide any of the desired product at 60 °C
nor at 110 °C. However, it is important to note that many olefin
substrates successfully employed in this study fail to provide
good amounts of the desired coupling product when benzamides
or related substrates are employed (Scheme 1, left; for example,
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COMMUNICATION
external oxidants also results in a clean and rather waste-free
process. Excitingly, we have discovered the effect of substituents
on the directing group that allows us to obtain either olefinated
benzamides or cyclized tetrahydroisoquinolones as products.
Arguably, this would be an exciting example of a C(sp3)-N
reductive elimination of a Rh(III) intermediate.
’ ASSOCIATED CONTENT
Figure 1. Switching the reaction pathway by choice of different
N-OR1 groups.
S
Supporting Information. Experimental procedures and
b
full spectroscopic data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Scheme 2. Test for the Nature of the Oxidant: Internal vs
External
’ AUTHOR INFORMATION
Corresponding Author
glorius@uni-muenster.de
’ ACKNOWLEDGMENT
Generous financial support by the NRW Graduate School
of Chemistry (S.R.) and the DFG (IRTG M€unster-Nagoya
and the SFB 858) is gratefully acknowledged. 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. We thank Dr. Frederic Patureau for
helpful discussions.
Table 2. Tetrahydroisoquinolinone Synthesisa
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(Figure 1). This clearly rules out the intermediacy of 3aa in the
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(12) Interestingly, using N-hydroxybenzamide as substrate, 72% of
product 3aa was obtained.
(13) See Supporting Information for further details.
(14) No dehalogenation or demethoxylation was observed.
(15) In the case of 3ca, 3da, and 3ha, no side product was observed
(1H NMR).
(16) In Pd(II)-catalyzed oxidative Heck reactions, the amide group
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(21) Starting from intermediate A, a β-hydride elimination-reduc-
tive elimination (to give a RhI species)-oxidative addition sequence
might seem reasonable. Alternatively, a different order of these steps
involving the formation of a RhV species could be invoked.
(22) Hartwig, J. Organotransition Metal Chemistry - From Bonding to
Catalysis; University Science Books: Sausolito, CA, 2010.
(23) Other groups on nitrogen gave lower selectivities for the
formation of 5aa: OPiv (9:1 = 5aa:3aa) > O(CO)Tol (2:1) > OAc
(1:1) > OH = OMe (only 3aa); values based on either 1H NMR or GC-
MS of the crude reaction mixture. See Supporting Information for
further details.
’ NOTE ADDED AFTER ASAP PUBLICATION
After this paper was published ASAP January 28, 2011, new
citations were added to ref 11. The corrected version was
published February 2, 2011.
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