Redox-neutral atom-economic rhodium-catalyzed coupling of terminal alkynes with carboxylic acids toward branched allylic esters

Article abstract of DOI:10.1021/ja1108613

A new method for the preparation of a wide range of branched allylic esters from terminal alkynes that proceeds via a redox-neutral propargylic CH activation employing a rhodium(I)/DPEphos catalyst is reported.

Full text of DOI:10.1021/ja1108613

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pubs.acs.org/JACS
Redox-Neutral Atom-Economic Rhodium-Catalyzed Coupling of
Terminal Alkynes with Carboxylic Acids Toward Branched
Allylic Esters
Alexandre Lumbroso, Philipp Koschker, Nicolas R. Vautravers, and Bernhard Breit*
Institut f€ur Organische Chemie und Biochemie, Freiburg Institute for Advanced Studies (FRIAS), Albert-Ludwigs-Universit€at Freiburg,
Albertstrasse 21, 79104 Freiburg im Breisgau, Germany
S Supporting Information
b
Scheme 1. Oxidative Allylic versus Redox-Neutral Pro-
pargylic CH Activation for Formation of Allylic Esters
ABSTRACT: A new method for the preparation of a wide
range of branched allylic esters from terminal alkynes that
proceeds via a redox-neutral propargylic CH activation
employing a rhodium(I)/DPEphos catalyst is reported.
ranched allylic alcohols and their ester derivatives are im-
Scheme 2. Rhodium-Catalyzed Addition of Carboxylic Acids
to Alkynes in the Presence of Either DPEphos (L) or
2-(Diphenylphosphinomethyl)pyridine (L0)
B
portant building blocks in organic synthesis. Numerous
approaches for their preparation are known, including asym-
metric versions.1-6 More recently, formation of allylic esters via
CH bond oxidation has attracted considerable interest and is
emerging as a new tool in the synthesis of complex molecules
(Scheme 1).7-9 A drawback of these reactions with regard to
atom economy is the requirement of stoichiometric amounts of
an oxidant. Furthermore, while palladium catalysts usually allow
for regioselective formation of the linear allylic esters, only one
method for regioselective generation of the branched product B
is known (Scheme 1).8b,8d We wondered whether replacing the
alkene starting material with the corresponding terminal alkyne
could lead to an internal redox-neutral formal propargylic CH
oxidation with concomitant hydride shift.10,11 Thus, the alkyne
would serve as an internal oxidant to be reduced simultaneously
toward the alkene, thus avoiding the need for an external oxidant.
The overall process would be a highly attractive atom- and redox-
economic one-pot reaction toward allylic esters from readily
available terminal alkynes and carboxylic acids.12,13
We recently reported on the rhodium-catalyzed addition of
carboxylic acids to alkynes to furnish (Z)-enol esters (AM-Z)
employing the P,N ligand 2-(diphenylphosphinomethyl)-
pyridine (L0; Scheme 2).14 In this work, we have found that
when this P,N ligand is replaced with the diphosphine ligand
DPEphos (L), which has a wider bite angle, a complete chemos-
electivity switch occurs, leading to the formation of the branched
allylic esters B (Scheme 2).
obtained for the addition of benzoic acids bearing either elec-
tron-withdrawing or -donating substituents to 1-octyne to give
products 1a-f. Notably, the reaction between p-toluic acid and
1-octyne (1b, Table 1) was run on a 5 mmol scale and gave an
even better yield (84%) and the same selectivity (B/M = 97/3).
Also, an aryl bromide function was compatible with this catalyst
system (1g). Furthermore, benzoic acid could be coupled to
either 1-hexyne (2) or 3-cyclohexyl-1-propyne (3). Unsaturated
acids (4-7), aliphatic carboxylic acids (8 and 9), heteroarylcar-
boxylic acids (10-12), and even N-protected R-amino acids
were excellent reaction partners. Finally, the compatibility of this
new methodology with a series of oxygen- and nitrogen-function-
alized alkynes, including standard protecting groups, was demon-
strated (14-20).
A first hint concerning the reaction mechanism was found
when cyclohexylallene was employed as a substrate and subjected
to our optimized reaction conditions. A clean addition of benzoic
acid occurred, furnishing allylic benzoate 3 in 76% yield
(Scheme 3).17 The corresponding 3-cyclohexyl-1-propyne re-
acted with a slightly lower yield (60%) and chemoselectivity
(83/17). Hence, a plausible reaction mechanism might take the
formation of an intermediate allene into account (see Scheme 4).
The best results in terms of yield and selectivity for the
branched product B over the gem-enol ester M (the Markovnikov
product; see Table 1) were obtained by employing
[(COD)RhCl]2 (2.5 mol %) and DPEphos (5 mol %) in 1,2-
dichloroethane at 70 °C for 16 h (for optimization of the reaction
conditions, see the Supporting Information).15,16 The reaction is
rather general, and Table 1 depicts an overview of the reaction
scope. Reasonable yields and chemoselectivities (B vs M) rang-
ing from 84 to 65% and 98/2 to 87/13, respectively, were
Received: December 3, 2010
Published: February 3, 2011
r
2011 American Chemical Society
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Table 1. Rhodium-Catalyzed Redox-Neutral Coupling of
Terminal Alkynes and Carboxylic Acids: Preparation of
Branched Allylic Esters Ba
Scheme 4. Proposed Mechanism for the Rhodium-Catalyzed
Redox-Neutral Formal Progargylic CH Oxidation of Terminal
Alkynes and Carboxylic Acids To Form Branched Allylic
Esters B
Scheme 5. Isotopic Labeling Experimentsa
a Reaction conditions: 0.011 mmol of [(COD)RhCl]2, 0.022 mmol of
DPEphos, 0.44 mmol of acid, and 0.88 mmol of alkyne in 4.4 mL of 1,2-
dichloroethane (DCE) were heated in a closed Schlenk flask at 70 °C.
b Isolated yields. c The B/M ratio was obtained by integration of
ethylenic protons in the crude 1H NMR spectrum and/or by GC
a The extent of deuterium incorporation was determined using 1H NMR
spectroscopy and mass spectrometry (see the Supporting Information
for details).
e
f
analysis. d 74% conversion. 65% conversion. 75% conversion. g 71%
at the most substituted carbon atom would furnish the desired
branched allylic ester (step V).19 The regiochemistry of this
reductive elimination is typical for rhodium4,20 and iridium3,21
catalysts and has been noted previously in allylic substitution
chemistry.
conversion.
Scheme 3. Control Experiment with Cyclohexylallene
To gain further experimental support for this reaction mec-
hanism, labeling experiments with deuterated benzoic acid on the
one hand and 1-octyne-d1 on the other hand were performed
(Scheme 5). Consistent with the proposed mechanism, we found
deuterium incorporation at the terminal alkene positions (Ha/c
)
to 20% each. We also found 7% incorporation of deuterium in the
2 position (Ha/b) which is consistent with a (at least partial)
dissociation of the allene from the rhodium center in step III
followed by intermolecular hydrometalation with a H/D-rho-
dium-O-acyl species (step IV). Conversely, the reaction with
1-octyne-d1 (2 equiv) led to the incorporation of deuterium at
the terminal alkene positions (Ha/c) to 42% each. H/D exchange
between a terminal alkyne and benzoic acid is well-known22,23
and may account for the 10% deuterium incorporation at
the 2-position in accordance with the proposed reaction
mechanism.24
A first reasonable step is the oxidative addition of the
carboxylic acid to the Rh(I) center, as the prevalence of O-H
oxidative addition over that of C-H from terminal alkynes has
previously been demonstrated (step I).18 Markovnikov-selective
hydrometalation furnishes a σ-vinylrhodium complex (step
II), which may undergo either reductive elimination to form
the gem-enol ester byproduct M or β-hydride elimination
to release an allene (step III). A subsequent second hydro-
metalation of this allene would form a π-allylrhodium species
(step IV), which after intramolecular reductive elimination
We also looked briefly at an asymmetric variant of the redox-
neutral atom-economic coupling between carboxylic acids and
terminal alkynes. Thus, exchanging DPEphos with (R,R)-DIOP
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Scheme 6. Enantioselective Coupling Using (R,R)-DIOP as
the Ligand
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furnished 1a in moderate 42% yield with a promising enantios-
electivity of 70% ee (Scheme 6), demonstrating the potential for
asymmetric catalysis.
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In summary, we have developed an efficient method for the
first redox-neutral propargylic CH activation of terminal alkynes
and their coupling with carboxylic acids under rhodium catalysis
to furnish valuable branched allylic esters. This simple atom- and
redox-economic procedure is compatible with many functional
groups and tolerates substantial structural variation on both the
alkyne and the carboxylic acid reaction partner. Future studies
will address the extension of this propargylic activation mode to
coupling with other nucleophiles and the elaboration of intra-
molecular and enantioselective variants.
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
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Langer, V.; Koꢀcovskꢁy, P. Org. Lett. 2000, 2, 3047–3049. (b) Eames, J.;
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dures and spectral data for new compounds, including scanned
images of 1H and 13C NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
(10) For a related palladium-catalyzed reaction using special pro-
pargylic acetates with internal alkyne functions, see: Trost, B. M.;
Brieden, W.; Baringhaus, K. H. Angew. Chem., Int. Ed. Engl. 1992, 31,
1335–1336.
Corresponding Author
bernhard.breit@chemie.uni-freiburg.de
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(13) For a recent review of the concept of redox economy, see:
Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew. Chem., Int. Ed. 2009,
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’ ACKNOWLEDGMENT
This work was supported by the DFG, the International
Research Training Group “Catalysts and Catalytic Reactions
for Organic Synthesis” (IRTG 1038), the Fonds der Chemischen
Industrie, the Krupp Foundation (Alfried Krupp Award for
Young University Teachers to B.B.), and the Humboldt Founda-
tion (postdoctoral fellowship to N.R.V.). We thank Umicore,
BASF, and Wacker for generous gifts of chemicals.
(14) Lumbroso, A.; Vautravers, N. R.; Breit, B. Org. Lett. 2010, 12,
5498–5501.
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