Catalytic carbon-carbon ? bond activation: An intramolecular carbo-acylation reaction with acylquinolines

Full text of DOI:10.1021/ja8066308

Published on Web 12/23/2008
Catalytic Carbon-Carbon σ Bond Activation: An Intramolecular
Carbo-Acylation Reaction with Acylquinolines
Ashley M. Dreis and Christopher J. Douglas*
Department of Chemistry, UniVersity of MinnesotasTwin Cities, 207 Pleasant Street SE,
Minneapolis, Minnesota 55455
Received August 21, 2008; E-mail: cdouglas@umn.edu
Table 1. Optimization of Catalytic Conditions
Carbon-carbon sigma-bond activation has emerged as a con-
temporary challenge for organometallic chemistry.1 Similar to the
recent emergence of C-H activation in synthetic chemistry, C-C
σ bond activation could change the way chemists approach the
construction of complex molecules by allowing nontraditional
retrosynthetic disconnections.2 To be an effective synthetic strategy,
the activation of a C-C σ bond should result in metal-carbon
bonds that can be converted into a more complex product. The
most common C-C σ bond activation processes involve either the
release of ring strain or aromatization to overcome the high kinetic
barriers associated with the activation step.3,4 An alternative strategy
is to utilize functional groups to direct a metal to a particular C-C
bond, allowing activation to take place. In the 1980s, it was
demonstrated that rhodium can be directed by the nitrogen of a
quinoline to activate the C-C bond of a ketone at the 8-position.5
Since then, a variety of additional systems that exploit chelation-
assisted C-C activation have been discovered.1 Catalytic activation
and functionalization of unstrained C-C bonds by these methods,
however, are often fragmentation reactions, wherein one metal
carbon bond is converted into a low value byproduct.6-8 For
example, 8-benzoylquinoline can be catalytically fragmented under
ethylene pressure to deliver styrene and ethyl quinolinyl ketone
via hydroacylation.9 Developing processes that allow atom eco-
nomical10 use of unstrained C-C σ bonds as versatile synthons
for the construction of complex molecules remains a contemporary
challenge. Herein, we report a rhodium-catalyzed C-C σ bond
activation process that performs the first direct alkene carboacylation
starting from a ketone, which allows the construction of an all-
carbon quaternary center (Scheme 1).11
entry
catalyst
mol %
Ln
yield 2 (%)
1
2
3
4
5
6
7
8
{RhCl(C2H4)2}2
Rh(OTf)(COD)2
RhCl(PPh3)3
RhCl(PPh3)3
{RhCl(C2H4)2}2
{RhCl(C2H4)2}2
Rh(OTf)(COD)2
Rh(OTf)(COD)2
Pd2dba3
5
5
10
2
5
5
5
5
5
5
none
none
none
none
PCy3
PMe3
PMe3
BINAP
none
none
PPh3
PPh3
95
62
96
90a
62
53
72
<5b
0
9
10
11
12
Ni(COD)2
Pd2dba3
Ni(COD)2
0
5
5
0a,c
0
a As determined using 1H NMR spectroscopy after 48 h. b The major
product resulted from alkene isomerization to an enol ether. c Cleavage
of the allyl ether to the corresponding phenol was the major product.
mol % gave a slightly lower yield after 48 h, with the remainder
of the material being unreacted 1.
With identification of the optimal reaction conditions, the scope
of the reaction was investigated (Table 2). Styrenyl alkene 3 was
also an excellent substrate, and cyclization provided product 4,
which contains a diaryl all-carbon quaternary center (entry 1). The
reaction tolerated electron-deficient alkenes, as methacrylate ester
7 cyclized to benzofuranone 8 in 80% yield (entry 3). The
cyclization of 7 required the addition of a small amount (10 mol
%) of hydroquinone to inhibit thermal polymerization of the
methacrylate ester. The tether length between the activated C-C
σ bond could be extended allowing for the synthesis of a
dihydrobenzopyran 10 from alkene 9 in 81% yield (entry 4).
Although we expected competitive pathways involving beta-
hydrogen elimination to complicate cyclizations involving alpha-
olefins such as 11 (entry 5), this did not appear to be the main
problem with the substrate. Rather, cleavage of the allyl ether to
the phenol in substrate 11 proved to be the dominant decomposition
pathway. A 25% yield of the corresponding dihydrobenzofuran 12
was obtained from reaction of 11 when Rh(OTf)(COD)2 was the
catalyst. A substrate in which the alkene was tethered by a nitrogen
(entry 6) cyclized very slowly with {RhCl(C2H4)2}2 as the catalyst,
with 13 reaching ∼10% conversion to 14 after 48 h (1H NMR).
Wilkinson’s catalyst proved optimal for this nitrogen-tethered
substrate, providing dihydroindole 14 in good yield. The alkene
did not require a heteroatom linker, as dihydroindene 16 was
prepared in 93% yield from substrate 15 (entry 7). The aryl ketone
Scheme 1
In our initial attempts to convert alkene 1 to benzofuran 2, we
found that many combinations of rhodium(I) complexes and
phosphines would catalyze the transformation in good to excellent
yields (Table 1). An exception was the use of BINAP, which
favored alkene isomerization rather than C-C activation and
cyclization. Omitting phosphine ligands from the reaction mixture
did not prevent cyclization. With 5 mol % {RhCl(C2H4)2}2 or
Wilkinson’s catalyst, benzofuran 2 was formed in excellent yield
(entries 1 and 3).12 Attempts to use other late-metal alkene
complexes such as Pd2dba3 or Ni(COD)2 did not result in the
formation of 2 according to 1H NMR analysis of the crude reaction
mixtures, returning only 1. Lowering the RhCl(PPh3)3 loading to 2
9
412 J. AM. CHEM. SOC. 2009, 131, 412–413
10.1021/ja8066308 CCC: $40.75
2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Intramolecular C-C Activation/Carboacylation Reactionsc
providing access to carbocyclic and heterocyclic compounds in good
to excellent yields. Current efforts are directed toward both
intermolecular and asymmetric carboacylation as well as discovering
other new catalytic processes triggered by C-C σ bond activation.
Acknowledgment. Financial support was provided by the
University of Minnesota with startup funds and the donors of the
American Chemical Society Petroleum Research Fund by a Type
G award. We thank Profs. Tom Hoye and Andrew Harned for
helpful discussions and chemicals. We thank Dr. Leticia Yao for
assistance with NMR spectroscopy and Matthew Meyers and Jacob
Schmidt for assistance with mass spectrometry.
Supporting Information Available: Experimental procedures,
tabulated data, copies of NMR spectra, and copies of 2D NMR for
compound 2 are provided. This material is available free of charge via
the Internet at http://pubs.acs.org.
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In summary, we have disclosed a new alkene carboacylation
reaction initiated by quinoline-directed, rhodium-catalyzed C-C
bond activation. The alkene carboacylation allows for the construc-
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(12) Compound 2 was characterized by 1H NMR, 13C NMR, COSY, HMQC,
HMBC, IR, and MS. See Supporting Information for details.
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