2-aminobenzaldehydes as versatile substrates for rhodium-catalyzed alkyne hydroacylation: Application to dihydroquinolone synthesis

Article abstract of DOI:10.1002/anie.201308127

Amine for it! A cationic rhodium catalyst, which was assembled insitu from commercial components, promoted the reaction of a range of simple 2-aminobenzaldehydes with terminal and internal alkynes in a series of intermolecular hydroacylation reactions. The products of this reaction, amino-substituted enones, were efficiently converted into the corresponding dihydro-4-quinolones.

Full text of DOI:10.1002/anie.201308127

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Angewandte
Communications
DOI: 10.1002/anie.201308127
Hydroacylation
2-Aminobenzaldehydes as Versatile Substrates for Rhodium-Catalyzed
Alkyne Hydroacylation: Application to Dihydroquinolone Synthesis**
Matthias Castaing, Sacha L. Wason, Beatriz Estepa, Joel F. Hooper, and Michael C. Willis*
Alkene and alkyne hydroacylation reactions are archetypal
examples of simple addition processes that display excellent
atom economy.[1] Both reactions result in the formation of
ꢀ
a new C C bond and deliver synthetically useful carbonyl-
containing products.[2] In recent years, there has been consid-
erable interest in converting these processes into synthetically
useful transformations. Transition-metal-catalyzed variants
represent the largest class of hydroacylation reactions, and
amongst these, processes that involve some form of chelation
control dominate. The need to employ a chelating substrate
stems from the fact that the majority of the metal-catalyzed
examples proceed through an inherently unstable acyl metal
intermediate 1 (Scheme 1), which can lead to the formation of
unwanted side products formed by decarbonylation. A
limitation of the chelation-controlled strategy is that the
coordinating group, which is present to stabilize the metal–
acyl intermediate 2, will also be present in the product. If this
group is not needed in the final product, then it must be
removed or converted into an alternative functional group.[3]
Scheme 1. Chelation-free (a) and chelation-controlled intermolecular
Despite this limitation, the advantages of this chelation-
controlled process, such as mild reaction conditions, control of
enantio- and regioselectivity,[4,5] and broad substrate scope,
have resulted in widespread applications of this approach.
One strategy to overcome the innate limitation of a chelation-
controlled approach is to develop catalytic methods that
function without the need for such coordinating groups;
although there are notable examples of success with this
approach,[2c,6] significant limitations with regard to substrate
scope and enantio- and regioselectivity remain. An alterna-
tive strategy is to consider the need for a chelating unit as an
opportunity, and to expand the range of effective coordinat-
ing groups, so that a large variety of useful functional groups
can act as the crucial chelating motif. As synthetic chemistry is
generally concerned with the preparation of functionalized
molecules, an approach that is tolerant of, or indeed benefits
alkyne hydroacylation (b). The most common chelating aldehyde
motifs are also shown (3–7), along with the 2-aminobenzaldehyde
framework 8 and examples demonstrating the ubiquity of the 2-amino-
carbonyl unit in biologically significant heterocycles.
from, as many useful functional groups as possible should find
wide application. Herein, we demonstrate that simple and
readily available 2-aminobenzaldehydes are excellent sub-
strates for intermolecular Rh-catalyzed alkyne hydroacyla-
tion, and in doing so add to the motifs available for use in
these valuable processes. Furthermore, the products of these
reactions, amino-substituted enones, were directly converted
into a series of useful dihydroquinolone heterocycles.
The first intermolecular metal-catalyzed alkene hydro-
acylation, which employed an aldehyde with a coordinating
[7]
=
C C bond, was reported by Lochow and Miller. Since this
initial report, the most popular substrates for chelation-
controlled reactions feature heteroatom coordination, and
systems that include oxygen (3),[8] sulfur (4, 5),[9,10] and, to
a more limited extent, phosphorus[11] substituents have all
been reported. Although there are also some precedents for
the use of nitrogen-based functional groups, examples are
scarce and mostly either poor yielding or limited to very
specific substrates. Suggs first reported the use of nitrogen
chelation when he employed quinoline-8-carboxyaldehyde
(6) as a substrate in the presence of a stoichiometric amount
of Wilkinsonꢀs complex.[12] Picolyl imines 7 were first used as
removable or catalytic chelating groups by Suggs;[13] signifi-
cant advances were then achieved by Jun et al. and other
groups.[14] However, these reactions require harsh reaction
[*] M. Castaing, S. L. Wason, B. Estepa, Dr. J. F. Hooper,
Prof. M. C. Willis
Department of Chemistry, University of Oxford
Chemistry Research Laboratory
Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: michael.willis@chem.ox.ac.uk
Homepage: http://mcwillis.chem.ox.ac.uk/MCW/Home.html
[**] This work was supported by the EPSRC.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201308127.
ꢀ 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
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conditions (typically 130–1708C) and high catalyst loadings.
More recently, Stemmler and Bolm have shown that a single
aniline derivative is an effective substrate for intermolecular
alkene hydroacylation, but only strained and highly reactive
norbornadiene was a suitable reaction partner.[15] Bendorf
et al. have shown that N-tethered aldehydes can be employed
in intramolecular reactions.[16,17] Given the importance of
nitrogen-containing molecules to a great number of applica-
tions, we were attracted to the idea of developing a simple,
readily available family of aldehydes that feature N-chelation
for intermolecular hydroacylation reactions.
The ortho-amino-carbonyl scaffold is a versatile synthetic
unit in its own right,[18] but this moiety is also embedded in
a variety of important heterocycles, such as 4-quinolones,[19]
acridones,[20] benzodiazepines,[21] and dibenzoazepinones,[22]
which feature in a number of important medicinal agents
and natural products. Given this versatility, we targeted the
use of simple ortho-aminobenzaldehydes 8 in intermolecular
hydroacylation reactions. Using 2-(pyrrolidin-1-yl)benzalde-
hyde 8a and 1-hexyne as the test substrates, we evaluated
a number of Rh-based catalysts (Table 1). In agreement with
Scheme 2. Variation of the 2-aminobenzaldehyde coupling partner in
Table 1: Catalyst screening for the hydroacylation of 1-hexyne with
aldehyde 8a.[a]
Rh-catalyzed hydroacylation reactions with phenylacetylene. Reaction
conditions: 8 (1.0 equiv), phenylacetylene (1.5 equiv), [Rh(nbd)2]BF4
(5 mol%), dcpm (5 mol%), MeCN (10 mol%), acetone (0.15m),
558C. Yields of isolated products are given. DMB=3,4-dimethoxyben-
zyl.
nent in reactions with phenylacetylene (Scheme 2). The
reaction was found to proceed well with a number of different
tertiary amines at the 2 position (9b–e). Benzaldehydes
substituted with secondary or primary amines were also
competent substrates for this transformation (9 f,g). With N-
methyl-N-3,4-dimethoxybenzyl (DMB)-derived aldehydes,
we were able to establish that both electron-donating (9h,i)
and electron-withdrawing (9k,l) substituents could be posi-
tioned around the arene core. Only substitution at the
C6 position was not tolerated (9j). Pleasingly, it was possible
to employ a heterocyclic aldehyde, as a thiophene-derived
aldehyde delivered the corresponding enone 9m in excellent
yield. In all cases, we only observed formation of the linear
isomer. For pragmatic reasons, all of the examples presented
in Scheme 2 were performed using 5 mol% of the catalyst.
However, we were also able to significantly reduce this
loading. For example, enone 9e, which features DMB and Me
substituents on the nitrogen atom, was efficiently prepared
using either 2 mol% (2 h, 95% yield) or 1 mol% (4 h, 84%)
of catalyst. When the loading was further reduced to
0.5 mol%, a maximum yield of 45% was obtained.
We next evaluated the variation of the alkyne component
and initially selected N-DMB-N-Me-2-aminobenzalde-
hyde 8b as the standard coupling partner (Scheme 3). A
number of alkyl acetylenes were efficiently transformed
under the standard reaction conditions (9n,o), including
a sterically demanding derivative with a tert-butyl substituent
(9p). A variety of functional groups, such as chloro- or cyano-
substituents (9q,r) as well as a vinyl silane (9s) and
a ferrocenyl unit (9t), were also smoothly incorporated into
Entry Ligand
[Rh] [mol%] MeCN [mol%] t [h] Conv.[b] [%]
1
2
3
4
5
6
7
8
9
DPEphos
dppm
dppe
dppp
dcpm
dcpm
dcpm
dcpm
dcpm
10
10
10
10
10
5
0
0
0
0
0
16
16
16
16
25
94
78
8
0.5 100 (82)[c]
0
2
2
2
2
95
100
11
5
2
10
0
2
4
93
[a] Reaction conditions: 8a (1.0 equiv), 1-hexyne (1.5 equiv),
[Rh(nbd)2]BF4, ligand, acetone (0.15m), 558C. [b] Determined by
1H NMR spectroscopy. [c] Yield of isolated product. nbd=norborna-
diene.
our recent studies on sulfur-chelating aldehydes,[23] electron-
rich diphosphine ligands with a small bite angle were found to
generate the most active catalysts; a complex that incorpo-
rates dcpm as the ligand achieved complete conversion of the
aldehyde after 30 min in acetone at 558C (entries 1–5). In line
with our previous reports, the addition of small quantities of
MeCN allowed the catalyst loading to be reduced; the
reactions still proceeded efficiently with only 2 mol% of the
rhodium precursor (entries 7–9).[23]
With suitable reaction conditions in hand, we next
explored the variation of the 2-aminobenzaldehyde compo-
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Scheme 3. Variation of the alkyne coupling partner in Rh-catalyzed
hydroacylation reactions with aminobenzaldehydes 8b and 8c. Reac-
tion conditions: 8b or 8c (1.0 equiv), alkyne (1.5 equiv), [Rh(nbd)2]BF4
(5 mol%), dcpm (5 mol%), MeCN (10 mol%), acetone (0.15m),
558C. Yields of isolated products are given. [a] Regioisomeric ratio
>20:1, determined by 1H NMR spectroscopy.
the corresponding products. A fluoro-substituted aryl acety-
lene could also be employed (9u). It was also possible to use
internal alkynes, with 1-phenyl-1-propyne delivering enone
9v essentially as a single isomer. We were pleased to discover
that functionalized alkynes could be effectively combined
with the parent, primary amine-derived, 2-aminobenzalde-
hyde (8c); reaction with 1-octyne, cyclohexylacetylene, and
3-hexyne all furnished the expected enones (9w–y) in good
yields.
Having established efficient conditions for the prepara-
tion of a broad range of 2-aminoaryl enones using hydro-
acylation chemistry, we explored the conversion of these
functionalized building blocks into useful heterocyclic prod-
ucts. Dihydro-4-quinolones are a family of heterocycles that
display a variety of biological properties, including antibacte-
rial and antitumor activities.[24] They have also been used as
building blocks in the synthesis of natural products.[25] For
products that bear primary amines (9g, 9w–y), cyclization to
the dihydroquinolones was achieved by treatment with
antimony trichloride, following a procedure by Maiti and
co-workers (Scheme 4).[26,27] Good yields were obtained with
aryl- and alkyl-substituted enones (10a and 10b,c, respec-
tively). Cyclization of 2,3-disubstituted enone 9y provided the
corresponding dihydroquinolone as a 3:1 mixture of diaste-
reomers (10d). Treatment of the DMB-protected hydroacy-
lation products with triflic acid resulted in smooth removal of
the DMB group and conversion into the secondary anilines,
which were directly employed in the cyclization reactions.
With the exception of the trimethylsilyl-substituted enone
(9s!10k), the hydroacylation products could all be con-
Scheme 4. Conversion of amino-substituted enones 9 into 4-quino-
lones 10. Method A: 2-amino-aryl enone (1.0 equiv), SbCl3 (0.3 equiv),
MeCN (0.3m), 558C. Method B: 2-amino-aryl enone (1.0 equiv), TfOH
(3.0 equiv), CH2Cl2 (0.1m), 258C; followed by SbCl3 (0.3 equiv), MeCN
(0.3m), 558C. [a] d.r.=3:1, determined by 1H NMR spectroscopy.
1
[b] d.r. =4:1, determined by H NMR spectroscopy. Cy=cyclohexyl.
verted into the corresponding dihydroquinolones using anti-
mony trichloride. Pleasingly, the thiophene-derived enone
also cyclized efficiently to provide the interesting thienyl
dihydropyridone 10s. All of these results demonstrate that
a combined hydroacylation/cyclization approach allows the
efficient synthesis of dihydroquinolones in two operations
from commercially available or readily prepared starting
materials with substituents possible at every position bar one.
In summary, we have developed an efficient and versatile
method for the hydroacylation of a wide range of alkynes with
2-aminobenzaldehyde derivatives, the products of which can
be easily cyclized to give dihydroquinolones, an important
class of heterocycles. The hydroacylation reactions proceeded
in high yields with low catalyst loadings and short reaction
times, and a commercially available catalyst was employed.
The effective use of 2-aminobenzaldehydes provides another
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Received: September 16, 2013
Published online: November 12, 2013
Keywords: aldehydes · amines · dihydroquinolones · enones ·
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rhodium catalysis
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