Organocatalytic oxidative annulation of benzamide derivatives with alkynes

Article abstract of DOI:10.1002/anie.201404222

Organocatalytic annulation by functionalization of benzamide derivatives with alkynes has been developed. We report a new approach of cycloaddition under mild reaction conditions using simple catalysts, such as iodobenzene and peracetic acid, as oxidant. Those novel, mild reaction conditions provided a straightforward synthesis of isoquinolones with fast reaction rate. Notable selectivity in annulation of unsymmetrically disubstituted alkynes was demonstrated.

Full text of DOI:10.1002/anie.201404222

Angewandte
Chemie
DOI: 10.1002/anie.201404222
Organocatalysis
Organocatalytic Oxidative Annulation of Benzamide Derivatives
with Alkynes**
Srimanta Manna and Andrey P. Antonchick*
Abstract: Organocatalytic annulation by functionalization of
benzamide derivatives with alkynes has been developed. We
report a new approach of cycloaddition under mild reaction
conditions using simple catalysts, such as iodobenzene and
peracetic acid, as oxidant. Those novel, mild reaction con-
ditions provided a straightforward synthesis of isoquinolones
with fast reaction rate. Notable selectivity in annulation of
unsymmetrically disubstituted alkynes was demonstrated.
À
C
H bond functionalization has emerged over the last few
decades and represents an attractive strategy to enhance
À
molecular complexity. C H bond functionalization catalyzed
by transition metals is an intensively investigated area of great
significance.[1] Methods of direct coupling between non-
functionalized compounds represent an environmentally
benign and economically attractive synthetic strategy to the
desired products. However, these methods are limited. The
development of new efficient, direct oxidative cross-coupling
methods is highly demanded.[1]
Isoquinoline and isoquinolones represent important het-
erocyclic scaffolds with broad ranges of biological activities.[2]
Several attractive synthetic routes to isoquinolones were
developed using transition-metal-catalyzed processes in last
years.[3–8] Impressive annulation with alkynes was first devel-
Scheme 1. Annulation of benzamide and benzenesulfonamide deriva-
tives with alkynes
and organocatalytic synthesis of isoquinolones by annulation
of alkynes and benzamide is demanded. Herein we report the
discovery of the first metal-free annulation of alkynes by
oped by Fagnou and co-workers employing rhodium cata-
[3a]
À
À
À
lyzed directed C H activation. Interestingly, Rovis’ group
cascade C C and C N bond formation under organocatalytic
reaction conditions [Scheme 1, Eq. (4)].
independently demonstrated the annulation of benzamide
with alkynes and alkenes through rhodium-catalyzed C H
We began our studies[9] on annulation using N-methox-
ybenzamide (1a) and diphenylacetylene (2a) as starting
materials in presence of (diacetoxyiodo)benzene (PIDA) as
a oxidant in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) at
room temperature (Table 1).[10] To our delight, the product
of annulation 3a was isolated with 40% yield.[11] Furthermore,
the use of PhI(OCOCF3)2 did not provide the desire product
at all (Table 1, entries 1–2). Encouraged by the initial result,
we tested organocatalytic conditions using iodobenzene as
catalyst in presence of oxidants such as m-CPBA. The
application of substoichiometric amounts of iodobenzene
resulted in formation of product 3a with higher yield (Table 1
entry 3). In the screening of various oxidants, peracetic acid
was found as best oxidant to provide isoquinolone 3a in 68%
yield (Table 1 entries 3–6). HFIP was the best solvent giving
the desired product of annulation. The formation of product
3a was not observed using EtOAc, CHCl3, MeOH, and DCE
as solvents (Table 1, entries 7–11; see also the Supporting
Information). The application of CF3CH2OH as a solvent
resulted in reduced yield of the desired product 3a. We next
investigated different aryl iodides as potential catalysts
(Table 1, entries 12–15). Of the tested compounds, iodoben-
zene delivered the best result for the synthesis of annulated
À
functionalization [Scheme 1, Eq. (1)].[4a] Recently, the Acker-
mann and Wang groups reported an efficient ruthenium
catalyzed approach to annulation of benzamine and alkyne
[Scheme 1, Eq. (2)].[5] Very recently, palladium-catalyzed
synthesis of isoquinolones has been developed by Huang
and co-workers [Scheme 1, Eq. (3)].[6] Typically, transition-
metal-catalyzed annulations require high temperature, exter-
nal oxidant and long reaction time. It is notable that metal-
free approaches to annulation of benzamide derivatives with
alkynes have never been reported. Moreover, a mild, efficient
[*] S. Manna, Dr. A. P. Antonchick
Abteilung Chemische Biologie
Max-Planck-Institut fꢀr Molekulare Physiologie
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
and
Fakultꢁt Chemie, Chemische Biologie
Technische Universitꢁt Dortmund
Otto-Hahn-Strasse 6, 44221 Dortmund (Germany)
E-mail: andrey.antonchick@mpi-dortmund.mpg.de
[**] We thank Prof. Dr. Herbert Waldmann for his generous support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201404222.
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Table 1: Optimization of organocatalytic isoquinolone synthesis.[a]
Entry
Solvent
RI
Oxidant
Yield [%][b]
1
2
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
CF3CH2OH
HFIP/CH2Cl2 (1:1)
CHCl3
MeOH
ClCH2CH2Cl
HFIP
HFIP
HFIP
HFIP
HFIP
–
–
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
4-MeO-C6H4I
4-Me-C6H4I
4-NO2-C6H4I
A
PhI(OAc)2
PIFA
m-CPBA
AcOOH
DTHP
40
n.d.
52
3[c]
4
68
5
6
7
8
n.d.
n.d.
44
H2O2
AcOOH
AcOOH
AcOOH
AcOOH
AcOOH
AcOOH
AcOOH
AcOOH
AcOOH
AcOOH
AcOOH
AcOOH
41
9
n.d.
n.d.
n.d.
5
20
n.d.
64
73
78
55
10
11
12
13
14
15[d]
16[e]
17[e,f]
18[g,e]
PhI
PhI
PhI
HFIP
HFIP
[a] Reaction conditions: 1a (0.15 mmol), 2a (0.18 mmol), RI (20 mol%)
and oxidant (2 equiv) in solvent (1.0 mL) and open flask for 30 min.
[b] Yield of isolated product after column chromatography. [c] m-CPBA
(1.5 equiv) used. [d] 2,2’-Diiodo-4,4’,6,6’-tetramethyl-1,1’-biphenyl (A)
(10 mol%) was used. [e] 1.5 equiv of AcOOH [f] AcOOH acid was added
portion wise in 15 min. [g] PhI (15 mol%) was used. n.d.=not detected.
product. The yield of product was increased when peracetic
acids was added portion-wise. It was found that the optimal
amount of peracetic acid is 1.5 equivalents and catalyst
loading is 20 mol% (Table 1, entries 16–18; see also the
Supporting Information). Under optimized conditions, the
desired product 3a was obtained with 78% yield in 30 min
(Table 1, entry 17).
With optimal reaction conditions, we next explored the
scope of reaction with a variety of substituted alkynes
(Scheme 2). Annulations of alkyne-bearing electron-with-
drawing and electron-donating groups worked well and
afforded the cyclized products in good yield. Symmetrically
disubstituted diphenyl acetylenes react well and provided the
desired products in 60–82% yield (Scheme 2, 3b–d). Notably,
the application of N,3,4-trimethoxybenzamide as coupling
partner allowed selective formation of one regioisomer
(Scheme 2; 3b, 3c). A variety of functional groups such as
trifluoromethyl-, fluoro-, nitro-, and methoxy- were tolerated
under the developed mild organocatalytic reaction conditions
(Scheme 2, 3e–j). Unsymmetrical diphenylacetylenes substi-
tuted with methoxy-, nitro- and trifluoromethyl groups,
regioselectively delivered single regioisomers which was
unapproachable by analogous transition-metal-catalyzed pro-
cesses (Scheme 2; 3e, 3 f, 3i, 3j). Nevertheless, the application
of diphenylacetylenes substituted with weak electronic-effect
groups, for example fluorine, led to formation of regioisomer
mixtures (Scheme 2, 3g, 3h).
Scheme 2. Scope of the organocatalyzed annulation. Reaction condi-
tions: 1 (0.15 mmol), 2 (0.18 mmol), 20 mol% PhI and AcOOH
(1.5 equiv) in HFIP at room temperature. [a] 25 mol% of PhI was
used. [b] Major isomer is shown. [c] PhI(OAc)2 (1.5 equiv) used instead
of PhI and AcOOH. [d] Catalyst A (10 mol%), CF3CO2H (5 equiv) and
AcOOH (2 equiv) were used in 1,2-dichloroethane (2 mL).
After investigation of the scope of alkynes, different
substituents on the nitrogen atom of benzamides were tested
in annulation with diphenylacetylene. We observed that
a broad range of alkoxy groups can be employed under
organocatalytic reaction conditions providing products in
56–85% yield (Scheme 2, 3k–o). It is notable that a double
bond is tolerated under the oxidative reaction conditions
2
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(Scheme 2, 3o). Unfortunately, an application of N-alkyl and
N-aryl benzamides in the annulation did not allow the
formation of desired products. Therefore, the presence of
alkoxy groups on the nitrogen atom of benzamides is essential
for a successful organocatalytic annulation.
We next turned our attention to the different benzamides
substituted in aromatic part (Scheme 2, 3p–u). In general,
ortho-, meta-, and para-substitutions were tolerated. Never-
theless, the utilization of meta-substituted derivative resulted
in formation of a mixture of regioisomers (Scheme 2, 3s, 3t).
Benzamides with electron-donating and electron-neutral
substituents allowed formation of desired isoquinolones
while electron-withdrawing groups suppressed the formation
of annulated products.
Crafts process resulted in the desired isoquinolone 3a
(Scheme 4).
In conclusion, we have described an iodobenzene-cata-
lyzed regioselective annulation of N-alkoxybenzamide deriv-
atives with readily available alkynes. Simple organocatalysts
offer a novel straightforward approach for the synthesis of
isoquinolones. The desired products formed smoothly at
ambient temperature in short times using peracetic acid as the
oxidant. A notably high regioselectivity was described in
annulation of unsymmetrical diarylacetylenes demonstrating
that the developed organocatalytic approach is superior to
transition-metal-catalyzed reactions.
Received: April 11, 2014
Published online: && &&, &&&&
The products could be straightforwardly deprotected by
À
cleavage of the N O bond to provide substituted isoquinolin-
1(2H)-ones.[6] For example, the treatment of 3a with sodium
Keywords: alkynes · annulation · heterocycles ·
hypervalent iodine · organocatalysis
.
hydride gave the desired product
(Scheme 3).
4 with 83% yield
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Organocatalysis
S. Manna,
A. P. Antonchick*
&&&& — &&&&
Organocatalytic Oxidative Annulation of
Benzamide Derivatives with Alkynes
Annulation without hesitation: N-alkoxy-
benzamides convert into isoquinolones
smoothly and rapidly under organocata-
lytic conditions. The annulation of unsy-
mmetrical diarylacetylenes proceeds with
a high regioselectivity. The transforma-
tion is based on the hypervalent-iodine
mediated generation of nitrenium ions.
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