Table 1. Optimization of the conditions for the bromocarbocyclization
using NBS.
With these mild reaction conditions in hand, we investi-
gated the substrate scope of this carbocyclization starting
with methacrylamides 4, which differ in the aryl portion and
the substituent at the nitrogen (Scheme 2a). Reduction- and
oxidation-prone moieties at the nitrogen (R2), such as
benzyl and p-methoxybenzyl, were well tolerated. An alter-
native cyclization mode that employs the benzyl fragments
in 4b and c as nucleophiles, leading to the corresponding
isoquinolones, was not observed. In general, the use of start-
ing materials with electron-donating groups at the aryl ring
gave the cyclized products 5 in good yields, like the C-5-
alkyl-substituted oxoindoles 5d and e (89–91%). The o-tolyl
derivate 4 f was also successfully converted into a single
product 5 f, while treatment of the corresponding m-methyl
analogue 4g yielded a 1:1.4 mixture of regioisomers 5g and
h in favor of the 6-methyl compound. Naphthalene com-
pounds were also transformed easily into the corresponding
products 5i and j.
Entry NBS
[equiv]
Catalyst Additive
[mol%] [mol%]
t
Conver-
Yield
G
G
ACHTUNGTRENNUNG
[h] sion [%][b] [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
1.2
1.2
1.2
1.2
1.2
1.2
1.2
2.4
2.4
2.4
2.4
2.4
2.4
–
–
–
24
–
–
–
<5
–
–
n.d.
n.d.
n.d.
3
p-TsOH (120) 24
–
p-TsOH (10)
DMA
–
TFA (10)
TFA (10)
H3PO4 (10)
p-TsOH (10)
HOAc (10)
NH4Cl (10)
NH4Cl (10)
SC (10)
SC (10)
–
24
24
24
24
3
3
3
3
3
n.d.
n.d.
6 (10)
6 (10)
6 (10)
6 (10)
6 (10)
6 (10)
6 (10)
–
52
41[d]
>99
>99
83
36
>99
–
83
90
74
30
94
3
24
n.d.
The ring-closure of starting materials with electron-with-
drawing groups at the phenyl ring proceeded smoothly
under the developed reaction conditions, but needed, as ex-
pected, longer reaction times (up to 24 h) to achieve good
yields. The outcome of oxoindoles 5k–o was highly depen-
dent on the kind of halogen atom present (51–81%) and
systematically increased, as anticipated, with decreasing ÀI
effect. Because of the mild reaction conditions, substrates
bearing chemically sensitive functional groups, like for ex-
ample, silyl ethers or ketones, were well accepted, giving the
heterocycles 5p–r in good yields. It is worth noting that aro-
matic bromination of substrates with deactivated aryl moiet-
ies was avoided by using 1.2 equivalents of NBS. Increasing
the amount of NBS, however, resulted in additional bromi-
nation at the phenyl ring, as exemplified for the benzophe-
nones 5q and r.
In the next step, substrates with different substituents at
the a-position of the Michael-acceptor unit were tested
(Scheme 2b). Like for the formation of 5b and c, only the
aromatic residue of the anilide moiety in 4s–v acted as a nu-
cleophile, forming oxoindoles 5s–v in 61–95% yield. Aro-
matic halogenation at the a-phenyl and a-benzyl fragment
was not observed likewise. Compounds comprising ester
groups and acid-labile silyl ethers were also accepted, owing
to the mild reaction conditions. a,b-Substituted amides 4w–
y were readily transferred into the heterocyclic compounds
5w–y in good yields. Only the ring closure of (E)-a-methyl-
cinnamic acid amide 4y did not take place following the 5-
exo-trig mode, as observed in all other examples before, but
resulted exclusively in the formation of the six-membered
ring product, the quinolone 5y (94% yield). All cyclizations
described here proceeded under complete stereocontrol, af-
fording one single diastereomer. The relative configuration
of the C-3 methyl and C-4 phenyl unit in 5y was assigned to
trans, as expected for a carbocyclization via an intermediate
bromonium ion.
[a] Methacrylamide 4a (0.3 mmol), catalyst (10 mol%), and additive
(10 mol%) were dissolved in CH2Cl2 (3.0 mL). NBS was added at RT
and the mixture was stirred for the given time in the dark. DMA=N,N-
dimethylaniline, n.d.=not determined, NBS=N-bromosuccinimide, SC=
Schreinerꢀs catalyst, TsOH=p-toluenesulfonic acid, TFA=trifluoroacetic
acid. [b] Determined by GC using nitrobenzene as an internal standard.
[c] Isolated yield. [d] Compound 4a was reisolated in 40% yield.
tional oxidation reactions, but also in heteroatom-transfer
reactions.[9] The application of bromoiodinanes for the bro-
mination of electron-rich arenes and alkenes was described
by Martin[10] already in 1979 and later refined by Braddock,
who showed that the halogen-transferring bromo-iodoACHTUNTRGNEUNG(III)
compounds can, in principle, also be generated in situ.[11]
Therefore, we treated starting material 4a with 1.2 equiva-
lents of NBS and 10 mol% of o-iodobenzamide 6, which un-
fortunately did not result in the formation of the desired
product 5a (Table 1, entry 6). The isolation of oxoindole 5a
(41%, entry 7), together with nonconverted starting materi-
al 4a (40%), was not possible until the addition of Brønsted
acids, such as TFA (10 mol%), to the reaction mixture. In-
creasing the amount of NBS then selectively delivered the
5-exo-trig compound 5a in good 83% yield. The observed
acceleration of catalyst activity is in accordance to other
iodineACHTUNGTRENNUNG(III)-promoted transformations, in which a strong
acid, such as TFA, is decisive to achieve high turnover num-
bers.[12] Here, variations of the acid additive clearly revealed
a similar trend, since a correlation between the acid strength
and the amount of isolated product 5a (entries 8–11) was
obvious. One exception was the use of NH4Cl, which gave
5a in excellent yield within 3 h (94%, entry 12). It is specu-
lated that, in this case, activation of 7 may occur through
noncovalent interactions, like for example, hydrogen bond-
ing, thus, resulting in the good conversion of 4a. Control ex-
periments without iodobenzamide 6 showed no formation of
the desired product 5a (entry 13), pointing at the decisive
role of 6 in this transformation.
One disadvantage of the presented method, especially in
the context of the development of modern, environmentally
friendly, and sustainable synthetic methods, is the poor atom
&
2
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ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!