Rhodium catalyzed C-H olefination of N-benzoylsulfonamides with internal alkenes

Article abstract of DOI:10.1039/c2cc16963k

An annulation via tandem rhodium catalyzed C-H olefination of N-benzoylsulfonamides with internal olefins followed by C-N bond formation is disclosed. A N-substituted quaternary center is formed during the reaction thus providing efficient access to a series of 3,3-disubstituted isoindolinones. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc16963k

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COMMUNICATION
Rhodium catalyzed C–H olefination of N-benzoylsulfonamides with
internal alkenesw
Chen Zhu* and John R. Falck
Received 9th November 2011, Accepted 26th November 2011
DOI: 10.1039/c2cc16963k
An annulation via tandem rhodium catalyzed C–H olefination of
N-benzoylsulfonamides with internal olefins followed by C–N
bond formation is disclosed. A N-substituted quaternary center
is formed during the reaction thus providing efficient access to a
series of 3,3-disubstituted isoindolinones.
during the process affords a series of intriguing 3,3-disubstituted
isoindolinones.
ð1Þ
Isoindolinones represent a significant class of nitrogen-containing
heterocycles, which are ubiquitous in natural products and
biologically active compounds.1 As depicted in Fig. 1, Pestala-
chloride A 1 is a strongly antifungal metabolite isolated from
the plant endophytic fungus Pestalotiopsis adusta;2 Pagoclone
2 has been commercialized as an anxiolytic drug;3 spirocyclic
compound 3 is described as an aldose reductase inhibitor.4
Consequently, the development of efficient methods to con-
struct such scaffolds is of great importance.
ð2Þ
We have reported the palladium catalyzed C–H olefination
of N-benzoylsulfonamides with terminal olefins.7 These results
prompted us to explore C–H olefinations using internal (1,2-
disubstituted) olefins as coupling partners. Very recently,
rhodium catalyst [{RhCl2Cp*}2] has been successfully applied
in the reaction of amide-directed C–H activation.8 For
instance, the annulation of amides with alkynes via C–H
activation has been developed by several groups, respectively.9
In addition, Li et al. and Glorius et al. reported C–H activa-
tion of amides with alkenes using the same rhodium catalyst.10
However, in their chemistry, the scope of olefin was as well
limited to the terminal olefins. Our initial investigation was
performed with electron-deficient diethyl fumarate as the
olefin of choice. Gratifyingly, the desired transformation
proceeded readily in the presence of catalyst [{RhCl2Cp*}2].11
As shown in eqn (3), the optimized conditions afforded the
annulated product 6a in high chemical yield, and the newly
formed N-substituted quaternary center was unambiguously
assigned via the X-ray crystal structure of 6a.12
C–H olefination has evolved into a powerful tool for C–C
bond formation and offers a straightforward approach to the
construction of various heterocycles.5 Despite the versatility
of C–H olefination, the transformation is still mostly limited
to terminal olefins (eqn (1)). Only a few examples involving
internal olefins have been reported in intramolecular settings
and only one example has been achieved in intermolecular
settings.6 Therefore, the establishment of a general method for
intermolecular C–H olefination with internal olefins is strongly
desired. Herein, we disclose a tandem approach of rhodium
catalyzed C–H olefination of N-benzoylsulfonamides with internal
olefins followed by subsequent annulation (eqn (2)). More
importantly, a N-substituted quaternary center constructed
ð3Þ
Fig. 1 Representative structures involving isoindolinone.
With the optimized conditions in hand, we then evaluated the
scope of the reaction (Table 1). The satisfactory outcome lasted
in the investigation of substrate scope, and was compatible with
various substituents regardless of the electronic or steric properties.
When a 2-naphthyl substrate was used, notably, the conver-
sion to 6b occurred with excellent regioselectivity as only the
b-positional product was observed (entry 2). Surprisingly, during
Departments of Biochemistry and Pharmacology, University of Texas
Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas
75390-9038, USA. E-mail: chen.zhu@utsouthwestern.edu
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, NMR spectra, and X-ray crystallo-
graphic information of 6a (CIF). CCDC 843998. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/
c2cc16963k
c
1674 Chem. Commun., 2012, 48, 1674–1676
This journal is The Royal Society of Chemistry 2012

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Table 1 Reaction scope of the annulationa
Table 1 (continued )
Entry
4
5
Product
Yieldb (%)
12
4a
80
51
Entry
4
5
Product
Yieldb (%)
13
14
4a
1
4a
82
2c
4b
4c
5a
5a
81d
4a
4a
66
73
15c
3c
85e
a
Standard condition: 4 (0.10 mmol), 5 (0.12 mmol), [RhCl2Cp*]2
(0.004 mmol) and Cu(OAc)2ꢀH2O (0.21 mmol) in 0.8 mL toluene,
b
c
d
4
5
6
4d
4e
4f
5a
5a
5a
76
80
84
130 1C for 24 h. Isolated yield. 48 h. Regioisomeric ratio:
b/a > 19 : 1. Combined yield (6c/6b = 1 : 1). Regioisomeric ratio:
para/ortho = 16 : 1.
e
f
the examination of a 1-naphthyl substrate, the rearranged
product 6b was isolated concurrently with the expected product
6c (entry 3).13 The electron-donating methoxy and methyl
groups, as well as fluoride, all furnished their respective adducts
in high yields (entries 4–6). The chemoselective formation of 6g,
without competitive reaction by the aryl bromide is noteworthy,
as the latter provides the functionality for subsequent cross-
coupling reactions (entry 7). Good yields were also achieved
when strong electron-withdrawing groups were present, e.g.,
CF3 (entry 8). Finally, both meta- and ortho-occupied sub-
strates afforded the products in useful yields, albeit prolonged
reaction times were required (entries 9–11). Once again good
regioselectivity was exhibited and the para-positional product 6i
was predominant in high yield (entry 9).
7
4g
4h
4i
5a
5a
5a
70
76
72f
8
The range of acceptable olefins was also investigated
(Table 1, entries 12–15). The adaptability of other electron-
deficient internal olefins to this transformation provides the
capacity to construct diverse quaternary centers. Furthermore,
the olefin configuration was observed to be unimportant to the
reaction, since replacing 5a with diethyl maleate 5b provided
the same product 6a without diminishing the chemical yield
(entry 12). E-1,2-Diketone conjugated olefin 5c was also a
suitable substrate affording the corresponding product 6l in
useful outcome (entry 13). Interestingly, the transformation
demonstrated excellent electronic discrimination with respect
to the unsymmetric olefin 5d so that the regioisomeric product
6m was exclusively generated (entry 14). Cyclic olefins were
also compatible with the reaction conditions (entry 15). Coupling
with maleimide 5e offered a facile access to the spiroiso-
indolinone 6n, the scaffold of bioactive compound 3 described
9c
10c
4j
5a
5a
46
84
11c
4k
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 1674–1676 1675

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Notes and references
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Fig. 2 Plausible mechanism.
above. However, the conversion did not proceed when ethyl
crotonate was used.
The KIE value (kH/kD = 1) of the C–H olefination might
suggest that the C–H cleavage is fast, thus not involved as the
rate-limiting step (eqn (4)). The postulated mechanism is
summarized in Fig. 2. Rapid C–H activation of 4 generates
a five-membered rhodacycle (I), which subsequently undergoes
the well-established mechanistic route of C–H olefination to
generate a Rh–H complex (II). Two pathways (A and B) could
possibly lead to the desired product 6. Path B is the commonly
accepted C–H olefination/C–N bond formation sequence,
however, without experimental evidence.14 To probe this
pathway, deuterium-labelled olefin 7 was synthesized and
subjected to the standard conditions (eqn (5)). The appearance
of proton on the methylene position indicates that the adduct 8
might come from the intermediate IV (Fig. 2), since the acidic
N–H (or N–D) is exchangeable with external protons.
4 J. Wrobel, A. Dietrich, S. A. Woolson, J. Millen, M. McCaleb,
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Y. Fujiwara, Synthesis, 1973, 524; (b) C. Jia, T. Kitamura and
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Chem., 2011, 9, 4736.
ð4Þ
ð5Þ
In summary, we describe a tandem rhodium catalyzed C–H
olefination of N-benzoylsulfonamides with internal olefins followed
by C–N bond formation. A new N-substituted quaternary
centre is formed during the reaction thus providing efficient access
to a series of 3,3-disubstituted isoindolinones. Other applications
of this methodology are currently ongoing in our laboratory.
We thank the NIH (GM31278) and the Robert A. Welch
Foundation (GL625910) for financial support.
11 For details, see ESIw.
12 For X-ray crystallographic information of 6a, see ESIw (CIF).
13 HNMR spectrum of crude reaction as the proof is attached in
ESIw.
14 For selected examples, see: (a) M. Miura, T. Tsuda, T. Satoh,
S. Pivsa-Art and M. Nomura, J. Org. Chem., 1998, 63, 5211;
(b) M. Wasa, K. M. Engle and J.-Q. Yu, J. Am. Chem. Soc., 2010,
132, 3680; (c) B. S. Kim, S. Y. Lee and S. W. Youn, Chem.–Asian J.,
2011, 6, 1952.
c
1676 Chem. Commun., 2012, 48, 1674–1676
This journal is The Royal Society of Chemistry 2012