C−H Bond Functionalization by Nitrene Insertion
A R T I C L E S
Scheme 1. Nitrene Sources (a) and Substrates (b) Commonly Employed for the C-H Functionalization by Nitrene Insertiona
a Arrows indicate the insertion site.
Table 1. Trispyrazolylborate Ligands Tpx Employed in This Work
proposed as an alternative to rhodium, after the report by Che
et al.12 on interesting mechanistic studies using ruthenium-
porphyrins as the catalyst. Since that report, an extensive and
exhaustive nitrene-transfer amidation procedure, either stoichio-
metric13 or catalytic,14 has been developed by this group in
recent years. It is also worth mentioning the use of cobalt-based
catalysts by Cenini and co-workers for the amination of the
benzylic C-H bond with aryl azides.15
It is quite surprising that, considering the importance of the
formation of carbon-nitrogen bonds, only the few systems
mentioned above have been reported to date. This is also in
contrast with the considerable number of contributions appearing
in the literature describing metal-based catalysts for nitrene
addition to olefins, in the well-known aziridination reaction.3a,16
A closer look at the literature leads to the following conclu-
sions: (i) most of these results involve the transfer of a nitrene
group from iminoiodanes of formula PhIdNR, with some
exceptions that employs chloramine-T or aryl azides (Scheme
1a); (ii) the substrates studied very often undergo nitrene
insertion into allylic or benzylic C-H bonds, and usually at
secondary carbons (Scheme 1b), examples with less reactive
carbon-hydrogen bonds such as cyclohexane being rare; and
(iii) the conversions into the desired products ranged from low
to moderate. Thus, work in this area to improve the current
state of the art should be focused on the development of an
active catalyst for the general nitrene-transfer reaction from
several sources to the C-H bond of a given substrate. With
this aim in mind, we decided to study the catalytic potential of
copper-homoscorpionate17 complexes TpxCu(L) for this trans-
Tpx
R1
R2
R3
TpBr3
TpMs
TpCy
Tp*
Br
H
H
CH3
Br
H
H
H
Br
2,4,6-Me3C6H2
C6H11
CH3
formation (Table 1). These studies have led to the discovery of
an outstanding catalytic activity of the complex TpBr3Cu(NCMe)
(1) for the insertion of NTs units (Ts ) p-toluenesulfonyl) into
a variety of substrates, with either PhIdNTs or chloramine-T
as the nitrene source and under mild conditions.
Results and Discussion
Amination of Cyclohexane, Benzene, and Other Aromatics
with PhIdNTs. In a preliminary report,18 we described the
functionalization of the carbon-hydrogen bonds of benzene (eq
3) and cyclohexane (eq 4) by direct reaction with PhIdNTs in
the presence of catalytic amounts of TpBr3Cu(NCMe) (1) at room
temperature. We later learned that an increase in the reaction
temperature does not alter the conversion in the cyclohexane
case but nearly doubles that of benzene. These degrees of
conversion for the two substrates are, to the best of our
knowledge, the highest described to date for these transforma-
tions, the formal insertion of the nitrene NTs unit into the sp2
and sp3 C-H bonds of benzene and cyclohexane, respectively.
The yields correspond to the amount of the initial nitrene source
incorporated into the hydrocarbon, the remainder being con-
verted into TsNH2 due to the presence of adventitious water.
As mentioned above, the catalytic tosylamidation of cyclohexane
by nitrene insertion has been known for years, since the seminal
work by Breslow.4 However, the conversions reported to
(12) Zhou, X.-G.; Yu, X.-Q.; Huang, J.-S.; Che, C.-M. Chem. Commun. 1999,
2377.
(13) Stoichiometric amidation reactions: (a) Leung, S. K.-Y.; Tsui, W.-M.;
Huang, J.-S.; Che, C.-M.; Liang, J.-L.; Zhu, N. J. Am. Chem. Soc. 2005,
127, 16629. (b) Leung, S. K.-Y.; Huang, J.-S.; Liang, J.-L.; Che, C.-M.;
Zhou, Z.-Y. Angew. Chem., Int. Ed. 2003, 42, 340. (c) Li, Y.; Huang, J.-
S.; Zhou, Z.-Y.; Che, C.-M. J. Am. Chem. Soc. 2001, 123, 4843. (d) Au,
S.-M.; Huang, J.-S.; Yu, W.-Y.; Fung, W.-H.; Che, C.-M. J. Am. Chem.
Soc. 1999, 121, 9120.
(14) Catalytic amidation reactions: (a) Zhang, J.; Chan, P. W. H.; Che, C.-M.
Tetrahedron Lett. 2005, 46, 5403. (b) He, L.; Chan, P. W. H.; Tsui, W.-
M.; Yu, W.-Y.; Che, C.-M. Org. Lett. 2004, 6, 2405. (c) Liang, J.-L.; Yuan,
S.-X.; Huang, J.-S.; Che, C.-M. J. Org. Chem. 2004, 69, 3610. (d) Liang,
J.-L.; Yuan, S.-X.; Chan, P. W. H.; Che, C.-M. Org. Lett. 2002, 4, 4507.
(e) Liang, J.-L.; Huang, J.-S.; Yu, X.-Q.; Zhu, N.; Che, C.-M. Chem. Eur.
J. 2002, 8, 1563. (f) Liang, J.-L.; Yuan, S.-X.; Huang, J.-S.; Yu, W.-Y.;
Che, C.-M. Angew. Chem., Int. Ed. 2002, 41, 3465. (g) Au, S.-M.; Huang,
J.-S.; Che, C.-M.; Yu, W.-Y. J. Org. Chem. 2000, 65, 7858. (h) Yu, X.-
Q.; Huang, J.-S.; Zhou, X.-G.; Che, C.-M. Org. Lett. 2000, 2, 2233.
(15) (a) Caselli, A.; Gallo, E.; Ragaini, F.; Oppezzo, A.; Cenini, S. J. Organomet.
Chem. 2005, 690, 2142. (b) Ragaini, F.; Penoni, A.; Gallo, E.; Tollari, S.;
Gotti, C. L.; Lapadula, M.; Magioni, E.; Cenini, S. Chem. Eur. J. 2003, 9,
249. (c) Cenini, S.; Tollari, S.; Penoni, A.; Cereda, C. J. Mol. Catal. A
1999, 137, 135.
(17) Trofimenko, S. Scorpionates, The Coordination Chemistry of Polypyra-
zolylborate ligands: Imperial College Press: London, 1999.
(18) D´ıaz-Requejo, M. M.; Belderrain, T. R.; Nicasio, M. C.; Trofimenko, S.;
Pe´rez, P. J. J. Am. Chem. Soc. 2003, 125, 12078.
(16) Halfen, J. A. Curr. Org. Chem. 2005, 9, 657.
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J. AM. CHEM. SOC. VOL. 128, NO. 36, 2006 11785