10.1002/anie.201810556
Angewandte Chemie International Edition
COMMUNICATION
Table 3. Methylene selectivity in the C–H amidation of cyclic
employed the UNT Chemistry high-performance computing
facility, supported by a grant from the NSF (CHE-1531468).
substrates.
10%
[IPr*2NN]Cu
RT
R
+
N
3
Bz
R
H
PhC(O)
PhF,
N
H
Keywords: Site-selectivity • Copper • Nitrene • C-H
-
N2
1.0
2
12
equiv.
NHBz
functionalization • Catalysis
BzHN
NHBz
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Me
Me
Me
NHBz
NHBz
12d.
X-ray
12e.
X-ray
12c.
12a.
12b.
62%
51%
55%
49%
49%
single
°
° =
°
° =
°
° =
°
° =
2 /1
8.3 2 /1
9.0 2 /1
5.0 2 /1
1.3
regioisomer
R
NHBz
3
1
2
NHBz
H
2
3
1
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2018, 9, 5360; b) C. Le, Y. Liang, R. W. Evan, X. Li, D. W. C.
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A
H
H
.
12f.
62%
66%
12g
(comb.)
(comb.)
BzHN
.
12h
X-ray
31%
H
°
2
° >
/3
°
2
° >
/3
a
: =
3.88
b
99%
99%
3
=
R
12h
of
X-ray
M in
PhF,
Conditions:
0.01
slow addition of
BzN solution
RT,
Isolated
(4.1
3
mL/min).
yields.
functionalization occurs with cis-and trans-decalin with C3/C2
selectivities of 2.1 and 1.3, respectively (Table 3, entries 12f,g).
Selective C-H amidation of 5α-cholestane (entry 12h, 48 sp3 C-H
bonds; 7 3° C−H bonds and 13 unique 2° sites) takes place at
the steroidal A-ring at the sterically most accessible, most
electron-rich methylene site (C3) to give the b-C-3 benzamide
product 12h in 31% yield, along with 8% of the a-C-3 product
(b/a = 3.88) with no evidence of functionalization at other sites.
Previous C-H chlorination of this substrate with a N-chloroamide
reagent or under Mn catalysis showed significantly lower
selectivities (kC3/kC2 = 2[17a] and 1.5,[17b] respectively). These
examples further outline the unique capabilities of this catalyst
system to differentiate among closely related C−H bonds within
substrates.
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In summary, the high reactivity of the Cu-nitrene
intermediate [Cu](NC(O)Ph) along with the tremendous steric
influence of the supporting b-diketiminate ligand leads to site-
selectivities that favor stronger, yet more exposed 1° C-H bonds
over weaker, more hindered 3° C-H bonds. Rigid cyclic
substrates demonstrate a preference for amidation of 2° C-H
bonds over 1° and 3° sites, allowing for selective
functionalization of cycloalkanes. As such, this Cu-acylnitrene
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M. R. Fructos, S. Trofimenko, M. M. Díaz-Requejo, P. J.
system provides
a credible starting point for the further
Pérez, J. Am. Chem. Soc. 2006, 128, 11784.
development of catalyst-controlled site-selectivity to introduce N-
based functionalities into 1° and 2° sites in more complex
molecules for applications in late-stage C-H functionalization
and diversification.
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Acknowledgements
This work has been supported by the US National Science
Foundation under awards CHE-1300774 and CHE-1665348
(T.H.W.). Q.J. and T.R.C. thank the U.S. Department of Energy,
Office of Basic Energy Sciences (Division of Chemical Sciences,
Geosciences, and Biosciences) for partial support of this
research via grant DE-FG02-03ER15387. Calculations
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J. Peng, Z. Xie, M. Chen, J. Wang, Qiang Zhu, Org. Lett. 2014,
16, 4702; c) J. Ryu, J. Kwak, K. Shin, D. Lee, S. Chang, J. Am.
Chem. Soc. 2013, 135, 12861.
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