Copper-Catalyzed C(sp3)?H Amidation: Sterically Driven Primary and Secondary C?H Site-Selectivity

Article abstract of DOI:10.1002/anie.201810556

Undirected C(sp³)?H functionalization reactions often follow site-selectivity patterns that mirror the corresponding C?H bond dissociation energies (BDEs). This often results in the functionalization of weaker tertiary C?H bonds in the presence of stronger secondary and primary bonds. An important, contemporary challenge is the development of catalyst systems capable of selectively functionalizing stronger primary and secondary C?H bonds over tertiary and benzylic C?H sites. Herein, we report a Cu catalyst that exhibits a high degree of primary and secondary over tertiary C?H bond selectivity in the amidation of linear and cyclic hydrocarbons with aroyl azides ArC(O)N₃. Mechanistic and DFT studies indicate that C?H amidation involves H-atom abstraction from R-H substrates by nitrene intermediates [Cu](κ²-N,O-NC(O)Ar) to provide carbon-based radicals R^. and copper(II)amide intermediates [Cu^II]-NHC(O)Ar that subsequently capture radicals R^. to form products R-NHC(O)Ar. These studies reveal important catalyst features required to achieve primary and secondary C?H amidation selectivity in the absence of directing groups.

Full text of DOI:10.1002/anie.201810556

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Copper Catalyzed sp3 C-H Amidation: Sterically Driven Primary
and Secondary C-H Site-Selectivity
Authors: Abolghasem Gus Bakhoda, Quan Jiang, Yosra Badiei, Jeffery
A. Bertke, Thomas R. Cundari, and Timothy H. Warren
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201810556
Angew. Chem. 10.1002/ange.201810556
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10.1002/anie.201810556
Angewandte Chemie International Edition
COMMUNICATION
Copper Catalyzed sp3 C-H Amidation: Sterically Driven Primary
and Secondary C-H Site-Selectivity
Abolghasem (Gus) Bakhoda,[a] Quan Jian,[b] Yosra M. Badiei,[a] Jeffery A. Bertke,[a] Thomas R.
Cundari,[b]* and Timothy H. Warren[a]*
Abstract: Undirected sp3 C−H functionalization reactions often
a
Site selective C-C formation via
[Rh]=CR2
follow site-selectivity patterns that mirror the corresponding C−H
bond dissociation energies (BDEs). This often results in the
functionalization of weaker 3° C−H bonds in the presence of
stronger 2° and 1° bonds. An important, contemporary challenge is
the development of catalyst systems capable of selectively
functionalizing stronger 1° and 2° C−H bonds over 3° and benzylic
C−H sites. Herein, we report a Cu catalyst that exhibits a high
degree of 1° and 2° over 3° C-H bond selectivity in the amidation of
linear and cyclic hydrocarbons with aroyl azides ArC(O)N3.
Mechanistic and DFT studies indicate that C−H amidation involves
H−atom abstraction from R−H substrates by nitrene intermediates
[Cu](κ2−N,O−NC(O)Ar) to provide carbon−based radicals R• and
copper(II)−amide intermediates [CuII]−NHC(O)Ar that subsequently
capture radicals R• to form products R−NHC(O)Ar. These studies
reveal important catalyst features required to achieve 1° and 2° C-H
amidation selectivity in the absence of directing groups.
cat.
[Rh]
+
N
Me
2C(Ph)CO2
3
3
H
Me
CH(Ph)CO2
Ar
Ar
combined
51%
primary/secondary
N
yield
=
9.8
Me
cat.
[Rh]
b
N
N
Rh
S
=
N
Ar
Ph
H2
3-C6
2,4,6-
=
S
MeOH
Ar
Ar
Site selective C-O formation via
[Fe]=O
OAc
OAc
OAc
66%
R
Fe(PDP)CF3
Fe(PDP)
N
Fe
N
N
NCMe
NCMe
H
H
2O2
2O2
H
O
N
H
OH
51%
R
=
R
R
H,
Fe(PDP)
CF3
=
H
-C6
,
3 Fe(PDP)
3,5-(CF3)2
c
This work: Site selective C-N formation via
[Cu]=NR
H
NHR'
*=NR'
[Cu]
H
H
Ph
Ph
Catalyst-controlled site-selectivity that overcomes
a
substrate’s innate preferences based on steric and electronic
properties of individual C-H bonds in the absence of directing
groups is a crucial challenge in the development of C-H
functionalization.[1,2] In sp3 C-H functionalization, selectivities
often follow C-H bond strengths since a common mechanism
involves H-atom abstraction (HAA) from the C-H bond.[1c] Thus,
these reactions typically occur at weaker benzylic and allylic as
well as more electron−rich 3° C−H bonds over stronger 1° and
2° C−H bonds.[1] The electrophilic nature of many HAA agents
can further amplify selectivity towards electron-rich C-H
bonds.[1,2b,2g-i] Recognizing that 3° C-H bonds are sterically
somewhat hindered, however, suggests a strategy to achieve
selective functionalization of more exposed 1° and 2° C-H bonds
through catalyst-centered steric control.[1a-c,2g-j] Thus, the
challenge becomes the design of a catalyst system potent
enough to react with very strong 1° and 2° C-H bonds, yet with
the capability to sterically differentiate among the wide range of
C-H bonds typically found within substrate molecules.
bulk
to
in site
selectivity
Effect of
ligand
CHPh2
R
R
=
R
N
N
access
Limited
Cu
four-coordinate Cu-nitrene
N
O
tBu
R
R
tBu
*=NR'
Ph
[Cu]
Figure 1. State of the art in site selective C-H functionalization
controlled by catalyst structure.
and co-workers showed that a sterically encumbered Rh–
porphyrin catalyst demonstrates high 1° selectivity in carbenoid
transfer reactions (Figure 1a).[4] Most recently, Davies group
reported a new dirhodium catalyst that is highly effective for the
functionalization of 1° C–H bonds with high levels of site- and
enantioselectivity via [Rh]=CR2 intermediates.[5a] By altering the
sterics of the carboxylate ligands, site-selectivity can be tuned to
prefer either 3°, 2° or 1° C–H bonds.[5]
Catalyst centered steric control may also override innate
selectivity in C-H hydroxylations.[2g-i] White group reported that
steric enhancement of
a Fe(PDP) catalyst switches the
Early, seminal work by Callot et al. demonstrated that 1°
C-H bond selectivity for carbene insertion reactions of n-alkanes
with ethyl diazoacetate catalyzed by [Rh(por)I] (where por =
meso-tetraarylporphyrinato) increases with the increase of the
sterics of the ortho groups of the meso-aryl rings.[3] In 2008, Che
selectivity from 3° to 2° C-H bonds due to decreased
accessibility to the putative [Fe]=O intermediate (Figure 1b).[2g]
Structurally related chiral Fe and Mn catalysts also become both
more enantioselective through addition of steric bulk.[2d-e]
Despite
these
advances
in
redirecting
C-H
functionalization away from weaker C-H bonds in metal-carbene
and -oxo based methods, progress with metal-nitrene based
protocols has been much slower. In 2006 Peréz and coworkers
[a]
M. Sc. A. Bakhoda, Dr. Y. M. Badiei, Dr. J. A. Bertke, Prof. Dr. T. H.
Warren
Department of Chemistry, Georgetown University
Box 571227, Washington, DC 20057-1227 (USA)
E-mail: thw@georgetown.edu (T.H.W.)
Q. Jiang, Prof. T. R. Cundari
Department of Chemistry, Center for Advanced Scientific Computing
and Modeling (CASCaM) University of North Texas
Denton, TX 76203 (USA)
reported that very bulky substituents in TpCu (Tp
=
tris(pyrazolyl)borate) catalysts could greatly favor C-H amination
of cumene with PhI=NTs at the unactivated 1° site over the
electronically favored 3° C-H bond.[6] Unfortunately, overall
amination yields were low, despite using a large excess of the
C-H substrate. Based on our development of discrete b-
diketiminato copper nitrene complexes [Cu]2(µ-NR’) and
[b]
Email: t@unt.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/....
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10.1002/anie.201810556
Angewandte Chemie International Edition
COMMUNICATION
[Cu]=NR’ for stoichiometric and catalytic C-H amination with
alkyl and aryl azides N3R’,[7] we felt that steric modification of the
b-diketiminate ligand could result in the selective amination of
stronger 1° C-H bonds provided that copper nitrenes with
heightened reactivity could be generated.
PhC(O)N3, however, led to a significant increase in the C-H
amidation yield to 57% with a concomitant decrease in the
undesired parent benzamide PhC(O)NH2 (14%). Slow addition
techniques have been used in other C-H functionalization
protocols where the reactive intermediates are susceptible to
dimerization or degradation or to simulate high catalyst
loadings.[9] The use of the highly electrophilic aroyl azide
PhC(O)N3 enables C-H amidation at RT; in contrast, scouting
experiments with the aryl azide PhN3 under similar conditions
reveal only PhN=NPh formation.
To enhance the reactivity of our copper nitrene
intermediates [Cu]=NR’, we employed aroyl azides ArC(O)N3 as
potentially more electrophilic nitrene sources than alkyl or aryl
azides.[8] Demonstrating the exceptional reactivity of a putative
copper benzoylnitrene intermediate, addition of
1 equiv.
PhC(O)N3 (BzN3, 2) to 1 equiv. catalyst [Cl2NN]Cu (1) in neat
ethylbenzene at -35 °C gives the 2° C-H amination product in
70% yield (Figure 2b). Unfortunately, very low C-H amidation
yields under catalytic conditions (see Supporting Information,
Section 4) suggest that highly reactive [Cu](NC(O)Ph)
intermediates undergo decomposition pathways that preclude
catalysis. For instance, a 1:1 mixture of BzN3 and [Cl2NN]Cu in
benzene gave the diazene BzN=NBz in 46% isolated yield.
Coupled with C-H amination behavior in the presence of
ethylbenzene, the formation of this diazene in the absence of a
sp3 R-H substrate suggests the generation of a [Cu](NC(O)Ph)
intermediate that can dimerize or undergo an attack by excess
BzN3 with loss of N2 to form BzN=NBz (3) (Figure 2b).
Table 1. Benzylic, 2° and 3° C-H amidation by 4.
10%
[IPr*2NN]Cu
+
N
3
R
H
R
Bz
PhC(O)
RT
PhF,
N
H
-
N2
1.0
2
6
equiv.
NHBz
NHBz
NHBz
NHBz
NHBz
O
S
6a.
6f.
6b.
6c.
6d.
6e.
53%
52%
78%
68%
61%
NHBz
NHBz
NHBz
NHBz
NHBz
6h.
6i.
71%
63%
49%
55%
53%
PhF,
6g.
6j.
a
1 and 4
Structure of
catalysts
slow addition of
BzN solution
M in
Conditions:
=
=
R
R'
RT,
(4.1
3
Cl,
H;
R
R
0.01
Isolated
mL/min).
yields.
1
N
N
[Cl2NN]Cu ( )
Cu
Both benzylic as well as unactivated 2° C-H bonds
undergo amidation upon slow addition of BzN3 catalyzed by 10
mol% 4 as presented in Table 1. Notably, good yields are
obtained with using the R-H substrates as the limiting reagent
(1.0 equiv.) at room temperature. Benzylic C-H bonds undergo
smooth C-H amidation (entries 6a-6e). This catalytic system
functionalizes the unactivated 2° C-H bonds of cyclohexane
(BDE = 99.5 kcal/mol)[10] (entry 6f) in 71% yield. Likewise,
amidation of norbornane at 2° C-H bonds (entry 6g) gives the
exo regioisomer (dr = 13:1; crude 1H NMR), which may be
isolated in 63% yield. On the other hand, adamantane and 1,3-
dimethyladamantane underwent selective amidation at the 3° C-
H sites to provide the benzamide products 6h and 6i. The latter
furnished the N-benzoyl derivative of the Alzheimer’s disease
medication memantine in 55% yield.
=
=
R
R'
CHPh
tBu;
R
R
2 (IPr*),
[IPr*2NN]Cu ( )
R'
R'
4
b
Formation of
dibenzoyldiazene
NHBz
Bz
[Cl2NN]Cu
[Cl2NN]Cu
3
N
N
BzN3
H
Ph
H6 RT
,
C6
2
Bz
characterized
Ph
X-ray
by X-ray
h2-C
c
6H
of
[IPr*2NN]Cu(
6) (4)
We note that 4 catalyzes C-H amidation with many aroyl
azides ArC(O)N3 under analogous conditions (Table S1), though
sterically hindered azides such as anthracene 9-carbonyl azide
give lower yields. A curious finding is that 2-picolinoyl azide
leads to only a trace amount of the C-H amidation product (entry
7o). We hypothesize that pyridyl group coordination inhibits
azide activation. Consistent with this observation, we find that
addition of 2-picoline to 4 gives [IPr2*NN]Cu(2-picoline) (8)
(Figure S30) that is inactive in the C-H amidation of
ethylbenzene with BzN3, even at elevated temperatures (60 °C).
To probe the pathway for catalytic C-H amidation, we
employed (2-methylcyclopropyl)benzene as R-H substrate with
BzN3 that provided the ring-opened product 9 in 23% yield along
with PhC(O)NH2 and some unreacted starting material (Scheme
1). The absence of any amidation product with the cyclopropane
Figure 2. Development of hindered b-diketiminato copper
catalyst 4 for sp3 C-H amidation with BzN3.
To discourage bimolecular interactions between transient
acylnitrene intermediates [Cu](NC(O)Ph) that could lead to N-N
coupling, we synthesized
a novel copper(I) b-diketiminate
complex [IPr*NN]Cu(h2-benzene) (4) that features extremely
sterically demanding o-CHPh2 and p-tBu substituents on the b-
diketiminato N-aryl groups. Deprotonation of the free b-
diketimine [IPr*2NN]H (5) with n-BuLi to give [IPr*2NN]Li followed
reaction of CuCl in benzene provided 4 in 72% yield. A space-
filling model of the X-ray structure of 4 makes apparent the
considerable steric influence of the four o-CHPh2 substituents
(Figure 2c).
Preliminary screening experiments that employed
ethylbenzene and benzoyl azide (BzN3) in a 1 : 1 ratio in
fluorobenzene (PhF) catalyzed by 10 mol% 4 at RT showed
complete conversion of the azide, but produced the desired
amide PhCH(NHC(O)Ph)Me in only 29% yield with a significant
amount of benzamide PhC(O)NH2 (57%). Slow addition of
ring intact suggests
a HAA pathway to generate the 1°
cyclopropylmethyl radical that rapidly ring opens (k = 4 × 1011 s-
1
)
[11] followed by capture by a copper(II) benzamide intermediate
[CuII]-NHC(O)Ph. We identified a kinetic isotope effect (KIE) of
3.4 ± 0.3 for cyclohexane, and 5.5 ± 0.3 for tert-butylbenzene
(See Supporting Information section 7). These KIE values are
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10.1002/anie.201810556
Angewandte Chemie International Edition
COMMUNICATION
Radical clock
Table 2. Catalyst-dictated site selectivities in C–H amidation of
experiment
NHBz
diverse straight-chain hydrocarbon substrates.
10%
[IPr*2NN]Cu
PhF
H
+
BzN3
Ph
HAT
10%
[IPr*2NN]Cu
Ph
+
N
R
H
R
PhC(O)
Bz
3
8
RT
PhF,
-
N
H
N
NH
RC
N2
[Cu]= C(O)Ph
[Cu]- C(O)Ph
1.0
2
11
equiv.
NHBz
BzHN
BzHN
ring opening
Ph
+
NH
Ph
[Cu]- C(O)Ph
Ph
Ph
11
=
x
10
k
4
9
Ph
Ph
10
NHBz
69%
Scheme 1. Radical clock: C-H amidation occurs solely with ring
11a.
11b.
11c.
62%
11d.
67%
71%
opening.
° ° =
1
/3
7.8
°
1
=
°
1
=
/benz.
10
/benz.
12.5
similar to that identified for C-H amination of ethylbenzene,
adamantane and cumene via N-adamantyl (5.3), N-tosyl (4.9
and 4.1) and N-nosyl (3.1 and 3.2) copper nitrene intermediates,
respectively,[7b,12] a bit lower than observed in the C-H amination
of cyclohexane via b-diketiminato copper N-adamantyl nitrene
intermediates (6.6).[7c]
NHBz
NHBz
NHBz
49%
11e.
11f.
48%
53%
12.3
11g.
° =
°
°
° =
1 /2
3.6
1 /2
°
1
° =
8.8
/3
°
3
no
°
1
no
product
tBu product
Employing theory at the uBP86/mixed basis set level of
theory (see Section 10 of Supporting Information for
details),[7b,13] κ1-N, κ1-O, and κ2-N,O binding modes of the highly
reactive intermediates were evaluated for copper nitrenes
[IPr*2NN]Cu(NC(O)Ph) (Figure 3) and [Cl2NN]Cu(NC(O)Ph)
(Supporting Information Figure S35). Geometry optimizations
indicate the κ1-N and κ1-O isomers were higher in energy (>13
kcal/mol) than the κ2-N,O isomer and are not considered further.
The ground state computed for nitrene [IPr*2NN]Cu(κ2-N,O-
NC(O)Ph) (10) is a singlet that is 21.1 kcal/mol lower than the
triplet. Moreover, MCSCF (multi-configuration self-consistent-
field) calculations at the DFT-optimized geometries also predict
the ground state is a singlet, but this structure has significant
multi-configuration character as evidenced by deviation of
natural orbital occupation numbers (NOONs) from single-
determinant values (1.6 and 0.4 e- in Supporting Information
Figure S37). Therefore, like reported Cu-alkynitrenes, copper
acylnitrenes have significant multi-reference (singlet biradical)
character.[7a,7c,13]
NHBz
NHBz
49%
NHBz
11h.
11i.
53%
48%
° =
11j.
° =
°
1
7.3
product
°
/3
°
° =
1 /1
°
4.3
1 /2
5.9
°
2
no
°
or
3
product
no
°
3
no
2
product
2
NHBz
2
NHBz
1
1
3
3
11k.
11l.
66%
° =
75%
° =
°
°
2 /1
3.2
2 /1
3.4
BzN solution
M in
Conditions:
0.01
slow addition of
Isolated
yields.
RT,
mL/min).
PhF,
(4.1
3
This catalyst system also differentiates between the 1°, 2°,
and 3° C-H bonds present in branched hydrocarbons (Table 2,
entries 11e – 11j) to deliver the 1° functionalized benzamide as
the major product. Amidation of 2,3-dimethylbutane and 2,2-
dimethylbutane (entries 11e and 11f) occur in 48% and 53%
yield with 1°/3° and 1°/2° selectivities of 8.8 and 12.3,
respectively. 2,4-dimethylpentane (entry 11h) led to amidation
principally at the 1° C−H bonds with small amount of the 3°
product (r.r. = 7.3), reversing the site-selectivity reported for
other related C-H functionalization reactions.[4-5,14-16]
Surprisingly, 4 is capable of differentiating more hindered
methyl C-H bonds from less hindered ones. For instance,
amidation of isooctane proceeds with exclusive 1° selectivity that
targets the slightly less hindered Me C-H bonds in the i-Pr vs.
the t-Bu ends of the molecule (r.r = 4.3; entry 11j). While 1° over
2° C-H amidation occurs when 2° sites are hindered (entries 11c,
d, f-j), straight chain alkanes lead to a preference for CH2 sites
(entries 11k, l). The C−H amidation of n-pentane and n-hexane
principally furnished C2-products with overall k2°/k1° = 6.3 and
k2°/k1° = 9.4 in combined yields of 66% and 75%, respectively.
This system shows a high degree of methylene selectivity
Figure 3. DFT calculated structure of [Cu](κ2-NC(O)Ph) (10).
This catalytic system can efficiently functionalize 1° C-H
bonds as illustrated in the reaction of BzN3 with tert-
butylbenzene (BDE ~ 99 kcal/mol)[10] to furnish the 1° C-H
amidation product in 67% isolated yield (Table 2, entry 11a).
Remarkably, amidation of the 1° sp3 C-H bond of cumene (BDE
~ 101 kcal/mol)[10] occurs with synthetically useful selectivity over
the more hindered, yet weaker 3° benzylic C-H bond (BDE ~ 85
kcal/mol)[10] to give a 71% yield (Table 2, entry 11b). A small
amount of 3° amidation product is observed to give a (regiomeric
ratio (r.r.) of 7.8:1. Indeed, synthetically useful 1° selectivity also
occurs in the presence of benzylic and methine C-H bonds in
isobutylbenzene and neopentylbenzene (entries 11c and 11d) to
give 1° amidation products in 62% and 69% isolated yields,
respectively, with r.r. ≥10:1 in each case.
in
methylated
cycloalkanes.
Amidation
of
cis-1,3-
dimethylcyclohexane principally targets the two methylene sites
C4 and C5 with k2°/k1° = 8.3 (Table 3, entry 12a) while cis-1,4-
dimethylcyclohexane gives a 2:1 ratio of 2° products with k2°/k1°
= 10 (entry 12b). In contrast, trans-1,4-dimethylcyclohexane
furnishes a single 2° product in 55% yield with k2°/k1° = 10 (entry
12c).
Heavily
methylated
cis-1,3,5-trimethylcyclohexane
produces a single 2° isomer along with the 1° product (k2°/k1°
2.5; entry 12d).
=
We were profoundly interested in establishing the potential
for site-selective amidation of more complex molecules. The
amidation of trans-pinane occurred at a single methylene site
(C-3) in 49% yield (Table 3, entry 12e). Exclusive methylene
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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
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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Chen, M. C. White, Science 2010, 327, 566. j) M. S. Chen, M. 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.
[3] H. J. Callot, F. Metz, Tetrahedron Lett. 1982, 23, 4321.
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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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Musaev, H. M. L. Davies, Nature 2017, 551, 609; b) K. Liao, S.
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Catalyst-controlled, undirected site-
Abolghasem (Gus) Bakhoda,[a] Quan
Jian,[b] Yosra M. Badiei,[a] Jeffery A.
Bertke,[a] Thomas R. Cundari,[b]* and
Timothy H. Warren[a]*
via Cu-nitrenes
selectivity
that
overcomes
a
+
Cu
R-H
N
R-NH
ArC(O)
C(O)Ar
3
substrate’s innate C-H bond reactivity
represents a crucial challenge for C-H
functionalization. We report a new b-
diketiminate Cu(I) catalyst system for
C-H amidation with aroyl azides via
copper nitrene intermediates whose
steric bulk targets stronger, more
accessible 1° and 2° C-H bonds in the
presence weaker, hindered 3° C-H
bonds.
R
R
N
N
Previous
reports
Cu
R
tBu
Page No. – Page No.
R
N
O
tBu
H
H
Copper Catalyzed sp3 C-H Amidation:
Ph
This
study
=
=
=
BDE 100 kcal/mol
BDE 85 kcal/mol
R
CHPh2
Sterically
Driven
Primary
and
Secondary C-H Site-selectivity
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