Cobalt catalyzed sp3 C-H amination utilizing aryl azides

Article abstract of DOI:10.1039/c5sc01162k

A dinuclear Co(ii) complex supported by a modular, tunable redox-active ligand system is capable of selective C-H amination to form indolines from aryl azides in good yields at low (1 mol%) catalyst loading. The reaction is tolerant of medicinally relevant heterocycles, such as pyridine and indole, and can be used to form 5-, 6-, and 7-membered rings. The synthetic versatility obtained using low loadings of an earth abundant transition metal complex represents a significant advance in catalytic C-H amination technology.

Full text of DOI:10.1039/c5sc01162k

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Cobalt catalyzed sp3 C–H amination utilizing aryl
azides†
Cite this: DOI: 10.1039/c5sc01162k
*
*
Omar Villanueva,‡ Nina Mace Weldy, Simon B. Blakey and Cora E. MacBeth
A dinuclear Co(II) complex supported by a modular, tunable redox-active ligand system is capable of
selective C–H amination to form indolines from aryl azides in good yields at low (1 mol%) catalyst
loading. The reaction is tolerant of medicinally relevant heterocycles, such as pyridine and indole, and
can be used to form 5-, 6-, and 7-membered rings. The synthetic versatility obtained using low loadings
of an earth abundant transition metal complex represents a significant advance in catalytic C–H
amination technology.
Received 31st March 2015
Accepted 20th July 2015
DOI: 10.1039/c5sc01162k
www.rsc.org/chemicalscience
for C–H amination reactions with alkyl azides, but these reac-
tions are complicated by competitive a-hydride migration.29,30
Introduction
Recent reports by Betley and coworkers have established the
advantage of incorporating a dipyrromethene redox-active
ligand system31–33 at Fe(II) centers to promote efficient catalytic
C–H amination of aliphatic34 and olenic35 substrates. Appli-
cation of this ligand system in a Co(I) complex proved to
stabilize a cobalt(III)-imido species derived from aryl and alkyl
azides capable of carrying out C–H bond activation. However,
this system was not reported to be catalytic.36
In this manuscript we report the development of a cobalt
catalyst for C–H amination that is tolerant of medicinally rele-
vant heterocycles, such as pyridine and indole, and is capable of
delivering 5-, 6-, and 7-membered rings. This combination of
robust functional group tolerance and versatility with respect to
ring size obtained, with low loadings of an earth-abundant
transition metal complex, represents a signicant advance in
C–H amination catalysis.
The direct amination of C–H bonds in a mild, functional group
tolerant manner represents an important technology for the
synthesis of biologically active molecules, including natural
products and pharmaceutical agents.1 Signicant progress has
been made in the development of catalysts capable of
promoting metallonitrene initiated C–H amination utilizing
carbamate,2–6 sulfamate,2,7–12 sulfonamide,13,14 sulfamide,15–18
and phosphoramide19 reagents for both intra- and intermolec-
ular C–H amination, and in some cases, useful levels of enantio-
induction can also be achieved.20–24
On occasion, these C–H amination reactions install the
desired nitrogen functionality, but more frequently depro-
tection and subsequent elaboration are required. Robust C–H
functionalization reactions to directly incorporate alkyl or aryl
amines into a target molecule have proven to be more chal-
lenging and are the focus of this study.25
We have previously disclosed that Co(II) complexes sup-
ported by a coordinatively versatile redox-active ligand derived
from the NH(o-PhNHC(O)iPr)2 scaffold are capable of
promoting catalytic dioxygen activation to carry out O-atom
Alkyl and aryl azides have been recognized as important
reagents for these reactions, offering the potential to deliver the
C–H amination product in the presence of an appropriate
catalyst, with nitrogen gas as the only byproduct. In early work,
Driver and coworkers described [(cod)Ir(OMe)]2 as uniquely
effective in catalyzing the intramolecular sp3 C–H insertion of a
presumed metallonitrene intermediate obtained by aryl azide
decomposition.26 Subsequent studies have shown that
27
Rh2(esp)2 and Fe(TPP)28 are also capable of inducing these
reactions.
The pioneering studies of Tim Warren and coworkers
established b-diketimide copper complexes as effective catalysts
Department of Chemistry, Emory University, USA. E-mail: sblakey@emory.edu;
cmacbet@emory.edu
† Electronic supplementary information (ESI) available. CCDC 1057198–1057200.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c5sc01162k
Fig. 1 Left: family of dinuclear Co(II) complexes investigated in this
study (R ¼ iPr, tBu, Ph, CF3); right: molecular structure of 4 determined
by single crystal X-ray diffraction.
‡ Present Address: Department of Natural Sciences, Dalton State College, USA.
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transfer processes at impressive rates.37 The multi-electron molecular sieves, a cyclized ligand byproduct (see ESI†) was
processes required for this oxygen activation chemistry parallel observed, along with diminished indoline yields.
those implicit in the azide activation/C–H amination sequence,
Under optimized conditions, azide 5 was converted to
suggesting that these novel dinuclear Co(II) complexes should indoline in 80% isolated yield, notably without formation of the
be investigated as catalysts for metallonitrene chemistry (Fig. 1). corresponding aniline or over-oxidation to the 2-phenylindole
(Table 2, entry 1). The reaction was found to be robust with
respect to the electronic nature of the homobenzylic aryl ring
(83% and 81%, entries 2 and 3, respectively). Modulation of
Results and discussion
the aryl azide substitution resulted in a slight decrease in yield
to 72% for CF3-substituted azide (entry 4). Notably, OMe
substitution of the aryl azide resulted in 60% yield of 5-
ortho-Homobenzyl substituted aryl azide 5 was selected as a test
substrate to explore the possibility of the cobalt(II)-catalyzed
intramolecular amination of aryl azides and establish effective
reaction conditions (Table 1). No reaction was observed at room
methoxy-2-phenylindole (entry 5). A 2 : 1 mixture of indoline to
indole was observed by crude 1H NMR of the reaction mixture,
temperature with complex 1 and azide 5 over the course of 24
but the indoline was oxidized upon exposure to silica gel
hours (entry 1). However, performing the reaction at elevated
temperature (110 ꢀC) produced indoline 6 as the only product in
43% yield (entry 2). To take advantage of the modularity of the
ligand, dinuclear Co(II) complexes with varying acyl substituents
(R ¼ CF3, Ph, tBu) were evaluated for catalytic activity for
chromatography during purication. The previously reported
[(cod)Ir(OMe)]2 did not catalyze indoline formation with this
particular substrate.26
Extending the alkyl linker resulted in selective formation of
the tetrahydroquinoline under these conditions, demonstrating
six-membered ring formation is possible via this catalytic C–H
amination reaction (Table 2, entry 6). Additionally, by extending
the alkyl chain further, the seven-membered tetrahy-
drobenzoazepine was formed, albeit in diminished yield (30%,
entry 7).
Novel heteroaromatic-containing substrates were also
investigated with this catalyst system (Table 2, entries 8 and 9).
Prior to investigating insertion at the benzylic position adjacent
to pyridine, 1 equivalent of pyridine was added to the standard
reaction of 1-azido-2-phenethylbenzene (5), and it was observed
that the reaction proceeded normally (Scheme 1). This is
notable due to the expectation that the high binding affinity of
pyridine to transition metals might inhibit reactivity, as has
been observed for other azide amination systems in the pres-
ence of exogenous coordinating ligands.34 Based on these
results, the ortho-homopyridinyl-substituted aryl azide was
synthesized and found to undergo amination in identical yield
to the comparable benzylic insertion (entry 8). This tolerance of
t
intramolecular C–H amination using aryl azide 5. Butyl- and
phenyl-substituted Co(II) complexes 2 and 3 furnished lower
indoline yields of 20% and 10%, respectively (entries 3 and 4).
Substitution of an electron-withdrawing CF3 group on the
ligand in complex 4 resulted in trace amounts of 6 (entry 5).
Carrying out the reaction with lower catalyst loading (1 mol%)
of the best-performing catalyst 1 resulted in a yield of 11% 6
over 24 hours (entry 6). Extending the reaction time to 48 hours
resulted in an optimal yield of 83% 6 (entry 7). Control experi-
ments show that under these reaction conditions azide 5
remains intact in the absence of a Co(II) catalyst (entry 8).
Furthermore, performing this reaction in the presence of a
simple Co(II) salt (CoBr2) resulted in no product formation
(entry 9), suggesting that the ligand framework is essential to
promote this transformation using Co(II). It is important to note
that this system is sensitive to water, and molecular sieves are
required to achieve optimal indoline yields. In the absence of
pyridine functionality,
a privileged heterocycle for drug
Table 1 Optimization of reaction conditions for C–H amination
discovery, demonstrates the usefulness of this catalyst system
for targets of pharmaceutical interest.38
In expanding to other biologically-relevant heteroaromatics,
we investigated amination at the benzylic position adjacent to a
protected indole and observed excellent conversion to product
(85%, Table 2, entry 9). This also demonstrates the reaction is
tolerant of an oxidation-sensitive substrate. However, in testing
insertion into a benzylic 3ꢀ C–H center (Table 2, entry 10), we
found amination was suppressed, resulting in 90% recovery of
unreacted azide. Notably, when the alkyl chain was extended by
one carbon, 3ꢀ C–H insertion was achieved to form the tetra-
hydroquinoline in 85% yield (Table 2, entry 11).
In order to probe the reaction pathway, the deuterated ortho-
homobenzyl-aryl azide 7 was synthesized27 to measure the
kinetic isotope effect (KIE) of this reaction. The deuterated
substrate was subjected to the standard reaction conditions,
and analysis of the crude reaction mixture by 1H NMR provided
a KIE of 3.4 (Scheme 2). This kinetic isotope effect is lower than
those observed for benzylic insertion by Driver and coworkers
Entry
Catalyst
Mol%
Time (h)
T (ꢀC)
Yielda (%)
1
2
3
4
5
6
7
8
9
1
1
2
3
4
1
1
—
10
10
10
10
10
1
1
—
1
24
24
24
24
24
24
48
48
48
25
110
110
110
110
110
110
110
110
0
43
20
10
trace
11
83
0
CoBr2
0
a
Determined by 1H NMR using 1,3,5-trimethoxybenzene as an internal
standard.
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Table 2 Scope of Co(II)-catalyzed C–H amination with aryl azides
Entry Substrate
Product
Yielda
80
Scheme 1 C–H amination in the presence of pyridine.
1
2
3
4
83
81
72
Scheme 2 Kinetic isotope effect of intramolecular amination.
for the aryl azide system with [(cod)Ir(OMe)]2 (5.06)26 and
Rh2(esp)2 (6.0)27 and by Betley and coworkers for their Fe-cata-
lyzed alkyl azide amination (5.3).34 Zhang and coworkers
observed a similarly greater value (6.2) for allylic insertion of a
sulfonyl azide.17 While the value measured for the Co system is
lower than these examples, it is higher than the KIE of 1.9
observed for dirhodium(II) catalyzed intramolecular benzylic
amination with sulfamate esters.39 These data suggest a
hydrogen-atom abstraction/radical recombination mechanism
maybe operative in this system. Further studies to propose a
mechanism for these reactions are currently underway in our
laboratories.
5
6
60b
70
7
8
30c
80
Conclusions
In conclusion, we have shown a Co(II) complex with a modular,
redox-active ligand is capable of selectively catalyzing benzylic
C–H amination with aryl azides utilizing a variety of substrates
in good yields. This robust catalyst system holds potential for
application in pharmaceutical and total synthesis, as well as
extension to other substrate classes.
9
85
Acknowledgements
This research was supported by the National Science Founda-
tion under the Center for Chemical Innovation in Selective C–H
Functionalization (CHE-1205646).
10
0d
Notes and references
11
85
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