Second-Generation palladium catalyst system for transannular C-H functionalization of azabicycloalkanes

Article abstract of DOI:10.1021/jacs.8b02142

This article describes the development of a second-generation catalyst system for the transannular C-H functionalization of alicyclic amines. Pyridine- and quinoline-carboxylate ligands are shown to be highly effective for increasing the reaction rate, yield, and scope of Pd-catalyzed transannular C-H arylation reactions of azabicyclo[3.1.0]hexane, azabicyclo[3.1.1]heptane, azabicyclo[3.2.1]octane, and piperidine derivatives. Mechanistic studies reveal that the pyridine/quinoline-carboxylates play a role in impeding both reversible and irreversible catalyst decomposition pathways. These ligands enable the first reported examples of the transannular C-H arylation of the ubiquitous tropane, 7-azanorbornane, and homotropane cores. Finally, the pyridine/quinoline-carboxylates are shown to promote both transannular C-H arylation and transannular C-H dehydrogenation on a homotropane substrate.

Full text of DOI:10.1021/jacs.8b02142

Article
pubs.acs.org/JACS
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Second-Generation Palladium Catalyst System for Transannular C−H
Functionalization of Azabicycloalkanes
Pablo J. Cabrera, Melissa Lee, and Melanie S. Sanford*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
S
* Supporting Information
ABSTRACT: This article describes the development of a
second-generation catalyst system for the transannular C−H
functionalization of alicyclic amines. Pyridine- and quinoline-
carboxylate ligands are shown to be highly effective for
increasing the reaction rate, yield, and scope of Pd-catalyzed
transannular C−H arylation reactions of azabicyclo[3.1.0]-
hexane, azabicyclo[3.1.1]heptane, azabicyclo[3.2.1]octane, and
piperidine derivatives. Mechanistic studies reveal that the pyridine/quinoline-carboxylates play a role in impeding both reversible
and irreversible catalyst decomposition pathways. These ligands enable the first reported examples of the transannular C−H
arylation of the ubiquitous tropane, 7-azanorbornane, and homotropane cores. Finally, the pyridine/quinoline-carboxylates are
shown to promote both transannular C−H arylation and transannular C−H dehydrogenation on a homotropane substrate.
Scheme 1. (a) Linear Synthesis of Epibatidine and (b) Late
Stage C−H Functionalization Approach to Substituted 7-
Azanorbornanes
INTRODUCTION
■
Alicylic amines appear in a wide variety of bioactive molecules
for the treatment of diverse indications including Parkinson’s
disease, depression, pain, obesity, and drug addiction (Figure
1).1 Indeed, alicyclic amine scaffolds feature in over 20% of the
In this context, C−H bond functionalization could serve as a
complementary and enabling approach for the late-stage
derivatization of alicyclic amines. As shown in Scheme 1b,
preassembly of the amine core and subsequent C−H arylation
would enable the rapid preparation of analogues bearing diverse
substituents. This approach has been widely used for the
introduction of functional groups onto alicyclic amines at the
activated C−H sites α to nitrogen.5 In contrast, selective C−H
functionalization of alicyclic amines at unactivated C−H sites
that are remote from nitrogen remains much more challeng-
ing.6−10
Our group recently reported a Pd-catalyzed method for the
selective transannular C−H arylation of alicyclic amines.11 As
summarized in Scheme 2, this approach leverages coordination
of the amine nitrogen atom in combination with a tethered
secondary directing group (DG) to direct C−H activation via a
Figure 1. Examples of bioactive alicyclic amines.
top 200 pharmaceuticals.2 Traditional synthetic approaches to
alicyclic amines involve multistep sequences to build up the
amine core.3 This is exemplified by Corey’s synthesis of
epibatidine, wherein the bicyclic amine scaffold is assembled in
seven steps starting from 6-chloronicatinaldehyde (Scheme
1a).4 While this represents an elegant approach to this specific
target, it is not well-suited for the rapid synthesis of analogues
bearing different (hetero)aryl substituents since de novo
synthesis would be required to access each new derivative.
Received: February 22, 2018
© XXXX American Chemical Society
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selected as a model system based on its modest reactivity
under the first generation Pd(OAc)2-catalyzed C−H arylation
conditions, which afforded just 46% yield of the C4-arylated
product 1a at 150 °C using 30 equiv of PhI as the arylating
reagent and solvent (Table 1, entry 1). Monodentate pyridine-
Scheme 2. First-Generation Pd-Catalyzed Method for
Transannular C−H Arylation of Alicyclic Amines
a
Table 1. Ligand Evaluation with Substrate S1
boat conformer. Our first-generation catalyst system proved
effective for the transannular C−H arylation of a variety of
alicyclic amine scaffolds, and this method was utilized to access
arylated analogues of bioactive molecules such as amitifadine,
varenicline, and cytisine.
However, there were a number of key limitations associated
with this first-generation method. For instance, the yields were
often modest, particularly with bicyclic amines like varenicline.
In addition, most of the reactions required high temperatures
(>140 °C) and large excesses of the aryl iodide oxidant.
Further, a number of important alicyclic amine cores (e.g.,
tropane, homotropane, and 7-azanorbornane derivatives)
exhibited very low reactivity (Scheme 3a). Finally, the original
reaction was limited to C−H arylation, and no other C−H
functionalization products were accessed.
entry
L
L (mol %)
yield 1a
1
−
−
5
46%
44%
47%
43%
40%
46%
56%
68%
80%
78%
24%
77%
77%
2
L1
L2
L3
L4
L5
L6
L7
L8
L8
L8
L9
L9
L9
3
5
4
5
5
5
6
5
7
5
8
5
9
5
10
11
12
13
14
10
20
5
Scheme 3. Ligand-Enabled C−H Arylation of Tropane,
Homotropane, and 7-Azanorbornane Derivatives
10
20
b
85% (82% )
a
Conditions: S1 (0.03 mmol, 1 equiv), Pd(OAc)2 (10 mol %), ligand
b
L (5−20 mol %) CsOPiv (3 equiv), PhI (30 equiv), 150 °C. Isolated
yield of 1a (0.3 mmol scale).
type ligands were explored first based on their well-established
utility in enhancing both reactivity and selectivity in related Pd-
catalyzed C−H functionalization reactions.12−16 However, as
shown in Table 1, the addition of 5 mol % of monodentate
pyridine, quinoline, or acridine derivatives L1−L5 had minimal
impact on the yield of 1a (entries 2−6).
This article focuses on the development of a second-
generation catalyst system that addresses many of these
limitations. A variety of reports from our group12 and
others13−15 have shown that pyridine and carboxylic acid-
based ligands can be used to enhance reactivity and modulate
selectivity in other Pd-catalyzed C−H functionalization
reactions.16 We demonstrate herein that ligands that combine
these two functional groups are effective for increasing the
reaction rate, yield, and scope of the Pd-catalyzed transannular
C−H functionalization of alicyclic amines. Most notably, we
show that pyridine-carboxylate and quinoline-carboxylate
derivatives enable the first reported examples of transannular
C−H functionalization on the ubiquitous tropane core
(Scheme 3b). We also present studies on the role of these
pyridine/quinoline carboxylates and show that they impact
both reversible and irreversible catalyst decomposition path-
ways.
We hypothesized that the bidentate coordination of substrate
S1 might out-compete the binding of monodentate pyridine
derivatives.10g,17 As such, we next explored a series of quinoline-
oxazoline and quinoline/pyridine-carboxylate ligands exempli-
fied by L6−L9 in Table 1. The addition of 5 mol % of
quinoline-oxazoline L618 resulted in a modest improvement in
the yield of 1a compared to the ligand-free reaction (56%
versus 46%, respectively, entry 7). Even more significant
increases were observed with quinoline/pyridine-carboxylate
ligands L7−L9.19 In particular, the use of 5 mol % of 2-picolinic
acid (L8) or of 2-quinaldic acid (L9) resulted in an
approximately 80% yield of 1a (entries 9 and 12). With
picolinic acid, the reaction was sensitive to the ligand loading,
and the yield of 1a dropped to 24% upon the addition of 20
mol % of L8 (entry 11). In contrast, varying L9 from 5 to 20
mol % had minimal impact on the yield of 1a (77−85%, entries
12−14). Using 20 mol % of L9, 1a was isolated in 82% yield20
RESULTS AND DISCUSSION
■
Ligand Identification. Our initial investigations focused on
probing ligand effects on the C−H arylation of the benzo-fused
azabicyclo[3.2.1]octane substrate S1. This substrate was
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(entry 14), which represented an almost doubling of the yield
relative to the ligand-free reaction.
We next sought to lower the reaction temperature from 150
°C as well as to move away from the use of solvent quantities of
PhI. As shown in Table 2, with 5 mol % of L9, this reaction
Table 3. Application of Pyridine-Carboxylates in
Transannular C−H Arylation of Other Alicyclic Amine
Substrates
a
Table 2. Reaction Optimization with L9
entry
temp
solvent
neat
PhI (equiv)
yield 1a
1
2
3
4
5
6
7
8
150 °C
120 °C
120 °C
120 °C
120 °C
120 °C
110 °C
100 °C
100 °C
100 °C
30
30
30
15
3
77%
60%
87%
85%
87%
79%
86%
84%
85%
29%
neat
t-amylOH
t-amylOH
t-amylOH
t-amylOH
t-amylOH
t-amylOH
t-amylOH
t-amylOH
1
3
3
Scheme 4. Two Possible Roles for L8/L9 in C−H Arylation
of S1
b
9
3
c
10
3
a
Conditions: S1 (0.03 mmol, 1 equiv), Pd(OAc)2 (10 mol %), L9 (5
mol %) CsOPiv (3 equiv), PhI (1−30 equiv), 100−150 °C. Calibrated
b
c
GC yields for 1a. L8 (5 mol %). No ligand added.
proceeded at temperatures as low as 100 °C and with just 3
equiv of PhI in t-amyl alcohol solvent. Under these conditions,
1a was obtained in 84% yield (entry 8). Nearly identical yield
was obtained using picolinic acid (L8) under these conditions
(entry 9). In contrast, in the absence of L8/L9, 1a was obtained
in just 29% yield (entry 10).
Use of L8/L9 with Other Substrates. We next explored
the application of L8/L9 in the transannular C−H arylation of
other substrates. Initial investigations focused on alicyclic
amines that underwent moderate to low yielding C−H
arylation under our first-generation conditions.11 The addition
of 5 mol % of L8 or L9 to these reactions under otherwise
identical conditions to the first-generation system resulted in
increases in the yield of transannular C−H arylation products
across the board. Notably, L8 and L9 afforded very similar
results in most cases; thus, only the results with L8 are shown
in Table 3. The observed increases in yield were particularly
dramatic in the formation of products 3−5, where the yields
were more than doubled. In addition, C−H arylation to form
derivatives of the bioactive molecules varenicline and
amitifadine (8 and 9, respectively) proceeded with significantly
enhanced yields relative to the first generation conditions.
Mechanistic Role of L9. We next probed the mechanistic
role of the ligand in this transformation. At the outset, we
considered two general possibilities, which are summarized in
Scheme 4. In the first (mode A), L9 could bind to the Pd
catalyst at some stage of the catalytic cycle for C−H arylation,
thereby enhancing the rate or selectivity of a key step (for
example, C−H activation). Alternatively, in the second (mode
B), L9 could play a role outside of the primary catalytic cycle by
limiting product inhibition, slowing catalyst decomposition, or
rescuing other off-cycle intermediates. Notably, there is
precedent for both mode A12,13,17c,e,21 and mode B14,15,17f in
other Pd-catalyzed C−H functionalizations as well as related
reactions. We conducted a series of different experiments to
differentiate these possibilities.
We first examined the initial rate of the C−H arylation of
substrate S1 in the presence and absence of 5 mol % of L9. As
shown in Figure 2, the initial rate with L9 is approximately
double that without it (0.0013 versus 0.00062 mol L−1 min−1,
respectively). This led us to an initial hypothesis that the role of
Figure 2. Initial rate for reaction of S1 with PhI in the presence of 5
mol % L9 (red curve) and absence of ligand (blue curve). Conditions
red curve: S1 (0.03 mmol, 1 equiv, 0.12 M), Pd(OAc)2 (0.012 M),
CsOPiv (0.36 M), PhI (0.36 M), L9 (0.006 M), t-amylOH (0.25 mL),
100 °C. Conditions blue curve: S1 (0.03 mmol, 1 equiv, 0.12 M),
Pd(OAc)2 (0.012 M), CsOPiv (0.36 M), PhI (0.36 M), t-amylOH
(0.25 mL), 100 °C.
C
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L9 might be to accelerate the turnover-limiting step of the
catalytic cycle.
DFT calculations of these transannular C−H arylation
reactions have suggested that C−H activation is turnover-
limiting.22 To test for this experimentally in our system, we first
determined the hydrogen/deuterium kinetic isotope effect (kH/
kD) for the ligand-free Pd-catalyzed C−H arylation of S1 versus
S1-d5 (Scheme 5).23 In the absence of L9, a kH/kD of 3.3 was
Scheme 5. Kinetic Isotope Effect for S1 and S1-d5 with and
a
without L9
Figure 3. Full reaction profile for the reaction of S1 with PhI in the
presence of 5 mol % L9 (red curve) and absence of ligand (blue
curve). Conditions red curve: S1 (0.03 mmol, 1 equiv, 0.12 M),
Pd(OAc)2 (0.012 M), CsOPiv (0.36 M), PhI (0.36 M), L9 (0.006 M),
t-amylOH (0.25 mL), 100 °C. Conditions blue curve: S1 (0.03 mmol,
1 equiv, 0.12 M), Pd(OAc)2 (0.012 M), CsOPiv (0.36 M), PhI (0.36
M), t-amylOH (0.25 mL), 100 °C.
approach has been used previously to probe for product
inhibition in related Pd catalyzed C−H functionalization
reactions.15 As summarized in Table 4, the addition of
a
Table 4. Addition of 1b to C−H Arylation of S1
a
Conditions: S1 or S1-d5 (0.03 mmol, 0.12 M), Pd(OAc)2 (0.012 M),
CsOPiv (0.36 M), PhI (0.36 M), t-amylOH (0.25 mL), 100 °C, with
and without L9 (0.006 M).
observed. The magnitude of this value is consistent with a
primary isotope effect24 and provides experimental evidence
supporting C−H cleavage as the turnover-limiting step of this
reaction.
[1b]
1b
yield 1a
yield 1a
We next probed the isotope effect in the presence of 5 mol %
of L9. As shown in Scheme 5, these experiments show a kH/kD
value of 3.2. Again, this result is consistent with turnover-
limiting C−H activation. However, we note that the
magnitudes of the KIE values in the ligand-free and L9
conditions are virtually identical. This is in marked contrast to
other Pd-catalyzed C−H functionalization reactions in which
added ligands often have a dramatic impact on kH/kD.13b,17c
These changes in kH/kD are generally rationalized based on the
ligand playing an integral role in the nature/position of the
transition state for the C−H cleavage step.10g Conversely, the
lack of such a change in our system suggests that the ligand may
not be involved in C−H activation.
We next conducted rate studies to examine the full reaction
profile of the ligand-free and L9-containing reactions. In the
ligand-free reaction (Figure 3, blue curve), the concentration of
product starts to plateau after approximately 60 min, and the
reaction completely stalls after 480 min to afford a maximum
concentration of 0.035 M of product 1a (29% yield). In
contrast, in the presence of 5 mol % of L9 (Figure 3, red
curve), the reaction continues to progress over 1200 min to
afford 0.1 M of 1a (84% yield).
b
entry
(M)
(equiv)
(no ligand)
(5 mol % L9)
1
2
3
4
5
0
0
13%
13%
13%
13%
11%
28%
29%
30%
28%
28%
0.01
0.03
0.06
0.09
0.1
0.25
0.50
0.75
a
Conditions: S1 (0.03 mmol, 1 equiv, 0.12 M), 1b (0−0.09 M),
Pd(OAc)2 (0.012 M), CsOPiv (0.36 M), PhI (0.36 M), t-amylOH
b
(0.25 mL), 100 °C. Reaction with L9 (0.006 M).
0.012−0.09 M of 1b (0.1−0.75 equiv relative to S1) had
essentially no impact on the yield after 45 min, either in the
presence or absence of ligand. Furthermore, nearly identical
initial reaction rates were observed in the presence and absence
of 0.06 M 1b (Figures SI-9 and SI-10). Overall, these results
suggest against product inhibition in this system.
Experimentally, we observe that the ligand-free reaction
changes from a yellow homogeneous solution to a dark
heterogeneous mixture over approximately 30 min at 100 °C.
This suggests that catalyst deactivation might be the reason for
the stalling of the ligand-free reaction. In this scenario, the role
of L9 could be either to prevent/slow an irreversible catalyst
deactivation pathway or to recover Pd catalyst that is
sequestered reversibly as an off-cycle intermediate (mode B
in Scheme 4).
One possible explanation for the observed stalling of the
ligand-free reaction would be product inhibition via, for
example, the formation of an off-cycle adduct between the
product and the Pd catalyst. To preliminarily test for product
inhibition in the conversion of S1 to 1a, we added varying
amounts of a closely related product (1b) at the reaction onset.
We then compared the yield of product 1a at an early time
point (45 min) as well as the initial reaction rates. Notably, this
To preliminarily test for these possibilities, we conducted the
ligand-free reaction of S1 with PhI for 240 min (the time at
which the reaction stalls at [1a] = 0.035 M; 29% yield) and
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then added 5 mol % of L9. As shown in Figure 4, the addition
of L9 resulted in significant recovery of catalytic activity (final
Scheme 6. Catalytic Activity of Precipitate (I) for C−H
a
Arylation of S1 with and without L9
Figure 4. Catalyst recovery by addition of quinalidic acid after 4 h.
Conditions: S1 (0.03 mmol, 0.12 M), Pd(OAc)2 (0.012 M), CsOPiv
(0.36 M), PhI (0.36 M), t-AmylOH (0.25 mL), 100 °C, 4 h. Then add
L9 (0.006 M) and heat to 100 °C.
[1a] = 0.07 M; 58% yield). This provides preliminary evidence
that L9 plays a role in reversing the deactivation of the Pd
catalyst. However, the final yield is not as high as that obtained
when L9 was present at the start of the reaction (0.1 M 1a; 84%
yield), suggesting that an irreversible catalyst decomposition
pathway is likely occurring as well.
a
Conditions A: S1 (0.03 mmol), Pd(OAc)2 (0.003 mmol), CsOPiv
(0.09 mmol), PhI (0.09 mmol), t-amylOH (0.25 mL), 100 °C, 90 min.
Conditions B: Centrifuge and decant supernatant. Conditions C/D:
S1 (0.03 mmol), precipitate (I), CsOPiv (0.09 mmol), with or without
L9 (0.0015 mmol), 4-iodoanisole (0.09 mmol), t-amylOH (0.25 mL),
100 °C, 18 h.
A visual inspection of the stalled ligand-free reaction showed
the formation of a dark precipitate (I). This material was
isolated by centrifugation and analyzed by ICP-OES, which
showed the presence of palladium.25 Analysis of I via NMR
spectroscopy and mass spectrometry did not provide conclusive
evidence regarding the structure of the Pd-containing materi-
al.26 Nonetheless, we hypothesized that I might contain the off-
cycle Pd-intermediate(s) that are being recovered by L9 in the
experiment in Figure 4. To test this hypothesis, we explored the
ability of the precipitate (I) to catalyze the C−H arylation of S1
(Step C and D, Scheme 6). These reactions were conducted
using 4-iodoanisole as the aryl iodide coupling partner to
distinguish the product (1b) from residual 1a that was formed
in the initial precipitate-generating reaction with PhI (Scheme
6A). In the absence of L9, the I-catalyzed reaction of S1 with 4-
iodoanisole afforded <10% yield of 1b, suggesting that only a
small amount of the Pd present in the precipitate is accessible
to catalyze C−H arylation (Scheme 6C). However, upon the
addition of 5 mol % of L9 under otherwise analogous
conditions (Scheme 6D), this reaction afforded a significantly
enhanced 47% yield of 1b. This result suggests that a key role
of L9 is to rescue off-cycle Pd species from precipitate I.
Application of L8/L9 To Expand Reaction Scope. A
final set of studies focused on using L8/L9 to expand the scope
of this transformation beyond that of the first-generation
system. We were particularly interested in tropane substrate
S10 and derivatives thereof, as the tropane core is the second
most common bicyclic heterocycle in US FDA approved
drugs.1,27 In particular, 3β-arylated tropanes have applications
in radiology as well as in the treatment of cocaine addiction,
obesity, and Alzheimer’s and Parkinson’s diseases (see Figure 1
for examples).28
alkaloids and other bioactive molecules.4b,29,30 Notably, under
the ligand-free conditions, all of these reactions showed the
formation of a dark precipitate similar to that described above,
suggesting that catalyst deactivation is limiting the yields in
these systems. As such, we hypothesized that L8/L9 would be
effective in enhancing reactivity in these systems.
Indeed, the addition of 5 mol % of L8 to the C−H arylation
of S10 under otherwise identical conditions to those in eq 1
resulted in 49% isolated yield of the C−H arylation product
10a.31 As shown in Table 5, this second-generation catalyst
system could be applied to the 3β-arylation of S10 using
electronically diverse aryl and heteroaryl iodides to form
products 10b−10j. Additionally, several tropane derivatives as
well as a homotropane S12 underwent remote arylation to form
13a−15a. All of these reactions afforded moderate to good
isolated yields, and provided a single detectable diastereomer of
product. As such, this method represents a versatile and
expedient route to diverse 3β-aryl tropanes.
As shown in eq 1, under our first-generation, ligand-free
conditions, S10 showed very low reactivity, affording only 4%
of the C-3 arylation product 10a. Similarly poor results were
obtained with the related alicyclic amine cores S11 and S12,
which are also of high interest due to their prevalence in
We also applied the second-generation catalyst to the
selective C−H arylation of the azanorbornane scaffold (S11),
which is the core of epibatidine and epiboxidine (Figure 1 and
Scheme 1).4,29 Notably, S11 afforded <10% yield of the C−H
arylation product 11a under the first-generation conditions. In
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Table 5. Application of Pyridine-Carboxylate Ligands in
Transannular C−H Arylation of Tropane Derivatives
of 12-ene, this second reaction involves dehydrogenation at the
C-6−C-7 position,32 presumably via transannular C−H
activation and subsequent β-hydride elimination.33 Product
12-ene-OPiv is then formed via an allylic C−H pivaloylation of
12-ene. Consistent with this proposal, subjecting 12-ene to the
reaction conditions yielded 12-ene-OPiv in 30% yield based on
1H NMR spectroscopic analysis. Control experiments show
that Pd(OAc)2 is required for the conversion of 12-ene to 12-
ene-OPiv, although L9 is not necessary for this transformation.
Overall, these results open the door for exciting new classes of
transannular C−H functionalization reactions of alicylic amines,
which will be pursued independently.
CONCLUSIONS
■
In summary, this article describes the development of a second-
generation Pd catalyst system for the transannular C−H
functionalization of azabicycloalkanes. The addition of 2-
picolinic acid or 2-quinaldic acid was found to dramatically
improve reactivity, and studies suggest that these additives play
a key role in recovering active catalyst from a precipitate that
forms over the course of the reactions. Ultimately, this second-
generation catalyst system was leveraged to achieve trans-
annular C−H arylation of the tropane, 7-azanorbornane, and
homotropane cores, which were not viable substrates with the
first generation catalyst system. Finally, preliminary results
show that the second-generation catalyst also opens up new
transannular C−H functionalization processes including
dehydrogenation to form cyclic alkenes. Future studies will
focus on further exploiting this new catalyst to expand the
scope of transannular C−H functionalization reactions with
alicyclic amines as well as on developing next generation
catalysts that exhibit further enhancements in reactivity and
selectivity.
contrast, upon the addition of 5 mol % of L9, product 11a was
isolated in 42% yield (eq 2).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b02142.
■
S
Crystallographic data (CIF)
Crystallographic data (CIF)
Experimental details, characterization, NMR and X-ray
data for isolated compounds (PDF)
A final set of studies focused on substrate S12, which
contains two equivalent transannular C−H sites that could
potentially react to afford diarylated product 12a (eq 3). While
12a was formed in 15% yield under the second generation
conditions with ligand L9, this was not the major product.
Instead, the major products were 12-ene (24% isolated yield)
and 12-ene-OPiv (31% isolated yield), in which a single C−H
arylation occurred along with a second, completely different
transannular C−H functionalization reaction. In the formation
AUTHOR INFORMATION
Corresponding Author
*E-mail: mssanfor@umich.edu.
ORCID
■
Melanie S. Sanford: 0000-0001-9342-9436
F
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Laforteza, B. N.; Miura, M.; Yu, J.-Q. Nat. Chem. 2014, 6, 146−150.
(i) Wang, P.-L.; Li, Y.; Wu, Y.; Li, C.; Lan, Q.; Wang, X.-S. Org. Lett.
Notes
The authors declare no competing financial interest.
́
2015, 17, 3698−3701. (j) Hernando, E.; Villalva, J.; Martínez, A. M.;
Alonso, I.; Rodríguez, N.; Gomez Arrayas, R.; Carretero, J. C. ACS
́
ACKNOWLEDGMENTS
■
Catal. 2016, 6, 6868−6882. (k) Ye, S.; Yang, W.; Coon, T.; Fanning,
D.; Neubert, T.; Stamos, D.; Yu, J. Chem. - Eur. J. 2016, 22, 4748−
4752. (l) Van Steijvoort, B. F.; Kaval, N.; Kulago, A. A.; Maes, B. U. W.
ACS Catal. 2016, 6, 4486−4490.
We acknowledge financial support from NIH NIGMS
(GM073836). P.J.C. thanks the Rackham Predoctoral Fellow-
ship for support in research. M.L. thanks Rackham (RMF) and
NSF for graduate fellowships. We thank Jeff W. Kampf for
carrying out X-ray crystallographic analysis as well as Bryant
James for performing ICP-OES experiments.
(8) For examples of the C−H functionalization of aliphatic amines in
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