N-acyloxyphthalimides as nitrogen radical precursors in the visible light photocatalyzed room temperature C-H amination of arenes and heteroarenes

Article abstract of DOI:10.1021/ja501906x

This paper reports a room temperature visible light photocatalyzed method for the C-H amination of arenes and heteroarenes. A key enabling advance in this work is the design of N-acyloxyphthalimides as precursors to nitrogen-based radical intermediates for these transformations. A broad substrate scope is presented, including the selective meta-amination of pyridine derivatives. A radical aromatic substitution mechanism is proposed.

Full text of DOI:10.1021/ja501906x

Communication
pubs.acs.org/JACS
N‑Acyloxyphthalimides as Nitrogen Radical Precursors in the Visible
Light Photocatalyzed Room Temperature C−H Amination of Arenes
and Heteroarenes
Laura J. Allen, Pablo J. Cabrera, Melissa Lee, and Melanie S. Sanford*
Department of Chemistry, University of Michigan, 930 N. University Ave., Ann Arbor, Michigan 48109, United States
S
* Supporting Information
Scheme 1. Benzene C−H Amination via UV Photolysis of N-
Bromophthalimide
ABSTRACT: This paper reports a room temperature
visible light photocatalyzed method for the C−H
amination of arenes and heteroarenes. A key enabling
advance in this work is the design of N-acyloxyphthali-
mides as precursors to nitrogen-based radical intermedi-
ates for these transformations. A broad substrate scope is
presented, including the selective meta-amination of
pyridine derivatives. A radical aromatic substitution
mechanism is proposed.
romatic and heteroaromatic amines are widely prevalent in
Scheme 2. (a) Known and (b) Proposed Reductive
Fragmentation Pathways for N-Acyloxyphthalimides
A
pharmaceuticals,1 agrochemicals,2 and organic materials.3
These molecules are most commonly prepared by nucleophilic
aromatic substitution,4 transition-metal-catalyzed cross-cou-
pling,5 or reduction of nitroarenes.6 While all of these methods
have proven valuable for a variety of applications, they suffer
from the disadvantage of requiring prefunctionalized starting
materials.
Over the past decade, there has been increasing effort to
circumvent the requirement for prefunctionalization by
achieving the direct C−H amination of aromatic substrates.7
The vast majority of synthetically useful arene C−H amination
methods involve either ligand-directed8−11 or intramolecu-
lar12,13 C−N bond formation. In contrast, intermolecular C−H
amination of simple arenes/heteroarenes remains significantly
more challenging.14−19 Current methods suffer from significant
limitations, including the requirement for high temperatur-
es,14b,c,15,19 UV photolysis,18,19 and/or superstoichiometric
quantities of expensive oxidants.14−16 Additionally, some
reported systems require specialized catalyst scaffolds.15 Finally,
competitive formation of C−H oxygenation15 or C−H
bromination18 side products is observed in several cases.
We sought to develop a new photocatalytic method for the
intermolecular C−H amination of arenes and heteroarenes that
would address many of the challenges described above. Our
approach to this problem was inspired by the work of Skell,
who demonstrated that UV photolysis of N-bromophthalimide
releases PhthN• and Br•, which can participate in competing
C−H amination and C−H bromination of the benzene solvent
(Scheme 1).18,20 We hypothesized that visible light photo-
catalysis21,22 could be used to form analogous nitrogen-based
radical intermediates under much milder conditions from
readily available starting materials (Scheme 2).23 We
anticipated that this could render these reactions synthetically
useful by (1) precluding the concomitant formation of Br•, (2)
affording enhanced yields of the desired aryl amines, and (3)
enabling an expansion of the (currently extremely narrow)
substrate scope.
Our initial efforts toward this goal focused on the use of N-
acyloxyphthalimides (1) as aminating reagents. These com-
pounds can be readily synthesized from N-hydroxyphthalimide
and carboxylic acid derivatives.24 In addition, several reports
have shown that they undergo visible light photocatalyzed
reduction.25 With R = alkyl, this reduction results in
decarboxylative fragmentation to release CO2, R•, and
phthalimide anion (Scheme 2a). However, we hypothesized
that the use of more electron-withdrawing R substituents would
enhance the leaving group ability of the carboxylate anion,
−
thereby favoring fragmentation to release RCO2 and PhthN•
(Scheme 2b). The PhthN• could then participate in C−H
amination of diverse substrates.
To test this hypothesis, we examined the C−H amination of
benzene with a series of electronically different N-acyloxyph-
thalimides in the presence of 5 mol % of commercially available
Received: February 23, 2014
Published: April 4, 2014
© 2014 American Chemical Society
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Communication
26
a
Ir(ppy)3 and visible light. As shown in Table 1, entry 1,
Table 2. Arene Substrate Scope
acyloxyphthalimide 1a (with R = CH3) did not react to afford
Table 1. Visible Light Photocatalyzed C−H Amination of
Benzene with N-Acyloxyphthalimide Derivatives
a
entry
R
yield
b
1
2
3
4
5
6
7
CH3 (1a)
p-MeOPh (1b)
Ph (1c)
nd
7%
8%
p-CF3Ph (1d)
C6F6 (1e)
20%
53%
62%
81%
CH2CF3 (1f)
CF3 (1g)
a
General conditions: 1 (1 equiv), Ir(ppy)3 (5 mol %), benzene (10
equiv), MeCN (0.1 M in 1), visible light, 24 h, rt. Yields determined by
b
GC. nd = not detected.
a
Conditions: 1g (1 equiv), Ir(ppy)3 (5 mol %), arene (10 equiv),
MeCN (0.1 M in 1g), visible light, 24 h, rt. Major product shown.
Yields and selectivities are of isolated products.
detectable quantities of C−H amination product 2. This is
consistent with literature reports showing that alkyl-substituted
acyloxyphthalimides undergo selective decarboxylative frag-
mentation via pathway a (Scheme 2).25 However, as predicted,
increasing the electron-withdrawing character of the R
substituent resulted in the formation of product 2 in modest
to excellent yield (entries 2−7). In particular, trifluoromethy-
lacyloxyphthalimide (1g), which is available in a single step
from commercial N-hydroxyphthalimide and trifluoroacetic
anhydride, afforded 81% yield of 2.27
a
Table 3. Heteroarene Substrate Scope
Control reactions confirm that C−H amination product 2 is
not formed in the absence of either photocatalyst or visible light
(Table S1). Further optimization revealed that the photo-
catalyst loading can be decreased to as low as 0.5 mol %, while
maintaining a yield of 55%. Furthermore, the reaction can be
conducted with benzene loadings as low as 1 equiv relative to
1g, albeit with a decrease in chemical yield to 23%.
We next examined the scope of arenes that participate in this
C−H amination reaction.28 As summarized in Table 2, a wide
range of mono-, di-, and trisubstituted arenes underwent C−H
amination under these conditions. The site selectivity of these
reactions is consistent with that anticipated for a radical
aromatic substitution pathway.29 For instance, with arenes
bearing electron-donating substituents such as alkyl and alkoxy
groups, moderate to high levels of ortho/para selectivity were
observed (e.g., products 4 and 5). With electron-withdrawing
substituents, such as trifluoromethyl, meta-C−H functionaliza-
tion products were formed with modest selectivity (3). In
general, arenes bearing electron-withdrawing substituents
afforded lower yields than those with electron-donor groups.
This is further consistent with a pathway involving the reaction
of a nitrogen-based radical with the aromatic substrates. Finally,
it is noteworthy that this reaction is high yielding and selective
for arene C−H amination in the presence of benzylic C−H
bonds (cf., products 4, 6, and 8).
a
Conditions: 1g (1 equiv), Ir(ppy)3 (5 mol %), heteroarene (10
equiv), MeCN (0.1 M in 1g), visible light, 24 h, rt. Major product
shown. Yields and selectivities are of isolated products. Heteroarene
(20 equiv), MeCN (0.2 M in 1g).
b
hypothesized that it might be compatible with heterocyles.
Indeed, as summarized in Table 3, electron-rich heterocycles
such as furan, thiophene, and 1-methylpyrrole all underwent C-
2 selective C−H amination in moderate to good yield under
our optimal conditions (products 13−15). Importantly, these
substrates are not stable in the presence of the high
temperatures and/or strong oxidants required for many
previously reported C−H amination methods.14,15 Both
electron-rich and electron-deficient pyridine derivatives are
The C−H amination of simple arene substrates can be
achieved using several other synthetic methods.14−19 In
contrast, selective and high-yielding processes for the C−H
amination of diverse heterocycles remain exceedingly rare.16
Due to the mild nature of the current transformation, we
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Journal of the American Chemical Society
Communication
also viable substrates, providing meta-substituted products with
good selectivity (17−23). Notably, there does not appear to be
any catalyst inhibition with these pyridine substrates,
presumably because the Ir contains strongly coordinating
cyclometalated phenylpyridine ligands.
A proposed catalytic cycle for the current transformation is
shown in Scheme 3. This cycle begins with photoexcitation of
AUTHOR INFORMATION
■
Corresponding Author
mssanfor@umich.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Scheme 3. Proposed Mechanism
We acknowledge NIH (GM073836) for support.
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ASSOCIATED CONTENT
* Supporting Information
Experimental details and complete characterization data for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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