Room-temperature C-H arylation: Merger of Pd-catalyzed C-H functionalization and visible-light photocatalysis

Article abstract of DOI:10.1021/ja208068w

This communication describes the development of a room-temperature ligand-directed C-H arylation reaction using aryldiazonium salts. This was achieved by the successful merger of palladium-catalyzed C-H functionalization and visible-light photoredox catalysis. The new method is general for a variety of directing groups and tolerates many common functional groups.

Full text of DOI:10.1021/ja208068w

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pubs.acs.org/JACS
Room-Temperature CÀH Arylation: Merger of Pd-Catalyzed CÀH
Functionalization and Visible-Light Photocatalysis
Dipannita Kalyani, Kate B. McMurtrey, Sharon R. Neufeldt, and Melanie S. Sanford*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
S Supporting Information
b
result led us to hypothesize that the rate of the reaction could be
ABSTRACT: This communication describes the develop-
ment of a room-temperature ligand-directed CÀH arylation
reaction using aryldiazonium salts. This was achieved by the
successful merger of palladium-catalyzed CÀH functionali-
zation and visible-light photoredox catalysis. The new
method is general for a variety of directing groups and toler-
ates many common functional groups.
accelerated (and therefore the temperature lowered) by substituting
diaryliodonium salts with more kinetically reactive arylating reagents.
We report herein the use of this strategy for the rational design of a
new room-temperature CÀH arylation reaction. This achievement
was made possible by merging Pd-catalyzed CÀH functionalization
with visible-light photoredox catalysis.
We reasoned that room-temperature CÀH arylation could be
achieved by using Ph as a highly kinetically reactive alternative
3
to the diaryliodonium oxidant in Scheme 1. A recent report by Yu
suggested that phenyl radicals can participate in Pd-catalyzed
CÀH arylation reactions.7 However, high temperatures were
he biaryl motif is an important structural component of
T
numerous natural products, pharmaceutical agents, and
organic materials.1 As a result, the design of mild, general, and
efficient methods for arylÀaryl bond construction continues to
be an area of tremendous research effort.2 Over the past decade,
transition-metal-catalyzed CÀH arylation reactions have been
particularly well studied, and there have been numerous advances
in the substrate scope, functional group tolerance, and range of
different catalysts for promoting these transformations.2 How-
ever, despite this progress, the vast majority of CÀH arylation
methods still require elevated temperatures (>80 °C).3 The
development of general room-temperature CÀH arylation reac-
tions (particularly in nonacidic solvents) remains an important
challenge for the field.3,4
required in that system in order to generate Ph from dibenz-
3
oylperoxide via decarboxylation (eq 1b).7 We sought to identify
reagents that could form aryl radicals at room temperature, and a
literature survey uncovered Deronzier’s Ru(bpy)3Cl2-photoca-
talyzed generation of aryl radicals at 25 °C from aryldiazonium
salts.8aÀe Inspired by this transformation, we envisioned that
CÀH activation intermediates could potentially be intercepted
by aryl radicals formed at room temperature via visible-light
photocatalysis (eq 1a).9
In 2005, our group reported the Pd-catalyzed, ligand-directed
CÀH arylation of amide and arylpyridine substrates with diaryl-
iodonium salts.5 This transformation proceeds in high yield at
100 °C; however, as shown in Scheme 1, very little product is
obtained at room temperature. A detailed mechanistic study revealed
that the rate-determining step of the catalytic cycle involves oxidation
of dimeric intermediate 1 by [MesÀIÀPh]BF4 (Scheme 1).6 This
Initial investigations focused on the Pd-catalyzed CÀH aryla-
tion of 2 with phenyldiazonium tetrafluoroborate. Ru(bpy)3Cl2
3
6H2O was employed as the photocatalyst, and a 26 W household
fluorescent compact bulb was utilized as the source of visible
light. We were pleased to find that the desired CÀH arylation
product 2a was formed in 31% yield at room temperature with
Scheme 1. Pd-Catalyzed CÀH Arylation with Diaryl-
iodonium Salts
10 mol % Pd(OAc)2, 2.5 mol % Ru(bpy)3Cl2 6H2O, and 2
3
equiv of PhN2BF4 in MeOH (Table 1, entry 1). The yield was
improved to 84% by using 4 equiv of PhN2BF4 in conjunction
with 10 mol % Ag2CO3 as an additive (entry 3). Importantly,
[Pd], [Ru], and visible light were all critical for this transforma-
tion. In the absence of any of these components, significantly
reduced yields of 2a (e8%) were observed (Table 1, entries
4À6). This transformation has several attractive features in
comparison with most current CÀH arylation methods,2
Received: August 26, 2011
Published: November 02, 2011
r
2011 American Chemical Society
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|

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COMMUNICATION
Table 1. Optimization of the Reaction between 2 and
PhN2BF4
Table 2. Substrate Scope of the Room-Temperature Pd/Ru-
a
Catalyzed CÀH Arylation of 2-Arylpyridine Derivativesa
Entry
PhN2BF4 (equiv)
Additive (equiv)
Yieldb
1
2
4
4
4
4
4
none
31%
49%
84%
0%
2
none
3
Ag2CO3 (0.10)
Ag2CO3 (0.10)
Ag2CO3 (0.10)
Ag2CO3 (0.10)
4c
5d
6e
8%
5%
a General conditions: Pd(OAc)2 (0.1 equiv), Ru(bpy)3Cl2 6H2O
3
(0.025 equiv), MeOH (0.1 M in substrate), rt, 4 h, 26 W compact
fluorescent light bulb. b Calibrated yields determined by gas chromato-
graphic analysis of the crude reaction mixtures. c General conditions, but
with no Pd(OAc)2. d General conditions, but with no Ru(bpy)3Cl2
3
6H2O. e General conditions, but with no light.
including a low operating temperature (25 °C),10 a nonacidic
solvent (MeOH), and the generation of innocuous nitrogen
and easily removable HBF4 as the only stoichiometric by-
products. In addition, this is the first example of palladium-
catalyzed CÀH functionalization using visible-light photoredox
catalysis.
With the optimal conditions in hand, we next explored the
functional group compatibility of this transformation using a
series of 2-arylpyridine derivatives. As shown in Table 2, CÀH
phenylation proceeded at room temperature in modest to good
yields with a variety of electronically diverse pyridine substrates.
In all cases, Pd(OAc)2, Ru(bpy)3Cl2 6H2O, and visible light
3
were required to achieve >9% yield [see the Supporting Informa-
tion (SI) for control reactions]. Electron-donating and electron-
withdrawing substituents were well-tolerated on both the
pyridine (entries 1À6) and the aryl ring undergoing functional-
ization (entries 7 and 8). Additionally, chloride and bromide
substituents on the pyridine ring were compatible with the
reaction conditions (entries 3 and 4), suggesting against the
intermediacy of Pd0 in this transformation.
This room-temperature CÀH arylation reaction was also
effective for substrates containing different directing groups,
including amides, pyrazoles, pyrimidines, and oxime ethers
(Table 3, entries 1À5). In addition, the mild reaction conditions
enabled the first example of Pd-catalyzed CÀH functionalization
directed by a free oxime (entry 6). This functional group typically
undergoes rapid hydrolysis in the acidic solvents and at the
elevated temperatures required for most related reactions.11 The
oxime serves as a versatile functional handle for elaboration of the
products, as it can be readily transformed into a ketone, alcohol,
amine, or amide.11b Again, for the examples in Table 3, Pd-
a General procedure: Substrate (1.0 equiv), Pd(OAc)2 (0.1 equiv),
Ru(bpy)3Cl2 6H2O (0.025 equiv), PhN2BF4 (4.0 equiv), MeOH
3
(0.1 M in substrate), rt, 4 h, 26 W compact fluorescent light bulb.
b Ag2CO3 (0.1 equiv) was used as an additive. c General conditions, but
with 0.15 equiv of Pd(OAc)2. d MeOH (0.05 M in substrate). e 5.0 equiv
f
of PhN2BF4. Reaction was run for 10 h. g Reaction was run for 8 h.
h Reaction was run for 9.5 h.
the absence of Ru(bpy)3Cl2 6H2O. In one of the most pronounced
3
cases, 10 underwent Pd-catalyzed photoreaction with [4-
CF3C6H4N2]BF4 to afford 23 in 97% calibrated GC yield without
[Ru] (Scheme 2). This yield was comparable to that obtained using
(OAc)2, Ru(bpy)3Cl2 6H2O, and visible light were all critical for
3
achieving good yields of the products (see the SI for details).
We next examined the use of diverse aryldiazonium salts in
these transformations. As depicted in Table 4, CÀH arylation
proceeded in good to excellent yields with electron-deficient,
electron-rich, and relatively sterically hindered arylating reagents.
Interestingly, the electron-deficient derivatives 17À19 showed mod-
est to high photoreactivities with 1-phenylpyrrolidin-2-one (10) in
2.5 mol % Ru(bpy)3Cl2 6H2O under otherwise analogous condi-
3
tions (92% by GC). Interestingly, this uncatalyzed photoreaction was
highly substrate-dependent; for example, relatively little reaction was
observed between [4-CF3C6H4N2]BF4 and oxime ether 14 in the
absence of [Ru] (Scheme 2).12
Although the mechanistic details of this Pd/Ru photocata-
lyzed CÀH arylation remain to be elucidated, a possible catalytic
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COMMUNICATION
Table 3. Scope of Directing Groups for the Pd/Ru-Catalyzed
Table 4. Scope of Aryldiazonium Salts for the Pd/Ru-
CÀH Arylationa
Catalyzed CÀH Arylationa
a General procedure: Substrate (1.0 equiv), Pd(OAc)2 (0.1 equiv), Ru-
(bpy)3Cl2 6H2O (0.025 equiv), [arylÀN2]BF4 (4.0 equiv), MeOH (0.1 M
3
in substrate), rt, 4 h, 26 W compact fluorescent light bulb. b Reaction was run
a General procedure: Substrate (1.0 equiv), Pd(OAc)2 (0.1 equiv),
for 6 h. c General conditions, but with 3.4 equiv of [arylÀN2]BF4. d General
Ru(bpy)3Cl2 6H2O (0.025 equiv), PhN2BF4 (4.0 equiv), MeOH
3
conditions, but with 0.05 equiv of Ru(bpy)3Cl2 6H2O. e Reaction was run
(0.1 M in substrate), rt, 4 h, 26 W compact fluorescent light bulb.
3
for 10 h. f MeOH (0.2 M in substrate).
b General conditions, but with 0.05 equiv of Ru(bpy)3Cl2 6H2O.
3
c Ag2CO3 (1.0 equiv) was used as an additive. d Reaction was run for
5 h. e 3.5 equiv of PhN2BF4. f General conditions, but with 0.20 equiv of
Pd(OAc)2. g Reaction was run for 5.5 h. h MeOH (0.2 M in substrate).
Scheme 2. Background Reactions with Electron-Deficient
Aryldiazonium Salts
cycle is shown in Figure 1. The key steps include (i) photo-
excitation of the Ru catalyst to generate Ru(bpy)32+*, (ii)
reduction of the aryldiazonium salt to Ar and concomitant
3
oxidation of the Ru center to Ru(bpy)33+,8 (iii) reaction of Ar
3
with palladacycle 29 (generated by CÀH activation of the
3+
substrate) to afford the PdIII intermediate 30, (iv) one-electron
oxidation of 30 by Ru(bpy)3 to regenerate the photocatalyst
and form PdIV intermediate 31, and finally (v) CÀC bond-
forming reductive elimination to release the arylated product
and regenerate the PdII catalyst. Efforts to obtain a detailed
mechanistic understanding of this transformation are currently
underway.
In summary, this communication has described a mild ap-
proach for palladium-catalyzed, ligand-directed arylation of aro-
matic CÀH bonds. These reactions proceed at room
temperature and are compatible with a range of functional
groups, directing ligands, and aryldiazonium salts. This system
introduces the idea of merging visible-light photoredox catalysis
(which can be used to generate diverse reactive intermediates)
with palladium-catalyzed CÀH functionalization. We anticipate
that this new concept will find application in the development of
many new synthetically useful transformations.
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Figure 1. Possible mechanism for the Pd/Ru-catalyzed CÀH arylation
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details and spec-
b
troscopic and analytical data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
mssanfor@umich.edu
’ ACKNOWLEDGMENT
We gratefully acknowledge the NIH NIGMS (GM073836) as
well as an ARRA supplement to this grant for financial support of
this work.
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