Auxiliary-Directed C(sp3)?H Arylation by Synergistic Photoredox and Palladium Catalysis

Article abstract of DOI:10.1002/chem.201704045

Herein we describe the auxiliary-directed arylation of unactivated C(sp³)?H bonds with aryldiazonium salts, which proceeds under synergistic photoredox and palladium catalysis. The site-selective arylation of aliphatic amides with α-quaternary centres is achieved with high selectivity for β-methyl C(sp³)?H bonds. This operationally simple method is compatible with carbocyclic amides, a range of aryldiazonium salts and proceeds at ambient conditions.

Full text of DOI:10.1002/chem.201704045

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Title: Auxiliary-Directed C(sp3)-H Arylation by Synergistic Photoredox
and Palladium Catalysis
Authors: Anastasios Polyzos, David W Lupton, and Milena Czyz
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10.1002/chem.201704045
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Auxiliary-Directed C(sp3)-H Arylation by Synergistic Photoredox
and Palladium Catalysis
Milena L. Czyz,a David W. Luptonb and Anastasios Polyzosa,c*
This manuscript is dedicated to Professor Steven V. Ley.
Abstract: Herein we describe the auxiliary-directed arylation of
unactivated C(sp3)-H bonds with aryldiazonium salts, which
proceeds under synergistic photoredox and palladium catalysis.
The site-selective arylation of aliphatic amides with -quaternary
centers is achieved with high selectivity for -methyl C(sp3)-H
bonds. This operationally simple method is compatible with
carbocyclic amides, a range of aryldiazonium salts and proceeds
at ambient conditions.
application of synergistic photoredox and palladium catalysis
(Scheme 1).
Scheme 1: This work: Auxiliary-directed arylation of C(sp3)-H bonds by
The direct, chemoselective functionalization of unactivated
aliphatic C-H bonds is a strategic transformation, which enables
the straightforward diversification of simple organic molecules to
complex molecular architectures. The broad application of C-H
activation reactions has been impeded by the lack of methods
with acceptable regio- and chemo-selectivity. Over the last
decade, transition metal-catalyzed activation of distal C(sp2)-H
bonds with auxiliary-directing group assistance has developed
into a useful synthetic method.1-3
synergistic photoredox and palladium catalysis
Given the effectiveness of the 8-aminoquinoline auxiliary in
Pd catalyzed activation of C-H bonds,16-23 we hypothesized that
palladacycle II would be a suitable intermediate for a one electron
oxidative addition step (Figure 1). The reaction design requires
irradiation of a photocatalyst, PCn, to produce the excited state
complex *PCn which undergoes exergonic single electron
,
transfer (SET) with aryl radical precursor. This SET process
generates an aryl radical that intercepts palladacycle II to afford
the Pd(III) intermediate III. We proposed that the oxidized PCn+1
subsequently oxidizes the Pd(III) intermediate III, to re-generate
the photocatalyst PCn in an overall redox-neutral process.
Reductive elimination from Pd(IV) complex IV releases the
product and closes the Pd cycle. Reductive elimination from III
followed by oxidation of the resulting Pd(I) species cannot be
excluded.24 We reasoned that the proposed synergistic catalytic
cycle reduces the kinetic barrier to direct C(sp3)-H arylation,
leading to milder reaction conditions, without the need for a range
of additives typical in C-H activation methodologies.25
In contrast, extension of this stratagem to less reactive
aliphatic C-H bonds remains scarce.4 Despite ongoing progress,
transition metal-catalysed activation of distal C(sp3)-H centers via
directing auxiliaries remains a noteworthy challenge and available
methods usually mandate high temperatures, stoichiometric
additives and extended reaction times to be viable.5 Recently,
synergistic photoredox and transition metal catalysis, also known
as metallaphotoredox catalysis, has emerged to address the
associated limitations of traditional cross-coupling chemistry.6, 7
The method harnesses a visible light photoredox catalytic cycle to
generate carbon-centred radicals under mild conditions, which
then engage in single electron oxidative addition8-12 or
transmetallation13-15 steps. In a pioneering study, Sanford and co-
workers applied synergistic catalysis to develop an auxiliary-
directed arylation of C(sp2)-H bonds.8 However, the development
of auxiliary-directed functionalization of unactivated C(sp3)-H
bonds under metallaphotoredox conditions remains largely
unexplored. Herein we report the direct and selective β-arylation
of C(sp3)-H bonds in quaternary aliphatic amides through the
[a]
[b]
[c]
Dr. Milena L. Czyz, Dr Anastasios Polyzos
CSIRO Manufacturing
Research Way, Clayton VIC 3168, Australia
A/Prof David W. Lupton
School of Chemistry, Monash University
Clayton 3800, Victoria, Australia
Dr Anastasios Polyzos
School of Chemistry, The University of Melbourne
Melbourne, Victoria 3010, Australia
E-mail: anastasios.polyzos@unimelb.edu.au
Figure 1: Reaction design for C(sp3)-H arylation by synergistic photoredox and
Supporting information for this article is given via a link at the end of
the document
palladium catalysis
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Table 1. Screening of aryl radical precursorsa
Studies commenced by examining stoichiometric formation of
palladacycle 2 at ambient temperature (Scheme 2). Reaction of
amide 1 with one equivalent of Pd(OAc)2 in MeCN at 23 °C
afforded palladacycle 2 quantitatively.
Total
Entry
Ar-X
Solvent
Photocatalyst
yield
[%]d
1b
2b
3c
Ar-I (3)
MeCN
MeOH
MeOH
Ir(ppy)3
Ir(ppy)2(dtbpy)
PF6
8
[Ph2I]BF4 (4)
trace
15
[pOMeArN2] BF4 (5)
Ru(bpy)3Cl2
[a] General conditions: Ar-X (1.0 equiv.), Pd(OAc)2 (10 mol%), PC (2.5 mol%),
solvent (0.1 M in substrate), r.t., 16 h, light source. [b] reaction irradiated with
10 W Blue LEDs [c] reaction irradiated with 15 W CFL [d] Yield determined by
1H NMR spectroscopy using sulfolene as an internal standard. Q = quinoline
Chatani28 and Rao29 reported that substitution at the 5-position of
the 8-aminoquinoline ring improved C-H activation. Accordingly,
a series of modified C-5-substituted 8-aminoquinolines, were
prepared and examined in our system (See Supporting
Information). It was found that the 5-chloro-8-aminoquinoline
derivative 8 resulted in improved yields of mono- and diarylated
products 8a, and 8b to 25%. Consequently, the 5-chloro-8-
aminoquinoline auxiliary (Q’) was selected for further optimization
of catalyst loading and concentration of aryldiazonium salt (Table
2). We initially turned our attention to photocatalyst stoichiometry.
A loading of 5 mol% of Ru(bpy)3Cl2 significantly increased yield of
mono- and diarylated products 8a, and 8b (Table 2, entry 2).
Scheme 2: Formation and reactivity of palladacycle
2 under photoredox
conditions
We next evaluated the propensity of palladacycle 2 to intercept a
radical generated under photoredox conditions and subsequently
undergo a single electron transfer with the oxidized PCn+1. Methyl-
4-iodobenzoate (3) (E1/2red  -1.3 V vs SCE)26 served as a radical
precursor with fac-Ir(ppy)3 (E1/2red[*IrIII/IrIV] = -1.76 V vs SCE).
Reaction of palladacycle 2 with 2 equivalents of 3 and 1.0 mol %
of fac-Ir(ppy)3 in MeCN produced a mixture of mono- di- and
triarylated products 1 a-c in a combined, isolated yield of 87 %
(Scheme 2). Encouraged by these preliminary results, we
proceeded with the development of a catalytic reaction with
respect to Pd(II) and photocatalyst. With the addition of 10 mol%
of Pd(OAc)2, monoarylated (1a) and diarylated (1b) products were
Table 2. Screening of palladium catalysts and aryldiazonium salt stoichiometrya
1
detected by H NMR spectroscopic analysis, albeit in 8% yield
(Table 1, entry 1). Further investigation revealed a dependence of
reaction yield on Pd(OAc)2 loading, implying that Pd(II) turnover
was not occurring (see Supporting Information). Substantial
formation of Pd black was generated in each reaction suggesting
that the catalytic reaction may not be operating due to the
undesired electron transfer from *IrIII(ppy)3 to Pd(II) or Pd(I),
resulting in Pd(0) and effectively shutting down the reaction.
[Ar–N2]
BF4
(equiv.)
Total
Yield
[%]b
[Ru]
[mol%]
Cat.
[mol%]
Entry
Cat.
1
2
2.5
5
Pd(OAc)2
Pd(OAc)2
Pd(OPiv)2
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
10
10
10
10
15
20
15
15
15
0
1
1
25
42
3
5
1
12
red
4
5
1
31
The two-electron reduction potential of Pd(II) to Pd(0) (E1/2
 +0.951 V vs NHE)27 is sufficiently low for Pd(II) reduction to
occur. Furthermore, oxidation potential of the Pd(III) intermediate
may not be sufficient to promote electron transfer to IrIV(ppy)3
(E1/2red[IrIV/IrIII] = +0.77 V vs SCE) and regenerate IrIII(ppy)3 under
catalytic conditions. Attention shifted to the phenyl iodonium salt
4 in conjunction with [Ir(ppy)2(dtbpy)]PF6 (E1/2red[*IrIII/IrIV] = -0.96 V
vs SCE) and these gave traces of the desired products 6a and 6b.
Conversely, the use of aryldiazonium salt 5 and [Ru(bpy)3]Cl2
(E1/2red[*RuII/RuIII] = -0.81 V vs SCE) produced a mixture of mono-
and diarylated products 7a and 7b in an overall 15% yield, without
formation of Pd black precipitate. Thus, diazonium salts were
chosen for further optimization.
5
5
1
48
6
5
1
39
55 (52)c
7
5
1.5
2
8
5
38
9
0
1.5
1.5
1.5
N.D.
N.D.
N.D.
10
11
5
5d
15
[a] General conditions: MeOH (0.1 M in substrate), r.t., 16 h, 15 W CFL. [b] Yield
determined by 1H NMR spectroscopy using sulfolene as an internal standard.
[c] Isolated yield in parentheses. [d] General conditions, without light irradiation.
Q’ = 5-chloroquinoline.
Replacing Pd(OAc)2 with Pd(TFA)2 or Pd(OPiv)2 resulted in a
lower yield of arylated products (Table 2, entries 3-4) and we
reverted to screening additional reaction conditions with Pd(OAc)2.
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An observable dependence on equivalents of Pd(II) was
evidenced (Table 2 entries 2, 5-6). With an affiliated increase of
diazonium tetrafluoroborate 5 to 1.5 equivalents, mono- and
diarylated products were formed in an overall yield of 55% (Table
2, entry 7).
Furthermore, control experiments (Table 2, entries 9-11)
demonstrate that Pd(II), Ru(bpy)3Cl2 and light are essential for the
transformation.
With the establishment of the optimized conditions, we then
turned attention to the amide scope and a series of aliphatic
amides derived from carboxylic acids with α-quaternary centers
were examined (Table 3). There are two reported examples of
direct C-H arylation of a quaternary aliphatic amide, highlighting
the challenging nature of this transformation.30, 31 Selectivity for
monoarylation over diarylation was higher for sterically congested
substrates (entries 1 and 2).
Table 3. The arylation of aliphatic amides under synergistic photoredox and
palladium catalysisa
We then investigated selectivity for substrates containing β-
methyl C(sp3)-H bonds and β-methylene C(sp3)-H bonds
(substrates 10-12). Arylation of the β-methyl C(sp3)-H bonds was
exclusively observed, demonstrating high selectivity for β-methyl
C(sp3)-H bonds (entries 3-5).32 This selectivity was also observed
for the benzylic substrate (19) (entry 12). Carbocyclic rings were
compatible with the arylation reaction and longer alkyl chains,
methoxy, chloride, and phenyl groups were tolerated. It should be
noted that substrates 8–15 have not been previously studied with
C-H arylation chemistry, probably due to competitive
intramolecular C-N amidation.33-37
Entry
Substrate
Products
Yield [%]b
The scope of para-substituted aryldiazonium salts was examined
(Table 4). Electron donating and electron withdrawing
substituents were compatible with reaction conditions. The
presence of ester and halogen functionalities was also well
tolerated. Although aryl bromides have been reported to engage
in Pd(II)-catalyzed arylation of unactivated C(sp3)-H bonds at
120 °C,23 excellent chemoselectivity was noted for the brominated
derivative 26 under our conditions (Table 4, entry 7).
Table 4. Scope for the aryldiazonium saltsa
Yield
[%]b
Yield
[%]b
Entry
Product
Entry
Product
[a] General conditions: [Ar-N2]BF4 (1.5 equiv.) Pd(OAc)2 (15 mol%), Ru(bpy)3Cl2
(5 mol%), MeOH (0.1 M in substrate), r.t., 16 h, 15 W CFL [b] Isolated yields. Q’
= 5-chloroquinoline.
[a] General conditions: [p-OMePh-N2]BF4, 5 (1.5 equiv.), Pd(OAc)2 (15 mol%),
Ru(bpy)3Cl2 (5 mol%) MeOH (0.1 M in substrate), r.t., 16 h, 15 W CFL. [b]
Isolated yields. Q’ = 5-chloroquinoline.
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Likewise, aryl bromides (E1/2red = -1.76 V vs SCE) which may be
redox active under the reaction conditions, did not interfere with
the photoredox catalytic cycle. Interestingly, electron poor
diazonium salts tended to give slightly higher yields than electron
rich analogs, which contrasts with transition-metal catalyzed
C(sp3)-H arylation with aryl iodides.18, 31, 38
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Keywords: C-H Activation • Metallaphotoredox • Photoredox •
Arylation • Palladium
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COMMUNICATION
COMMUNICATION
Milena L. Czyz, David W. Lupton and
Anastasios Polyzos*
Page No. – Page No.
Auxiliary-Directed C(sp3)-H Arylation
by Synergistic Photoredox and
Palladium Catalysis
Of Earth and Light: An auxiliary-directed arylation of unactivated C(sp3)-H bonds with
synergistic photoredox and palladium catalysis is reported. This approach enables the site-
selective arylation of aliphatic amides with -quaternary centers and high selectivity for -
methyl C(sp3)-H bonds. The operationally simple method is compatible with a range of
amides, aryldiazonium salts and proceeds at room temperature. 
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