A general strategy for organocatalytic activation of c-h bonds via photoredox catalysis: Direct arylation of benzylic ethers

Article abstract of DOI:10.1021/ja411596q

Direct C-H functionalization and arylation of benzyl ethers has been accomplished via photoredox organocatalysis. The productive merger of a thiol catalyst and a commercially available iridium photoredox catalyst in the presence of household light directly affords benzylic arylation products in good to excellent yield. The utility of this methodology is further demonstrated in direct arylation of 2,5-dihydrofuran to form a single regioisomer.

Full text of DOI:10.1021/ja411596q

Communication
pubs.acs.org/JACS
A General Strategy for Organocatalytic Activation of C−H Bonds via
Photoredox Catalysis: Direct Arylation of Benzylic Ethers
Katrine Qvortrup, Danica A. Rankic, and David W. C. MacMillan*
Merck Center for Catalysis, Princeton University, Princeton, New Jersey 08544, United States
S
* Supporting Information
ABSTRACT: Direct C−H functionalization and arylation
of benzyl ethers has been accomplished via photoredox
organocatalysis. The productive merger of a thiol catalyst
and a commercially available iridium photoredox catalyst
in the presence of household light directly affords benzylic
arylation products in good to excellent yield. The utility of
this methodology is further demonstrated in direct
arylation of 2,5-dihydrofuran to form a single regioisomer.
unctionalization of sp3 C−H bonds in a predictable,
F
selective, and efficient manner has become a central
challenge in modern organic chemistry.1 In this context, our
laboratory recently introduced a unique activation mode that
enables the direct arylation of α-methylene amines via visible
light photoredox catalysis (eq 1).2 This strategy relies on the
Figure 1. Photoredox strategy toward diaryl alkyl ethers.
dissociation energies (BDEs),4 hydrogen-atom transfer (HAT)
exchange constants,5 and oxidation potentials) that are
predictable across a wide range of organic structure types. As
shown in Figure 1, we postulated that thiol organocatalysts
should undergo proton-coupled electron transfer (PCET)
oxidation6 in the presence of photoexcited catalysts to generate
electrophilic R−S• radicals.7 These transiently formed open-shell
thiyls should selectively serve to abstract H• from substrate
partners that contain C−H bonds, which are both weak and
hydridic based on the confluence of two known physical
constants: (a) a low C−H BDE and (b) a high HAT exchange
constant.8 Moreover, the seminal studies by Roberts in the 1990s
demonstrated the remarkable utility of electrophilic thiyl systems
for H• abstraction within traditional radical-based reactions.9 On
this basis, we hoped to provide a C−H functionalization
mechanism that is amenable to a broad range of organic subunits
including benzylic, allylic, amine, or oxygen-bearing methyl,
coupling of two catalytically generated radicals: an arene radical
anion formed by photocatalytic reduction of an arylnitrile, and a
nucleophilic α-amino radical formed via oxidation and
deprotonation of an N-phenylamine. A remarkable feature of
this activation mode is the capacity for regioselective C−H
arylation adjacent to electron-rich N-phenylamines in the
presence of other moieties that have similar or weaker C−H
bond strengths (including other α-amino methylene groups). As
exemplified in eq 1, this oxidation-potential-gated mechanism
allows for predictive and selective C−H bond functionalization
of α-CH2-N systems via the judicious selection of nitrogen
protecting groups.3
Recently, we sought to broadly expand the classes of organic
molecules that will participate in photoredox-mediated C−H
activation. More specifically, we hoped to introduce a new
photoredox−organocatalytic C−H functionalization mechanism
that exploits several established physical properties (e.g., bond
Received: November 13, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja411596q | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 1. Proposed Catalytic Cycles for Benzylic C−H
Arylation
Table 1. Initial Studies toward Benzylic C−H Arylation
a
entry
thiol catalyst
solvent
additive
none
yield (%)
1
11
11
11
11
12
13
14
13
13
13
13
13
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMSO
DMF
14
32
25
19
44
55
48
68
72
16
77
31
2
octanal
pivaldehyde
benzaldehyde
octanal
octanal
octanal
octanal
octanal
none
3
4
5
6
7
8
9
10
11b
12
acetone
DMA
octanal
none
DMA
a
Yield determined by 1H NMR using 1-bromo-3,5-bis-
b
(trifluoromethyl)benzene as the internal standard. Isolated yield.
methylenes, or methines (within acyclic or cyclic frameworks).
Furthermore, we proposed that this C−H oxidation step would
be electronically balanced with a photocatalyst-mediated
reduction of an accompanying arylcyano substrate to generate
an arene radical anion (redox-neutral mechanism). Coupling of
the two catalytically generated organic radicals would then
provide a general pathway to directly introduce aromatic and
heteroaromatic rings onto a diverse range of organic
substructures (using visible light as the driving force).10 Here
we describe the successful execution of these ideals and present a
new synergistic catalysis approach to the direct arylation of
benzylic and allylic ethers with cyanoaromatics via the
combination of photoredox and organocatalysis (eq 2). As
exemplified in Figure 1, bis-benzylic oxyalkyl groups are a
prominent structural motif found in pharmaceutically active
compounds,11 complex natural products,11 and asymmetric
catalysts.12 As such, we expect that this new C−H bond arylation
strategy will find broad application across a variety of fields that
rely on organic molecule construction.
facilitate efficient formation of electrophilic thiyl radical 7 via a
concerted PCET event.17 Based on the BDEs of the various
catalysts and substrates involved in this reaction (e.g., methyl 2-
mercaptoacetate S−H BDE = 86.8−87.2 kcal/mol),18 we
hypothesized that 7 should readily engage in a HAT reaction
with benzyl ether substrate 8 (e.g., benzyl methyl ether αC−H
BDE = 85.8 kcal/mol)19 to regenerate the thiol catalyst while
forming the corresponding α-benzyl ether radical 9. At this stage
we presumed that a radical−radical coupling reaction between
the intermediates 9 and 4 would then represent the key bond-
forming step prior to rapid elimination of cyanide to form the
desired arylated benzyl ether product 10. It should be noted that,
in all transformations involving radical anions derived from
cyanoaromatics (such as 4), we have not observed a substrate
homodimerization coupling (a step that we expect would be
reversible). On this basis, we hypothesized that benzylic radical−
radical anion coupling would predominate to generate the
desired product. Although we postulate a PCET mechanism, we
recognize that a stepwise pathway could also be operative,
wherein a thiol anion will undergo electron transfer with 5 to
generate the thiyl-activated catalyst 7. This alternative mecha-
nism would require a thiol deprotonation step ahead of the
oxidation event.
Evaluation of the proposed tandem catalysis strategy was first
examined with benzyl methyl ether, K2HPO4, cysteine (11),
Ir(ppy)3, a 26 W fluorescent lamp, and 1,4-dicyanobenzene as
the arene coupling partner. As shown in Table 1, initial
experiments revealed that the proposed C−H functionalization
arylation was indeed possible (entry 1, 14% yield). Moreover, we
serendipitously found in early studies that the presence of an
aldehyde additive (octanal) had a beneficial effect on the reaction
efficiency, presumably sequestering the cyanide anion formed
during the course of the arylation step (entry 2, 32% yield). With
respect to the HAT catalyst, we found methyl 2-mercaptoacetate
(13) to be the most suitable, delivering the desired benzhydryl
ether in 55% yield (entry 6). Next we determined that solvent
selection had a significant influence on the coupling yield, with
The specific mechanistic details of our proposed benzyl ether
C−H arylation are outlined in Scheme 1. Irradiation of tris(2-
phenylpyridinato-C2,N)iridium(III) [Ir(ppy)3] (1) by visible
light (for example, a household light bulb) at room temperature
produces a long-lived (1.9 μs) photoexcited state, *IrIII(ppy)3
IV/ III
(2). 2 is a strong reductant (E
*
1/2
= −1.73 V vs SCE in
CH3CN)13 and could undergo single-electron transfer (SET)
with an electron-deficient arene, such as 1,4-dicyanobenzene (3,
Er1e/d2 = −1.61 V vs SCE in CH3CN),14 to afford the corresponding
arene radical anion (4) and oxidized photocatalyst IrIV(ppy)3
(5). We expected that the oxidation potentials of typical thiols
(E = +0.85 V vs SCE (cysteine))15 should render electron
red
1/2
13
IV/III
1/2
transfer to 5 (E
= +0.77 V vs SCE) inefficient. Similarly,
thiols are weakly acidic (e.g., pKa = 9.35 (methyl L-cysteinate)
and 8.04 (methyl 2-mercaptoacetate)),16 requiring strong bases
to generate significant concentration of thiol anions. However,
we anticipated that the joint action of a suitable base and
electron-deficient photocatalyst 5 on the thiol catalyst 6 could
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Journal of the American Chemical Society
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Table 2. Organocatalytic C−H Activation: Aryl Ether
Table 3. Organocatalytic C−H Activation: Cyanoarene
a b
,
a b
,
Scope
Scope
a
b
Yield of isolated material. See SI for experimental details.
c
Regiomeric ratios (rr) determined by 1H NMR (major isomer is
d
e
f
g
shown; see SI for minor isomer). 2:1 rr. 2:1 rr. 1.4:1 rr. 3 equiv of
K2HPO4 was used. Na2CO3 was used as base. DMA/DMSO (1:1)
was used as solvent.
h
i
without formation of the corresponding aldehyde or ketone
products (entries 4−6, 14−16, 70−77% yield). Intriguingly, we
have found that the octanal additive plays a critical role with such
benzylic alcohol substrates. Specifically, 1H NMR studies of the
coupling of benzyl alcohol with 1,4-dicyanobenzene clearly
demonstrate the reversible formation of a hemiacetal inter-
mediate from the substrate alcohol and octanal under our
standard reaction conditions. These investigations suggest that
transient acetol formation is required for selective C−H
functionalization, as control experiments, performed without
aldehyde additive, led exclusively to benzyl alcohol oxidation in
lieu of aryl coupling (e.g., benzaldehyde from benzyl alcohol).
This mechanistic bifurcation as a function of acetol vs alcohol
incorporation seems consistent with the capacity of benzylic
alcohol radicals to undergo a rapid deprotonation−oxidation
sequence that is not available to the corresponding acetol-bearing
radical. Importantly, we have also demonstrated the utility of this
new activation mode to allow C−C bond formation at highly
sterically congested centers, as highlighted with methine-bearing
alcohol substrates (entries 5, 14−16). In each case, fully
substituted tertiary oxy stereocenters are formed with excellent
levels of efficiency (entries 5, 14−16, 70−75% yield). The broad
scope of this arylation methodology was further demonstrated
using a range of heteroaromatic-containing ethers. Pyridines,
furans, and thiophenes all undergo selective C−H arylation in
a
b
c
Yield of isolated material. See SI for experimental details. 2 equiv of
d
Na2CO3 was used as base. 2 equiv of K2HPO4 was used.
DMA proving to be the optimal medium (entry 11, 77% yield).
As anticipated, control experiments established the requirement
of both the organocatalyst and the photocatalyst, as no desired
reaction was observed in the absence of light, Ir(ppy)3, or thiol.
With the optimized conditions in hand, we next sought to
define the scope of the benzyloxy coupling partner. As revealed in
Table 2, a broad array of benzyl alkyl ethers can serve as
competent substrates, including cyclic analogues, such as
phthalan (entry 7, 71% yield) and isochroman (entry 8, 70%
yield). Notably, the use of dibenzyl ethers led to monoarylation
adducts exclusively (entry 3, 80% yield), a mechanistic selectivity
that is not readily rationalized at the present time. With respect to
widespread application, it is important to note that this activation
mode can also be used for the arylation of both benzyl silyl ethers
(entries 10−13, 61−74% yield) and MEM-protected benzyl
alcohols (entry 9, 62% yield). We also found that these mild
redox conditions are compatible with a wide range of functional
groups, including acetals, alkyl chlorides, alcohols, and amines
(entries 9, 14−16, 62−75% yield). Perhaps most remarkable is
the capacity of benzyl alcohols to undergo selective C-arylation
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Journal of the American Chemical Society
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high yield (entries 11−13, 61−73% yield), a notable feature with
respect to medicinal agent synthesis and applications.
K.Q. thanks the Carlsberg Foundation for a postdoctoral
fellowship.
We next examined the structural diversity of the arene
coupling partner in this synergistic catalysis protocol. As shown
in Table 3, a range of cyanobenzenes and cyanoheteroaromatics
have been found to be suitable substrates. Moreover, a variety of
ortho-, meta-, and para-substituted terephthalonitriles readily
couple to the activated benzylic silyl ether substrate (entries 1−3,
6, and 7, 41−72% yield). When unsymmetrical dicyanoarenes
were used, mixtures of regioisomers were observed (entries 2, 3,
and 6). In addition, benzonitriles substituted with sulfones or
esters are tolerated as radical anion coupling partners (entries 4
and 5, 55−71% yield). In recognizing the prevalence of
heteroaromatic rings in pharmaceutical compounds, we were
delighted to find that a range of substituted cyanopyridines as
well as azaindole (an important indole isostere) underwent
addition to the silyl benzyl ether with high efficiencies (entries
8−12, 51−86% yield).
A defining attribute of this new C−H arylation protocol is its
potential to provide direct access to a broad array of C−H
arylated products. One particular challenge is the selective C−H
functionalization of dihydrofuran, a ring system often found in
the molecular skeletons of naturally occurring and biologically
active substances.20 A major mechanistic concern, however, was
the possible formation of two regioisomeric arylation products
after the C−H activation step. As shown in eq 3, exposing 2,5-
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
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AUTHOR INFORMATION
Corresponding Author
dmacmill@princeton.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support was provided by the NIHGMS (R01
GM103558-01) and kind gifts from Merck, Amgen, and AbbVie.
■
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dx.doi.org/10.1021/ja411596q | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX