A Metallaphotoredox Strategy for the Cross-Electrophile Coupling of α-Chloro Carbonyls with Aryl Halides

Article abstract of DOI:10.1002/anie.201909072

Here, we demonstrate that a metallaphotoredox-catalyzed cross-electrophile coupling mechanism provides a unified method for the α-arylation of diverse activated alkyl chlorides, including α-chloroketones, α-chloroesters, α-chloroamides, α-chlorocarboxylic acids, and benzylic chlorides. This strategy, which is effective for a wide variety of aryl bromide coupling partners, is predicated upon a halogen atom abstraction/nickel radical-capture mechanism that is generically successful across an extensive range of carbonyl substrates. The construction and use of arylacetic acid products have further enabled two-step protocols for the delivery of valuable building blocks for medicinal chemistry, such as aryldifluoromethyl and diarylmethane motifs.

Full text of DOI:10.1002/anie.201909072

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Accepted Article
Title: A Metallaphotoredox Strategy for the Cross-Electrophile Coupling
of Alpha-Chloro Carbonyls with Aryl Halides
Authors: Tiffany Q. Chen and David William Cross MacMillan
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10.1002/anie.201909072
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COMMUNICATION
A Metallaphotoredox Strategy for the Cross-Electrophile Coupling
of -Chloro Carbonyls with Aryl Halides
Tiffany Q. Chen and David W. C. MacMillan*
Abstract: Here, we demonstrate that a metallaphotoredox-catalyzed
cross-electrophile coupling mechanism provides a unified method for
the -arylation of diverse activated alkyl chlorides, including -
chloroketones, -chloroesters, -chloroamides, -chlorocarboxylic
acids, and benzylic chlorides. This strategy, which is effective for a
wide variety of aryl bromide coupling partners, is predicated upon a
halogen atom abstraction/nickel radical-capture mechanism that is
generically successful across an extensive range of carbonyl
substrates. The construction and use of arylacetic acid products
have further enabled two-step protocols for the delivery of valuable
building blocks for medicinal chemistry, such as aryldifluoromethyl
and diarylmethane motifs.
A Broad Platform for Metallaphotoredox-Mediated α-Arylation
O
O
Ir
Ni
Br
Cl
N
Z
Z
Si•
N
aryl
α-chloro
α-arylated
carbonyl
product
halide
utilizes commercially available activated alkyl chlorides
Design Principle: Alkyl Radical via Halogen Atom Abstraction
Alpha-aryl carbonyl groups – including -aryl-esters, amides,
and ketones – are important structural motifs found widely
among medicinal agents, such as non-steroidal anti-
inflammatory drugs (NSAIDs) and naturally occurring alkaloids.[1]
Canonical methods to access these -aryl carbonyl motifs
traditionally rely on the formation and coupling of nucleophilic
enolates with electrophilic metal-aryl salts derived from
numerous aryl halide/metal catalyst combinations.[2,3] More
recently, palladium- and nickel-catalyzed cross-couplings of -
halocarbonyl electrophiles with aryl nucleophiles, such as
boronic acids or organozinc reagents, have also been
introduced.[4,5] Not surprisingly, these powerful methodologies
employ a wide array of divergent reaction conditions based on
the nature of the nucleophile/electrophile coupling partners
involved. For example, with enolate couplings, the pKa of the -
C–H bond varies significantly depending on the nature of the
carbonyl motif (e.g., 22–27 for ketones versus 30–35 for amides
in DMSO),[6] often requiring a change in the ligand/base
combination for each C=O class employed. On this basis, we
recogniz ed an opportunity to design a complementary and
unifying method for the direct -arylation of carbonyls using a
photo-mediated cross-electrophile coupling pathway. Herein,
we describe an -arylation protocol that employs -
halocarbonyls in a halogen atom abstraction/nickel radical-
capture mechanism that is generically successful across an
extensive range of carbonyl substrates.
narrow range of C–Cl BDEs for activated alkyl halides
O
O
O
Cl
Cl
Cl
NMe2
OH
OMe
77.0 kcal/mol
74.3 kcal/mol
72.1 kcal/mol
O
O
R
R
Si
Cl
R
alkyl radical
halogen atom abstraction
enables a general platform
Ir
Ni
for α-arylation
O
O
O
N
N
N
NMe2
OH
OMe
Scheme 1. Cross-electrophile coupling of -chloro carbonyls.
As highlighted in Scheme 1, our unifying strategy is founded
upon the knowledge that carbon–chlorine bond dissociation
energies (BDEs) for a wide range of -chloro carbonyls fall
within a narrow range (e.g., 74 kcal/mol for chloroacetic acid to
77 kcal/mol for chloroacetamides).[7] In addition, these C–Cl
systems are expected to have bond polarization characteristics
that are similar with respect to their influence on the kinetics of
chlorine atom transfer pathways using silyl radicals. As such, we
hypothesized that -carbonyl radical formation via irreversible
halogen atom abstraction using a silyl radical[8,9] should exhibit
similar rates for a broad range of -chloro C=O substrates.
Furthermore, the resulting -acyl radicals should readily
combine with Ni(II)aryl salts (derived from aryl halide oxidative
addition) to enable -arylation cross-coupling across a wide
array of carbonyls, providing a generically useful reaction
platform.
[*]
T. Q. Chen, Prof. Dr. D. W. C. MacMillan
Merck Center for Catalysis at Princeton University
Washington Road, Princeton, NJ 08544, (USA)
E-mail: dmacmill@princeton.edu
Homepage: http://www.princeton.edu/chemistry/macmillan/
A proposed mechanism for this -acyl cross-coupling is
detailed in Scheme 2. Excitation of photoredox catalyst
[Ir[dF(CF3)ppy]2(dtbbpy)]PF6 (1) using visible light, followed by
Supporting information can be found under xxxxx.
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10.1002/anie.201909072
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COMMUNICATION
bromopropionate in lieu of the 2-chloro analog led to
quantitative dehalogenation of the -carbonyl substrate, with no
desired product formation. Given that the rate of chlorine atom
abstraction from an activated C(sp3)–Cl bond via a (TMS)3Si•
radical is two orders of magnitude slower than the
corresponding bromine atom abstraction (e.g., k = 2.0 x 107 M-1
s-1 for benzyl chloride vs. 2.4 x 109 M-1 s-1 for benzyl bromide
silyl radical-mediated halogen atom abstraction),8b we presume
that the rate of radical formation in the latter case is too rapid to
efficiently interface with the slower kinetics of the nickel
catalytic cycle. Subsequently, a survey of silyl radical sources
revealed that a substantial increase in yield and decrease in
alkyl chloride protodehalogenation, was possible using the
O
R3SiH
R
R
Cl
Br
OMe
R
Si
– HBr
Me
R = SiMe3, SiEt3
silyl radical (4)
O
Me
Me
Ar
CO2Me
Me
OMe
OMe
NiIII
N
N
9
alkyl radical
5
O
N
fragment-coupled
Br
product
10
NiII
N
N
Ar
Nickel
bulkier,
commercially
available
tris(triethylsilyl)silane
Catalytic
Cycle
((TES)3SiH) in comparison to (TMS)3SiH (entry 5).[13] Control
experiments indicated that the photocatalyst, nickel salt, silane,
and light are all necessary for this new cross-coupling to be
operative (entries 6–9), and no products of multiple arylation
events were observed under any of the utilized conditions.
LnNiI(dtbbpy)
11
8
IrII (3)
SET
Br
LnNi0(dtbbpy)
6
Br
Photoredox
Catalytic
Cycle
Table 1. Cross-electrophile coupling optimization studies.[a]
IrIII (1)
SET
N
aryl bromide
7
CO2Me
O
Br
O
Ir
Ni
Cl
EtO
Br
EtO
base, silane
DME, rt, 8 h
MeO2C
Me
via visible light
excitation
Me
*IrIII (2)
aryl
α-arylated
α-chloro
carbonyl
product
bromide
Scheme 2. Plausible mechanism for -carbonyl arylation.
entry
yield
conditions
Si source
base
intersystem crossing, leads to the strongly oxidizing triplet
1
2
3
4
5
6
7
8
9
0.1 M
0.1 M
(TMS)3SiH
(TMS)3SiH
(TMS)3SiH
(TMS)3SiH
(TES)3SiH
(TES)3SiH
(TES)3SiH
–
LiOH
33%
48%
56%b
65%c
80%b
0%b
0%b
0%b
0%b
red
excited state (2) (E1/2 [*IrIII/IrII] = +1.21 V vs. saturated calomel
lutidine
lutidine
lutidine
lutidine
lutidine
lutidine
lutidine
lutidine
electrode (SCE) in CH3CN)[10] This photocatalyst excited state
(2) should engage bromide anion (derived from the aryl bromide
substrate) in an oxidation event (Epa = +0.80 V vs. SCE in
CH3CN)[9] to deliver an electrophilic bromine radical, which is
known to rapidly abstract a hydrogen atom from the silane Si–H
moiety.[11] The resulting silyl radical 4 should rapidly participate
in chlorine atom abstraction from the activated -carbonyl
chloride to generate electrophilic alkyl radical species 5.
Simultaneously, Ni0 complex 6 is expected to undergo oxidative
addition into aryl bromide 7 to generate the aryl–NiII intermediate
8. Oxidative capture of -acyl radical 5 would then deliver an
(alkyl)(aryl)–NiIII species (9) with the enolate being either the
carbon- or oxygen-bound nickel adduct.[12] Subsequent reductive
elimination from the carbon-bound form would then furnish the
C(sp3)–C(sp2) coupled product (10) and NiI species 11. Finally,
0.5 M
0.5 M
0.5 M
no photocatalyst
no light
no silane
no Ni
(TES)3SiH
CF3
F
–
PF6
N
Ir
t-Bu
t-Bu
Ir
N
N
Cl
Cl
N
N
F
F
(1)
Ni
Ni
t-Bu
N
t-Bu
electron transfer between reduced IrII photocatalyst
3
NiCl2•dtbppy
F
CF3
(E1/2red[IrIII/IrII] = –1.37 V vs. SCE in CH3CN)[9] and the NiI salt
(11) would reconstitute the Ni0 complex 6 and the ground-state
photocatalyst 1, completing both catalytic cycles at the same
time.
key components of cross-electrophile coupling system
SiEt3
key silyl radical (TES)3Si•
Et3Si Si
Initial studies into the new -chloro carbonyl cross-
electrophile coupling were performed with ethyl 2-
SiEt3
optimally matched
chloropropionate,
methyl
4-bromobenzoate,
halogen atom abstraction
Si•
[Ir[dF(CF3)ppy]2(dtbbpy)]PF6 1 (1 mol%), NiCl2•dtbbpy (5 mol%),
(TMS)3SiH with exposure to a 40 W blue LED light source in
DME (Table 1, entry 1, 33% yield). Increasing the reaction
concentration, photocatalyst loading, and changing the base to
2,6-lutidine proved to further benefit the overall reaction
efficiency (entries 2–4). In contrast, initial investigations using 2-
[a] Performed with photocatalyst 1 (1 mol%), NiCl2•dtbbpy (5 mol%), silane
(1.5 equiv), base (1.1 equiv), and alkyl chloride (1.5 equiv) on 0.25 mmol scale
in DME. Yields determined by 1H NMR analysis vs. mesitylene. [b] Performed
with 2.5 equiv. base. [c] Performed with 2 mol% photocatalyst 1.
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Table 2. Scope for the cross-electrophile coupling of activated -carbonyl and benzyl chlorides with aryl halides[a]
[a] Reactions performed with 1.5 equiv. activated alkyl chloride, 1.5 equiv. (TES)3SiH, and 2.5 equiv. 2,6-lutidine on 0.5 mmol scale. Yields isolated unless
otherwise noted. [b] 1 mol% nickel catalyst. [c]With 0.25 M reaction concentration. [d]With aryl chloride and tetrabutylammonium bromide (0.05 equiv., see SI for
discussion). [e] 5,5'-d(Me)bpy as ligand. [f] [Ir[d(CF3)(Me)ppy]2(dtbbpy)]PF6 as photocatalyst. [g] NaOAc as base. [h] Na2CO3 as base. [i] Yield determined using 19
F
NMR vs. 3,5-bis(trifluoromethyl)bromobenzene. [j] Using an in situ silyl masking protocol. See SI for additional substrates and for experimental details.
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With these optimized conditions in hand, we next examined
the generality of this photomediated cross-electrophile coupling
protocol. As summarized in Table 2, we have found that a broad
range of -chloro carbonyls and aryl bromides are suitable
coupling partners. For example, bromoarene moieties that
incorporate functional handles that can be subsequently
elaborated using orthogonal technologies, e.g., chloride and
boronic ester substituents (14 and 15, 72% and 58% yield,
respectively), are well-tolerated. Notably, ortho-substitution of
the aryl coupling partner can be accommodated (18, 54% yield).
Heterocyclic bromoarenes – substrates that are of significant
utility to medicinal chemists – were also found to be suitable
coupling partners, e.g., 2-, 3-, and 4-bromopyridines (S2, 25–28,
52–70% yield). As five-membered bromoarenes are traditionally
O
access to
diverse classes
of compounds
in two steps
Cl
modular
OH
R
R
carboxylic acid
Br
functional handle
F3CO
Si•
Ir
Ni
F3CO
F3CO
O
a
difficult class of electrophile for fragment-couplings in
O
general,[14] we were pleased to find that a bromopyrazole and 4-
bromothiazole were readily incorporated in useful yields (34 and
35, 53% and 45% yield, respectively). Moreover, multi-N-bearing
heteroarenes were also competent substrates (29 and 32, 58%
and 60% yield, respectively). Finally, activated aryl chlorides,
such as 2-chloropyrazine derivative 30 (68% yield) as well as a
2-chloropyridine (24, 53% yield), could be coupled in moderate
to good yields using catalytic amounts of tetrabutylammonium
bromide as a bromine radical source.
OH
OH
R = F R = H
F
F
52, 59% yield
53, 72% yield
decarboxylative
arylation
hydrodecarboxylation
Br
Ir
(PhS)2
e
±
Ni
With respect to the alkyl chloride scope, we were delighted to
find that various classes of -chloro carbonyl substrates could
be employed in good to excellent yields using this unified
manifold. For example, esters performed well using our standard
protocol, including primary -chloroesters (36, 78% yield),
secondary -chloroesters (model substrate 12, 80% yield), as
well as -chloro--butyrolactone (38, 61% yield). Additionally, -
chloroacetamide derivatives were also effective coupling
partners (41 and 42, 55% and 57% yield, respectively), including
acetamides that bear N–H moieties (43, 55% yield). Cyclic
N
CF3
F3CO
N
H
F3CO
CF3
F
F
54, 62% yieldb
55, 65% yield
ketones
such
as
-chlorocyclopentanone
and
-
Scheme 3. Linchpin catalysis sequence via photoredox.[a]
chlorocyclohexanone could also be successfully coupled (39
[a] Reactions performed on 0.5 mmol scale. Yields isolated unless otherwise
noted. [b] Yield determined by 19F NMR vs. 1,3-bis(trifluoromethyl)-5-
bromobenzene. See SI for experimental details.
and 40, 75% and 63% yield, respectively), via the application of
red
a less-oxidizing photocatalyst (51, E1/2 [*IrIII/IrII] = +1.03 V vs.
SCE in CH3CN).[15] Moreover, the implementation of 3-chloro-2-
butanone (37, 51% yield) allows arylation at the more
substituted -carbonyl position, a variant that demonstrates
complementary selectivity to the traditional palladium-catalyzed
-arylation of enolizable ketones wherein the methyl group is
favored.[16] Notably, the construction of pharmaceutically
valuable -fluorinated -aryl motifs[20a] could be readily achieved
in good yields (44 and 45, 71% and 75% yield, respectively)
using mixed 1,1-chlorofluoro- and chlorodifluoro-bearing -
carbonyls.
Intriguingly, we also found that benzylic chlorides are equally
effective as activated alkyl chloride substrates in this mechanism
(46 and 47, 73% and 54% yield, respectively). For example, a
diaryldifluoromethane benzylic linkage (47) was generated in
one step from commercially available materials using this
protocol. The capacity to rapidly incorporate fluorine-bearing
groups at a metabolically labile benzylic position via a fragment
coupling step is likely to be of interest to practitioners of
medicinal chemistry.
situ silyl masking protocol enabled the delivery of reaction
efficiencies that were comparable to the corresponding ester
substrates, while an aqueous workup allowed for quantitative
access to the aryl carboxylic acid product.
Given that
decarboxylation has emerged in recent years as a useful cross-
coupling strategy with nickel catalysis,[18,19] we envisioned that
these arylacetic acid products might be directly incorporated into
subsequent photoredox steps to rapidly furnish medicinally
relevant compounds. To showcase this concept and the
modularity of these arylacetic acid products, we developed a
series of two-step protocols that employ -chloroacids as a
linchpin catalysis substrate (Scheme 3). More specifically,
applying the title cross-electrophile coupling method, arylacetic
acids 52 and 53 can be accessed in one step from the
corresponding -chlorocarboxylic acids and aryl bromide (59%
and 72% yield, respectively). The resulting carboxylic acid
moieties of these products can then undergo further
diversification, as shown. Hydrodecarboxylation of 52 (62%
analytical yield) and decarboxylative arylation of 53 (65% yield)
Finally, we were gratified to find that, by silyl masking the
carboxylic acid moiety in situ using bis(trimethylsilyl)acetamide
or hexamethyldisilazane,[16] unprotected arylacetic acid products
can be directly accessed in one step using this new arylation
reaction–a transformation that is traditionally challenging for
palladium catalysis (48–50, 65–69% yield).[2] Leveraging this in
provide an aryl–CF2H and
a
diarylmethane motif,[20,21]
respectively, with good efficiencies using known photoredox
protocols.[19,22]
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[21] For examples of diarylmethane motifs in pharmacological compounds,
see: a) R. E. Boyd, C. R. Rasmussen, J. B. Press, R. B. Raffa, E. E.
Codd, C. D. Connelly, Q. S. Li, R. P. Martinez, M. A. Lewis, H. R.
Almond, A. B. Reitz, J. Med. Chem. 2001, 44, 863; b) J. S. Wai, M. S.
Egbertson, L. S. Payne, T. E. Fisher, M. W. Embrey, L. O. Tran, J. Y.
Melamed, H. M. Langford, J. P. Guare, L. Zhuang, V. E. Grey, J. P.
Vacca, M. K. Holloway, A. M. Naylor-Olsen, D. J. Hazuda, P. J. Felock,
A. L. Wolfe, K. A. Stillmock, W. A. Schleif, L. J. Gabryelski, S. D. Young,
J. Med. Chem. 2000, 43, 4923.
Acknowledgements
Financial support provided by the NIHGMS (R01 GM093213)
and kind gifts from Merck, Janssen, and Pfizer.
Conflicts of Interest
The authors declare no conflicts of interest.
[22] J. D. Griffin, M. A. Zeller, D. A. Nicewicz, J. Am. Chem. Soc. 2015, 137,
11340.
Keywords: -arylation • carboxylic acids • heterocycles • nickel
• photocatalysis
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Entry for the Table of Contents
COMMUNICATION
Tiffany Q. Chen, David W. C. MacMillan*
Page No. – Page No.
A Metallaphotoredox
Strategy for the Cross-
Electrophile Coupling of -
Chloro Carbonyls and Aryl
Halides
A metallaphotoredox-catalyzed cross-electrophile coupling mechanism provides a
unified method for the -arylation of diverse activated alkyl chlorides, including -
chloroketones, -chloroesters, -chlorocarboxylic acids, and -chloroamides. This
strategy is effective for a wide range of (hetero)aryl bromides under mild conditions.
The utility of this protocol is showcased in the construction of important building
blocks in medicinal chemistry, such as aryldifluoromethyl and diarylmethane motifs.
This article is protected by copyright. All rights reserved.