Metallaphotoredox Difluoromethylation of Aryl Bromides

Article abstract of DOI:10.1002/anie.201807629

Herein, we report a convenient and broadly applicable strategy for the difluoromethylation of aryl bromides by metallaphotoredox catalysis. Bromodifluoromethane, a simple and commercially available alkyl halide, is harnessed as an effective source of difluoromethyl radical by silyl-radical-mediated halogen abstraction. The merger of this fluoroalkyl electrophile activation pathway with a dual nickel/photoredox catalytic platform enables the difluoromethylation of a diverse array of aryl and heteroaryl bromides under mild conditions. The utility of this procedure is showcased in the late-stage functionalization of several drug analogues.

Full text of DOI:10.1002/anie.201807629

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Angewandte
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Accepted Article
Title: Metallaphotoredox Difluoromethylation of Aryl Bromides
Authors: Vlad Bacauanu, Sébastien Cardinal, Motoshi Yamauchi,
Masaru Kondo, David Fernández Fernández, Richard Remy,
and David William Cross MacMillan
This manuscript has been accepted after peer review and appears as an
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201807629
Angew. Chem. 10.1002/ange.201807629
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10.1002/anie.201807629
Angewandte Chemie International Edition
COMMUNICATION
Metallaphotoredox Difluoromethylation of Aryl Bromides
Vlad Bacauanu+, Sébastien Cardinal+, Motoshi Yamauchi+, Masaru Kondo, David F. Fernández,
Richard Remy, and David W. C. MacMillan*
Abstract: Herein we report a convenient and broadly applicable
Incorporation of fluorinated moieties – broadly studied
strategy for the difluoromethylation of aryl bromides via
metallaphotoredox catalysis. Bromodifluoromethane, a simple and
F
X
CF3
commercial alkyl halide, is harnessed as an effective source of
difluoromethyl radical via silyl radical-mediated halogen abstraction.
The merger of this fluoroalkyl electrophile activation pathway with a
aryl halide
CF3–arene
fluoroarene
dual
nickel/photoredox
catalytic
platform
enables
the
difluoromethylation of a diverse array of aryl and heteroaryl bromides
under mild conditions. The utility of this protocol is showcased in the
late-stage functionalization of several drug analogues.
Installation of difluoromethyl group – emerging area
N
N
Increased metabolic stability
CF2H
Within the realm of drug design, the chemoselective
incorporation of fluorine or polyfluorinated alkyl substituents is a
powerful and widely employed tactic to enhance binding
selectivity, elevate lipophilicity, and/or circumvent metabolism
issues arising from in vivo C–H bond oxidation.[1,2] While the
implementation of the trifluoromethyl group (–CF3) has been
widely studied in medicinal chemistry, the relatively
underexplored difluoromethyl group (–CF2H) has recently
garnered significant attention by virtue of its capacity to serve as
a lipophilic hydrogen bond donor and to act as a bioisostere for
thiol and alcohol functionalities.[3,4] Modern approaches to the
direct and selective introduction of the difluoromethyl group into
aromatic rings typically rely on the metal-catalyzed cross-
coupling of aryl electrophiles or nucleophiles with an appropriate
CF2HR reagent, often designed for facile transmetallation or
formal oxidative addition by the metal catalyst.[5,6] Given the
pronounced practical significance of this emerging area, one of
the greatest challenges is the rendering of readily available
CF2H sources as effective difluoromethylating agents in cross-
coupling. Crucially, this coupling platform must display high
functional tolerance and amenability towards medicinally
relevant scaffolds. As such, the development of novel,
Lipophilic hydrogen bond donor
Bioisostere of thiol and alcohol
N
Me
F
N
NMDAR antagonist
Previous work – silane-mediated cross-electrophile coupling
O
Ir
Ni Si•
H2N
Br
H2N
O
Br
N
N
ꢀꢁmild conditions
ꢀꢁbroad arene scope
ꢀꢁunique mechanism
Can we engage CF2H electrophiles via a silyl radical platform?
Si•
TMS
Si TMS
TMS
H
Br
F
H
F
F
F
halogen
abstraction
commercially
available
CF2H
radical
Silane-Mediated Difluoromethylation of Aryl Bromides
operationally
convenient,
yet
general
routes
to
Ir
Ni Si•
Me
Br
Me
CF2H
F
F
difluoromethylarenes and heteroarenes remains of high interest.
Metallaphotoredox catalysis has emerged in recent years as
a valuable platform for the production of previously elusive
C(sp3)–C(sp2) bonds, thereby enabling access to novel
constructs of importance in medicinal chemistry.[7] One example
from our laboratory involves a dual nickel/photoredox-catalyzed
cross-electrophile coupling protocol, wherein the union of a
broad range of aryl and alkyl halides is accomplished at room
temperature using visible light irradiation.[8] A unique design
feature of this mechanism is the implementation of silyl radical-
mediated abstraction of bromine atoms from C(sp3)–Br bonds,[9]
a pathway that allows alkyl halides to readily participate in metal-
Br
H
N
N
aryl bromide CF2H source
difluoromethylarene
Figure 1. Silane-mediated difluoromethylation of aryl bromides.[10]
catalyzed cross-couplings. Most notably, the scope of these
silane-mediated cross-electrophile couplings has been
determined to be extensive with respect to both arene
substitution pattern and functional group tolerance,
a
characteristic that has led to widescale adoption by medicinal
chemistry groups within the pharmaceutical sector.[11]
[*]
V. Bacauanu[+], S. Cardinal[+], M. Yamauchi[+], Masaru Kondo, David
F. Fernández, Richard Remy, Prof. Dr. D. W. C. MacMillan
Merck Center for Catalysis at Princeton University
Washington Road, Princeton, NJ 08544, (USA)
E-mail: dmacmill@princeton.edu
Inspired by the success of this silyl radical-mediated cross-
electrophile coupling, we wondered if an analogous strategy
could serve as the basis for a general and direct synthesis of
Homepage: http://www.princeton.edu/chemistry/macmillan/
These authors contributed equally to this work.
difluoromethylarenes.
Specifically,
we
considered
[+]
bromodifluoromethane, a simple and commercial alkyl halide, as
a potential source of CF2H radical via a previously unexplored
halogen abstraction step. Crucially, this pathway would be
Supporting information can be found under xxxxx.
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10.1002/anie.201807629
Angewandte Chemie International Edition
COMMUNICATION
species 14. Finally, single electron transfer between 14 and
reduced photocatalyst 4 would simultaneously regenerate low-
valent nickel catalyst 9 and ground-state photocatalyst 1.
(TMS)3SiH
– HBr
TMS
TMS
Br
Br
Si TMS
F
H
F
We began our investigation by examining three separate aryl
halide precursors in the proposed difluoromethylation protocol:
namely, cyanopyridine 16, as well as trifluoromethyl- and fluoro-
substituted bromobenzenes (17 and 18, respectively; see Table
1). For each substrate, we employed photocatalyst 1, nickel
catalyst NiBr2•dtbbpy (15), commercially available (TMS)3SiH,
2,6-lutidine as the base, DME as solvent, and blue LEDs as the
photon source. In the case of the electron-deficient heteroaryl
bromide 16, optimal levels of reaction efficiency were observed
using excess CF2HBr (4 equiv., 77% yield). Remarkably,
however, with the less electron-deficient CF3-arene 17, the use
of 2 equivalents of bromodifluoromethane gave a superior
outcome, while electron-neutral para-fluoro substrate 18
achieved the highest yield with a 1:1 stoichiometry of arene to
CF2HBr.[17] Perhaps more surprising, the use of a large excess
of bromodifluoromethane (4 equiv.) led to dramatically
diminished yields in the latter two cases.[18,19]
5
6
7
8
TMS
Silyl Radical-Mediated
F
TMS Si Br
TMS
+
H
F
Generation of CF2H Radical
difluoromethyl
radical
CF2H
NiIII
N
N
Ar
12
Me
CF2H
Br
N
NiII
N
N
Ar
Nickel
13
11
Catalytic
Cycle
CF2H–arene
(dtbbpy)NiILn
14
IrII (4)
(dtbbpy)Ni0Ln
SET
To rationalize these trends, we propose that when less
electron-deficient arenes are employed, the catalytic nickel
Br
9
5
Photoredox
Me
Br
Table 1. Effect of stoichiometry of bromodifluoromethane.[a]
IrIII (1)
Catalytic
Cycle
SET
N
Key Components for Difluoromethylation System
aryl bromide 10
–
Br
CF3
–
PF6
tBu
tBu
F
Br
Br
3
N
N
Ir
Ni
*IrIII (2)
tBu
tBu
15
N
Ir
visible light excitation
N
N
F
F
1
Ni
Si•
Scheme 1. Proposed mechanism for metallaphotoredox difluoromethylation.
N
TMS
TMS
Si TMS
6
F
CF3
thermodynamically feasible given that the HF2C–Br bond (bond
dissociation energy of 69 kcal/mol) is far weaker than the Si–Br
bond in a typical abstraction product (e.g., 96 kcal/mol for
Me3Si–Br).[12] Moreover, given the electron-rich character of the
silyl radical, we surmised that halogen abstraction from
bromodifluoromethane would be polarity matched and hence
kinetically faster than from previously utilized alkyl bromide
substrates.[13] Herein we disclose the successful implementation
of these ideals and present a mild, convenient and broadly
applicable metallaphotoredox-catalyzed difluoromethylation of a
wide array of aryl and heteroaryl halides.
1 mol% photocatalyst 1
5 mol% NiBr2•dtbbpy (15)
(TMS)3SiH, 2,6-lutidine
CF2H
Br
F
F
Br
H
R
X
R
X
DME
30 ºC, 18 h
aryl halide
CF2H source
CF2H–arene
CF2H
CF2H
CF2H
stoichiometry
of CF2HBr
F3C
NC
N
F
1.0 equiv.
2.0 equiv.
4.0 equiv.
74%
16%
3%
52%
72%
77%
77%
84%
56%
The proposed mechanism for this silane-mediated
difluoromethylation is shown in Scheme 1. Visible-light excitation
of IrIII photocatalyst [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (1)[14] is known
*
to generate the excited-state IrIII complex 2 which can readily
with TMS–CF2Br[b]
31%
30%
27%
oxidize bromide anion (3) (E1/2red [*IrIII/IrII] = +1.21 V vs. saturated
red
calomel electrode (SCE) in MeCN; E1/2 [Br•/Br–] = +0.80 V vs.
SCE in DME).[8,15] The resulting bromine radical (5) can
participate in hydrogen atom transfer with (TMS)3SiH to yield the
nucleophilic silyl radical 6.[13] Bromine abstraction from
bromodifluoromethane (7) by open shell silyl species 6 would
then afford the key difluoromethyl radical (8). Concurrently with
the photoredox catalytic cycle, Ni0 catalyst 9[16] is expected to
undergo facile oxidative addition into aryl bromide 10 to
generate NiII–aryl intermediate 11. Trapping of difluoromethyl
radical (8) would then generate the corresponding aryl–NiIII–
CF2H complex 12, which upon reductive elimination should
afford the desired difluoromethylarene product 13 and NiI
Faster oxidative addition into ArBr
Br CF2H
Br
Br
Br
Ni
NC
N
F3C
F
N
N
CF2H
X
Ni
16
17
Competitive addition into CF2HBr
18
unproductive
[a] Performed with photocatalyst 1 (1 mol%), NiBr2•dtbbpy (5 mol%), aryl
bromide (0.2 mmol), CF2HBr (1–4 equiv.), (TMS)3SiH (1.05 equiv.), and 2,6-
lutidine (2 equiv.) in DME for 18 h. Yields were obtained via 19F NMR analysis.
[b] See Supporting Information for experimental details.
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10.1002/anie.201807629
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COMMUNICATION
Table 2. Scope of aryl halide electrophiles in silyl radical-mediated difluoromethylation using bromodifluoromethane as a CF2H source[a]
CF3
–
PF6
F
1 mol% Ir photocatalyst 1
Br
CF2H
tBu
N
Ir
F
F
1
5 mol% NiBr2•dtbbpy
R
R
N
N
F
F
Br
H
X
X
Ir
(TMS)3SiH, 2,6-lutidine
DME, blue LEDs, 18 h
tBu
N
aryl bromide
1–2 equiv.
difluoromethylarene
F
CF3
arenes
CF2H
CF2H
CF2H
CF2H
CF2H
CF2H
EtO2C
EtOC
NC
MeO2S
F
Me
19, 83% yield
20, 81% yield
21, 75% yield
22, 83% yield
23, 80% yieldb
24, 67% yieldb
CF2H
CF2H
CF2H
CF2H
CF2H
CF2H
HO
Me Me
pinB
BocHN
MeO
Cl
TMS
25, 74% yield
26, 55% yieldb
27, 80% yieldb
28, 85% yieldb
29, 71% yield
30, 75% yield
Boc
EtO2C
CF2H
BocHN
CF2H
CF2H
CF2H
CF2H
CF2H
N
N
CN
Me
Me
N
31, 78% yield
32, 73% yield
33, 73% yield
34, 60% yieldb,c,d
35, 69% yield
36, 75% yield
heteroarenes
CF2H
MeO2C
CF2H
Me2N
CF2H
CF2H
NC
CF2H
CF2H
N
N
N
N
NC
N
N
F3C
37, 54% yieldb,e
38, 71% yield
39, 84% yield
40, 75% yieldf
41, 69% yield
42, 46% yieldb,g
N
N
CF2H
CF2H
CF2H
N
CF2H
CF2H
Cl
N
CF2H
N
N
N
N
N
N
N
N
43, 76% yielde
44, 78% yielde
45, 65% yieldb
46, 66% yieldb
47, 60% yieldh,i
48, 61% yielde
Me
CF2H
Boc
N
CF2H
O
N
N
N
N
N
Ph
CF2H
Ac
CF2H
N
CF2H
N
N
CF2H
N
S
S
N
Me
CO2Et
N
Me
O
Ac
49, 51% yieldb,c,j
50, 75% yieldk
51, 70% yieldk
52, 55% yieldf,l
53, 57% yieldm
54, 45% yieldk
[a] Isolated yields unless otherwise indicated. Performed with photocatalyst 1 (1 mol%), NiBr2•dtbbpy (5 mol%), aryl bromide (0.5 mmol), CF2HBr (1–2 equiv.),
(TMS)3SiH (1.05 equiv.), and 2,6-lutidine (2 equiv.) in DME for 18 h. See Supporting Information for experimental details and additional examples. [b] Yield
determined by 19F NMR (average of two runs). [c] 10 mol% Ni catalyst. [d] 42 h. [e] Na2CO3 as base. [f] 3 equiv. CF2HBr. [g] LiOH as base. [h] 2 mol% Ni catalyst.
[i] Acetone as solvent. [j] N,N-Diisopropylethylamine as base. [k] Quinuclidine as base. [l] K2CO3 as base. [m] DABCO as base.
species can undergo oxidative addition with the electron-
deficient CF2HBr reagent at a rate competitive with the aryl
bromide insertion step.[20] Moreover, we believe that such a
pathway would be deleterious, given that the resultant NiII–CF2H
complex would be unlikely to participate in further oxidative
addition steps with the aryl bromide.[21] As such, for more
electron-rich or hindered aryl halides that undergo relatively slow
oxidative addition with nickel, the issue of competitive CF2HBr
insertion is mitigated by employing lower concentrations of the
CF2H source. However, at the other end of the electronic
spectrum, higher stoichiometry of CF2HBr ensures that the
silane-mediated generation of CF2H radical occurs in
synchronicity with the rapid oxidative addition of the nickel
catalyst into highly electron-deficient arenes (e.g., 16).[22]
With optimized conditions in hand, we next evaluated the
scope of the aryl bromide component (Table 2). Notably,
substrates bearing electron-withdrawing groups, such as esters,
ketones, nitriles, and sulfones, generated the respective
difluoromethyl adducts in high yields (19–22, 75–83% yield). In
accord with our optimization studies, electron-neutral and
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10.1002/anie.201807629
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COMMUNICATION
O
NH2
O
Br
S
OMe
O
Br
Br
O
O
N
HN
N
N
N
O
N
Me
F3C
O
N
S
MeO
N
O
CO2Me
Me
O
Br
MeO
sulfadimethoxine analogue
celecoxib analogue
indometacin analogue
pomalidomide analogue
O
S
NH2
O
CF2H
O
OMe
CF2H
CF2H
O
O
N
N
N
N
N
HN
Me
O
F3C
O
N
S
MeO
N
O
CO2Me
Me
MeO
O
CF2H
55, 66% yield
56, 64% yield
57, 82% yield
58, 74% yield
Ir
Ni Si•
Scheme 2. Application of difluoromethylation: late-stage functionalization for the expedient synthesis of difluoromethyl analogues of pharmaceutical agents.
electron-rich bromoarenes performed well using lower loadings
of CF2HBr (23–26, 55–80% yield). As a useful demonstration of
the mild conditions and functional group tolerance of this new
coupling protocol, we found that aryl electrophiles bearing
chloride and boronate ester groups can be readily implemented
(27 and 28, 80% and 85% yield, respectively). This
characteristic was further underscored by the performance of
substrates containing alcohol and silylalkyne moieties (29 and
30, 71% and 75% yield, respectively). Meta- and ortho-
substituted aryl bromides were also shown to be competent
electrophiles in this transformation (31–34, 60–78% yield).
We next turned our attention to the scope of heteroaryl
halides, a critical group of substrates with respect to the utility of
this protocol in the medicinal chemistry sector. As shown in
Table 2, a broad range of 2-, 3-, and 4-bromopyridines were
found to be suitable coupling partners (37–42, 46–84% yield).
Moreover, bromoquinolines afforded the desired products with
good efficiency (43 and 44, 76% and 78% yield, respectively).
Multi-nitrogen-bearing heteroaryls, such as pyrimidines,
pyrazines and quinoxalines, have long been viewed as
problematic substrates for a range of cross-coupling reactions.
As such, it was notable that all of these heteroaryl ring classes
containing
derivatives
of
sulfadimethoxine,
celecoxib,
indometacin, and pomalidomide were obtained in good to high
yields from the aryl bromide precursors (55–58, 64–82% yield).
These results further highlight the real-world utility of this
metallaphotoredox technology with respect to tolerance of
medicinally relevant functionality, such as sulfonamides, imides,
electron-rich pyrimidines, pyrazoles, and indoles.
In
conclusion,
we
have
developed
a
novel
metallaphotoredox platform for the difluoromethylation of a
broad range of aryl and heteroaryl halides. This protocol
employs commercially available bromodifluoromethane as a
direct source of CF2H radical via a silyl radical-mediated halogen
abstraction pathway previously unexplored for fluoroalkyl
electrophiles within the realm of cross-coupling. Given its distinct
convenience and broad applicability to pharmaceutically relevant
scaffolds, we expect this method to be widely adopted within the
synthetic and medicinal chemistry community.
Acknowledgements
Financial support provided by the NIHGMS (R01 GM103558-05),
and kind gifts from Merck, BMS, Pfizer, Janssen, and Eli Lilly.
S.C. gratefully thanks the Fonds de Recherche du Québec –
Nature et Technologies (FRQNT) for a postdoctoral fellowship
(#198859). M.Y. thanks Daiichi Sankyo Co., Ltd. for funding.
M.K. thanks the Japan Society for the Promotion of Science for
Grant-in-Aid for JSPS Fellows. D.F.F. thanks the MINECO for a
fellowship (BES-2014-068776 and EEBB-I-17-11925). R.R.
thanks the Swiss National Science Foundation for a postdoctoral
fellowship (P2FRP2-178091). The authors acknowledge C. Liu
for assistance in preparing the manuscript.
were
readily
converted
to
their
corresponding
difluoromethylarenes (45–48, 60–66% yield). In the same
context, five-membered bromoarenes were also found to be
competent electrophiles. In particular, difluoromethyl derivatives
of pyrazole, indazole, benzimidazole, and caffeine were
obtained in good to high yields (49–52, 51–75% yield). Perhaps
most notable, bromothiazoles, a traditionally difficult cross-
coupling class,[23] were readily transformed to their
corresponding CF2H adducts (53 and 54, 57% and 45% yield,
respectively).
Keywords: difluoromethylation
•
photoredox catalysis
•
Finally, given the pharmaceutical relevance of the CF2H
group, we sought to showcase the utility of our protocol in the
late-stage difluoromethylation of analogues of several known
medicinal agents (Scheme 2). Specifically, difluoromethyl-
heterocycles • nickel • fluorine
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10.1002/anie.201807629
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COMMUNICATION
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[3]
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[14]
[15]
[16]
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4,4¢-di-t-Bu-2,2¢-bipyridine.
M. S. Lowry, J. I. Goldsmith, J. D. Slinker, R. Rohl, R. A. Pascal, G. G.
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[18]
The fluoro substituent has a Hammett sp value of –0.06. See: C.
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Control experiments with aryl halide 17 revealed that light,
photocatalyst, nickel, and silane are all required for the success of the
transformation (<1% yield in the absence of at least one component).
Reduction of CF2HBr to CF2H2 was observed when the nickel catalyst
was excluded, an observation that supports the capacity of the silyl
radical to engage in halide abstraction with CF2HBr. See Supporting
Information for details.
[19] The
implementation
of
commercially
available
(bromodifluoromethyl)trimethylsilane as
a
CF2H source was also
possible, but not pursued due to lower reaction efficiency (Table 1).
[20] For reports of proposed NiI catalytic intermediates undergoing formal
oxidative
addition
into
bromodifluoromethane
and
[7]
For reviews on metallaphotoredox catalysis, see: a) K. L. Skubi, T. R.
Blum, T. P. Yoon, Chem. Rev. 2016, 116, 10035; b) M. D. Levin, S.
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P. Zhang, M. H. Shaw, R. W. Evans, D. W. C. MacMillan, Nat. Rev.
Chem. 2017, 1, 0052.
chlorodifluoromethane, see: a) X.-P. Fu, Y.-L. Xiao, X. Zhang, Chin. J.
Chem. 2018, 36, 143; b) ref 6i.
[21] For experimental observations consistent with the deactivation of the
nickel catalyst (i.e., poor conversion of starting material), see
Supporting Information.
[8]
[9]
P. Zhang, C. C. Le, D. W. C. MacMillan, J. Am. Chem. Soc. 2016, 138,
8084.
[22] In support of the dramatic differences among rates of oxidative addition,
competition experiments between 16 and 18 revealed that at early
reaction time points the difluoromethyl product from electron-deficient
18 is obtained in up to 45% yield, whereas electron-neutral bromoarene
16 remains entirely unreacted. See Supporting Information.
[23] M. Su, S. L. Buchwald, Angew. Chem. Int. Ed. 2012, 51, 4710.
a) M. Ballestri, C. Chatgilialoglu, K. B. Clark, D. Griller, B. Giese, B.
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10.1002/anie.201807629
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Metallaphotoredox Difluoromethylation of Aryl Halides
Vlad Bacauanu, Sébastien Cardinal,
Motoshi Yamauchi, Masaru Kondo,
David F. Fernández, Richard Remy, and
David W. C. MacMillan*
CF2H
CF2H
HO
Me Me
N
N
F
F
Br
Ni
R
Ir
Si•
Br
H
Cl
X
CF2H source
CF2H
aryl bromide
N
N
CF2H
N
Page No. – Page No.
S
ꢀꢁcommercial reagents
ꢀꢁmild conditions
ꢀꢁbroad (hetero)arene scope
ꢀꢁlate-stage functionalization
CO2Et
difluoromethylarenes
Metallaphotredox
Difluoromethylation of Aryl
Bromides
Bromodifluoromethane, a commercial alkyl halide, is harnessed as an effective
source of difluoromethyl radical via silyl radical-mediated halogen abstraction. The
merger of this fluoroalkyl electrophile activation pathway with
a
dual
nickel/photoredox catalytic platform enables the difluoromethylation of a diverse
array of aryl and heteroaryl bromides under mild conditions. The utility of this
protocol is showcased in the late-stage functionalization of several drug analogues.
This article is protected by copyright. All rights reserved.