Merging photoredox with nickel catalysis: Coupling of α-carboxyl sp3-carbons with aryl halides

Article abstract of DOI:10.1126/science.1255525

Over the past 40 years, transition metal catalysis has enabled bond formation between aryl and olefinic (sp²) carbons in a selective and predictable manner with high functional group tolerance. Couplings involving alkyl (sp³) carbons have proven more challenging. Here, we demonstrate that the synergistic combination of photoredox catalysis and nickel catalysis provides an alternative cross-coupling paradigm, in which simple and readily available organic molecules can be systematically used as coupling partners. By using this photoredox-metal catalysis approach, we have achieved a direct decarboxylative sp³-sp² cross-coupling of amino acids, as well as α-O- or phenyl-substituted carboxylic acids, with aryl halides. Moreover, this mode of catalysis can be applied to direct cross-coupling of C_sp3-H in dimethylaniline with aryl halides via C-H functionalization.

Full text of DOI:10.1126/science.1255525

Reports
cies via the oxidative addition of a
Ni(0) catalyst to an aryl, alkenyl, or
alkyl halide coupling partner, and (ii) a
Merging photoredox with nickel
catalysis: Coupling of α-carboxyl sp3-
carbons with aryl halides
carbon-centered
radical
generated
through photo-mediated oxidation
a
event (Fig. 2). Given that organic radi-
cals are known to rapidly combine with
Ni(II) complexes (15, 16), we hoped
that this dual catalysis mechanism
would successfully converge in the
form of Ni(III)(Ar)(Alkyl), that upon
reductive elimination would deliver our
desired C–C fragment coupling prod-
uct. One of our laboratories has demon-
Zhiwei Zuo, Derek Ahneman, Lingling Chu, Jack Terrett, Abigail G.
Doyle,* David W. C. MacMillan*
Merck Center for Catalysis at Princeton University, Princeton, NJ 08544, USA.
*Corresponding author. E-mail: agdoyle@princeton.edu (A.G.D.); dmacmill@princeton.edu (D.W.C.M.)
strated that photoredox catalysis affords
access to α-amino radicals by two dis-
tinct methods: via decarboxylation of a
carboxylic acid, or by an oxidation,
deprotonation sequence with N-aryl or
trialkyl amines (17, 18). The other la-
boratory has explored Ni-catalyzed
cross-coupling reactions with iminium
ions that proceed via a putative α-
aminonickel intermediate (19–21).
Given our respective research areas, we
sought to jointly explore the capacity of
Over the last 40 years, transition metal catalysis has enabled bond formation
between aryl and olefinic (sp2) carbons in a selective and predictable manner with
high functional group tolerance. Couplings involving alkyl (sp3) carbons have
proven more challenging. Here we demonstrate that the synergistic combination of
photoredox catalysis and nickel catalysis provides an alternative cross-coupling
paradigm, in which simple and readily available organic molecules can be
systematically employed as coupling partners. Using this photoredox-metal
catalysis approach, we have achieved a direct decarboxylative sp3–sp2 cross
coupling of amino acids, as well as α-O- or phenyl-substituted carboxylic acids, with
aryl halides. Moreover, this mode of catalysis can be applied to direct cross-
Csp3
coupling of
–H in dimethylaniline with aryl halides via C–H functionalization.
a nickel(II) aryl species to intercept a
photoredox-generated α-amino radical,
Visible light photoredox catalysis has emerged in recent years as a pow-
erful technique in organic synthesis. This class of catalysis makes use of
transition metal polypyridyl complexes that, upon excitation by visible
light, engage in single-electron transfer (SET) with common functional
groups, activating organic molecules toward a diverse array of valuable
transformations (1–5). Much of the utility of photoredox catalysis hinges
on its capacity to generate non-traditional sites of reactivity on common
substrates via low-barrier, open–shell processes, thereby fostering the
use of abundant and inexpensive starting materials.
Over the past century, transition metal-catalyzed cross-coupling re-
actions have evolved to be amongst the most utilized C–C and C–
heteroatom bond-forming reactions in chemical synthesis. In particular,
nickel catalysis has provided numerous avenues to forge carbon–carbon
bonds via a variety of well-known coupling protocols (Negishi, Suzuki–
Miyaura, Stille, Kumada, and Hiyama couplings among others) (6, 7).
The broad functional group tolerance of these reactions enables a highly
modular building block approach to molecule construction. Organome-
tallic cross-coupling methods are traditionally predicated upon the use of
aryl or vinyl boronic acids, zinc halides, stannanes or Grignard frag-
ments that undergo addition to a corresponding aryl or vinyl halide part-
ner.
thereby setting the stage for the fragment coupling. We recognized that
the sum of these two catalytic processes could potentially overcome a
series of limitations that exist for each of these catalysis methods in their
own right.
A detailed description of our proposed mechanistic cycle for the de-
carboxylative coupling is outlined in Fig. 2. We presumed that initial
irradiation
of
heteroleptic
iridium(III)
photocatalyst
Ir[dF(CF3)ppy]2(dtbbpy)PF6 [dF(CF3)ppy = 2-(2,4-difluorophenyl)-5-
(trifluoromethyl)pyridine, dtbbpy = 4,4´-di-tert-butyl-2,2´-bipyridine]
(1) would produce the long-lived photoexcited *IrIII state 2 (τ = 2.3 μs)
(22). Deprotonation of the α-amino acid substrate 3 with base and oxida-
tion by the excited-state *IrIII complex (E1/2 [*IrIII/IrII] = +1.21 V vs.
red
saturated calomel electrode (SCE) in CH3CN) (22) via a single-electron
transfer event (SET) would then generate a carboxyl radical, which upon
rapid loss of CO2 would deliver the α-amino radical 4 and the corre-
sponding IrII species 5. Given the established oxidation potential of pro-
totypical amino acid carboxylate salts, we expected this process to be
red
thermodynamically favorable (Boc-Pro-OCs, E1/2 = +0.95 V vs. SCE
in CH3CN) (17). Concurrently with this photoredox cycle, we hoped that
oxidative addition of the Ni(0) species 6 into an aryl halide would pro-
duce the Ni(II) intermediate 7. We anticipated that this Ni(II)-aryl spe-
cies would rapidly intercept the α-amino radical 4, forming the
organometallic Ni(III) adduct 8. Subsequent reductive elimination would
forge the requisite C–C bond, while delivering the desired α-amino ary-
lation product 10 and expelling the Ni(I) intermediate 9. Finally, single-
electron transfer between the IrII species 5 and the Ni complex 9 would
accomplish the exergonic reduction of Ni(I) to Ni(0) (based on the estab-
lished two electron reduction potential of Ni(II) to Ni(0), we presume
that reduction of Ni(I) to Ni(0) should be thermodynamically favorable,
We recently questioned if visible light photoredox and nickel transi-
tion metal catalysis might be successfully combined to create a dual
catalysis platform for modular C–C bond formation (Fig. 1) (8–14).
Through a synergistic merger of these two activation modes, we hoped
to deliver a mechanism by which feedstock chemicals that contain com-
C
Csp3
–H bonds)
sp3
mon yet non-traditional leaving groups (
–CO2H or
could serve as useful coupling partners. Among many advantages, this
multi-catalysis strategy would enable a modular approach to sp3–sp2 or
sp3–sp3 bond formations that is not currently possible using either photo-
redox or transition metal catalysis alone. We sought to develop a general
method that would exploit naturally abundant, inexpensive, and orthog-
onal functional handles (e.g., C–CO2H, C–H with C–Br, C–I).
red
red
E1/2 [NiII/Ni0] = –1.2 V vs. SCE in DMF) by the IrII species 5 (E1/2
[IrIII/IrII] = –1.37 V vs. SCE in CH3CN) (22, 23), thereby completing
both the photoredox and nickel catalytic cycles simultaneously.
With this mechanistic hypothesis in hand, we first examined the pro-
posed coupling using N-Boc proline, para-iodotoluene, and a wide range
of photoredox and ligated nickel catalysts. To our delight, we found that
the combination of Ir[dF(CF3)ppy]2(dtbbpy)PF6 and NiCl2•glyme,
We proposed that two interwoven catalytic cycles might be engi-
neered to simultaneously generate (i) an organometallic nickel(II) spe-
/ http://www.sciencemag.org/content/early/recent / 5 June2014 / Page 1 / 10.1126/science.1255525

dtbbpy, in the presence of 1.5 equivalents of Cs2CO3 base and white provide an alternative pathway to the open-shell carbon intermediate
light from a 26 W compact fluorescent bulb, achieved the desired frag- (corresponding to 4, Fig. 2), and should similarly intercept the putative
ment coupling in 78% yield.. During our optimization studies, we found Ni(II) intermediate 8. Assuming that the remaining dual catalysis mech-
that use of a bench-stable Ni(II) source, such as NiCl2•glyme, was suffi- anism would be analogous to that shown in Fig. 2, we expected that a
cient to generate the arylation product with comparable efficiency to a
Csp3
range of direct
–H functionalization protocols should be possible.
Ni(0) source. We attribute this result to in situ photocatalytic reduction
of Ni(II) to Ni(0) via two discrete single electron transfer events, with
excess amino acid likely serving as the sacrificial reductant to access the
active Ni-catalyst (E1/2red [NiII/Ni0] = –1.2 V vs. SCE in DMF) (23). We
believe it is unlikely that the Ni(II)(Ar)X intermediate 7 undergoes a
SET event to form Ni(I)Ar, given the poorly matched reduction poten-
tials of the species involved (cf. E1/2red [NiIIArX/NiIAr] = –1.7 V vs. SCE
Indeed, we were able to demonstrate that dimethylaniline undergoes α-
amine coupling with a variety of aryl halides in the presence of
Ir[dF(CF3)ppy]2(dtbbpy)PF6 and NiCl2•glyme, as shown in Fig. 4B.
Electron-deficient and electron-rich iodoarenes give good to excellent
yields (34 to 36, 72 to 93% yield). Moreover, aryl bromides are compe-
tent coupling partners, enabling the installation of medicinally important
heterocyclic motifs (37, 60% yield). Last, control experiments have re-
vealed that the combination of light, photoredox catalyst 1, and the
NiCl2•dtbbpy complex is essential for product formation in all examples
listed in Figs. 3 and 4. This reaction represents a powerful foray into
direct C–H activation using orthogonal cross-coupling reactivity.
red
in CH3CN and E1/2 [IrIII/IrII] = –1.37 V vs. SCE in CH3CN) (22, 24).
We do, however, recognize that an alternative pathway could be opera-
ble wherein the oxidative addition step occurs from the Ni(I) complex to
form a Ni(III) aryl halide adduct. In this pathway, photocatalyst-
mediated reduction of the aryl-Ni(III) salt to the corresponding Ni(II)
species followed by the α-amino radical addition step would then form
the same productive Ni(III) adduct 8 as shown in Fig. 2. Given that (i)
Ni(0) complexes undergo oxidative addition more readily than Ni(I)
complexes with aryl halides (25), and (ii) Ni(II) complexes are believed
to rapidly engage with sp3 carbon-centered radicals to form Ni(III) spe-
cies (enabling sp3–sp2 and sp3–sp3 C–C bond formations) (15, 16), we
favor the dual catalysis mechanism outlined in Fig. 2.
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Acknowledgments: The authors are grateful for financial support provided by the
NIH General Medical Sciences (Grant NIHGMS (R01 GM103558-01 and
R01 GM100985-01) and gifts from Merck, Amgen, Eli Lilly and Roche. Z. Z.
and L. C. are grateful for postdoctoral fellowships from the Shanghai Institute
of Organic Chemistry. The authors would like to thank Professor Gary
Molander and co-workers for graciously offering to concurrently publish a
related study, that was submitted slightly ahead of our own.
Supplementary Materials
www.sciencemag.org/cgi/content/full/science.1255525/DC1
Material and Methods
Supplementary Text
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Fig. 1. The merger of photoredox and nickel catalysis: access to direct sp3-sp2 cross coupling.
Fig. 2. Photoredox-nickel catalyzed decarboxylative arylation: proposed mechanistic pathway. Boc, tert-butyl carbamoyl; SET =
single-electron transfer.
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Fig. 3. Photoredox-nickel catalyzed decarboxylative cross-coupling: Aryl halide scope.
/ http://www.sciencemag.org/content/early/recent / 5 June2014 / Page 5 / 10.1126/science.1255525

Csp3
Fig. 4. (A) Evaluation of the amino acid coupling partner in the decarboxylative-arylation protocol. (B) The direct
–H, C–X
cross-coupling via photoredox-nickel catalysis. All yields listed in Figs. 3 and 4 are isolated yields. Reaction conditions for (A)
are the same as in Fig. 3. Reaction conditions for (B): photocatalyst 1 (1 mol%); NiCl2 glyme (10 mol%), dtbbpy (15 mol%), KOH
(3 equiv.), DMF, 23°C, 26 W light. Iodoarenes employed as aryl halide, X = I. †Bromoarene employed, X = Br.
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