Merging Photoredox and Nickel Catalysis: The Direct Synthesis of Ketones by the Decarboxylative Arylation of α-Oxo Acids

Article abstract of DOI:10.1002/anie.201501908

The direct decarboxylative arylation of α-oxo acids has been achieved by synergistic visible-light-mediated photoredox and nickel catalysis. This method offers rapid entry to aryl and alkyl ketone architectures from simple α-oxo acid precursors via an acyl radical intermediate. Significant substrate scope is observed with respect to both the oxo acid and arene coupling partners. This mild decarboxylative arylation can also be utilized to efficiently access medicinal agents, as demonstrated by the rapid synthesis of fenofibrate. The direct decarboxylative arylation of α-oxo acids has been achieved by synergistic visible-light-mediated photoredox and nickel catalysis. This method offers rapid entry to aryl and alkyl ketone architectures from simple α-oxo acid precursors via an acyl radical intermediate. Significant substrate scope is observed with respect to both the oxo acid and arene coupling partners.

Full text of DOI:10.1002/anie.201501908

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International Edition: DOI: 10.1002/anie.201501908
German Edition: DOI: 10.1002/ange.201501908
Dual Catalysis Very Important Paper
Merging Photoredox and Nickel Catalysis: The Direct Synthesis of
Ketones by the Decarboxylative Arylation of a-Oxo Acids**
Lingling Chu, Jeffrey M. Lipshultz, and David W. C. MacMillan*
Abstract: The direct decarboxylative arylation of a-oxo acids
has been achieved by synergistic visible-light-mediated photo-
redox and nickel catalysis. This method offers rapid entry to
aryl and alkyl ketone architectures from simple a-oxo acid
precursors via an acyl radical intermediate. Significant sub-
strate scope is observed with respect to both the oxo acid and
arene coupling partners. This mild decarboxylative arylation
can also be utilized to efficiently access medicinal agents, as
demonstrated by the rapid synthesis of fenofibrate.
and electronic materials (including photovoltaics).[5]
Common methods for ketone synthesis currently include
1) organometallic additions to Weinreb amides,[6] 2) Stille
couplings between acyl chlorides and stannanes,[7] 3) metal-
catalyzed carbonylations between aryl halides and prefunc-
tionalized transmetalation reagents (e.g., boronic acids),[8]
and 4) alkene hydroacylations (Figure 1).[9] Whereas the
P
hotoredox catalysis employing visible light has recently
emerged as a valuable platform for the design of unique one-
electron-transfer pathways that allow the invention of val-
uable new chemical reactions.[1] In this vein, our laboratory
has described the decarboxylative coupling of a-amino, a-oxy,
and alkyl carboxylic acids with aryl halides, a method that
À
enables broad access to Csp3 Csp2 bonds using abundant and
inexpensive starting materials.[2] This new fragment coupling
relies on the capacity of photoredox catalysts to simultane-
ously modulate the oxidation states of organometallic inter-
mediates while generating open-shell organic species that can
interface with transition-metal catalysts (e.g., Pd, Ni, Cu).[2,3]
Recently, we questioned whether this synergistic catalysis
pathway might provide a direct and mild route to ketones by
the radical decarboxylative coupling of simple a-oxo acids
and aryl halides, a transformation that to our knowledge has
not previously been described.[4] Herein, we detail the
successful execution of these ideals, and present a new
mechanism for the production of diaryl, alkyl–aryl, and
dialkyl carbonyl compounds at room temperature without the
requirement for CO, strong bases, or organometallic reagents.
Ketones have long been established as a linchpin func-
tional group in organic chemistry owing to their innate
capacity to function as electrophiles across a tremendous
Figure 1. Metallaphotoredox decarboxylative arylation of a-oxo acids.
synthetic value of these coupling strategies is self-evident,
the development of new catalytic transformations that
provide access to structurally diverse ketones using simple,
inexpensive substrates would be welcomed by synthetic
chemists.
À
=
array of bond-forming reactions (e.g., to form C C, C C,
À
À =
C N, and RO C O bonds). Moreover, ketones are
a common structural element found in a wide range of
agrochemicals, bioactive natural products, pharmaceuticals,
Within the realm of open-shell chemistry, acyl radicals
derived from acyl selenides and tellurides have long been
used to initiate cyclization cascades to generate complex
ketones in formal hydroacylation reactions.[10] However, the
synthetic utility of acyl radicals has been somewhat limited
owing to their innate nucleophilicity[11] along with the
immoderate conditions required for their generation (typi-
cally entailing high temperatures, UV light, or stoichiometric
amounts of tin reagents). As a critical advantage, we
postulated that the implementation of photoredox-mediated
decarboxylation[2,12] would allow for a broad range of acyl
radicals to be accessed from a-oxo acids, such as pyruvic acid,
thereby allowing ketone production from an abundant, non-
[*] Dr. L. Chu, J. M. Lipshultz, 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/
[**] We are grateful for financial support provided by the NIH General
Medical Sciences (NIHGMS; R01 GM093213-01) and gifts from
Merck, AbbVie, and Bristol Myers Squibb. L.C. acknowledges
a postdoctoral fellowship from the Shanghai Institute of Organic
Chemistry.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201501908.
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metal-based source. As a key design element, this photoredox
approach to nickel acyl complex formation would allow facile
generation of a series of carbonyl products using mild
conditions (room temperature) without the need for toxic
reagents or stoichiometric oxidants.[13]
A detailed mechanism for the proposed metallaphoto-
redox aryl cross-coupling with a-oxo acids is shown in
Scheme 1. It is well established that photoredox catalyst
required Ni0 oxidation state in an exergonic process. Indeed,
the thermodynamic requirements of the two-electron reduc-
tion of NiII to Ni0 are favorable (E1/2II/0 = À1.2 V vs. SCE in
DMF),[17] given the corresponding reduction potential of IrII
complex 4 (E1/2III/II = À1.37 V vs. SCE in CH3CN).[15] It should
be noted that this second photoredox-mediated SET event
regenerates the ground-state IrIII catalyst 1 while reconstitut-
ing the requisite Ni0 complex 6, completing the photoredox
and nickel cycles simultaneously.
We began our investigations into this new acyl cross-
coupling method using phenylglyoxylic acid and para-iodo-
toluene in the presence of [Ir{dF(CF3)ppy}2{dtbbpy}]+ 1, Ni
complex 12, Cs2CO3, and DMF. Given the findings from our
previous studies into the decarboxylative nickel-catalyzed
arylation of amino acids, we presumed that a strongly
oxidizing photocatalyst (e.g., 1) would be required to oxidize
the carboxylate and initiate the CO2 extrusion step. Indeed,
we were delighted to achieve proof of concept using the
optimized catalytic conditions from our earlier studies;
however, the efficiency of ketone product formation was
poor (Table 1, entry 1, 13% yield). Pleasingly, changing from
Table 1: Optimization of the decarboxylative a-oxo acid arylation.[a]
Scheme 1. Merged photoredox and nickel catalytic cycles.
[Ir{dF(CF3)ppy}2{dtbbpy}]+ 1[14] readily absorbs photons upon
visible-light irradiation to generate the oxidizing excited state
III
*[Ir{dF(CF3)ppy}2{dtbbpy}]+ 2 [E1/2
*
/II = +1.21 V vs. satu-
Entry
Base
Light source
H2O [equiv]
Yield [%]
rated calomel electrode (SCE) in CH3CN].[15] Base-mediated
deprotonation of an a-oxo acid substrate [such as pyruvic acid
(3), see Scheme] and subsequent single-electron oxidation of
the resulting carboxylate functional group (E1/2red =+ 1.03 V
vs. SCE in DMSO)[13d] by the excited photocatalyst 2 should
generate the reduced photocatalyst 4 and a corresponding
carboxyl radical species. At this stage, we presumed that this
open-shell dicarbonyl intermediate would rapidly extrude
CO2 to deliver the critical acyl radical species 5. Within the
same time frame, the second catalytic cycle would be initiated
by oxidative addition of the Ni0 catalyst 6[16] into the aryl
halide (e.g., 4-iodotoluene (7), as shown) to generate NiII aryl
complex 8. The resulting electrophilic metal species 8 would
then rapidly trap the nucleophilic acyl radical 5 to produce
nickel acyl complex 9. At this stage, reductive elimination
from this NiIII complex would be expected to forge the
1
2
3
Cs2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
blue LED strips
blue LED strips
34 W blue LED
34 W blue LED
34 W blue LED
34 W blue LED
34 W blue LED
0
0
0
0
2
8
2
13
38
60
74
84
54
88
4[b]
5[b]
6[b]
7[b,c]
1
[a] Yield determined by H NMR spectroscopy using 1,3-bis(trifluoro-
methyl)-5-bromobenzene as an internal standard. [b] Reaction time:
72 h. [c] 2 mol% of the photocatalyst.
Cs2CO3 to Li2CO3 led to a notable increase in reaction
efficiency (entry 2, 38% yield). Moreover, implementation of
a more powerful 34 W blue LED lamp in lieu of the standard
blue LED strips provided further improvement (entry 3, 60%
yield), highlighting that the reaction is likely photon-limited.
The addition of two equivalents of water produced a modest
boost in yield while adding further equivalents was detrimen-
tal, presumably owing to protonolysis of the putative NiII aryl
À
requisite Csp2 Csp2 bond of compound 10, while expelling the
corresponding NiI complex 11. Finally, single-electron trans-
fer (SET) from the photocatalyst, IrII species 4, to the
NiI–dtbbpy complex 11 would return the metal catalyst to the
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complex at high H2O concentration (entries 5 and 6).[18]
Ultimately, increasing the photocatalyst loading to 2 mol%
provided superior conditions, delivering the desired diaryl
ketone adduct in excellent yield (entry 7, 88%).
With optimized conditions in hand, we next examined the
scope of the a-oxo acid component in this new cross-coupling
method. As described in Table 2, a wide range of a-keto acids
rich aryl glyoxylic acids readily served as efficient nucleo-
philes, generating the product ketones in good yields (prod-
ucts 14 and 16, 92% and 65% yield).
As further detailed in Table 2, a range of aliphatic keto
acids can also serve as efficient coupling partners. Particularly
notable are cyclic systems, such as cyclopropyl and cyclohexyl
glyoxylic acids (products 17 and 18, 88% and 80% yield).
Moreover, a variety of acyclic alkyl-substituted ketones were
readily accessible using the appropriate a-oxo acids (products
19–23, 83–92% yield). Perhaps most pleasingly, pyruvic acid,
which is available from biomass, can be readily harnessed to
generate aryl acylation adducts directly (product 10, 57%
yield).
Table 2: Decarboxylative coupling: scope of the a-oxo acid.[a]
With respect to the electrophilic coupling partner, the
mild conditions employed with this photoredox/nickel
method allow for a wide range of aryl halides to be employed
(Table 3). For example, iodoarenes bearing fluoride and
chloride substituents could be used to generate halogenated
ketones without the formation of dehalogenated adducts
(products 24 and 25, 70% and 90% yield). The enhanced rate
of oxidative addition to aryl iodides relative to aryl chlorides
allows for chemoselectivity in the cross-coupling of 1-chloro-
4-iodobenzene, which allows the chloride group to be
retained as a handle for further synthetic manipulations or
as a structural element for medicinal chemistry. In this
context, it is important to note that a trifluoromethyl group
can also be incorporated on the arene ring (product 26, 88%
yield). Electron-rich arenes can also serve as electrophiles,
albeit with increased reaction times (products 27 and 28, both
70% yield). Not surprisingly, electron-deficient arenes are
highly competent in this cross-coupling reaction, enabling the
use of bromoarenes as electrophiles in these cases (products
29–36, 64–85% yield). As a critical requirement for the
broad-scale implementation of this transformation, hetero-
arenes could be successfully employed to rapidly build
nitrogen-containing aryl ketone adducts (products 32–36,
64–85% yield). Specifically, 3-bromopyridines could be
coupled effectively (products 33 and 34, 80% and 64%
yield). Last, we have further determined that 4-bromopyr-
idines are valuable coupling partners, and that the steric
environment around the nitrogen atom is inconsequential
with respect to reaction yield (products 32, 35, and 36, 80–
85% yield).
To further demonstrate the utility and generality of this
novel cross-coupling reaction, we sought to employ electro-
philes beyond the realm of aromatic halides. As shown in
Scheme 2a, hindered vinyl halides can be readily utilized in
the procedure to build a,b-unsaturated ketones directly.
Perhaps more importantly, alkyl halides, such as bromocyclo-
pentane, were successfully utilized in this new transformation
to generate dialkyl ketones (Scheme 2b). This latter example
highlights the use of nickel catalysis to enable oxidative
insertion into Csp3–halogen bonds without the intervention of
detrimental b-hydride elimination pathways.
Finally, we sought to highlight the value of this new
method for medicinal chemistry by the rapid production of
a biologically active small molecule incorporating a diaryl
ketone. Within this context, fenofibrate, a cholesterol-mod-
ulating pharmaceutical of the fibrate class, currently ranked
[a] Reactions performed using the optimized conditions from Table 1
(see the Supporting Information for details). Yields of isolated products
are given.
bearing aromatic and aliphatic substituents were amenable to
this CO2 extrusion mechanism. Pleasingly, this open-shell
pathway allows for the ready implementation of an ortho-
substituted aryl ring on the keto acid component (product 14,
92% yield), a significant limitation for many previous cross-
coupling systems owing to the accompanying steric
demands.[4] Surprisingly, electron-deficient arenes were tol-
erated on the keto acid, despite the inherent difficulty of the
carboxylate oxidation step (product 15, 60% yield). Electron-
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Table 3: Decarboxylative coupling: scope of the aryl halide.[a]
Scheme 2. Metallaphotoredox decarboxylation and its application.
[1] a) C. K. Prier, D. A. Rankic, D. W. C. MacMillan, Chem. Rev.
2013, 113, 5322; b) J. W. Tucker, C. R. J. Stephenson, J. Org.
Chem. 2012, 77, 1617; c) J. M. R. Narayanam, C. R. J. Stephen-
son, Chem. Soc. Rev. 2011, 40, 102; d) D. Nicewicz, D. W. C.
MacMillan, Science 2008, 322, 77; e) M. A. Ischay, M. E.
Anzovino, J. Du, T. P. Yoon, J. Am. Chem. Soc. 2008, 130, 12886.
[2] Z. Zuo, D. T. Ahneman, L. Chu, J. A. Terrett, A. G. Doyle,
D. W. C. MacMillan, Science 2014, 345, 437.
[3] a) W.-Y. Yu, W. N. Sit, Z. Zhou, A. S.-C. Chain, Org. Lett. 2009,
11, 3174; b) D. Kalyani, K. B. McMurtrey, S. R. Neufeldt, M. S.
Sanford, J. Am. Chem. Soc. 2011, 133, 18566; c) Y. Ye, M. S.
Sanford, J. Am. Chem. Soc. 2012, 134, 9034; d) S. R. Neufeldt,
M. S. Sanford, Adv. Synth. Catal. 2012, 354, 3517; e) J. C. Tellis,
D. N. Primer, G. A. Molander, Science 2014, 345, 433; f) A.
Noble, S. J. McCarver, D. W. C. MacMillan, J. Am. Chem. Soc.
2015, 137, 624; g) D. N. Primer, I. Karakaya, J. C. Tellis, G. A.
Molander, J. Am. Chem. Soc. 2015, 137, 2195.
[4] For Cu-catalyzed decarboxylative couplings of a-oxo acids at
1708C, see: L. J. Gooßen, F. Rudolphi, C. Oppel, N. Rodríguez,
Angew. Chem. Int. Ed. 2008, 47, 3043; Angew. Chem. 2008, 120,
3085.
[5] a) M. W. Walter, Nat. Prod. Rep. 2002, 19, 278; b) R. McDaniel,
A. Thamchaipenet, C. Gustafsson, H. Fu, M. Betlach, M.
Betlach, G. Ashley, Proc. Natl. Acad. Sci. USA 1999, 96, 1846;
c) N. A. McGrath, M. Brichacek, J. T. Njardarson, J. Chem.
Educ. 2010, 87, 1348; d) P. V. Kamat, Chem. Rev. 1993, 93, 267.
[6] a) S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3818; b) J.
Singh, N. Satyamurthi, I. S. Aidhen, J. Prakt. Chem. 2000, 342,
340.
[a] Reactions performed using the optimized conditions from Table 1
(see the Supporting Information for details). Yields of isolated products
are given. [b] Reaction performed using 5.0 equiv of the acid and Li2CO3.
[c] 84 h. [d] 90 h.
47th in American retail sales,[5c] was synthesized in a single
decarboxylation step (3 steps overall) in 71% yield
(Scheme 2c).
Keywords: arylation · decarboxylation · nickel catalysis ·
photoredox catalysis · a-oxo acids
How to cite: Angew. Chem. Int. Ed. 2015, 54, 7929–7933
Angew. Chem. 2015, 127, 8040–8044
[7] J. K. Stille, Angew. Chem. Int. Ed. 1986, 25, 508; Angew. Chem.
1986, 98, 504 – 519.
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[8] a) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457; b) X.-F.
Wu, H. Neumann, M. Beller, Chem. Soc. Rev. 2011, 40, 4986.
[9] M. C. Willis, Chem. Rev. 2010, 110, 725.
Int. Ed. 2014, 53, 502; Angew. Chem. 2014, 126, 512; d) M.
Majek, A. J. von Wangelin, Angew. Chem. Int. Ed. 2015, 54,
2270; Angew. Chem. 2015, 127, 2298.
[10] a) C. Chatgilialoglu, D. Crich, M. Komatsu, I. Ryu, Chem. Rev.
1999, 99, 1991; for the hydroacylation of a,b-unsaturated esters
[14] dF(CF3)ppy = 2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyri-
dine, dtbbpy = 4,4’-di-tert-butyl-2,2’-bipyridine.
[15] M. S. Lowry, J. I. Goldsmith, J. D. Slinker, R. Rohl, R. A.
Pascal, Jr., G. G. Malliaras, S. Bernhard, Chem. Mater. 2005,
17, 5712.
À
by aerobic C H activation, see: b) V. Chudasama, R. J. Fitz-
maurice, S. Caddick, Nat. Chem. 2010, 2, 592.
[11] A. Citterio, F. Minisci, O. Porta, G. Sesana, J. Am. Chem. Soc.
1977, 99, 7960.
[16] To reduce the NiII catalyst to Ni0, a sacrificial amount of acid
must be oxidized by 2 to turn over the photocatalytic cycle; see
Refs. [2, 11d].
[12] a) M. Rueda-Becerril, O. MahØ, M. Drouin, M. B. Majewski,
J. G. West, M. O. Wolf, G. M. Sammis, J.-F. Paquin, J. Am. Chem.
Soc. 2014, 136, 2637; b) Z. Zuo, D. W. C. MacMillan, J. Am.
Chem. Soc. 2014, 136, 5257; c) L. Chu, C. Ohta, Z. Zuo, D. W. C.
MacMillan, J. Am. Chem. Soc. 2014, 136, 10886; d) A. Noble,
D. W. C. MacMillan, J. Am. Chem. Soc. 2014, 136, 11602.
[13] a) T. Caronna, G. Frona, F. Minisci, O. Porta, J. Chem. Soc.
Perkin Trans. 2 1972, 2035; b) F. Fontana, F. Minisci, M. C. N.
Barbosa, E. Vismara, J. Org. Chem. 1991, 56, 2866; c) J. Liu, Q.
Liu, H. Yi, C. Qin, R. Bai, X. Qi, Y. Lan, A. Lei, Angew. Chem.
[17] Y. Rolling, M. Troupel, D. G. Tuck, J. Perichon, J. Organomet.
Chem. 1986, 303, 131.
[18] M. Ueda, A. Saitoh, S. Oh-tani, N. Miyaura, Tetrahedron 1998,
54, 13079.
Received: March 3, 2015
Published online: May 26, 2015
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