Nickel-Catalyzed Cross-Coupling of Redox-Active Esters with Boronic Acids

Article abstract of DOI:10.1002/anie.201605463

A transformation analogous in simplicity and functional group tolerance to the venerable Suzuki cross-coupling between alkyl-carboxylic acids and boronic acids is described. This Ni-catalyzed reaction relies upon the activation of alkyl carboxylic acids as their redox-active ester derivatives, specifically N-hydroxy-tetrachlorophthalimide (TCNHPI), and proceeds in a practical and scalable fashion. The inexpensive nature of the reaction components (NiCl₂?6 H₂O—$9.5 mol^?1, Et₃N) coupled to the virtually unlimited commercial catalog of available starting materials bodes well for its rapid adoption.

Full text of DOI:10.1002/anie.201605463

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International Edition: DOI: 10.1002/anie.201605463
German Edition: DOI: 10.1002/ange.201605463
Cross-Coupling Reactions
Hot Paper
Nickel-Catalyzed Cross-Coupling of Redox-Active Esters with Boronic
Acids
Jie Wang, Tian Qin, Tie-Gen Chen, Laurin Wimmer, Jacob T. Edwards, Josep Cornella,
Benjamin Vokits, Scott A. Shaw, and Phil S. Baran*
Abstract: A transformation analogous in simplicity and
functional group tolerance to the venerable Suzuki cross-
coupling between alkyl-carboxylic acids and boronic acids is
described. This Ni-catalyzed reaction relies upon the activation
of alkyl carboxylic acids as their redox-active ester derivatives,
specifically N-hydroxy-tetrachlorophthalimide (TCNHPI),
and proceeds in a practical and scalable fashion. The
inexpensive
nature
of
the
reaction
components
(NiCl2·6H2O—$9.5molÀ1, Et3N) coupled to the virtually
unlimited commercial catalog of available starting materials
bodes well for its rapid adoption.
Alkyl carboxylic acids and boronic acids are amongst the
most widely available building blocks for modern organic
synthesis (Figure 1A). Recent surveys and informatic
approaches to mining chemical reaction space within drug
discovery explain this phenomenon: Amide bond formation
and Suzuki couplings are the most often employed reac-
tions.[1,2] A reaction that could therefore marry these ubiq-
uitous and convenient building blocks in one diversifying step
would likely be of great utility in all areas of chemical science.
Earlier this year we reported that common activated esters
(such as HOAt, HOBt, and NHPI) normally employed in
amide-bond formation could also engage in Negishi-type
couplings with aryl- and alkylzinc reagents under nickel-based
catalysis.[3,4] The fact that all of these activated esters not only
prime the carboxyl for nucleophilic attack but also accept an
electron from a low-valent metal in an SET-based thermal
process was previously unrecognized.[5,6] Whereas the former
process allows for ester and amide formation, the latter
enables a simple thermal decarboxylative radical formation
with immediate capture by that transition metal (Ni).[3–5,7]
Herein, a reaction analogous to the venerable Suzuki
coupling for the cross-coupling of activated alkyl carboxylic
acids with aryl and vinyl boronic acids is reported exhibiting
a broad substrate scope, scalability, functional group toler-
ance, and inherent accessibility.[8]
Figure 1. A) Boronic acids and carboxylic acids as desired coupling
partners in a new cross-coupling reaction. B) Optimization of a Ni-
catalyzed cross-coupling between boronic acids and redox-active
esters.
Although conceptually simple, the execution of this
coupling relied on extensive experimentation and some
empirical observations that are at this time poorly under-
stood.
Figure 1B presents an abbreviated picture of the optimi-
zation conducted on ester 1 and boronic acid 2, culminating in
78% isolated yield of 3. Solvent and concentration played
a crucial role in this chemistry, with a mixture of 1,4-dioxane
and N,N-dimethylformamide (DMF, 0.023m) emerging as the
optimal.[9] For example, exclusion of DMF diminished the
yield (entry 1) and when 1,4-dioxane was substituted for THF
this seemingly trivial change essentially shut down the
reaction (entry 2). The choice of base was also unusually
important with excess triethylamine furnishing the best
results (entries 3–6).
[*] Dr. J. Wang, Dr. T. Qin, Dr. T.-G. Chen, Dr. L. Wimmer, J. T. Edwards,
Dr. J. Cornella, Prof. P. S. Baran
The Scripps Research Institute (TSRI)
North Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: pbaran@scripps.edu
B. Vokits, Dr. S. A. Shaw
Discovery Chemistry, Bristol-Myers Squibb
350 Carter Road, Hopewell, NJ 08540 (USA)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201605463.
Next, numerous ligands were screened and it was found
that a 1:1 ratio of Ni/L performed the best with L1 and L4
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providing the most reliable outcomes (entries 7–10). The
choice of ester was also critical as the more electron-rich
redox-active NHPI derivative was an incompetent coupling
partner under these conditions (entry 11). TCNHPI, an
activating agent used for the first time in synthesis as a catalyst
for hydrogen atom transfer,[10] proved to be ideal for this
coupling (Commercially available from Sigma-Aldrich, cata-
log # ALD00564). Control experiments pointed to the
essential roles of the catalyst and ligand (entries 12–13).
Curiously, even in the absence of base the reaction proceeds
to some extent, possibly due to the basic nature of the ligands
employed (entry 14). It is worth mentioning that a preformed
Ni-ligand complex in DMF added to a 1,4-dioxane solution of
boronic acid, base, and activated ester gave the most robust
results.[9]
Over thirty examples of this cross-coupling are depicted in
Scheme 1. The reaction appears to be general for both
coupling partners and largely undeterred by a wide variety of
functional groups such as aryl halides (3–13, 15, 17, 19, 20, 23,
26, 28, 35, 41), common protecting groups (4, 11, 13–16, 21–
38), esters (12, 15, 16), nitriles (25, 39), ketones (17, 22),
carbamates (15–16), and even medicinally relevant hetero-
cycles (14, 16, 18, 28–34). Both primary and secondary alkyl
carboxylic acids with or without a radical stabilizing groups
are viable (11, 18–19) and N-Boc protected amino acid side
chains show no erosion of optical activity (15–16). Both
electron-rich (24, 27, 34, 40) and electron-poor (22–23, 25–26,
28–33, 39) aryl boronic acids can be employed as well as vinyl
boronic acids (35–36).
Scheme 1. Initial scope of the Ni-catalyzed cross-coupling of TCNHPI redox-active esters with boronic acids. Reaction conditions: Redox-active
ester (1 equiv), NiCl2·6H2O (20 mol%), L1 (20 mol%), Et3N (10 equiv), boronic acid (3 equiv) in 1,4-dioxane:DMF (10:1) at 758C for 12 h.
[Isolated] refers to yields from the isolated redox-active ester, and [in situ] refers to yields from the carboxylic acid. a=for in situ preparation, see
the Supporting Information. b=using L4 instead of L1. c=using 10 mol% NiCl2·6H2O, 10 mol% L1, at 858C. d=reaction at 858C. e=5 equiv of
boronic acid.
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An important feature of this new cross-coupling hinges on
the simplicity of its setup and the development of a new one-
pot protocol. Hence, the transformation could be conducted
without the need for isolation of the activated esters, as
exemplified by 10 representative substrates in Scheme 1 (3–5,
8, 21–25, 29). A simple activation of the carboxylic acid by
DCC, followed by the Suzuki protocol, afforded comparable
yields as starting from the isolated redox-active ester. This
rapid access coupled with the experimental ease of the union
might have a tangible impact on the speed with which many
organic compounds can be made. For example, the prepara-
tion of p-bromophenyl substituted species such as 5 has
previously required as many as five steps to procure.[11] Most
routes to compounds such as 3–10 involve organometallic
additions to ketones followed by cationic or radical-based
reductions.[12] The simple ester 12 has previously required
more than five steps to prepare.[13] The unnatural amino acids
15 and 16 have required multistep pathways involving
homologation of aspartic acid rather than a direct coupling
with glutamic acid as in the present work.[14] A direct
comparison to reported substrates for Ni-catalyzed protocols
using alkyl bromides and arylboronic species resulted similar
yields of the cross-coupling product when the redox-active
ester is utilized (39–40).[8a, b] Albeit the apparent similarities of
both protocols, we hypothesized that a different mechanism
could be operating under our optimized conditions. To test
the hypothesis, an alkyl bromide was embedded in a pending
chain of a linear redox-active ester and subjected to the
optimized conditions. Interestingly, complete chemoselectiv-
ity favoring coupling of the redox-active ester was obtained
for substrate 41, which highlights the orthogonal compatibil-
ity with other protocols in the area of Suzuki arylations. It is
worth mentioning that the catalyst loading was standardized
to 20 mol% across the examples in Scheme 1 for optimal
yields. However, we demonstrated that comparable yields
could also be obtained when the catalyst loading was lowered
to 10% (4, 21–23, 29).
Scheme 2. A) Reaction carried out with wet solvents and opened to air.
B) Reaction performed at gram-scale. C) Ring-opening of a cyclopropyl-
methylene redox-active ester. D) Working hypothesis for the redox-
active ester cross-coupling with aryl- and vinylboronic acids.
The experimental ease of this transformation cannot be
overemphasized as the demanding environment of medicinal
chemistry prioritizes those reactions that require minimal
experimental precaution. Thus, as depicted in Scheme 2A,
a reaction of 1 was conducted using wet solvents without any
precaution to exclude air or moisture (open-flask) to produce
adduct 3 in 65% isolated yield. The scalability was also
evaluated using 42 and it was found to proceed smoothly to
deliver 3 on a gram-scale (Scheme 2B). In accord with our
previous findings,[3,4] the reaction of redox-active esters with
in situ generated low valent Ni species generates radical
intermediates as evidenced by the cyclopropane-opened
product 44 derived from 43 (Scheme 2C).
A postulated mechanism for this transformation is
depicted in Scheme 2D. By analogy to prior mechanistic
investigations of Ni-catalyzed cross-coupling reactions with
alkyl halides,[7] and our previous studies using organozinc
reagents,[3,4] a related pathway is postulated for the coupling
of redox-active esters with boronic acids. Initially, a NiI
complex I undergoes transmetalation with an arylboronic
acid aided by Et3N and H2O delivering aryl-NiI complex II.[15]
Reduction of the redox-ester by complex II affords species III
which, upon fragmentation, ultimately leads to the alkyl
radical and the parent phthalimide anion.[3–5] Subsequent
recombination[7,16] with complex IV delivers intermediate
complex V which, after reductive elimination, affords the
desired product and regenerates the catalytically active
species I.
Although it is perhaps too early to cite specific limitations
of this transformation, currently ortho-methoxy groups on the
boronic acid lead to diminished yield. Acids for which the
activated ester is hydrolytically labile leads to lower yields
due to competing hydrolysis.[9] Aryl boronic acids that have
difficulty in transmetallation, such as 4-pyrimidyl, are also
low-yielding. It is possible that optimization of the ligands and
redox-active ester might improve the yield of such substrates.
Our lab is currently involved in the study of such drawbacks as
well as the investigation of the mechanism, in particular the
origin of the chemoselectivity with alkyl halides.
A surprisingly simple union of the two most popular
building blocks in modern organic chemistry has been
enabled through the exclusive use of a redox-active ester
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1988, 110, 8736; d) K. Okada, K. Okamoto, N. Morita, K. Okubo,
M. Oda, J. Am. Chem. Soc. 1991, 113, 9401.
(TCNHPI). Numerous examples have been presented to
demonstrate the broad scope of this transformation and it has
already found use in the context of drug development.[17] It is
likely that many other branches of chemistry will benefit from
this cross-coupling as well. Studies to expand the scope of
coupling to alkyl boronic acids, develop asymmetric variants,
and deeply probe the mechanism of this fascinating trans-
formation are underway and will be reported in due course.
[7] As mentioned in ref. [3], redox-active esters are analogous to
alkyl halides. Thus, a mechanistic parallel can be directly drawn
to pioneering work in the area of Ni-catalyzed single-electron
transfer cross-coupling of those species, see: a) T. J. Anderson,
G. D. Jones, D. A. Vicic, J. Am. Chem. Soc. 2004, 126, 8100;
b) G. D. Jones, J. L. Martin, C. McFarland, O. R. Allen, R. E.
Hall, A. D. Haley, R. J. Brandon, T. Konovalova, P. J. Desroch-
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d) V. B. Phapale, E. BuÇuel, M. Garcꢀa-Iglesias, D. J. Cꢁrdenas,
Angew. Chem. Int. Ed. 2007, 46, 8790 – 8795; Angew. Chem.
2007, 119, 8946 – 8951; e) O. Gutierrez, J. C. Tellis, D. N. Primer,
G. A. Molander, J. Am. Chem. Soc. 2015, 137, 4896; f) A. N.
Vedernikov, ChemCatChem 2014, 6, 2490; g) B. Zheng, F. Tang,
J. Luo, J. W. Schultz, N. P. Rath, L. M. Mirica, J. Am. Chem. Soc.
2014, 136, 6499; h) J. Breitenfeld, J. Ruiz, M. D. Wodrich, X. Hu,
J. Am. Chem. Soc. 2013, 135, 12004; i) S. Biswas, D. J. Weix, J.
Am. Chem. Soc. 2013, 135, 16192.
[8] For selected examples of Ni-catalyzed alkyl--aryl Suzuki–
Miyaura cross-couplings, see: a) J. Zhou, G. C. Fu, J. Am.
Chem. Soc. 2004, 126, 1340; b) F. Gonzꢁlez-Bobes, G. C. Fu, J.
Am. Chem. Soc. 2006, 128, 5360; c) P. Lundin, G. C. Fu, J. Am.
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T. P. Pathak, M. S. Sigman, Chem. Rev. 2011, 111, 1417.
[9] See Supporting Information for details.
Acknowledgements
Financial support for this work was provided by NIH (grant
number GM-097444), Bristol-Myers Squibb, the Shanghai
Institute of Organic Chemistry, Zhejiang Medicine Co., and
Pharmaron (postdoctoral fellowship for J.W.), Austrian
Science Fund (FWF, Schrçdinger Fellowship to L. W.),
Department of Defense (NDSEG fellowship to J. T. E.) and
Catalan Government (Beatriu de Pinos Postdoctoral Fellow-
ship to J.C.). We thank David E. Hill for help in HPLC
measurements. We also thank Ke Chen, Michael Schmidt, and
Martin D. Eastgate for helpful discussions. We are grateful to
D.-H. Huang and L. Pasternack (The Scripps Research
Institute) for assistance with nuclear magnetic resonance
(NMR) spectroscopy. We also thank A. L. Rheingold, C. E.
Moore, and M. A. Galella for X-ray crystallographic analy-
sis.[18]
[10] E. J. Horn, B. R. Rosen, Y. Chen, J. Tang, K. Chen, M. D.
Eastgate, P. S. Baran, Nature 2016, 533, 77.
[11] a) K. Ueda, H. Umihara, S. Yokoshima, T. Fukuyama, Org. Lett.
2015, 17, 3191; For an older route involving Friedel – Crafts of
benzene with cyclohexene followed by bromination, see: b) B. B.
Corson, V. N. Ipatieff, Org. Synth. 1939, 19, 36.
Keywords: decarboxylation · homogeneous catalysis ·
nickel catalysts · redox-active esters · Suzuki cross-coupling
[12] a) I. Papanastasiou, S. Riganas, G. B. Foscolos, A. Tsotinis, S. A.
Akhtar, M. A. Khan, K. M. Rahman, D. E. Thurston, Lett. Org.
Chem. 2015, 12, 319; b) D. M. Allwood, D. C. Blakemore, A. D.
Brown, S. V. Ley, J. Org. Chem. 2014, 79, 328.
[13] M. Zaidlewicz, A. Wolan, J. Organomet. Chem. 2002, 657, 129.
[14] R. F. W. Jackson, J. L. Frase, N. Wishart, B. Porter, M. J. Wythes,
J. Chem. Soc. Perkin Trans. 1 1998, 1903.
[15] Recently, the formation of hydroxy-bridged species between
a boronate and the metal center have disclosed as key step for
transmetalation in Suzuki cross-couplings with Pd: A. A.
Thomas, S. E. Denmark, Science 2016, 352, 329.
[16] The capture of similar radicals was also invoked during the
decarboxylative coupling of a-heteroatom stabilized acids with
aryl halides: Z. Zuo, D. T. Ahneman, L. Chu, J. A. Terrett, A. G.
Doyle, D. W. C. MacMillan, Science 2014, 345, 437.
[17] This reaction is currently being enlisted at Bristol-Myers Squibb
in several ongoing programs, including one involving the co-
authors (B.V. and S.A.S.).
[1] N. Schneider, D. M. Lowe, R. A. Sayle, M. A. Tarselli, G. A.
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[3] J. Cornella, J. T. Edwards, S. Kawamura, J. Wang, C.-M. Pan, R.
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[4] T. Qin, J. Cornella, C. Li, L. Malins, J. T. Edwards, S. Kawamura,
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[5] Shortly after ref. [3] was published, D. J. Weix reported that
NHPI esters could undergo reductive cross-coupling with aryl
iodides using Zn0 as the reducing agent: K. M. M. Huihui, J. A.
Caputo, Z. Melchor, A. M. Olivares, A. M. Spiewak, K. A.
Jonhson, T. A. DiBenedetto, S. Kim, L. K. G. Ackerman, D. J.
Weix, J. Am. Chem. Soc. 2016, 138, 5016.
[18] X-ray information for compound 17 can be obtained free of
charge from The Cambridge Crystallographic Data center with
number CCDC 1477360.
[6] For the use of NHPI esters in photochemically initiated SET
processes, see: a) M. J. Schnermann, L. E. Overman, Angew.
Chem. Int. Ed. 2012, 51, 9576; Angew. Chem. 2012, 124, 9714;
b) G. Pratsch, G. L. Lackner, L. E. Overman, J. Org. Chem. 2015,
80, 6025; c) K. Okada, K. Okamoto, M. Oda, J. Am. Chem. Soc.
Received: June 5, 2016
Published online: && &&, &&&&
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Communications
Cross-Coupling Reactions
J. Wang, T. Qin, T.-G. Chen, L. Wimmer,
J. T. Edwards, J. Cornella, B. Vokits,
S. A. Shaw, P. S. Baran*
&&&& — &&&&
Nickel-Catalyzed Cross-Coupling of
Redox-Active Esters with Boronic Acids
A cross-coupling between alkyl carboxylic
acids and aryl boronic acids is enabled by
a new activation/cross-coupling strategy
under Nickel catalysis. The operational
simplicity and the wide range of hetero-
cyclic compounds make a convenient
strategy for obtaining aryl–alkyl cross-
coupling products.
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