Organic chemistry: A general alkyl-alkyl cross-coupling enabled by redox-active esters and alkylzinc reagents

Article abstract of DOI:10.1126/science.aaf6123

Alkyl carboxylic acids are ubiquitous in all facets of chemical science, from natural products to polymers, and represent an ideal starting material with which to forge new connections. This study demonstrates how the same activating principles used for decades to make simple C-N (amide) bonds from carboxylic acids with loss of water can be used to make C-C bonds through coupling with dialkylzinc reagents and loss of carbon dioxide. This disconnection strategy benefits from the use of a simple, inexpensive nickel catalyst and exhibits a remarkably broad scope across a range of substrates (>70 examples).

Full text of DOI:10.1126/science.aaf6123

REPORTS
Cite as: T. Qin et al., Science
10.1126/science.aaf6123 (2016).
A general alkyl-alkyl cross-coupling enabled by redox-
active esters and alkylzinc reagents
Tian Qin,1* Josep Cornella,1* Chao Li,1* Lara R. Malins,1 Jacob T. Edwards,1 Shuhei Kawamura,1 Brad D.
Maxwell,2 Martin D. Eastgate,3 Phil S. Baran1†
1Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA. 2Discovery Chemistry Platforms–Radiochemistry, Bristol-
Myers Squibb, Post Office Box 4000, Princeton, NJ, USA. 3Chemical Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, NJ 08903, USA.
*These authors contributed equally to this work.
†Corresponding author. Email: pbaran@scripps.edu
Alkyl carboxylic acids are ubiquitous in all facets of chemical science, from natural products to polymers
and represent an ideal starting material with which to forge new connections. This study demonstrates
how the same activating principles used for decades to make simple C–N (amide) bonds from carboxylic
acids with loss of water can be employed to make C–C bonds through coupling with dialkylzinc reagents
and loss of carbon dioxide. This disconnection strategy benefits from the use of a simple, inexpensive
nickel catalyst and exhibits a remarkably broad scope across a range of substrates (>70 examples).
The heart of chemical synthesis relies on forging new C–C strated to engage in cross-coupling reactions (19), the use of
bonds with the evolution and advancement of the field be- alkyl carboxylic acids in alkyl-alkyl cross-coupling remains
ing easily correlated to new developments on this front. For elusive.
example, pioneering work on the cross-coupling of halogen-
Carboxylic acids can be primed for reaction by a process
ated aromatic or vinylic (sp2) systems (Heck, Suzuki, known as activation (such as formation of an active ester, –
Negishi, Stille) has transformed the practice of organic syn- OA*), dating back to the classic work of Sheehan in the syn-
thesis (1). Similarly, a general and practical approach to thesis of penicillin (20). Once activated, a gateway opens to
C(sp3)–C(sp3) variants, would have the potential to open up access a myriad of related functional groups such as amides,
new vistas in retrosynthetic analysis. Indeed, such trans- ketones, esters or alcohols via addition of a nucleophile or
formations have been on organic chemists' wish list for well alternative oxidation states by the formal addition of hydro-
over a century (2, 3). Historically, alkyl-alkyl transition met- gen. In this Report, a broadly useful transform, able to forge
al-catalyzed cross-coupling reactions have been difficult to C(sp3)–C(sp3) bonds via this age-old activation process, is
accomplish, but examples can be traced to the early work of presented.
Kharasch in the 1950s (4), followed by Noller (5, 6), Kochi
We recently reported a Ni-catalyzed decarboxylative
and Tamura (7, 8) in the 1960s to more recent work from cross-coupling of alkyl carboxylic acids with arylzinc rea-
the groups of Suzuki (9), Fu (10), Knochel (11), Kambe (12), gents to forge C(sp3)–C(sp2) bonds by repurposing activating
Oshima (13), and many others (14). Thus far, the vast major- methods more typically associated with amide-bond for-
ity of approaches to this problem have involved the coupling mation (21, 22). Certain active esters (e.g., HOAt (aza –N-
of alkyl halides (or related species) to organometallic rea- hydroxybenzotriazole), HOBt (N-hydroxybenzotriazole),
gents (15–18). However, the limited availability, perceived NHPI (N-hydroxyphathalimide) TCNHPI (tetrachloro N-
instability, and frequent toxicity of alkyl halides has perhaps hydroxyphthalimide)) can accept an electron to trigger an
prevented the area of alkyl cross-coupling from blossoming. ensuing cascade of events that liberates CO2 from the parent
If one only considers convenience, stability, and availability alkyl group (Alk1); such esters (23) are termed redox-active
as desired attributes in a functional group for such a cou- (21, 22). The application of this chemistry to sp3–sp3 C–C
pling, the carboxylic acid reigns supreme (Fig. 1A). Alkyl bond formation poses a number of substantial challenges,
carboxylic acids are ubiquitous in every aspect of chemistry with potentially unproductive pathways far outnumbering
and can be readily found in medicines, materials, natural the desired reaction (Fig. 1B) (15–18). For example, ß-
products, and in the pages of commercial chemical supplier hydride elimination from the alkyl metal intermediates, di-
catalogs. They are a stable functional group, non-toxic, and merization of the organometallic reagent, reduction of the
eminently diversifiable owing to the field of combinatorial electrophile, and proto-demetallation are problems which
chemistry where they are the “workhorse” building block. also historically plague traditional C(sp3)–C(sp3) cross-
Although certain carboxylic acids have already been demon- coupling reactions. With a redox-active ester as an electro-
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phile, oxidative addition of low valent Ni into the activated trate-derived materials. Many of these products would be
C–O bond could result in formation of an acyl-Ni complex, either inconvenient or chemically intractable to access from
which could reductively eliminate and ultimately result in the corresponding alkyl halide starting materials (27, 28,
undesired ketone byproducts. These fundamental challenges 30, 31 and 32).
notwithstanding, described below is a straightforward solu-
Primary alkyl carboxylic acids, representing some of the
tion to this problem.
most inexpensive organic materials available, could also be
Dialkylzinc reagents were chosen for the organometallic readily employed. Of the eight examples depicted in Fig. 2C,
coupling partner due to their ease of preparation from the most notable are the use of mono-methyladipic acid (34, 2.5
parent alkyl halide, high functional group tolerance, and billion kg of adipic acid are produced per year) (25), a pyri-
their propensity for facile transmetallation. Over the years, dine-containing substrate (36), and a polyfluorinated acid
mono and dialkylzinc reagents have been shown to be viable (40). Tertiary alkyl carboxylic acids (Fig. 2D) could also be
cross-coupling partners in Negishi cross-coupling using al- employed to generate quaternary centers. Although limited
kyl halides and related species using Ni-based catalysts (16, in scope, bridgehead systems such as adamantane (41 and
18). Thus, an exploration of the coupling of redox-active es- 42) or bicyclo[2.2.2]octane (43) smoothly participated in
ters 1a and 1b (Fig. 1C) with diethylzinc (2) was undertaken. the cross-coupling. The preparation of such bridged-systems
An exhaustive screen of ligands, including bipy (L1, entry 1 is traditionally performed via a 3-step Wittig/hydrogenation
– 2) and di-tBubipy (L2, entries 3 and 4) showed that the sequence from the parent aldehyde (26). Although pivalic
electron-deficient TCNHPI ester 1b with L2 afforded the acid (44) did not couple in this context, its failure led to a
desired product in 84% isolated yield (entry 4). TCNHPI can distinct type of coupling (vide infra).
be easily prepared from tetrachlorophthalic anhydride, an
Simple primary and secondary α-oxyacids could also be
industrial non-toxic flame retardant (ca. $48/kg from VWR) employed (Fig. 2E, 45-49), representing a practical route to
(24) and it has recently been commercialized by Aldrich form ethers that would not be possible using alkyl halides.
(catalog # ALD00564). Additional screening of ligands based The classic Williamson ether synthesis is still the staple
on phenanthroline (L3 – L5, entries 5 – 7) and terpyridine transform for constructing ethers but in many cases the SN2
(L6 and L7, entries 8 and 9) did not improve the yield and reaction is either sluggish or unworkable due to steric hin-
were in many cases detrimental. When the reaction was per- drance. This cross coupling opens a distinct disconnection
formed in the absence of NiCl2·glyme, the desired product
was not formed (entry 10).
strategy for ether synthesis by using easily obtained α-
oxyacids (either commercial or derived via alkylation with
bromoacetic acid) as progenitors for a virtually limitless
array of new ethers.
With an optimized set of conditions in hand, the scope of
this new reaction was explored and found to be remarkably
broad. First, a range of dialkylzinc reagents (sixteen, Fig. 2A)
was explored with piperidine esters 1a and 1b. With the ex-
ception of dibenzylzinc reagents, all primary dialkylzinc re-
agents explored were viable in the cross coupling. From
dimethylzinc (4) and simple alkyl chains (3, 5, 6, 9, 10) to
derivatives harboring olefins (7-8), alkynes (11-12), acetals
(16), ethers (14-15), and even alkyl halides (13) were toler-
ated. The reaction was easily run on a gram scale (as exem-
plified by 3) and could even be employed to produce
isotopically labeled piperidine 4-13C. In addition to 3, this
example highlights that a lower loading of dialkylzinc rea-
gent (0.5 equiv) could be employed when a highly valuable
alkyl group is involved. Secondary alkylzinc reagents such as
cyclopropylzinc could also be accommodated as exemplified
by 17.
Next, the scope of secondary alkyl carboxylic acids (fif-
teen, Fig. 2B) was explored. Cyclic (18, 19, 21), heterocyclic
(20, 22, 26-28, 31), bridging (25), indane (24), acyclic
(29), and even fluorinated (23, 30) alkyl carboxylic acids
were all viable coupling partners. Substrates 30 through 32
are particularly striking and open the door to access a vast
array of fluorinated building blocks and optically pure tar-
Redox-active esters enable the cross-coupling of alkylzinc
reagents with high chemoselectivity (Fig. 2F) even in com-
plex contexts, reminiscent of that exhibited in classic amide-
bond formation. For example, a variety of sensitive fatty
acids reacted smoothly to give the corresponding alkyl
chains (50, 57 and 58) without olefin isomerization or
epoxide opening. Naturally occurring carboxylic acids such
as biotin, cholic acid and dehydrocholic acid were also ame-
nable to alkylation (54-56). Pharmaceuticals such as
pregabalin, 2,4-D, cetirizine and atorvastatin smoothly re-
acted with alkylzinc reagents to afford good yields of the
alkyl coupling products (51-53 and 59).
In perhaps the most impressive feat of chemoselectivity
for this methodology, the cross-coupling could be conducted
on solid phase in the context of peptide synthesis. On-resin
coupling of dialkylzinc reagents to proteinogenic amino ac-
ids (both side-chain and α-carboxylic acids) facilitates the
late-stage introduction of designer amino acids, which
would otherwise require de novo synthesis. Valuable syn-
thetic handles including alkenes (60 and 62) and alkyl
ethers (63) could be readily incorporated into resin-bound
substrates (Fig. 3), and the installation of an aliphatic side-
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chain (61) provides a facile approach to the modulation of in the cases where an alkyl halide would be chemically sta-
peptide lipophilicity (27). Double activation of a peptide ble, only a handful are commercially available. Conceptually,
substrate bearing both Asp and Glu residues also enables carboxylic acids can perhaps be considered as Nature's ver-
the simultaneous introduction of multiple non- sion of a boronic acid. For the past seven decades these
proteinogenic side-chains (64 and 65). This convenient ap- ubiquitous functional groups have usually been dehydrated
proach to diversely functionalized peptides provides a tool with incorporation of a nucleophile (such as an amine to
for the construction of therapeutic peptide leads, stapled make an amide). This method extends the native diversifica-
peptides (28, 29) and for applications in bioconjugation tion of this functional group (33), to allow for the addition
(30).
of a new carbon framework via extrusion of CO2. As such it
Returning to the limitations posed by tertiary systems, is anticipated that this technique will greatly expand plan-
mechanistic studies involving 5-exo-dig cyclization, racemi- ning options in retrosynthetic analysis.
zation and ring-strain opening experiments clearly point to
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ACKNOWLEDGMENTS
Financial support for this work was provided by Bristol-Myers Squibb, Catalan
Government (Postdoctoral Fellowship to J.C.), Department of Defense (NDSEG
fellowship to J.T.E.), NIH (F32GM117816 Postdoctoral Fellowship to L.R.M.)
China Scholarship Council (postdoctoral fellowship to C.L.) and NIGMS
(GM106210). We thank Dr. D.-H. Huang and Dr. L. Pasternack for assistance with
NMR spectroscopy; Dr. M. Collins for providing samples of atorvastatin,
cetirizine and pregabalin; Mr. Riley Mills for experimental assitance; Dr. A.
Rheingold, Dr. C. E. Moore, and Dr. M. A. Galella for x-ray crystallographic
analysis; and Dr. K. Chen for helpful discussions. Metrical parameters for the
structures of 11 and 73 are available free of charge from the Cambridge
Crystallographic Data Center under reference numbers CCDC-1457710 and
CCDC-1457711 respectively.
SUPPLEMENTARY MATERIALS
www.sciencemag.org/cgi/content/full/science.aaf6123/DC1
Materials and Methods
Supplementary Text
Figs. S1 to S3
Tables S1 to S6
References (34–60)
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4

4 March 2016; accepted 11 April 2016
Published online 21 April 2016
10.1126/science.aaf6123
First release: 21 April 2016
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5

Fig. 1. Development of a Ni-
catalyzed decarboxylative alkyl-alkyl
cross-coupling. (A) Activation of
carboxylic acids in organic synthesis.
(B) Potential side-products. (C) Ni-
catalyzed cross-coupling of redox-
active esters and alkylzinc reagents.
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6

Fig. 2. Scope of the Ni-catalyzed decarboxylative alkyl-alkyl cross-coupling. Standard conditions: redox-
active ester (1 equiv.), dialkylzinc reagent (2 equiv.), NiCl2·glyme (20 mol%), L2 (40 mol%), THF:DMF, 25°C,
8-14 hours. THF=tetrahydrofuran; DMF=dimethylformamide.
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7

Fig. 3. Ni-catalyzed decarboxylative alkyl-alkyl coupling in solid phase synthesis. *See Supplementary
Materials for experimental details.
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8

Fig. 4. Scope of the Ni-catalyzed
three-component conjunctive
cross-coupling. Standard
conditions: redox-active ester (1
equiv.), acceptor (2.5 equiv.),
PhZnCl·LiCl complex (3 equiv.),
NiCl2·glyme (20 mol%), L2 (40
mol%), THF:DMF, 25°C, 8 hours.
THF, tetrahydrofuran; DMF,
dimethylformamide. All the
products shown were obtained in a
racemic form.
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9

A general alkyl-alkyl cross-coupling enabled by redox-active esters
and alkylzinc reagents
Tian Qin, Josep Cornella, Chao Li, Lara R. Malins, Jacob T. Edwards,
Shuhei Kawamura, Brad D. Maxwell, Martin D. Eastgate and Phil S.
Baran (April 21, 2016)
published online April 21, 2016
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