Stereospecific nickel-catalyzed cross-coupling reactions of benzylic ethers with isotopically-labeled grignard reagents

Article abstract of DOI:10.1021/acs.oprd.5b00148

In this manuscript we highlight the potential of stereospecific nickel-catalyzed cross-coupling reactions for applications in the pharmaceutical industry. Using an inexpensive and sustainable nickel catalyst, we report a gram-scale Kumada cross-coupling reaction. Reactions are highly stereospecific and proceed with inversion at the benzylic position. We also expand the scope of our reaction to incorporate isotopically labeled substituents.

Full text of DOI:10.1021/acs.oprd.5b00148

Communication
pubs.acs.org/OPRD
Stereospecific Nickel-Catalyzed Cross-Coupling Reactions of Benzylic
Ethers with Isotopically-Labeled Grignard Reagents
David D. Dawson and Elizabeth R. Jarvo*
Department of Chemistry, University of California, Irvine, California 92697-2025, United States
S
* Supporting Information
riched benzylic ether or ester undergoes a cross-coupling
ABSTRACT: In this manuscript we highlight the
potential of stereospecific nickel-catalyzed cross-coupling
reactions for applications in the pharmaceutical industry.
Using an inexpensive and sustainable nickel catalyst, we
report a gram-scale Kumada cross-coupling reaction.
Reactions are highly stereospecific and proceed with
inversion at the benzylic position. We also expand the
scope of our reaction to incorporate isotopically labeled
substituents.
reaction in the presence of an achiral nickel catalyst (Figure 2).
Reactions proceed with a high degree of stereochemical fidelity
and inversion at the benzylic center. Our lab has successfully
developed Kumada,6 Suzuki,7 and Negishi8 cross-coupling
reactions that incorporate methyl, n-alkyl and aryl substituents.
These reactions can be employed, for example, to introduce a
benzylic methyl substituent, a moiety that can provide a
compound with increased potency and protection against
metabolism.9 Additionally, as a nonprecious metal, nickel
catalysts provide a sustainable alternative to palladium catalysts
and are particularly well-suited to cross-coupling reactions that
connect sp3-centers.10 In this manuscript, we describe the
expansion of our nickel-catalyzed Kumada cross-coupling
reaction to certain pharmaceutical applications. We began by
increasing the scale of our methodology to the gram-scale. We
also describe incorporation a new class of nucleophiles,
Grignard reagents that carry isotopically labeled alkyl and aryl
groups, for synthesis of compounds bearing stable isotope
tracers.
he emergence of reliable cross-coupling protocols has had
T
a substantial effect on the pharmaceutical industry.1
Transition-metal catalyzed reactions, particularly those involv-
ing palladium and copper catalysts, are widely used to
synthesize libraries of compounds for SAR studies.1,2 The
prominence of cross-coupling reactions is due to in part to the
generality of the methods, the broad functional group tolerance,
and the commercial availability of the starting materials.
2
However, the ubiquity of Csp2−Csp cross-couplings can cause
a bias toward planar compounds that lack complex stereo-
chemical information.3 One strategy to enter underutilized
areas of chemical space is incorporation of increased sp3
character and stereogenic centers into the backbones of
molecules.3 For example, combretastatin A-4 (1, Figure 1) is
Figure 2. Stereospecific cross-coupling reactions of benzylic ethers and
esters.
To challenge our methodology with a preparative-scale
Kumada cross-coupling reaction, we first selected a representa-
tive substrate. We have recently developed ring-opening
reactions of aryl-substituted tetrahydropyrans (THPs) and
tetrahydrofurans (THFs) that occur in conjunction with
Figure 1. Tubulin-binding compounds.
a potent tubulin-binding anticancer agent. Analogues such as 2
replace the alkene linkage with a stereocenter.4 Incorporation
stereogenic centers is a strategy to identify molecules that have
greater selectivity for their target proteins and present fewer off-
target interactions.3 A cross-coupling protocol that could
stereospecific Csp3−Csp bond formation.6d This Kumada
3
cross-coupling reaction provides the distinct diversity elements
necessary for a diversity oriented synthesis (DOS) approach,11
as a novel appendage (hydroxyl functional handle) is formed in
3
3
reliably form Csp −Csp bonds with control of absolute and
relative stereochemistry could provide synthetic access to new
lead compounds for drug discovery efforts.
Special Issue: Non-precious Metal Catalysis
Received: May 11, 2015
Recently, our laboratory has developed a series of stereo-
specific nickel-catalyzed alkyl cross coupling reactions that form
5
3
new Csp −Csp3 bonds. In these transformations, an enantioen-
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.5b00148
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Scheme 1. Cross-Coupling of Aryl-Substituted Tetrahydropyran 3 with Methylmagnesium Iodide on a 5 g Scale
conjunction with a skeletal rearrangement of the molecule
(ring-opening). Requisite starting materials are prepared in one
step with high diastereoselectivity from the corresponding
aldehydes via clay-mediated Prins reaction.12 We were happy to
see that the Kumada reaction works well on a multigram scale.
Utilizing an air-stable preformed catalyst, 2-aryltetrahydropyran
3 undergoes the cross-coupling reaction to afford the ring-
opened product 4 with 2.5 mol % catalyst loading (Scheme
1).13 Consistent with our previous studies, the reaction was
highly stereospecific, with clean inversion at the benzylic center.
One previously unexplored application of our cross-coupling
methodology involves the incorporation of isotopic tracers into
biologically relevant molecules. Tracers that utilize stable
Scheme 2. Cross-Couplings of Isotopically-Labeled Grignard
Reagents
a
2
isotopes (e.g., H, 13C) have a range of applications, including
stable isotope dilution assays, metabolite identification, and
chronic administration studies.14 Importantly, stable isotopes
do not have the health risks associated with radioactive isotopes
and therefore can be used in studies of pregnant women and
young children.15 Stable isotope dilution assays (SIDA), for
example, rely on a mixture of isotopomers that are traced
through living systems and can be used to elucidate complex
biological pathways.16 These studies typically require coad-
ministration of both enriched and nonenriched substrates.
Therefore, a synthetic method that could easily incorporate
labeled or nonlabeled substituents would suit these applica-
tions.
We hypothesized that our Kumada-type cross-coupling
reaction could be employed in synthesis of biologically relevant
compounds and their isotopologues. The desired isotopomer
can be synthesized by proper choice of the alkyl halide
precursor. Isotopically labeled alkyl and aryl halides are
commercially available and are readily transformed into the
corresponding Grignard reagents (Scheme 2). To test this
hypothesis, we turned to enantioenriched diarylethane 2, which
displays activity against colon cancer lines.4 Our laboratory has
previously synthesized 2 by Kumada coupling of ether 5 with
methylmagnesium iodide.6a Cross-coupling of 5 with 13C-
methylmagnesium iodide afforded 13C-2 in 60% yield with
>99% enantiospecificity. As anticipated, the yield was similar to
that which we had previously reported with unlabeled reagent.5
With 13C-2 in hand, we turned to incorporating stable
isotope tracers with a mass increase ≥3 amu, as is typically
required for stable isotope dilution assay applications.14a,17
Another common stable isotope is deuterium (2H), and a
variety of deuterated alkyl and aryl halides are commercially
available. Kumada cross-coupling of 3-furyl tetrahydropyran 6
with d3-methylmagnesium iodide provided CD3-labeled 7 in
84% yield. This acyclic product had no loss of stereochemical
fidelity, with a dr of >20:1 for both substrate and product, and
possesses numerous reactive functional group handles. Aryl
Grignard reagents can also be incorporating using our
methodology;6b,c thus we sought to incorporate a d5-phenyl
tracer. Compound 3 underwent Kumada cross-coupling with
d5-phenylmagnesium bromide, which yielded 8 in good yield
a
b
Reactions carried out on a 0.2 mmol scale. Yield after two steps. See
SI for more details.
and high dr. The yields of both 7 and 8 were comparable to
those of their respective nonlabeled analogues.6d
In conclusion, the stereospecific nickel-catalyzed Kumada
cross-coupling reaction of benzylic ethers has potential for
applications in pharmaceutical chemistry settings. The trans-
formation can be carried out on a synthetically useful scale with
low loadings of an inexpensive base metal catalyst. Cross-
coupling reactions of benzylic ethers proceed in high yields
with excellent stereospecificity on gram-scale. Our protocol can
be used to prepare biologically active molecules and their
isotopologues using a single set of reaction conditions and
commercially available reagents.
EXPERIMENTAL SECTION
■
General Notes. a. Catalyst Choice. For each class of
Grignard reagent employed, a specific nickel precatalyst will
provide optimal yield in the cross-coupling reaction.
i. Reactions of Aryl and n-Alkyl Grignard Reagents. All aryl
and n-alkyl Grignard reagents are successfully incorporated by
utilizing a Ni(dppe)Cl2 precatalyst; this precatalyst is bench
stable and provides high ease-of-use since reactions setup does
not require use of a glovebox. Ni(dppe)Cl2 is a fine, red powder
that produces a black, opaque reaction mixture after addition of
Grignard reagent.
ii. Reactions of Methylmagnesium Iodide. For cross-
coupling reactions involving methyl Grignard reagent, catalysts
prepared in situ from Ni(cod)2 and a bidentate phosphine
ligand afford high yields of the desired product. Ni(cod)2 is a
yellow, granular solid which forms reaction mixtures of various
B
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hues, depending on choice of ligand. Generally, rac-BINAP is
our ligand of choice; however, in cases of heteroaromatic-
containing substrates, DPEPhos affords higher yields.18 Ni-
(cod)2 is air sensitive and best stored in glovebox freezer. If a
less sensitive catalyst precursor is desired, a preformed (rac-
BINAP)NiCl2 complex or combination of Ni(acac)2, cyclo-
octadiene, and the requisite phosphine ligand can be
employed.19,20 Across a range of conditions (e.g., employing
0.2−25 mmol of ether starting material and 1−10 mol %
catalyst loading), the air stable Ni(II) salt, (rac-BINAP)NiCl2,
afforded the desired product 4 in similar yields to the
Ni(cod)2/rac-BINAP precatalyst system.
b. Grignard Reagent Preparation. Grignard reagents are
prepared as solutions in Et2O. Grignard reagents prepared in
THF do not provide product, likely due to inhibition of the
nickel catalyst by THF. In some cases, particularly in reactions
employing aryl Grignard reagents, we have noted that higher
molarity Grignard reagents provide a higher yield of the desired
product. In reactions of methylmagnesium iodide, Grignard
molarity is typically between 2.0 and 3.5 M in Et2O. For
sluggish substrates, addition of an equivalent of MgI2 frequently
accelerates the cross-coupling reaction.5
solution in H2O, 1 mol % relative to styrene), 6 mL of acetone,
and 2 mL of water. The reaction was allowed to stir open to air
for 24 h, at which point saturated NaHCO3 (15 mL) was
added, and the mixture was filtered over Celite. The mixture
was extracted with EtOAc (3 × 10 mL), and the combined
organics were washed with brine, dried over MgSO4, filtered,
and concentrated in vacuo. The product was purified by flash
column chromatography (20% EtOAc/hexanes) to afford the
title compound as a yellow oil (3.67 g, 12.1 mmol, dr >20:1,
70%).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.5b00148.
■
S
Experimental procedures and characterization data for all
new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: erjarvo@uci.edu.
■
c. Workup. After quenching with methanol, the reaction can
be worked up in one of two ways to remove residual nickel
catalyst. The first method is by aqueous extraction. For this
method, the reaction mixture is diluted in diethyl ether, washed
with water (×3), dried over Na2SO4, and concentrated in
vacuo. Alternatively, workup can be accomplished by quenching
the reaction with methanol (to consume excess Grignard
reagent) and elution of the mixture through a plug of silica gel
eluting with neat Et2O.
d. Purification. After workup, products are typically purified
by silica gel flash column chromatography. In certain instances
the reaction mixture contains a small amount (typically <5%) of
a styrene byproduct that results from β-hydride elimination.
When necessary, such styrenes can be removed by two
methods. The first method is by flash column chromatography
employing silver-impregnated silica gel.21 Alternatively, Upjohn
dihydroxylation of the unpurified reaction mixture (employing
1 mol % Os relative to styrene) and facile separation by
standard silica gel chromatography may be employed.22
A representative procedure for the cross-coupling reaction is
detailed below. For complete experimental details see the
Supporting Information.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by NIH NIGMS (R01GM100212).
■
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1). A flame-dried 500 mL round-bottom flask equipped with a
stir bar was charged with tetrahydropyran 3 (5.00 g, 17.3 mmol,
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