Nickel-Catalyzed Hydrogenolysis and Conjugate Addition of 2-(Hydroxymethyl)pyridines via Organozinc Intermediates

Article abstract of DOI:10.1021/acs.orglett.7b03049

2-Hydroxymethylpyridines undergo nickel-catalyzed hydrogenolysis upon activation with a chlorophosphate. Reactions employ diethylzinc and are proposed to proceed through secondary benzylzinc reagents. Quenching with deuteromethanol provides straightforward incorporation of a deuterium label in the benzylic position. Intramolecular conjugate additions with α,β-unsaturated esters are also demonstrated and support the intermediacy of a benzylzinc complex.

Full text of DOI:10.1021/acs.orglett.7b03049

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Nickel-Catalyzed Hydrogenolysis and Conjugate Addition of
2‑(Hydroxymethyl)pyridines via Organozinc Intermediates
Luke E. Hanna,‡ Michael R. Harris,‡ Kenji Domon, and Elizabeth R. Jarvo*
Department of Chemistry, University of California, Irvine, California 92697-2025, United States
S
* Supporting Information
ABSTRACT: 2-Hydroxymethylpyridines undergo nickel-catalyzed hydroge-
nolysis upon activation with a chlorophosphate. Reactions employ diethylzinc
and are proposed to proceed through secondary benzylzinc reagents.
Quenching with deuteromethanol provides straightforward incorporation of a
deuterium label in the benzylic position. Intramolecular conjugate additions
with α,β-unsaturated esters are also demonstrated and support the
intermediacy of a benzylzinc complex.
ickel catalysts have been employed to activate C(sp3)−O
upon quenching with methanol provides the product of net
hydrogenolysis (Scheme 1c).
N
bonds for many transformations, including cross-
coupling, cross-electrophile coupling, and metalation reac-
tions.1,2 Nickel-catalyzed hydrogenolysis of benzylic ethers has
also been reported3,4 with recent advances employing hydrogen
gas (Scheme 1a).5,6 We hypothesized that a reaction that
In this paper, we report nickel-catalyzed formation of
secondary benzylzinc reagents from readily accessible 2-
pyridylcarbinols (Scheme 1c). We propose that the pyridyl
substituent serves as a directing group and stabilizes the
benzylzinc reagent, slowing possible side reactions, including β-
hydride elimination and Negishi-type cross-coupling.12,13 This
method provides reduction of (hydroxymethyl)pyridines with
incorporation of deuterium in the benzylic position, which can
be useful in elucidation of metabolic pathways and improve
metabolic stability.14 The intramolecular capture of the
organozinc intermediate, via conjugate addition, to provide
disubstituted cyclopentanes and cyclohexanes is also reported.
We examined hydroxymethylpyridine 1 as our model
substrate for the hydrogenolysis reaction. Reactions were
performed employing diethylchlorophosphate to activate the
alcohol, a series of nickel catalysts, and diethylzinc as a
transmetalating agent. We found that at room temperature
Ni(dppe)Cl2 furnishes the desired deoxygenated product 2 in
high yield (Table 1, entry 1). The data in Table 1 illustrate how
changes in the reaction parameters affect the transformation.
When the nickel catalyst or diethyl chlorophosphate is omitted,
the reaction does not afford the desired product (entries 2−4).
These results are consistent with a mechanism of benzylic
alcohol activation prior to reaction with a nickel catalyst.
Employing toluene as solvent or ZnMe2 instead of ZnEt2 does
not significantly affect the efficiency of the reaction (entries 5
and 6). A decreased yield of 2 was observed when catalysts
ligated by other bidendate or monodentate phosphine ligands
were used in the reaction (entries 7−10). Under optimized
conditions, the reaction provides the desired product in high
yield, even on a 1-g scale (entry 11).
Scheme 1. Nickel-Catalyzed Hydrogenolysis Reactions
effected net hydrogenolysis of a benzylic alcohol, via
stoichiometric formation of an intermediate organozinc
complex, would provide a mild, functional group tolerant
method for deoxygenation.7 We based our hypothesis in part
on related hydrogenolysis reactions of primary benzylic
alcohols that proceed through organomagnesium intermediates
(Scheme 1b).8 By employing nickel catalysis to generate
organozinc reagents in situ, this reaction also provides access to
secondary heterobenzylzinc reagents, which can be challenging
intermediates to generate by traditional methods.9,10 We
reasoned that using C−O electrophiles and a nickel catalyst
would result in a polar oxidative addition, thereby suppressing
competitive Wurtz-type coupling resulting from benzylic
radicals. In situ activation of the alcohol is achieved using
diethyl chlorophosphate;11 subsequent oxidative addition
generates a benzylnickel intermediate. Transmetalation with
diethylzinc generates the desired benzylzinc reagent, which
Having developed robust conditions for the deoxygenation of
1, we turned our attention to investigating the source of “H”
Received: September 28, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03049
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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a
Table 1. Effect of Reaction Parameters on Hydrogenolysis of
Scheme 3. Reaction Scope
1
a
entry
change from standard conditions
yield (%)
1
none
77
<5
<5
<5
72
74
42
55
21
50
2
dppe instead of NiCl2(dppe)
no NiCl2(dppe)
3
4
no P(O)(OEt)2Cl
5
PhMe instead of THF
6
ZnMe2 instead of ZnEt2
7
NiCl2·DME/DPEphos instead of NiCl2(dppe)
NiCl2·DME/dppf instead of NiCl2(dppe)
NiCl2·DME/PCy3 instead of NiCl2(dppe)
NiCl2·DME/PPh3 instead of NiCl2(dppe)
1.0 g scale of 1
8
9
10
11
b
72
a
Yield determined by 1H NMR based on comparison with PhSiMe3 as
b
internal standard. Isolated yield after column chromatography.
found in the product. We proposed that 2 is formed from the
methanol quench of the benzylzinc reagent generated in situ.
To test our hypothesis, we performed an isotopic labeling study
with methanol-OD. Upon quenching the deoxygenation
reaction of 3 with CH3OD, we observed high yield and high
deuterium incorporation of the corresponding product 5
(Scheme 2). The result of the isotopic labeling experiment
provides strong support for our proposed hypothesis that the
reaction proceeds by formation of a benzylzinc reagent (4).
a
All yields are isolated yields after column chromatography.
We reasoned that a pendant pyridine could direct the
reaction, which would expand the scope of the reaction beyond
2-hydroxymethylpyridines.16 We synthesized benzylic alcohol
15, with a pyridine disposed for formation of a six-membered
metallocycle (16, Scheme 4). We were pleased to see that upon
subjecting 15 to the reaction conditions the expected
hydrogenolysis product 17 was formed in high yield.
Scheme 2. Deuterium Incorporation
Scheme 4. Formation of a Six-Membered Metallocycle
Next, we examined the hydrogenolysis of a range of
heterobenzylic alcohols (Scheme 3). Secondary benzylic
alcohols bearing alkyl chains were well tolerated under the
reaction conditions (2, 6, and 7). Substrates containing acetal
and olefin functional groups provided deoxygenated products
in good yield (8−10). The high yield of 9 demonstrates
tolerance of olefins and highlights the reaction’s orthogonality
to hydroboration−transmetalation procedures that are often
used to prepare secondary benzylzinc reagents.15
Modification of the pyridine moiety was also tolerated in the
reaction. When the arene was changed from 2-pyridyl to a 1-
isoquinoline derivative, a modest yield of the deoxygenated
product was obtained (10). Substitution of the pyridine ring
was also tolerated, affording deoxygenated pyridines in high
yield (11). Diarylmethanols were converted to diarylmethanes
under the reaction conditions, providing access to products that
bear electron-donating and electron-withdrawing substituents
(12−14).
A plausible mechanism for the hydrogenolysis reaction that
proceeds through a benzylzinc reagent is outlined in Figure 1.
The active catalyst is formed by reduction of Ni(dppe)Cl2 with
ZnEt2 to give a Ni(0)(dppe) complex. Oxidative addition with
the phosphorylated alcohol 18 forms the benzylnickel(II)
intermediate 19. Transmetalation results in formation of
benzylzinc reagent 4 and ethylnickel complex 20. β-Hydride
elimination followed by loss of ethylene gas yields nickel
hydride species 22. A second transmetalation from an ethylzinc
species allows formation of 23, whereupon extrusion of ethane
by reductive elimination regenerates the Ni(0) catalyst.17
B
DOI: 10.1021/acs.orglett.7b03049
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03049.
Experimental procedures and spectroscopic and analyt-
ical data for all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: erjarvo@uci.edu.
ORCID
Michael R. Harris: 0000-0001-8653-0843
Elizabeth R. Jarvo: 0000-0002-2818-4038
Author Contributions
‡L.E.H. and M.R.H. contributed equally.
Notes
The authors declare no competing financial interest.
Figure 1. Proposed mechanism.
ACKNOWLEDGMENTS
■
This work was supported by NIH NIGMS (R01GM100212),
the National Science Foundation (GRF DGE-1321846 to
M.R.H.), DoEd (GAANN PA200A120070 to L.E.H.), and The
University of Tokyo (GPLLI Fellowship to K.D.). We thank
Materia for providing the Hoveyda−Grubbs II catalyst.
To demonstrate the utility of this method further, we
coupled the formation of a benzylzinc reagent to an
intramolecular conjugate addition (Scheme 5).18−20 2-Pyridyl
Scheme 5. Intramolecular 1,4-Addition
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