Nickel-catalyzed reductive defunctionalization of esters and amides to aromatic hydrocarbons

Article abstract of DOI:10.1039/c7nj02488f

The removal of ester and amide groups is of fundamental significance in organic syntheses. Under non-catalytic conditions, hydride sources are chiefly used for their reduction. Recently developed Ni-catalyzed one-pot reductive activation of esters and ami

Full text of DOI:10.1039/c7nj02488f

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ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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Nickel-Catalyzed Reductive Defunctionalization of Esters and
Amides to Aromatic Hydrocarbons
Received 00th January 20xx,
Accepted 00th January 20xx
Manoj Mondal* and Pankaj Bharali
Removal of ester and amide group is of fundamental significance in organic syntheses. Under non-catalytic conditions,
hydride sources are chiefly used for their reduction. Recently developed Ni-catalyzed one-pot reductive activation of
esters and amides followed by tandem C-CO bond cleavage- decarbonylation facilitates their cleavage to aromatic
hydrocarbons. Isolation and characterization of key reaction intermediates provides insight into this acyl C-O bond
activation pathway.
DOI: 10.1039/x0xx00000x
www.rsc.org/
selective and is possibly directed by the presence of heteroatom
groups which promotes the site-selective cleavage of unreactive C-
Esters and amides are widespread in organic molecules
including natural products, pharmaceuticals, agrochemicals
and materials, and are useful synthetic building blocks.1 Owing O bonds via the generation of acyl ruthenium complex. This
to high chemical stability they are often preferred as
protecting or directing groups during long and harsh multi-step
reactions. They are useful candidates for the late-stage
modification of compounds or reaction sequences in which
carboxylic acid derivatives are initially used as directing groups
for aromatic substitution reactions or C-H functionalization.
However, their removal or deprotection is a challenging and
fundamentally significant transformation in organic synthesis.
Under non-catalytic conditions, hydrides, such as NaBH4,
LiAlH4, Bu3SnH or (n-Bu3Sn)2 are chiefly used for such
transformations.2 In contrast, the catalytic hydrosilylation of
esters produces ethers, alcohols or aldehydes, whereas,
amines or nitriles are obtained from amides (Scheme 1).3
strategy was later used in the selective cross-couplings of activated
pyridyl esters with aryl boronates or 9-alkyl- 9-BBN for ketone
synthesis.5
Despite the great importance of these methods, which mainly
focused on functional group transformation, particularly on
aromatic systems, a mild and selective approach for their direct
removal is highly desired. Among various transition metals,
palladium and nickel plays a dominant role in C-X (functional group)
bond activation led coupling process. However, palladium catalysis
is not readily applied to reactions involving phenol-derived
electrophiles, largely due to their higher C-O bond strength relative
to C-halogen bonds. Whereas, due to high nucleophilic and small
atomic radius of nickel compared to palladium, less reactive bonds
such as C-O, C-H and C-C bonds often undergo oxidative addition to
nickel.6
R1
O
R
O
Si-H
R
H
R
OH
R
Si-H
Si-H
In late 1980, Yamamoto et al. demonstrated that nickel
activates C(acyl)-O bond of ester (RCOOAr) to form acyl-nickel-
O
Ni
R1
O
Ni
(ArBO)3
Ar
Ar
ArB(OH)2
or Ar-H
R
OR1
phenoxide complex, which undergoes β-elimination followed
by reductive elimination via decarbonylation to yield phenols
(ArOH).7 On the basis of this discovery, nickel catalyzed
decarbonylative cross-coupling methodology for aryl
carboxylates with organoborons6,8 and 1,3-azoles9 has been
developed (Scheme 1).10 Moreover, with bulky(NHC)-palladium
catalyst having low binding affinity for carbonyl oxygen of
ester, stable acyl-metal species could be generated, that could
readily undergo coupling with arylboronic acids or amine to
provide ketone or amide derivatives, respectively (Scheme
CN
or
or
Si-H
Mo
R
R
NR1R2
NR1R2
R
R
R
NR1R2
CHO
O
O
O
R
O
Ru
H
R
Ru
R
HO
+
N
N
N
2
).11 However, the development of simple metal-catalyzed
Scheme 1. Reduction of esters and amides.
The ruthenium catalyzed reductive decarboxylation in esters to
produce hydrocarbons was also reported.4 The method is highly
methods for the removal of ester or amide group has
remained dormant for a variety of reasons that include
expense, lack of generality, or operational complexity.12
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Thus, in the defunctionalization of carboxylic acid derivatives,
challenging aspects are: i) to understand the fundamental
rules that govern the generation of acyl electrophile via the C-
O or C-N group cleavage, ii) the structural characterization of
the acylmetal intermediates, iii) to understand the
fundamental
rules
that
differentiates
between
decarbonylation and non-carbonylation processes, and iv) to
design an effective metal catalyst with reduced reductive
elimination rates and high tendency for C-O oxidative addition
led decarbonylation.
Nickel-catalyzed decarbonylative borylation13 and silylation13,14
of esters has recently appeared as an attractive strategy
(Scheme 3).
Recently, Maiti and co-workers realized a simpler system
comprising Ni(cod)2, EtPPh2, and TMDSO in toluene, which
catalyses the activation of CO-C bond of planar amides
followed by decarbonylative reductive deamidation (Scheme
5
).15 Initially, to control the electron donation from nN to π*CO
,
which is necessary for the successful oxidative addition of
nickel into the CO-N bond, they envisaged to use amides with
destabilized ground state. Twisted amides, having rotational
barrier, or electron rich naphthamide derivatives (fused ring
increases π-electron density on acyl portion of amides) failed
to produce any fruitful results. Interestingly, pyrrole amide
system with coplanar CO-N bond have electronically deficient
amine group, however, the catalytic system was not effective
for such derivatives. This encourages them to investigate
pyrazole amide, in which pyrazole ligated carbonyl center
activates the C-N bond. It also destabilizes the ground state
and increases the electrophilic character of the attached
carbonyl group (Scheme 4). The combination of Ni(cod)2 and
EtPPh2 transformed each of 23 amides, irrespective of
electronic nature or sterically hindered in their aryl rings, into
deaminative derivatives in yields of 48-98%.
Recently, the group of Shi presents the first experimental
evidence for the decarbonylative intermediates (Figure 1).13
detailed mechanistic study suggested rapid oxidative
A
a
addition into the C(acyl)-O bond followed by the elimination of
CO and product formation. Interestingly, two key
intermediates were isolated and structurally characterized
(using NMR and X-ray analysis) during the borylation process.
Complex (B) having square-planar geometry with carbene
ligands coordinated in mutually trans-positions assist in the
decarbonylation. Decarbonylation of the complex (B) produces
arylnickel species
substitution with bis(neopentyl glycolato)diboron
produces four-membered intermediate ). cis-Reductive
elimination delivers the target borylated product and
regenerates Ni(ICy)2 species. Although, they have successfully
(
C
), which undergoes nucleophilic
2
to
(
D
3
prepared and characterized the decarbonylative product (
its reduction to aromatic hydrocarbons was not attempted.
C),
Evidence of regioselective oxidative addition of Ni to the CO-N
bond was provided (by ESI-MS), with acylnickel intermediate
(
II) being obtained after reaction of stoichiometric Ni(cod)2 and
ligand with amide substrate Figure 2). β-Carbonyl migration
delivered the Ni(II)-intermediate (III) needed for the hydride
4
(
transfer from TMDSO to nickel center. Hydride transfer
followed by substitution of pyrazole by a second ligand in (III
provides the hydride intermediate (IV). It was proposed that
IV), after reductively elimination, coupled with the in situ
)
(
generated CO to give the Ni(CO)n(EtPPh2)2 to further continue
the catalytic cycle. Ni(CO)n(EtPPh2)2 was isolated in the
absence of hydride source and confirmed using IR and X-ray
analysis.
2 | J. Name., 2012, 00, 1-3
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esters also underwent defunctionalization in high yields.
However, the method delivers low yield with sterically
hindered ortho biphenyl ester. Defunctionalization of alky
ester was not described. Moreover, under current conditions,
heteroaryl esters were also found to deliver moderate to
excellent yields. When applied to a set of aryl and heteroaryl
amides, the reaction proved to be effective for deamidation on
increasing the reaction time to 48 h (Scheme 6). A plausible
mechanism was also proposed for the reaction which is
consistent with that presented by Maiti.15
The Rueping group reported the direct reductive
defunctionalization of aryl and heteroaryl esters and amides,
which are known to be challenging substrates owing to their
lower reactivity (Scheme 5).16 Within a series of Ni0 and NiII
catalyst, the inexpensive and air-stable Ni(OAc)2.4H2O provides
best results. In contrast to the monodentate phosphine ligand
employed by Maiti group, Rueping et al. chose to use a
Conclusions
Selective removal of ester and amide groups from arenes and
heteroarenes through Ni-catalyzed respective C-O and C-N
bond activation summarized in this focus represents
a
breakthrough in the area of reductive defunctionalization, but
further exploration on the reaction conditions and substrate
scope are needed for advancing the frontiers of this method.
Important challenges lie in the design of simpler reagents and
the application to alkyl esters and diversely functionalized
architectures. Since esters and amides are readily prepared
and easily accessible, it should be anticipated that these new
synthetic methods will find extensive application in multi-step
and pharmaceutical processes. Moreover, in Nickel chemistry,
the catalytic cycle involving Ni(0)/Ni(II) or Ni(I)/Ni(III) or even
more complicated system is still arguable. Studies involving
computations, kinetics, and other experiments can uncover
these details in near future.
bidentate
phosphine
ligand
1,2-
bis(dicyclohexylphosphanyl)ethane
(dcype).
Using
monodentate ligands (e.g. PCy3= trace and PnBu3= 43%), poor
results were obtained with phenyl naphthalene-2-carboxylate,
but on switching to bidentate phosphine ligand, in double
equivalent to catalyst, the reaction prove feasible. In fact, a
whole extra equivalent of reducing agent (polymethyl
hydrosiloxane, PMHS) was added to carry the hydride transfer.
High temperature conditions (170 °C, toluene, 24 h) were
required to ensure the removal of ester groups in good to
excellent yields. A wide range of aryl esters containing
functional groups such as pinacol boronate, fluoro,
trifluoromethyl, tert-butyl, methylthio, ketone, amide, acetal
groups and double bonds are well tolerated. Polycyclic esters
and π-extended esters, along with para and meta biphenyl
Acknowledgments
M. M. is grateful to the DST-SERB, New Delhi for a National Post-
Doctoral Fellowship (PDF/2016/003650). Referee’s suggestions are
highly acknowledged.
Notes and references
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Table of Content
Nickel-Catalyzed Reductive Defunctionalization of Esters and Amides to Aromatic
Hydrocarbons
Manoj Mondal* and Pankaj Bharali
In two recent studies, nickel has been used in the removal of ester and amide group to
aromatic hydrocarbons via a one-pot reductive activation followed by tandem C-CO bond
cleavage-decarbonylation step. Isolation and characterization of key intermediates provides
insight into this acyl C-O bond activation pathway. This access to selective
defunctionalization by careful ligand selection expands the synthetic portfolio of carboxylic
acid derivatives for the diversification of interesting molecular scaffolds.