Nickel-Catalyzed Oxidative Decarboxylative Annulation for the Synthesis of Heterocycle-Containing Phenanthridinones

Article abstract of DOI:10.1021/acs.orglett.8b03144

A nickel-catalyzed oxidative decarboxylative annulation reaction of simple benzamides and (hetero)aromatic carboxylates has been developed. This reaction provides access to a large array of phenanthridinones and their heterocyclic analogues, highlighting the utility and versatility of oxidative decarboxylative coupling strategies for C-C bond formation.

Full text of DOI:10.1021/acs.orglett.8b03144

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nickel-Catalyzed Oxidative Decarboxylative Annulation for the
Synthesis of Heterocycle-Containing Phenanthridinones
Aaron P. Honeycutt and Jessica M. Hoover*
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, West Virginia, United States
S
* Supporting Information
ABSTRACT: A nickel-catalyzed oxidative decarboxylative annulation
reaction of simple benzamides and (hetero)aromatic carboxylates has
been developed. This reaction provides access to a large array of
phenanthridinones and their heterocyclic analogues, highlighting the
utility and versatility of oxidative decarboxylative coupling strategies
for C−C bond formation.
Scheme 1. Selected Examples of Synthetic Routes to
Phenanthridinones
henanthridinones are key structures found in a variety of
1
Pnatural products and biologically active compounds
including antiviral and anticancer therapeutics,2 aurora kinase,3
and polymerase (PARP) inhibitors4 as well as serve as
important building blocks toward complex polycyclic targets.5
The corresponding heterocycle-containing phenanthridinones,
however, are less explored due, in part, to a shortage of efficient
synthetic routes to these compounds. Because of the
prevalence of heterocycles with important biological proper-
ties,6 the ability to access such heterocycle-containing
phenanthridinones could provide new libraries of compounds
with novel properties and activities.
Typically, construction of these scaffolds7,8 relies on
traditional cross-coupling reactions,3 such as Suzuki−Miyaura
coupling (Scheme 1, eq 1) or Buchwald−Hartwig amination
reactions.9 These methods, however, require prefunctionalized
aryl halide and arylboronic ester or acid coupling partners.
Alternatively, oxidative C−H arylation routes enable the
utilization of simple arenes as coupling partners,10 yet we are
aware of only a single report in which efficient incorporation of
heteroarenes into phenanthridinone structures is achieved
(Scheme 1, eq 2).10f Baidya and co-workers have reported the
copper-mediated dehydrogenative annulation of amides with
fluorinated arenes in which 3,5-difluoropyridine is also a
competent coupling partner (Scheme 1, eq 2).
More recently, transition-metal catalyzed oxidative decar-
boxylative coupling (ODC) reactions11 have been applied to
the synthesis of phenanthridinones. Wang and co-workers
reported the synthesis of phenanthridinones utilizing a Pd-
catalyzed ODC strategy to effect the coupling of aryl acyl
peroxides in fair yields.12 Similarly, Miura13 and co-workers
reported an analogous copper-mediated ODC reaction for the
synthesis of phenanthridinones from ortho-nitrobenzoates
(Scheme 1, eq 3). Unfortunately, both catalyst systems are
limited to select benzoic acids, and heteroaryl carboxylates are
ineffective coupling partners under these reported conditions.
We have recently developed a new nickel catalyst system for
the efficient ODC reactions of a large scope of heteroaryl
carboxylates.14 In this work, we highlight the utility of a related
nickel-catalyzed oxidative decarboxylative annulation strategy
Received: October 2, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03144
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
for the synthesis of heterocycle-containing phenanthridinones
(Scheme 1, eq 4).
Scheme 2. Scope of Heteroaromatic Carboxylate Coupling
Partners in the Ni-Catalyzed Oxidative Decarboxylative
Annulation Reaction
a
During the course of our previous studies, we observed the
formation of the oxidative decarboxylative annulation product
3 in low yields when ortho-fluoro substituted (hetero)aromatic
carboxylates 2 were employed as coupling partners. Following
this initial discovery, we focused our attention on optimizing
the conditions for the coupling of quinolinylbenzamide 1a15
with the 2-fluoronicotinic carboxylate 2a (Table 1). Ni(OAc)2·
a
Table 1. Optimization of Reaction Conditions
b
c
entry
[Ni]
oxidant
yield 3a (%)
1
2
3
4
5
6
7
8
Ni(acac)2
Ni(OTf)2
NiCl2
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
AgOPiv
AgOAc
Ag3PO4
AgNO3
AgNO3
AgNO3

4
3
5
a
Isolated yields. Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol) in
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O

25
63
51
35
72
81 (80)
0
0
b
DMA (2 mL). Q = 8-quinolyl. 130 °C for 8 h then 170 °C for 16 h.
c
170 °C.
these catalytic conditions. Finally, this protocol could also be
conducted on a 1 mmol scale without a significant reduction in
yield (75% of 3a).
We then examined the scope of the substituted benzoate
coupling partners (Scheme 3). The decarboxylative annulation
d
e
9
10
11
d
d
Ni(OAc)2·4H2O
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol) in DMA (2
b
mL). Q = 8-quinolyl. 4.0 equiv of Ag were used in all reactions (0.4
mmol of Ag2CO3, 0.8 mmol of AgOPiv, AgOAc, and AgNO3, and
Scheme 3. Scope of Benzoate Coupling Partners in the Ni-
Catalyzed Oxidative Decarboxylative Annulation Reaction
a
c
0.26 mmol of Ag3PO4). 1H NMR yield with 1,3,5-trimethoxybenzene
d
e
as an internal standard. 2a (0.4 mmol). Isolated yield.
4H2O was identified to be the most efficient precatalyst
generating 3a in 25% yield (Table 1, entry 4), while all other
Ni salts tested provided only low yields of the product (<10%,
Table S1). Replacing Ag2CO3 with AgNO3 was found to
dramatically increase the yield of 3a to 72% (Table 1, entry 8).
Finally, increasing the loading of 2a to 2 equiv led to an
increase in yield of 3a to 81% (Table 1, entry 9). No coupled
product 3a was observed when either nickel or silver was
omitted from the reaction (entries 10 and 11, respectively).
Therefore, the optimized reaction conditions employ 20 mol %
Ni(OAc)2·4H2O, AgNO3 (4.0 equiv), and Na2CO3 (4.0 equiv)
in DMA at 130 °C for 24 h.
a
Isolated yields. Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol) in
DMA (2 mL). Q = 8-quinolyl.
With the optimized reaction conditions in hand, we turned
our attention to the heteroaromatic carboxylate coupling
partners (Scheme 2). We focused our attention on halide-
substituted 2-fluoronicotinic carboxylates because they are the
most accessible from existing synthetic routes.16 The reaction
is compatible with both electron-withdrawing (2d, 2e, 2g) and
electron-donating (2b, 2c, 2f) substituents on the nicotinic
carboxylate. Substitution in the 6-position (2b−2e) resulted in
lower yields than that obtained with the parent (2a) nicotinate,
while substitution in the 5-position was better-tolerated (2f
and 2g). This reaction system also tolerates bromo- and
chloro-substitution allowing for further functionalization of the
cyclized products 3e and 3g. Quinoline and thiophene
scaffolds are found in pharmacologically active compounds17
and material sciences,18 and the corresponding carboxylates
2h−2j also proved to be competent coupling partners under
of ortho-fluorobenzoates proceeded smoothly at 170 °C when
a variety of electron-donating (2m, 2n) and electron-
withdrawing substituents (2l, 2o, 2p) were included.
Unfortunately, the di-ortho-substituted benzoate 2q was an
ineffective coupling partner under these reaction conditions
(Chart S1).
Finally, we explored the scope of substituted benzamide
coupling partners (Scheme 4). Although other directing groups
have proven valuable in related catalytic coupling reactions,19
this decarboxylative annulation reaction appears to be limited
to the 8-aminoquinoline directing group (Chart S1), which can
be removed under oxidizing conditions.20 Substrates with
electron-donating groups para to the benzamide functionality
(1r, 1s) afforded higher yields (75% and 71%, respectively)
than those bearing electron-withdrawing groups (1t, 63%).
B
DOI: 10.1021/acs.orglett.8b03144
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Letter
Scheme 4. Scope of Benzamide Coupling Partners in the Ni-
Catalyzed Oxidative Decarboxylative Annulation Reaction
Scheme 6. Kinetic Isotope Effect in the Ni-Catalyzed
a
a
Oxidative Decarboxylative Annulation Reaction
a
Q = 8-quinolyl.
the C−H bond is an irreversible process, similar to that
observed in our prior studies of the Ni-catalyzed ODC
reaction.14
Finally, we explored the C−N bond-forming step. Treat-
ment of independently synthesized fluorinated biaryl benza-
mide 1z with 4.0 equiv of sodium carbonate in the absence of
both silver and nickel resulted in the formation of the cyclized
product 3k in nearly quantitative yield (>95%, Scheme 7).
a
Isolated yields. Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol) in
DMA (2 mL). Q = 8-quinolyl.
Similarly, substrates with electron-donating groups in the meta-
position (1u, 1v) provided higher yields (70% and 54%
respectively) than those with electron-withdrawing function-
alities (1w, 31% yield). It should be mentioned that the
absence of ortho-substitution resulted in a lower yield (1x,
48%). This new catalyst system also tolerates heterocyclic
benzamide 1y providing the opportunity to access additional
classes of substituted phenanthridinones with this method-
ology.
a
Scheme 7. Base-Promoted SNAr-Type Cyclization
We hypothesized that this new decarboxylative annulation
reaction likely proceeds via an initial oxidative decarboxylative
heteroarylation step,14 followed by an SNAr-type ring closing
reaction10f,13,21 (Scheme 5). To explore the possibility of such
a
Q = 8-quinolyl.
Taken together, these data are consistent with a pathway
involving initial Ni-catalyzed oxidative decarboxylative aryla-
tion followed by a based-promoted ring closing reaction as
proposed in Scheme 5.
Scheme 5. Proposed Pathway for the Ni-Catalyzed
Oxidative Decarboxylative Annulation Reaction
a
In conclusion, we have developed the first nickel-catalyzed
oxidative decarboxylative annulation reaction for the synthesis
of heterocycle-containing phenanthridinones. This new
method is effective not only for the coupling of heteroaromatic
carboxylates but also for that of ortho-fluorobenzoates. As a
result, this reaction allows access to a series of new heterocycle-
containing phenanthridinones of potential biological impor-
tance.
a
Q = 8-quinolyl.
a pathway, we conducted a series of control experiments. First,
we performed the standard reaction in the presence of
common radical trapping reagents. The reaction of 1a and
2a in the presence of 1.0 equiv of TEMPO or 9,10-
dihydroanthracence resulted in only a slight decrease in the
yields (74% and 78% respectively, Table S7). These data are
consistent with the absence of trappable radical intermedi-
ates.22
Next, to gain insight into the C−H activation step, we
carried out a pair of deuterium-exchange and kinetic isotope
effect (KIE) experiments (Scheme 6). First, we measured the
KIE from an intermolecular competition experiment. The
reaction of an equimolar mixture of 1a and 1a-d7 was treated
under the standard reaction conditions. After 30 min, the
product was obtained as a mixture of 3a and 3a-d6 in 16% and
4% yields, respectively, giving a KIE of 4.5. We then carried out
a hydrogen−deuterium exchange experiment of the deuterated
benzamide 1a-d7. When the standard reaction is conducted
with 1a-d7 for 30 min, less than 1% H incorporation is
observed. These combined data suggest that the cleavage of
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.8b03144.
Experimental procedures and characterization data for
starting materials and products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: Jessica.Hoover@mail.wvu.edu.
ORCID
Aaron P. Honeycutt: 0000-0002-4797-4158
Jessica M. Hoover: 0000-0003-0254-5090
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.8b03144
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Organic Letters
Letter
(13) Takamatsu, K.; Hirano, K.; Miura, M. Angew. Chem., Int. Ed.
2017, 56, 5353−5357.
ACKNOWLEDGMENTS
■
We are grateful to the NSF (CHE-1454879), the NIH
(1R15GM126514-01), and West Virginia University for
financial support of this work. NMR spectroscopy facilities
were partially supported by the NSF (CHE-1228336).
(14) Honeycutt, A. P.; Hoover, J. M. ACS Catal. 2017, 7, 4597−
4601.
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