Synthesis of Aminated Phenanthridinones via Palladium/Norbornene Catalysis

Article abstract of DOI:10.1021/acs.orglett.0c02850

An ortho-amination, ipso-C-H arylation mediated by palladium/norbornene cooperative catalysis is reported. This reaction proceeds through a sequential intermolecular C-N bond formation process followed by intramolecular C-H activation of a tethered arene. The products, aminated phenanthridinones, were generated in moderate to good yields. This method is also applicable to the formation of dibenzazepinones.

Full text of DOI:10.1021/acs.orglett.0c02850

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Letter
Synthesis of Aminated Phenanthridinones via Palladium/
Norbornene Catalysis
Xavier Abel-Snape, Andrew Whyte, and Mark Lautens*
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ABSTRACT: An ortho-amination, ipso-C−H arylation mediated by palladium/norbornene cooperative catalysis is reported. This
reaction proceeds through a sequential intermolecular C−N bond formation process followed by intramolecular C−H activation of a
tethered arene. The products, aminated phenanthridinones, were generated in moderate to good yields. This method is also
applicable to the formation of dibenzazepinones.
ransition-metal-catalyzed domino reactions have emerged
Tas useful approaches to construct complex molecules in a
single step without having to isolate intermediates.1 The
merging of C−H activation with diverse reactions has allowed
chemists to access different mechanistic pathways and to serve
as a complementary means to cross-coupling reactions.2 In
contrast to chelated-assisted reactions,3 the absence of a
directing group offers a powerful and useful strategy since the
Figure 1. Selected examples of bioactive phenanthridinones.
resulting molecule does not require a subsequent deprotection
or functional group interconversion step. A transient directing
In 2004, Catellani reported the Pd/NBE-catalyzed synthesis
group is known to be an applicable approach, yet selectivity
of phenanthridinones through ortho intermolecular arylation
issues may arise and as such constitute a significant
followed by intramolecular C−N coupling (Scheme 1a).16
More recently in 2016, Jiao constructed the same type of
compounds via a Pd/NBE-catalyzed intermolecular ortho
acylation followed by intramolecular C−H arylation (Scheme
1b).17
Until 2013, functionalization at the ortho-position via this
approach was broadly limited to carbon substituents.8 That
year, Dong reported ortho-amination was feasible using O-
benzoylhydroxylamines as coupling partners.18 Since then
numerous ipso functionalizations have been paired with the
ortho amination method including vinylation,19−21 arylation,22
alkynylation,23,24 cyanation,25,26 alkylation,27,28 and boryla-
tion.29 Cyclizations making use of ortho-amination have also
been reported such as a phenol dearomatization and a C(sp3)−
disadvantage.4
One extremely powerful reaction in its use of a transient C−
H bond activating agent is the Catellani reaction,5 also
described by some as palladium/norbornene (Pd/NBE)
cooperative catalysis, a well-known methodology that allows
dual functionalization at the ortho- and ipso-positions of aryl
halides through C−H bond activation.6,7 The functionalization
typically employs electrophilic reagents which react at the ortho
position with the aid of a norbornyl fragment as a transient
directing group and traditional palladium(0) cross-couplings to
functionalize the ipso position.8 This type of domino reaction
enables otherwise challenging disconnections, and notably, it
represents a novel route toward functionalized heterocycles.
We have been exploring the synthetic potential of the
annulative Catellani reaction since our first report in 2000
and C−H terminating reactions since 2005, and now report a
new route to the phenanthridinone skeleton.9−11
Received: August 25, 2020
The phenanthridinone motif is found in natural products as
well as anticancer drugs.9,10 Examples include the PJ34 PARP
inhibitor,12,13 a therapeutic agent for hepatitis C,14 and
pancratistatin, which displays antitumor activity (Figure 1).15
https://dx.doi.org/10.1021/acs.orglett.0c02850
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
report (see Supporting Information for more details). We
started with 2 equiv of 2, 10 mol % of Pd(PPh3)4, 3 equiv of
K2CO3, and 4 equiv of norbornene in toluene [0.05 M] at 100
°C for 16 h, which gave 3a in 77% yield (Table 1, entry 1).
Single-crystal X-ray diffraction was performed on 3a (see the
Supporting Information for details). Testing PivOH as an
additive decreased the yield of 3a to 62% while generating the
direct-cyclization side-product 3a′ in trace amount (entry 2).33
Replacing K2CO3 with Cs2CO3 or reducing the equivalence of
base led to no improvement in yield (entries 3−4). Increasing
the temperature, concentrating the reaction, or reducing the
equivalence of norbornene (entries 5−7) all resulted in lower
yields. However, further studies demonstrated that 5 mol % of
Pd(PPh3)4 was sufficient for just a slightly lower yield of 3a
(entry 8). Combining this reduced catalyst loading with only
1.2 equiv of 2 resulted in an isolated yield of 74% (entry 9).
Following optimization, we turned our attention to
investigating the scope of the reaction (Scheme 2). Exploring
different N-substitutions gave products 3b, 3c, and 3d in 85%,
67%, and 82% yields, respectively. Methyl substituents at the
para, meta, and ortho positions gave rise to 3e, 3f, and 3g in
74%, 74%, and 69% yields, respectively. A 10:1 regioisomeric
ratio was observed for the meta product 3f, likely stemming
from steric challenges of C−H activation to the di-ortho
substituted position. Examples 3h, 3i, and 3j revealed a clear
trend with respect to electronic effects of the carbonyl-tethered
arene moiety’s para substituent. Indeed, as the para
substitutent’s electron-withdrawing nature increased, so did
the corresponding yield (p-OMe, p-Me, p-H, p-F, p-CF3, 63%
to 83%). A 1.0-mmol-scale synthesis of 3j was performed,
which resulted in a 63% yield. 2-Naphthyl-derived 3k was only
generated in a low NMR yield of 22%. Heteroaryl motifs were
examined, and though thienyl-containing product 3l was
obtained in good yield, product 3m bearing a pyridine was
only generated in 30% yield. In contrast, 3n and 3o derived
from the corresponding 5-substituted anilines were generated
in good yields of 79% and 86%, respectively. It must be noted
that the 4-chloroaniline derivative did not manage to furnish
the desired product. It is known that bulky and/or non-
coordinating meta substituents relative to the iodide on the
substrate can lead to byproducts retaining the norbornene
fragment as steric hindrance prevents ortho C−H functional-
ization.34,35 We also tried synthesizing 3a from the
corresponding aryl bromide. However, the product was only
generated in 13% NMR yield.
Scheme 1. Previously Reported Pd/NBE-Catalyzed Domino
Reactions
H arylation.30,31 Our group has long been interested in the
application of the Catellani reaction toward the synthesis of
heterocycles. In 2017 we reported a Pd/NBE-mediated ortho-
amination ipso-amidation wherein sequential inter- and
intramolecular C−N bond formations took place (Scheme
1c).32
We wondered whether it would be possible to synthesize
phenanthridinone-type molecules, e.g. 3a, by means of a
different sequence of bond-forming events via Pd/NBE
cooperative catalysis, such as ortho-amination followed by
intramolecular C−H arylation (Table 1). To the best of our
knowledge, there are no reports of 1-amino-substituted
phenanthridinones. As such, these molecules constitute
unexplored chemical space.
We began investigating the assembly of ortho-aminated
phenanthridinones by reacting benzamide 1a with O-benzoyl-
hydroxylamine 2 using conditions resembling Dong’s initial
Table 1. Effect of Varying Reaction Conditions
Compound 1a was reacted with various electrophilic
amination reagents (Scheme 3). Ketal-protected 3p was
obtained in 50% yield, which can be further deprotected to
generate the primary aniline,29 while the aryl piperazinyl
product 3q was isolated in 72% yield. However, 1,2,3,4-
tetrahydroisoquinoline and hexamethylenimine products 3r
and 3s were only generated in 10% and 12% NMR yields,
respectively. As for piperidine and pyrrolidine products 3t and
3u, these were obtained in 29% and 17% yields, respectively.
A borane reduction of the phenanthridinone’s amide
functionality provided access to the amine 4 in 69% yield
(Scheme 4).
Inspired by Cramer’s work on the formation of dibenzaze-
pinones,36 we explored the possibility of generating seven-
membered heterocycles. As such, triphenylacetic acid derived
substrates 5a (R = H) and 5b (R = Me) were successfully
coupled with 2, both furnishing the atropisomers 6a and 6b in
55% yields (Scheme 5). The presence of three phenyl rings on
a
a
entry
variation(s)
3a (%)
3a′ (%)
1
2
3
4
5
6
7
8
9
none
77
62
77
58
75
68
62
75
0
1
4
0
0
0
0
0
0
PivOH as additive (30 mol %)
Cs2CO3 instead of K2CO3
K2CO3 (2 equiv)
120 °C
[0.1 M]
NBE (3 equiv)
Pd(PPh3)4 (5 mol %)
Pd(PPh3)4 (5 mol %), 2 (1.2 equiv)
b
79 (74)
a
1
Yields were determined by H NMR spectroscopy analysis of crude
reaction mixture using 1,3,5-trimethoxybenzene as an internal
b
standard. Isolated yield.
B
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a
a
Scheme 2. Substrate Scope
Scheme 3. O-Benzoylhydroxylamines Scope
a
Reactions were performed on a 0.2 mmol scale according to the
standard conditions shown above; isolated yields are shown.
a
Scheme 4. Derivatization of Compound 3a
a
Reaction was performed on a 0.2 mmol scale according to the
conditions shown above; isolated yield is shown.
a
Scheme 5. Dibenzazepinones Synthesis
a
Reactions were performed on a 0.2 mmol scale according to the
b
standard conditions shown above; isolated yields are shown. The
corresponding aryl bromide was used instead. 1.0 equiv of 2 was
used. 10 mol % of Pd(PPh3)4 was used. 1 mmol scale.
c
d
e
the starting material was essential for good yields (see the
Supporting Information for details).
a
The synthesis of 8 from 7 was attempted to generate other
isomers of the phenanthridinone (Scheme 6a). However, 8 was
only formed in 28% yield (by 1H NMR). During the
elaboration of this project, a carboxylate-assisted Pd/NBE-
catalyzed ortho-amination followed by C(sp2)−H arylation
methodology in order to synthesize 1-amino substituted
dihydrophenanthridines, phenanthridines, and 6H-benzo[c]-
chromenes was reported by Liang.37 Attempted synthesis of
one of the products included in the authors’ table, under our
conditions at 110 °C (Scheme 6b), gave 10 in 42% yield from
9, compared to the reported yield of 59%.
Reactions were performed on a 0.2 mmol scale according to the
conditions shown above; isolated yields are shown.
Carbopalladation with norbornene forms the syn intermediate
II. A subsequent K2CO3-assisted concerted metalation−
deprotonation (CMD) process gives rise to the key
intermediate in Catellani reactions: an aryl-norbornyl-pallada-
cycle (ANP). C−N bond formation occurs via either a Pd(IV)
intermediate IV stemming from a second oxidative addition
with O-benzoylhydroxylamine 2 followed by reductive
elimination or direct electrophilic substitution with 2
illustrated as transition state VI, both delivering V. Norbornene
extrusion occurs and leads to VII due to the “ortho effect”. A
second K2CO3-assisted CMD step as shown in transition state
Based on previous work reported by Catellani, our group,
and others,8,18,32,33,38 a plausible mechanism for this trans-
formation is shown in Scheme 7. Substrate 1a undergoes
oxidative addition to furnish aryl-Pd(II) intermediate I.
C
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Scheme 6. Synthesis of Analogous Six-Membered
Heterocycles
ASSOCIATED CONTENT
* Supporting Information
■
a
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02850.
Experimental procedures, characterization and X-ray
data, and NMR spectra (PDF)
Accession Codes
CCDC 2025322 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Mark Lautens − Davenport Research Laboratories, Department
of Chemistry, University of Toronto, Toronto M5S 3H6,
Canada; orcid.org/0000-0002-0179-2914;
Email: mark.lautens@utoronto.ca
a
Reactions were performed on a 0.2 mmol scale according to the
conditions shown above; isolated yields are shown.
Scheme 7. Proposed Mechanism
Authors
Xavier Abel-Snape − Davenport Research Laboratories,
Department of Chemistry, University of Toronto, Toronto M5S
3H6, Canada; orcid.org/0000-0003-3785-7617
Andrew Whyte − Davenport Research Laboratories, Department
of Chemistry, University of Toronto, Toronto M5S 3H6,
Canada; orcid.org/0000-0001-7261-4309
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02850
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the University of Toronto (U of T), the Natural
Science and Engineering Research Council (NSERC) and
Kennarshore, Inc. for financial support. X.A.-S. thanks the
NSERC for a CGS-M scholarship and the Province of Ontario
(OGS) for funding. A.W. thanks the Walter C. Summer
Memorial Fellowship and the Province of Ontario (OGS) for
funding. We thank Dr. Alan Lough (U of T) for X-ray
crystallography of 3a. We thank Dr. Darcy Burns and Dr. Jack
Sheng (U of T) for their assistance in NMR experiments. Jon
Bajohr (U of T) is acknowledged for the initial synthesis of
compound 6a.
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