KOtBu mediated synthesis of phenanthridinones and dibenzoazepinones

Article abstract of DOI:10.1021/ol301077y

Synthesis of substituted phenanthridinones and dibenzoazepinones has been realized from 2-halo-benzamides in the presence of potassium tert-butoxide and a catalytic amount of 1,10-phenanthroline or AIBN. This new carbon-carbon bond forming reaction gives direct access to various biaryl lactams containing six- and seven-membered rings chemoselectively. Carbon-carbon coupling seems to proceed by the generation of a radical in the amide ring which leads to C-H arylation of aniline.

Full text of DOI:10.1021/ol301077y

ORGANIC
LETTERS
KOtBu Mediated Synthesis of
Phenanthridinones and
Dibenzoazepinones
XXXX
Vol. XX, No. XX
000–000
Bhagat Singh Bhakuni, Amit Kumar, Shah Jaimin Balkrishna, Javeed Ahmed Sheikh,
Sanjit Konar, and Sangit Kumar*
Department of Chemistry, Indian Institute of Science Education and Research Bhopal,
(IISER), Bhopal, MP 462 023, India
sangitkumar@iiserb.ac.in
Received April 23, 2012
ABSTRACT
Synthesis of substituted phenanthridinones and dibenzoazepinones has been realized from 2-halo-benzamides in the presence of potassium tert-
butoxide and a catalytic amount of 1,10-phenanthroline or AIBN. This new carbonÀcarbon bond forming reaction gives direct access to various
biaryl lactams containing six- and seven-membered rings chemoselectively. CarbonÀcarbon coupling seems to proceed by the generation of a
radical in the amide ring which leads to CÀH arylation of aniline.
The search for a novel method to construct biaryls is a
topic of current interest in academia. Although the Pd-
catalyzed carbonÀcarbon coupling reaction is one of the
most reliable methods for synthesizing biaryls, consider-
able effort is being made to develop palladium-free ap-
proaches for the synthesis of biaryls due to a substantial
increase in the price of palladium over the past five years.
Among these palladium-free approaches, the catalytic
system using less expensive metals like Cu, Fe, Co, and
Ni or bases such as MOtBu (M = Na, K)/ligand mediated
CÀC coupling via CÀH arylation of arenes, has attracted
considerable interest for the construction of biaryls.
Recently potassium tert-butoxide mediated inter- and
intramolecular arylation of various substituted arenes
has been reported.1,2 For the first time, here we report a
potassium tert-butoxide mediated intramolecular carbonÀ
carbon coupling reaction through CÀH arylation of
an aniline ring for the synthesis of biologically active
phenanthridinones and related lactams. By using this alter-
native chemical reaction, six-membered phenanthridinone
and seven-membered dibenzoazepinone biaryl lactams
can be generated under mild reaction conditions from
2-halo-benzamide substrates using potassiumtert-butoxide
and a catalytic amount of 1,10-phenanthroline or azoiso-
butylonitrile (AIBN) eq 1.
Biaryl lactams are privileged cores present in many
alkaloids and pharmaceutically relevant organic mole-
cules.3,4 Earlier reported synthetic protocols involve a
multistep strategy for the construction of phenathridi-
nones and related lactams. Palladium-catalyzed biaryl
coupling is one of the key steps in the construction of
phenanthridinones.5À8 Recently a palladium-catalyzed
(1) (a) Yanagisawa, S.; Ueda, K.; Taniguchi, T.; Itami, K. Org. Lett.
2008, 10, 4673. (b) Sun, C.-L.; Li, H.; Yu, D.-G.; Yu, M.; Zhou, X.; Lu,
X.-Y.; Huang, K.; Zheng, S.-F.; Li, B.-J.; Shi, Z.-J. Nat. Chem. 2010, 2,
1044. (c) Liu, W.; Cao, H.; Zhang, H.; Zhang, H.; Chung, K. H.; He, C.;
Wang, H.; Kwong, F. Y.; Lei, A. J. Am. Chem. Soc. 2010, 132, 16737. (d)
Shirakawa, E.; Itoh, K.-i.; Higashino, T.; Hayashi, T. J. Am. Chem. Soc.
2010, 132, 15537. (e) Studer, A.; Curran, D. P. Angew. Chem., Int. Ed.
2011, 50, 5018. (f) Sun, C.-L.; Gu, Y.-F.; Wang, B.; Shi, Z.-J. Chem.;
Eur. J. 2011, 17, 10844. (g) Sun, C.-L.; Gu, Y.-F.; Huang, W.-P.; Shi,
Z.-J. Chem. Commun. 2011, 47, 9813. (h) Yanagisawa, S.; Itami, K.
ChemCatChem 2011, 3, 827. (i) Shirakawa, E.; Zhang, X.; Hayashi, T.
Angew. Chem., Int. Ed. 2011, 50, 4671. (j) For KOtBu mediated CÀN
(3) (a) Simanek, V. In The Alkaloids; Brossi, A., Ed.; Academic Press:
NewYork, 1985; Vol. 26, pp 185À229. (b) Lee, S.; Hwang, S.; Yu, S.; Jang,
W.; Lee, Y. M.; Kim, S. Arch. Pharm. Res. 2011, 34, 1065. (c) Fang,
S. D.; Wang, L. K.; Hecht, S. M. J. Org. Chem. 1993, 58, 5025.
(4) Hegan, D. C.; Lu, Y.; Stachelek, G. C.; Crosby, M. E.; Bindra,
R. S.; Glazer, P. M. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 2201.
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coupling reactions, see: Thome, I.; Bolm, C. Org. Lett. 2012, 14, 1892.
(2) (a) Rueping, M.; Leiendecker, M.; Das, A.; Poisson, T.; Bui, L.
Chem. Commun. 2011, 47, 10629. (b) Bajracharya, G. B.; Daugulis, O.
Org. Lett. 2008, 10, 4625. (c) Roman, D. S.; Takahashi, Y.; Charette,
A. B. Org. Lett. 2011, 13, 3242.
r
10.1021/ol301077y
XXXX American Chemical Society

one pot synthetic strategy was realized from N-methox-
ybenzamides and aryl iodide/arene coupling partners.7c,d
Charette et al. have reported an example of N-benzyl
phenanthridinone from a N-methyl-N-(2-iodophenyl)-
benzamide substrate.2c Nonetheless, these one pot proto-
cols have been reported only for the synthesis of six-
membered biaryl lactams.5À7 Moreover, deprotection of
NÀR (R = benzyl, methoxy) to NÀH is required after
biaryl coupling in most of these methodologies.3b,5a,5b,8c,8d
Recently, we have developed a copper catalyzed Se/SÀN
bond forming reaction from 2-halo-benzamides and sele-
nium/sulfur powder.9 Serendipitously, formation of phe-
nanthridinone 1 is observed while attempting the isolation
of a copperÀamide complex. It is worth noting that the
formation of 1 occurred even without the addition of
copper. In continuation of our work on coupling reactions
using 2-halo-arylamide substrates, here, we disclose a
new KOtBu mediated CÀC coupling reaction in 2-halo-
benzamides.
Optimization of reaction conditions is briefly summar-
izedinTable1. The yield ofcoupled product1 wasverylow
when the reaction was carried out in DMSO and DMF
despite the complete conversion of the substrate. The
reaction gave better a yield of phenanthridinone 1 from
2-iodo-N-phenylbenzamide in solvents such as benzene,
xylene, and mesitylene (Table 1, entriy 2). Various bases
such as K2CO3, KOH, NaOH, and nBuLi were also
screened for the optimization of reaction conditions, but
KOtBu was found to be a better base for the promotion
of coupling reactions. Next, ligands such as TMEDA,
Table 1. Optimization of Reaction Conditionsa
subs.
entry
M/ligand
solvent
t (h)
conv. (%)
1 (%)
1
2
3
4
5
6
7
8
CuI/Lb
DMF
24
14
14
7
100
100
97
20
CuI/L
benzene
benzene
benzene
benzene
benzene
benzene
benzene
45
À/L
90c
96
À/L/AIBNd
À/AIBNd
À/TMEDA
À/pyridine
À/ene
100
100
40
6
96
24
24
24
20
10
<10
trace
<5
a Reaction was carried out at a 1 mmol scale using 5 equiv of KOtBu.
L = 1,10-phenanthroline. b 20 mol % of CuI/L was used. c Trace of
decoupled product was observed. d 0.2 equiv of AIBN was used.
DMEDA, ethylenediamine (ene), and 1,10-phenanthro-
line were screened in the reaction (entries 6À8, Table 1).
In the presence of TMEDA, DMEDA, pyridine, and ene,
the reaction was sluggish and a poor yield of the coupled
product was obtained. 1,10-Phenanthroline provides a
90% yield of coupled product. KOtBu alone is not effective
for the CÀC coupling, as only 35% of product was formed
in 24 h and 60% of the unreacted substrate was recovered
from the reaction. When 0.2 equiv of a radical initiator,
AIBN, was employed, the coupled product was obtained
in excellent yield (Table 1, entry 5).
After extensive screening, we chose KOtBu (5À7 equiv)
and 1,10-phenathroline (20 mol %) orAIBN (0.2 eqiv) and
benzene/mesitylene as a solvent to study the substrate
scope and limitation of the reaction. Synthesized phenan-
thridinones and related lactams are presented in Table 2.
Phenanthridinone 1 was obtained in 96%, 70%, and 49%
yield from 2-iodo-, 2-bromo-, and 2-chloro-benzamides,
respectively. Substrates with an electron-withdrawing
fluoride, difluoride, chloride, bromide or the donating
group methyl, methoxy, and dimethoxy on either aryl ring
were tolerated under our reaction conditions (entries 2À8,
Table 2). Further, the scope of the reaction extended to
different aryl substrates. Naphthalene and thiophene
based 2-halo-arylamide substrates were successfully uti-
lized to form coupled products 9À10 and 28 under opti-
mized reactionconditions. Pyridine asanamidicring failed
to undergo a CÀC coupling reaction. Instead, hydroxyla-
tion of 2-bromo-N-phenyl-nicotinamide was observed (see
Supporting Information, pp S31À32). However, pyridine
as an amine ring coupled to form desired product 29 in
good yield (Table 3 entry 13). After studying the synthesis
of six-membered phenanthridinones 1À10 and 18À29
(vide infra), we turned our attention to seven-membered
dibenzoazepinones. Worthy of note, 2-(2-iodophenyl)-N-
phenylacetamide substrates underwent a CÀC coupling
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Michel, S.; Tillequin, F.; Poree, F.-H. Org. Lett. 2010, 12, 156. (j)
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Tetrahedron 2010, 66, 5008. (k) Donati, L.; Leproux, P.; Prost, E.;
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2011, 17, 12809. (l) Blanchot, M.; Candito, D. A.; Larnaud, F.; Lautens,
M. Org. Lett. 2011, 13, 1486.
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2768. (b) Banwell, M. G.; Lupton, D. W.; Ma, X.; Renner, J.; Sydnes,
M. O. Org. Lett. 2004, 6, 2741. (c) Ashburn, B. O.; Carter, R. G.;
Zakharov, L. N. J. Org. Chem. 2008, 73, 7305.
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3133. (b) Lee, S.; Hwang, S.; Yu, S.; Jang, W.; Lee, Y. M.; Kim, S. Arch.
Pharm. Res. 2011, 34, 1065–1070. (c) Wang, G.-W.; Yuan, T.-T.; Li,
D.-D. Angew. Chem., Int. Ed. 2011, 50, 1380. (d) Karthikeyan, J.; Cheng,
C.-H. Angew. Chem., Int. Ed. 2011, 50, 9880.
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. KOtBu-Mediated Synthesis of Biaryl Lactams
Table 3. Regioselective Cyclization on Substituted Aniline
a Yield obtained using 1,10-phenanthroline (20 mol %) and KOtBu
1
(5À7 equiv). b Ratio of isomers was determine by H NMR. c Isomers
were identified by comparison with reported data and 1D NOE experi-
ments on 22, 25, 26a, and 26b. d Both isomers separated. e Ratio and yield
were obtained by using AIBN and KOtBu.
with a substituted aniline ring were obtained in one pot
(entries 11À17, Table 2).
Variation of the substitution in the aniline ring is
documented in Table 3 to study the regioselective outcome
in the coupling reaction. Substrates with an ortho-substi-
tuted aniline ring gave a 5-exo regioisomer as the major
product (entries 1À3, Table 3). Substrates with a meta-
substituted aniline ring produced 5-exo and 6-exo/endo
regioisomers in a 1:1 ratio. It seems that the selectivity is
not influenced by the nature of the substituent at the meta
position, as the ratio remains unchanged in the presence of
an electron-withdrawing F and a donating methoxy sub-
stituent. Interestingly substrates with electron-withdraw-
ing substituents in the aniline ring at the para position
gavethe 6-exo/endo product exclusively whereas substrates
with electron-donating ÀCH3 and ÀOCH3 substituents
gave both regioisomers (entries 6À10, Table 3). N-1-
Naphthyl and N-2-pyridyl substrates gave 5-exo and
6-exo/endo regioisomers in 9.5:1 and 5.1:1 ratios, respec-
tively. In the case of seven-membered analogues 11À17
only one regioisomer was observed regardless of the posi-
tion and the nature of the substituent in the aniline ring
(entries 12À17, Table 2). The regiochemistry of seven-
membered dibenzoazepinone 12 was also established by
a Yield obtained using 1 mmol of substrate, 0.2 equiv of AIBN or
1,10-phenanthroline, and 5À7 equiv of KOtBu. AIBN and 1,10-phenan-
throline were used for compounds 1À10 and 11À18, respectively.
Structures of 12À17 were predicted based on a crystal structure study.
reaction chemoselectively to form seven-membered diben-
zoazepinones (11À17) under our reaction conditions,
despite the possibility of a CÀN coupling reaction.
From our literature survey, it seems that synthesis of
seven-membered dibenzoazepinones involved multisteps
including Pd-catalyzed biaryl coupling as one of the
key steps.8 Moreover, present multistep methods have
only been applied to the synthesis of dibenzoazepinones
with unsubstituted aniline rings.8a,c,e Under our reaction
conditions, several seven-membered dibenzoazepinones
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 1. Proposed Mechanism for CÀH Arylation of Aniline
Scheme 2. Control Experiment on 2-Iodobenzamide
only 28% of the N-methyl analogue of 1 and the rest of the
substrate converted into the decoupled product under
optimized reaction conditions (please see Supporting In-
formation for control experiment, p S34). Therefore it is
reasonable to assume that the presence of NÀH is crucial
for the complete conversion of the substrate into the CÀC
coupled product. Radical II could attack on the aniline
ring in an 6-exo/endo-trig or 5-exo-trig fashion leading to
intermediates IV and VI respectively. Ring expansion in
the intermediate IV would give the more stable hexadienyl
radical V. Intermediates V and VI could be deprotonated
in the presence of KOtBu leading to anion radicals VII and
VIII, respectively.10 In the last step, these radical anions
would undergo electron transfer with intermediate I togive
respective products, KI, and new radical II, thus continu-
ing the radical chain with concomitant release of the
product.
single crystal X-ray studies (see Figure S5 in the Support-
ing Information).
As the position of the substituent in the aniline ring
remains unchanged in the substrates and seven-membered
biaryl lactams (entries 12À17, Table 2), it seems that
formation of a seven-membered ring occurred by 7-exo/
endo-trig radical cyclization.
In summary, we have developed a simple palladium-free
approach for the synthesis of phenanthridinone and re-
lated biaryl lactams from readily available 2-halo-benza-
mides. The use of KOtBu and a catalytic amount of
1,10-phenanthroline or AIBN is enough to obtain a high
yield of the coupled product by the CÀH arylation of the
anilinering.Mostimportantly,aonepot synthesisofseven-
membered dibenzoazepinones from 2-halo-arylamides of-
fers a unique process to traditional Pd-catalyzed reactions.
Studies for a further understanding of this reaction and
its application for the synthesis of other classes of organic
molecules are underway in our laboratory.
A possible reaction mechanism is depicted in Scheme 1
for the KOtBu-mediated CÀC coupling reaction in 2-halo-
benzamides. CarbonÀcarbon coupling occurred smoothly
in the presence of radical initiator AIBN, and the presence
of radical was also confirmed by EPR spectroscopy in the
reaction mixture (please see Supporting Information for
EPR experiment). In conclusion, we believe that this is a
radical pathway by which CÀH arylation of the aniline
ring occurrs.1g,2c,10 The first step seems to be deprotona-
tionof NÀH by KOtBu leading tointermediate I asstudied
radical II by KOtBu to initiate the radical process.
To gain insight into the generation of the radical step,
whether the radical is generated in the aniline or amide
ring, a control experiment was carried out between 2-iodo-
benzamide and iodobenzene vs benzene (eq 2, Scheme 2).
Only one cross-coupled product, 30, was observed and
arylation of the aniline ring was not detected, thereby
suggesting the generation of the radical in the amide ring
as presented in Scheme 2.
1
by H NMR. The next step could be the generation of
Acknowledgment. We are thankful to Department of
Science and Technology(DST), New Delhi, India, Depart-
ment of Atomic Energy (DAE-BRNS) Mumbai, and
IISER Bhopal for financial support. We thank the Edi-
tor/the Reviwers for proof reading, Professor Vinod K.
Singh and Mr. R. Unhale for EPR experiments, and Dr. S.
Katukojvala for mechanistic discussions.
Generated carbon centered radical II in an amide ring
seems to be stabilized by the ÀC(O)NH functionality
leading to intermediate III. The 2-iodo-N-methyl-N-
phenylbenzamide substrate lacking the NÀH proton gave
Supporting Information Available. Experimental de-
tails, characterization data for compounds, and CIF file
for 12 (CCDC No. 870848). This material is available free
of charge via the Internet at http://pubs.acs.org.
~ꢀ~
(10) Rossi, R. A.; Pierini, A. B.; Penenory, A. B. Chem. Rev. 2003,
103, 71.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX