Palladium-Catalyzed Direct Synthesis of Phenanthridones from Benzamides through Tandem N–H/C–H Arylation

Article abstract of DOI:10.1002/ejoc.201701039

We report a palladium-catalyzed method for the direct synthesis of phenanthridones from benzamides in a single step. Unlike previous reports, the current protocol does not need any directing groups or any harsh conditions. This methodology has a wide functional group tolerance therefore a series of phenanthridones were synthesized with a yield up to 87 %. The efficacy of this protocol was further explored by synthesizing some important naturally occurring amaryllidaceae alkaloids in a single step with very good yields.

Full text of DOI:10.1002/ejoc.201701039

A Journal of
Accepted Article
Title: Palladium-catalyzed Direct Synthesis of Phenanthridones from
Benzamides through Tandem N-H/C-H Arylation
Authors: Biswadip Banerji, Satadru Chatterjee, K Chandrasekhar,
Chinmay Nayan, and Sunil Kumar Killi
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701039
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701039
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10.1002/ejoc.201701039
European Journal of Organic Chemistry
COMMUNICATION
Palladium-catalyzed Direct Synthesis of Phenanthridones from
Benzamides through Tandem N-H/C-H Arylation
Biswadip Banerji*a,b, Satadru Chatterjeea, K. Chandrasekhara, Chinmay Nayana, Sunil Kumar
Killia
phenanthridone and its derivatives (Figure 2), these have
number of limitations also.[6b, 7] In each case either a directing
group dictates course of the reaction or the ligand used, played
a pivotal role. Moreover, in most of the cases, the conditions
used were too harsh and the substrate scopes were limited.
Abstract: We here in report a palladium catalyzed method for the
direct synthesis of phenanthridones from benzamides in a single
step. Unlike previous reports, the current protocol does not need any
directing groups or any harsh conditions. This methodology has a
wide functional group tolerance therefore
a
series of
Therefore
a
quick and easy access to
a
variety of
phenanthridones were synthesized with a yield up to 87%. The
efficacy of this protocol was further explored by synthesizing some
important naturally occurring amaryllidaceae alkaloids in a single
step with very good yields.
phenanthridones is still a synthetic challenge.
Synthesis of new heterocycles continues to be a major part in
pharmaceutical research as most of the bioactive compounds or
Figure 1: Some natural products along with some popular drugs having
phenanthridone as a core motif.
Its congeners belong to either a direct heterocycle or a hybrid
scaffold.[1] Phenanthridones are one such heterocyclic motif
which are present in wide class of bioactive alkaloids (like
amaryllidaceae alkaloids etc).[2] Different anticancer and antiviral
drugs,[3] PARP inhibitors[4] and acetylcholine esterase inhibitors[5]
contain phenanthridones as a core motif (Figure 1). Due to their
significant pharmaceutical importance, phenanthridones are
always under the limelight in the therapeutic domain. Serious
research works are going on to enrich the chemistry of
phenanthridones by evolving new efficient synthetic routes.
[6]Though a number of methods are available for the synthesis of
Figure 2: Previously reported synthetic protocols of phenanthridones with
respect to our current work
In recent years, transition metal catalyzed construction of
different heterocycles and carbocyles is common practice.[8]
Palladium catalysts are the mostly used transition metal
catalysts due to their efficiency and compatibility with a large
number of functional groups. Most of the previously reported
phenanthridone derivatives were synthesized using palladium
catalysts as a key element.[6d, e, 9]
[a,b] Biswadip Banerji*a,b, Satadru Chatterjeea, K Chandrasekhara,
Chinmay Nayana , Sunil Kumar Killia
aOrganic & Medicinal Chemistry Division, Indian Institute of Chemical
Biology (CSIR-IICB)bAcademy of Scientific and Innovative Research,
(AcSIR), 4 Raja S. C. Mullick Road, Kolkata, Country. India-700032;
Fax: (+) 91 33 24735197, 91 33 24723967; Tel: (+) 91 33 24995709;
Email ID: biswadip.banerji@gmail.com
In the present study, we developed a new synthetic
method to construct a group of phenanthridone derivatives with
ease from different simple amides in moderate to good yield. No
directing group or external ligand was required for the reaction to
proceed. The reaction condition is relatively mild and clean
products were achieved in decent yields. The reaction is
intermolecular and simultaneously forms a C-C and C-N bond to
Supporting information for this article is given via a link at the end of the
document
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10.1002/ejoc.201701039
European Journal of Organic Chemistry
COMMUNICATION
generate the desired phenanthridone moiety. As the reaction
needs no directing groups or ligand to proceed, a large number
of target heterocycles can be synthesized by this simple method
in shorter time. Our study therefore unveiled a new way to
access a wide variety of phenanthridones quickly and efficiently.
the best. Thus, having the best reaction condition in hand, we
explored this methodology to prepare wide varieties of
phenanthridones in good yields (Figure 3). Both N- substituted
benzyl and phenyl groups react equally well in this case.
Different simple and heteronuclear amides afforded the
The synthetic scheme started by preparing different simple
and substituted benzamides (1).It was then subjected to reaction
with 1-bromo-2-iodobenzene (2) in a sealed tube in
Entry Catalyst
Ligand
Base
Solvent Yield(%)
1
2
Pd(OAc)2
X-Phos Cs2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
18
16
Scheme 1: One pot synthesis of phenanthridones
Pd(OAc)2 Xantphos Cs2CO3
presence of Pd(PPh3)2Cl2 as a catalyst, Cs2CO3 as base in dry
DMF at 140 oC under N2 atmosphere for 16 hrs. to form different
phenanthridone derivatives (3) via simultaneous formation of an
Intermolecular C-C and C-N bond in good to excellent yield.
3
PdCl2
X-Phos Cs2CO3
X-Phos Cs2CO3
X-Phos Cs2CO3
X-Phos Cs2CO3
Trace
Trace
Trace
59
4
Pd(acac)2
Pd(dba)3
Pd(PPh3)4
Optimization studies were performed in search of best
condition to carry forward and to get better yield. At first, an
oxidative condition using molecular oxygen as oxidant, Pd(OAc)2
as catalyst, X-Phos as ligand and Cs2CO3 as base in dry DMF at
5
o
6
140 Cwas tried but, to our disappointment, no desired product
was formed. Then we have tried various other ligands (like dppf,
Xantphos etc.) but still ended up with the same result.
Subsequently, we varied the catalyst system as well as different
ligands but still no satisfactory results were obtained. Then we
changed the reaction from O2 to N2 atmosphere and to our
surprise the desired compound was formed in poor yield using
Pd(OAc)2 as catalyst, X-Phos as ligand and Cs2CO3 as base in
dry DMF at 140 oC after 16 hours. The yield was further
increased by changing the catalyst system to Pd(PPh3)4 and
finally to Pd(PPh3)2Cl2. Thereafter we observed that the
presence or absence of ligand in the reaction medium does not
affect the yield of the final product (Table 1, entry 10)..
7
Pd(PPh3)4 Xantphos Cs2CO3
57
8
Pd(PPh3)4
X-Phos K2CO3
49
9
Pd(PPh3)2Cl2 X-Phos Cs2CO3
88
10
11
12
13
14
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
-
Cs2CO3
87
-
K2CO3
76
-
Cs2CO3 1,4-dioxane
67
-
-
Cs2CO3
Cs2CO3
Toluene
DMSO
58
79
Table 1: Optimization of the reaction condition.
Figure 3: Schematic representation of cyclisation
corresponding products in good yields. Substitution at different
It was also observed that lowering the reaction temperature
ended up in lesser yield. Cs2CO3 was found to be superior over
K2CO3. Among different solvents tested, DMF was found to be
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10.1002/ejoc.201701039
European Journal of Organic Chemistry
COMMUNICATION
isopropyl), the reactions did not proceed at all. The positions of
the different functional groups were also equally examined and
gratifyingly it was observed that substitution at different positions
of ring A & B did not actually affect the yield of the final product.
Surprisingly, We have got only single isomer for compound 3m
instead of a mixture of two which might be due to the negative
inductive effect (-I) of chlorine at ortho position which facilitated
the coupling at that position.
The success of any good methodology lies in its fruitful
application. Thus, we tried to utilize this new method by
synthesizing two important naturally occurring amaryllidaceae
alkaloids, N-methylcrinasiadine (4B) and N-isopentylcrinasiadine
(5B) in a single step. Most of the previously reported procedures
were multistep, under very harsh conditions. Surprisingly, in this
reaction course two regioisomers (4A, 4B & 5A, 5B in Fig. 5)
were formed in ratio 6:4 (4A:4B) & 7:3 (5A:5B) .To best of our
knowledge; the new regioisomeric compounds 4A and 5A (with
yield more than or equals to 60%) belong to a new class of
phenanthridone.
On the basis of the aforementioned results, we propose a
tentative mechanism for the phenanthridone synthesis (Fig. 6).
Figure 4: Substrate scope of the reaction with various kinds of amides along
with isolated yields in %.
positions as well as electronic nature of the aromatic rings were
thoroughly studied. It was observed that the presence of
electron withdrawing or electron donating groups did not affect
much in the yield of the final product except for –NO2 group in
the B ring which resulted a sluggish reaction and for –CN group,
the reaction yield was poor (Fig. 4). A dimer product was
obtained using aliphatic diaminopropane (3l in Fig. 4). In case of
amides with bulky aliphatic groups (such as tertiary butyl or
Figure 6: Proposed reaction mechanism.
The reaction cycle started with the formation of the intermediate
I through oxidative insertion of palladium (0) to C-I bond.
Intermediate I was then converted to intermediate II via a C-N
bond formation, eliminating HI. Again oxidative insertion of
palladium (0) to C-Br bond resulted intermediate III which was
further transformed to the palladacycle (intermediate IV),
eliminating HBr. Finally, via reductive elimination, the desired
phenanthridones were generated ending the catalytic cycle.
In conclusion, an efficient method was developed to
synthesize phenanthridone derivatives from easily available
synthones. This new methodology opens up new avenues to
Figure 5: Application of Pd-catalysed synthesis of phenanthridone.
successfully synthesize
a variety of different substituted
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10.1002/ejoc.201701039
European Journal of Organic Chemistry
COMMUNICATION
phenanthridones in moderate to good yields. This was further
employed to synthesize two natural products along with their
regioisomers in single steps. Owing to the therapeutic
importance of this particular heterocycle, the present
methodology will be a valuable addition towards its present
synthetic endeavours.
Chemistry–A European Journal 2016, 22, 3506-3512; c) B.
Banerji, S. Chatterjee, K. Chandrasekhar, S. Bera, L. Majumder,
C. Prodhan and K. Chaudhuri, Organic
& Biomolecular
Chemistry 2017; d) C. Chen, G. Shang, J. Zhou, Y. Yu, B. Li and
J. Peng, Organic letters 2014, 16, 1872-1875; e) L. Ye, K.-Y. Lo,
Q. Gu and D. Yang, Organic Letters 2017.
[9] a) R. Bernini, S. Cacchi, G. Fabrizi and A. Sferrazza,
Synthesis 2008, 2008, 729-738; b) R. Ferraccioli, D. Carenzi, O.
Rombola and M. Catellani, Organic letters 2004, 6, 4759-4762;
c) K. Tanimoto, N. Nakagawa, K. Takeda, M. Kirihata and S.
Tanimori, Tetrahedron Letters 2013, 54, 3712-3714.
Acknowledgements
The authors thank CSIR for funding in this project. SC & CN
want to thank UGC for a Senior Research Fellowship; KC wants
to thank CSIR for a Senior Research Fellowship. We thank Mr.
E. Padmanaban Mr. Tapas Sarkar for recording the NMR and
Mr. Sandip Chakraborty for recording the EI Mass spectra.
Keywords: Palladium catalyzed • Tandem reaction •
Phenanthridone
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