Two step, one-pot sequential synthesis of functionalized hybrid polyheterocyclic scaffolds: Via a solid state melt reaction (SSMR)

Article abstract of DOI:10.1039/c9ra02590a

A new one pot assembly of highly functionalized benzo[a]phenazinone fused chromene/bicyclic scaffolds via a domino Knoevenagel intramolecular hetero-Diels-Alder (IMHDA) strategy using a solid state melt reaction (SSMR) of 2-hydroxynaphthalene 1,4-dione, o

Full text of DOI:10.1039/c9ra02590a

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Two step, one-pot sequential synthesis of
functionalized hybrid polyheterocyclic scaffolds via
a solid state melt reaction (SSMR)†
Cite this: RSC Adv., 2019, 9, 24314
a
Jayakumar Srinivasan,a Mir Ashiq Hussaina
*
*
Manickam Bakthadoss,
and Duddu S. Sharada
b
A new one pot assembly of highly functionalized benzo[a]phenazinone fused chromene/bicyclic scaffolds
via a domino Knoevenagel intramolecular hetero-Diels–Alder (IMHDA) strategy using a solid state melt
reaction (SSMR) of 2-hydroxynaphthalene 1,4-dione, o-phenylenediamine, O-allyl salicylaldehyde/O-
vinyl salicylaldehyde derivatives is reported. The formation of five new bonds (two C–C bonds and three
C–O bonds), three six-membered rings, and three stereogenic centers in a one-pot manner is very
attractive. Ease of reaction with short time, good yields with water as the only byproduct and work up
free procedure are some of the excellent features of the present protocol.
Received 6th April 2019
Accepted 24th July 2019
DOI: 10.1039/c9ra02590a
rsc.li/rsc-advances
Multicomponent reactions (MCRs)1 are known to construct dentate N atoms with three fused aromatic rings and an elec-
complex structures from simple starting materials in a rapid tron decient conjugated system. The presence of the above
and highly efficient manner where the production of wastes is features in phenazines give them an ability to form hydrogen
minimized. Those multicomponent reactions which are carried bonds, ionic bonds, and p–p interactions with relative ease,
out in a ‘one-pot’ MC sequential manner provide a high degree and their use has also been demonstrated in supramolecular
of reaction mass efficiency, which is crucial in the development chemistry for molecular recognition (MR), supramolecular self-
of modern synthetic methodology for drug discovery and assembly (MS-A), and organic optic electronics materials.6 Few
pharmaceutical programs.2 Enormous work has been carried representative examples of phenazine and its derivatives are
out in the eld of multicomponent reactions in the past decade shown in the Fig. 1.
where several MCRs have been developed and extensively used
Chromenes and their derivatives are privileged scaffolds due
in natural product synthesis and drug discovery. The Ugi reac- to their ubiquitous presence in many natural products and
tion is a prime example of a four-component reaction that has synthetic molecules.7 Chromenes are also an important class of
been found to be a powerful and efficient method for the compounds displaying interesting biological activities against
preparation of a-amino amides both in academia and industry.3 prostate cancer (DU-145) and breast cancer (MCF-7).8 Addi-
Therefore, the development of new MCRs for the synthesis of tionally, they have medicinal qualities such as antiviral and
biologically active molecules continues to attract considerable antimicrobial activity.9 Chromenes have also found their use in
attention for their atom- and step economy features.
medicine, health-promoting agents, and photochromic
Heterocycles having nitrogen atom are widely available in materials.10
nature and possess diverse and important biological activities.4
In recent years, the domino-Knoevenagel-hetero-Diels–Alder
Phenazines are a group of organic compounds known to the reaction (DKHDA) which was extensively studied by Tietze's
mankind since past 150 years and are known to exhibit signif- group constitutes an important process for the preparation of
icant biological activities such as antimalarial, fungicidal, try- complex compounds having interesting biological properties.11
panocidal, antiplatelet, etc.5 A large number of drug molecules The Diels–Alder reaction is important since it allows the
bearing the phenazine scaffold have been designed and evalu-
ated in the recent years. The phenazines motif possess two
aDepartment of Chemistry, Pondicherry University, Pondicherry-605 014, India.
E-mail: bhakthadoss@yahoo.com
bDepartment of Chemistry, Indian Institute of Technology Hyderabad, Kandi, 502285,
Sangareddy, Telangana, India
† Electronic supplementary information (ESI) available. CCDC [1906333 and
1906667]. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c9ra02590a
Fig. 1 Some of naturally occurring phenazine derivatives.
24314 | RSC Adv., 2019, 9, 24314–24318
This journal is © The Royal Society of Chemistry 2019

View Article Online
Paper
RSC Advances
formation of functionalized rings where there is complete (1) were rst melted at 180 ꢀC for 10 minutes to form the
control on regio-, diastereo-, and enantioselectivity. Moreover, intermediate benzo[a]phenazin-5-ol. Subsequently, (E)-methyl
the concerted nature of the Diels–Alder reactions allow the 2-((2-formylphenoxy)methyl)-3-phenylacrylate 3a was added and
selective formation of up to three stereogenic centers in a single the mixture was melted under the same temperature for 1 h
reaction step. Majority of the reactions reported on DKHDA which afforded the desired hybrid product chromene fused
have utilized 1,3-dicarbonyl compounds such as dimethyl bar- benzo[a]phenazinone 4a (ester moiety in ring junction) in 78%
bituric acid, Meldrum's acid and 1,3-indanedione.12 Addition- yield as shown in Table 1.
ally, other active methylene compounds like 1-phenyl-3-methyl
This two-step procedure allows the one-pot three-component
pyrazolone, 4-hydroxy-coumarin, dihydroindole-2-thione, ben- reaction to be controlled, avoiding the separation of interme-
zoylacetonitrile, 4-hydroxydithiocoumarin have been also diates, as well as time-consuming and costly purication
used;13 but phenazinones have never been employed in DKHDA processes. It is also important to mention here that the reaction
reactions. To the best of our knowledge, there are no reports on is not only diastereoselective, but also chemoselective. Among
intramolecular DKHDA reactions using phenazinone as the the two possible hetero diene such as C]O and C]N from
coupling partner. Due to our interest in the construction of phenazine ring, only the C]N diene is involved in the reaction
bioactive fused chromenophenazinone derivatives and since which clearly shows the chemo-selective nature of the reaction
this molecule contains a 1,3-dicarbonyl as well as a 1,3-imine (Fig. 2).
moiety, it would be very challenging to control the regiose-
To expand the scope of this one pot reaction, by following the
lectivity of the molecule; therefore phenazinone scaffold can act aforementioned procedure, we treated a variety of O-allylated
as a model substrate for an intramolecular DKHDA. We envis-
aged that a series of angular polycyclic chromeno fused phe-
nazinone derivatives could be obtained and it is possible that
Table
1 Synthesis of heptacyclic chromene fused benzo[a]
the nal hybrid compounds will result in being more selective
and efficient than chromene and phenazinone compounds in
biological assays.
phenazinonesa,b,c
In this direction, we have decided to develop a new method
for the preparation of novel benzo[a]phenazinone fused
chromene/bicyclic scaffolds via a domino Knoevenagel intra-
molecular hetero-Diels–Alder (IMHDA) strategy using a solid
state melt reaction (SSMR). As part of our research program for
the development of new synthetic methods in heterocyclic
chemistry14 and solid state melt reactions,15,16 we would like to
report a simple and a general domino three-component reac-
tion of 2-hydroxynaphthalene-1,4-dione, o-phenylenediamine
and O-allylated/vinylated salicylaldehyde for the synthesis of
pentacyclic benzo[a]phenazinone fused chromene/bicyclic
scaffolds under environmentally benign reaction conditions
(Scheme 1).
We have started this study by melting 2-hydroxynaphthalene-
1,4-dione (2), o-phenylenediamine (1), and (E)-methyl 2-((2-
formylphenoxy)methyl)-3-phenylacrylate (3) at 180 ꢀC for 1 h in
solvent free condition. Unfortunately, we could not obtain any
desired product and the formation of a complex mixture was
observed. To minimize the formation of the side products, the
2-hydroxynaphthalene-1,4-dione (2) and o-phenylenediamine
a
All reactions were carried out on 1 mmol scale of o-phenylenediamine
(1a–c)
2-hydroxynaphthalene-1,4-dione
(2),
and
O-allylated
b
salicylaldehyde derivatives (3a–o) at 180 ꢀC for 1 h. Isolated yield of
c
Scheme
1 Synthetic approach to benzo[a]phenazinone fused
the pure products (4a–q). All compounds were fully characterized
(see ESI).
chromenes.
This journal is © The Royal Society of Chemistry 2019
RSC Adv., 2019, 9, 24314–24318 | 24315

View Article Online
RSC Advances
Paper
Fig. 3 X-ray crystal structure of 4l and 8b.17
Fig.
2 Competitive two different heterodienes present in the
intermediate.
salicylaldehyde derivatives (3b–o) and melted with o-phenyl-
enediamine (1a–c), 2-hydroxynaphthalene-1,4-dione (2), which
Table
phenazinonesa,b,c
2 Synthesis of heptacyclic chromene fused benzo[a] successfully yielded the desired fused novel benzo[a]phenazi-
none fused chromene derivatives 4b–q in 71–80% yields. The
isolated yields of the pure products (4b–q) are summarized in
Table 1. The reaction is highly diastereoselective and chemo-
selective in nature, which has been, clearly evidenced in the 1H
NMR spectroscopy.
To check the generality of the reaction, we melted the O-
allylated salicyldehyde derivatives (5a–e) bearing nitrile func-
tionality,
with
o-phenylenediamine
(1a–b)
and
2-
hydroxynaphthalene-1,4-dione (2) for 1 h at 180 ꢀC which
successfully provided the anticipated hybrid benzo[a]phenazi-
none fused chromene derivatives (6a–f) (angularly substituted
nitrile moiety) in 65–70% yield (Table 2).
Further, to explore this methodology, we have prepared
a variety of vinylogous carbonate derivatives (7a–d) and treated
with o-phenylenediamine (1) and 2-hydroxynaphthalene-1,4-
dione (2) for 1 h at 180 ꢀC which successfully provided the
novel benzo[a]phenazinones fused bicyclic scaffolds
compounds (8a–d) in 94–96% yields (Table 3).
This one pot domino reaction is highly stereoselective in
nature and was evidenced by single crystal X-ray analyses.17 The
stereochemistry of the compounds 4l and 8b is conrmed by X-
ray crystallographic analysis (Fig. 3). It can be seen from the
crystal structure that the phenyl group and the adjacent ester
moiety are in the anti-orientation in benzo[a]phenazinone-
fused chromene (4l) which is due to the initial trans geometry
of the phenyl group and ester moiety present in the double
bond at vicinal position of the compound 4l. Similarly, the
ORTEP diagram of compound 8b (Fig. 3) clearly demonstrates
that the relative stereochemistry of the ester at the ring junction
and the ring junction hydrogen are in syn-orientation with each
other.
a
All reactions were carried out on 1 mmol scale of o-phenylenediamine
(1a–b),
2-hydroxynaphthalene-1,4-dione
(2),
and
O-allylated
b
salicylaldehyde derivatives (5a–e) at 180 ꢀC for 1 h. Isolated yield of
c
the pure products (6a–f). All compounds were fully characterized
(see ESI).
Table
scaffoldsa,b,c
3 Synthesis of benzo[a]phenazinones fused bicyclic
Conclusions
In conclusion, we have successfully developed a novel and
efficient method for the synthesis of heptacyclic frameworks
containing a benzo[a]phenazinone fused chromene/bicyclic
scaffolds via one pot multicomponent domino Knoevenagel
intramolecular hetero Diels–Alder (IMHDA) strategy using
a
All reactions were carried out on 1 mmol scale of o-phenylenediamine a Solid State Melt Reaction (SSMR) in a highly diastereoselective
(1a), 2-hydroxynaphthalene-1,4-dione (2), and vinylogous carbonate
and chemoselective fashion. This one pot two-step reaction
leads to a novel class of heterocyclic skeleton, which creates ve
b
derivatives (7a–d) at 180 ꢀC for 1 h. Isolated yield of the pure
c
products (8a–d). All compounds were fully characterized (see ESI).
new bonds, three new rings, three contiguous stereogenic
24316 | RSC Adv., 2019, 9, 24314–24318
This journal is © The Royal Society of Chemistry 2019

View Article Online
Paper
RSC Advances
centres and one of them being an all carbon quaternary centre.
Various advantages of this procedure include solvent and
catalyst free synthesis, high yields and short reaction time.
Additionally, the only by-product in this reaction is water, which
makes this protocol very attractive in green chemistry point of
view.
5010; (e) Q. Miao, Adv. Mater., 2014, 26, 5541; (f)
U. H. F. Bunz, J. U. Engelhart, B. D. Lindner and
M. Schaffroth, Angew. Chem., Int. Ed., 2013, 52, 3810; (g)
S. Horiuchi, F. Ishii, R. Kumai, Y. Okimoto, H. Tachibana,
N. Nagaosa and Y. Tokura, Nat. Mater., 2005, 4, 163.
7 (a) E. E. Schweizer, N. O. Meeder, and G. P. Ellis in
Chromenes, Chromanes, Chromones, Wiley-Interscience, New
York, 1977; (b) G. Zeni and R. C. Larock, Chem. Rev., 2004,
104, 2285–2309; (c) K. C. Nicolaou, J. A. Pfefferkorn,
A. J. Roecker, G. Q. Cao, S. Barluenga and H. J. Mitchell, J.
Am. Chem. Soc., 2000, 122, 9939–9953; (d) K. C. Nicolaou,
J. A. Pfefferkorn, H. J. Mitchell, A. J. Roecker, S. Barluenga,
G. Q. Cao, R. L. Affleck and J. E. Lillig, J. Am. Chem. Soc.,
2000, 122, 9954–9967; (e) K. C. Nicolaou, J. A. Pfefferkorn,
S. Barluenga, H. J. Mitchell, A. J. Roecker and G. Q. Cao, J.
Am. Chem. Soc., 2000, 122, 9968–9976.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
We thank CSIR (New Delhi) [02(0303)/17/EMR-II] for the
nancial support. J. S. thanks CSIR, New Delhi for his SRF
fellowship.
8 A. Kumar, S. Sharma, R. A. Maurya and J. Sarkar, J. Comb.
Chem., 2010, 12, 20–24.
9 (a) J. Hiramoto, A. Nasuhara, K. Michiloshi, T. Kato and
K. Kikugawa, Mutat. Res., 1997, 395, 47–56; (b) G. Shanthi
and P. T. Perumal, Tetrahedron Lett., 2007, 48, 6785–6789.
Notes and references
1 For some reviews on MC reactions, see: (a) R. M. Armstrong,
A. P. Combs, P. A. Brown and T. A. Keating, Acc. Chem. Res.,
¨
1996, 29, 123–131; (b) A. Domling and I. Ugi, Angew. Chem., 10 (a) T. A. Engler, K. O. LaTessa, R. Iyengar, W. Chai and
´
Int. Ed., 2000, 39, 3169–3210; (c) H. Bienayme, C. Hulme,
K. Agrios, Bioorg. Med. Chem., 1996, 4, 1755–1769; (b)
G. Oddon and P. Schmitt, Chem. –Eur. J., 2000, 6, 3321–
A. Elomri, S. Mitaku, S. Michel, A. L. Skaltsounis,
¨
`
3329; (d) A. Domling, Curr. Opin. Chem. Biol., 2000, 4, 318–
F. Tillequin, M. Koch, A. Pierre, N. Guilbaud, S. Leonce,
¨
323; (e) A. Domling, Chem. Rev., 2006, 106, 17–89; (f)
L. Kraus, Y. Rolland and G. Atassi, J. Med. Chem., 1996, 39,
4762–4766; (c) M. Kidwai, S. Saxena, M. K. R. Khan and
S. S. Thukral, Bioorg. Med. Chem. Lett., 2005, 15, 4295–
4298; (d) C. Tahtaoui, A. Demailly, C. Guidemann,
C. Joyeux and P. Schneider, J. Org. Chem., 2010, 75, 3781–
3785; (e) K. Mukai, K. Okabe and H. Hosose, J. Org. Chem.,
1989, 54, 557–560; (f) J. Jankun, S. H. Selman and
R. Swiercz, Nature, 1997, 387, 561; (g) S. Paramonov,
S. Delbaere, O. Fedorova, Y. Fedorov, V. Lokshin, A. Samat
and G. J. Vermeersch, J. Photochem. Photobiol., A, 2010,
209, 111–120; (h) R. A. Evans and G. K. Such, Aust. J.
Chem., 2005, 58, 825–830.
N. Isambert and R. Lavilla, Chem. –Eur. J., 2008, 14, 8444–
8454; (g) B. Ganem, Acc. Chem. Res., 2009, 42, 463–472; (h)
E. Ruijter, R. Scheffelaar and R. V. Orru, Angew. Chem., Int.
Ed., 2011, 50, 6234–6246.
2 J. Andraos, Org. Process Res. Dev., 2005, 9, 149–163.
3 (a) A. Doemling and I. Ugi, Angew. Chem., Int. Ed. Engl., 2000,
´
39, 3169–3210; (b) H. Bienayme, C. Hulme, G. Oddon and
P. Schmitt, Chem.–Eur. J., 2000, 6, 3321–3329.
4 Dictionary of Alkaloids, ed., I. W.Southon and J.Buckingham,
Chapman & Hall, New York, 1989.
5 (a) J. B. Laursen and J. Nielsen, Chem. Rev., 2004, 104, 1663–
1686; (b) M. Makgatho, R. Anderson, J. O'Sullivan, T. Egan, 11 (a) L. F. Tietze and U. Beifuss, Angew. Chem., 1993, 105, 137;
J. Freese, N. Cornelius and C. Van Rensburg, Drug Dev.
Res., 2000, 50, 195–202; (c) V. Andrade-Nieto, M. Goulart,
J. F. da Silva, M. J. da Silva, M. Pinto, A. Pinto, M. Zalis,
L. Carvalho and A. Krettli, Bioorg. Med. Chem. Lett., 2004,
14, 1145–1149; (d) C. Neves-Pinto, V. Malta, M. Pinto,
R. Santos, S. Castro and A. Pinto, J. Med. Chem., 2002, 45,
(b) L. F. Tietze, G. Brasche, and K. Gericke, Domino Reactions
in Organic Synthesis, Wiley-VCH, Weinheim, 2006, p. 160; (c)
L. F. Tietze, Chem. Rev., 1996, 96, 115; (d) L. F. Tietze, J.
Heterocycl. Chem., 1990, 27, 47; (e) L. F. Tietze in
Selectivity–A Goal for Synthetic Efficiency, ed W. Bartmann,
and B. M. Trost, VerlagChemie, Weinheim, 1984, p. 299.
740–743; (e) D. Cartwright, W. Chilton and D. Benson, 12 (a) M. J. Khoshkholgh, S. Balalaie, H. R. Bijanzadeh and
Appl. Microbiol. Biotechnol., 1995, 43, 211–216; (f) J. Ligon,
S. Dwight, P. Hammer, N. Torkewitz, D. Hofmann,
H. Kempf and K. Pee, Pest Manage. Sci., 2000, 56, 688–695;
J. H. Gross, ARKIVOC, 2009, ix, 114–121; (b) P. Biswas,
J. Ghosh and C. Bandyopadhyay, Tetrahedron Lett., 2014,
55, 6882–6886.
(g) M. Muller and T. Sorrell, Prostaglandins, 1995, 50, 301– 13 (a) M. J. Khoshkholgh, M. Loi, S. Balalaie and F. Rominger,
311.
Tetrahedron, 2009, 65, 4228–4234; (b) M. Mollazadeh,
M. J. Khoshkholgh, S. Balalaie, F. Rominger and
H. R. Bijanzadeh, J. Heterocycl. Chem., 2010, 47, 1200–1208;
(c) N. J. Parmar, B. R. Pansuriya, B. M. Labana,
T. R. Sutariya, R. Kant and V. K. Gupta, Eur. J. Org. Chem.,
2012, 2012, 5953–5964; (d) T. R. Sutariya, B. M. Labana,
B. D. Parmar, N. J. Parmar, R. Kantb and V. K. Gupta, RSC
6 (a) H. Xue, X.-J. Tang, L.-Z. Wu, L.-P. Zhang and C.-H. Tung, J.
Org. Chem., 2005, 70, 9727; (b) M. R. Gill, D. Cecchin,
M. G. Walker, R. S. Mulla, G. Battaglia, C. Smythe and
J. A. Thomas, Chem. Sci., 2013, 4, 4512; (c) S. M. Brombosz,
A. J. Zucchero, R. L. Phillips, D. Vazquez, A. Wilson and
U. H. F. Bunz, Org. Lett., 2007, 9, 4519; (d) S. Horiuchi,
R. Kumai and Y. Tokura, J. Am. Chem. Soc., 2005, 127,
This journal is © The Royal Society of Chemistry 2019
RSC Adv., 2019, 9, 24314–24318 | 24317

View Article Online
RSC Advances
Paper
Adv., 2015, 5, 23519–23529; (e) K. C. Majumdar, T. Abu and 15 (a) M. Bakthadoss, G. Sivakumar and D. Kannan, Org. Lett.,
N. R. Kumar, Tetrahedron, 2012, 68, 5693–5718.
2009, 11, 4466; (b) M. Bakthadoss, D. Kannan,
N. Sivakumar, P. Malathi and V. Manikandan, Org. Biomol.
Chem., 2015, 13, 5597; (c) M. Bakthadoss and
G. Sivakumar, Tetrahedron Lett., 2014, 55, 1765; (d)
M. Bakthadoss, R. Selvakumar and J. Srinivasan,
Tetrahedron Lett., 2014, 55, 5808; (e) M. Bakthadoss and
D. Kannan, RSC Adv., 2014, 4, 11723.
14 (a) M. Bakthadoss, D. Kannan and R. Selvakumar, Chem.
Commun., 2013, 49, 10947–10949; (b) M. Bakthadoss,
A. Devaraj and D. Kannan, Eur. J. Org. Chem., 2013, 1505–
1513; (c) M. Bakthadoss and G. Sivakumar, Tetrahedron
Lett., 2014, 1765–1770; (d) M. Bakthadoss, D. Kannan,
J. Srinivasan and V. Vinayagam, Org. Biomol. Chem., 2015,
13, 2870; (e) M. Bakthadoss and N. Sivakumar, Synlett, 16 (a) S. Paul and Y. R. Lee, Green Chem., 2016, 18, 1488–1494;
2009, 1014; (f) M. Bakthadoss and G. Murugan, Synth.
Commun., 2008, 38, 3406; (g) M. Bakthadoss and
R. Selvakumar, J. Org. Chem., 2016, 81, 3391–3399; (h)
(b) S. Vidyacharan, C. Adhikari, V. S. Krishna, R. S. Reshma,
D. Sriram and D. S. Sharada, Bioorg. Med. Chem. Lett., 2017,
27(7), 1593–1597.
M. Bakthadoss, N. Sivakumar and A. Devaraj, Synthesis, 17 CCDC number for the crystal structure 4l and 8b are 1906333
2011, 4, 0611–0618.
and 1906667.
24318 | RSC Adv., 2019, 9, 24314–24318
This journal is © The Royal Society of Chemistry 2019