β-Cyclodextrin mediated MCR in water: Synthesis of dihydroisoindolo[2,1-a]quinazoline-5,11-dione derivatives under microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2013.09.138

We report a faster and greener approach for the synthesis of dihydroisoindolo[2,1-a]quinazoline-5,11-dione derivatives of potential pharmacological interest via a β-CD mediated MCR in water under microwave irradiation.

Full text of DOI:10.1016/j.tetlet.2013.09.138

Accepted Manuscript
β-Cyclodextrin mediated MCR in water: Synthesis of dihydroisoindolo[2,1-
a]quinazoline-5,11-dione derivatives under microwave irradiation
G. Rajeshwar Reddy, T. Ram Reddy, R. Gangadhara Chary, Suju C. Joseph,
Soumita Mukherjee, Manojit Pal
PII:
S0040-4039(13)01713-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.09.138
TETL 43638
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 August 2013
29 September 2013
30 September 2013
Please cite this article as: Rajeshwar Reddy, G., Ram Reddy, T., Gangadhara Chary, R., Joseph, S.C., Mukherjee,
S., Pal, M., β-Cyclodextrin mediated MCR in water: Synthesis of dihydroisoindolo[2,1-a]quinazoline-5,11-dione
derivatives under microwave irradiation, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.
2013.09.138
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β-Cyclodextrin mediated MCR in water: Synthesis of
dihydroisoindolo[2,1-a]quinazoline-5,11-dione derivatives
under microwave irradiation
Leave this area blank for abstract info.
G. Rajeshwar Reddy, T. Ram Reddy, R. Gangadhara Chary, Suju C. Joseph, Soumita Mukherjee, and
Manojit Pal*
O
O
O
R
N
O
+
OH
X
N
X
N
O
H
O
O
+ RNH2
β-CD mediated MCR in water under microwave irradiation afforded dihydroisoindolo[2,1-a]quinazoline-5,11-dione
derivatives of pharmacological interest.
2

β-Cyclodextrin mediated MCR in water: Synthesis of dihydroisoindolo[2,1-
a]quinazoline-5,11-dione derivatives under microwave irradiation
G. Rajeshwar Reddy,a,b T. Ram Reddy,a R. Gangadhara Chary,a Suju C. Joseph,a Soumita Mukherjee,c
and Manojit Palc,*
aCustom Pharmaceutical Services, Dr. Reddy’s Laboratories Limited, Bollaram Road Miyapur,
Hyderabad 500 049, India
bJNT University, Kukatpally, Hyderabad 500085, Andhra Pradesh, India
cDr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500
046, India
E-mail: manojitpal@rediffmail.com
--------------------------------------------------------------------------------------------------------------------------------------------------
Abstract. We report a faster and greener approach for the synthesis of dihydroisoindolo[2,1-
a]quinazoline-5,11-dione derivatives of potential pharmacological interest via a β-CD mediated MCR
in water under microwave irradiation.
Keywords: β-CD; MCR; water; dihydroisoindolo[2,1-a]quinazoline-5,11-dione; microwave
----------------------------------------------------------------------------------------------------------------------------------------------------
-------------------------------------------
*Corresponding author. Tel.: +91 40 6657 1500; E-mail: manojitpal@rediffmail.com (MP)
3

Multi-component reactions1,2 (MCRs) that provide diversity based combinatorial library of small
molecules required by pharmaceutical and agrochemical industries are of great demand when
performed under green conditions. Such methodologies often address the growing concern about
environmental safety and hazard. Since performing chemical reactions in water in the presence of a
catalyst derived from biomass enhances the greenness of the process, the development of such
economic and eco-friendly methodologies therefore is the central focus in the area of green and
sustainable chemistry. Recently, cyclodextrin-mediated reactions in aqueous media have been
explored for this purpose.3 Being cyclic oligosaccharides, cyclodextrins (CDs) possess cavities (Fig.
1), that are less hydrophilic than water and bind substrates selectively thereby catalyzing the reactions
with high selectivity (indeed, these reactions are facilitated by supramolecular catalysis involving
reversible formation of host-guest complexes by non-covalent bonding). Additionally, CDs are
Non-polar cavity at
the center
Primary hydroxyl rim
Fig. 1. A view of cyclodextrin.
nontoxic and considered to be metabolically safe.3a Due to the importance of TNF-α (Tumor Necrosis
Factor-alpha) inhibition4a in the treatment of inflammatory disorders such as rheumatoid arthritis,
Crohn’s disease, and ulcerative colitis, a monoclonal antibody i.e. infliximab4b has been discovered
and is being used as a TNF-α inhibitor. In our effort to design and synthesize novel small molecules5
as inhibitors of TNF-α, we have recently reported6 the synthesis of 6,6a-dihydroisoindolo[2,1-
a]quinazoline-5,11-diones (4, Scheme 1) as potential inhibitors. In continuation of this research, we
required a wide variety of close analogues for our SAR (Structure Activity Relationship) studies. In
order to develop a robust and faster synthesis of this class of compounds, CDs attracted our attention
due to their favorable properties amenable to eco-friendly approaches. During recent years microwave
assisted reactions7-11 have gained considerable attention in organic synthesis especially in the area of
drug discovery. These green processes have remarkable advantages over the reactions performed
under conventional heating. Herein we report a greener synthesis of 4 mediated by β-CD in water
under microwave irradiation (Scheme 1).
4

Montmorillonite K10
O
N
O
O
O
EtOH
(earlier work
ref 6; X = H)
R
N
O
+ RNH2
+
OH
X
β
-CD
X
N
H
O
O
3
H2O, MW
(present work)
2
1
4
Scheme 1. Earlier and present synthesis of 4..
Initially, the reaction of isatoic anhydride (1a), aniline (2a) and 2-formylbenzoic acid (3) was
examined in the presence of a range of commercially available catalysts in water under microwave
Table 1. Optimization of reaction conditions.a
O
O
PhNH2 (2a)
O
Ph
N
Catalyst
O
+
OH
Solvent
N
N
H
O
O
O
3
4a
1a
Heating time
Microwaveb Conventional (h);
Conversion (%)
Catalyst
(w/w%)
Entry
(min)
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
90-100 ºC
14-16
14-16
14-16
14-16
14-16
14-16
14-16
14-16
14-16
14-16
14-16
14-16
14-16
--
1
Iodine (20)
p-TSA (10)
p-TSA (20)
p-TSA (30)
30
2
45
3
55
4
55
5
NaHSO3 –SiO2 (10)
NaHSO3 –SiO2 (20)
INDION 225H (5)
INDION 225H (15)
INDION 225H (25)
β-CD (5)
45
6
50
7
55
8
70
9
71
10
11
12
13
14
15
16
70
β-CD (10)
80 (78,77,75)c
β-CD (15)
80
No catalyst
15
β-CD (15)
65d
50e
60f
β-CD (15)
--
β-CD (15)
--
5

aAll the reactions were carried out using isatoic anhydride 1a (1.0 mmol), aniline 2a (1.2 mmol), 2-
formylbenzoic acid 3 (1.0 mmol) and catalyst in water (5 mL).
bThe reaction mixture was irradiated in a CEM Explorer microwave.
cRecovered aqueous β-CD was used.
di-PrOH was used in place of water.
eMeOH was used in place of water.
f1,4-Dioxane was used in place of water.
and conventional heating separately (Table 1). While the reaction proceeded in the presence of I2
(entry 1, Table 1), p-TSA (entries 2-4, Table 1), NaHSO3-SiO2 (entry 5 and 6, Table 1), or INDION
225H (entries 7-9, Table 1) affording the desired product 4a, the degree of conversion varied from 30
to 71% depending on the nature and quantity of catalyst used. Improved conversion was observed
when 10 w/w% of β-CD was used (entry 11 vs 10 and 12, Table 1). An increase in reaction time from
10 min to 15 min did not improve the degree of conversion significantly. The poor conversion in the
absence of a catalyst (entry 13, Table 1) indicated its key role in the present MCR. Thus, β-CD was
found to be the catalyst of choice and was used for our further studies. As expected, all these reactions
required much longer time (14-16 h) when performed under conventional heating as compared to
microwave heating (entries 1-13, Table 1). The role of other solvent e.g. i-PrOH, MeOH or 1,4-
dioxane was also examined and found to be less effective (entries 14-16, Table 1). To test the
recyclability of the catalyst, the aqueous β-CD was recovered after usual work-up with organic
solvent and reused12 to afford 4a without changing of the degree of conversion significantly (entry 11,
Table 1).
We then performed the β-CD-mediated MCR12 using various aromatic and aliphatic amines 2 (Table
2). Substituents like Br and Cl or electron donating OMe and But or electron withdrawing CN and
CO2Me groups on the aryl ring were well tolerated and afforded 4 in good to excellent yields.
Aliphatic amines e.g. methyl, cyclopropyl or 2-phenylethanamine or N1,N1-dimethylpropane-1,3-
diamine as well as disubstituted aromatic amines and α-naphthyl amine also participated well in the
MCR. The presence of a chloro group on the aryl ring of 1 was tolerated (entries 18 and 19, Table 2).
Overall, ninteen compounds were prepared by using this methodology and all the synthesized
compounds were characterized by spectral (NMR, IR, and HRMS) data. A chiral HPLC performed
using the compound 4i and 4p individually indicated the presence of a 1:1 mixture of both
enantiomers in both cases (see ESI for chromatograms).
6

Table 2. β-CD mediated synthesis of 6-substituted-6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-
diones in water under microwave.a
O
O
O
R
β
-CD
N
O
+ RNH2 +
H2O
microwave
OH
X
N
X
N
H
O
O
O
3
2
1
4
Compd (1);
X =
Amine
(2); R =
2a; Ph
Product
(4)
4a
Entry
Yieldb (%)
1
1a; H
1a; H
1a; H
1a; H
1a; H
1a; H
1a; H
1a; H
1a; H
1a; H
1a; H
1a; H
1a; H
1a; H
1a; H
1a; H
1a; H
1b; Cl
1b; Cl
70
88
85
85
77
80
75
75
85
60
85
70
77
72
87
95
80
81
90
2
2b; CH2Ph
4b
4c
3
2c; c-propyl
4
2d; CH2C6H4OMe-p
2e; C6H4Br-p
4d
4e
5
6
2f; CH2C6H3Cl2-o,p
2g; (CH2)3NMe2
2h; α-Naphthyl
2i; C6H4Me-p
4f
7
4g
8
4h
4i
9
10
11
12
13
14
15
16
17
18
19
2j; C6H4CN-p
4j
2k; C6H4(But)-p
2l; C6H4(CO2Me)-p
2m; CH2C6H4Cl-p
2n; C6H3(Cl-o)Me-m
2o; (CH2)2C6H5
2p; Me
4k
4l
4m
4n
4o
4p
4q
4r
2q; C6H3Me2-o,m
2r; C6H4Me-p
2s; Me
4s
aAll the reactions were carried out using isatoic anhydride 1 (1.0 mmol), amine 2 (1.2 mmol), 2-
formylbenzoic acid 3 (1.0 mmol) and β-CD (w/w 10%) in water (5 mL) under microwave.12
bIsolated yield.
Based on the earlier 1H NMR studies indicating the association of isatoic anhydride and
cyclodextrin during the reaction3a and formation of a β-CD complex from the primary rim of the
cylinder, a plausible scheme for the present β-CD mediated MCR is shown in Scheme 2. Since the
7

MCR is less efficient in the absence of β-CD, the catayst appears to play an important role in
increasing the efficiency of the reaction especially by activating the anhydride carbonyl group of 1 in
addition to aiding the water solubility of all the reactants. A subsequent nucleophilic attack by the
amine 2 on the activated carbonyl carbon was also facilitated by β-CD leading to the generation of 2-
amino-N-arylbenzamide intermediate E-1 in situ. Once formed, the E-1 then reacts with 2-
formylbenzoic acid (3) affording the second intermediate E-2. The azomethine moiety of E-2
subsequently participates in an intramolecular concurrent cyclization involving the carboxylic acid
and amide group to give the desired product 4.
O
H
X
O
O
CO2
O
HN
N
NHR
H
O
X
NH2
O
R
E-1
3
O
H2O
H2O
NHR
4
X
N
E-2
HO2C
Scheme 2. Plausible scheme for the β-CD-mediated MCR under microwave irradiation.
In conclusion, we have described for the first time a β-CD mediated MCR in water under
microwave irradiation affording
a
faster and greener approach for the synthesis of
dihydroisoindolo[2,1-a]quinazoline-5,11-dione derivatives of potential pharmacological interest. The
methodology worked under neutral conditions and is free from the use of any metal catalyst. It is
amenable for the synthesis of diversity based library of small molecules required by pharmaceutical /
chemical industries.
Acknowledgements
GRR thanks Dr. Vilas Dahanukar, Dr. Upadhya Timmanna and the analytical group of DRL.
References and notes
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Ganem, B. Acc. Chem. Res. 2009, 42, 463.
8

2. For a thematic series, see: “Multicomponent reactions”, Müller, T. J. J. (Editor) Beilstein J.
Org. Chem. 2011, vol 7, pp 950-1507.
3. (a) Kumar, A.; Tripathi, V. D.; Kumar, P. Green Chem. 2011, 13, 51; (b) Murthy, S. N.;
Madhav, B.; Kumar, A. V.; Rao, K. R.; Nageswar, Y. V. D. Helvetica Chim. Acta 2009, 92,
2118.
4. (a) Pfeffer, K. Cytokine Growth Factor Rev. 2003, 14, 185; (b) Scheinfeld, N. J. Dermatolog.
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L.; Abagyan, R.; Leung, C.-H.; Ma, D.-L. Angew. Chem. Int. Ed. 2010, 49, 2860.
5. For our earlier endeavour on the synthesis of bioactive novel small molecules, see: (a) Kumar,
K. S.; Kumar, P. M.; Reddy, M A.; Ferozuddin, M.; Sreenivasulu, M.; Jafar, A. A.; Krishna, G.
R.; Reddy, C. M.; Rambabu, D.; Kumar, K. S.; Pal, S.; Pal, M. Chem. Commun. 2011, 47,
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M.; Krishna, G. R.; Reddy, C. M.; Rambabu, D.; Kapavarapu, R.; Lakshmi, C.; Meda, T.;
Priya, K. K.; Parsa, K. V. L.; Pal, M. Chem. Commun. 2011, 47, 7779; (c) Kumar, P. M.;
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Commun. 2012, 48, 431. (d) Prasad, B.; Adepu, R.; Sandra, S.; Rambabu, D.; Krishna, G. R.;
Reddy, C. M.; Deora, G. S.; Misra, P.; Pal, M. Chem. Commun. 2012, 48, 10434; (e) Adepu,
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12. General procedure for the preparation of compound 4a: To a mixture of 1a (1.0 mmol), 2a
(1.2 mmol), and 3 (1.0 mmol) in water (5.0 mL) was added β-CD (w/w 10%). The reaction
vessel was sealed with a pressure cap and irradiated in a CEM Explorer microwave for 10 min
at 120 °C (300 W). The progress of the reaction was monitored by TLC. After completion of
the reaction (1st run) the mixture was cooled to room temperature and extracted with
dichloromethane (10 mL). The organic layer was collected and filtered through celite. The
celite was washed with dichloromethane (5.0 mL). The combined filtrate was concentrated and
9

the residue was purified by column chromatography on silica gel (230-400 mesh) using ethyl
acetate/hexane (0-30%) to give the desired product. Reuse of β-CD: The aqueous layer
separated containing β-CD was collected. To this was added 1a (1.0 mmol), 2a (1.2 mmol) and
3 (1.0 mmol) in a reaction vessel that was then sealed with a pressure cap and irradiated in a
CEM Explorer microwave for 10 min at 120 °C (300 W). Up to four cycles of recyclability of
the catalyst was examined. Recovery of β-CD: the aqueous layer was left overnight at 5 °C.
Due to its low solubility the β-CD was precipitated at lower temperature. It was then filtered,
dried and used for the next reaction.
10