Expedient synthesis of 6-aryl derivatives of 3,4-dihydro-1,4,4a,6a- tetraaza-benzo[a]fluoren-2-one: A new heterocyclic framework

Article abstract of DOI:10.1080/00397910802238742

3,4-Dihydro-1,4,4a,6a-tetraaza-benzo[a]fluoren-2-one, a new tetracyclic heterocyclic framework, is designed through a simple and convenient synthetic sequence. Its 6-aryl derivatives are synthesized starting from 1H-indole-2-carboxylic acid. The reaction of differently substituted phenacyl bromides with 1H-indole-2-carboxylic acid and POCl3-mediated cyclization of the resultant 1H-indole-2-carboxylic acid phenacyl ester provided 2-oxa-4a-aza-fluoren-1-one, and its sequential reaction with hydrazine and 2-chloro-acetamide furnished the desired new heterocyclic compounds 7a-f. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802238742

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Expedient Synthesis of 6-
Aryl Derivatives of 3,4-
Dihydro-1,4,4a,6a-tetraaza-
benzo[a]fluoren-2-one: A New
Heterocyclic Framework
Gade Srinivas Reddy a b , Kadaboina Rajasekhar a
, Cherukupally Praveen a , Kaga Mukkanti b & Padi
Pratap Reddy a
a Integrated Product Development, Dr. Reddy's
Laboratories Limited , Bachupally, Qutubullapur,
Ranga Reddy District , Andhra Pradesh , India
b Institute of Science and Technology , Jawaharlal
Nehru Technological University , Kukatpally
Hyderabad , Andhra Pradesh , India
Published online: 20 Oct 2008.
To cite this article: Gade Srinivas Reddy , Kadaboina Rajasekhar , Cherukupally
Praveen , Kaga Mukkanti & Padi Pratap Reddy (2008) Expedient Synthesis of 6-
Aryl Derivatives of 3,4-Dihydro-1,4,4a,6a-tetraaza-benzo[a]fluoren-2-one: A New
Heterocyclic Framework, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 38:22, 3884-3893, DOI:
10.1080/00397910802238742
To link to this article: http://dx.doi.org/10.1080/00397910802238742

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Synthetic Communications1, 38: 3884–3893, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802238742
Expedient Synthesis of 6-Aryl Derivatives of
3,4-Dihydro-1,4,4a,6a-tetraaza-benzo[a]fluoren-
2-one: A New Heterocyclic Framework
Gade Srinivas Reddy,1,2 Kadaboina Rajasekhar,1
Cherukupally Praveen,1 Kaga Mukkanti,2 and Padi Pratap Reddy1
1Integrated Product Development, Dr. Reddy’s Laboratories Limited,
Bachupally, Qutubullapur, Ranga Reddy District, Andhra Pradesh, India
2Institute of Science and Technology, Jawaharlal Nehru Technological
University, Kukatpally Hyderabad, Andhra Pradesh, India
Abstract: 3,4-Dihydro-1,4,4a,6a-tetraaza-benzo[a]fluoren-2-one, a new tetracyc-
lic heterocyclic framework, is designed through a simple and convenient synthetic
sequence. Its 6-aryl derivatives are synthesized starting from 1H-indole-
2-carboxylic acid. The reaction of differently substituted phenacyl bromides with
1H-indole-2-carboxylic acid and POCl3-mediated cyclization of the resultant
1H-indole-2-carboxylic acid phenacyl ester provided 2-oxa-4a-aza-fluoren-1-
one, and its sequential reaction with hydrazine and 2-chloro-acetamide furnished
the desired new heterocyclic compounds 7a–f.
Keywords: 2-Amino-4-phenyl-2H-pyrazino[1,2-a]indol-1-one, 3,4-dihydro-1,4,4a,6a-
tetraaza-benzo[a]fluoren-2-one, 1H-indole-2-carboxylic acid, phenacyl bromide,
phenacyl ester, 4-phenyl 2-oxa-4a-aza-fluoren-1-one
Received March 28, 2008.
Address correspondence to Padi Pratap Reddy, Research and Development,
Active Pharmaceutical Ingredients, Integrated Product Development, Innovation
Plaza, Dr. Reddy’s Laboratories Ltd., Survey Nos. 42, 45, 46, and 54, Bachupally,
Qutubullapur mandal, Hyderabad 500 072, Andhrapradesh, India. E-mail:
prataprp@drreddys.com.
3884

Synthesis of Tetraaza-benzo[a]fluorenone Derivatives
3885
INTRODUCTION
The substituted indole nucleus is found in several natural products.[1–3]
Because it is very important in medicinal chemistry, synthesis of fused
heterocyclic compounds with indole moieties has assumed immense
significance.[4–8] As part of our ongoing research work on the synthesis
of new indole-based heterocycles, we became interested in the design
and synthesis of new fused tetracyclic heterocyclic compounds 7a–f.
1H-Indole-2-carboxylic acid phenacyl ester (2), which can be readily
accessed from commercially available 1H-indole-2-carboxylic acid (1),
was chosen as the starting material.
RESULTS AND DISCUSSION
As a representative example, 1H-indole-2-carboxylic acid 1 was reacted
with phenacyl bromide in the presence of triethylamine in ethyl acetate
at room temperature to provide the phenacyl ester derivative 2a. Mass
(m=e 280, Mþ1), IR [1701 cmꢀ1 (C ¼ O), 3324 cmꢀ1 (NH)], and 1H NMR
[d 5.6 (s, 2H), 7.1–8.1 (m, 10H), 12 (s, 1H)] spectral data of compound 2a
are in conformity with its 1H-indole-2-carboxylic acid 2-oxo-2-phenyl-
ethyl ester structure. An alternative structure, 3, was ruled out by its inde-
pendent preparation and comparison with compound 2a. The phenacyl
ester derivative 2a could be smoothly cyclized to 4-phenyl-2-oxa-4a-
aza-fluoren-1-one 4a in refluxing toluene in the presence of phosphorus
oxychloride. The assigned structure of 4a is based on its mass, IR, and
1H NMR spectral data. The mass spectrum of 4a displayed the molecular
ion peak at m=e 262 (M þ 1). The IR spectrum is characterized by the
presence of a sharp lactone carbonyl peak (1731 cmꢀ1) and was devoid
1
of indole NH absorption. The H NMR spectrum of 4a showed all the
signals in the downfield region (d 7.1–7.9, m), and 13C NMR spectrum
of 4a showed signals at d 109.3, 113.1, 121.9, 122.0, 122.3, 123.1, 125.5,
127.6, 127.7, 128.9, 129.2, 130.3, 130.5, 133.4, and 155.7 ppm. If the
b-position of indole moiety is involved in cyclization, it will lead to an
alternate isomeric compound 5 in this reaction. In the 13C NMR spectrum
of 4a, the signal due to the b-carbon of the indole nucleus is displayed at
d 109.3 ppm, which is comparable to the literature values of similar com-
pounds.[9–11] These data, coupled with the fact that the IR spectrum is
lacking the indole NH absorption, ruled out the structure 5 and strongly
favor the structure 4a.
Reaction of 4a with hydrazine hydrate in ethanol at reflux tempera-
ture gave 2-amino-4-phenyl-2H-pyrazino [1,2-a] indol-1-one derivative 6a
in quantitative yield. Structural assignment of compound 6a was done

3886
G. S. Reddy et al.
1
with the help of its mass, IR, and H NMR spectral data. To build a
triazinone skeleton on pyrazine ring of 6a, it was condensed with chloro
acetamide in refluxing N,N0-dimethyl formamide. The resulting crystalline
product was characterized as 6-phenyl-3,4-dihydro-1,4,4a,6a-tetraaza-
benzo[a] fluoren-2-one (7a). Mass spectrum of 7a has shown the molecular
ion peak at m=e 315 (Mþ1), corresponding to the molecular formula
C19H14N4O. IR spectrum of 7a displayed carbonyl (1670 cmꢀ1), NH
1
(3313 cmꢀ1), and C ¼ N (1649 cmꢀ1) absorptions. In the H NMR spec-
trum, the methylene proton signal appeared as a singlet at d 5.7 and
the aromatic proton resonated as a multiplet in the region d 6.5–7.8. The
signal corresponding to methine proton was observed at d 6.3. All these
spectral data are fully in agreement with the assigned structure of 7a.
The 3,4-dihydro-1,4,4a,6a-tetraaza-benzo[a]fluoren-2-one skeleton of 7a
is a new fused tricyclic heterocyclic system hitherto unreported.
To verify the generality of this synthetic sequence, it was extended to
five other substituted phenacyl bromides, and in all the cases, the corre-
sponding 6-aryl-3,4-dihydro-1,4,4a,6a-tetraaza-benzo[a]fluoren-2-ones
7b-f were obtained as final products (Fig. 1). All the compounds, 2a-f,
1
4a-f, 6a-f and 7a-f, are fully characterized based on their IR, H NMR
and mass spectral data (Tables 1 and 2).
EXPERIMENTAL
The 1H and 13C NMR spectra were recorded at 200 and 400 MHz,
respectively, on a Varian Gemini 200-MHz FT NMR spectrometer.
The chemical shifts are reported in d ppm relative to TMS. The Fourier
transform–infrared (FT-IR) spectra were recorded in the solid state as a
KBr dispersion using a Perkin-Elmer 1650 FTIR spectrophotometer. The
mass spectrum (70 eV) was recorded on
a
HP-5989a liquid
chromatography–mass spectrometry (LC-MS) spectrometer. The melting
points were determined by using the capillary method on a Polmon
(model MP-96) melting-point apparatus. The solvents and reagents were
used without further purification. The reactions were monitored by thin-
layer chromatography (TLC) on silica-gel plates.
General Procedure for the Preparation of 1-(2-Oxo-2-phenyl-
ethyl)-1H-indene-2-carboxylic Acid 3
2-Bromoacetophenone (52.6 g, 0.264 mol) and potassium carbonate
(110.4 g, 0.8 mol) were added to a solution of 1H-indole-2-carboxylic acid
ethyl ester I (50 g, 0.264 mol) in acetone (400 mL). The reaction mixture

Synthesis of Tetraaza-benzo[a]fluorenone Derivatives
3887
Figure 1. Synthetic scheme of 6-phenyl-3, 4-dihydro-1,4,4a,6a-tetraaza-benzo[a]
fluoren-2-one. Reagents and conditions: (i) para-substituted phenacyl bromide,
ethyl acetate, triethylamine, Rt; (ii) toluene, POCl3, reflux; (iii) hydrazine hydrate,
ethanol, reflux; (iv) chloroacetamide, DMF, reflux; and (v) 2-bromoacetophe-
none, acetone, K2CO3, aq. ethanolic NaOH.
was stirred at reflux temperature for 4 h, and acetone was stripped off
under vacuum. The residue was diluted with water (250 mL) and extracted
with methylene chloride (3 ꢁ 100 mL). The organic layer was concentrated
under vacuum, and the ester was hydrolyzed in 100 mL of ethanol and
925 mL of 1N sodium hydroxide solution at reflux temperature. The
crude indole-2-carboxylic acid derivative 3 was isolated by acidifying it
with an aqueous hydrochloric acid and recrystallizing it from methanol.
General Procedure for the Preparation of 1H-Indole-2-carboxylic
Acid 2-Oxo-2-aryl-ethyl Esters 2a–f
Phenacyl bromide (0.264 mol) and triethyl amine (0.3 mol) were added to
a solution of 1H-indole-2-carboxylic acid 1 (42.5 g, 0.264 mol) in ethyl
acetate (350 mL), and the reaction mixture was stirred at room tempera-
ture for 4 h. The reaction mixture was diluted with water (100 mL) and
filtered to get the crude product 2a–f, which were recrystallized from
2-propanol.

3888

3889

3890

Synthesis of Tetraaza-benzo[a]fluorenone Derivatives
3891
General Procedure for the Preparation of Ethyl 4-Aryl-2-oxa-4a-
aza-fluoren-1-ones 4a–f
A mixture of ethyl 1H-indole-2-carboxylic acid 2-oxo-2-aryl-ethyl ester 2
(0.05 mol) and phosphorus oxychloride (40 mL) in toluene (130 mL) was
refluxed for 2 h. The excess phosphorus oxychloride and toluene were dis-
tilled off under reduced pressure. The resultant crude was purified by
silica-gel column chromatography, eluting with 5% ethyl acetate in
hexanes to provide 4a–f.
General Procedure for the Preparation of 2-Amino-4-(aryl)-2H-pyrazino
[1,2-a] indol-1-ones 6a–f
Hydrazine hydrate (2.3 g, 0.046 mol) was added to a solution of ethyl
4-aryl-2-oxa-4a-aza-fluoren-1-one 4 (0.038 mol) in 50 mL of ethanol,
and the mixture was refluxed for 2 h. The reaction mixture was cooled
to give compounds 6a–f, which were used in a subsequent stage without
further purification.
General Procedure for the Preparation of 6-Aryl-3,4-dihydro-1,4, 4a,6a-
tetraaza-benzo[a]fluoren-2-ones 7a–f
2-Chloro-acetamide (1.7 g, 0.018 mol) was added to a solution of com-
pound 6 (0.018 mol) in DMF (25 mL), and the reaction mixture was
refluxed for 3 h. The reaction mass was quenched with water (250 mL),
and crude products 7a–f were filtered and recrystallized from methanol.
CONCLUSION
In conclusion, we have described a simple and efficient synthetic route for
the 3,4-dihydro-1,4,4a,6a-tetraaza-benzo[a]fluoren-2-one system, a new
tetracyclic heterocyclic framework, and its 6-aryl derivatives. Further inves-
tigations are in progress to explore the scope of this synthetic sequence.
ACKNOWLEDGMENTS
We thank the management of Dr. Reddy’s Laboratories Ltd. for extend-
ing support to the work. Cooperation from the project colleagues and
analytical department is highly appreciated.

3892
G. S. Reddy et al.
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