Synthesis of linear dibenzo[1,8]naphthyridines using 2-chloro-4-methylquinolines

The attempted synthesis of linear dibenzonaphthyridines utilizing 2-chloro-4-methylquinolines leads to the formation of hitherto unknown compounds. The reaction of 2-chloro-4-methylquinoline with 2-amino-5-chlorobenzophenone afforded 6-chloro-10 H - dibenzo[ b,g ]naphtho[1,2,3-de ][1,8]naphthyridine. In an alternate way, anilinoquinolines were reacted with benzoic acid but yielded (dibenzo[ b,g ][1,8]naphthyridin-11(6 H )-ylidene)-1- phenylethanone.


Introduction
2][3] After the discovery of cinchona alkaloids as antimalarial agents several anilinoquinolines were also established as synthetic antimalarials 4 and have been utilized as synthons in obtaining various fused heterocycles like indoloquinoline alkaloids. 5,6Among the quinoline derivatives, pyrido fused quinolines (benzonaphthyridines) and quinoline fused quinolines (dibenzonaphthyridines) play an important role in living cells and in pharmaceuticals.Many reports represent the synthesis of linear 7,8 and angular dibenzonaphthridines [9][10][11] and only very few accomplish their construction through anilinoquinolines. 12,135][16] Aaptamine i.e., 8,9-dimethoxy-1H-benzo[de] [1,6]  naphthyridine was first isolated from marine sponge Aaptos aaptos and was found to possess various biological activity like anti-neoplastic activity, cancer cell growth inhibitory activity 17 and recently found to activate p21 promoter in a p53 independent manner. 18Isoaaptamine (8methoxy-1-methyl-1H-benzo[de] [1,6]naphthyridin-9-ol), a novel benzo[de] [1,6]naphthyridine alkaloid of the aaptamine class isolated from an Indonesian marine sponge 19 was also reported to possess various biological activities.A formal total synthesis of the marine alkaloid aaptamine 20 and the synthetic conversion of aaptamine to isoaaptamine and other aaptamine derivatives 21 were also carried out with multisteps since simple construction of benzo[de]naphthyridine core structure is quiet tedious.Our present investigation though aimed in the preparation of linear dibenzonaphthyridines from 2-chloro-4-methylquinolines (1) by two methods (i) condensation of 1 with 2-amino-5-chlorobenzophenone 2 in single step.(ii)condensation of 1 with aniline 4 followed by cyclisation using benzoic acid in presence of PPA as represented in Scheme 1, ended up in hitherto unknown naphthyridine derivatives which also includes dibenzo[b,g]naphtho[1,2,3-de] [1,8]naphthyridine.
Scheme 1. Reaction sequences to achieve linear dibenzonaphthyridines.

Results and Discussion
In addition to our earlier work for the preparation of the angular dibenzonaphthyridines 22,23 from 4-chloro-2-methylquinolines and linear 24,25 and angular 26 dibenzonaphthyridines from 2,4dichloroquinolines the objective of the present investigation was aimed in the preparation of some linear dibenzonaphthyridines from 2-chloro-4-methylquinolines.With regard to the earlier idea, the reaction of 2-chloro-4-methylquinolines 1a-c with 2-amino-5-chlorobenzophenone 2 under neat condition at 160 °C (Scheme 2) afforded the products, namely 2[(2'-benzoyl-4'chlorophenyl)amino]-4-methylquinolines 6a-c and not the expected products 3 as observed in earlier work. 22,23In its 1 H NMR spectrum apart from the methyl groups in the aliphatic region all the aromatic protons resonated between δ 7.00-8.00except for one proton doublet which was very much deshielded to~δ 9.50 and assigned to C6'-H (2D NMR pattern of similar compounds is discussed in our earlier work 24,25 ).A broad singlet around δ 11.00 showed the presence of C2-NH (Hydrogen bonded).The conformations of the compounds 6a-c is shown in Figure 1.After obtaining the methylquinolines 6a-c we aimed to cyclise them under acidic condition and hence 2[(2'-benzoyl-4'-chlorophenyl)amino]-4-methylquinolines 6a-c were heated in presence of PPA at 160 °C for 5 hours to give the new products 7a-c.Its 1 H NMR spectrum showed the absence of C3-H.The C7-and C9-CH3 were observed around δ 2.50 for all the derivatives whereas the expected C11-CH3 methyl group was absent.The appearance of a broad singlet at~δ 7.40 was due to N5-H/N6-H.Its 13 C NMR spectrum showed the presence of 24 carbons with the absence of C11-methyl carbon signal.The absence of methyl group and the presence of a NH group indicate that the methyl group might have involved further in reaction with the neighbouring phenyl ring.Finally the molecular ion peak for the compounds 7a,b appeared at (m/z) 366 and M+2 at 368 in its mass spectrum and the elemental analysis showed the molecular formula to be C24H15ClN2 for its methyl derivative which confirmed that the compounds obtained were 6-chloro-10H-dibenzo[b,g]naphtho[1,2,3-de] [1,8] Now we chose an alternate way to diversify the target dibenzonaphthyridine where the anilinoquinolines were utilized as intermediates.Hence for the preparation of the anilinoquinoline, 2-chloro-4-methylquinolines 1a-c were reacted with p-chloroaniline 4 under neat condition to afford 4-methyl-2(4'-chloro-phenylamino)quinolines 5a-c (Scheme 5).

Scheme 5. Preparation of anilinoquinolines 5a-c.
The anilinoquinolines 5a-c thus obtained were treated with benzoic acid (slight excess) in presence of PPA at 150-155 °C.In the obtained products 8a-c, besides the C7-and C9-CH3 in the aliphatic region and aromatic protons, a broad singlet appeared around δ 9.00 due to N6-H.In this case also the appearance of a NH and the absence of C11-methyl protons suggest the formation of an unexpected product.Its 13 C NMR spectrum supported the presence of 31 carbons with the carbonyl carbon at~δ 185.4 which further supported by its IR spectrum.All these observations confirm the formation of the C11-benzoylated products.Finally its mass spectrum exhibited the molecular ion peak at (m/z) 472 and elemental analyses showed the molecular formula as C31H21ClN2O for its methyl derivative which confirmed the structure of the product formed as 2-(2-chloro-12-phenyldibenzo[b,g][1,8]naphthyridin-11(6H)-ylidene)-1phenylethanones 8a-c (Scheme 6).Scheme 6. Reaction of anilinoquinolines 5a-c with benzoic acid.
Similarly a set of reaction was performed in which 1a-c were reacted with p-toluidine 9 to afford the corresponding anilinoquinolines 10a-c and they were treated with benzoic acid to give 2-(2-methyl-12-phenyldibenzo[b,g][1,8]naphthyridin-11(6H)-ylidene)-1-phenylethanones 11a-c (Scheme 7).In both the above cases for the formation of products 8 and 11 from the starting materials 5 and 10 respectively, the yield was poor (~ 20%) and the starting materials were recovered.When the same reaction was done with twice the quantity of benzoic acid no starting materials were recovered and the yield was good (~ 40%).Various reaction conditions were optimized to isolate the possible intermediate 3, but unsuccessful, perhaps the reason might be due to the less stability of the intermediate at the experimental condition.The similarity of the above couple of reactions conclude that after the formation of the target cyclised dibenzonaphthyridines (in situ) the methyl group reacts further with the neighbouring phenyl ring or benzoic acid through its tautomeric form, thus ending up in the formation of hitherto unknown dibenzonaphthyridines.It is pertinent to mention here that anilinoquinolines do not react with benzoic acid unless PPA is present.

Scheme 9. Reaction of 2-chloro-4-methylquinolines 1a-c with o-aminoacetophenone.
As mentioned in the earlier case the peculiar deshielded C6'-H was assigned on the basis of the 2D NMR pattern of similar compound in our earlier work. 24,25The conformation of the compound 12b (similar to  The attempted synthesis of linear dibenzonaphthyridines leads to the formation of novel compounds.The reaction of 2-chloro-4-methylquinolines 1 with amino ketones afforded the uncyclised 6 which further on acid catalysed cyclisation yielded hitherto unknown [de]dibenzonaphthyridines. In an alternate way to diversify the target compounds, 1 was converted to 5,10 and its further reaction with carboxylic acid led to the unknown dibenzonaphthyridin-ylidene-ones 8,11.The reason for not realizing the target compounds 3 as expected might be the following reasons (i) less stability of the target compounds (ii) higher reactivity of C11-methyl group of the compound 3.

Experimental Section
General.Melting points (m.p) were determined on Mettler FP 51apparatus (Mettler Instruments, Switzerland) and are uncorrected.They are expressed in degree centigrade (C).IR spectra were recorded on Schimadzu FTIR-8201PC spectrophotometer (Schimadzu, Japan) using KBr disc. 1 H NMR and 13 C NMR spectra were recorded on Bruker AMX 400 (400 MHz ( 1 H) and 100 MHz ( 13 C)) and AV 300 (300 MHz ( 1 H) and 75 MHz ( 13 C)) NMR spectrometer using tetramethylsilane (TMS) as an internal reference.The chemical shifts are expressed in parts per million (ppm).Mass spectra (MS), were recorded on AutoSpec EI+ shimadzu QP 2010 PLUS GC-MS mass spectrometer.Micro analyses were performed on a Vario EL III model CHNS analyser (Vario, Germany) at the Department of Chemistry, Bharathiar University.The purity of the products was tested by TLC with plates coated with silica gel-G with petroleum ether, ethyl acetate and methanol as developing solvents.

General procedure for the preparation of 4-methyl-2-(4'-methyl-phenylamino)quinoline (10)
A mixture of appropriate 2-chloro-4-methylquinoline 1 (0.010 mol) and p-toluidine 9 (0.010 mol) was heated under neat condition at 160 ο C for half an hour.The product obtained was washed with water, dried purified by column chromatography over silica gel and eluted with ethyl acetate methanol mixture (95 5) to get 10.It was recrystallised using methanol.

General procedure for the preparation of 2-(2-methyl-12-phenyldibenzo[b,g][1,8]naphthyridin-11(6H)-ylidene)-1-phenylethanone (11)
An appropriate mixture of 4,4'-dimethyl-2-(N-phenylamino)quinoline 10 (0.0010 mol) and benzoic acid (0.0011 mol) was added to polyphosphoric acid (3 g of P2O5 in 1.5 mL of H3PO4) and kept at 160 °C for 5 hours.The reaction was monitored by TLC.The spot for the starting compounds 10 was not completely disappeared.The reaction mixture was poured into ice water and neutralised with saturated NaHCO3 solution to remove the excess of benzoic acid.The precipitate was filtered, dried and purified by column chromatography over silica gel using petroleum ether ethyl acetate (99 1) mixture to get 11.It was recrystallised using ethyl acetate.

X-Ray Crystallographic data
Crystallographic data of the structure 12b in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication.CCDC No. 755306.Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK.Or email: deposit@ccdc.cam.ac.UK.