Synthesis of novel 3-arylcyclopenta[ c ]quinolines via acid-induced domino cyclization of 2-arylamino-2-methylthioethenyl 2-arylcyclopropyl ketones

A novel acid-induced domino cyclization of N,S -anilinoacetals of type 3 derived from 2-arylcyclopropyl ketones, is reported which yields a wide range of substituted-and fused- 3-arylcyclopenta[ c ]quinolines 6 with concomitant formation of a cyclopentane and a quinoline ring.


Introduction
Substituted quinolines and their benzo-or hetero-fused analogues represent an important class of heterocyclic compounds because of their presence in numerous biologically active natural products, along with the wide spectrum of physiological activities displayed by these class of compounds. 1,2As a consequence, much attention has been focused towards developing new synthetic methods for substituted-and fused quinolines. 1,3Domino reactions are of growing interest in synthetic organic chemistry because they allow rapid construction of polycyclic structures in a single operation and confer great strategic value in molecular construction. 4Our own interest in this regard has been concerned with the elaboration of domino reactions involving acid-induced rearrangements of 2-aryl-(or heteroaryl-)cyclopropyl ketones with an α-(bismethylthio)-methylene functionality as the cationic cyclization terminator, which yield a range of carbocyclic products such as substituted cyclopentanones, 5a,b cyclopenta[b]indanes, 5c-d diquinanes, 5d 1-arylindanes, 5e bicyclo[3.2.1]octene, 5f and other cyclopentano-fused heterocycles.5g-i In continuation of these studies, we now report the domino carbocationic cyclization of arylcyclopropyl ketones of type 3 carrying an (N,S-aminomethylene) functionality, yielding 3-arylcyclopenta[c]quinolines (compound 6) in a single one-pot operation.
The cyclopropyl ketone (compound 1) was prepared in quantative yield by treatment with dimethyloxosulphonium methylide generated from the corresponding sulphonium salt to the corresponding unsaturated ketene S,S-acetals in the presence of phase transfer catalyst.5a,5i, 6 The N,S-arylaminoacetals (compounds 3a-j) required for studying this transformation were prepared by displacement of one of the methylthio groups of the corresponding α-oxoketene dithioacetals (compound 1) by a substituted aniline in the presence of n-BuLi in THF. 7The structures of all these newly synthesized N,S-acetals (compounds 3a-j) were confirmed with the help of spectral and analytical data.The 1 H NMR spectra of these N,S-acetals show that they exist in the intramolecular H-bonded form 3A.

Scheme 1
The cyclization of the N,S-anilinoacetal (compound 3a), bearing two strongly activating methoxy groups, was first examined in the presence of various protic and Lewis acids.It was envisaged that the initial acid-assisted ring-opening of the cyclopropyl ketone (compound 3) would furnish the stable benzylic carbocation 4 which could be intercepted by the electron-rich N,S-anilino(methylene) double bond via a 5-exo process followed by intramolecular cyclocondensation of the resulting cyclopentanone N,S-acetal 5 to afford angularly-fused cyclopenta[c]quinolines (compound 6) (Scheme 2, pathway a).Alternatively, the cyclopropyl The cyclization of compound 3a was found to be most efficient in the presence of polyphosphoric acid at 90 °C; therefore all the subsequent cyclizations were carried out in the presence of this acid.Thus, Scheme 3 shows cyclization-rearrangement of the various substituted N,S-anilinoacetals (compounds 3a-j) in the presence of PPA yielding the respective substituted 3-arylcyclopenta[c]quinolines (compounds 6a-j) in 46-56% overall yields, which we were not able to improve.

Scheme 5
Finally, we have also attempted ruthenium tetraoxide-mediated oxidative degradation of the 3-arylcyclopenta[c]quinoline (compound 6j) with a view to obtaining the corresponding cyclopenta[c]quinoline 3-carboxylic acid (compound 8j) (Scheme 6).However, analysis of the reaction mixture showed the formation only of sulfone (compound 9j) instead of compound 8j, which could not be obtained even when excess of catalyst (8 mol.%) was taken.Our attempts in this direction are still in progress.

Experimental Section
General Procedures. 1 H NMR (400 MHz) and 13 C NMR (100 MHz) spectra (JEOL JNM LA-400) were recorded in CDCl 3 .TMS was used as internal reference.Melting points were obtained on Mel-Temp melting point apparatus (capillary method) and were uncorrected.The IR spectra were recorded on a Perkin Elmer 1320 spectrophotometer.The FAB mass spectra were recorded on a JEOL SX 102/DA-6000 Mass Spectrometer/Data System.Elemental analyses of the compounds were obtained using an Elementar Vario EL III Carla Erba 1108 model.Column chromatography used 100-200 mesh silica gel obtained from Acme Synthetic Chemicals (India).Substituted anilines, BF 3 •OEt 2 , SnCl 4 , TFA, H 3 PO 4 (88%), Cu(OTf) 2 and triflic acid were purchased from commercial sources.The cyclopropyl ketone 1 was prepared according to the reported procedure.5a

General procedure for preparation of N,S-arylaminoacetals (3a-k)
To a stirred solution of aniline (10 mmol) in dry THF (20 mL), n-BuLi (15 mmol) was added, dropwise, under argon, over a period of 20 min.at -78 °C and the reaction mixture was stirred for 30 min.at room temperature.It was cooled to 0 °C, followed by addition of ketene S,S-acetal (10 mmol) in dry THF (20 mL).The reaction mixture was further stirred at room temperature for 45 minutes followed by refluxing (12-15 h) then cooled, poured into saturated NH 4 Cl solution (100 mL) and extracted with CHCl 3 (3 x 25 ml).The combined organic extracts were washed with H 2 O (2x50 mL), then brine (50 mL), and dried (Na 2 SO 4 ).The solvent was evaporated (reduced pressure) to afford a crude residue, which was purified by filtration through a small silica gel column using EtOAc-hexane as eluent.

General procedure for PPA-induced cyclization of N,S-arylaminoacetals (3a-k) to cyclopenta[c]quinolines (6a-k)
A mixture of N,S-arylaminoacetals 3 (1 mmol) and freshly prepared PPA (10 g) was heated at 90 °C for 6-10 h.The reaction mixture was cooled, neutralized with sat.NaHCO 3 solution and the aqueous layer was extracted with CH 2 Cl 2 (3 x 20 ml).The combined extracts were washed with H 2 O (3 x 30 mL), brine (30 mL), dried (Na 2 SO 4 ) and evaporated under reduced pressure to give crude products 6 which were purified on a small silica gel column using EtOAc/hexane as eluent.