H2N 1 R3 R4 R2 R1 R5 + N R4 R3 R2 R1 H 1 2 3 4 5 7 8 9 10 11 12 5a-e: i 5f-h: ii 5a–h 2a–h N R3 R2 R1 H 1 2 3 4 5 7 6 9 10 11 3a–e O 8 N R3 R2 R1 H 1 2 3 4 5 7 6 9 10 11 4a,b,e O 8 + 2a–e iii N S R3 R2 R1 H 1 2 3 4 5 7 6 9 10 11 3f,g 8 N S R3 R2 R1 H 1 2 3 4 5 7 6 9 10 11 4f–h 8 + 2f–h iv 4 J. CHEM. RESEARCH (S), 1998 J. Chem. Research (S), 1998, 4–5 J. Chem. Research (M), 1998, 0115–0125 Synthesis of New Cyclopenta-acridinone and -phenothiazine Derivatives Sandrine Morel, Florence Chatel, G�erard Boyer* and Jean-Pierre Galy ESA 6009, Univ. d’Aix-Marseille III, case 552, Avenue Escadrille Normandie-Neimen, 13397 Marseille Cedex 20, France The synthesis of new cyclopenta-acridinones and -phenothiazines by cyclization of N-aryl indanes under acidic conditions or via Bernthsen thionation is reported.Acridines and phenothiazines are well known therapeutic agents1 and some significant derivatives have been prepared with a supplementary heterocyclic fourth ring.3,5,6 We are interested in the preparation of a new class of tetracycles bearing a cyclopentane ring fused to an acridine or phenothiazine moiety.The indane 1 was used as starting material and we prepared both cyclopenta-acridinones and cyclopenta-phenothiazines according to the synthetic pathway shown in Scheme 1. The substitution patterns of the derivatives are given in Tables 1–3. The aminoindane 1 was first arylated with the benzoic acids 5a–e in order to obtain the corresponding N-substituted anthranilic acids 2a–e in 33–66% yields.The next step involved cyclization of these acids by either PPA or sulfuric acid. Depending on the regioselectivity of the cyclization position (5 or 7, Scheme 1), either one or two isomers could be obtained: the angular [a]-fused tetracycle (type 3) and/or its homologue, the linear [b] isomer (type 4). In the case of 2a, 2b and 2e, a mixture of both isomers was obtained, purification and separation of which led to the corresponding 1,2,3,6- tetrahydrocyclopenta[a]acridin-11-ones 3a, 3b and 3e and to Scheme 1 Reagents and conditions: i, Cu, K2CO3, pentan-1-ol, 110 °C, 4–12 h; ii, CH2Cl2, Cu(OAc)2, room temp., 4 h; iii, PPA or H2SO4, 90 °C, 2 h; iv, S8, I2, o-C6H4Cl2, reflux, 6 h Table 1 Synthesis of N-arylamines derivatives 2a–h Starting material Compound no.R1 R2 R3 R4 R5 Product 5a 5b 5c 5d 5e 5f 5g 5h HHHH NO2 HHH HHH NO2 HHHH H OMe NO2 HHH OMe Me CO2H CO2H CO2H CO2H CO2H HHH Cl Br Cl Cl Br Bi(OAc)2 Pb(OAc)3 Pb(OAc)3 2a 2b 2c 2d 2e 2f 2g 2h Table 2 Synthesis of acridinones derivatives 3a–e, 4a, b and e Starting material Compound no.R1 R2 R3 R4 Products 2a 2b 2c 2d 2e HHHH NO2 HHH NO2 H H OMe NO2 HH CO2H CO2H CO2H CO2H CO2H 3a/4a 3b/4b 3c 3d 3e/4e Table 3 Synthesis of phenothiazines derivatives 3f, g and 4f–h Starting material Compound no. R1 R2 R3 R4 Products 2f 2g 2h HHH HHH H OMe Me HHH 3f/4f 3g/4g 4h *To receive any correspondence (e-mail: gerard.boyer@mvcf.u-3mrs.fr).J.CHEM. RESEARCH (S), 1998 5 the linear 1,2,3,5-tetrahydrocyclopenta[b]acridin-10-ones 4a, 4b and 4e. In other cases only the angular acridinones were recovered. Cyclopenta-phenothiazines were also prepared from commercial 1 but using a copper-catalysed arylation with organometallic reagents such as 5f–h. Under mild conditions, the diarylamines 2f–h were synthesized in good yields (64–85%) and subsequently cyclized by Bernthsen thionation in o-dichlorobenzene.Work-up of mixtures gave also the corresponding angular or linear cyclopenta[b] or -[c]-phenothiazines 3f,g and 4f–h. Moreover, difficulties associated with the method of purification and rapid oxidation of the final products could explain the absence of [c]-fused 3h. All the compounds prepared were characterized unambiguously by 1H and 13C NMR spectroscopy. In particular, the multiplet pattern of the C-ring protons of the final products was especially checked: 4-H and 5-H would resonate as two doublets in the case of [a] or [c] fusion, but as two singlets in the case of [b] fusion (4-H and 11-H).We found, for example, two doublets at d 7.55 and 7.31 which correspond to ‘bent’ 1,2,3,6-tetrahydrocyclopenta[a]acridin-11-one 3a and two singlets at 7.46 and 8.02 ppm respectively for linear 1,2,3,5-tetrahydrocyclopenta[b]acridin-1-one 4a (4-H and 11-H). All the 13C NMR chemical shifts are given in the Experimental section of the full paper.Techniques used: 1H and 13C NMR Referneces: 13 Scheme:1 Received, 28th July 1997; Accepted, 16th September 1997 Paper E/7/05425D References cited in this synopsis 1 Phenothiazines and 1,4-Benzothiazines. Chemical and Biomedical Aspects (Bioactive Molecules, Vol. 4), ed. R. R. Gupta, Elsevier, Amsterdam, 1988; R. M. Acheson, Acridines, Wiley, New York, 1973. 3 J. P. Galy, S. Morel, G. Boyer and J. Elguero, J. Heterocycl. Chem., 1996, 33, 1551. 5 G. Boyer, J. P. Galy, R.Faure, J. Elguero and J. Barbe, J. Chem. Res., 1990, (S) 350; (M) 2601; M. Boyer, J. P. Galy, R. Faure, J. Elguero and J. Barbe, Magn. Reson. Chem., 1991, 6, 638. 6 G. Boyewr, J. P. Galy and J. Barbe, Heterocycles, 1995, 41, 487; G. Boyer, J. P. Galy, R. Faure and J. Barbe, Magn. Reson. Chem., 1994, 32, 537. Table 4 1H NMR chemical shifts of N-aryl amines 2a–h (d values, [2H6]DMSO) Amine Proton 2a 2b 2c 2d 2e 2f 2g 2h 1-H 2-H 3-H 4-H 5-H 7-H 8-H 9-H 10-H 11-H 12-H OCH3 CH3 2.83 2.00 2.83 7.17 6.95 7.08 9.59 7.10 7.32 6.69 7.87 —— 2.79 1.99 2.79 7.15 6.91 7.04 9.11 7.16 7.06 — 7.37 3.70 — 2.84 2.02 2.84 7.26 7.04 7.14 10.29 6.99 8.09 — 8.66 —— 2.85 2.07 2.85 7.26 7.06 7.14 9.80 7.70 — 7.43 8.07 —— 2.76 1.97 2.76 7.06 6.66 6.78 9.90 — 8.17 7.02 8.03 —— 2.80 1.99 2.77 7.08 6.88 7.00 7.97 7.04 7.19 6.76 ——— 2.84 2.06 2.84 7.08 6.73 6.84 5.40 7.03 6.85 —— 3.79 — 2.77 1.97 2.75 7.04 6.91 7.81 6.93 7.00 ——— 2.20 Table 5 1H NMR chemical shifts of acridinones 3a–e, 4a,b and e (d values, [2H6]DMSO) Acridinone Proton 3a 4a 3b 4b 3c 3d 3ea 4ea 1-H 2-H 3-H 4-H 5-H 6-H 7-H 8-H 9-H 10-H 11-H OCH3 3.53 2.07 2.87 7.55 7.31 11.51 7.45 7.65 7.17 8.14 —— 2.95 2.05 2.95 7.46 12.13 7.58 7.66 7.18 8.18 — 8.02 — 3.55 2.07 2.86 7.52 7.29 11.50 7.45 7.34 — 7.58 — 3.83 2.96 2.05 2.96 7.33 11.56 7.48 7.34 — 7.60 — 8.03 3.83 3.48 2.08 2.88 7.60 7.32 12.09 7.54 8.35 — 8.85 —— 3.50 2.08 2.86 7.61 7.31 11.95 8.29 — 7.85 8.32 —— 3.62 2.18 2.96 7.56 7.21 11.16 — 8.65 7.25 8.77 —— 2.99 2.12 2.99 7.30 11.20 — 8.68 7.29 8.86 — 8.24 — aCDCl3 as solvent.Table 6 1H NMR chemical shifts of phenothiazines 3f, g and 4f–h (d values, [2H6]DMSO) Phenothiazine Proton 3f 4f 3g 4g 4h 1-H 2-H 3-H 4-H 5-H 6-H 7-H 8-H 9-H 10-H 11-H OCH3 CH3 2.62 1.96 2.69 6.79 6.45 8.37 6.63 6.96 6.68 6.87 ——— 2.70 1.93 2.68 6.74 — 6.89 6.72 6.94 6.69 8.42 6.59 –— 2.63 1.97 2.72 6.79 6.42 8.14 6.63 6.59 — 6.56 — 3.64 — 2.70 1.93 2.68 6.77 — 6.56 — 6.58 6.58 8.19 6.58 3.65 — 2.70 1.93 2.70 6.75 — 6.72 — 6.76 6.57 8.30 6.56 — 2.