1. J. Perron,a B. Joseph,b J.-Y. Méroura
Access to Ring-fused Azepino[3,4-b]indole-1,5-dione Derivatives by Ring-closing Olefin Metathesis
J. Perron,a B. Joseph,b J.-Y. Méroura
aInstitut de Chimie Organique et Analytique, UMR-CNRS 6005, Université d’Orléans, B.P. 6759, Orléans Cedex 2, France  
bLaboratoire de Chimie Organique 1, UMR-CNRS 5181, Université Claude Bernard – Lyon 1, CPE - Bâtiment 308, 43 Bd du 11 Novembre 1918,
69622 Villeurbanne Cedex, France
The azepino framework is encountered in potent kinase inhibitors such as natural marine hymenialdisine1 and closed derivatives of 1.2 Recently, Meijer et al have been reported that 5-arylhydrazinoazepino[5,6-b]indole exhibited good inhibitory activities against cyclin-dependant kinases.3 In our ongoing research of new azepino[5,6-b]indole derivatives,4 we have recently described the preparation of pyrrolo[1,2:1’,2’]azepino[5,6-b]indole 2, related to anthramycin structure, from indole-2-carboxylic acid and b-aminoester through intramolecular electrophilic cyclisation (Figure 1).5 With the discovery of new well-defined catalysts, the ring-closing metathesis (RCM) is, now, considered as one of the most powerful synthetic tools in organic chemistry.6,7 Based on a ring-closing metathesis (RCM) approach, we investigated several synthetic pathways to get new ring-fused azepino[5,6-b]indole derivatives 3,4 and 5 from azepino[5,6-b]indoles 1a or 1b.4b
II] Preparation of spiro derivatives 4
The synthesis of spiro derivatives 4 required two successive C-alkylations on the same position. Two routes were developed to give access to the desired dienes. The simplest way was a diallylation reaction on position-4 of 2b to give 9 in 77% yield. We needed an alternative way to introduce two different olefin side chains since monoallylation of 2b failed. The key intermediate 10 was obtained from 2b in two steps (92% yield). Compound 10 was then reacted with halide derivative to give C-alkylated derivatives 11a-d in fair yield. Decarboxylation of 11 was carried out with lithium hydroxide in almost quantitative yield. Final C-allylation on 12b and 12c was performed to reach the desired dienes 13b-c. The corresponding spiro derivatives 4 were again obtained by RCM in excellent yield.
III] Synthesis of compounds 5
On the basis of the synthetic results collected from both first families, we reasoned that combining the use of monoalkylated derivative 12 as starting material and the Sakurai reaction to introduce the alkenyl chain on position-3 could provide the key diene 15. a,b-Ethylenic ketones 14 were obtained following the sequence bromination – elimination and then, the allyl chain was effectively introduced on position-3 in fair yield by Sakurai reaction. compounds 15 were isolated as a mixture of diastereomers (ratio 4:5). According to RCM reaction described above, dienes 15 underwent ring closure in very high yield to afford tetracyclic derivatives 5 (Table 3).
I] Synthesis of derivatives 3
A double alkylation of 1a on position-2 and 3 was investigated to generate the diene precursor. The first olefin chain was introduced on position-2 by classical N-alkylation. The Sakurai reaction (1,4-addition) was found the best method for the attachment of the allyl chain on the azepinic ring. RCM reaction on the diene precursors 8 was performed with Grubb’s first generation catalyst in CH2Cl2 at room temperature to afford tetracyclic derivatives 3 in good yield.
(a) NaH (1.1 equiv.), DMF, 0°C, 1 h; (b) R-Br (1.5 equiv.), DMF, rt, 1 or 12 h, (6a n= 1 88%, 6b n= 2 54%, 6c n= 3 64%, 6d n= 4 76%); (c) LiHMDS (1.8 equiv.), THF, -78°C, 2 h; (d) Br2 (1 equiv.), THF, -78°C, 15 min; (e) DBU (1.5 equiv.), DMF, rt, 2 h, (7a-d 80-83%); (f) TiCl4 (4 equiv.), allylTMS (6 equiv.), CH2Cl2, -40°C to rt, 15 h, (8a n= 1 69%, 8b n= 2 54%, 8c n= 3 50%, 8d n= 4 48%); (g) Grubb’s reagent (10% mol), 0.03 M solution, CH2Cl2, rt, (3a n= 1, 1 h, 84%, 3b n= 2, 2 h, 96%, 3c n= 3, 1 h, 98%, 3d n= 4, 48 h, 86%).
(a) LiHMDS (1.5 equiv.), THF, -78°C, 2 h; (b) Br2 (1.2 equiv.), rt, 2 h; (c) DBU (1.5 equiv.), 45 min (14a n= 1 88%, 14b n= 2 84%, 14c n= 3 87%); (d) TiCl4 (4 equiv.), allylTMS (6 equiv.), CH2Cl2, -40°C to rt, 15 h (15a n= 1 51%, 15b n= 2 56%, 15c n= 3 68%); (e) Grubb’s reagent (10% mol), 0.03 M solution, CH2Cl2, rt, (5a n= 1, 8 h, 96%, 5b n= 2, 12 h, 93%).
(a) NaH (2 equiv.), THF, 0°C, 3 h; (b) 3-bromopropene (5 equiv.), THF, rt, 16 h, (77%); (c) LiHMDS (1.8 equiv.), THF, -78°C, 1 h; (d) NCCO2Et (1.1 equiv.), THF, -78°C, 15 min, (92%); (e) K2CO3 (5 equiv.), Br-(CH2)n-CH=CH2 (5 equiv.), acetone, rflx, h, (11a n= 1 92%, 11b n= 2 47%, 11c n= 3 59%, 11d n= 4 68%); (f) LiOH (2 equiv.), EtOH/H2O, rflx, 30 min, (12a-d 97-99%); (g) NaH (1.5 equiv.), THF, 0°C, 1 h; (h) 3-bromopropene (1.2 equiv.), rt, 16 h, (13b n= 2 93%, 13c n= 3 89%); (i) Grubb’s reagent (10% mol), 0.03 M solution, CH2Cl2, rt, (4a n= 1, 8 h, 84%, 4b n= 2, 2 h, 92%, 4c n= 3, 48 h, 90%).
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