One‐Pot Procedure for the Synthesis of 1,5‐Benzodiazepines from N‐Allyl‐2‐bromoanilines

Abstract

A new one-pot procedure that includes an initial titanium-catalyzed intermolecular hydroaminoalkylation of N-allyl-2-bromoanilines with N-methylanilines and a subsequent intramolecular Buchwald-Hartwig amination directly gives access to pharmacologically relevant 1,5-benzodiazepines. The process takes advantage of the excellent regioselectivity of the initial hydroaminoalkylation performed in the presence of a titanium mono(formamidinate) catalyst and the fact that the exclusively formed branched hydroaminoalkylation products can only undergo palladium-catalyzed cyclization to 1,5-benzodiazepines.

Hydroaminoalkylation of Allylsilanes and a One‐Pot Procedure for the Synthesis of 1,5‐Benzoazasilepines

“…Because overall the best result of the intramolecular Buchwald-Hartwig amination of 22 waso btained with RuPhos, this ligand was then used for the finally planned development of ao ne-pot procedure for the synthesis of 1,5-benzoazasilepines from allyl(2-bromophenyl)silanes ( Table 5). [7] However, the sensitivity of the titanium catalyst against alcohols and carbonyl compounds rules out the possibility to develop ar elated one-pot protocol in which both the titaniuma nd the palladium catalysta re added to the flask at the same time. [7] However, the sensitivity of the titanium catalyst against alcohols and carbonyl compounds rules out the possibility to develop ar elated one-pot protocol in which both the titaniuma nd the palladium catalysta re added to the flask at the same time.…”

“…For that purpose, ah ydroaminoalkylation reaction mixture of allylsilane 21 and N-methylaniline (1)i nt oluene was initially heatedt o1 40 8Cf or 24 hi nt he presence of 10 mol %o fc atalyst IV.A fterwards, 2.5 mol %P d 2 (dba) 3 ,7mol %R uPhos, sodium tert-butoxide and additional toluene were added and the resulting reactionm ixture was heatedt o1 10 8Cf or additional 24 h. The yield of 83 % in which 1,5-benzoazasilepine 23 was obtained after chromatographic purification ( Table 5, entry 1) again underlines the wellestablished fact that the Buchwald-Hartwig amination tolerates the presence of the reagents used in hydroaminoalkyla-tion reactions. [7] However, the sensitivity of the titanium catalyst against alcohols and carbonyl compounds rules out the possibility to develop ar elated one-pot protocol in which both the titaniuma nd the palladium catalysta re added to the flask at the same time. To finally investigate the scope of the onepot procedure, we then reacteda dditional ortho-, meta-, and para-substituted N-methylanilines with allylsilane 21.A se xpecteda nd in good agreement with the results obtained for the hydroaminoalkylation of simple allylsilanes presented in Ta ble 2, it was found that para-o rmeta-substituted N-methylanilinesu ndergo smooth reactiont og ive the desired 1,5-benzoazasilepines in good yields between 66 and 84 %( Ta ble 5, entries [3][4][5][6][7][8][9][10][11].…”

“…[7] However, the sensitivity of the titanium catalyst against alcohols and carbonyl compounds rules out the possibility to develop ar elated one-pot protocol in which both the titaniuma nd the palladium catalysta re added to the flask at the same time. To finally investigate the scope of the onepot procedure, we then reacteda dditional ortho-, meta-, and para-substituted N-methylanilines with allylsilane 21.A se xpecteda nd in good agreement with the results obtained for the hydroaminoalkylation of simple allylsilanes presented in Ta ble 2, it was found that para-o rmeta-substituted N-methylanilinesu ndergo smooth reactiont og ive the desired 1,5-benzoazasilepines in good yields between 66 and 84 %( Ta ble 5, entries [3][4][5][6][7][8][9][10][11]. On the other hand, it is worth mentioning that even the sterically demanding ortho-methyl-substituted 1,5benzoazasilepine 24 could be isolated in am oderate yield of 47 %( Ta ble 5, entry 2).…”

“…Benzodiazepines are able to bind to the inhibitory important GABA receptors (GABA: γ‐aminobutyric acid) of the central nervous system and as a result, they show sedative, muscle relaxant, anticonvulsant, and anxiolytic effects . Very recently, we were able to develop a new one‐pot procedure for the synthesis of 1,5‐benzodiazepines . The corresponding reaction sequence includes an initial highly regioselective titanium‐catalyzed intermolecular hydroaminoalkylation, which takes place by the addition of an α‐C(sp 3 )−H bond of an N ‐methylaniline across a C−C double bond of an N ‐allyl‐2‐bromoaniline, and a subsequent intramolecular Buchwald–Hartwig amination (Scheme , path A) .…”

“…[5,6] Very recently, we were abletodevelop anew one-pot procedure for the synthesiso f1 ,5-benzodiazepines. [7] The corresponding reaction sequence includes an initial highly regioselective titanium-catalyzed intermolecularh ydroaminoalkylation, [8,9] which takes place by the addition of an a-C(sp 3 )ÀHbond of an N-methylaniline across aC ÀCd ouble bond of an N-allyl-2-bromoaniline, and as ubsequenti ntramolecular Buchwald-Hartwig amination (Scheme 1, path A). [10] In continuation of this studya nd inspiredb yt he fact that until now,u nsaturateds ilanes have not been used as substrates for titanium-catalyzed hydroaminoalkylation reactions, we recently decided to investigate the scopeo fa llylsilanes as startingm aterials for corresponding transformations.…”