Abstract
This project was concerned with investigating the electrophilic cyclisation reactions of 3- phenylpenta-1,4-diyn-3-ols possessing either an ortho-N-linked- or an ortho-S-linked- sulfonamide function. Cyclisations of both series of sulfonamides meditated by alkynophilic initiators [e.g. I2, ICl, AgOAc or In(OTf)3] provided access to novel functionalised heterocycles. Thus, addition of methyl 2-(arenesulfonamido)benzoates to alkynyllithium reagents furnished 3-[(2-arenesulfonamido)phenyl]penta-1,4-diyn-3-ols in which the alkyne termini possess identical substituents. Dialkynols having unsymmetrical alkyne terminal groups have been obtained from the addition of an alkynyllithium reagent or HC≡CMgBr to 3-aryl-1-(2-tosylamidophenyl)prop-2-yn-1- ones. The ortho-S-linked sulfonamides have been accessed directly from N-substituted saccharins that readily add alkynyllithiums to provide 3-(2-sulfamoylphenyl)penta-1,4-diyn-3-ols in good yields.
Desilylation (5M NaOH in MeOH) of 1,5-bis(trimethylsilyl)-3-(2-tosylamidophenyl)penta-1,4-diyn-3-ol also triggered cyclisation via a 5-exo-dig pathway and gave a quantitative yield of 3-ethynyl-2- methylene-1-tosylindolin-3-ol. However, when both silyl functions were replaced with either a propyl- or a phenyl- group, cyclisation to the 1-tosylindolin-3-ol did not occur with base. A quantitative yield of 3-(phenylethynyl)-1-tosyl-1H-indol-2-yl(1-phenyl)methanol was obtained from treatment of 1,5-diphenyl-3-(2-tosylamidophenyl)penta-1,4-diyn-3-ol with AgOAc in MeCN. The analogous reaction with 6-(2-tosylamidophenyl)undeca-4,7-diyn-6-ol, provided 1-[3-(pent-1-yn-1-yl]- 1-tosyl-1H-indol-2-yl)butan-1-ol, together with smaller amounts of (E)-2-but-1-en-1-yl-3-pentyn-1-yl1-tosyl-1H-indole and 4-pentyn-1-yl-2-propylquinoline. It was found that when 3-(2- tosylamidophenyl)penta-1,4-diyn-3-ols possessed bulky groups on the alkyne units, the reaction followed an alternative course giving access to the (Z)-2-benzylidene-, (Z)-2-(2,2- dimethylpropylidene)- and (Z)-2-(trimethylsilylmethylene)- derivatives of 3-alkynyl-1-tosylindolin-3- ols. Mechanisms to account for these outcomes have been proposed. Contrasting behavior was observed from the In(OTf)3-mediated cyclisation of 1,5-diphenyl-3-(2-tosylaminophenyl)penta-1,4- diyn-3-ol, which promoted an unexpected and remarkable cascade pathway leading to 2,4-diphenyl1-tosyl-4,5-dihydrofuro[2,3-c]quinoline, albeit in moderate yield.
Attempted iodocyclisation (ICl in MeCN) of 1,5-diphenyl-3-[2-(N-methylsulfamoyl)phenyl]penta-1,4- diyn-3-ol resulted only in cyclodehydration to give the novel 3,3-bis(phenylethynyl)-2-methyl-1,2- benzisothiazole 1,1-dioxide. However, application of these conditions to 1,5-diphenyl-3-[2-(N-ptolylsulfamoyl)phenyl]penta-1,4-diyn-3-ol provided a novel derivative of the unusual 1,2- benzisothiazolo[2,3-a]quinoline system that was characterised by X-ray crystallography; the corresponding 2-aryl-3,3-di(alkynyl)-1,2-benzisothiazole 1,1-dioxide was also formed. The latter also underwent iodocyclisation to give the 1,2-benzisothiazolo[2,3-a]quinolines. It was established that the 3,3-di(alkynyl)-1,2- enzisothiazole 1,1-dioxides could be generated most efficiently by treatment of the 3-[2-(sulfamoyl)phenyl]penta-1,4-diyn-3-ols with In(OTf)3 in DCM.
Iodocyclisation (ICl in MeCN) of 3-(2-tosylamidophenyl)penta-1,4-diyn-3-ols having symmetrical alkyne substituents afforded novel 4-alkynyl-3-iodoquinolines. However, the unsymmetricall ysubstituted pentadiynols cyclised less efficiently to give, in some cases, mixtures of regioisomeric 3- iodoquinolines. The cyclisation of 1-(4-methoxyphenyl)-5-phenyl-3-(2-tosylamidophenyl)penta-1,4- diyn-3-ol regiospecifically generated 3-iodo-2-(4-methoxyphenyl)-4- phenylethynyl)quinoline, as anticipated.
Silver-catalysed cyclisation (AgOAc in MeCN) of 3-[2-(N-arylsulfamoyl)phenyl]penta-1,4-diyn-3-ols proceeds stereoselectively to (Z)-3-alkylidene-4-alkynyl-2-aryl- and (Z)-4-alkynyl-2-aryl-3-arylidene1,2-benzothiazin-4-ol 1,1-dioxides via a 6-endo-dig pathway in good to excellent yields, constituting a new approach to this ring system. Two of the pentadiynols also furnished 1,2-benzothiazepine 1,1- dioxides derived via a 7-endo-dig ring closure. Mechanisms for the formation of these novel compounds are proposed.
With a range of heterocycles to hand some were subjected to functionalisation or annulation reactions. Of note is the Pd-mediated domino-amination-hydroamination of 4-alkynyl-3- iodoquinolines with a range of primary amines. This approach was exploited to access novel 2,3,4- trisubstituted pyrrolo[2,3-c]quinolines, analogues of the biologically active Marinoquinolines. However, in some instances the hydroamination step was suppressed and the major or exclusive
product was a 4-alkynyl-3-amino-2-arylquinoline.
Suzuki-Miyaura couplings to 4-alkynyl-2-iodo-3-arylquinolines and efforts to effect iodocyclisations of the products are also described.
| Date of Award | 12 Apr 2021 |
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| Original language | English |
| Supervisor | Christopher Gabbutt (Main Supervisor), Mark Heron (Co-Supervisor) & Stuart Aiken (Co-Supervisor) |