Woods, Tom MacDonald (2008) Phosphinates as new electrophilic reagents for cross-coupling reactions. Doctoral thesis, Durham University.
Activated esters, e.g. triflates, sulfonates, nonaflates and phosphates are excellent electrophiles for a variety of cross-coupling reactions. However, other phosphorus-based esters have received little attention in these protocols. This thesis discusses the synthesis and cross-coupling chemistry of vinyl phosphinates, a new class of electrophilic species. A simple model vinyl phosphinate, N-(tert-butyloxycarbonyl)-4,5,6,7-tetrahydro-1H-azepin-2-yl-diphenylphosphinate, was prepared in excellent yield from commercially available caprolactam. A screening study identified Suzuki cross-coupling conditions under which this phosphinate smoothly coupled with a variety of electron-rich, electron-poor and sterically-hindered boronic acids. The scope and limitations of this chemistry were investigated and a variety of electron-withdrawing nitrogen protecting groups, e.g. Boc, CO(_2)Ph, C0(_2)Bn and Ts could be used without problem. However, electron-donating protecting groups, e.g. Me and Bn proved unsuccessful. Additionally, where seven and eight-membered ring lactam phosphinates coupled efficiently, five and six-membered ring derivatives proved largely unsuccessful. Relative reactivity studies were carried out with N-phenyloxycarbonyl-2- (diphenylphosphinoyloxy)-3,4-dihydro-6-bromoquinolone and indicated that the reactivity of vinyl phosphinates lies between that of aryl chlorides and aryl bromides in the Suzuki reaction. Attempts to improve the efficiency of the cross-coupling of this substrate using DoE and PCA modelling was attempted, but was largely unsuccessful. Studies towards the total synthesis of Lennoxamine via a cross-coupling reaction between a benzazepine-derived vinyl phosphinate and 2,3-dimethoxy-N-(2'-phenylpropan-2-yl)-6-(tributylstannyl) benzamide were commenced. Synthesis of the stannane was achieved in high yield via a directed metallation strategy. Unfortunately, preliminary attempts to cross-couple this stannane with N-(benzyloxycarbonyl)-4,5,6,7- tetrahydro-1 H-azepin-2-yl diphenylphosphinate in a model reaction were unsuccessful. Synthesis of the desired benzazepine phosphinate fragment proved more difficult and although progress has been made, this work remains unfinished. Additionally, treatment of N-([4'-methylphenyl]sulfonyl)-2-oxo-azepane with LDA/TMEDA in the presence of diphenylphosphoryl chloride afforded the sultam 1,2,3,4-tetrahydro-7-methylazepino[1,2-b][1,2]benzothiazole-10,10-dioxide in moderate yield. A range of aryl sulfonamides could be used affording the corresponding sultams in moderate yields.
|Item Type:||Thesis (Doctoral)|
|Award:||Doctor of Philosophy|
|Copyright:||Copyright of this thesis is held by the author|
|Deposited On:||08 Sep 2011 18:26|