On the rearrangement of N-aryl-N-Boc-phosphoramidates to N-Boc-protected o-aminoarylphosphonates

V = On the rearrangement of N-aryl-N-Boc-phosphoramidates to N-Boc-protected o-aminoarylphosphonates Edyta Kuliszewska 0 1 Friedrich Hammerschmidt 0 1 0 Institute of Organic Chemistry, University of Vienna , Vienna , Austria 1 & Friedrich Hammerschmidt Various arylamines were converted in two steps to N-Boc-N-arylphosphoramidates. LiTMP and LDA induced directed ortho-metalation at temperatures from -78 to 0 C. The ensuing [1,3]-migration of the phosphorus atom with its substituents from the nitrogen to the ortho-carbanionic carbon atom gave N-Boc-protected oaminoarylphosphonates. The nature of the substituent of 3-substituted phenylphosphoramidates strongly influenced the regioselectivity of phosphonate formation. A crossover experiment with a deuterated phosphoramidate proved the intramolecular course of the rearrangement. Three representative N-Boc-o-aminoarylphosphonates were deprotected to access the corresponding o-aminoarylphosphonic acids. Graphical Abstract Phosphorus compounds; Rearrangements; Amines; Carbanions; Arenes Introduction Phosphorus atoms in phosphonic and phosphoric acid derivatives can be induced to migrate with their substituents within molecules. The most important isomerization reactions are [ 1,2 ]- and [ 1,3 ]-rearrangements. Pudovik and Konovalova discovered that ahydroxyphosphonates with certain structural requirements isomerize to phosphates under basic conditions and they named this reaction phosphonate–phosphate rearrangement [ 1–3 ] (Scheme 1). They and others extended it to a-mercapto- and a-aminophosphonates (X = S, NR) [ 1 ]. These isomerizations are reminiscent of the 1,2-Wittig [ 4 ] and 1,2-Brook rearrangement [ 5, 6 ]. When strong bases such as LDA, LiTMP, n-BuLi, or s-BuLi are used to deprotonate 4 to give 3, the reverse process is induced. Then, the phosphorus atom migrates from the hetero- to the carbanionic carbon atom in 3, a [ 1,2 ]-rearrangement as found by Sturtz and Corbel [ 7 ] and preparatively and mechanistically extensively studied by the group of Hammerschmidt [ 8–10 ]. Aryl phosphates 5 (X = O) can be isomerized to o-hydroxyarylphosphonates 8 with strong bases [ 11–15 ] (Scheme 2). As the phosphate group effects directed orthometalation [ 16, 17 ], aryl lithiums 6 are formed, which undergo migration of the phosphorus atom from the oxygen to the carbanionic carbon atom to give phosphonates 7 and on workup 8. The driving force for the rearrangement is the formation of the strong O–Li bond. A large variety of dialkyl aryl phosphates and derivatives thereof were rearranged. In analogy to the Fries-rearrangement this reaction was named anionic phospho-Fries rearrangement [11]. We prefer the more general term [ 1,3 ]-phosphate–hydroxyphosphonate rearrangement. The isomerization was applied to S-aryl thiophosphates and their derivatives Scheme 1 Scheme 1 . Scheme 2 Scheme 2 . [ 18–20 ]. Analogously, this isomerizations might be dubbed [ 1,3 ]-thiophosphate–sulfanylphosphonate rearrangement. Only one example for a [ 1,3 ]-phosphoramidate– aminophosphonate rearrangement (X = NMe) has been reported by Modro et al. [ 21 ]. Interestingly, they also found, that diphenyl N-methyl-N-phenylphosphoramidate underwent the first migration of phosphorus from the oxygen to the carbon atom when treated with 1 equiv of LDA, two migrations from O to C, when treated with 4 equiv of LDA and a third one from N to C with 8 equiv of LDA. We reasoned that N-arylphosphoramidates with an additional electron-withdrawing group on the nitrogen atom could first facilitate o-metalation of the phenyl ring and migration of the phosphorus atom from N to C and second expand the scope of the P to O to the P to N rearrangement. Results and discussion We found recently that dialkyl N-benzylphosphoramidates underwent a base-catalyzed [ 1,2 ]-phosphoramidate-aaminophosphonate rearrangement when the secondary nitrogen atom was protected with a Boc or dialkoxyphosphoryl group [ 22, 23 ]. Importantly, both Boc and (RO)2P(O) at the nitrogen atom favor directed o-metalation [ 16, 17 ] with lithium bases. In order to test this idea, aniline was phosphorylated with diethyl chlorophosphate/pyridine to give N-phenylphosphoramidate 10 in 83% yield (Scheme 3). N-Boc protection was effected by deprotonation of 10 at the nitrogen atom with s-BuLi at -78 C, followed by addition of Boc2O and allowing the reaction mixture to slowly warm to room temperature. Bases nBuLi or s-BuLi were not used for metalation because of possible attack at the carbonyl group of the Boc group, which would regenerate phosphoramidate 10. Therefore, we opted for strong encumbered amide bases such as lithium 2,2,6,6-tetramethylpiperidide (LiTMP) and LDA. When LiTMP was reacted with 11 in THF for 2 h at -78 C, phosphonate 12 was obtained in 55% yield by flash chromatography. Surprisingly, even LiTMP removed the Boc group from part of 11 so that phosphoramidate 10 was isolated in 30% yield as (...truncated)