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

Abstract 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 o-aminoarylphosphonates. 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

Only one example for a [1,3]-phosphoramidateaminophosphonate 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) 2 P(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 Boc 2 O and allowing the reaction mixture to slowly warm to room temperature. Bases n-BuLi 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 well. LDA as alternative base in Et 2 O in combination with slowly warming the reaction mixture for 18 h furnished the same phosphonate in 62% yield and 10 as side product, too. These two experiments demonstrate that N-Boc-protected N-phenylphosphoramidate 11 can be rearranged by [1,3]-migration of phosphorus from the nitrogen to the carbon atom induced by strong lithium amide bases. Migration of the Boc group was not detected. We tested also 14a, the isopropyl analog of 10, as substrate for the rearrangement to optimize the reaction conditions (Scheme 4). It was prepared from aniline and diisopropyl bromophosphate [24] in 95% yield and then Boc-protected as before (92% yield). The rearrangement was performed in THF with three bases, s-BuLi/TMEDA, LDA, and LiTMP at -78°C. The combination of s-BuLi with TMEDA delivered a mixture of recovered starting material 14a and Boc-deprotected 13a as crude product, which did not contain phosphonate 15a unexpectedly. The other two bases gave the desired phosphonate 15a in 25 and 79% yield, respectively. In summary, these results demonstrated that N-Boc-protected N-arylphosphoramidates can be isomerized to N-Boc-protected oaminoarylphosphonates. As isopropyl protecting groups at the phosphorus atom seemed to shield it better than the ethyl groups and to give higher yields, all further experiments were performed with diisopropyl phosphoramidates. In order to address the regioselectivity of metalation and expand the scope of the rearrangement, meta-substituted anilines 9b-9e were transformed into N-Boc-protected phosphoramidates 14b-14e by the previous methods in combined unoptimized yields ranging from 58 to 90% yield. All rearrangements were performed in THF with LiTMP as well as LDA, normally at -78°C, sometimes for comparison reasons also at 0°C, for 1 h in the majority of experiments (Table 1). Yields could possibly be increased by longer reaction times for certain substrates. Varying amounts of starting material 14 and the corresponding phosphoramidate 13 formed by base-catalyzed removal of Boc from 14 were present (TLC) in the crude reaction products, but were not isolated. In the case of the N-Boc-N-(m-chlorophenyl)phosphoramidate 14b the two phosphonates 15b and 16b were formed in yields of 55 and 35% for LiTMP as base at -78°C and 55 and 32% for the same base at 0°C, respectively. LDA delivered exclusively 15b in 96% yield, surprisingly. The preferred deprotonation ortho to both substituents might be explained by their additive acidifying and o-directing effect, although the bases were very encumbered. Consequently, the preferred formation of phosphonates 15b is predetermined. When chloride as substituent was replaced by iodide being larger in size and lower in electronegativity compared to chloride, the quantity of phosphonate 16c (60 and 66%, see Table 1) outweighed those of 15c (19 and 23%) for LiTMP, independent of the reaction temperature. Remarkably, LDA delivered a yield of only 4% for 15c but 78% for 16c. The next two N-Boc-protected phosphoramidates, 14d and 14e, followed the expectations. The methoxy group with its strong ortho directing metalation effect in combination with the P=O group directed deprotonation exclusively to carbon atom 2, leading to the exclusive formation of phosphonate 15d. However, the methyl group which reduces the acidity of the hydrogen atoms in the phenyl ring and is additionally of significant size effected that the rearrangement of 14e furnished low yields of 16e (5 and 6%), despite a reaction time of 20 h with slow warming to room temperature. The main components of the crude product were starting material 14e and its precursor 13e formed by base-catalyzed removal of Boc.

Scheme 4
Scheme 4 . When we started this project we surmised that the migration of phosphorus from the nitrogen to the carbon atom is an intramolecular process proceeding via a cyclic four-membered transition state. As it is unfavorable, we reasoned that the formal [1,3]-migration could also be exclusively or in part an intermolecular process with phenyllithium attacking at the electrophilic phosphorus atom of a second molecule. We conceived a crossover experiment with an equimolar mixture of deuterated and nondeuterated N-Boc-N-(3-methoxyphenyl)phosphoramidate, [D 17 ]14d and 14d (Scheme 7). The latter was synthesized from [D 3 ]methyl tosylate [25] and tris(heptadeuterioisopropyl) phosphite [24] by the methods used for the unlabeled species. The rearrangement of the 1:1 mixture furnished a 1:1 mixture of phosphonates 15d and [D 17 ]15d in 98% yield. No phosphonates containing 3 or 14 deuterium atoms could be detected by EI-MS, indicative of an intermolecular transfer of the phosphorus atom with its labeled substituents. Therefore, the migration of the phosphorus atom from the nitrogen to the ortho-carbon atom in N-Boc-N-arylphosphoramidates proceeds exclusively intramolecularly and represents a [1,3]-sigmatropic rearrangement. A modified crossover experiment was carried out by Heinicke et al. [26] demonstrating that aryl dialkyl phosphates isomerize to o-hydroxyphenylphosphonates intramolecularly.
o-Aminophenylphosphonic acid was tested for its anticholesterinase activity [27] and 2-amino-4methylphenylphosphonic acid for removing formaldehyde adducts [28] from RNA and DNA bases. The protected oaminoarylphosphonates prepared by [1,3]-migration of phosphorus can be deprotected to give o-aminoarylphosphonic acids as shown for three examples (Scheme 8). N-Boc-o-aminophenylphosphonate 15a was deprotected by refluxing with 6 M HCl or with TMSBr/allylTMS [29] in CH 2 Cl 2 under milder conditions, resulting in a higher yield. The o-aminophenylphosphonic acid (25) was purified by cation exchange chromatography (Dowex 50 W 9 8, H ? ) and crystallization from water. 2-Naphthylphosphonate 20 had to be deprotected with TMSBr/allylTMS and crystallized from methanol because of its lability in hot water, where it decomposed to 1-naphthylamine (detected by TLC) and H 3 PO 4 (detected by 31 P NMR). Pyridin-3ylphosphonate 23 was converted to 2-amino-3-pyridin-3ylphosphonic acid (27) using refluxing 6 M HCl, followed by purification as for 25. Selective removal of the Boc group with CF 3 CO 2 H would give dialkyl o-aminophosphonates. As the amino group in aromatic compounds can be replaced by a variety of substituents, the globally or partially deprotected N-Boc-o-aminophoshonates prepared here are useful starting materials for other o-substituted phosphonic acid derivatives.

Conclusion
In summary, we have shown that arylamines can be easily converted to N-Boc-N-arylphosphoramides. Treatment with LiTMP or LDA mediated [1,3]-phosphoramidateaminophosphonate rearrangements. Three phosphonates were globally deprotected. This approach extends the scope for the synthesis of 2-amino-substituted phosphonic acids derived from aromatic and heteroaromatic amines. Additionally, selective removal of the Boc-protecting group will give a free amino group amenable to fuctional group manipulation and incorporation of the 2-aminophosphonates into peptides.
Experimental NMR pectra ( 1 H, 13  , and external H 3 PO 4 (85%; d P = 0.00). IR spectra of compounds soluble in CDCl 3 or CH 2 Cl 2 were recorded on a Perkin-Elmer FT 1600 IR Spectrometer. The solution was applied to a silicon disc [30] and the solvent was allowed to evaporate before the measurement. IR spectra of the aminophosphonic acids were recorded on a Perkin-Elmer Spectrum 2000 IR spectrometer in ATR mode. Melting points were determined on a Reichert Thermovar instrument. New compounds were checked for purity by means of appropriate combustion analysis results. Flash (column) chromatography was performed with Merck silica gel 60 (230-400 mesh). Thin layer chromatography (TLC) was carried out on 0.25 mm thick Merck plates, silica gel 60 F 254 . Spots were visualized by UV and/or dipping the plate into a solution of (NH 4 ) 6-Mo 7 O 24 Á4H 2 O (24.0 g) and Ce(SO 4 ) 2 Á4H 2 O (1.0 g) in 10% aqueous H 2 SO 4 (500 cm 3 ), followed by heating with a heat gun. Pyridine was dried by refluxing over powdered CaH 2 , then distilled and stored over molecular sieves (4 Å ). Dichloromethane was dried by storage over molecular sieves (3 Å ). All other chemicals and solvents were of the highest purity available and used as received.
General procedure A-N-phosphorylation of aromatic amines with diisopropyl bromophosphate A solution of bromine (18 cm 3 , 18 mmol, 1 M in dry CH 2 Cl 2 ) was added dropwise to a stirred solution of 4.44 cm 3 (i-PrO) 3 P (3.75 g, 18 mmol) in 10 cm 3 dry CH 2 Cl 2 under Ar at -50°C [24]. Stirring was continued for 30 min at 0°C. After cooling again to -50°C, a solution of aromatic amine (15 mmol) in 2 cm 3 dry CH 2 Cl 2 and 4.18 cm 3 Et 3 N (3.04 g, 30 mmol) was added. The reaction mixture was allowed to warm to RT (18 h). HCl (12 cm 3 , 2 M) and 20 cm 3 water were added. The organic layer was separated and the aqueous one was extracted twice with CH 2 Cl 2 . The combined organic layers were dried with Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash chromatography and/or crystallization.
General procedure B-conversion of N-arylphosphoramidates to N-Boc-N-arylphosphoramidates s-BuLi (5.14 cm 3 , 7.2 mmol, 1.4 M in cyclohexane) was added to a stirred solution of phosphoramidate (6 mmol) in 10 cm 3 dry THF (or Et 2 O) under Ar at -78°C. After 15 min a solution of 1.44 g Boc 2 O (6.6 mmol) in 5 cm 3 dry THF (or Et 2 O) was added. The reaction mixture was allowed to slowly warm to RT in the cooling bath (18 h). After the addition of 3 cm 3 solution of AcOH in Et 2 O (2 M) and 10 cm 3 H 2 O the organic phase was separated and the aqueous one extracted with CH 2 Cl 2 (3 9 10 cm 3 ). The combined organic layers were washed with a saturated aqueous solution of NaHCO 3 , dried with Na 2 SO 4 , and concentrated under reduced pressure. The residue was purified by flash chromatography.