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 α-hydroxyphosphonates with certain structural requirements isomerize to phosphates under basic conditions and they named this reaction phosphonate–phosphate rearrangement [1,2,3] (Scheme 1). They and others extended it to α-mercapto- and α-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 [8,9,10].

Scheme 1
scheme 1

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Aryl phosphates 5 (X = O) can be isomerized to o-hydroxyarylphosphonates 8 with strong bases [11,12,13,14,15] (Scheme 2). As the phosphate group effects directed ortho-metalation [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 [18,19,20]. 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.

Scheme 2
scheme 2

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Results and discussion

We found recently that dialkyl N-benzylphosphoramidates underwent a base-catalyzed [1,2]-phosphoramidate-α-aminophosphonate 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 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 Et2O 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 o-aminoarylphosphonates. 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.

Scheme 3
scheme 3

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Scheme 4
scheme 4

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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.

Table 1 [1,3]-Rearrangement of N-Boc-N-arylphosphoramidates 14b–14e to N-Boc-protected o-aminoarylphosphonates 15b–15e and 16b–16e a
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Two more amines were transformed into N-protected phosphoramidates. 1-Naphthylamine was phosphorylated and N-Boc protected in the usual way to give compound 19, which was smoothly subjected to the [1,3]-phosphoramidate–aminophosphonate rearrangement with LiTMP in Et2O at −78 °C for 2 h (Scheme 5). The 2-napthylphosphonate 20 was isolated in 84% yield. The second amine was 2-aminopyridine (21), which was converted to diphosphoramidate 22 with 2 equiv of diisopropyl bromophosphate/excess pyridine in 72% yield in one step (Scheme 6). We found previously that two diethylphosphoryl groups at the nitrogen atom of benzyl amine allowed to perform a [1,2]-phosphoramidate-α-aminophosphonate rearrangement [22]. Here, LiTMP and LDA mediated a [1,3]-phosphoramidate-aminophosphonate rearrangement of diphosphoramidate 22 to phosphonate 23 in yields of 36 and 72%, respectively.

Scheme 5
scheme 5

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Scheme 6
scheme 6

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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, [D17]14d and 14d (Scheme 7). The latter was synthesized from [D3]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 [D17]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.

Scheme 7
scheme 7

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o-Aminophenylphosphonic acid was tested for its anticholesterinase activity [27] and 2-amino-4-methylphenylphosphonic acid for removing formaldehyde adducts [28] from RNA and DNA bases. The protected o-aminoarylphosphonates 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 CH2Cl2 under milder conditions, resulting in a higher yield. The o-aminophenylphosphonic acid (25) was purified by cation exchange chromatography (Dowex 50 W × 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 H3PO4 (detected by 31P NMR). Pyridin-3-ylphosphonate 23 was converted to 2-amino-3-pyridin-3-ylphosphonic acid (27) using refluxing 6 M HCl, followed by purification as for 25. Selective removal of the Boc group with CF3CO2H 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.

Scheme 8
scheme 8

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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]-phosphoramidate-aminophosphonate 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 (1H, 13C, and 31P) were recorded in CDCl3 or D2O on a Bruker DRX 400 (1H: 400.13 MHz, 13C: 100.61 MHz, 31P: 161.98 MHz), spectrometer at 25 °C, respectively. Chemical shifts δ (ppm) were referenced to residual CHCl3 (δ H = 7.24), CDCl3 (δ C = 77.00), HDO (δ H = 4.67), and external H3PO4 (85%; δ P = 0.00). IR spectra of compounds soluble in CDCl3 or CH2Cl2 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 F254. Spots were visualized by UV and/or dipping the plate into a solution of (NH4)6Mo7O24·4H2O (24.0 g) and Ce(SO4)2·4H2O (1.0 g) in 10% aqueous H2SO4 (500 cm3), followed by heating with a heat gun. Pyridine was dried by refluxing over powdered CaH2, 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 cm3, 18 mmol, 1 M in dry CH2Cl2) was added dropwise to a stirred solution of 4.44 cm3 (i-PrO)3P (3.75 g, 18 mmol) in 10 cm3 dry CH2Cl2 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 cm3 dry CH2Cl2 and 4.18 cm3 Et3N (3.04 g, 30 mmol) was added. The reaction mixture was allowed to warm to RT (18 h). HCl (12 cm3, 2 M) and 20 cm3 water were added. The organic layer was separated and the aqueous one was extracted twice with CH2Cl2. The combined organic layers were dried with Na2SO4 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 cm3, 7.2 mmol, 1.4 M in cyclohexane) was added to a stirred solution of phosphoramidate (6 mmol) in 10 cm3 dry THF (or Et2O) under Ar at −78 °C. After 15 min a solution of 1.44 g Boc2O (6.6 mmol) in 5 cm3 dry THF (or Et2O) was added. The reaction mixture was allowed to slowly warm to RT in the cooling bath (18 h). After the addition of 3 cm3 solution of AcOH in Et2O (2 M) and 10 cm3 H2O the organic phase was separated and the aqueous one extracted with CH2Cl2 (3 × 10 cm3). The combined organic layers were washed with a saturated aqueous solution of NaHCO3, dried with Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography.

General procedure C—rearrangement of N-Boc-N-arylphosphoramidates with lithium tetramethylpiperidide (LiTMP)

n-BuLi (0.94 cm3, 1.50 mmol, 1.6 M in hexane) was added to a stirred solution of 0.25 cm3 2,2,6,6-tetramethylpiperidine (0.212 g, 1.5 mmol) in 8 cm3 dry THF (or Et2O) at 0 °C under Ar. Stirring was continued for 30 min at 0 °C. Subsequently, the mixture was cooled at −78 °C and a solution of N-Boc-N-arylphosphoramidate (1 mmol) dissolved in 2 cm3 dry THF (or Et2O) was added. After stirring for 2 h at −78 °C the reaction was quenched with 1 cm3 AcOH (2 M in Et2O) and 5 cm3 H2O. The organic layer was separated and the aqueous one was extracted twice with CH2Cl2. The combined organic layers were dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography.

General procedure D—rearrangement of N-Boc-N-arylphosphoramidates with LDA

s-BuLi (1.07 cm3, 1.5 mmol, 1.4 M in hexane) was added to a stirred solution of 0.21 cm3 diisopropylamine (0.152 g, 1.5 mmol) in 5 cm3 dry Et2O (or THF) at −20 °C under Ar. Stirring was continued for 20 min. Subsequently, a solution of N-Boc-N-arylphosphoramidate (1 mmol) dissolved in 2 cm3 dry Et2O was added. The stirred solution was allowed to slowly warm to RT (20 h) and then the reaction was quenched with 2 cm3 AcOH (2 M in Et2O) and 5 cm3 H2O. The organic layer was separated and the aqueous one was extracted twice with CH2Cl2. The combined organic layers were dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography.

Diethyl N-phenylphosphoramidate (10)

Diethyl chlorophosphate (3.451 g, 2.89 cm3, 20 mmol) was added to a stirred solution of 1.83 cm3 aniline (1.862 g, 20 mmol) and 3.35 cm3 Et3N (2.429 g, 24 mmol) in 36 cm3 dry CH2Cl2 under Ar at RT. After stirring for 19 h at RT the reaction was quenched with 20 cm3 H2O. The organic layer was separated and the aqueous one was extracted twice with CH2Cl2. The combined organic layers were dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by crystallization from hexanes to give 3.79 g phosphoaramidate 10 (83%) as colorless crystals. M.p.: 93–94 °C (Ref. [31] 94–95 °C).

Diethyl N-(t-butoxycarbonyl)-N-phenylphosphoramidate (11, C15H24NO5P)

Diethyl N-phenylphosphoramidate (10, 1.15 g, 5 mmol) was converted to the N-Boc derivative in THF and purified by flash chromatography (hexanes/EtOAc = 1/2, R f  = 0.45) to give 1.55 g N-Boc-phosphoramidate 11 (94%) as a colorless oil. 1H NMR (400.13 MHz, CDCl3): δ = 1.253 (dt, J = 1.0, 7.1 Hz, 3H), 1.251 (dt, J = 1.0, 7.1 Hz, 3H), 1.47 (br. s, 9H), 4.07 (m, 2H), 4.17 (m, 2H), 7.23 (m, 2H), 7.29 (m, 1H), 7.36 (m, 2H) ppm; 13C NMR (100.61 MHz, CDCl3): δ = 15.8 (d, J = 7.7 Hz, 2C), 27.8 (3C), 63.7 (d, J = 6.1 Hz, 2C), 82.6, 127.5 (d, J = 1.5 Hz), 128.7 (2C), 128.8 (d, J = 2.3 Hz, 2C), 138.1, 153.2 (d, J = 8.4 Hz) ppm; 31P NMR (161.98 MHz, CDCl3): δ = 0.2 ppm; IR (Si, CDCl3): \( \bar{V} \) = 2982, 1728, 1492, 1369, 1302, 1160, 1099, 1028, 983 cm−1.

Diethyl 2-(t-butoxycarbonylamino)phenylphosphonate (12, C15H24NO5P)

Diethyl N-Boc-N-phenylphosphoramidate (11, 0.329 g, 1 mmol) was rearranged according to general procedure C in THF and flash chromatogaphed (hexanes/EtOAc = 3/1, R f  = 0.45) to give 0.182 g 2-(N-Boc-amino)phenylphosphonate 12 (55%) as a colorless oil and 0.078 g phosphoramidate 10 (30%). When 11 (0.329 g, 1 mmol) was rearranged according to general procedure D in Et2O and flash chromatographed (hexanes/EtOAc = 3/1), the yield of phosphonate 12 was 0.203 g (62%). 1H NMR (400.13 MHz, CDCl3): δ = 1.30 (t, J = 7.1 Hz, 6H), 1.49 (s, 9H), 4.03 (m, 2H), 4.12 (m, 2H), 7.01 (ddt, J = 1.0, 3.0, 7.7 Hz, 1H), 7.47 (ddt, J = 1.5, 7.3, 7.7 Hz, 1H), 7.52 (ddd, J = 1.5, 7.7, 14.4 Hz, 1H), 8.32 (ddd, J = 1.0, 7.3. 7.8 Hz, 1H), 9.61 (br. s, 1H) ppm; 13C NMR (100.61 MHz, CDCl3): δ = 16.2 (d, J = 6.9 Hz, 2C), 28.3 (3C), 63.2 (d, J = 5.5 Hz, 2C), 80.4, 112.9 (d, J = 179.7 Hz), 119.2 (d, J = 11.5 Hz), 121.7 (d, J = 13.8 Hz), 132.6 (d, J = 6.1 Hz), 133.9 (d, J = 2.2 Hz), 143.4 (d, J = 7.7 Hz), 153.0 ppm; 31P NMR (161.98 MHz, CDCl3): δ = 34.1 ppm; IR (Si, CDCl3): \( \bar{V} \) = 3247, 3117, 2981, 1732, 1587, 1538, 1443, 1305, 1243, 1160, 1094, 1044, 1022, 972 cm−1.

Diisopropyl N-phenylphosphoramidate (13a, C12H20NO3P)

Aniline (1.40 g, 1.37 cm3, 15 mmol) was phosphorylated according to general procedure A and flash chromatographed (hexanes/EtOAc = 1/1, R f  = 0.68) to yield 3.65 g phosphoramidate 13a (95%) as colorless crystals. M.p.: 120–121 °C (hexanes); 1H NMR (400.13 MHz, CDCl3): δ = 1.19 (d, J = 6.3 Hz, 6H), 1.36 (d, J = 6.3 Hz, 6H), 4.66 (dsept, J = 6.3, 7.6 Hz, 2H), 6.22 (br. s, 1H), 6.90 (tt, J = 1.0, 7.6 Hz, 1H), 6.97 (m, 2H), 7.20 (br. t, J = 7.6 Hz, 2H) ppm; 13C NMR (100.61 MHz, CDCl3): δ = 23.5 (d, J = 5.4 Hz, 2C), 23.9 (d, J = 4.6 Hz, 2C), 71.6 (d, J = 5.4 Hz, 2C), 117.4 (d, J = 7.7 Hz, 2C), 121.2, 129.0 (2C), 140.2 ppm; 31P NMR (161.98 MHz, CDCl3): δ = 1.3 ppm; IR (Si): \( \bar{V} \) = 3161, 2981, 2919, 1604, 1504, 1426, 998, 963 cm−1.

Diisopropyl N-(t-butoxycarbonyl)-N-phenylphosphoramidate (14a, C17H28NO5P)

Diisopropyl N-(phenyl)phosphoramidate (13a, 2.01 g, 7.81 mmol) was converted to the N-Boc derivative in 15 cm3 dry Et2O according to general procedure B. The crude product was purified by flash chromatography (CH2Cl2/EtOAc = 7/1, R f  = 0.40) to give 2.57 g N-Boc-N-phenylphosphoramidate 14a (92%) as a colorless oil. 1H NMR (400.1 MHz, CDCl3): δ = 1.16 (d, J = 6.3 Hz, 6H), 1.31 (d, J = 6.3 Hz, 6H), 1.45 (s, 9H), 4.70 (dsept, J = 6.3, 7.3 Hz, 2H), 7.19 (m, 2H), 7.27 (m, 1H), 7.33 (m, 2H) ppm; 13C NMR (100.6 MHz, CDCl3): δ = 23.3 (d, J = 6.1 Hz, 2C), 23.9 (d, J = 3.8 Hz, 2C), 28.0 (3C), 72.8 (d, J = 6.1 Hz, 2C), 82.7, 127.5 (d, J = 1.5 Hz, 2C), 128.8, 129.1 (d, J = 2.3 Hz, 2C), 138.8, 153.6 ppm; 31P NMR (161.98 MHz, CDCl3): δ = 11.6 ppm; IR (Si, CDCl3): \( \bar{V} \) = 2981, 1729, 1492, 1386, 1370, 1299, 1259, 1161, 1097, 1002 cm−1.

Diisopropyl 2-(t-butoxycarbonylamino)phenylphosphonate (15a, C17H28NO5P)

Diisopropyl N-(t-butoxycarbonyl)-N-phenylphosphoramidate (14a, 0.514 g, 1.44 mmol) was converted to phenylphosphonate 15a by general procedure C in THF. The crude product was purified by flash chromatography (hexanes/EtOAc = 5/1, R f  = 0.64) to give 0.404 g phosphonate 15a (79%) as a colorless oil. Rearrangement of 0.514 g phosphoramidate 14a (1.44 mmol) according to general procedure D in THF and flash chromatography (hexanes/EtOAc = 3/1, R f  = 0.60) of the crude product furnished 0.128 g phosphonate 15a (25%). 1H NMR (400.13 MHz, CDCl3): δ = 1.20 (d, J = 6.3 Hz, 6H), 1.36 (d, J = 6.3 Hz, 6H), 1.49 (s, 9H), 4.64 (dsept, J = 6.3, 7.6 Hz, 2H), 7.00 (ddt, J = 1.0, 3.0, 7.7, 1H), 7.45 (ddt, J = 1.5, 7.3, 7.7 Hz, 1H), 7.55 (ddt, J = 1.5, 7.7, 14.6 Hz, 1H), 8.28 (ddd, J = 1.0, 7.3, 7.5 Hz, 1H), 9.56 (br. s, 1H) ppm; 13C NMR (100.63 MHz, CDCl3): δ = 23.7 (d, J = 4.6 Hz, 2C), 24.0 (d, J = 3.8 Hz, 2C), 28.3 (3C), 71.4 (d, J = 5.4 Hz, 2C), 80.3, 114.8 (d, J = 181.3 Hz), 119.2 (d, J = 11.5 Hz), 121.6 (d, J = 13.8 Hz), 132.8 (d, J = 6.1 Hz), 133.6 (d, J = 2.3 Hz), 142.8 (d, J = 6.9 Hz), 153.0 ppm; 31P NMR (161.98 MHz, CDCl3): δ = 31.9 ppm; IR (Si, CDCl3): \( \bar{V} \) = 3247, 1732, 1587, 1305, 1243, 1160, 985 cm−1.

Diisopropyl N-(3-chlorophenyl)phosphoramidate (13b, C12H19ClNO3P)

3-Chloroaniline (1.021 g, 0.84 cm3, 8 mmol) was converted to (3-chlorophenyl)phosphoramidate 13b according to general procedure A. The crude product was purified by flash chromatography (hexanes/EtOAc = 2/1, R f  = 0.18) to give 2.22 g phosphoramidate 13b (95%) as colorless crystals. M.p.: 121–122 °C (hexanes); 1H NMR (400.13 MHz, CDCl3): δ = 1.21 (d, J = 6.3 Hz, 6H), 1.37 (d, J = 6.3 Hz, 6H), 4.66 (dsept, J = 6.3, 7.6 Hz, 2H), 6.87 (m, 2H), 6.90 (br. s, 1H), 7.01 (t, J = 2.0 Hz, 1H), 7.11 (t, J = 8.1 Hz, 1H) ppm; 13C NMR (100.61 MHz, CDCl3): δ = 23.5 (d, J = 5.4 Hz, 2C), 23.8 (d, J = 4.6 Hz, 2C), 71.9 (d, J = 5.4 Hz, 2C), 115.5 (d, J = 7.6 Hz), 117.4 (d, J = 7.6 Hz), 121.2, 130.0, 134.7, 141.7 ppm; 31P NMR (161.98 MHz, CDCl3): δ = 0.8 ppm; IR (Si): \( \bar{V} \) = 3153, 2980, 1599, 1498, 1481, 1388, 1225, 995 cm−1.

Diisopropyl N-(t-butoxycarbonyl)-N-(3-chlorophenyl)phosphoramidate (14b, C17H27ClNO5P)

Diisopropyl N-(3-chlorophenyl)phosphoramidate (13b, 1.46 g, 5 mmol) was converted to N-Boc derivative 14b in Et2O, using general procedure B. The crude product was purified by flash chromatography (hexanes/EtOAc = 1/1, R f  = 0.48) to give 1.36 g N-Boc-phosphormadiate 14b (69%) as colorless crystals. M.p.: 80 °C (hexanes); 1H NMR (400.13 MHz, CDCl3): δ = 1.21 (d, J = 6.3 Hz, 6H), 1.33 (d, J = 6.3 Hz, 6H), 1.45 (s, 9H), 4.71 (dsept, J = 6.3, 7.1 Hz, 2H), 7.11 (m, 1H), 7.21 (m, 1H), 7.26 (m, 2H) ppm; 13C NMR (100.65 MHz, CDCl3): δ = 23.4 (d, J = 5.4 Hz, 2C), 23.9 (d, J = 4.6 Hz, 2C), 28.0 (3C), 73.0 (d, J = 6.1 Hz, 2C), 83.1, 127.5 (d, J = 2.3 Hz), 127.8, 129.5 (d, J = 2.3 Hz), 129.7, 134.1, 139.9, 153.2 (d, J = 7.7 Hz) ppm; 31P NMR (161.98 MHz, CDCl3): δ = −2.4 ppm; IR (Si, CDCl3): \( \bar{V} \) = 2981, 1729, 1302, 1267, 1159, 1000 cm−1.

Diisopropyl (2-t-butoxycarbonylamino-6-chlorophenyl)phosphonate and diisopropyl (2-t-butoxycarbonylamino-4-chlorophenyl)phosphonate (15b and 16b, C17H27ClNO5P)

N-(t-Butoxycarbonyl)-N-(3-chlorophenyl)phosphoramidate (14b, 0.392 g, 1 mmol) was rearranged in THF according to general procedure C for 1 h at −78 °C. The crude product was purified by flash chromatography (hexanes/EtOAc = 5/1, 15b: R f  = 0.70, 16b: R f  = 0.60) to give 0.216 g phosphonate 15b (55%) as colorless crystals, m.p.: 70–75 °C (hexanes), and 0.137 g phosphonate 16b (35%) as colorless oil. When the same experiment was performed according to general procedure C for 1 h at 0 °C, 0.215 g 15b (55%) and 0.125 g 16b (32%) were obtained. When 392 mg N-(t-butoxycarbonyl)-N-(3-chlorophenyl)phosphoramidate (14b, 1 mmol) was rearranged according to general procdure D in THF for 1 h at −78 °C, 0.377 g phosphonate 15b (96%) was obtained.

15b: 1H NMR (400.13 MHz, CDCl3): δ = 1.23 (d, J = 6.3 Hz, 6H), 1.38 (d, J = 6.3 Hz, 6H), 1.50 (s, 9H), 4.68 (dsept, J = 6.3, 7.8 Hz, 2H), 7.01 (ddd, J = 1.0, 4.3, 7.8 Hz, 1H), 7.33 (br. t, J = 8.3 Hz, 1H), 8.41 (ddd, J = 1.0, 5.6, 8.6 Hz, 1H), 11.11 (s, 1H) ppm; 13C NMR (100.61 MHz, CDCl3): δ = 23.5 (d, J = 4.6 Hz, 2C), 23.9 (d, J = 4.6 Hz, 2C), 28.3 (3C), 72.2 (d, J = 6.1 Hz, 2C), 80.4, 112.1 (d, J = 179.7 Hz), 117.2 (d, J = 10.7 Hz), 124.0 (d, J = 9.9 Hz), 133.7 (d, J = 1.5 Hz), 137.9, 146.3 (d, J = 6.1 Hz), 153.2 ppm; 31P NMR (161.98 MHz, CDCl3): δ = 15.4 ppm; IR (Si, CDCl3): \( \bar{V} \) = 2981, 1732, 1582, 1444, 1397, 1298, 1269, 1239, 1160, 1124, 1061, 995 cm−1.

16b: 1H NMR (400.13 MHz, CDCl3): δ = 1.18 (d, J = 6.1 Hz, 6H), 1.33 (d, J = 6.1 Hz, 6H), 1.47 (s, 9H), 4.61 (dsept, J = 6.1, 7.8 Hz, 2H), 6.96 (dt, J = 1.8, 8.3 Hz, 1H), 7.43 (dd, J = 8.3, 14.4 Hz, 1H), 8.40 (dd, J = 1.8, 5.8 Hz, 1H), 9.71 (br.s, 1H) ppm; 13C NMR (100.61 MHz, CDCl3): δ = 23.6 (d, J = 5.4 Hz, 2C), 23.9 (d, J = 3.8 Hz, 2C), 28.2 (3C), 71.6 (d, J = 5.4 Hz, 2C), 80.8, 112.8 (d, J = 183.6 Hz), 118.9 (d, J = 11.5 Hz), 121.8 (d, J = 14.5 Hz), 133.8 (d, J = 6.9 Hz), 139.9 (d, J = 3.8 Hz), 143.9 (d, J = 8.4 Hz), 152.6 ppm; 31P NMR (162.0 MHz, CDCl3): δ = 17.7 ppm; IR (Si, CDCl3): \( \bar{V} \) = 3233, 2981, 1732, 1599, 1577, 1520, 1411, 1275, 1240, 1160, 1077, 987 cm−1.

Diisopropyl N-(3-iodophenyl)phosphoramidate (13c, C12H19INO3P)

Iodoaniline (1.752 g, 0.95 cm3, 8 mmol) was converted to N-(2-iodophenyl)phosphoramidate 13c. The crude product was purified by flash chromatography (hexanes/EtOAc = 1/1, R f  = 0.51) to give 2.60 g phosphoramidate 13c (85%) as colorless crystals. M.p.: 136–137 °C (hexanes); 1H NMR (400.13 MHz, CDCl3): δ = 1.22 (d, J = 6.3 Hz, 6H), 1.37 (d, J = 6.3 Hz, 6H), 4.67 (dsept, J = 6.3, 7.6 Hz, 2H), 6.24 (br. d, J = 8.8 Hz, 1H), 6.90 (dt, J = 1.8, 7.8 Hz, 1H), 7.03 (dt, J = 1.8, 7.8 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 7.14 (t, J = 1.8 Hz, 1H) ppm; 13C NMR (100.61 MHz, CDCl3): δ = 23.6 (d, J = 5.4 Hz, 2C), 23.8 (d, J = 4.6 Hz, 2C), 72.0 (d, J = 4.6 Hz, 2C), 116.0 (d, J = 7.7 Hz), 120.3 (d, J = 7.7 Hz), 122.8, 124.3, 130.4, 141.6 ppm; 31P NMR (161.98 MHz, CDCl3): δ = 0.4 ppm; IR (Si): \( \bar{V} \) = 3148, 2979, 1581, 1480, 1220, 994, 974 cm−1.

Diisopropyl N-(t-butoxycarbonyl)-N-(3-iodophenyl)phosphoramidate (14c, C17H27INO5P)

n-BuLi (1.63 cm3, 2.6 mmol, 1.6 M in hexane) was added to a stirred solution of 0.44 cm3 TMP (0.367 g, 2.6 mmol) in 4.5 cm3 dry THF at 0 °C under argon. After stirring for 15 min at 0 °C a solution of 0.39 cm3 TMEDA (0.302 g, 2.6 mmol) was added and stirring was continued for 15 min. Then, the mixture was cooled at −78 °C and a solution of 0.990 g N-(3-iodophenyl)phosphoramidate 13c (2.6 mmol) dissolved in 2 cm3 dry THF was added, followed 15 min later by 0.567 g Boc2O (2.6 mmol) dissolved in 2 cm3 dry THF. The stirred solution was allowed to warm to RT (20 h) and then the reaction was quenched with 1.5 cm3 AcOH (2 M in dry Et2O) and 5 cm3 H2O. The organic layer was separated and the aqueous one was extracted twice with CH2Cl2. The combined organic layers were dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2/EtOAc = 7/1, R f  = 0.31) to give 0.850 g N-Boc-phospharamidate 14c (68%) as colorless crystals. M.p.: 75–77 °C (hexanes); 1H NMR (400.13 MHz, CDCl3): δ = 1.20 (d, J = 6.3 Hz, 6H), 1.32 (d, J = 6.3 Hz, 6H), 1.45 (s, 9H), 4.71 (dsept, J = 6.3, 7.1 Hz, 2H), 7.06 (t, J = 7.8 Hz, 1H), 7.18 (ddt, J = 1.0, 1.7, 7.8 Hz, 1H), 7.55 (dt, J = 1.0, 1.7 Hz, 1H), 7.61(dq, J = 1.0, 7.8 Hz, 1H) ppm; 13C NMR (100.61 MHz, CDCl3): δ = 23.4 (d, J = 6.1 Hz, 2C), 23.9 (d, J = 3.8 Hz, 2C), 28.0 (3C), 73.1 (d, J = 6.1 Hz, 2C), 83.1, 93.3, 128.6 (d, J = 2.3 Hz), 130.2, 136.6, 138.1 (d, J = 2.3 Hz), 139.9, 153.2 (d, J = 7.6 Hz) ppm; 31P NMR (161.98 MHz, CDCl3): δ = −2.4 ppm; IR (Si): \( \bar{V} \) = 2980, 2930, 1727, 1300, 1159, 1098, 1002 cm−1.

Diisopropyl (2-t-butoxycarbonylamino-6-iodophenyl)- and diisopropyl (2-t-butoxycarbonylamino-4-iodophenyl)phosphonate (15c and 16c, C17H27INO5P)

N-(t-Butoxycarbonyl)-N-(3-iodophenyl)phosphoramidate (14c, 0.483 g, 1.0 mmol) was rearranged according to general procedure C in THF at −78 °C for 1 h. The crude product was purified by flash chromatography (hexanes/EtOAc = 5/1, 15c: R f  = 0.62, 16c: R f  = 0.53) to give 0.093 g 15c (19%) as colorless crystals, m.p.: 75–77 °C (hexanes), and 0.288 g 16c (60%) as a colorless oil. When this experiment was repeated except that the rearrangement was perfomed at 0 °C for 1 h, 0.112 g 15c (23%) and 0.319 g 16c (66%) were obtained. When 0.483 g N-Boc-phosphoramidate 14c (1 mmol) was rearranged according to general procedure D in THF at −78 °C for 1 h, 0.019 g 15c (4%) and 0.376 g 16c (78%) were obtained.

15c: 1H NMR (400.13 MHz, CDCl3): δ = 1.28 (d, J = 6.3 Hz, 6H), 1.41 (d, J = 6.3 Hz, 6H), 1.49 (s, 9H), 4.71 (dsept, J = 6.3, 7.3 Hz, 2H), 7.01 (dd = ~t, J = 7.8, 8.6 Hz, 1H), 7.66 (ddd, J = 1.0, 3.4, 7.8 Hz, 1H), 8.48 (ddd, J = 1.0, 5.6, 8.6 Hz, 1H), 11.16 (br. s, 1H) ppm; 13C NMR (100.61 MHz, CDCl3): δ = 23.7 (d, J = 4.6 Hz, 2C), 24.0 (d, J = 4.6 Hz, 2C), 28.4 (3C), 72.5 (d, J = 4.4 Hz, 2C), 80.4, 99.1 (d, J = 1.5 Hz), 116.8 (d, J = 182.8 Hz), 118.8 (d, J = 10.7), 133.8 (d, J = 2.3 Hz), 135.9 (d, J = 11.5 Hz), 146.4 (d, J = 7.7 Hz), 153.2 ppm; 31P NMR (161.98 MHz, CDCl3): δ = 15.1 ppm; IR (Si, CDCl3): \( \bar{V} \) = 2980, 1731, 1577, 1437, 1388, 1252, 1160, 1116, 1059, 993 cm−1.

16c: 1H NMR (400.13 MHz, CDCl3): δ = 1.19 (d, J = 6.3 Hz, 6H), 1.35 (d, J = 6.3 Hz, 6H), 1.49 (s, 9H), 4.62 (dsept, J = 6.3, 7.8 Hz, 2H), 7.13 (~dt, J = 2.0, 8.3, 1H), 7.37 (dd, J = 8.3, 14.4, 1H), 8.57 (dd, J = 1.5, 5.8, 1H), 9.70 (bs, 1H, NH) ppm; 13C NMR (100.61 MHz, CDCl3): δ = 24.1 (d, J = 5.4 Hz, 2C), 24.4 (d, J = 3.8 Hz, 2C), 28.7 (3C), 71.7 (d, J = 5.4 Hz, 2C), 80.8, 113.3 (d, J = 183.6 Hz), 121.8 (d, J = 11.5 Hz), 124.7 (d, J = 14.5 Hz), 128.5 (d, J = 3.8 Hz), 133.8 (d, J = 6.9 Hz), 143.8 (d, J = 7.7 Hz), 152.7 ppm; 31P NMR (161.98 MHz, CDCl3): δ = 17.8 ppm; IR (Si, CDCl3): \( \bar{V} \) = 3233, 2980, 1731, 1594, 1575, 1408, 1274, 1238, 1160, 1073, 987 cm−1.

Diisopropyl N-(3-methoxyphenyl)phosphoramidate (13d, C13H22NO4P)

3-Methoxyaniline (0.985 g, 0.90 cm3, 8 mmol) was converted to phosphoramidate 13d according to general procedure A. The crude product was purified by flash chromatography (CH2Cl2/EtOAc = 10/1, R f  = 0.08) to give 2.21 g 13d (96%) as colorless crystals. M.p.: 139–141 °C (hexanes); 1H NMR (400.13 MHz, CDCl3): δ = 1.22 (d, J = 6.3 Hz, 6H), 1.36 (d, J = 6.3 Hz, 6H), 3.75 (s, 3H), 4.66 (dsept, J = 6.3, 7.6 Hz, 2H), 5.55 (br. d, J = 9.1 Hz, 1H), 6.47 (ddd, J = 1.0, 2.0, 8.0 Hz, 1H), 6.53 (m, 2H), 7.10 (t, J = 8.1 Hz, 1H) ppm; 13C NMR (100.61 MHz, CDCl3): δ = 23.6 (d, J = 5.4 Hz, 2C), 23.9 (d, J = 4.6 Hz, 2C), 55.2, 71.8 (d, J = 4.6 Hz, 2C), 103.4 (d, J = 7.7 Hz), 106.9, 110.0 (d, J = 7.7 Hz), 129.9, 141.2, 160.4 ppm; 31P NMR (161.98 MHz, CDCl3): δ = 0.7 ppm; IR (Si): \( \bar{V} \) = 3169, 2979, 1608, 1488, 1408, 1277, 1233, 1161, 1054, 982 cm−1.

Diisopropyl N-(t-butoxycarbonyl)-N-(3-methoxyphenyl)phosphoramidate (14d, C18H30NO6P)

Diisopropyl N-(3-methoxyphenyl)phosphoramidate (13d, 1.436 g, 5 mmol) was converted to N-Boc derivative 14d by general procedure B in Et2O at −78 °C. The crude product was flash chromatographed (EtOAc, R f  = 0.60) to give 1.78 g 14d (92%) as a colorless oil. 1H NMR (400.13 MHz, CDCl3): δ = 1.17 (d, J = 6.3 Hz, 6H), 1.32 (d, J = 6.3 Hz, 6H), 1.46 (s, 9H), 3.77 (s, 3H), 4.70 (dsept, J = 6.3, 7.6 Hz, 2H), 6.75 (m, 1H), 6.81 (m, 2H), 7.23 (t, J = 8.1 Hz, 1H) ppm; 13C NMR (100.61 MHz, CDCl3): δ = 23.3 (d, J = 6.1 Hz, 2C), 23.9 (d, J = 3.8 Hz, 2C), 28.0 (3C), 55.3, 72.9 (d, J = 6.1 Hz, 2C), 82.8, 113.3, 115.1 (d, J = 2.3 Hz), 121.5 (d, J = 1.5 Hz), 129.4, 139.7 (d, J = 2.3 Hz), 153.5 (d, J = 8.4 Hz), 159.9 ppm; 31P NMR (161.98 MHz, CDCl3): δ = −1.9 ppm; IR (Si, CDCl3): \( \bar{V} \) = 2981, 1729, 1605, 1492, 1370, 1302, 1257, 1163, 1097, 1008 cm−1.

Diisopropyl (2-t-butoxycarbonylamino-6-methoxyphenyl)phosphonate (15d, C18H30NO6P)

N-(t-Butoxycarbonyl)-N-(3-methoxyphenyl)phosphoramidate (14d, 0.387 g, 1 mmol) was rearranged by general procedure C in THF at −78 °C for 1 h. The crude product was flash chromatographed (hexanes/EtOAc = 5/1, R f  = 0.61) to give 0.156 g 15d (40%) as colorless crystals, m.p.: 85–87 °C (hexanes). When 0.387 g 14d (1 mmol) was rearranged by general procedure D in THF at −78 °C for 1 h 0.260 g phosphonate 15d (67%) was obtained. 1H NMR (400.13 MHz, CDCl3): δ = 1.15 (d, J = 6.1 Hz, 6H), 1.34 (d, J = 6.1 Hz, 6H), 1.49 (s, 9H), 3.80 (s, 3H), 4.59 (dsept, J = 6.1, 8.3 Hz, 2H), 6.50 (ddd, J = 0.8, 5.3, 8.4 Hz, 1H), 7.38 (t, J = 8.4 Hz, 1H), 8.06 (ddd, J = 0.8, 5.8, 8.4 Hz, 1H), 11.00 (s, 1H) ppm; 13C NMR (100.61 MHz, CDCl3): δ = 23.5 (d, J = 4.6 Hz, 2C), 24.0 (d, J = 4.6 Hz, 2C), 28.4 (3C), 55.5, 71.0 (d, J = 5.4 Hz), 79.9, 101.8 (d, J = 175.2 Hz), 104.1(d, J = 8.4 Hz), 111.3 (d, J = 11.5 Hz), 134.6, 145.7 (d, J = 5.4 Hz), 153.3, 162.2 ppm; 31P NMR (161.98 MHz, CDCl3): δ = 17.9 ppm; IR (Si, CDCl3): \( \bar{V} \) = 3172, 3085, 2980, 1729, 1603, 1586, 1469, 1413, 1268, 1241, 1204, 1161, 1046, 995 cm−1.

Diisopropyl N-(3-methylphenyl)phosphoramidate (13e, C13H22NO3P)

m-Toluidine (0.857 g, 0.86 cm3, 8 mmol) was converted to phosphoramidate 13e by general procedure A. The crude product was flash chromatographed (CH2Cl2/EtOAc = 1/1, R f  = 0.56) and gave 1.98 g 13e (91%) as colorless crystals. M.p.: 90–93 °C (hexanes); 1H NMR (400.13 MHz, CDCl3): δ = 1.20 (d, J = 6.3 Hz, 6H), 1.36 (d, J = 6.3 Hz, 6H), 2.27 (s, 3H), 4.65 (dsept, J = 6.3, 7.8 Hz, 2H), 5.68 (br. d, J = 9.1 Hz, 1H), 6.73 (d, J = 7.3 Hz, 1H), 6.76 (s, 1H), 6.77 (d, J = 7.3 Hz, 1H), 7.09 (t, J = 7.3 Hz, 1H) ppm; 13C NMR (100.61 MHz, CDCl3): δ = 21.5, 23.6 (d, J = 5.4 Hz, 2C), 23.9 (d, J = 3.8 Hz, 2C), 71.6 (d, J = 4.6 Hz, 2C), 114.4 (d, J = 6.9 Hz), 118.1 (d, J = 7.4 Hz), 122.2, 128.9, 139.0, 139.9 ppm; 31P NMR (161.98 MHz, CDCl3): δ = 1.2 ppm; IR (Si): \( \bar{V} \) = 3172, 2980, 1610, 1595, 1487, 1387, 1231, 1176, 990 cm−1.

Diisopropyl-N-(t-butoxycarbonyl)-N-(3-methylphenyl)phosphoramidate (14e, C18H30NO5P)

Diisopropyl N-(3-methylphenyl)phosphoramidate (13e, 1.36 g, 5 mmol) was converted to N-Boc phosphoramdiate 14e by general procedure B in Et2O. The crude product was flash chromatographed (hexanes/EtOAc = 1/1, R f  = 0.55) and delivered 1.69 g 14e (91%) as colorless crystals. M.p.: 54–55 °C (hexanes); 1H NMR (400.13 MHz, CDCl3): δ = 1.17 (d, J = 6.3 Hz, 6H), 1.32 (d, J = 6.3 Hz, 6H), 1.46 (s, 9H), 2.32 (s, 3H), 4.69 (dsept, J = 6.3, 7.1 Hz, 2H), 6.99 (br. d, J = 7.6 Hz, 1H), 7.00 (br. s, 1H), 7.07 (br. d, J = 7.6 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H) ppm; 13C NMR (100.61 MHz, CDCl3): δ = 21.2, 23.3 (d, J = 6.1 Hz, 2C), 23.9 (d, J = 3.8 Hz, 2C), 28.1 (3C), 72.7 (d, J = 5.4 Hz, 2C), 82.6, 126.0 (d, J = 1.5 Hz), 128.4, 128.6, 129.7 (d, J = 2.3 Hz), 138.6 (d, J = 2.3 Hz), 138.7, 153.7 ppm; 31P NMR (161.98 MHz, CDCl3): δ = −1.7 ppm; IR (Si, CDCl3): \( \bar{V} \) = 2981, 1729, 1386, 1369, 1300, 1256, 1160, 1098, 1001 cm−1.

Diisopropyl (2-t-butoxycarbonylamino-4-methylphenyl)phosphonate (16e, C18H30NO5P)

Diisopropyl N-(t-butoxycarbonyl)-N-(3-methylphenyl)phosphoramidate (14e, 0.743 g, 2 mmol) was rearranged to N-Boc phosphonate 16e according to general procedure C in THF for 5 h. The crude product, which contained a large amount of starting material, was flash chromatographed (hexanes/EtOAc = 7/1, R f  = 0.27) and furnished 0.038 g 16e (5%) as a colorless oil. When this experiment (1 mmol) was repeated, except that 0.3 cm3 TMEDA (2 mmol) was added before cooling to −78 °C and that the reaction mixture was allowed to warm to RT within 5 h, 0.024 g N-Boc phosphonate 16e (6%) was obtained as colorless oil. 1H NMR (400.13 MHz, CDCl3): δ = 1.18 (d, J = 6.3 Hz, 6H), 1.34 (d, J = 6.3 Hz, 6H), 1.49 (s, 9H), 2.33 (s, 3H), 4.60 (dsept, J = 6.3, 7.8 Hz, 2H), 6.81 (br. d, J = 7.8 Hz, 1H), 7.42 (dd, J = 7.8 Hz, 1H), 8.12 (d, J = 6.3 Hz, 1H), 9.55 (s, 1H) ppm; 13C NMR (100.61 MHz, CDCl3): δ = 22.0, 23.6 (d, J = 5.4 Hz, 2C), 24.0 (d, J = 3.8 Hz, 2C), 28.3 (3C), 71.2 (d, J = 5.4 Hz, 2C), 80.2, 111.6 (d, J = 184.3 Hz), 120.9 (d, J = 11.5 Hz), 122.6 (d, J = 14.5 Hz), 132.7 (d, J = 6.9 Hz), 142.7 (d, J = 7.6 Hz), 144.5 (d, J = 2.3 Hz), 153.0 ppm; 31P NMR (161.98 MHz, CDCl3): δ = 19.1 ppm; IR (Si, CDCl3): \( \bar{V} \) = 3247, 2980, 1731, 1580, 1244, 1162, 1089, 985 cm−1.

Diisopropyl N-(1-naphthyl)phosphoramidate (18, C16H22NO3P)

1-Naphthylamine (1.146 g, 8.0 mmol) was converted to phosphoramdiate 18 by general procedure A. The crude product was purified by flash chromatography (hexanes/EtOAc = 2/1, R f  = 0.30) and delivered 1.21 g 18 (49%) as colorless crystals. M.p.: 149 °C (hexanes); 1H NMR (400.13 MHz, CDCl3): δ = 1.18 (d, J = 6.1 Hz, 6H), 1.38 (d, J = 6.1 Hz, 6H), 4.71 (dsept, J = 6.1, 7.6 Hz, 2H), 5.71 (d, J = 7.8 Hz, 1H), 7.36 (m, 2H), 7.49 (m, 3H), 7.82 (m, 1H), 7.90 (m, 1H) ppm; 13C NMR (100.61 MHz, CDCl3): δ = 23.6 (d, J = 5.4 Hz, 2C), 23.9 (d, J = 3.8 Hz, 2C), 71.9 (d, J = 5.4 Hz, 2C), 114.0 (d, J = 2.3 Hz), 120.0, 122.3, 125.1 (d, J = 9.9 Hz), 125.9, 125.9, 126.0, 128.8, 134.3, 135.0 ppm; 31P NMR (161.98 MHz, CDCl3): δ = 1.5 ppm; IR (Si): \( \bar{V} \) = 2979, 1470, 1244, 991 cm−1.

Diisopropyl N-(t-butoxycarbonyl)-N-(1-naphthyl)phosphoramidate (19, C21H30NO5P)

Diisopropyl N-(1-naphthyl)phosphoramidate (18, 0.922 g, 3.0 mmol) was converted to Boc derivative 19 by general procedure B in Et2O. The crude product was purified by flash chromatography (CH2Cl2/EtOAc = 10/1, R f  = 0.35) and gave 0.960 g 19 (79%) as brownish oil. 1H NMR (400.13 MHz, CDCl3): δ = 0.89 (d, J = 6.1 Hz, 3H), 1.11 (d, J = 6.1 Hz, 3H), 1.25 (d, J = 6.1 Hz, 3H), 1.28 (d, J = 6.1 Hz, 3H), 1.40 (s, 9H), 4.62 (dsept, J = 6.1, 7.1 Hz, 1H), 4.72 (dsept, J = 6.1, 7.1 Hz, 1H), 7.38 (td, J = 7.3, 1.5 Hz, 1H), 7.44 (dd, J = 7.7, 7.3 Hz, 1H), 7.46 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 7.52 (ddd, J = 8.3, 6.8, 1.5 Hz, 1H), 7.79 (br. d, J = 8.3 Hz, 1H), 7.82 (br. d, J = 7.7 Hz, 1H), 8.02 (br. d, J = 8.6 Hz, 1H) ppm; 13C NMR (100.61 MHz, CDCl3): δ = 22.9 (d, J = 6.9 Hz), 23.3 (d, J = 6.9 Hz), 23.8 (d, J = 3.1 Hz), 24.0 (d, J = 3.1 Hz), 27.9 (3C), 73.0 (d, J = 6.1 Hz), 73.1 (d, J = 6.1 Hz), 82.6, 123.0, 125.4, 126.0, 126.6 (d, J = 3.1 Hz), 126.7, 128.1, 128.3 (d, J = 1.5 Hz), 131.7, 134.3, 135.4, 153.6 (d, J = 9.2 Hz) ppm; 31P NMR (161.98 MHz, CDCl3): δ = −1.5 ppm; IR (Si, CDCl3): \( \bar{V} \) = 2980, 1727, 1301, 1159, 1002 cm−1.

Diisopropyl (1-t-butoxycarbonylamino-2-naphthyl)phosphonate (20, C21H30NO5P)

Diisopropyl N-(t-butoxycarbonyl)-N-(1-naphthyl)phosphoramidate (19, 0.469 g, 1.15 mmol) was rearranged to N-Boc phosphonate 20 according to general procedure C in Et2O at −78 °C for 2 h. The crude product was flash chromatographed (hexanes/EtOAc = 2/1, R f  = 0.54) and gave 0.393 g 20 (84%) as a colorless oil. 1H NMR (400.13 MHz, CDCl3): δ = 1.21 (d, J = 6.1 Hz, 6H), 1.38 (d, J = 6.1 Hz, 6H), 1.50 (s, 9H), 4.72 (dsept, J = 6.1, 8.1 Hz, 2H), 7.53 (m, 2H), 7.76 (m, 3H), 8.0 (m, 1H), 8.17 (br. s, 1H) ppm; 13C NMR (100.61 MHz, CDCl3): δ = 23.8 (d, J = 4.6 Hz, 2C), 24.0 (d, J = 3.8 Hz, 2C), 28.3 (s, 3C), 71.4 (d, J = 5.4 Hz, 2C), 80.4, 119.7 (d, J = 183.6 Hz), 125.8, 126.0, 126.3, 127.1 (d, J = 7.7 Hz), 127.8, 128.1, 129.3 (d, J = 13.0 Hz), 136.3, 139.2 (d, J = 5.4 Hz), 154.0 ppm; 31P NMR (161.98 MHz, CDCl3): δ = 17.0 ppm; IR (Si, CDCl3): \( \bar{V} \) = 3401, 3271, 2979, 2930, 1733, 1243, 1161, 986 cm−1.

Tetraisopropyl N-(pyridin-2-yl)diphosphoramidate (22, C17H32N2O6P2)

2-Aminopyridine (0.753 g, 8 mmol) was converted to diphosphoramidate 22 by general procedure A except that 19.2 mmol bromine and 19.2 mmol (i-PrO)3P, 32 mmol Et3N and 3 cm3 2 N HCl were used. The crude product was purified by flash chromatography (EtOAc/EtOH = 10/1, R f  = 0.55) to give 3.13 g 22 (93%) as a colorless oil. 1H NMR (400.13 MHz, CDCl3): δ = 1.23 (d, J = 6.3 Hz, 12H), 1.30 (d, J = 6.3 Hz, 12H), 4.83 (m, 4H), 7.16 (m, 1H), 7.32 (br. d, J = 7.8 Hz, 1H), 7.66 (dt, J = 1.8, 7.8 Hz, 1H), 8.46 (dd, J = 1.8, 4.8 Hz, 1H) ppm; 13C NMR (100.61 MHz, CDCl3): δ = 23.4 (d, J = 3.2 Hz, 2C), 23.4 (d, J = 3.1 Hz, 2C), 23.8 (dd, J = 2.3 Hz, 2C), 23.8 (d, J = 1.5 Hz, 2C), 72.8 (d, J = 3.2 Hz, 2C), 72.8 (dd, J = 3.1 Hz, 2C), 122.2, 123.2 (t, J = 2.7 Hz), 138.0, 148.9, 152.3 ppm; 31P NMR (161.98 MHz, CDCl3): δ = −1.5 ppm; IR (Si): \( \bar{V} \) = 2980, 2936, 1589, 1467, 1433, 1386, 1375, 1279, 1179, 1143, 1109, 1000 cm−1.

Diisopropyl (2-(diisopropylphosphorylamino)pyridin-3-yl)phosphonate (23, C17H32N2O6P2)

Tetraisopropyl N-(pyridin-2-yl)diphosphoramidate (22, 1.27 g, 3 mmol) was rearranged to pyridin-3-ylphosphonate 23 by general procedure D in THF for 20 h. The crude product was flash chromatographed (CH2Cl2/EtOH = 20/1, R f  = 0.38) to give 0.920 g 23 (72%) as an oil. When this experiment was repeated with LiTMP according to general procedure C, 0.460 g 23 (36%) was obtained. 1H NMR (400.13 MHz, CDCl3): δ = 1.20 (d, J = 6.1 Hz, 6H), 1.30 (d, J = 6.1 Hz, 6H), 1.34 (d, J = 6.1 Hz, 6H), 1.36 (d, J = 6.1 Hz, 6H), 4.65 (dsept, J = 6.1 Hz, 7.8 Hz, 2H), 4.83 (dsept, J = 6.1, 7.8 Hz, 2H), 6.83 (ddd, J = 2.0, 4.8, 7.3 Hz, 1H), 7.76 (ddt, J = 2.0, 7.3, 14.9 Hz, 1H), 8.40 (dt, J = 2.0, 4.8 Hz, 1H), 8.56 (br. d, J = 10.9 Hz, 1H) ppm; 13C NMR (100.61 MHz, CDCl3): δ = 23.6 (d, J = 5.4 Hz, 2C), 23.7 (d, J = 4.6 Hz, 2C), 23.9 (d, J = 4.6 Hz, 2C), 24.0 (d, J = 4.6 Hz, 2C), 71.7 (d, J = 5.4 Hz, 2C), 72.1 (d, J = 6.1 Hz, 2C), 108.8 (dd, J = 10.3, 185.9 Hz), 115.8 (d, J = 9.9 Hz), 142.1 (d, J = 6.9 Hz), 152.4, 156.1 (d, J = 10.7 Hz) ppm; 31P NMR (161.98 MHz, CDCl3): δ = −1.1 (d, J = 2.0 Hz), 16.9 (d, J = 2.0 Hz) ppm; IR (Si, CDCl3): \( \bar{V} \) = 3218, 2980, 2935, 1575, 1445, 1262, 1231, 998 cm−1.

Crossover experiment

3-[Methyl-D 3 ]methoxyaniline ([D3]9d, C7H6D3NO)

To a stirred mixture of 0.546 g 3-aminophenol (5 mmol) and 0.786 g t-BuOK (7 mmol) in 8 cm3 dry THF under argon at RT was added 1.136 g [D3]methyl p-toluenesulfonate (6 mmol) [25] dropwise. After stirring for 18 h 5 cm3 H2O and CH2Cl2 were added. The organic phase was separated and the aqueous one was extracted with CH2Cl2. The combined organic layers were dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2, R f  = 0 42) to give 0.400 g labeled 3-methoxyaniline [D3]9d (63%) as a colorless oil. 1H NMR (250.13 MHz, CDCl3): δ = 3.63 (br. s, 2H), 6.22 (d, J = 2.2 Hz, 1H), 6.28 (ddd, J = 0.9, 2.2, 8.0 Hz, 1H), 7.04 (t, J = 8.0 Hz, 1H).

Di-[D7]isopropyl N-(3-[methyl-D3]methoxyphenyl)phosphoramidate ([D17]13d, C13H5D17NO4P)

3-[Methyl-D3]methoxyaniline (0.630 g, 5 mmol) was converted to 1.28 g phosphoramidate [D17]13d (84%) as colorless crystals by the method used for the unlabled compound except that (i-PrO)3P was replaced by the deuterated species [24]; m.p.: 141–143 °C (hexanes). The 1H and 13C NMR spectrum of [D17]13d were identical to those of the unlabeled compound except for the missing signals because of deuteration.

Di-[D7]isopropyl N-(t-butoxycarbonyl)-N-(3-[methyl-D3]methoxyphenyl)phosphoramidate ([D17]14d, C18H13D17NO6P)

Di-[D7]isopropyl N-(3-[methyl-D3]methoxyphenyl)phosphoramidate ([D17]13d) (0.609 g, 2 mmol) was converted to 0.760 g N-Boc phosphoramidate [D17]14d (94%) as a colorless oil. The 1H and 13C NMR spectrum of [D17]14d were identical to those of the unlabeled compound except for the missing signals because of deuteration. 31P NMR (161.98 MHz, CDCl3): δ = −1.9 ppm; IR (Si, CDCl3): \( \bar{V} \) = 2980, 1728, 1604, 1491, 1289, 1156, 1112, 990, 914 cm−1.

Crossover experiment with a 1:1 mixture of deuterated and nondeuterated diisopropyl N-(t-butoxycarbonyl)-N-(3-methoxyphenyl)phosphoramidate

A mixture of 0.202 g deuterated N-(t-butoxycarbonyl)-N-(3-methoxyphenyl)phosphoramidate [D17]14d (0.5 mmol) and 0.194 g nondeuterated N-(3-methoxyphenyl)-N-(t-butoxycarbonyl)phosphoramidate 14d (0.5 mmol) was rearranged in the same way (LDA, THF, 1 h, 78 °C) as phosphoramidate 14d and gave 0.390 g 1:1 mixture of deuterated phosphonate [D17]15d and nondeuterated 15d (98%) as colorless crystals. M.p.: 87–89 °C (hexanes); 1H NMR (400.13 MHz, CDCl3): δ = 1.15 (d, J = 6.1 Hz, 6H), 1.34 (d, J = 6.1 Hz, 6H), 1.49 (s, 18H), 3.81 (s, 3H), 4.60 (dsept, J = 6.1, 8.3 Hz, 2H), 6.50 (dddd, J = 0.8, 2.8, 5.3, 8.3 Hz, 2H), 7.38 (t, J = 8.6, 2H), 8.06 (dd, J = 5.8, 8.6, 2H), 11.01 (br. s, 1H) ppm; 31P NMR (161.98 MHz, CDCl3): δ = 17.88 (P(O)(Oi-Pr)2), 17.93 (br. s, P(O)(OCD(CD3)2)2) ppm; IR (Si, CDCl3): \( \bar{V} \) = 3503, 3172, 3085, 2980, 2933, 1729, 1603, 1586, 1534, 1469, 1439, 1413, 1387, 1368, 1309, 1268, 1241, 1204, 1161, 1127, 1109, 1066, 1046, 995 cm−1. MS before rearrangement: EI-MS (70 eV, 50 °C): m/z (%) = 404 (6.3, MD17 +), 387 (5.5, M+), 203 (94), 208 (100); after rearrangement: EI-MS (70 eV, 50 °C): m/z (%) = 404 (23.7, MD17 +), 387 (25.3, M+), 203 (100), 208 (94). There were no signals with m/z = 401 or 390.

2-Aminophenylphosphonic acid (25)

Method A: A mixture of 0.335 g diisopropyl 2-(t-butoxycarbonylamino)phenylphosphonate (15a, 0.94 mmol) and 10 cm3 HCl (6 M) was refluxed for 7 h. The cooled solution was concentrated under reduced pressure and the residue was dried over KOH in a vacuum desiccator. Then, it was dissolved in H2O and applied to an ion exchange column (Dowex 50 W × 8; H+) and eluted with H2O. Fractions containing product (TLC: i-PrOH/H2O/NH3 = 6/3/1, R f  = 0.38) were pooled and concentrated to give 0.138 g phosphonic acid 24 (85%) as a brownish crystalline product containing an impurity (6%, by 1 NMR); m.p.: 186 °C (water) [Ref. [27] 199–200 °C (water/ethanol)].

Method B: A solution of 0.530 g diisopropyl 2-(t-butoxycarbonylamino)phenylphosphonate (15a, 1.48 mmol), 0.48 cm3 allyltrimethylsilane (0.343 g, 3 mmol), and 1.73 cm3 bromotrimethylsilane (2.050 g, 13.4 mmol) [29] in 5 cm3 dry CH2Cl2 was refluxed under Ar for 20 h. Volatiles were removed under reduced pressure (0.5 mbar), CH2Cl2 (2 × 10 cm3) was added and removed again under reduced pressure. Water (15 cm3) was added and the reaction mixture was stirred for 15 min. The solvent was removed under reduced pressure and the residue was dried. Crystallization of the crude product from H2O gave 0.240 g 24 (95%) of brownish crystals, m.p.: 198–201 °C.

1H NMR (400.13 MHz, D2O/NaOD): δ = 6.70 (dd, J = 4.8, 7.6 Hz, 1H), 6.73 (br. t, J = 7.6 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.49 (dd, J = 7.6, 12.9 Hz, 1H) ppm; 13C NMR (100.63 MHz, D2O/NaOD): δ = 117.3 (d, J = 10.0 Hz), 118.6 (d, J = 12.2 Hz), 125.3 (d, J = 162.9 Hz), 130.7, 132.8 (d, J = 6.9 Hz), 147.8 (d, J = 5.4 Hz) ppm; 31P NMR (161.98 MHz, D2O/NaOD): δ = 11.7 ppm; IR (ATR): \( \bar{V} \) = 2325, 1580, 1538, 1483, 1446, 1168, 1148, 1124, 1074, 1007, 903 cm−1.

1-Amino-2-naphthylphosphonic acid (26, C10H10NO3P)

Diisopropyl [1-N-(t-butoxycarbonylamino)-2-naphthyl]phosphonate (20, 0.618 g, 1.52 mmol) was deblocked by method B used for the preparation of 25 for the phenyl analog, except that the final procedure was different. After removing all volatiles under reduced pressure the residue was dissolved in 90 cm3 MeOH. Slow concentration of the reddish-brown solution on the rotary evaporator at RT to about 7 cm3 gave reddish crystals, which were collected by centrifugation. They were washed with 3 cm3 MeOH and dried for 1 h (50 °C/0.5 mbar) to give 0.204 g analytically pure naphthylphosphonic acid 26 (60%); m.p.: 236–239 °C; from the mother liquor a second crop (0.085 g, 95% pure by 31P NMR) was obtained. 1-Amino-2-naphthylphosphonic acid seemed to be stable for short periods of time in refluxing MeOH. It could not be crystallized from hot H2O, as it decomposed to phosphoric acid (by 31P NMR) and 1-naphthylamine (by TLC after extraction) within 30 min. 1H NMR (400.13 MHz, D2O/NaOD): δ = 7.20 (m, 1H), 7.37 (m, 1H), 7.56 (m, 1H), 7.69 (m, 2H), 7.86 (m, 1H) ppm; 13C NMR (100.61 MHz, D2O/NaOD): δ = 118.0 (d, J = 12.2 Hz), 120.0 (d, J = 164.5 Hz), 122.2, 124.6 (d, J = 10.7 Hz), 125.7, 127.0, 128.5, 130.3 (d, J = 7.7 Hz), 134.6, 143.7 (d, J = 6.1 Hz) ppm; 31P NMR (161.98 MHz, D2O/NaOD): δ = 12.5 ppm; IR (ATR): \( \bar{V} \) = 2547, 1586, 1559, 1506, 1462, 1432, 1373, 1352, 1173, 1110, 1005, 944 cm−1.

2-Aminopyridin-3-ylphosphonic acid (27, C5H7N2O3P)

Diisopropyl 2-(diisopropylphosphorylamino)pyridin-3-ylphosphonate (23, 0.887 g, 2.10 mmol) was deblocked with refluxing HCl by method A used for the preparation of 25. Fractions containing product (TLC: i-PrOH/H2O/NH3 = 6/3/1, R f  = 0.43) were pooled and concentrated to give 0.319 g 27 (87%) as nearly colorless crystals. M. p.: 256–259 °C (H2O/EtOH); 1H NMR (400.13 MHz, D2O): δ = 6.72 (ddd, J = 1.7, 6.3, 7.1 Hz, 1H), 7.60 (dt, J = 1.7, 6.3 Hz, 1H), 7.99 (ddd, J = 1.7, 7.1, 13.1 Hz, 1H) ppm; 13C NMR (100.61 MHz, D2O): δ = 130.1 (d, J = 11.5 Hz), 123.7 (d, J = 163.7 Hz), 136.6, 146.9 (d, J = 5.4 Hz), 154.4 (d, J = 12.2 Hz) ppm; 31P NMR (161.98 MHz, D2O): δ = 5.9 ppm; IR (ATR): \( \bar{V} \) = 3401, 3297, 3079, 2627, 2325, 1650, 1615, 1593, 1554, 1456, 1401, 1334, 1244, 1169, 1144, 1011, 908 cm−1.