N-(diphenoxyphosphoryl)succinimide: Synthesis and reaction with alkoxides

Article abstract of DOI:10.1080/10426507.2011.608098

Reaction of succinimide with diphenylchlorophosphate in the presence of lithium bis(trimethylsilyl)amide followed by aqueous work-up led to the formation of amidophosphate 3. The same reaction performed in the presence of sodium hydride yield N-(diphenylp

Full text of DOI:10.1080/10426507.2011.608098

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Phosphorus, Sulfur, and Silicon and the
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N-(Diphenoxyphosphoryl)Succinimide:
Synthesis and Reaction with Alkoxides
Ryszard Andruszkiewicz a & Ewa Liedke-Przybysz a
a Department of Pharmaceutical Technology and Biochemistry ,
Gdańsk University of Technology , Gdańsk, Poland
Published online: 31 Oct 2011.
To cite this article: Ryszard Andruszkiewicz & Ewa Liedke-Przybysz (2011) N-
(Diphenoxyphosphoryl)Succinimide: Synthesis and Reaction with Alkoxides, Phosphorus, Sulfur, and
Silicon and the Related Elements, 186:12, 2274-2278, DOI: 10.1080/10426507.2011.608098
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Phosphorus, Sulfur, and Silicon, 186:2274–2278, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.608098
N-(DIPHENOXYPHOSPHORYL)SUCCINIMIDE: SYNTHESIS
AND REACTION WITH ALKOXIDES
Ryszard Andruszkiewicz and Ewa Liedke-Przybysz
Department of Pharmaceutical Technology and Biochemistry, Gdan´sk University
of Technology, Gdan´sk, Poland
GRAPHICAL ABSTRACT
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Abstract Reaction of succinimide with diphenylchlorophosphate in the presence of
lithium bis(trimethylsilyl)amide followed by aqueous work-up led to the formation of
amidophosphate 3. The same reaction performed in the presence of sodium hydride yield
N-(diphenylphosphoryl)succinimde 4, which undergoes nucleophilic ring opening with sodium
alkoxides resulted in the formation of phosphoroamidate analogues 5 a-d in good yields.
Keywords Phosphorylated succinimide; nucleophilic ring opening; phosphoramidates
INTRODUCTION
Recently, N-phosphoryl oxazolidinones1,2 as well as N-phosphoryl thiazolidine
derivatives3 have been proposed as useful and stable reagents for phosphorylation of alco-
hols. Lal et al. applied diphenyl phosphoryl azide (DPPA) – the known acyl azide forming
reagent4 – also for the conversion of alcohols into azides through the formation of phosphate.
This shows that N-phosphorylated compounds containing a cleavable P N bond may be
used as an alternative of phosphorochloridates, in which a reactive P Cl bond is present.
Moreover, other compounds containing labile P N bonds, e.g., diethylphosphorosuccinim-
idate, have been used for the phosphorylation of alcohols under acidic or neutral conditions.5
Hydrolysis of di(n-butyl)phosphorosuccinimidate in the presence of sodium borohydride
in aqueous ethanol gives O,O-di(n-butyl)phosphoramidate.6 In the course of our investiga-
tions on phosphorylation reactions,7 the synthesis of diphenylphosphoro-succinimidate has
been attempted with the aim of using this reagent for reaction with alcohols.
Received 22 April 2011; accepted 15 July 2011.
This work was supported by the Faculty of Chemistry, Gdan´sk University of Technology, Gdan´sk, Poland.
Address correspondence to Ryszard Andruszkiewicz, Department of Pharmaceutical Technology and Bio-
chemistry, Gdan´sk University of Technology, Gdan´sk, Poland. E-mail: ryszarda@chem.pg.gda.pl
2274

N-(DIPHENOXYPHOSPHORYL)SUCCINIMIDE SYNTHESIS
2275
RESULTS AND DISCUSSION
Reaction of diphenyl chlorophosphate 1 with succinimide 2 and lithium
bis(trimethylsilyl)amide (LiHMDS) in acetonitrile or tetrahydrofurane (THF) solu-
tion followed by aqueous workup surprisingly yielded not the succinimide derivative but
the amidophosphate 3, suggesting that the succinimide ring is cleaved in the course of the
reaction (Scheme 1). However, treatment of succinimide with 1 equivalent of either n-butyl
lithium (n-BuLI) or sodium hydride in acetonitrile or THF followed by the addition of
diphenyl chlorophosphate yielded the expected N-(diphenoxyphosphoryl)succinimide 4 in
good yield. Although compound 4 is a low melting reagent, it can be stored for months
and is easily handled.
Scheme 1 Synthetic route to the substituted phosphoroamidates 5 and 6.
Chlorophosphates usually react with alcohols in the presence of triethylamine as a
hydrochloric acid scavenger. Interaction of alcohols with compound 4 in the presence of
triethylamine did not result in the formation of products. As the leaving-group ability of
the succinimide anion is worse than that of chloride, the nucleophilicity of the alcohol was
increased by formation of the corresponding alkoxide. In our study, lithium and sodium
alkoxides were prepared. Unexpectedly, when lithium benzyloxide was reacted with N-
(diphenoxyphosphoryl)succinimide 4, the benzyl ester of succinic amide derivative 5a was
obtained, together with only traces of the corresponding phosphate triester. The same was
observed when methyl, ethyl, or n-butyl alcohols were used. Methyl, ethyl, or n-butyl esters
of succinic amide derivatives 5b, 5c, and 5d were thus prepared; the products contained
as impurity only a small amount of the corresponding monoalkyl phosphates. The results
presented clearly indicate that nucleophilic ring opening is the driving force leading to the
formation of esters of succinic acid. Moreover, reaction of 4 with 1 equivalent of aqueous

2276
R. ANDRUSZKIEWICZ AND E. LIEDKE-PRZYBYSZ
ammonia also led to ring opening and resulted in the formation of compound 3, the same
compound formed in the reaction of diphenyl chlorophosphate with succinimide in the
presence of LiHMDS, confirming presumably the same reaction pathway. This clearly
shows that the P N C O bond system makes the carbonyl carbon atom more susceptible
to the attack by nucleophilic species as compared with the pentavalent phosphorus atom.
Moreover, catalytic reduction (H2/PtO2) of phenyl ester 3 resulted in the formation of the
acid 6.
In conclusion, we have developed a simple method for functionalization of succinic
acid. This method makes it possible to prepare its monoesters or monoamides, together
with the phosphorylated amide, starting from N-(diphenoxyphosphoryl)succinimide. Since
phosphoroamidates containing a modified succinic acid have been shown to be putative
inhibitors of the enzyme aspartate-semi-aldehyde dehydrogenase,8 this method may also
be useful for the preparation of these compounds.
EXPERIMENTAL
All chemicals were commercially available and used without further purification.
Thin layer chromatography (TLC) was performed using Merck aluminum-backed plates
(Kieselgel 60 F254), and visualization was achieved by ultraviolet (UV) light. Separations
by column chromatography were performed using silica gel (0.063–0.200 mm). MALDI-
TOF-MS spectra were recorded with a Biflex III apparatus. FTIR spectra were measured for
crystalline compounds with a Momentum microscope (IR detector) attached to a Mattson
1
Genesis II Gold spectrometer (IR source). H, 13C, and 31P NMR spectra were recorded
with a Varian Unity Plus spectrometer (500 MHz) operating at 500 MHz, 125 MHz, and
200 MHz, respectively. Chemical shifts are given in parts per million (ppm) relative to
tetramethylsilane as internal or 85% H3PO4 as external standard.
Synthesis of Diphenyl (4-Amino-4-Oxobutanoyl)Amidophosphate (3)
To a solution of succinimide 1 (0,99 g, 10 mmol) in anhydrous acetonitrile (50 mL),
LiHMDS (10 mL of 1 M solution in THF) was added portionwise with stirring, while
the temperature was kept at −10◦C. After 20 min, diphenyl chlorophosphate (2.06 mL,
10 mmol) was added by means of a syringe and the reaction mixture was stirred for
additional 20 min. The solvent was evaporated; the residue was dissolved in ethyl acetate
(20 mL), washed with water (three times × 10 mL), and dried over MgSO4. The solvent
was evaporated again. The residue was dissolved in diethyl ether (20 mL) and kept in a
refrigerator. The precipitated product was collected. Yield: 2.57 g (74%). mp. 141–142◦C.
1H NMR (500 MHz, CDCl3): δ = 2.45–2.55 (m, 2H, CH2), 2.60–2.70 (m, 2H, CH2),
5.55–5.75 (br s, 2H, CONH2), 7.15–7.45 (br s, 10H, C6H5), 8.25 (br s, 1H, NH); 13C NMR
(125 MHz, DMSO-d6): δ = 29.0, 31.3, 120.5, 125.5, 130.0, 150.0, 172.9, 173.9; 31P NMR
(200 MHz, DMSO-d6): δ = −8.8. IR (solid, cm−1): ν = 1024, 1161, 1229, 1295, 1599,
1664. Anal. Calcd. for C16H17N2O5P (348.29): C, 55.18; H, 4.92; N, 8.04. Found: C, 55.32;
H, 5.05; N, 7.86. MS: m/z = 349 (MH+).
Synthesis of N-(Diphenoxyphosphoryl)-Succinimide (4)
To a solution of succinimide 1 (0.99 g, 10 mmol) in anhydrous acetonitrile (20 mL),
NaH (0.4 g as 60% suspension in mineral oil, 10 mmol) was added at −10◦C with stirring
under argon. After 10 min, diphenyl chlorophosphate (2.06 mL, 10 mmol) was added

N-(DIPHENOXYPHOSPHORYL)SUCCINIMIDE SYNTHESIS
2277
and the reaction mixture was kept for 4 h. The solvent was evaporated; the residue was
dissolved in ethyl acetate, the organic layer was washed with water, dried (over MgSO4),
and chromatographed on silica gel using ethyl acetate/hexane 2:1 v/v as eluent. Yield:
2.45 g (75%), low melting product, which solidified upon standing at low temperatures. 1H
NMR (500 MHz, CDCl3): δ = 2.35 (s, 4H, CH2 CH2 ), 7.25–7.45 (br s, 10H, C6H5),
13C NMR (125 MHz, DMSO-d6): δ = 29.0, 120.5, 125.5, 130.0, 150.0, 173.9; 31P NMR
(200 MHz, DMSO-d6): δ = −10.2. IR (solid, cm−1): ν = 1034, 1275, 1688. Anal. Calcd.
for C16H14NO5P (331.25): C, 58.01; H, 4.26; N, 4.23. Found: C, 57.89; H, 4.21; N, 4.12.
MS: m/z = 332 (MH+).
Synthesis of Substituted Phosphoroamidates: General Procedure
To a solution of the respective alcohol (5 mmol) in dry acetonitrile (10 mL), an
equimolar amount of sodium hydride or n-butyl lithium (2.5 M solution in hexane) was
added and the solution was kept at −10◦C for 10 min. Then, compound 4 (5 mmol) was
added under argon and the reaction mixture was allowed to stand for 2 h. Subsequently,
the reaction mixture was quenched with 1 N HCl (6 mL), the solvent was evaporated, and
the residue was extracted with ethyl acetate. The organic layers were dried (over MgSO4)
and the solvent was evaporated. In the case of 5a, the product was purified by column
chromatography using ethyl acetate/hexane 2:1 v/v as eluent.
Benzyl 4-[(Diphenoxyphosphoryl)Amino]-4-Oxobutanoate (5a)
1
Oil. Yield: 1.53 g (70%). H NMR (500 MHz, CDCl3): δ = 2.55–2.80 (m, 4H,
CH2 CH2 ), 5.20 (s, 2H, CH2–C6H5), 7.10–7.45 (br s, 15H, C6H5), 8.80 (br s, 1H,
NH). 13C NMR (125 MHz, DMSO-d6): δ = 28.9, 31.8, 67.8, 121.5, 125.6, 127.3, 127.9,
129.3, 130.0, 141.3, 150.0, 172.9, 173.9; 31P NMR (200 MHz, DMSO-d6): δ = −8.6. IR
(solid, cm−1): ν = 1025, 1164, 1239, 1285, 1655, 1724. Anal. Calcd. for C23H22NO6P
(439.39): C, 62.85; H, 5.05; N, 3.19. Found: C, 62.72; H, 4.97; N, 3.27. MS: m/z = 440
(MH+).
Methyl 4-[(Diphenoxyphosphoryl)Amino]-4-Oxobutanoate (5b)
Oil. Yield: 1.65 g (92%). 1H NMR (500 MHz, CDCl3): δ = 2.45–2.55 (m, 2H, CH2),
2.60–2.70 (m, 2H, CH2), 3.65 (s, 3H, CH3), 7.10–7.35 (br s, 10H, C6H5), 8.75 (br s, 1H,
NH). 13C NMR (125 MHz, DMSO-d6): δ = 29.0, 31.3, 52.0, 121.9, 125.4, 129.8, 149.8,
172.68, 173.6. 31P NMR (200 MHz, DMSO-d6): δ = −8.5. IR(solid, cm−1): ν = 1027,
1162, 1244, 1284, 1639, 1714. Anal. Calcd. for C17H18NO6P (363.30): C, 56.20; H, 4.99;
N, 3.86; P, 8.53. Found: C, 56.15; H, 4.91; N, 3.75. MS: m/z = 364 (MH+).
Ethyl 4-[(Diphenoxyphosphoryl)Amino]-4-Oxobutanoate (5c)
1
Oil. Yield: 1.69 g (90%). H NMR (500 MHz, CDCl3): δ = 1.3 (t, J = 7.0 Hz,
3H, CH3), 2.45–2.55 (m, 2H, CH2), 2.60–2.70 (m, 2H, CH2), 4.12 (q, J = 7.0 Hz, 2H,
CH2), 7.10–7.45 (br s, 10H, C6H5), 8.65 (br s, 1H, NH). 13C NMR (125 MHz, DMSO-d6):
δ = 16.3, 29.3, 32.5, 63.9, 121.5, 125.7, 130.0, 149.5, 172.5, 173.5. 31P NMR (200 MHz,
DMSO-d6): δ = −8.5. IR (solid, cm−1): ν = 1032, 1155, 1229, 1291, 1629, 1684. Anal.

2278
R. ANDRUSZKIEWICZ AND E. LIEDKE-PRZYBYSZ
Calcd. for C18H20NO6P (377.32): C, 57.30; H, 5.34; N, 3.71. Found: C. 57.10; H, 5.21; N,
3.55. MS: m/z = 378 (MH+).
n-Butyl 4-[(Diphenoxyphosphoryl)Amino]-4-Oxobutanoate (5d)
Oil. Yield: 1.88 g (93%). 1H NMR (500 MHz, CDCl3): δ = 1.1 (t, J = 7.0 Hz, 3H,
CH3), 1.35–1.55 (m 4H, CH2 CH2), 2.45–2.55 (m, 2H, CH2), 2.60–2.70 (m, 2H, CH2),
4.10 (m, 2H, CH2), 7.10–7.45 (br s, 10H, C6H5), 8.65 (br s, 1H, NH). 13C NMR (125 MHz,
DMSO-d6): δ = 16.0, 18.3, 29.6, 31.4, 32.3, 51.8, 121.6, 125.3, 129.7, 149.7, 172.6, 173.7.
31P NMR (200 MHz, DMSO-d6): δ = −8.6. IR (solid, cm−1): ν = 1028, 1165, 1232, 1295,
1621, 1678. Anal. Calcd. for C20H24NO6P (405.39): C, 59.26; H, 5.97; N, 3.46. Found: C,
59.10; H, 6.02; N, 3.34. MS: m/z = 406 (MH+).
Synthesis of (4-Amino-4-Oxobutanoyl)-Phosphoramidic Acid (6)
Compound 3 (0.35 g, 1 mmol) was dissolved in methanol (20 mL), PtO2 (50 mg)
was added, and the mixture was stirred under a hydrogen-rich atmosphere (1 bar) for
4 h. Filtration and evaporation of the solvent afforded a hygroscopic white powder. Yield:
0.18 g (93%). 1H NMR (500 MHz, D2O): δ = 2.45–2.55 (m, 2H, CH2), 2.60–2.70 (m, 2H,
CH2). 13C NMR (125 MHz, DMSO-d6): δ = 29.4, 32.8, 172.4, 174.0. 31P NMR (200 MHz,
DMSO-d6): δ = −8.2. IR (solid, cm−1): ν = 1042, 1152, 1220, 1292, 1589, 1662. Anal.
Calcd. for C4H9N2O6P (196.09): C, 24.50; H, 4.63; N, 14.29. Found: C, 24.55; H, 4.51; N,
14.17.
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