One-pot synthesis of N-Cbz-α-aminophosphonic acids

Article abstract of DOI:10.1080/10426507.2016.1248289

The paper describes the synthesis of N-protected-α-aminoalkylphosphonic acids, phosphoisosteres of amino acids, from phosphorous acid. A simple, milder and effective one-pot procedure for the amidoalkylation of phosphorous acid in a mixture of acetic anhy

Full text of DOI:10.1080/10426507.2016.1248289

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One-pot synthesis of N-Cbz-α-aminophosphonic acids
Alexei V.Vinyukov, Maxim E.Dmitriev, and Valery V.Ragulin*
Institute of Physiologically Active Compounds, Russian Academy of Sciences,
Severny pr.,1, Chernogolovka, Moscow Region, 142432, Russia
*Corresponding author. Fax: +7 496 524 95 08.
E-mail address:rvalery@dio.ru
Abstract
The paper describes the synthesis of N-protected-α-aminoalkylphosphonic acids,
phosphoisosteres of amino acids, from phosphorous acid. A simple, milder and effective one-pot
procedure for the amidoalkylation of phosphorous acid in a mixture of acetic anhydride and
acetyl chloride at room temperature allows the formation of amino phosphorylic function with
the protection on the nitrogen atom.
Keywords
amidoalkylation / phosphoisosteres of amino acids / triacetylphosphite / acylimine cation /
Arbuzov-type reaction / aminoalkylphosphonic acids
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INTRODUCTION
One of the most promising approaches to finding physiologically active compounds is the
incorporation of an aminophosphonic acid molecule into the corresponding peptide chain of
oligomeric structure.1,2 In this connection, N-protected α-aminophosphonic acids can be
successfully used as convenient building blocks for the synthesis of phosphorus-containing short
peptides.
Usually, the synthesis of N-protected α-aminophosphonic acids represents a two-stage
process: the construction of aminophosphorylic function and the protection of the nitrogen atom.
The creation of the aminophosphorylic fragment is realized by using the well-known procedures
of the three-component Kabachnik-Fields reaction3 or Michael-Pudovik-type addition of
hydrophosphorylic compounds to the corresponding Schiff bases.4 Although the acylation of
aminophosphonic acids seems to be a trivial reaction, the literature data on the preparation of N-
acylated aminophosphonic acids are contradictory, and in many cases the yields of the reaction
in aqueous media are moderate or even low.5,6 In this connection, the total pre-silylation of the
aminoalkylphosphonic acids was proposed for the preparation of N-acylated acids with good
yields.7
We propose to combine the construction of an α-aminophosphorylic function with the
protection on the nitrogen atom with the use of phosphorous acid, one of the simplest
hydrophosphorylic compounds. In this connection, the low popular and even maybe,
undeservedly forgotten, nonclassic amide version of Kabachnik-Fields reaction8,9 can be
effective approach for one-pot synthesis of N-protected α-aminophosphonic acids.
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The procedure for the Kabachnik–Fields-type reaction with amides as the amino component
and trivalent phosphorus chlorides, aldehydes or ketones in acetic acid was proposed the first by
Oleksyszyn (Oleksyszyn reaction)8 and then was modified by Yuan and Chen10 for dialkyl
phosphites with carbonyl compounds and amides or carbamates in acetyl chloride. The
amidoalkylation of dialkyl phosphites in acetyl chloride is often accompanied by a partial
dealkylation of the alkyloxyphosphorylic fragment. For that reason, as a rule, the reaction
mixture, containing N-acylated α-aminoalkylphosphorylic compounds, is subjected to acidic
hydrolysis followed by isolation of the free α-aminoalkylphosphonic acids.8-10 Milder
amidoalkylation of phosphorous acid in acetic anhydride in contrast to the more rigid conditions
proposed by Oleksyszyn11 can be more perspective approach for the synthesis of N-protected α-
aminophosphonic acids.
Recently, we proposed a milder procedure for the synthesis of N-protected α-
aminophosphorylic compounds in acetic anhydride at room temperature and the mechanism for
amidoalkylation of hydrophosphorylic compounds which includes an Arbuzov-type step of
phosphorus–carbon bond formation.12 We propose that the unique role of acetic anhydride in this
reaction consist in the generation in situ of intermediated PIII–OAc derivatives (1), as
nucleophilic component of reaction. Also we have isolated the N,N´-alkylidenebiscarbamates (2)
under the reaction conditions as the stable intermediates of this reaction.12a,b We proposed the
acid catalyzed generation in situ of N-alkyloxycarbonylimine cation, (positively charged Schiff
base) (3) as electrophilic reaction component from N,N´-alkylidenebiscarbamate (2).12a,d
Nucleophilic attack of the trivalent phosphorus atom of the generated in situ intermediated PIII–
OAc compound (1) (Scheme 2) on the positively charged carbon atom of the generated in situ N-
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alkoxycarbonylimine cation (salt) (3) occurs followed by the formation of the phosphorus–
carbon bond.
Our approach to the generation in situ of imine cations (3) from biscarbamates (2) was
recently successfully used for the formation of C-C bonds according to a Mannich-type
reaction.13 Moreover, we have studied the interaction of acetyldiethylphosphite (prepared
beforehand as well as generated in situ from tetraethylpyrophosphite) with the in situ generated
acyliminium cation and successfully confirmed the proposed reaction mechanism.12e
Thus, the earlier obtained results allow to search the convenient procedures for one-pot
synthesis of N-protected α-aminophosphonic acids.
RESULTS AND DISCUSSION
In this article we report good results on the direct amidoalkylation of the simplest
hydrophosphorylic compound - phosphorous acid.
We have found that milder conditions for the three-component condensation reaction of
phosphorous acid, benzylcarbamate and corresponding aldehydes in the mixture of acetic
anhydride and acetyl chloride (1:1) at room temperature allow N-benzyloxycarbonyl-α-
aminoalkylphosphonic acids (4-10) to be obtained with good yields (Scheme 3). This simple
synthetic procedure permit to combine the creation of aminophosphonic function with protection
of the nitrogen atom.
This results are in accordance with earlier obtained data confirming our version of the
mechanism for this reaction, described above.12
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As expected, the first attempts to get N-Cbz-α-aminoalkylphosphonic acids (4-10) via the
direct amidoalkylation of phosphorous acid in acetic anhydride in the presence of catalytic
quantities of trifluoroacetic (TFA) or p-toluenesulfonic (TSA) acids were minimally effective.
We have assumed that the reason for this is the difficulty of generation in situ of the PIII-OAc
nucleophilic component with trivalent phosphorus atom from the phosphorous acid, containing
three P-OH functions. TFA and TSA can catalyze only the generation of imine cation (3) and
cannot catalyze the generation of PIII-OAc intermediate with trivalent phosphorus atom.
We proposed the generation in situ of triacetylphosphite (11) as PIII-component which must
take part in the formation of desired phosphorus-carbon bond and phosphonium salt (12) in
accordance with the Arbuzov-step reaction. Acetic anhydride is a relatively weak acetylating
agent for the generation in situ of triacetylphosphite (11) from phosphorous acid. Therefore
acetyl chloride, as stronger acetylating agent, was added in the reaction mixture for improvement
of the conditions for generation in situ of triacetylphosphite (11) (Scheme 4).
Moreover, the hydrogen chloride generated in situ (three equivalents) is a more powerful
catalyst for the generation in situ of iminium salts (3) from biscarbamates (2). An additional
favorable factor is that the starting phosphorous acid do not have the acid-sensitive ester bonds,
and the N-benzyloxycarbonylic ester fragment is relatively resistant to the acid reaction
conditions at room temperature.
We have investigated the interaction of phosphorous acid, benzylcarbamate and
corresponding aldehydes in the mixture of acetic anhydride and acetyl chloride at room
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temperature at different relationship of Ac2O and AcCl (Table 1). We have found that the
optimal reaction mixture is Ac2O / AcCl = 1:1.
Thus, the interaction of phosphorous acid, benzylcarbamate and corresponding aldehydes in
the mixture of acetic anhydride and acetyl chloride (1:1 as optimal relationship) at room
temperature followed by the water hydrolysis of Arbuzov` type reaction product,
diacetylphosphonate (13), gave N-benzyloxycarbonyl-α-aminoalkylphosphonic acids (4-10) with
good yields (Table 1).
Moreover, we have found that the treatment of reaction mixture by alcohol can permit to
obtain the esters of aminophosphonic acid. In this case the mixture of aminophosphonic acid and
its monoalkyl ester was detected by NMR spectroscopy (see Supplemental Materials). Dialkyl
esters of the aminophosphonic acids were not found. We have been able isolate the monoethyl
ester of α-(N-benzyloxycarbonyl)amino-benzylphosphonic acid (8a) (Table 1). However, careful
investigation of conditions for esterification and isolation of esters of α-aminophosphonic acids
were no aim of this investigation.
CONCLUSIONS
A one-pot method for the synthesis of N-benzyloxycarbonyl-α-aminoalkylphosphonic acids (4-
10) in good yields by amidoalkylation of phosphorous acid with benzylcarbamate and
corresponding aldehyde in the mixture of acetic anhydride and acetyl chloride (1:1) at room
temperature was proposed in this paper.
EXPERIMENTAL
General and Reagents: All reagents (benzylcarbamate, phosphorous acid and aldehydes) used
in the reactions described in this manuscript are commercial, was purchased from Alfa Aesar and
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were used without purification. The reaction described in this paper were controlled using 31P
NMR spectroscopy and (or) TLC. All of the compounds, for which spectral and analytical data
are given, were gomogenous by TLC. TLC analyses were performed using 0.2 mm silica gel F
254 (Merck) glass plates and Alufol plates (aluminium oxide neutral on aluminium foil as base)
(Kavalier), eluent systems: n-buthyl alcohol:acetic acid:water (4:1:1) or chloroform:i-propanol:
acetic acid (100:5:1-3) as an eluents. The chromatograms were visualized under ultraviolet light
or iodine vapor. All reactions were performed under an atmosphere of argon with magnetic
stirring. Melting points were determined on a Boetius PHMK apparatus or in open glass
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31
capillaries and are uncorrected. The H, P and 13C NMR spectra were recorded on a Bruker
31
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DPX-200 Fourier spectrometer. P and C NMR spectra are fully proton decoupled. P NMR
chemical shifts are reported on a  scale (in ppm) downfield from 85% H3PO4.
Negative mode mass spectra were acquired using Thermo LXQ mass spectrometer with
electrospray ion source. Positive mode mass spectra were acquired using custom design home
built high resolution (15000 FWHM) Ortho-TOF mass spectrometer15a. The custom built micro-
electrospray ion source15b was used. The samples were dissolved in MeOH at concentration 3
mg/mL, and then they were diluted 300 times for the analysis. In negative mode 5 µL of the
resulting diluted solution was injected in the loop connected to the injection line via the valve.
Injection flow rate by syringe pump was 3 µL/min. In positive mode the sample flow rate was
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0.2 µL/min. The Supplemental Materials contains sample H, C, P NMR spectra and mass
spectra for the products 4-10 (Figures S 1 – S 36)
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General procedure for the synthesis of N-benzyloxycarbonyl-α-aminoalkylphosphonic
acids (4-10)
Dried phosphorous acid (5 mmol) and benzylcarbamate (5 mmol) were dissolved in the of the
mixture of acetic anhydride : acetyl chloride (1 : 1) (10-15 mL). The corresponding aldehyde (5-
6 mmol) was slowly added dropwise to the formed solution and the reaction mixture was stirred
for 17-20 h at room temperature (the reaction progress was controlled by NMR 31P spectroscopy
and TLC). Then reaction mixture was added to 30-40 mL of water/ice and obtained solution was
stirred 5-10 h and was evaporated in vacuo. The residue was dissolved in ethyl acetate or
chloroform (30-40 mL) and washed with water (2×7-10 mL) and the organic phase was
evaporated in vacuo. The residue was partitioned between hydrocarbonate solution (50 mL) and
ether or hexane (10 mL). Aqueous solution was separated and acidified to pH 2-3 with 6N HCl
and then was extracted by ethyl acetate or chloroform (3×15 mL). The organic extracts were
combined and dried over sodium sulphate and evaporated in vacuo.
Usually the residue was crystallized from ether or hexane and recrystallized from ether :
alcohol (10:1÷3) and N-protected acids was isolated as solid (Table 1).
Reaction mixture for the synthesis of α-(N-benzyloxycarbonyl)amino-benzylphosphonic acid
(8) in the acetic anhydride : acetyl chloride (1:1) was treated by excess of EtOH or MeOH (~50
ml) under cooling and then was evaporated in vacuo. The residue represented the mixture of acid
(8) and monoethyl (8a) or monomethyl (8b) ester of acid (8) (see NMR spectra in Supplemental
Materials) and was treated by ether or hexane. We have not a success in the isolation of methyl
ester (8b), but monoethyl ester of α-(N-benzyloxycarbonyl)amino-benzylphosphonic acid (8a)
was isolated (Table 1) and described with using 1H, 13C and 31P NMR spectroscopy.
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Data of 1H, 31P, and 13C NMR and analytical data of N-benzyloxycarbonyl-α-
aminoalkylphosphonic acids (4-10) and monoethyl ester 8a) and yields of acids (4-10) at the
conditions of different relationship Ac2O:AcCl in the reaction mixture.
1-(N-Benzyloxycarbonyl)amino-ethylphosphonic acid (4)
Yield 63.7% (Ac2O:AcCl=1:1), yield 66.8% (Ac2O:AcCl=1:4), yield 34.4% (Ac2O:AcCl=5:1).
1
White solid. M.p. 105-106ºС. 14Lit. m.p. 110ºC. H NMR (DMSO-d6, ppm): 1.18 (dd, 3H, CH3,
3JPH = 15.7 Hz, 3JHH = 6.9 Hz), 3.71 (m, 1H, PCHN), 5.01 (br. s., 2H, CH2O), 7.10-7.45 (m, 6H:
1
3
5H, Ph + 1H, NH). H NMR (CDCl3+drops of TFA, ppm): 1.43 (dd, 3H, CH3, JPH = 17.6 Hz,
3JHH = 6.4 Hz), 4.17 (m, 1H, PCHN), 5.14 (m, 2H, CH2O), 7.34 (m, 5H, Ph), 10.9 (br. s., OH).
1
13C NMR (DMSO-d6, ppm): 15.9, 44.3 (d, JPC = 154.8 Hz), 65.4, 127.7, 128.4, 137.2, 155.7
31
(C=O) (d, 3JPC = 5.9 Hz). 31P NMR (CDCl3, ppm): 24.8. P NMR (CDCl3+ drops of TFA, ppm
31
): 26.8. P NMR (DMSO-d6, ppm): 22.5. Found: C 46.23, 46.07; H 5.51, 5.57; N 5.56, 5.51; P
12.03, 12.13. Calc. for C10H14NO5P: C 46.34; H 5.44; N 5.40; P 11.95.
1-(N-Benzyloxycarbonyl)amino-2-methyl-propylphosphonic acid (5)
Yield 64.5% (Ac2O:AcCl=1:1), yield 67.7% (Ac2O:AcCl=1:2), yield 54.3% (Ac2O:AcCl=2:1).
1
3
White solid. M.p. 67-68ºС. H NMR (DMSO-d6, ppm): 0.91 (d, 3H, CH3, JHH 6.7 = Hz), 2.04
(m, 1H, CH), 3.60 (ddd, 1H, CHN, 2JPH 18.3 = Hz, 3JHH 10.3 = Hz, 3JHH = 4.9 Hz), 5.04 (m, 2H,
3
13
CH2O), 7.01 (d, 1H, NH, JHH = 10.3 Hz), 7.25-7.45 (m, 5H, Ph). C NMR (DMSO-d6, ppm):
3
3
2
1
18.3 (d, JPC = 5.5 Hz), 20.7 (d, JPC = 10.7 Hz), 28.6 (d, JPC = 4.8 Hz), 54.1 (d, JPC = 151.1
3
Hz), 65.4, 127.4, 127.7, 128.3, 137.3, 156.5 (C=O) (d, JPC = 7.0 Hz). 31P NMR (DMSO-d6,
ppm): 22.1. Found: C 49.83, 49.85; H 6.43, 6.47; N 5.11, 5.20. Calc. for C12H18NO5P: C 50.18;
H 6.32; N 4.88.
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1-(N-Benzyloxycarbonyl)amino-3-methyl-butylphosphonic acid (6)
Yields 75.3% (Ac2O:AcCl=1:1), 74.7% (Ac2O:AcCl=1:4), 54.1% (Ac2O:AcCl = 2:1). White
solid. M.p. 131-132ºС. 1H NMR (DMSO-d6 + drops of TFA, ppm ): 0.78 (d, 3H, CH3, 3JHH = 6.7
3
Hz), 0.82 (d, 3H, CH3, JHH = 7.3 Hz), 1.25-1.72 (m, 3H, CH + CH2), 3.66-3.97 (m, 1H, CHN),
5.00 (s. br., 2H, CH2O), 7.15 (d, 1H, NH, 3JHH = 9.8 Hz), 7.20-7.40 m (5H, Ph), 15.10 (s. br., 2H,
13
3
1
2POH). C NMR (DMSO-d6, ppm): 21.0, 23.4, 24.0 (d, JPC = 13.3 Hz), 47.0 (d, JPC = 155.2
3
Hz), 65.3, 127.5, 127.7, 128.3, 137.3, 156.1 (C=O) (d, JPC = 5.2 Hz). 31P NMR (DMSO-d6+
drops of TFA, ppm ): 23.6. Found: C 51.65, 51.57; H 6.87, 6.90; N 4.82, 4.77. Calc. for
C13H20NO5P: C 51.83; H 6.69; N 4.65.
1-(N-Benzyloxycarbonyl)amino-2-methyl-butylphosphonic acid (7)
1
Yield 56.0% (Ac2O:AcCl=1:1), yield 41.5% (Ac2O:AcCl=2:1). White solid. M.p. 96-97ºС. H
NMR (DMSO-d6, ppm ): 0.78-0.92 (m, 6H, CH3CH2 + CH3CH), 1.00-1.15 (m, 1H*, CHCH3),
1.15-1.40 (m, 1H, CHCH3), 1.50-1.80 (m, 2H, CH2CH3), 3.60 (m, 1H*, PCHN), 3.81 (m, 1H,
PCHN), 5.03 (br. s., 2H, CH2O), 6.82-6.97 (m, 1H, NH), 7.34 (m, 5H, Ph). 13C NMR (DMSO-d6,
ppm ): 11.3, 11.7*, 15.2, 16.5* (d, 3JPC 7.0 Hz), 24.4, 26.9*(d, 3JPC 11.3 Hz), 35.1*, 35.5, 51.6* (d,
1
3
1JPC = 150.8 Hz), 53.6 (d, JPC = 152.2 Hz), 65.3, 127.4, 127.6, 128.3, 137.3, 156.4 (d, JPC 8.0
Hz). 31P NMR (DMSO-d6, ppm ): 21.4, 21.6* (* minor diastereomer). Found: C 51.58, 51.47; H
6.87, 6.77; N 4.53, 4.47; P 9.95, 9.91. Calc. for C13H20NO5P: C 51.83; H 6.69; N 4.65; P 10.28.
α-(N-Benzyloxycarbonyl)amino-benzylphosphonic acid (8)
Yield 75.5% (Ac2O:AcCl=1:1), yield 72.5% (Ac2O:AcCl=1:4), yield 65.6% (Ac2O:AcCl=1:2),
1
yield 54.5% (Ac2O:AcCl=3:1). M.p. 156-157ºС. Lit. m.p. 159ºС17. H NMR (CDCl3, ppm ):
13
4.75-5.10 {m, 1H, PCHN + с (br.) 2H, CH2O}, 6.96 (m, 1H, NH), 7.05-7.45 (m, 10H, 2Ph). C
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NMR (DMSO-d6, ppm ): 53.6 (d, JPC = 143.4 Hz), 66.0, 126.4, 127.5, 127.9, 136.1, 137.4,
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31
155.7 (C=O) (d, JPC = 9.2 Hz). P NMR (CDCl3, ppm ): 19.0. Found: C 55.84, 55.87; H 5.17,
5.23; N 4.46, 4.54; P 9.45, 9.40. Calc. for C15H16NO5P: C 56.08; H 5.02; N 4.36; P 9.64.
Monoethyl ester of α-(N-benzyloxycarbonyl)amino-benzylphosphonic acid (8a)
1
Yield 31.3% (Ac2O:AcCl=1:1, and then treatment by EtOH). M.p. 189-190ºС. H NMR
(DMSO-d6 + drop of TFA, ppm ): 1.13 (t, 3H, CH3, 3JHH = 6.9 Hz), 3.86 (dk, 2H, 3JHH = 6.9 Hz,
2
3
3JPH = 14.2 Hz), 4.95 (dd, 1H, PCHN, JPH = 22.0 Hz, JHH = 9.7 Hz), 5.03 (AB, 2H, PhCH2O),
7.13-7.51 (m, 10H, 2Ph), 8.07 (d, 1H, NH, 3JHH = 9.7 Hz). 13C NMR (DMSO-d6 + drop of TFA,
3
1
2
ppm ): 16.3 (d, CH3, JPC = 5.5 Hz), 52.8 (d, PCN, JPC = 150.4 Hz), 61.6 (d, POC, JPC = 6.3
Hz), 65.7 (c, CH2Ph), 127.2, 127.3, 127.7, 127.8, 127.9, 128.0, 128.1, 128.2, 128.4, 136.9, 137.0,
3
31
156.1 (d, C=O, JPC = 8.9 Hz). P NMR (DMSO-d6 + drop of TFA, ppm): 19.8, 17.9 (2% of
acid 8). Found: C 58.26, 58.18; H 5.82, 5.90; N 3.94, 3.90. Calc. for C17H20NO5P: C 58.45; H
5.77; N 4.01.
α-(N-Benzyloxycarbonyl)amino-p-chloro-benzylphosphonic acid (9)
1
Yield 77.0% (Ac2O:AcCl=1:1), yield 58.5% (Ac2O:AcCl=3:1). M.p. 121-122ºС. H NMR
(DMSO-d6, ppm): 4.75 (m, 1H, PCHN), 5.02 (br. s., 2H, CH2O), 7.18-7.55 (m, 9H, C6H4+Ph),
1
8.00 (d. br., 1H, NH). H NMR (CDCl3+TFA, ppm ): 5.14 (br. s., 2H, CH2O), 5.25 (m, 1H,
13
PCHN), 6.14 (m, 1H, NH), 7.10-7.45 (m, 9H, C6H4), 10.80-11.15 (m, OH). C NMR (DMSO-
d6, ppm): 53.4 (d, PCN, 1JPC = 148.6 Hz), 65.7 (CH2O), 127.8, 128.4, 129.9, 130.0, 131.7, 137.0,
3
31
156.0 (C=O) (d, JPC = 9.5 Hz). P NMR (CDCl3+TFA, ppm ): 26.6. Found: C 50.36, 50.28; H
4.45, 4.33; N 4.08, 4.14; P 9.03, 8.94. Calc. for C15H15ClNO5P: C 50.65; H 4.25; N 3.94; P 8.71.
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α-(N-Benzyloxycarbonyl)amino-p-methyloxy-benzylphosphonic acid (10)
1
Yield 81.0% (Ac2O:AcCl=1:1), yield 58.0% (Ac2O:AcCl=3:1). M.p. 109-110ºС. H NMR
(DMSO-d6, ppm): 3.71 (s, 3Н, СН3О), 4.79 (dd, 1H, 2JPH = 21.5 Hz, 3JHH = 9.8 Hz, PCHN), 5.01
(br. s., 2H, CH2O), 6.82 (s, 1H, Ar), 6.87 (s, 1H, Ar), 7.25-7.45 (m, 7H, Ar), 7.88 (br. d, 1H, NH,
1
3JHH~8.9 Hz). H NMR (CDCl3, ppm ): 3.51 (s, 3Н, СН3О), 4.81 (m, 2H, CH2O), 6.19 (m, 1H,
PCHN), 6.60 (m, 1H, NH), 6.80-7.30 (m, 9H, Ar), 10.9-11.6 (m, 2H, 2POH). 13C NMR (DMSO-
1
d6, ppm): 53.2 (d, JPC = 150.1 Hz), 55.1 (CH3O), 65.6 (CH2O), 113.3, 127.7, 127.8, 128.3,
129.2, 129.3, 129.9, 137.0, 155.9 (C=O) (d, 3JPC = 9.6 Hz), 158.3 (Carom - O). 31P NMR (CDCl3,
ppm): 23.4. 31P NMR (DMSO-d6, ppm ): 18.3. 31P NMR (DMSO-d6 + drops of TFA, ppm): 21.8.
Found: C 54.44, 54.47; H 5.25, 5.31; N 4.15, 4.11; P 8.95, 9.03. Calc. for C16H18NO6P: C 54.71;
H 5.16; N 3.99; P 8.82.
Acknowledgments
This study was supported by the Russian Foundation for Basic Research (Grant No. 15-03-
06062). Authors would like to thank V. I. Kozlovskifor MS spectra and analyses.
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Table 1. N-Benzyloxycarbonyl-α-aminoalkylphosphonic acids (4-10)
Entry Compound
R
M.p., ºC
Yields, %
b67
1
2
3
4
4
5
6
7
Me
105-106, 14110 a64
d34
e54
e54
e42
i-Pr
i-Bu
sec-Bu
67-68
131-132
96-97
a65
a75
a56
c68
b75
-
b72,
c66
-
5
8
Ph
156-157,14159 a76
f54
-
6
7
8
g8a
9
Ph
189-190
121-122
109-110
a,g31
-
-
p-Cl-C6H5
p-MeO-C6H5
a77
a81
f58
f58
10
Ac2O ≤ AcCl : aAc2O / AcCl = 1:1; bAc2O / AcCl = 1:4; cAc2O / AcCl = 1:2;
Ac2O > AcCl : dAc2O / AcCl = 5:1, eAc2O / AcCl = 2:1; fAc2O / AcCl = 3:1; a,gyield of
monoethyl ester
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Scheme 1. Amide version of Kabachnik-Fields reaction
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Scheme 2. The generation in situ of PIII–OAc compound (1) and imine cations (3) on the
formation of P-C bond
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Scheme 3. Synthesis of N-Cbz-a-aminoalkylphosphonic acids 4-10
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Scheme 4
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