Amidoalkylation of phosphorous acid

Article abstract of DOI:10.1134/S1070363215020036

A convenient approach to prepare N-protected α-aminophosphonic acids (phospho-isosteres of natural amino acids) via amidoalkylation of phosphorous acid in a mixture of acetic anhydride and acetyl chloride upon cooling has been developed.

Full text of DOI:10.1134/S1070363215020036

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 2, pp. 366–369. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © A.V. Vinyukov, M.E. Dmitriev, V.V. Ragulin, 2015, published in Zhurnal Obshchei Khimii, 2015, Vol. 85, No. 2, pp. 192–195.
To the 80th Anniversary of B.I. Ionin
Amidoalkylation of Phosphorous Acid
A. V. Vinyukov, M. E. Dmitriev, and V. V. Ragulin
Institute of Physiologically Active Compounds, Russian Academy of Sciences,
Severnyi proezd 1, Chernogolovka, Moscow oblast, 142432 Russia
e-mail: rvalery@dio.ru
Received December 18, 2014
Abstract—A convenient approach to prepare N-protected α-aminophosphonic acids (phospho-isosteres of
natural amino acids) via amidoalkylation of phosphorous acid in a mixture of acetic anhydride and acetyl
chloride upon cooling has been developed.
Keywords: amino acids phospho-isostere, N-alkyloxycarbonyl-α-aminophosphonic acid, alkyl carbamate,
Oleksyszyn reaction
DOI: 10.1134/S1070363215020036
One of the approaches to discover promising physio-
logically active substances is synthesis of structural
analogs of natural compounds of oligopeptide nature
[1–5]. N-Protected phospho-isosteres of natural amino
acids are convenient building blocks for peptide
synthesis [4, 5]. Amide version of the Kabachnik–
Fields reaction can serve as a convenient method to
prepare N-protected α-amino-phosphoryl compounds
[6–9]. Originally, the reaction was carried out via
amidoalkylation of phosphorus(III) chlorides in acetic
acid medium (the Oleksyszyn reaction) [10–14].
Further modification with dialkyl phosphites in acetyl
chloride or in a mixture of acetic acid and thionyl
chloride involving aldehydes, ketones, amides, or
carbamates [15–19] was not widely applied, possibly
due to pronounced dealkylation of the ester moieties at
the phosphorus atom and hydrolysis of other functional
acid-sensitive groups [5–7].
phoryl compound containing no ester linkages, is
undoubtedly interesting. In this regard a pioneering
report on synthesis of free α-amino-phosphonic acids
starting from phosphorous acid in boiling acetic
anhydride followed by acid hydrolysis is remarkable
[20]. Herein, we propose a modification of the
approach described in ref. [20] in order to preserve the
protective group at the nitrogen atom of α-amino-
phosphonic acid. Aldehydes containing substituent
isosteric to the corresponding natural amino acid were
investigated as the carbonyl components (Scheme 1).
Previously we elaborated the optimal conditions of
N-protected α-amino-phosphoryl compounds prepara-
tion using alkyl carbamates as agent for amido-
alkylation of hydrophosphoryl compounds, more
efficient as compared with amides [6–9].
In the present work interaction of phosphorous acid
with the corresponding aldehydes and methyl or ethyl
carbamates as amide component was performed in a
Development of convenient methods of amido-
alkylation of phosphorous acid, a simple hydrophos-
Scheme 1.
O
O
NHC(O)OAlk
R
(2) H2O
(1) R−CH(O)
H
P
OH
+ H2NC(O)OAlk
HO
P
Ac2O/AcCl
OH
OH
I−VII
Alk = Me, Et; R = Me, i-Pr, i-Bu, Ph, p-Cl-C6H4.
366

367
AMIDOALKYLATION OF PHOSPHOROUS ACID
mixture of acetic anhydride and acetyl chloride upon
cooling. Those reaction conditions allowed
preservation of the protective function at the nitrogen
atom to obtain N-alkyloxycarbonyl-α-aminophos-
phonic acids I–VII in good yields. The proposed
approach is promising for peptide synthesis.
10 mL of chloroform and 25–35 mL of saturated aqueous
NaHCO3 solution. Then the aqueous layer was separated,
extracted with 5–7 mL of diethyl ether, acidified to
pH ~ 1, and extracted with chloroform or ethyl acetate
(3 × 15 mL). The organic layer was separated, dried
over magnesium or sodium sulfate, and evaporated.
The residue was crystallized from diethyl ether.
EXPERIMENTAL
1-(N-Methyloxycarbonyl)aminoethylphosphonic
acid (Ia). Yield 67%, oily substance. 1H NMR
1H, P and 13С NMR spectra were recorded with a
31
3
spectrum (MeОН-d4), δ, ppm: 1.33 d.d (3Н, СН3, JPH
Bruker DPX-200 Fourier spectrometer referenced to
internal TMS or external 85% H3PO4. Melting points
were determined with a Boetius PHMK instrument or
using open capillary method. TLC analysis was carried
out on Silufol plates, Merck glass plates coated with
silica gel UV-254 (0.2 mm) eluting with chloroform–
isopropanol (7–3%) mixture, or on Alufol plates
(Kavalier), developing with iodine vapor, UV light, or
ninhydrin solution for amino acid analysis.
3
16.1, JHH 7.3 Hz), 3.64 s (3Н, СН3О), 3.94 m (1Н,
РСНN). 13C NMR spectrum (MeОН-d4), δС, ppm:
16.1, 45.5 d (1JPC 157.0 Hz), 52.8, 159.0 d (3JPC
5.1 Hz). 31Р NMR spectrum (MeОН-d4): δР 24.9 ppm.
Bis(cyclohexylammonium) 1-(N-methyloxycarbo-
nyl)aminoethylphosphonate (Ib). Yield 73%, mp
1
136–138°С. H NMR spectrum (D2O), δ, ppm: 1.10–
1.35 m (13H, СН3СН, 10СН, cyclohexyl), 1.45–1.95
m (10Н, cyclohexyl), 3.03 m (2Н, 2CHN), 3.54 s (3H,
CH3O), 3.63 m (1Н, PCHN). 31P NMR spectrum
(D2O): δР 20.5 ppm. Found, %: C 50.21, 50.15; H 9.68,
9.57; N 10.82, 10.77. C4H10NO5P·2C6H11NH2. Cal-
culated, %: C 50.38; H 9.51. N 11.02
Methyl carbamate, ethyl carbamate, acetic an-
hydride, acetic acid, acetyl chloride, and phosphorous
acid were purchased from Alfa Aesar. Benzaldehyde,
acetaldehyde, and isobutyric and isovaleric aldehydes
were purchased from Acros Organics.
Bis(benzylammonium) 1-(N-methyloxycarbonyl)-
aminoethylphosphonate (Ic). Yield 81%, mp 86–89°С.
1H NMR spectrum (D2O), δ, ppm: 1.10 d.d (3Н, СН3,
N-Alkyloxycarbonyl-α-aminophosphonic acids
(I–VII) (general procedure). Crystalline phosphorous
acid (5 mmol) was added to 5–8 mL of a mixture of
acetic anhydride and acetyl chloride, (1–3) : 1 upon
stirring. Then 6.5 mmol of the appropriate aldehyde
was added dropwise at 5–10°C. The reaction progress
3
3JPH 15.2, JHH 7.3 Hz), 3.46 s (3Н, СН3О), 3.55 m
(1Н, РСНN), 4.01 br.s (4Н, 2СН2N), 7.30 br.s (10Н,
31
2Ph). P NMR spectrum (D2O): δР 20.4 ppm. Found,
%: C 54.21, 54.05; H 7.18, 7.27; N 10.42, 10.37.
C4H10NO5P·2C6H5CH2NH2. Calculated, %: C 54.40; H
7.10; N 10.57
31
was monitored with P NMR. After the reaction was
complete, the mixture was poured into 20–25 mL of
icy water, and volatile compounds were evaporated in
vacuum.
1-(N-Ethyloxycarbonyl)aminoethylphosphonic
1
acid (IIa). Yield 75%, oil. H NMR spectrum (D2O),
Acids I–IV prepared from aliphatic aldehydes were
isolated as follows. The oily residue was partitioned
between 20–25 mL of water and 10 mL of chloroform.
The aqueous layer was separated, washed with diethyl
ether (2 × 10 mL), and evaporated in vacuum. Pale
yellowish oily residue was treated with benzylamine or
cyclohexylamine (10 mmol) in an aqueous alcohol
solution, and the corresponding phosphonic acid salts
I–IV were crystallized from ethanol–diethyl ether
mixture [1 : (3–5)].
δ, ppm: 1.10 t (3Н, СН3), 1.20 d.d (3Н, СН3, 3JPH 16.6,
3JHH 7.3 Hz), 3.83 m (1Н, РСНN), 3.98 q (2Н, СH2O,
3JHH 7.0 Hz). 31P NMR spectrum (D2O): δР 24.7 ppm.
Bis(cyclohexylammonium) 1-(N-ethyloxycarbo-
nyl)aminoethylphosphonate (IIb). Yield 83%, mp
1
132–133°С. H NMR spectrum (D2O), δ, ppm: 1.00–
1.37 m (16H, СН3СН2, СН3СН, 10СН, cyclohexyl),
1.45–1.97 m (10Н, cyclohexyl), 3.03 m (2Н, 2CHN),
3
3.46 m (1Н, PCHN), 3.98 q (2H, CH2O, JHH 7.0 Hz).
31P NMR spectrum (D2O): δР 18.5 ppm. Found, %: C
51.40, 51.33; H 9.90, 10.05; N 10.54, 10.47. C5H12NO5P·
2C6H11NH2. Calculated, %: C 51.63; H 9.69; N 10.62.
Acids V–VII prepared from aromatic aldehydes
were isolated as follows. The oily residue was
partitioned between 20–25 mL of ethyl acetate and
10 mL of water. The organic layer was separated and
evaporated. The residue was partitioned between
Bis(benzylammonium) 1-(N-ethyloxycarbonyl)
aminoethylphosphonate (IIc). Yield 76%, mp 91–92°С.
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VINYUKOV et al.
1
1H NMR spectrum (D2O), δ, ppm: 1.05–1.35 m (6H,
СН3СН2, СН3СН), 3.44 m (1Н, РСHN), 3.98 q (2Н,
CH2O, 3JHH 7.0 Hz), 4.07 br.s (4Н, 2СH2N), 7.25–7.50
m (10Н, 2Ph). Found, %: C 55.19, 55.31; H 7.47, 7.53;
N 10.32, 10.40. C5H12NO5P·2C6H5CH2NH2. Calculated,
%: C 55.47; H 7.35; N 10.21.
mp 142–143°С. H NMR spectrum (DMSO-d6), δ,
ppm: 0.84 d (6Н, 2СН3, 3JHH 5.9 Hz), 1.10 t (3Н, СН3,
3JHH 7.1 Hz), 1.43 m (2Н, СН2), 1.60 m (1Н, СН), 3.50
m (1Н, PCHN), 3.81 br.s (4Н, 2СH2N), 3.92 m (2Н,
СН2О), 6.05 m (1Н, NH), 7.25–7.45 m (10Н, 2Ph).
13C NMR spectrum (D2O), δС, ppm: 13.9, 20.7, 23.1,
24.5 d (3JPC 11.7 Hz), 43.1, 48.8 d (1JPC 143.5 Hz),
61.6, 128.7, 129.0, 129.1, 133.1, 158.4 d (C=O, JPC
5.3 Hz). P NMR spectrum (DMSO-d6): δР 17.9 ppm.
Found, %: C 57.95, 57.88; H 8.16, 8.23; N 9.32, 9.36.
C8H18NO5P·2C6H5CH2NH2. Calculated, %: C 58.27; H
8. 00; N 9.27.
1-(N-Ethyloxycarbonyl)amino-2-methypropyl-
3
1
phosphonic acid (IIIa). Yield 64%, oil. H NMR
31
3
spectrum (DMSO-d6), δ, ppm: 0.87 d (6Н, 2СН3, JHH
3
6.4 Hz), 1.13 t (3Н, СН3, JHH 7.1 Hz), 2.05 m (1Н,
3
СН), 3.87 m (1Н, PCHN), 3.97 q (2Н, СН2О, JHH
3
1
7.1 Hz), 5.90 d (1Н, NH, JHH 8.3 Hz). H NMR
spectrum (CDCl3), δ, ppm: 0.98 br.s (6Н, 2СН3), 1.13 t
(3Н, СН3, 3JHH 6.9 Hz), 2.19 m (1Н, СН), 3.91 m (1Н,
α-(N-Methyloxycarbonyl)aminobenzylphosphonic
acid (V). Yield 92%, mp 220–221°С. H NMR spec-
1
3
PCHN), 4.13 m (2Н, СН2О), 5.65 d (1Н, NH, JHH
trum (DMSO-d6), δ, ppm: 3.51 s (3Н, CH3О), 4.81 d.d
(1Н, PCHN, 2JPH 22.5, 3JHH 9.8 Hz), 7.20–7.40 m (5Н,
Ph), 7.84 d (1Н, NH, 3JHH 9.8 Hz). 13C NMR spectrum
(DMSO-d6), δС, ppm: 51.7, 53.8 d (1JPC 148.9 Hz),
126.9, 127.5, 127.8, 128.0, 128.1, 137.9, 156.5 d
(С=О, 3JPC 9.5 Hz). 31P NMR spectrum (DMSO-d6): δР
17.9 ppm. Found, %: C 44.33, 44.08; H 5.10, 5.20; N
5.77, 5.76. C9H12NO5P. Calculated, %: C 44.09; H
4.93; N 5.71.
7.3 Hz), 8.90–9.80 m (2Н, 2РОН). 31P NMR spectrum
(СDCl3): δР 26.3 ppm. 31P NMR spectrum (DMSO-d6):
δР 22.7 ppm.
Bis(benzylammonium) 1-(N-ethyloxycarbonyl)
amino-2-methylpropylphosphonate (IIIb). Yield
1
70%, mp 108–109°С. H NMR spectrum (DMSO-d6),
δ, ppm: 0.90–1.30 m (6H, СН3СН2, СН3СН), 3.44 m
(1Н, РСHN), 3.65–4.05 m (6Н, CH2O, 2СH2N), 6.26
1
br.s (1Н, NH), 7.15–7.50 m (10Н, 2Ph). H NMR
α-(N-Ethyloxycarbonyl)aminobenzylphosphonic
3
1
spectrum (D2O), δ, ppm: 0.79 d (6Н, 2СН3, JHH 6.9
acid (VI). Yield 87%, mp 133–135°С. H NMR spec-
3
trum (DMSO-d6), δ, ppm: 1.14 t (3Н, CH3, 3JHH 7.0 Hz),
Hz), 1.13 t (3Н, СН3, JHH 6.9 Hz), 2.02 m (1Н, СН),
3
3
3
3.34 d.d (1Н, PCHN, JРH 18.1, JHH 3.5 Hz), 3.96 m
(2Н, СН2О), 4.03 br.s (4Н, 2СН2N), 7.28–7.43 m
3.97 q (2Н, CH2O, JHH 7.0 Hz), 4.82 d.d (1Н, PCHN,
2JPH 22.0, 3JHH 9.8 Hz), 7.10–7.45 m (5Н, Ph), 7.71 d.d
13
3
3
1
(10Н, 2Ph). C NMR spectrum (DMSO-d6), δС, ppm:
(1H, NH, JPH 2.9, JHH 9.8 Hz). H NMR spectrum
(D2O), δ, ppm: 1.09 t (3Н, CH3, JHH 7.0 Hz), 3.97 q
(2Н, CH2O, JHH 7.0 Hz), 4.86 m (1H, CHN), 7.30 m
14.7, 17.4, 43.7, 45.4 d (1JPC 146.4 Hz), 59.5, 122.3,
3
3
3
127.3, 128.1, 128.3, 130.1, 138.8, 155.9 d (С=О, JPC
9.9 Hz). 13C NMR spectrum (D2О), δС, ppm: 13.8,
16.9, 21.1 d (3JPC 11.3 Hz), 29.4, 43.3, 44.7, 55.7 d
(1JPC 140.2 Hz), 61.7, 126.6, 126.8, 128.5, 128.8,
129.1, 134.2, 159.2 d (3JPC 11.1 Hz). 31P NMR
spectrum (D2O): δР 18.8 ppm. 31P NMR spectrum
(DMSO-d6): δР 17.5 ppm. Found, %: C 57.15, 57.03;
H 7.95, 8.03; N 9.72, 9.57. C7H16NO5P·2C6H5CH2NH2.
Calculated, %: C 57.39; H 7.80; N 9.56.
(5Н, Ph). 13C NMR spectrum (DMSO-d6), δС, ppm:
14.7, 53.7 d (1JPC 148.6 Hz), 60.2, 126.9 d (2JPC
2.2 Hz), 127.9, 128.0, 128.2, 129.0, 137.9, 156.1 d
(C=O, 3JPC 9.5 Hz). 31P NMR spectrum (DMSO-d6): δР
18.0 ppm. 31P NMR spectrum (D2O): δР 18.2 ppm.
Found, %: C 46.08, 46.15; H 5.52, 5.65; N 5.47, 5.58.
C10H14NO5P. Calculated, %: C 46.34; H 5.44; N 5.40.
α-(N-Ethyloxycarbonyl)amino-p-chlorobenzyl-
phosphonic acid (VII). Yield 81%, mp 122°С. H
1-(N-Ethyloxycarbonyl)amino-3-methylbutylphos-
phonic acid (IVa). Yield 71%, oil. 1H NMR spectrum
(CDCl3 + drop of TFA), δ, ppm: 0.91 br.s (6Н, 2СН3),
1.23 t (3Н, СН3, 3JHH 7.0 Hz), 1.50–1.75 m (2Н, СН2),
1.90–2.05 m (1Н, СН), 3.74 m (1Н, PCHN), 4.12 m
(2Н, СН2О), 5.60 m (1Н, NH), 9.20–10.20 m (2Н,
2POH). 31P NMR spectrum (CDCl3 + drop of TFA): δР
27.4 ppm.
1
NMR spectrum (CDCl3 + drop of TFA), δ, ppm: 1.12 t
(3Н, CH3, 3JHH 7.0 Hz), 4.05 q (2Н, CH2O, 3JHH 7.0 Hz),
5.08 m (1Н, CHN), 6.00 m (1Н, NH), 7.05–7.55 m
1
(5Н, Ph), 10.6–10.8 br.s (ОН). H NMR spectrum
3
(DMSO-d6), δ, ppm: 1.12 t (3Н, CH3, JHH 6.9 Hz),
3
3.97 q (2Н, СН2О, JHH 6.9 Hz), 4.84 d.d (1Н, PСНN,
3
2JPH 22.5, JHH 9.8 Hz), 6.30–6.60 br.s (POH), 7.30–
Bis(benzylammonium) 1-(N-ethyloxycarbonyl)-
amino-3-methylbutylphosphonate (IVb). Yield 67%,
7.45 m (4Н, С6Н4), 7.79 d (3JHH 9.8 Hz). 13C NMR
spectrum (DMSO-d6), δС, ppm: 14.7, 53.2 d (1JPC
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AMIDOALKYLATION OF PHOSPHOROUS ACID
j.tetlet.2012.01.094.
148.6 Hz), 60.4, 127.9, 129.9, 130.0, 131.7, 137.1,
3
156.1 d (C=O, JPC 8.8 Hz). 31P NMR spectrum
9. Dmitriev, M.E. and Ragulin, V.V., Russ. J. Gen. Chem.,
2012, vol. 82, no. 11, p. 1882. DOI: 10.1134/
S107036321211028X.
(CDCl3 + drop of TFA): δР 27.0 ppm. 31P NMR
spectrum (DMSO-d6): δР 17.6 ppm. Found, %: C
41.03, 41.15; H 4.50, 4.53; N 4.97, 4.88. C10H13ClNO5P.
Calculated, %: C 40.90; H 4.46; N 4.77.
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1978, no. 6, p. 479. DOI: 10.1055/s-1978-24792.
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