Acetals and N,N′-alkylidenebiscarbamates in the synthesis of N-protected α-aminophosphinic acids

Full text of DOI:10.1134/S107036321211028X

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 11, pp. 1882–1885. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © M.E. Dmitriev, V.V. Ragulin, 2012, published in Zhurnal Obshchei Khimii, 2012, Vol. 82, No. 11, pp. 1919–1922.
LETTERS
TO THE EDITOR
Acetals and N,N'-Alkylidenebiscarbamates in the Synthesis
of N-Protected α-Aminophosphinic Acids
M. E. Dmitriev and V. V. Ragulin
Institute of Physiologically Active Substances, Russian Academy of Sciences,
Severnyi pr. 1, Chernogolovka, Moscow Region, 142432 Russia
e-mail: rvalery@dio.ru
Received May 31, 2012
DOI: 10.1134/S107036321211028X
A convenient procedure of the amide version of the
Kabachnik–Fields reaction is a promising approach to
the synthesis of N-protected α-aminophosphorylic
compounds. The amidoalkylation originally suggested
for the phosphorous chlorides in acetic acid (the
Oleksyszyn reaction) [1] was later modified to the
amidoalkylation of dialkylphosphites in acetyl chloride
or in a mixture of acetic acid and thionyl chloride
involving the carbonyl compounds and amides [2].
carbamate) [5, 6]. We failed to introduce some low-
stable aldehydes into the three-component amido-
alkylation of the hydrophosphorylic compounds. The
use of the aldehyde acetals was also unsuccessful or
ineffective [6]. In this regard, N,N'-alkylidenebis-
carbamates can be used as the stable synthetic equi-
valents of the low-stable aldehydes in the reaction with
the hydrophosphorylic compounds in accordance with
our procedure. The latter includes the generation of an
iminium cation and PIII-OC(O)CF3-derivative by adding
trifluoroacetic anhydride to the mixture of biscarbamate
and a PH-component (1:1:1) in an organic solvent [7].
This approach opens the possibility for the synthesis of
a number of the low-accessible phosphorylic analogs
of amino acids and peptides.
The study of the amidoalkylation of hydrophosphorylic
compounds in acetic anhydride [3] involving amides
[4] and alkylcarbamates [5, 6] allowed us developing a
new version of the multistep reaction mechanism,
comprising the formation of the phosphorus–carbon
bond by the Arbuzov reaction via the nucleophilic
attack of the phosphorous atom of the POAc-derivative
on a positively charged carbon atom of the iminium
cation, generated in situ in the reaction conditions from
starting the hydrophosphorylic compounds and the
In this work we developed a synthesis of the N-alkyl-
oxycarbonyl-α-aminophosphinic acids I from acetals
II, followed by the synthesis of alkylidenebis-
carbamates III. Their reaction with the hydrophos-
phorylic component in an organic medium occurs
intermediately
forming
N,N'-alkylidenebis(alkyl-
NHC(O)OAlk
OMe
а or b
R
NHC(O)OAlk
IIIа−IIId
R
OMe
O
P
IIа−IId
NHC(O)OAlk
c
Me
R
Iа−Ie
OH
O
EtO
CO(O)Et
CO(O)Et
NHCbz
CO(O)Et
CF3COOH
b
H
+
CF3COO−
C
−CF3COOH
OEt
EtO
−CbzNH2
NHCbz
NHCbz
IIIe
NHCbz
IV
IIe
V
(а) 2EtOC(O)NH2 + CF3COOH; (b) 2Сbz-NH2 + CF3COOH; (c) (1) Me-PH(O)OH + (CF3CO)2O; (2) H2O. Alk = Et, Bn;
R = H, i-Pr, BnO, Ph, C(O)OEt. Cbz – benzyloxycarbonyl.
1882

ACETALS AND N,N'-ALKYLIDENEBISCARBAMATES
1883
through the generation in situ of the highly reactive
intermediates by adding the equivalent of trifluoro-
acetic anhydride to the reagents mixture to give the
mixed РIV-OC(O)CF3 anhydrides via the Arbuzov
reaction. The target compounds I were obtained by
treating of the obtained anhydrides with water [7].
previously suggested procedure for generating the
reactive intermediates. The latter react in situ via the
Arbuzov reaction to form N-alkyloxycarbonyl-α-
aminophosphinic acids I [7]. The reaction of β-N-Cbz-
aminoacrylate IV with methylphosphonous acid and
trifluoroacetic anhydride was performed in toluene at
room temperature followed by treating with water to
give the corresponding N-Cbz-protected α-aminophos-
phinic acid Ie in a good yield. This confirm the in situ
generation of the corresponding bis(trifluoroacetyl)-
methylphosphonite and N-(benzyloxycarbonyl)imi-
nium ion under the reaction conditions. For com-
parison, earlier a more reactive analog of β-amino-
acrylate, acetamidomethylenemalonate, has been used
to obtain the phosphonous and phosphonic analogs of
aspartic acid via the addition of the PH-component in
the Michael reaction [8].
The acetals of acetic, isovaleric, benzyloxyacetic,
phenylacetic, and ethoxycarbonylacetic aldehydes IIa–
IIe were investigated as the starting compounds. They
are of interest due to the search for a suitable
procedure for constructing the isosteres of serine,
phenylalanine, and aspartic fragments to include in
future in a molecule of the phosphinic pseudopeptide
or phosphorylic analog of the corresponding amino
acid. Methylphosphonous acid was studied as a hydro-
phosphorylic component. We suggest to use the alde-
hydes generated in situ from acetals under the acid
catalysis, which is also necessary for the subsequent
reaction of aldehydes with alkylcarbamate to give the
corresponding N,N'-alkylidenebiscarbamates III [5, 6].
In this case the presence of trifluoroacetic acid
provides a satisfactory reaction course. The search for
a catalyst as well as the optimal content of CF3COOH
in the reaction mixture was not performed.
Thus, in this work we developed a general synthesis
of N-alkyloxycarbonyl-α-aminophosphinic acids I
including the compounds containing the structural
isostere fragment of serine, phenylalanine, and aspartic
acid, which opens the possibility for the synthesis of
some low-accessible phosphorylic amino acids analogs
and phosphinic pseudopeptides starting from the low-
stable aldehydes acetals.
As expected, the acetals of acetic, isovaleric,
benzyloxyacetic and phenylacetic aldehydes react with
2 equiv of alkylcarbamate in acetic anhydride in the
presence of trifluoroacetic acid to give the cor-
responding N,N'-alkylidenebiscarbamates IIIa–IIId.
However, the reaction of ethoxycarbonylacetic al-
dehyde diethylacetal with 2 equiv of benzylcarbamate
in the presence of 2.5 equiv of CF3COOH in acetic
anhydride unexpectedly resulted in ethyl β-(N-
benzyloxycarbonyl)aminoacrylate IV. Probably under
the acid catalysys the originally formed biscarbamate
IIIe is converted into N-Cbz-β-aminonoacrylate IV
with the release of the benzylcarbamate molecule and
the intermediate formation of N-(benzyloxycarbonyl)-
iminium cation (salt) V. Perhaps the transformation of
the latter into the acrylate IV is facilitated by means of
the electron-withdrawing ethyloxycarbonyl group. The
latter result confirms the acid-catalyzed formation of
the N-alkyloxycarbonyliminium ions from N,N'-alkyl-
idenebiscarbamates in the multistep amidoalkylation of
hydrophosphorylic compounds as we have previously
assumed [5–7].
General procedure for the synthesis of N-alkyl-
oxycarbonyl-α-aminophosphinic acids (I). a. To a
solution of alkylcarbamate (5.0 mmol) in acetic
anhydride (5 ml) were added with stirring at room
temperature trifluoroacetic acid (2.5–6.0 mmol) and
dropwise the corresponding acetal (2.5 mmol). The
reaction mixture was stirred for 3–10 h. The reaction
progress was monitored by TLC. Then the reaction
mixture was evaporated in vacuo. The residue was
crystallized from diethyl ether or hexane and
recrystallized from diethyl ether–alcohol mixture to
give the corresponding N,N'-alkylidenebiscarbamates
IIIa–IIId or ethyl β-(N-benzyloxycarbonyl) amino-
acrylate IV.
b. To a mixture of the appropriate N,N'-alkyl-
idenebiscarbamate IIIa–IIId (3 mmol) or β-(N-benz-
yloxycarbonyl) aminoacrylate IV (3 mmol) and methyl-
phosphonous acid (3 mmol) in toluene or methylene
chloride (3.5 ml) was added dropwise trifluoroacetic
anhydride (3 mmol) under stirring at room tem-
perature. The reaction mixture was stirred for 3–48 h at
room temperature. The reaction progress was moni-
tored by 31P NMR. After the solvent removal, the
semi-crystalline residue was partitioned between the
Biscarbamates IIIa–IIId react with methyl-
phosphonous acid and trifluoroacetic anhydride in
toluene or methylene chloride in accordance with the
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 11 2012

1884
DMITRIEV, RAGULIN
saturated aqueous sodium hydrocarbonate solution (10 ml)
and diethyl ether (10 ml) or a hexane–toluene mixture
(10:1). The precipitated alkylcarbamate was filtered
off. The aqueous layer was separated and acidified to
pH ~1–2, and then extracted with chloroform (3×10 ml).
The organic extract was dried over MgSO4 and
evaporated in vacuo. The residue was chromato-
graphed on a silica gel (CHCl3:i-PrOH:AcOH =
95:4:1). The N-protected α-aminophosphinic acids Ia–
Ie were obtained as white crystalline substances. Often
the residue was crystallized spontaneously or after the
treatment with ether or petroleum ether (40–60), and
the target compounds were isolated after further crys-
tallization without using the column chromatography.
spectrum (CD3OD + DMSO-d6, 4:1), δ, ppm: 1.47 d
(3Н, CH3P, 2JPH 14.2 Hz), 3.79 d (1Н, OCH2CHP, 3JPH
10.8 Hz), 3.81 d (1Н, OCH2CHP, 3JPH 9.3 Hz), 4.17 d.
2
t (1H, CHP, JPH 14.2 Hz), 4.55 br.s (2Н, OСН2Ph),
5.14 br.s [2Н, C(O)OСН2Ph], 7.34 m (10Н, Ph). 13С
NMR spectrum (CD3OD + DMSO-d6, 4:1), δC, ppm:
1
1
13.8 d (СН3Р, JPС 92.2 Hz), 53.0 d (РСНN, JPС
2
104.7 Hz), 67.7, 69.0 d (PCHCH2, JPС 7.0 Hz), 74.0,
128.8, 128.9, 129.1, 129.5, 129.6, 138.3, 139.4, 158.5
d (С=О, JPС 5.0 Hz). 31P NMR spectrum (CD3OD +
3
DMSO-d6, 4:1): δP 49.0 ppm. Found, %: C 59.31,
59.43; H 6.23, 6.15; P 8.73, 8.67. C18H22NO5P.
Calculated, %: C 59.50; H 6.10; P 8.52%.
1-(Ethoxycarbonylamino)-2-phenylethylmethyl-
1-(Benzyloxycarbonylamino)ethylmethylphosphinic
phosphinic acid (Id). Yield 51%, mp 163–164°С, Rf
1
acid (Iа). Yield 53%, mp 119–120°С (mp 121–122°С
~0.15 [CHCl3:CO(CH3)2 = 5:1]. H NMR spectrum
1
3
[6]), Rf ~ 0.15 [CHCl3:CO(CH3)2 = 4:1]. H NMR
(CDCl3 + CD3OD, 1:2), δ, ppm: 0.98 t (3Н, CH3, JHH
spectrum (CDCl3), δ, ppm: 1.33 d.d (3Н, CH3CH, 3JHH
7.1 Hz), 1.33 d (3Н, CH3P, 2JPH 13.7 Hz), 2.70 m (1Н,
CH2Ph), 3.16 m (1Н, CH2Ph), 3.90 q (CH2О, 3JHH 7.1 Hz),
4.05 m (1Н, СНР), 7.19 m (5Н, Ph). 13С NMR spec-
3
2
7.1, JPH 15.0 Hz), 1.42 d (3Н, CH3P, JPH 15.4 Hz),
3.99 m (1Н, СНN), 5.09 m (2Н, CH2Ph), 5.37 d (1H,
3
1
NH, JHH 9.7 Hz), 7.32 m (5H, Ph), 10.56 br.s (1Н,
trum (CD3OD), δC, ppm: 12.4 d (СН3Р, JPС 90.9 Hz),
POOH). 13С NMR spectrum (CDCl3), δC, ppm: 12.4 d
(1JPC 93.3 Hz), 13.9, 46.0 d (1JPC 107.6 Hz), 67.2,
128.1, 128.2, 128.5, 136.1, 155.9 d (3JPC 5.1 Hz). 31Р
NMR spectrum (CDCl3): δP 54.8 ppm.
14.9 (СН3), 34.5 (CH2Ph), 53.8 d (РСНN, 1JPС 108.6 Hz),
62.1 (OCH2СН3), 127.6 (СН), 129.4 (СН), 130.2
3
(СН), 139.0 d (3JPС 13.4 Hz), 158.7 d (С=О, JPС
3.3 Hz). 31P NMR spectrum (CDCl3 + + CD3OD, 1:2),
δP, ppm: 51.1, 50.0 (15%) [7]. 31P NMR spectrum
(CDCl3 + CF3COOH): δP 59.7 ppm. Found, %: C
53.01, 52.93; H 6.93, 6.95; P 11.53, 11.78. C12H18NO4P.
Calculated, %: C 53.14; H 6.69; P 11.42.
1-Ethoxycarbonylamino-3-methylbutylmethyl-
phosphinic acid (Ib). Yield 55%, mp 144–146°С, Rf
1
~0.10 [CHCl3:CO(CH3)2 = 4:1]. H NMR spectrum
(CDCl3 + CD3OD, 5:1), δ, ppm: 0.93 d (3H, CH3, 3JHH
3
6.6 Hz), 0.97 d (3H, CH3, JHH 6.6 Hz), 1.26 t (3H,
1-(Benzyloxycarbonylamino)-2-(ethyloxycar-
2
CH3), 1.38 d (3H, CH3, JPH 14.1 Hz,), 1.40–1.55 m
bonyl)ethylmethylphosphinic acid (Ie). Yield 68%,
1
(2H, CH2), 1.60–1.85 m (1H, CH), 3.82 m (1H, РCH),
mp 97–98°С. Rf ~0.2 [CHCl3:CO(CH3)2 = 5:1]. H
1
4.08 q (2H, CH2). H NMR spectrum (CCl4 + DMSO-
NMR spectrum (CDCl3), δ, ppm: 1.18 t (3Н, CH3, 3JHH
7.0 Hz), 1.48 d (3Н, CH3P, 2JPH 14.0 Hz), 2.66 m [1Н,
СH2С(О)], 2.77 m [1Н, СH2С(О)], 4.11 q (2Н, СH2О,
3JHH 7.0 Hz), 4.39 m (1Н, СНР), 5.10 br.s (2Н,
РhCH2O), 5.63 m (1Н, NH), 7.32 m (5Н, Ph), 8.00 br.s
(1Н, РООН). 13С NMR spectrum (CDCl3), δC, ppm:
12.8 d (СН3Р, 1JPС 92.6 Hz), 14.0 (СН3), 33.4 [СН2С(О)],
d6, 4:1), δ, ppm: 0.90 d (3H, CH3, 3JНH 6.2 Hz), 0.95 d
3
(3H, CH3, JHH 6.5 Hz), 1.25 t (3H, CH3), 1.3 d (3H,
CH3, 2JPH 14.0 Hz), 1.35–1.6 m (2H, CH2), 1.6–1.85 m
(1H, CH), 3.7 m (1H, CH), 4.0 q (2H, CH2), 6.9 d (1H,
3
13
NH, JHH 9.3 Hz). С NMR spectrum (DMSO-d6), δC,
ppm: 12.5 d (1JPC 89.6 Hz), 14.7, 20.9, 23.3, 24.1 d
(3JPC 11.7 Hz), 36.0, 49.0 d (1JPC 107.6 Hz), 59.9,
156.4. 31Р NMR spectrum (CCl4 + DMSO-d6, 4:1): δP
49.0 ppm. 31Р NMR spectrum (CCl4 + CD3OD, 5:1): δP
52.0 ppm. Mass spectrum, m/z (Irel, %): 238 (37) [M +
H]+, 158 (100) [(CH3)2CHCH2C+HNHC(O)OCH2CH3].
Found, %: C 45.70, 45.66; H 8.45, 8.51; N 5.87, 5.82.
C9H20NO4P. Calculated, %: C 45.57; H 8.50; N 5.90.
1
47.6 d (РСНN, JPС 110.2 Hz), 61.1 (СН3СН2О), 67.2
(PhСН2О), 128.0 (CH), 128.2 (CH), 128.5 (CH),
3
31
136.1, 155.8 (C=O), 170.3 d (С=О, JPС 11.7 Hz). P
NMR spectrum (CDCl3), δP, ppm: 53.6, 52.4 (13%)
[7]. Found, %: C 50.92, 50.93; H 6.23, 6.32; P 9.52,
9.68. C14H20NO6P. Calculated, %: C 51.07; H 6.12; P
9.41.
1-(Benzyloxycarbonylamino)-2-benzyloxyethyl-
N,N'-Ethylidenebis(benzylcarbamate) (IIIа). Yield
71%, mp 200–201°С (mp 203–204°С [6]), Rf 0.8
[CHCl3:CO(CH3)2 = 4:1].
methylaminophosphinic acid (Ic). Yield 53%, mp
1
98–99°С, Rf ~0.10 [CHCl3:CO(CH3)2 = 4:1]. H NMR
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 11 2012

ACETALS AND N,N'-ALKYLIDENEBISCARBAMATES
1885
3
N,N'-Isoamylidenebis(ethylcarbamate)
(IIIb).
3JHH 14.1 Hz], 7.07 d (1Н, NH, JHH 11.9 Hz), 7.36 m
3
3
Yield 67%, mp 129–130°С, Rf 0.7 [CHCl3:CO(CH3)2 =
(5Н, Ph), 7.80 d.d (1Н, СНNH, JHH 14.1, JHH
11.9 Hz). 13С NMR spectrum (CDCl3), δC, ppm: 14.2
(CH3), 60.1 (CH3CH2O), 68.1 (PhСH2O), 100.1
[С(О)СαН=], 128.4 (CН), 128.6 (CН), 135.1, 139.4
(NHСβН=), 152.9 (С=О), 167.3 (С=О). Found, %: C
62.34, 62.33; H 6.13, 6.20. C13H15NO4. Calculated, %:
C 62.64; H 6.07.
The 1H, 31P and 13С NMR spectra were recorded on
Bruker DPX-200 and Bruker CXP-300 spectrometers
relative to internal TMS and external 85% H3PO4. The
melting points were measured on a Boetius-PHMK
instrument or in an open capillary.
1
4:1]. H NMR spectrum (CDCl3), δ, ppm: 0.90 d (6H,
CH3, 3JHH 6.6 Hz), 1.21 t (6H, CH3, 3JHH 7.1 Hz), 1.52–
1.81 m (3H, CHCH2), 4.08 q (4H, CH2О, 3JHH1 7.1 Hz),
4.97 br.s (1H, CH), 5.50 br.s (2H, NH). H NMR
3
spectrum (DMSO-d6), δ, ppm: 0.80 d (6H, CH3, JHH
3
7.0 Hz), 1.10 t (6H, CH3, JHH 7.1 Hz), 1.30–1.55 m
3
(3H, CHCH2), 3.60–4.05 q (4H, CH2О, JHH 7.1 Hz),
3
5.04 m (1H, CH), 7.17 d (2H, NH, JHH 6.6 Hz). 13С
NMR spectrum (DMSO-d6), δ, ppm: 14.6 (CH3CH2),
22.2 (CH3CH), 24.1 (CHCH3), 43.5 (CH2CH), 57.8
(CHN), 59.5 (CH2O), 155.1 (C=O). Mass spectrum, m/z
(Irel, %): 247 (<1) [M + H]+, 189 (100) [CH+(NHC(O)·
OCH2CH3)2], 158 (51) [(CH3)2CHCH2CH+NHC(O)·
OCH2CH3]. Found, %: C 53.53, 53.44; H 8.89, 8.88; N
11.21, 11.23. C11H22N2O4. Calculated, %: C 53.64; H
9.00; N 11.37.
ACKNOWLEDGMENTS
This work was financially supported by the Russian
Foundation for Basic Research (grant no. 10-03-
01058-а).
N,N'-2-Benzyloxyethylidenebis(benzylcarbamate)
(IIIc). Yield 53%, mp 111–112°С, Rf 0.6 [CHCl3:
1
REFERENCES
CO(CH3)2 = 4:1]. H NMR spectrum (DMSO-d6), δ,
3
ppm: 3.47 d (2Н, ОCH2CH, JHH 6.4 Hz), 4.47 br.s
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(2Н, ОCH2Ph), 5.01 br.s [4Н, С(О)OСН2Ph], 5.28 t
(1Н, СНCH2О, 3JHH 6.4 Hz), 7.32 m (15Н, Ph), 7.68 d
(2H, NH, 3JHH 7.3 Hz). 13С NMR spectrum (DMSO-d6),
δC, ppm: 58.8, 65.4, 70.2, 72.0, 127.5, 127.8, 128.2,
128.3, 136.9, 138.2, 155.2 (С=О). Found, %: C 68.94,
69.04; H 5.96, 6.00; N 6.24, 6.33. C25H26N2O5. Cal-
culated, %: C 69.11; H 6.03; N 6.45.
N,N'-2-Phenylethylidenebis(ethylcarbamate) (IIId).
Yield 61%, mp 155–156°С, Rf 0.7 [CHCl3:CO(CH3)2 =
1
4:1]. H NMR spectrum (CDCl3), δ, ppm: 1.25 t (6Н,
2CH3), 3.18 m (2Н, CH2Ph), 4.13 q (4Н, СН2О), 5.21
m (1Н, CHN), 5.56 m (2H, 2NH), 7.28 m (5H, Ph). 1H
NMR spectrum (DMSO-d6), δ, ppm: 1.10 t (6Н, CH3,
3JHH 7.1 Hz), 2.84 d (2Н, СН2CH, 3JHH 7.1 Hz), 3.91 q
3. Oleksyszyn, J. and Gruszecka, E., Tetrahedron Lett.,
3
3
1981, vol. 22, no. 36, p. 3537.
(4Н, СН2О, JHH 7.1 Hz), 5.10 t (1Н, CHN, JHH
7.5 Hz), 7.23 m (5H, Ph). 7.47 br. d (2H, 2NH). 13C
NMR spectrum (CDCl3), δC, ppm: 14.4, 40.1, 61.0,
126.8, 128.6, 129.3, 136.5, 155.6 (С=О). Found, %: C
60.21, 60.13; H 7.11, 7.17; N 10.15, 10.04. C14H20N2O4.
Calculated, %: C 59.99; H 7.19; N 9.99.
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Obshch. Khim., 2011, vol. 81, no. 6, p. 898.
Ethyl β-(N-benzyloxycarbonyl)aminoacrylic acid
(IV). Yield 47%, mp 115–116°С, Rf ~0.5 [CHCl3:
CO(CH3)2 = 7:1]. 1H NMR spectrum (CDCl3), δ, ppm:
1.25 t (3Н, CH3, 3JHH 7.1 Hz), 4.16 q (2Н, СН2О, 3JHH
7.1 Hz), 5.19 br.s (2Н, PhСН2О), 5.36 d [1Н, СНС(О),
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2012, vol. 53, no. 13, p. 1634.
8. Khomutov, A.R., Osipova, T.I., Khurs, E.N., Alferov, K.V.,
and Khomutov, R.M., Izv. Akad. Nauk, Ser Khim., 1996,
no. 18, p. 2066.
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