Formation of phosphorus-carbon bond in the course of amidoalkylation of hydrophosphorylic compounds

Full text of DOI:10.1134/S1070363215020231

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 2, pp. 497–499. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © M.E. Dmitriev, L.L. Yurkova, S.A. Lermontov, V.V. Ragulin, 2015, published in Zhurnal Obshchei Khimii, 2015, Vol. 85, No. 2,
pp. 327–329.
LETTERS
TO THE EDITOR
To the 80th Anniversary of B.I. Ionin
Formation of Phosphorus–Carbon Bond in the Course
of Amidoalkylation of Hydrophosphorylic Compounds
M. E. Dmitriev, L. L. Yurkova, S. A. Lermontov, 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
Keywords: amidoalkylation, Arbuzov reaction, diethyl acetylphosphite, iminium cation, solid superacid catalyst
DOI: 10.1134/S1070363215020231
Amidoalkylation of hydrophosphorylic compounds,
a very promising general method for incorporation of
aminophosphoryl function retaining a protecting group
at the nitrogen atom of the target molecule, has been
undeservedly forgotten. We have earlier developed an
efficient procedure to perform reaction of hydrophos-
phoryl compounds with aldehydes and alkyl
carbamates in acetic anhydride upon cooling, and have
proposed the mechanism of this multi-stage reaction
[1–4]. According to the proposed mechanism, the
formation of phosphorus–carbon bond is as a result of
the Arbuzov reaction via nucleophilic attack of the
trivalent phosphorus atom of acetyloxy derivative I at
positively charged carbon atom of iminium cation II
[1, 2], the reactants being generated in situ under the
reaction conditions from hydrophosphorylic compound
III and N,N'-alkylidenebis(carbamate) IV, respectively
[1, 2]. Biscarbamates have been identified as stable
(isolated from the reaction medium) intermediates
formed from the reacting aldehydes and alkyl carba-
mates [1–4] (Scheme 1).
This work aimed to study of one of the proposed
stages, formation of phosphorus–carbon bond during
generation of the iminium cation from a pre-
synthesized alkylidenebiscarbamate III in an aprotic
solvent in the presence of solid superacid catalyst
[5, 6]. N,N'-Benzylidenebis(carbamates) IVa and IVb
synthesized from carbamate and benzaldehyde in
acetic anhydride medium were used as iminium ion
sources; diethyl acetylphosphite Ia [7] was used as the
AcOPIII-phosphorus component.
It was found that biscarbamates IVa and IVb did
not react with acetylphosphite Ia in an aprotic solvent
in the absence of acid catalyst, as conditions of the
iminium ion II generation were not met. We suggested
that transformation of biscarbamate IV into the
iminium cation II might occur in the presence of a
solid superacid via protonation of nitrogen or oxygen
atom (C=O) of amide fragment of biscarbamate with
Brønsted sites of the catalyst in an inert solvent
followed by evolution of the carbamate [1–4]. The so
Scheme 1.
O
H
R
O
H
R
O
OAlk
H
R
O
P+
O
N
N
OAlk
C+
O
H
−AcX
P
N
OAlk
P
O
O
H
H
X−
X−
II
V
I
497

498
DMITRIEV et al.
Scheme 2.
O
H
N
H
O
O
EtO
EtO
C+
OAlk
P
+
EtO P
O
Ph
N
H
OAlk
O
O
Ph
OEt
HSO4−
Iа
Vа, Vb
II
δP 22.4−23.1 ppm
δP 135 ppm
catalyst
−H2NC(O)OAlk
Ph
H
N
R1
AlkO
O
+
P
O
N
H
OAlk
V
without catalyst
R2
O
IVа, IVb
I
Ac2O
Ac2O
R = Ph
O
H
O
P
R1
N
Ac2O (H+)
O
H
OAlk
RCH(O) + AlkOC(O)NH2
R1
+
P
R2
R2
R
III
V
Alk = Et (а), tert-Bu (b).
generated iminium cation II was probably sufficiently
reactive, and a relatively weak nucleophile such as
acetylphosphite I could attack the positively charged
carbon atom of the iminium ion to form the target
phosphorus–carbon bond (Scheme 2).
carbamate in acetic anhydride medium in the presence of
trifluoroacetic acid (IVa) or without any catalyst (IVb) [1].
N,N'-Benzylidenebis(ethylcarbamate)
(IVa).
Yield 72%, mp 172–173°С, Rf [CHCl3–(CH3)2CO,
1
4 : 1] 0.8. H NMR spectrum (DMSO-d6–CCl4, 1 : 4),
3
Indeed, a relatively rapid formation of the desired
reaction product was observed when using sulfated
solid superacid TiO2/SO4 or Al2O3/SO4. The reaction
was monitored by 31P NMR: in the course of the
reaction, the signal of acetylphosphite Ia at ~135 ppm
disappeared and the signal of the corresponding α-
aminophosphonate V appeared at ~22–23 ppm in the
31P NMR spectrum of the reaction mixture. Pure phospho-
nates Va and Vb were isolated and characterized.
δ, ppm: 1.25 t (6H, CH3, JНH 7.0 Hz), 4.05 q (4H,
CH2, 3JНH 7.0 Hz), 6.15 d.d (1H, CH, JHH 9.3 Hz), 7.2–
7.5 m (5H, Ph, NH). 13C NMR spectrum (DMSO-d6),
δС, ppm: 14.6 (CH3CH2), 60.0 (CH2O), 61.5 (CHN);
126.3, 127.7, 128.3, 140.3 (Ph), 155.3 (C=O). Mass
spectrum, m/z (Irel, %): 267 (<1) [M + H]+, 104 (100)
[CH3NH2+C(O)OCH2CH3], 77 (80) [C6H5+], 178 (21)
[PhCH+NHC(O)OCH2CH3]. Found, %: C 58.51,
58.49; H 7.01, 6.93; N 10.21, 10.43. C13H18N2O4.
Calculated, %: C 58.64; H 6.81; N 10.52.
In summary, the results have confirmed the pre-
viously proposed mechanism of the phosphorus–
carbon bond formation during amidoalkylation of hydro-
phosphoryl compounds. Use of superacid catalyst allowed
for the first time to introduce aminophosphoryl
fragment into the compound structure retaining the
tert-butyloxycarbonyl protecting group at the nitrogen
atom; the process is promising for peptide synthesis.
N,N'-Benzylidenebis(tert-butylcarbamate) (IVb).
Yield 56%, mp143–145°С, Rf [CHCl3–(CH3)2CO,
4 : 1] 0.8. 1H NMR spectrum (DMSO-d6), δ, ppm: 1.37
3
s (18Н, 6СН3), 6.05 t (1Н, СHN, JНH 7.3 Hz), 7.23–
7.47 m (7Н, Ph, 2NH). 13C NMR spectrum (DMSO-d6),
δС, ppm: 28.2 (6CH3), 60.8 (CHN), 78.3 (CMe3);
126.1, 127.5, 128.2 (Ph), 140.9 and 154.3 (C=O).
Found, %: C 63.17, 63.07; H 8.33, 8.45; N 8.41, 8.54.
C17H26N2O4. Calculated, %: C 63.33; H 8.13; N 8.69.
Alkylidenebiscarbamates were synthesized by
reacting 2 eq. of benzaldehyde with ethyl or tert-butyl
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 2 2015

FORMATION OF PHOSPHORUS–CARBON BOND
499
Diethyl acetylphosphite (Ia). A mixture of anhyd-
rous sodium acetate (0.1 mol) and diethylchloro-
phosphite (0.1 mol) in 30 mL of absolute diethyl ether
was stirred during 12 h under argon atmosphere. The
precipitate was separated; the filtrate was evaporated
in vacuum. The residue was distilled in vacuum [7].
Yield 67%, oil, bp 75°C (10 mmHg). 1H NMR
spectrum (CDCl3), δ, ppm: 1.30 t (6H, 2CH3, J 7.3 Hz),
2.13 s (3H, CH3), 4.03 m (4H, 2CH2). 31P NMR spec-
trum (CDCl3): δР 134.8 ppm.
7.35–7.55 m (2Н, Ph). 13С NMR spectrum (CDCl3),
δС, ppm: 14.5, 16.1 d (3JPС 5.5 Hz), 16.4 d (3JPС 5.8 Hz),
52.3 d (1JPС 154.1 Hz), 61.5, 63.0 d (2JPС 7.3 Hz), 63.3
d (2JPС 6.6 Hz), 127.7, 127.8, 128.1, 128.6, 135.4,
155.8 d (3JPС 11.3 Hz). 31Р NMR spectrum (CDCl3): δР
22.4 ppm. Found, %: C 53.11, 53.05; H 7.11, 7.18.
C14H22NO5P. Calculated, %: C 53.33; H 7.03.
Diethyl α-(tert-butyloxycarbonylamino)benzyl-
phosphonate (Vb). Yield 37%, mp 102–104°С, Rf
1
[CHCl3–(CH3)2CO, 4 : 1] 0.7. H NMR spectrum
3
Solid superacid TiO2/SO4. Tetraisopropoxytita-
nium (28.4 g, 0.1 mol) was added dropwise to 400 mL
of an aqueous ammonia solution (pH 9). The
precipitate was filtered off and dried at 120°C during
3 h. The resulting hydrated titanium dioxide (4 g) was
thoroughly powdered and mixed with 100 mL of
1 mol/L solution of (NH4)2SO4, and the mixture was
stirred during 1 h at room temperature. The resulting
precipitate TiO2/SO4 was dried during 3 h at 120°C
and calcined at 600°C during 2 h immediately before
use.
(CCl4), δ, ppm: 1.10 t (3H, CH3, JНH 7.0 Hz), 1.28 t
3
(3H, CH3, JНH 7.0 Hz), 1.41 s (9H, 3CH3), 3.71 m
(1H, CH2OР), 3.91 m (1H, CH2OР), 4.09 m (2H,
CH2OP), 5.10 d.d (1H, PCHN, 3JНH 9.3, 2JPH 22.5 Hz),
6.10 br.s (1H, NH), 7.20–7.50 m (5Н, Ph). 13С NMR
spectrum (CDCl3), δC, ppm: 16.1 d (3JPС 5.1 Hz), 16.3
d (3JPС 5.1 Hz), 28.2, 51.7 d (1JPС 153.3 Hz), 62.9 d
(2JPС 7.3 Hz), 63.1 d (2JPС 6.6 Hz), 80.2, 127.8, 128.4,
128.9, 129.6, 135.4, 155.8 d (3JPС 9.5 Hz). 31Р NMR
spectrum (CCl4): δР 23.1 ppm. Found, %: C 55.83,
55.68; H 7.90, 7.77. C16H26NO5P. Calculated, %: C 55.97;
H 7.63.
1H, 31P, and 13С NMR spectra were recorded using
a Bruker DPX-200 Fourier spectrometer. Melting
points were determined with a Boetius PHMK instru-
ment or via open capillary method.
Solid superacid Al2O3/SO4. A mixture of 50 mL of
an aqueous 2 mol/L solution of Н2SO4 and 4 g of
Al2O3 was stirred during 1 h; then the catalyst was
filtered off and dried at 100°C during 2 h. The catalyst
was calcined at 600°C during 2 h before use.
Synthesis of α-(alkyloxycarbonylamino)benzyl-
phosphonates (V). A mixture of 1.0 g of superacid
(TiO2/SO4 or Al2O3/SO4) and 0.8 mmol of N,N'-benzyl-
idenebis(carbamate) IV in 7.5 mL of methylene chloride
was stirred under dry argon during 10–15 min. Then,
0.8 mmol of diethyl acetylphosphite I was added to the
reaction mixture under argon. The stirring was
continued during further 1 h. The catalyst was filtered
off, and the filtrate was evaporated in vacuum. The
residue was treated with petroleum ether, and alkyl
carbamate was filtered off. The mother liquor was
washed with water; then the organic layer was
separated, dried over sodium sulfate, and evaporated in
vacuum. The residue was crystallized from a mixture
of diethyl ether–hexane or from diethyl ether.
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1
(CH3)2CO, 4 : 1] 0.6. H NMR spectrum (CDCl3), δ,
3
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3
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CH2OP, CH2OС), 5.03 d.d (1H, PCHN, JНH 9.3, JPH
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 2 2015