Double Michael–Pudovik addition of generated in situ silylic esters of trivalent phosphorus to unsaturated compounds

Full text of DOI:10.1134/S1070363216120240

ISSN 1070-3632, Russian Journal of General Chemistry, 2016, Vol. 86, No. 12, pp. 2706–2709. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © V.V. Ragulin, 2016, published in Zhurnal Obshchei Khimii, 2016, Vol. 86, No. 12, pp. 2074–2077.
LETTERS
TO THE EDITOR
Double Michael–Pudovik Addition of Generated in situ Silylic
Esters of Trivalent Phosphorus to Unsaturated Compounds
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 September 8, 2016
Keywords: bis(trimethylsilyl) hypophosphite, acrylonitrile, acrylamide, diphenyl(vinyl)phosphine oxide, 1,4-
addition of silyl phosphonites, phosphorane hypothesis
DOI: 10.1134/S1070363216120240
Among hypophosphorous acid derivatives, bis(tri-
methylsilyl) hypophosphite is distinguished as a highly
reactive reagent capable of participating in trans-
formations like the Arbuzov reaction [1–3], as well as
of addition to unsaturated compounds according to
Michael–Pudovik reaction [4–7]. We have proposed and
are developing a methodology for the synthesis of
phosphinic acids, which ensures most effective
utilization of unique properties of bis(trimethylsilyl)-
phosphonite (1) for building up phosphorus–carbon
bonds via its generation in situ from hypophosphorous
acid salts [5–10]. The low-temperature addition of bis-
(trimethylsilyl) hypophosphite (1) to α-substituted
acrylates with formation of phosphonites 2 containing
isosteric fragment of natural amino acids underlies syn-
theses of pseudopeptides that are phosphinic acid
analogs of natural peptides [8–10] (Scheme 1). Under
more severe conditions in the presence of excess
acrylate, 1:2 addition products (phosphinic acids 3)
were obtained [4–7]. When vinyl phosphonate was
used as unsaturated component, bis(trimethylsilyl
diethoxyphosphinylethylphosphonite 4 was obtained
[11]. Bis[2-(diethoxyphosphinyl)ethyl]phosphinic acid
(5; 1:2 addition product) was isolated in the synthesis
of a bisphosphorylic analogue of γ-amino-butyric acid
[12]. Unlike acrylates and diethyl vinylphosphonate,
Scheme 1.
R
O
O
R
O
X = COOAlk
R = Alk
Me3SiO
O
P
(1) CH2=C(R)COOAlk
(2) H2O, EtOH
OAlk
P
P
P
OAlk
OH
AlkO
R
Me3SiO
Me3SiO
3
2
6
O
Ph
(1) CH2=CH−Ph
Ph
X = Ph
R = H
CH2=CR−X
[HP(OSiMe3)2]
P
(2) H2O, EtOH
1
Ph
Me3SiO
Me3SiO
OH
O
O
P
OEt
P
(1) CH2=CHP(O)(OEt)2
(2) H2O, EtOH
O
OEt
OEt
O
P
OEt
R = H
Me3SiO
EtO
P
X = P(O)(OEt)2
4
OH
OEt
5
2706

DOUBLE MICHAEL–PUDOVIK ADDITION
2707
Scheme 2.
O
O
O
Me3SiO
Me3SiO
NH2
P
(1) 2CH2=CH−C(O)NH2
P
OH
(2) H2O, EtOH
(1) CH2=CH−CN
2 equiv)
N
H2N
7
(
9
[HP(OSiMe3)2]
(2) H2O, EtOH
1
O
P
(1) 2CH2=CH−P(O)Ph2
O
Ph
O
O
P
P
(2) H2O, EtOH
H
P
Ph
Ph
N
OH
OH
10
Ph
8
styrene reacted with hypophosphite 1 to give only 1:1
addition product 6 even at elevated temperature in the
presence of excess unsaturated reagent [13].
δP ~50±5 ppm typical for dialkylphosphinic acid. Mild
hydrolysis of phosphonite 9 gave 2-cyanoethyl-
phosphinic acid 10 (Scheme 2) which is promising
reagent for further transformations.
In this work, I studied the reactions of acrylonitrile,
acrylamide, and diphenyl(vinyl)phosphine oxide as
unsaturated components with bis(trimethylsilyl)
hypophosphite (1) generated in situ with the goal of
obtaining the corresponding 1:2 addition products,
symmetrically substituted phosphinic acids. As shown
previously, the reaction of acrylamide with hypophos-
phorous acid gives 1:1 adduct [14]. I have found that
one-pot reaction of 2 equiv of acrylamide with
generated in situ bis(trimethylsilyl) hypophosphite (1)
yields 1:2 addition product, bis(3-amino-3-oxopropyl)
phos-phinic acid (7), after treatment of the reaction
mixture with excess of aqueous alcohol (Scheme 2).
Analogous one-pot reaction of 1 with 2 equiv of
diphenyl(vinyl)phosphine oxide affords bis[2-(di-
phenylphosphinyl)-ethyl]phosphinic acid (8) in good
yield (Scheme 2).
The formation of 1:1 addition products, phos-
phonites 6 and 9, and the absence of 1:2 adducts in the
reactions of 1 with styrene and acrylonitrile suggest
that these reactions involve 1,2-addition of phos-
phonite 1 as PH component to the C=C double bond of
the unsaturated reagent, where the P–C bond is formed
with the β-carbon atom. Furthermore, our results rule
out 1,2-addition of intermediate phosphonites 2 and 4
as the POSiMe3 reagent to the second molecule of
acrylate or vinylphosphonate. Presumably, the reaction
proceeds as 1,4-addition of the phosphorus atom to the
β-carbon atom of the unsaturated reagent and of the
trimethylsilyl group to the C=O or P=O oxygen atom
of the latter with intermediate formation of silyl enol
ether 11 or ylide 12 (Scheme 3).
The obtained data are consistent with the hypo-
thesized initial formation of phosphorane structure 13
or 14 via 1,4-cycloaddition of acrylate or vinyl-
phosphonate to phosphonite 2 or 4 to give unstable
five-coordinate phosphorus compounds containing a
2,3-dihydro-1,2λ5-oxaphosphole ring [16]. Probably,
unsaturated compounds incapable of 1,4-cycloaddition
to phosphorus(III) acid silyl esters generated in situ
could not give rise to 1:2 addition products. Opening
of the five-membered ring through cleavage of the
P–O bond and migration of the trimethylsilyl group to
the oxygen atom lead to silyl enol ether 11 or ylide 12,
and mild hydrolysis of the latter yields phosphinic acid
3 or 5.
The reaction of acrylonitrile with an equimolar
amount of previously isolated bis(trimethylsilyl) hypophos-
phite (1) was studied previously by Pudovik and co-
workers [15], but attempts to obtain 1:2 addition
product were not reported. Our results showed that,
generated in situ hypophosphite 1 reacts with acrylo-
nitrile in the cold, as well as on heating with excess
acrylonitrile [1 : (2–4)], to give only the corresponding
1:1 adduct bis(trimethylsilyl) 2-cyanoethylphosphonite
(9) [15], i.e., in a way similar to the reaction of 1 with
styrene. The 31P NMR spectrum of the reaction
mixture contained signals typical of trivalent phos-
phorus compounds, in particular at δP ~142 (1) and
~154 ppm (9). Signals were not detected in the region
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 12 2016

2708
RAGULIN
Scheme 3.
OSiMe3
P
R'
OSiMe3
2, 4
OAlk
R
O
O
P
EtOH, H2O
Me3SiO
P
O
P
HO
OSiMe3
OAlk
Me3SiO
R'
O
OAlk
R
O
R'
R'
R
R
OAlk
OSiMe3
13
11
3
Y
P
Y
O
O
P
Y
Y
O
EtOH, H2O
O
OSiMe3
P
HO
P
Me3SiO
O
Me3SiO
R'
Y
P
P
Y
P
R'
R'
Y
Y
OSiMe3
14
12
5
Bis[2-(diphenylphosphinyl)ethyl]phosphinic acid
(8). A mixture of 1.6 g (0.02 mol) of ammonium
hypophosphite and 9.2 g (0.04 mol) of diphenyl(vinyl)-
phosphine oxide in 10.0 mL (0.04 mol) of hexa-
methyldisilazane was refluxed for 5 h with stirring.
The mixture was cooled, 40 mL of aqueous ethanol
(1:1) was slowly added dropwise, and the mixture was
evaporated under reduced pressure. The residue was
dissolved in 50 mL of chloroform, and the solution
was washed in succession with a saturated aqueous
solution of sodium carbonate (3×15 mL), 0.5 N
aqueous HCl, and water. The organic phase was dried
over MgSO4 and evaporated, and the residue was
crystallized from diethyl ether. Recrystallization from
ethanol gave 7.2 g (71%) of 8, Rf 0.4 (Silufol, CHCl3–
phite and 1.4 g (0.02 mol) of acrylamide in 5.0 mL
(0.02 mol) of hexamethyldisilazane was refluxed for
6 h with stirring. The mixture was cooled, 20 mL of
aqueous ethanol (1:1) was slowly added dropwise, and
the mixture was evaporated under reduced pressure.
The residue was treated with weakly acidic water, the
mixture was evaporated, and the residue was
crystallized from ethanol. Recrystallization from a
minimum volume of water gave 1.4 g (67%) of
phosphinic acid 7 with mp 195–196°C. 1H NMR
spectrum (D2O), δ, ppm: 1.95 m (4H, PCH2), 2.42 m
[4H, CH2C(O)]. 13C NMR spectrum (D2O), δC, ppm:
23.9 d (1JPC = 92.4 Hz), 27.3 d (2JPC = 2.7 Hz), 177.4 d
(3JPC = 14.2 Hz). 31P NMR spectrum (D2O): δP 54.7
ppm. Found, %: C 34.55, 34.50; H 6.46, 6.52; N 13.45,
13.34. C6H13N2O4P. Calculated, %: C 34.62; H 6.30; N
13.46.
1
Me2CO, 4:1), mp 199–200°C. H NMR spectrum
(CDCl3), δ, ppm: 1.90 m (4H, CH2), 2.60 m (4H, CH2),
7.40 m and 7.70 m (20H, Ph), 10.12 s [1H, P(O)OH].
2-Cyanoethylphosphinic acid (10). a. A mixture
of 0.8 g (0.01 mol) of ammonium hypophosphite and
7.5 mL (0.03 mol) of hexamethyldisilazane was
refluxed for 3 h with stirring. The mixture was cooled
to room temperature in a stream of dry argon, 1.1–2.2 g
(0.02–0.04 mol) of acrylonitrile was added, and the
mixture spontaneously warmed up to 60–80°C. After
cooling, the mixture was stirred for 48 h, unreacted
13C NMR spectrum (CDCl3), δC, ppm: 20.5 d.d (1JPC
=
=
3
3
91.4, JPC = 4.0 Hz), 21.6 d.d (1JPC = 70.4, JPC
4.0 Hz), 128.6, 128.8, 130.5, 130.7, 132.0. 31P NMR
spectrum (CDCl3): δP 35.8 ppm, d [2P, P(O)Ph2, 3JPP
=
3
48.4 Hz], 49.2 t [1P, P(O)OH, JPP = 48.4 Hz]. Found,
%: C 64.90, 64.42; H 5.66, 5.59; P 17.77, 17.87.
C28H29O4P3. Calculated, %: C 64.37; H 5.60; P 17.79.
Bis(3-amino-3-oxopropyl)phosphinic acid (7). A acrylonitrile and excess hexamethyldisilazane were
mixture of 0.8 g (0.01 mol) of ammonium hypophos- distilled off under reduced pressure, and the residue
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 12 2016

DOUBLE MICHAEL–PUDOVIK ADDITION
doi 10.1007%2FBF00959918
2709
was distilled in a high vacuum to isolate 1.6–1.8 g
(62–69%) of bis(trimethylsilyl) 2-cyanoethylphosphonite
(9) as a colorless oily liquid, bp 68–74°C (1 mm). H
2. Kurdyumova, N.R., Ragulin, V.V., and Tsvetkov, E.N.,
1
Russ. J. Gen. Chem., 1994, vol. 64, no. 3, p. 380.
NMR spectrum (neat), δ, ppm: 0.00 s (18H, Me3Si),
1.80–1.95 m (2H, CH2P), 2.30–2.45 m (2H, CH2C). 31P
NMR spectrum (neat): δP 153.8 ppm.
3. Montchamp, J.L., Tain, F., and Frost, J.W., J. Org.
Chem., 1995, vol. 60, no. 19, p. 6076. doi 10.1021/
jo00124a018
Aqueous ethanol (1:1), 10 mL, was added to
phosphonite 9 isolated as described above, and the
mixture was stirred until it cooled down and eva-
porated under reduced pressure. The residue was
treated with toluene, the mixture was evaporated, and
the residue was dried under reduced pressure. The
product was ~0.6 g of 2-cyanoethylphosphinic acid 10
4. Boyd, E.A., Corless, M., James, K., and Regan, A.C.,
Tetrahedron Lett., 1990, vol. 31, no. 20, p. 2933. doi:
10.1016/0040-4039(90)80188-R
5. Ragulin, V.V., Kurdyumova, N.R., and Tsvetkov, E.N.,
Phosphorus, Sulfur Silicon Relat. Elem., 1994, vol. 88,
p. 271. doi 10.1080/10426509408036931
6. Kurdyumova, N.R., Ragulin, V.V., and Tsvetkov, E.N.,
Mendeleev Commun., 1997, no. 2, p. 69. doi 10.1070/
MC1997v007n02ABEH000721
1
as a low-melting semi-crystalline material. H NMR
spectrum (CD3CN), δ, ppm: 1.95–2.20 m (2H, CH2P),
1
2.60–2.80 m (2H, CH2C), 7.10 d (1H, PH, JPH
=
7. Kurdyumova, N.R., Rozhko, L.F., Ragulin, V.V., and
Tsvetkov, E.N., Russ. J. Gen. Chem., 1997, vol. 67,
no. 12, p. 1852.
549.8 Hz). 31C NMR spectrum (CD3CN), δC, ppm:
1
10.6 s (CCN), 26.0 d (PC, JPC = 92.5 Hz), 120.4 d
3
(CN, JPC = 15.5 Hz). 31P NMR spectrum: in CD3CN:
8. Rozhko, L.F. and Ragulin, V.V., Amino Acids, 2005,
δP 29.0 ppm; in D2O: δP 31.0 ppm; in CD3OD: δP
36.5 ppm. Found, %: P 14.40, 14.33. C3H6NO2P.
Calculated, %: P 14.88.
vol. 29, p. 139. doi 10.1007/s00726-005-0194-9
9. Dmitriev, M.E. and Ragulin, V.V., Tetrahedron Lett.,
2010, vol. 51, no. 19, p. 2613. doi 10.1016/
j.tetlet.2010.03.020
b. A mixture of 0.8 g (0.01 mol) of ammonium
hypophosphite, 7.5 mL (0.03 mol) of hexamethyldi-
silazane, and 1.1–2.2 g (0.02–0.04 mol) of acrylonitrile
was refluxed for 3 h with stirring. The mixture was
then treated as described above in a.
10. Dmitriev, M.E. and Ragulin, V.V., Tetrahedron Lett.,
2012, vol. 53, no. 13, p. 1634. doi 10.1016/
j.tetlet.2012.01.094
11. Pudovik, A.N., Romanov, G.V., and Nazmutdinov, R.Ya.,
Zh. Obshch. Khim., 1979, vol. 49, no. 9, p. 1942.
All operations were carried out under argon. The
1H, 31P, and 13C NMR spectra were recorded on a
Bruker DPX-200 spectrometer with Fourier transform.
The melting points were determined on a Boetius
PHMK melting point apparatus or in open capillaries.
12. Ragulin, V.V., Russ. J. Gen. Chem., 2008, vol. 78, no. 9,
p. 1655. doi 10.1134/S107036320809003X
13. Kurdyumova, N.R., Rozhko, L.F., Ragulin, V.V., and
Tsvetkov, E.N., Russ. J. Gen. Chem., 1997, vol. 67,
no. 12, p. 1857.
ACKNOWLEDGMENTS
14. Cates, L.A. and Li, V.-S., Phosphorus Sulfur Relat.
Elem., 1984, vol. 21, p. 187. doi 10.1080/
03086648408077655
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 15-03-06062).
15. Pudovik, A.N., Romanov, G.V., and Nazmutdinov, R.Ya.,
Zh. Obshch. Khim., 1977, vol. 47, no. 3, p. 555.
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 12 2016