Synthesis of mono-and diphosphorus-substituted proline derivatives containing P–C–N fragments

Article abstract of DOI:10.1007/s11172-016-1519-4

Convenient methods for the synthesis of new types of mono-and diphosphorus-substituted proline derivatives containing P–C–N fragments were developed based on special pre-prepared proline-containing synthons. The corresponding organophosphorus acids including a proline fragment were also synthesized.

Full text of DOI:10.1007/s11172-016-1519-4

Russian Chemical Bulletin, International Edition, Vol. 65, No. 7, pp. 1846—1854, July, 2016
1846
Synthesis of monoꢀ and diphosphorusꢀsubstituted proline derivatives
containing P—C—N fragments*
A. A. Prishchenko, M. V. Livantsov, O. P. Novikova, L. I. Livantsova, and V. S. Petrosyan
M. V. Lomonosov Moscow State University, Department of Chemistry,
Build. 3, 1 Leninskie Gory, 119991 Moscow, Russian Federation.
Eꢀmail: aprishchenko@yandex.ru
Convenient methods for the synthesis of new types of monoꢀ and diphosphorusꢀsubstituted
proline derivatives containing P—C—N fragments were developed based on special preꢀpreꢀ
pared prolineꢀcontaining synthons. The corresponding organophosphorus acids including a
proline fragment were also synthesized.
Key words: proline, trimethylsilyl esters, PHꢀacids, functionalized phosphonic, phosphinic,
and diphosphonic acids, organophosphorus compounds.
Functionalized phosphorusꢀcontaining aminocarboxꢀ
described earlier for other amino acids.11 The reaction of
proline 1 with diazomethane in dichloromethane proceeds
only in the presence of methanol and leads to the formaꢀ
tion of a mixture of esters 2 and 3 (Scheme 1), the prodꢀ
ucts of Oꢀ and N,Oꢀmethylation of proline with diazoꢀ
methane, in the ratio of 3 : 1 (cf. Ref. 12).
ylic acids, their derivatives, as well as peptides with organoꢀ
phosphorus fragments are widely used as polydentate
ligands and biologically active compounds possessing varꢀ
ious kinds of activity, that stimulates development of studꢀ
ies on the synthesis of these compounds and their reactivꢀ
ity.1—5 These compounds bearing hydrolytically stable
fragments are widely used as efficient herbicides6 and are
parts of the composition of a new type of antibiotics.7
Special attention is paid to phosphorusꢀcontaining pepꢀ
tides containing proline fragments, the heterocyclic proꢀ
teinogenic amino acid, which possess antiviral activity,
including that against HIV.8
Scheme 1
Recently, we have synthesized a number of aminoꢀ
methylphosphonates including glycine, βꢀalanine, and
γꢀaminobutyric acid fragments.9 In the present work, we
suggest convenient methods for the synthesis of the new
types of various monoꢀ and diphosphorusꢀsubstituted proꢀ
line derivatives containing the P—C—N fragments. Note
that among compounds with similar structure, only severꢀ
al insoluble in water compound with phosphine and phosꢀ
phonium groups have been described earlier.10
In the first stage, we developed preparative methods
for the synthesis of some functionalized derivatives of proꢀ
line 1, viz., prolineꢀcontaining synthons 2—9, which were
used as a basis for the preparation of the target phosphorusꢀ
substituted proline derivatives 10—29 (Schemes 1—18).
Thus, methyl prolinate 2 was obtained by esterification of
proline 1 with methanol in the presence of chlorotrimethylꢀ
silane according to a modified by us method, which was
Reagents and conditions: i. 1) MeOH, Me3SiCl, 50 °C; 2) K2CO3;
ii. MeOH, CH2Cl2, CH2N2, Et2O, 0 °C.
The aminomethyl esters 4 and aminal 5, containing
proline fragments in the molecule, are readily formed in
the reaction of ester 2 with chloromethylalkyl ethers and
paraformaldehyde, respectively. For the synthesis of amiꢀ
nal 5, we used also a mixture of esters 2 and 3, with the
ester 3, which does not react with paraformaldehyde, beꢀ
ing recovered in the pure form (Scheme 2).
* Based on the materials of the International Congress on the
Heterocyclic Chemistry "KOSTꢀ2015" (October 18—23, 2015,
Moscow, Russia).
Both proline 1 and its methyl ester 2 are smoothly
silylated with diethyl(trimethylsilyl)amine upon heating
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1846—1854, July, 2016.
1066ꢀ5285/16/6507ꢀ1846 © 2016 Springer Science+Business Media, Inc.

Derivatives of proline with P—C—N fragment
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
1847
Scheme 2
Scheme 4
Reagents and conditions: 1) HCOOH, 100 °C; 2) (Me3Si)2NH,
Me3SiCl, 130 °C.
derivatives 2—9. Thus, diethyl phosphite rapidly reacted
with a mixture of paraformaldehyde and proline upon heatꢀ
ing to 120 °C with the formation of Nꢀprolinomethylphosꢀ
phonate 10 after treatment of the reaction mixture with
bis(trimethylsilyl)amine (Scheme 5).
4: R = Me (a), Et (b)
Reagents and conditions: i. ClCH2OR, Et3N, Et2O, 0—20 °C;
ii. 1) CH2O, 60—80 °C; 2) K2CO3, Et2O, 40 °C.
to 130 °C with the distillation off of diethylamine from the
reaction mixture (cf. Ref. 13). However, among obtained
organosilicon proline derivatives, only Nꢀtrimethylsilylꢀ
substituted ester 7 is stable, while N,Oꢀbis(trimethylꢀ
silyl)proline 6 dimerizes at 20 °C with elimination of hexaꢀ
methyldisiloxane and formation of tricyclic dipeptide 8 in
high yield (Scheme 3), which is a valuable synthon for the
preparation of different tricyclic piperazines.14
Scheme 5
Reagents and conditions: 1) CH2O, 1, 100 °C; 2) (Me3Si)2NH,
Me3SiCl, 130 °C.
Scheme 3
The high yield of phosphonate 11 in a similar reaction
was reached when a mixture of bis(trimethylsilyl)phosphite
and excessive tris(trimethylsilyl)phosphite were used, since
the latter efficiently binds water forming in the course of
the process (Scheme 6).
Scheme 6
Reagents and conditions: 1) CH2O, 1, (Me3SiO)3P, 100 °C;
2) (Me3Si)2NH, Me3SiCl, 130 °C.
Reagents and conditions: i. Et2NSiMe3, (NH4)2SO4, 120 °C;
ii. 20 °C.
It unexpectedly turned out that under similar condiꢀ
tions in the course of the reaction of Oꢀethyl (methyl)ꢀ
phosphonite with paraformaldehyde and proline, a mixꢀ
ture of phosphinates 12 and 13 was obtained, with the
content of the target phosphinate 12, according to the
31P NMR data, only 7% in the mixture. This is related to
the hydrolysis of the starting phosphonite with water
formed in the course of the reaction under the drastic
conditions used (Scheme 7).
The earlier undescribed formamide 9 was obtained by
formylation of proline with subsequent treatment of the
reaction mixture with bis(trimethylsilyl)amine and chloroꢀ
trimethylsilane upon heating to 130 °C (Scheme 4).
For the synthesis of new phosphorusꢀcontaining proꢀ
line derivatives containing P—C—N fragments, we studꢀ
ied twoꢀ and threeꢀcomponent reactions of aminomethylꢀ
ation of different PHꢀacid esters, using proline 1 and its

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Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
Prishchenko et al.
Scheme 7
Reagents and conditions: i. CH2O, 1, 100 °C; ii. (Me3Si)2NH, 130 °C.
Scheme 10
Phosphinate 13 was isolated in the pure form only
after sequential treatment of the mixture of phosphinates
12 and 13 with concentrated hydrochloric acid and
bis(trimethylsilyl)amine (Scheme 8).
Scheme 8
Reaction conditions: 120 °C.
Scheme 11
Reagents and conditions: i. HCl, H2O; ii. (Me3Si)2NH, 130 °C.
Methyl prolinate hydrochloride in the presence of poꢀ
tassium carbonate was successfully used for the synthesis
of phosphonate 14 (Scheme 9).
Reaction conditions: 120 °C.
Scheme 9
The reaction of pivaloylphosphonite containing a labile
phosphorus—carbon bond16 with ester 4b in ethanol in the
presence of boron trifluoride diethyl etherate as a catalyst
upon heating to 70 °C gave prolineꢀcontaining phosꢀ
phonite 17 (Scheme 12), with diethoxyphosphine forming
as the intermediate product.
Reagents and conditions: 2•HCl, CH2O, K2CO3, 90 °C.
Scheme 12
Aminomethylation reactions of PHꢀacid esters proꢀ
ceeded the most smoothly when Nꢀalkoxymethyl derivaꢀ
tives of methyl prolinate 4a,b were used. Thus, the reacꢀ
tion of Oꢀethyl methylphosphonite with Nꢀ(ethoxymethꢀ
yl)proline methyl ester 4b led to phosphinate 15 in high
yield (Scheme 10).
The aminomethylation of hydrospirophosphorane with
Nꢀ(methoxymethyl)proline methyl ester 4a in the presꢀ
ence of zinc chloride as a catalyst gave Nꢀprolinomethylꢀ
spirophosphorane 16 (Scheme 11, cf. Ref. 15).

Derivatives of proline with P—C—N fragment
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
1849
An excess of aminal 5, similarly to aminals with comꢀ
mon structure,17 reacted with bis(trimethylsiloxy)phosꢀ
phine in the presence of zinc chloride upon heating to
120 °C following the double aminomethylation pathway
with the formation of phosphinate 18 containing two proꢀ
line fragments in the molecule (Scheme 13).
dichloromethane in the presence of trimethylsilyl triflate
as a catalyst with the formation of bisphosphonate 21 in
high yield. Undoubtedly, the catalytic effect of trimethylꢀ
silyl triflate is due to the intermediate formation of highly
reactive immonium salts in the course of the reaction19
(Scheme 16).
Scheme 13
Scheme 16
Reaction conditions: 120 °C.
More active ester 4b smoothly reacted with an excess
of bis(trimethylsiloxy)phosphine in dichloromethane alꢀ
ready at 10—20 °C with the formation of phosphonite 19
in high yield (Scheme 14, cf. Ref. 16).
Scheme 14
Note that the structural analog of aminomethyleneꢀ
diphosphonate 21, hydroxymethylenediphosphonate 22,
containing a pyrrolidine fragment is formed in high yield
in the sequential reaction of formamide 9 with thionyl
chloride, excessive diethyl (trimethylsilyl)phosphite, and
ethanol (Scheme 17).
Phosphonite 19 bearing a PH fragment is of great inꢀ
terest as a key compound in the synthesis of organophosꢀ
phorus proline derivatives. Thus, phosphonite 19 readily
adds to trimethylsilyl acrylate in the presence of triethylꢀ
amine or pyridine upon heating of the mixture to 100 °C
with the formation of the corresponding Oꢀtrimethylsilyl
phosphinate 20 in high yield (Scheme 15, cf. Ref. 18).
Scheme 17
Scheme 15
Reagents and conditions: i. SOCl2, CH2Cl2, 5—40 °C;
ii. (EtO)2POSiMe3 (2 equiv.), CH2Cl2, 5 °C; iii. EtOH, 40 °C.
The trimethylsilylꢀcontaining phosphonates 10 and 11,
phosphinates 13 and 18, and diphosphonate 21 under mild
conditions reacted with an excess of methanol with the
formation of phosphonic acids (23 and 24), phosphinꢀ
ic acids (25, 26, and 28), and diphosphonic acid (29) in
high yield. To obtain acid 28, it is necessary to hydroꢀ
The prolineꢀcontaining formamide 9 exothermically
reacted with an excess of tris(trimethylsilyl)phosphite in

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Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
Prishchenko et al.
Scheme 18
X = (EtO)2P(O) (23), (HO)2P(O) (24), Me(HO)P(O) (25)
Reagents and conditions: i. MeOH, 10—50 °C; ii. 1) HCl, H2O; 2) (Me3Si)2NH.
lyze phosphinic acid 26 with hydrochloric acid with the
Experimental
intermediate isolation of trimethylsilyl phosphinate 27
(Scheme 18).
1
H, 13C{1H}, and 31P{1H} NMR spectra were recorded on
a Bruker Avance 400 spectrometer (400, 100, and 162 Hz, respecꢀ
tively); the references were Me4Si (1H, 13C{1H}) and 85% H3PO4
in D2O (31P{1H}). All the reaction were carried out under dry
argon in anhydrous solvents. LꢀProline and Lꢀproline methyl
ester hydrochloride used in the work were purchased from Aldrich.
The starting trimethylsilyl ethers of tervalent phosphorus acids
were obtained according to the described procedures.20,21
Methyl prolinate (2). Chlorotrimethylsilane (95 g, 0.88 mol)
was added to a solution of proline (25 g, 0.22 mol) in methanol
(150 mL) with stirring, then the mixture was refluxed until evoꢀ
lution of hydrogen chloride stopped. The solvent was evaporatꢀ
ed, water (10 mL) and diethyl ether (100 mL) were added to the
residue, followed by a dropwise addition of a solution of sodium
hydroxide (8.6 g) in water (26 mL). Then, potassium carbonate
(30 g) was added to the mixture with stirring, the aqueous layer
was thrice extracted with diethyl ether (100 mL). The organic
layers were dried with potassium carbonate, the solvent was evapꢀ
orated, the residue was distilled to obtain ester 2, the yield was 19 g
The structures of obtained proline derivatives 2—29
1
were confirmed by the H, 13C{1H}, and 31P{1H} NMR
spectral data. Note that compounds containing formamide
fragments, as well as asymmetric phosphorus and carbon
atoms, were obtained as mixtures of two stereoisomers,
the ratios of which were determined based on the 31P{1H}
NMR spectra. Two diastereotopic phosphoryl groups of
compound 22 in the 31P{1H} NMR spectrum were found
as a characteristic ABꢀquartet. In the 1H NMR spectra of
compounds 2—29, the multiplets for the protons of the
methylene groups of the pyrrolidine ring were found in
the indicative regions, δ: 2.7—3.2 (C(3)H2), 1.5—1.6
(C(4)H2), 1.7—2.2 (C(5)H2), and are not reported in
the Experimental section. The carbon atoms numbering
1
scheme used for the description of the H and 13C{1H}
NMR spectra is shown for the model compounds 20 and
29 (see Schemes 15 and 18).
(68%), b.p. 65 °C (6 Torr). Found (%): C, 55.57; H, 8.68.
C6H11NO2. Calculated ( %): C, 55.79; H, 8.59. 1H NMR
(CDCl3), δ: 2.34—2.40 (m, 1 H, NH); 3.65 (dd, 1 H, C(2)H,
3JH,H = 5.7 Hz, 3JH,H = 8.6 Hz); 3.48 (s, 3 H, CH3O). 13C{1H}
NMR (CDCl3), δ: 59.93 (s, C(2)); 47.14 (s, C(3)); 25.80 (s, C(4));
30.33 (s, C(5)); 51.41 (s, CH3O); 175.80 (s, C(6)).
Reaction of proline with diazomethane. Nꢀmethylproline
methyl ester (3) and bis[Nꢀ(Oꢀmethylprolino)]methane (5). Methꢀ
anol (15 mL) was added to a suspension of proline (5.7 g,
0.05 mol) in dichloromethane (50 mL), followed by a dropwise
addition of a solution of diazomethane (4.2 g, 0.1 mol) in diethyl
ether (150 mL) with stirring and cooling to 0 °C. The mixture
was stirred until evolution of nitrogen stopped and the solution
In conclusion, we suggested convenient methods for
the synthesis of new types of monoꢀ and diphosphorusꢀsubꢀ
stituted proline derivatives of various structure containꢀ
ing P—C—N fragments with triꢀ, tetraꢀ and pentaꢀcoorꢀ
dinated phosphorus atoms. These compounds are of inꢀ
terest as promising polydentate ligands and biologically
active compounds with different properties, as well as
are convenient synthons for the preparation of new types
of monoꢀ and diphosphorusꢀcontaining peptides with
proline fragments in the central or the terminal part of
the peptide.

Derivatives of proline with P—C—N fragment
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
1851
became colorless. The solvent was evaporated, the residue was
NMR (CDCl3), δ: –0.56 (s, 2 Me3Si); 62.08 (s, C(2)); 47.12
(s, C(3)); 26.16 (s, C(4)); 31.84 (s, C(5)); 176.85 (s, C(6)).
NꢀTrimethylsilylproline methyl ester (7) was obtained similꢀ
arly, the yield was 81%, b.p. 65 °C (2 Torr). Found (%): C, 53.38;
H, 9.41. C9H19NO2Si. Calculated (%): C, 53.69; H, 9.51.
1H NMR (CDCl3), δ: 0.12 (s, 9 H, Me3Si); 3.91 (dd, 1 H, C(2)H,
3JH,H = 4.4 Hz, 3JH,H = 6.4 Hz); 3.47 (s, CH3O). 13C{1H} NMR
(CDCl3), δ: –0.78 (s, Me3Si); 60.74 (s, C(2)); 47.11 (s, C(3));
26.11 (s, C(4)); 31.70 (s, C(5)); 176.16 (s, C(6)); 51.02 (s, CH3O).
Octahydroꢀ5H,10Hꢀdipyrrolo[1,2ꢀa:1´,2´ꢀd]pyrazineꢀ5,10ꢀ
dione (8). Ester 6 (5.2 g, 0.02 mol) was allowed to stand at 20 °C
for a week until white crystals stopped to form. The crystals were
collected by filtration, washed with pentane, and were allowed
to stand in vacuo at 1 Torr to obtain compound 8, the yield was
1.85 g (96%), m.p. 143—145 °C. Found (%): C, 61.59; H, 7.03.
distilled to obtain a mixture of esters 2 and 3 (5 g), the ratio of
1
which according to the H NMR data was 3 : 1; b.p. 60—62 °C
(7 Torr). Paraformaldehyde (0.7 g, 0.023 mol) was added to this
mixture, which was heated to 70 °C. After addition of diethyl
ether (50 mL) and potassium carbonate (10 g), the mixture was
refluxed for 1 h. A precipitate was filtered off, the ether was
evaporated, the residue was distilled to obtain ester 3, the yield
was 1.4 g (20%), b.p. 64 °C (6 Torr). Found (%): C, 58.49; H, 9.07.
C7H13NO2. Calculated (%): C, 58.72; H, 9.15. 1H NMR
(CDCl3), δ: 2.35 (s, 3 H, MeN); 3.53 (dd, 1 H, C(2)H, 3JH,H
=
= 6.0 Hz, 3JH,H = 8.0 Hz); 3.49 (s, 3 H, CH3O). 13C{1H} NMR
(CDCl3), δ: 40.52 (s, MeN); 66.99 (s, C(2)); 56.10 (s, C(3));
23.59 (s, C(4)); 29.40 (s, C(5)); 50.98 (s, CH3O); 173.40 (s, C(6)).
In the highꢀboiling point fraction, aminal 5 was also obtainꢀ
ed, the yield was 3.6 g (74%), b.p. 120 °C (1 Torr) (see below).
Nꢀ(Ethoxymethyl)proline methyl ester (4b). Chloromethyl
ethyl ether (4.0 g, 0.042 mol) in diethyl ether (10 mL) was added
to a mixture of ester 2 (5 g, 0.039 mol) and triethylamine (4.7 g,
0.046 mol) in diethyl ether (50 mL) with stirring and cooling to
5 °C. The mixture was stirred at 20 °C for 2 h and was allowed to
stand for 12 h. A precipitate was filtered off, the solvent was
evaporated, the residue was distilled to obtain ester 4b, the yield
was 4.3 g (60%), b.p. 55 °C (1 Torr). Found (%): C, 57.89; H, 9.08.
C9H17NO3. Calculated (%): C, 57.73; H, 9.15. 1H NMR (CDCl3),
δ: 4.22 and 4.34 (ABꢀquartet, 2 H, C(1)H2, 2JH,H = 9.3 Hz); 3.74
C
10H14N2O2Si2. Calculated (%): C, 61.84; H, 7.27. 1H NMR
(CDCl3), δ: 3.65 (t, 2 H, 2 C(2)H, JH,H = 8.0 Hz). 13C{1H}
NMR (CDCl3), δ: 60.28 (s, C(2)); 45.05 (s, C(3)); 23.22 (s, C(4));
28.83 (s, C(5)); 165.95 (s, C(6)).
3
NꢀFormylproline trimethylsilyl ester (9). A mixture of proline
(20 g, 0.172 mol) and formic acid (50 g) was heated in boiling
water bath for 5 h with stirring, then the solvent was evaporated
in vacuo (7 Torr). Bis(trimethylsilyl)amine (56 g) and chlorotriꢀ
methylsilane (8 g) were added to the residue and the mixture was
refluxed until complete sublimation of ammonium chloride. The
residue was distilled to obtain ester 9, the yield was 27 g (72%),
b.p. 133 °C (2 Torr). Found (%): C, 49.97; H, 7.82. C9H17NO3Si.
Calculated (%): C, 50.20; H, 7.96.
(dd, 1 H, C(2)H, 3JH,H = 5.4 Hz, 3JH,H = 8.3 Hz); 3.47 (s, 3 H,
3
CH3O); 3.3—3.4 (m, 2 H, CH2O); 1.12 (t, 3 H, CH3, JH,H
=
= 7.4 Hz). 13C{1H} NMR (CDCl3), δ: 83.49 (s, C(1)); 63.23
(s, C(2)); 50.39 (s, C(3)); 24.69 (s, C(4)); 30.10 (s, C(5)); 174.18
(s, C(6)); 51.07 (s, CH3O); 61.23 (s, CH2O); 15.37 (s, CH3).
Nꢀ(Methoxymethyl)proline methyl ester (4a) was obtained
similarly. The yield was 47%, b.p. 65 °C (2 Torr). Found (%):
C, 55.29; H, 8.66. C8H15NO3. Calculated (%): C, 55.48; H, 8.73.
1H NMR (CDCl3), δ: 4.12 and 4.23 (ABꢀquartet, 2 H, C(1)H2,
The first isomer, the content was 60%. 1H NMR (CDCl3), δ:
7.91 (s, C(1)H); 4.08 (dd, C(2)H, 3JH,H = 8.4 Hz, 3JH,H = 3.6 Hz);
3.25—3.35 (m, C(3)H2); 1.5—2.0 (m, C(4)H2, C(5)H2); –0.06 (s,
Me3Si). 13C{1H} NMR (CDCl3), δ: 160.18 (s, C(1)); 57.17 (s, C(2));
45.90 (s, C(3)); 23.63 (s, C(4)); 29.03 (s, C(5)); 171.43 (s, C(6)).
The second isomer, the content was 40% 1H NMR (CDCl3),
δ: 7.86 (s, C(1)H); 3.99 (dd, C(2)H, 3JH,H = 8.4 Hz, 3JH,H = 4.0 Hz);
3.08—3.19 (m, C(3)H2); 1.5—2.0 (m, C(4)H2, C(5)H2); –0.06
(s, Me3Si). 13C{1H} NMR (CDCl3), δ: 161.21 (s, C(1)); 59.27 (s, C(2));
43.43 (s, C(3)); 22.43 (s, C(4)); 29.31 (s, C(5)); 171.82 (s, C(6)).
O,OꢀDiethyl [Nꢀ(Oꢀtrimethylsilylprolino)methyl]phosphonate
(10). A mixture of diethyl phosphite (5.5 g, 0.04 mol), proline
(3.5 g, 0.03 mol), and paraformaldehyde (1 g, 0.033 mol) was
heated to 120 °C and allowed to stand at these temperature until
complete dissolution of paraformaldehyde. Then, bis(trimethylꢀ
silyl)amine (20 g, 0.124 mol) and chlorotrimethylsilane (1 mL)
were added and the mixture was refluxed until ammonia stopped
to evolve. The mixture was distilled to obtain phosphonate 10,
the yield was 8.6 g (85%), b.p. 155 °C (3 Torr). Found (%): C,
46.03; H, 8.25. C13H28NO5PSi. Calculated (%): C, 46.27; H, 8.26.
1H NMR (CDCl3), δ: 0.15 (s, Me3Si); 2.93 and 3.24 (m, ABX,
2 H, C(1)H2, 2JH,H = 14.8 Hz, 2JP,H = 8.0 Hz, 2JP,H = 14.8 Hz);
3.28 (dd, 1 H, C(2)H, 3JH,H = 8.8 Hz, 3JH,H = 4.0 Hz); 3.6—4.0
(m, 4 H, 2 CH2OP); 0.9—1.0 (m, 6 H, 2 CH3). 13C{1H} NMR
2JH,H = 9.2 Hz); 3.70 (dd, 1 H, C(2)H, 3JH,H = 5.6 Hz, 3JH,H
=
= 8.1 Hz); 3.49 (s, 3 H, CH3O); 3.14 (s, 3 H, CH3OC(1)).
13C{1H} NMR (CDCl3), δ: 85.20 (s, C(1)); 61.18 (s, C(2)); 50.56
(s, C(3)); 24.74 (s, C(4)); 30.12 (s, C(5)); 174.17 (s, C(6)); 51.15
and 55.19 (both s, 2 CH3O).
Bis[Nꢀ(Oꢀmethylprolino)]methane (5). A mixture of ester 2
(10 g, 0.078 mol) and paraformaldehyde (1.2 g, 0.039 mol) was
heated at 60—80 °C until complete dissolution of paraformaldeꢀ
hyde, then diethyl ether (100 mL) and potassium carbonate (15 g)
were added. The mixture was refluxed for 1.5 h. A precipitate
was filtered off, the solvent was evaporated, the residue was
distilled to obtain aminal 5, the yield was 19 g (74%), b.p. 120 °C
(1 Torr). Found (%): C, 57.39; H, 8.28. C13H22N2O4. Calculatꢀ
ed (%): C, 57.76; H, 8.20. 1H NMR (CDCl3), δ: 3.59 (s, 2 H,
C(1)H2); 3.39 (t, 1 H, C(1)H2, 3JH,H = 6.7 Hz); 3.49 (s, 3 H,
CH3O). 13C{1H} NMR (CDCl3), δ: 72.79 (s, C(1)); 63.63
(s, C(2)); 50.92 (s, C(3)); 23.67 (s, C(4)); 29.43 (s, C(5)); 51.76
(s, CH3O); 174.17 (s, C(6)).
N,OꢀBis(trimethylsilyl)proline (6). A mixture of proline
(10 g, 0.086 mol), diethyl(trimethylsilyl)amine (332 g, 0.22 mol),
and ammonium sulfate (0.1 g) was heated at 120 °C with distillaꢀ
tion off of diethylamine. Then the mixture was distilled to obtain
compound 6, the yield was 20 g (89%), b.p. 68 °C (1 Torr).
Found (%): C, 51.03; H, 9.81. C11H25NO2Si2. Calculated (%):
C, 50.92; H, 9.72. 1H NMR (CDCl3), δ: 0.12 (s, 18 H, 2 Me3Si),
3.86 (dd, 1 H, C(2)H, 3JH,H = 3.6 Hz, 3JH,H = 8.0 Hz). 13C{1H}
1
(CDCl3), δ: 49.42 (d, C(1), JP,C = 161.2 Hz); 66.79 (d, C(2),
2
3JP,C = 13.3 Hz); 173.54 (s, C(6)); 62.05 (d, 2 CH2OP, JP,C
=
3
= 7.0 Hz); 16.16 (d, 2 Me, JP,C = 6.0 Hz); –0.14 (s, Me3Si).
31P{1H} NMR (CDCl3), δ: 23.62 (s).
O,OꢀBis(trimethylsilyl) [Nꢀ(Oꢀtrimethylsilylprolino)methyl]ꢀ
phosphonate (11) was obtained similarly to phosphonate 10 from
bis(trimethylsilyl)phosphite (7.9 g, 0.035 mol), tris(trimethylꢀ
silyl)phosphite (10.4 g, 0.035 mol), proline (4.0 g, 0.035 mol),
and paraformaldehyde (1.2 g, 0.04 mol). The yield of phosphoꢀ

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Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
Prishchenko et al.
nate 11 was 10.9 g (73%), b.p. 125 °C (1 Torr). Found (%):
C, 42.17; H, 8.39. C15H36NO5PSi3. Calculated (%): C, 42.32;
H, 8.53. 1H NMR (CDCl3), δ: 2.90 and 3.16 (both m, ABX, 2 H,
C(1)H2, 2JH,H = 14.6 Hz, 2JP,H = 8.0 Hz, 2JP,H = 16.0 Hz); 3.42
(dd, 1 H, C(2)H, 3JH,H = 8.8 Hz, 3JH,H = 5.2 Hz); 0.19 (s, 9 H,
Me3Si); 0.21 and 0.24 (both s, 18 H, 2 Me3SiOP). 13C{1H} NMR
9.1 g (83%), b.p. 127 °C (2 Torr). Found (%): C, 48.02; H, 7.95.
C10H20NO4P. Calculated (%): C, 48.19; H, 8.09.
The first isomer, the content was 65%. 1H NMR (CDCl3) δ:
2.71 and 3.01 (both m, ABX, 2 H, CH2, 2JH,H = 15.2 Hz, 2JP,H
=
= 8.0 Hz, 2JP,H = 12.4 Hz); 3.21 (dd, 1 H, CH, 3JH,H = 8.8 Hz,
3JH,H = 5.6 Hz); 1.33 (d, 3 H, CH3P, 2JP,H = 14.4 Hz); 3.36 (s, 3 H,
CH3O); 3.8—4.0 (m, 4 H, 2 CH2OP); 1.0—1.1 (m, 6 H, 2 CH3).
1
(CDCl3), δ: 51.28 (d, C(1), JP,C = 168.8 Hz); 66.68 (d, C(2),
3JP,C = 13.9 Hz); 54.13 (d, C(3), 3JP,C = 4.6 Hz); 23.35 (s, C(4));
29.27 (s, C(5)); 173.52 (s, C(6)); –0.15 (s, Me3Si); 1.07 (d,
Me3SiOP, 3JP,C = 4.7 Hz). 31P{1H} NMR (CDCl3), δ: 4.44 (s).
OꢀTrimethylsilyl methylꢀ[Nꢀ(Oꢀtrimethylsilylprolino)methyl]ꢀ
phosphinate (13) was obtained similarly to phosphonate 10 from
Oꢀethyl methylphosphonite (5.6 g, 0.052 mol), proline (4.0 g,
0.035 mol), and paraformaldehyde (1.2 g, 0.04 mol), which led
to a mixture of phosphinates 12 and 13 (10.5 g) in the ratio of
13C{1H} NMR (CDCl3), δ: 53.41 (d, C(1), JP,C = 114.5 Hz);
1
66.66 (d, C(2), 3JP,C = 13.5 Hz); 55.00 (d, C(3), 3JP,C = 8.1 Hz);
23.74 (s, C(4)); 29.11 (s, C(5)); 173.55 (s, C(6)); 12.95 (d, MeP,
1JP,C = 120.1 Hz); 51.21 (s, MeO); 59.8—60.0 (m, 2 CH2OP);
16.4—16.6 (m, 2 CH3). 31P{1H} NMR (CDCl3), δ: 50.16 (s).
The second isomer, the content was 35%. 1H NMR (CDCl3),
2
δ: 2.66 and 2.97 (both m, ABX, 2 H, C(1)H2, JH,H = 14.6 Hz,
2JP,H = 10.0 Hz, 2JP,H = 11.6 Hz); 3.14 (dd, 1 H, C(2)H, 3JH,H
=
7 : 93 according to the 31P{1H} NMR data (12: δ 48.17 and
= 8.4 Hz, 3JH,H = 6.0 Hz); 1.38 (d, 3 H, CH3P, 2JP,H = 14.0 Hz);
3.36 (s, 3 H, CH3O); 3.8—4.0 (m, 4 H, 2 CH2OP); 1.0—1.1 (m, 6 H,
2 CH3). 13C{1H} NMR (CDCl3), δ: 53.19 (d, C(1), 1JP,C = 111.7 Hz);
66.57 (d, C(2), 3JP,C = 12.3 Hz); 54.96 (d, C(3), 3JP,C = 11.7 Hz);
23.65 (s, C(4)); 29.05 (s, C(5)); 173.55 (s, C(6)); 12.73 (d, MeP,
1JP,C = 121.9 Hz); 51.21 (s, MeO); 59.8—60.0 (m, 2 CH2OP);
16.4—16.6 (m, 2 CH3). 31P{1H} NMR (CDCl3), δ: 48.94 (s).
[Nꢀ(OꢀMethylprolino)methyl]ꢀ1,4,6,9ꢀtetraoxaꢀ5ꢀphosphasꢀ
piro[4.4]nonane (16). A mixture of 1,4,6,9ꢀtetraoxaꢀ5ꢀphosꢀ
phaspiro[4.4]nonane (4.8 g, 0.032 mol), Nꢀ(methoxymethyl)ꢀ
proline methyl ester (5.2 g, 0.03 mol), and zinc chloride (0.1 g)
was heated at 100—120 °C until methanol was completely disꢀ
tilled off. Then, the residue was distilled to obtain spirophosꢀ
phorane 16, the yield was 6.5 g (74%), b.p. 168 °C (2 Torr).
Found (%): C, 44.91; H, 6.72. C11H20NO6P. Calculated (%):
C, 45.05; H, 6.87. 1H NMR (CDCl3), δ: 3.40 (m, ABX, 1 H, C(1)H2,
P
49.26; 13: δ 39.55 and 41.04). The mixture was added to conꢀ
P
centrated hydrochloric acid (50 mL) with stirring and refluxed
for 2 h, then, allowed to stand heated in a water bath in vacuo
(10 Torr). Bis(trimethylsilyl)amine (40 mL) was added to the
residue and the mixture was refluxed until ammonia stopped to
evolve, then distilled to obtained phosphinate 13, the yield was
9.6 g (78%), b.p. 117 °C (0.5 Torr). Found (%): C, 44.26; H, 8.49.
C
13H30NO4PSi2. Calculated (%): C, 44.42; H, 8.60.
The first isomer, the content was 60%. 1H NMR (CDCl3), δ: 2.66
and 3.03 (both m, ABX, 2 H, C(1)H2, 2JH,H = 14.0 Hz, 2JP,H
=
= 8.8 Hz, 2JP,H = 14.0 Hz); 3.25 (dd, 1 H, C(2)H, 3JH,H = 8.8 Hz,
3JH,H = 5.6 Hz); 1.40 (d, 3 H, CH3P, 2JP,H = 14.0 Hz). 13C{1H}
NMR (CDCl3), δ: 55.13 (d, C(1), 1JP,C = 117.2 Hz); 67.60 (d, C(2),
3JP,C = 14.3 Hz); 54.87 (d, C(3), 3JP,C = 3.7 Hz); 23.38 (s, C(4));
29.05 (s, C(5)); 173.52 (s, C(6)); –0.18 (d, Me3Si, 3JP,C = 2.9 Hz);
1.40 (s, Me3SiOP). 31P{1H} NMR (CDCl3), δ: 39.55 (s).
2
2JH,H = 15.8 Hz, JP,H = 4.5 Hz, the signals for the protons of
The second isomer, the content was 40%. 1H NMR (CDCl3),
the second part of ABX and the C(1)H proton overlap with
the signals of the spirophosphorane fragment), 3.6—4.0 (m,
2
δ: 2.60 and 2.99 (both m, ABX, 2 H, C(1)H2, JH,H = 14.0 Hz,
2JP,H = 11.2 Hz, 2JP,H = 14.0 Hz); 3.16 (dd, 1 H, C(2)H, 3JH,H
=
4 OCH2CH2OP). 13C{1H} NMR (CDCl3), δ: 54.05 (d, C(1), 1JP,C
=
= 8.4 Hz, 3JH,H = 6.0 Hz); 1.32 (d, 3 H, CH3P, 2JP,H = 14.0 Hz).
= 179.2 Hz); 65.13 (d, C(2), JP,C = 10.4 Hz); 54.40 (d, C(3),
3
1
4
13C{1H} NMR (CDCl3), δ: 55.03 (d, C(1), JP,C = 115.2 Hz);
3JP,C = 2.9 Hz); 174.31 (d, C(6), JP,C = 2.9 Hz); 59.0—61.0
67.45 (d, C(2), 3JP,C = 11.9 Hz); 54.85 (d, C(3), 3P,C = 2.0 Hz); 23.61
(m, 4 OCH2CH2OP). 31P{1H} NMR (CDCl3), δ: –9.37 (s).
Diethyl [Nꢀ(Oꢀmethylprolino)methyl]phosphonite (17). A mixꢀ
ture of O,Oꢀdiethyl pivaloylphosphonite (4.8 g, 0.023 mol), ester 4b
(5.3 g, 0.028 mol), ethanol (2 mL), and boron trifluoride diethyl
etherate (0.3 g) was allowed to stand at 70 °C and distilled to obtain
phosphonite 17, the yield was 4 g (66%), b.p. 103 °C (1 Torr).
Found (%): C, 50.32; H, 8.36. C11H22NO4P. Calculated (%):
C, 50.18; H, 8.42. 1H NMR (CDCl3), δ: 2.7—3.0 (m, ABX, 2 H,
C(1)H2); 3.4—3.6 (m, 1 H, C(1)H2); 3.47 (s, 3 H, CH3O);
3.7—3.9 (m, 4 H, 2 CH2OP); 1.0—1.1 (m, 6 H, 2 CH3). 13C{1H}
NMR (CDCl3), δ: 62.07 (d, C(1), 1JP,C = 9.9 Hz); 56.58 (d, C(2),
1JP,C = 9.9 Hz); 54.86 (d, C(3), 1JP,C = 5.0 Hz); 23.83 (s, C(4));
29.12 (s, C(5)); 173.10 (s, C(6)); 50.99 (s, CH3O); 62.0—63.5
(m, 2 CH2O); 17.2—17.5 (m, 2 CH3). 31P{1H} NMR (CDCl3),
δ: 170.43 (s).
(s, C(4)); 29.31 (s, C(5)); 173.63 (s, C(6)); –0.18 (d, Me3Si, 3JP,C
=
= 2.9 Hz); 1.40 (s, Me3SiOP). 31P{1H} NMR (CDCl3), δ: 41.03 (s).
O,OꢀDiethyl [Nꢀ(Oꢀmethylprolino)methyl]phosphonate (14).
A mixture of diethyl phosphite (8.3 g, 0.06 mol), proline methyl
ester hydrochloride (5 g, 0.033 mol), paraformaldehyde (1 g,
0.033 mol), and potassium carbonate (5.5 g, 0.04 mol) was heated
in a water bath until carbon dioxide stopped to evolve, then, diꢀ
ethyl ether (50 mL) was added and the reaction mixture was refluxed
for 1 h and filtered. The solvent was evaporated, the residue was disꢀ
tilled to obtain phosphonate 14, the yield was 5.6 g (67%), b.p.
128 °C (2 Torr). Found (%): C, 47.16; H, 8.06. C11H22NO5P.
Calculated (%): C, 47.31; H, 7.94. 1H NMR (CDCl3), δ: 2.89
and 3.18 (both m, ABX, 2 H, C(1)H2, 2JH,H = 15.0 Hz, 2JP,H = 8.0 Hz,
2JP,H = 14.8 Hz); 3.26 (dd, 1 H, C(2)H, 3JH,H = 4.0 Hz, 3JH,H
=
= 8.0 Hz); 3.34 (s, 3 H, CH3O); 3.8—4.0 (m, 4 H, 2 CH2OP);
OꢀTrimethylsilyl bis[Nꢀ(Oꢀmethylprolino)methyl]phosphinate
(18). A mixture of bis(trimethylsiloxy)phosphine (5.7 g, 0.027 mol),
aminal 5 (18.4 g, 0.069 mol), and zinc chloride (0.2 g) was alꢀ
lowed to stand at 120 °C for 2 h and then distilled to obtain
phosphinate 18, the yield was 10.2 g (93%), b.p. 183 °C (0.5 Torr).
Found (%): C, 48.23; H, 7.80. C17H33N2O6PSi. Calculated (%):
C, 48.55; H, 7.91. 1H NMR (CDCl3), δ: 2.6—3.3 (m, ABX, 2 H,
C(1)H2); 3.4—3.6 (m, 1 H, C(1)H2); 3.48 (s, 6 H, 2 CH3O); 0.29
(s, 9 H, Me3Si). 13C{1H} NMR (CDCl3), δ: 52.25 (d, C(1),
1JP,C = 111.8 Hz); 66.09 (d, C(2), 1JP,C = 10.9 Hz); 45.06 (s, C(3));
0.9—1.0 (m, 6 H, 2 CH3). 13C{1H} NMR (CDCl3), δ: 49.41
1
3
(d, C(1), JP,C = 161.0 Hz); 66.90 (d, C(2), JP,C = 13.5 Hz);
173.43 (s, C(6)); 51.14 (s, CH3O); 61.5—62.0 (m, 2 CH2OP);
16.4—16.6 (m, 2 CH3). 31P{1H} NMR (CDCl3), δ: 23.59 (s).
OꢀEthyl methyl[Nꢀ(Oꢀmethylprolino)methyl]phosphinate (15).
A mixture of Oꢀethyl methylphosphonite (5.2 g, 0.048 mol),
Nꢀ(ethoxymethyl)proline methyl ester (8.2 g, 0.044 mol) was
heated at 100—120 °C until ethanol was completely distilled off.
The residue was distilled to obtain phosphinate 15, the yield was

Derivatives of proline with P—C—N fragment
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
1853
1
23.72 (s, C(4)); 29.29 (s, C(5)); 173.63 (s, C(6)); 51.09 (s, CH3O);
1.34 (s, Me3Si). 31P{1H} NMR (CDCl3), δ: 38.58 (s).
4 Me3Si). 13C{1H} NMR (CDCl3), δ: 58.41 (t, C(1), JP,C
=
= 155.7 Hz); 63.8—64.5 (m, C(2)); 48.9—49.6 (m, C(3)); 22.97
(s, C(4)); 27.98 (s, C(5)); 171.82 (s, C(6)); 0.43 (s, Me3Si).
31P{1H} NMR (CDCl3, δ: –0.42 (br.s).
OꢀTrimethylsilyl [Nꢀ(Oꢀmethylprolino)methyl]phosphonite
(19). NꢀEthoxymethylproline methyl ester (11.2 g, 0.06 mol)
was added dropwise to a solution of bis(trimethylsiloxy)phosphine
(16.1 g, 0.077 mol) in dichloromethane (50 mL) with stirring
and cooling with cold water (10 °C). Dichloromethane was evapꢀ
orated using a water bath, the residue was distilled to obtain
phosphonite 19, the yield was 13.9 g (83%), b.p. 142 °C (2 Torr).
Found (%): C, 42.12; H, 7.86. C10H22NO4PSi. Calculated (%):
C, 42.30; H, 7.94. 1H NMR (CDCl3), δ: 2.71 and 3.01 (both m,
The second isomer, the content was 40%. 1H NMR (CDCl3),
2
δ: 3.42 (br.t, C(1)H, JP,H = 26.2 Hz); 3.6—3.8 (m, C(2)H);
2.6—2.8 (m, C(3)H2); 1.3—1.7 (m, C(4)H2, C(5)H2); –0.17
(s, 36 H, 4 Me3Si). 13C{1H} NMR (CDCl3), δ: 58.16 (t, C(1),
1JP,C = 156.5 Hz); 63.8—64.5 (m, C(2)); 48.9—49.6 (m, C(3));
22.97 (s, C(4)); 27.98 (s, C(5)); 171.54 (s, C(6)); 0.43 (s, Me3Si).
31P{1H} NMR (CDCl3), δ: 3.16 (br.s).
2
2
2
ABX, 2 H, C(1)H2, JH,H = 14.8 Hz, JP,H = 9.2 Hz, JP,H
=
O,O,O,OꢀTetraethyl (Nꢀformylpyrrolidinꢀ2ꢀyl)hydroxymethꢀ
ylenediphosphonate (22). A solution of thionyl chloride (3.6 g,
0.030 mol) in dichloromethane (5 mL) was added to a solution of
formamide 9 (6.1 g, 0.028 mol) in dichloromethane (10 mL)
with stirring and cooling to 5 °C. The mixture was heated to
boiling, the solvent was evaporated, the residue was allowed to
stand in vacuo (1 Torr) for 0.5 h, then dissolved in dichloꢀ
romethane (15 mL), followed by the addition of a solution of
diethyl (trimethylsilyl)phosphite (18.0 g, 0.086 mol) in dichloꢀ
romethane (15 mL) to the resulting solution cooled to 5 °C with
stirring. The solvent was evaporated, the residue was diluted
with ethanol (30 mL) and heated to 40 °C, ethoxy(trimethyl)ꢀ
silane and ethanol were evaporated, the residue was dissolved in
diethyl ether (15 mL), hexane (10 mL) and water (10 mL) were
added. An oil formed was allowed to stand in vacuo (1 Torr) for
0.5 h to obtain diphosphonate 22, the yield was 10.3 g (91%),
a dense oil. Found (%): C, 41.71; H, 7.22. C14H29NO8P2. Calculꢀ
ated (%): C, 41.90; H, 7.28. 1H NMR (CDCl3), δ: 7.84 (s, C(1)H);
3.6—4.0 (m, 1 H, C(2)H and 8 H, 4 CH2OP); 3.15—3.65
(m, C(3)H2); 1.3—1.6 (m, C(4)H2); 1.9—2.3 (m, C(5)H2); 0.9—1.0
(m, 12 H, 4 CH3). 13C{1H} NMR (CDCl3), δ: 164.22 (s, C(1));
62.7—64.3 (m, C(2) and 4 CH2OP); 48.50 (s, C(3)); 24.18
= 11.2 Hz); 3.24 (dd, 1 H, C(2)H, 3JH,H = 7.2 Hz, 3JH,H = 5.6 Hz);
1
3.35 (s, 3 H, CH3O); 7.15 (dt, 1 H, HP, JP,H = 548.7 Hz,
3JH,H = 1.6 Hz); 0.15 (s, 9 H, Me3Si). 13C{1H} NMR (CDCl3),
1
3
δ: 54.38 (d, C(1)H2, JP,C = 114.3 Hz); 54.67 (d, C(3), JP,C
=
= 2.8 Hz); 23.59 (s, C(4)); 28.92 (s, C(5)); 174.62 (s, C(6)); 51.18
(s, CH3O); 0.97 (s, Me3Si). 31P{1H} NMR (CDCl3), δ: 17.71 (s).
OꢀTrimethylsilyl [Nꢀ(Oꢀmethylprolino)methyl]ꢀ2ꢀ(trimethylꢀ
siloxycarbonyl)ethylphosphinate (20). Trimethylsilyl acrylate (6 g,
0.042 mol) and pyridine (2 mL) was added to a solution of phosꢀ
phonite 19 (5.8 g, 0.021 mol) in dichloromethane (10 mL). The
solvent was evaporated using a water bath, the residue was heated
at 100 °C for 1 h, and then distilled to obtain phosphinate 20, the
yield was 7 g (79%), b.p. 180 °C (2 Torr). Found (%): C, 45.23;
H, 8.01. C16H34NO6PSi2. Calculated (%): C, 45.37; H, 8.09.
The first isomer, the content was 60%. 1H NMR (CDCl3), δ:
2.68 and 3.08 (m, ABX, 2 H, C(1)H2, 2JH,H = 14.0 Hz, 2JP,H
=
= 9.0 Hz, 2JP,H = 14.0 Hz); 3.26 (dd, 1 H, C(2)H, 3JH,H = 8.6 Hz,
3JH,H = 5.4 Hz), the multiplets for the protons of pyrrolidine and
propionic fragments overlap, 0.1—0.16 (m, 18 H, 2 Me3Si).
13C{1H} NMR (CDCl3), δ: 54.21 (d, C(1)H2, 1JP,C = 122.4 Hz);
67.68 (d, C(2), 3JP,C = 14.4 Hz); 54.88 (d, C(3), 3JP,C = 2.8 Hz);
23.44 (s, C(4)); 28.92 (s, C(5)); 173.64 (s, C(6)); –0.2—1.2
2
(s, C(4)); 27.71 (s, C(5)); 77.90 (t, C(6)H, JP,C = 154.9 Hz);
15.9—16.2 (m, 4 Me). 31P{1H} NMR (CDCl3), δ: 15.87 and
1
(m, Me3Si, Me3SiOP); 28.01 (d, C(7), JP,C = 97.6 Hz); 28.90
(d, C(8), 2JP,C = 1 Hz); 173.25 (d, C(9), 3JP,C = 1 Hz). 31P{1H}
NMR (CDCl3), δ: 39.06 (s).
16.22 (ABꢀquartet, 2JP,P = 28.7 Hz).
O,OꢀDiethyl (Nꢀprolinomethyl)phosphonate (23). Methanol
(10 mL) was added to a solution of phosphonate 10 (8 g, 0.024
mol) in dichloromethane (30 mL) with stirring. The mixture was
refluxed for 1 h, then the solvent was evaporated, the residue was
allowed to stand in vacuo (1 Torr) for 1 h to obtain phosphonate
23, the yield was 6 g (97%), a dense oil. Found (%): C, 45.04;
H, 7.49. C10H20NO5P. Calculated (%): C, 45.28; H, 7.60. 1H NMR
The second isomer, the content was 40%. 1H NMR (CDCl3),
δ: 2.72 and 3.12 (m, ABX, 2 H, C(1)H2, 2JH,H = 14.0 Hz, 2JP,H
=
= 9.0 Hz, 2JP,H = 14.0 Hz); 3.28 (dd, 1 H, C(2)H, 3JH,H = 8.6 Hz,
3JH,H = 5.4 Hz), the multiplets for the protons of pyrrolidine and
propionic fragments overlap, 0.1—0.16 (m, 18 H, 2 Me3Si).
1
13C{1H} NMR (CDCl3), δ: 54.29 (d, C(1), JP,C = 124.3 Hz);
67.72 (d, C(2), 3JP,C = 14.2 Hz); 54.86 (d, C(3), 3JP,C = 3.0 Hz);
(CDCl3), δ: 3.00 and 3.13 (both m, ABX, 2 H, C(1)H2, 2JH,H
=
23.46 (s, C(4)); 28.88 (s, C(5)); 173.68 (s, C(6)); –0.2—1.2
= 15.2 Hz, 2JP,H = 9.6 Hz, 2JP,H = 13.6 Hz); 3.40 (dd, 1 H, C(2)H,
1
3
(m, Me3Si, Me3SiOP); 27.95 (d, C(7), JP,C = 99.3 Hz); 28.96
3JH,H = 4.4 Hz, JH,H = 9.6 Hz); 3.6—4.0 (m, 4 H, 2 CH2OP);
(d, C(8), 2JP,C = 1 Hz); 173.39 (d, C(9), 3JP,C = 1 Hz). 31P{1H}
NMR (CDCl3), δ: 41.09 (s).
0.9—1.0 (m, 6 H, 2 CH3). 13C{1H} NMR (CDCl3), δ: 49.68 (d, C(1),
1JP,C = 160.7 Hz); 66.97 (d, C(2), JP,C = 10.9 Hz); 55.32
3
O,O,O,OꢀTetra(trimethylsilyl) Nꢀ(Oꢀtrimethylsilylprolino)ꢀ
methylenediphosphonate (21). Trimethylsilyl trifluoromethaneꢀ
sulfonate (0.9 g, 0.004 mol) was added to a solution of trisꢀ
(trimethylsilyl)phosphite (10 g, 0.033 mol) and ester 9 (2.2 g,
0.01 mol) in dichloromethane (8 mL) with stirring. The mixture
was allowed to stand at 20 °C for 24 h, then the solvent was
evaporated, hexane (3 mL) was added to the residue and cooled
to 5 °C. The solvent was decanted, the residue was allowed to
stand in vacuo (0.5 Torr) to obtain diphosphonate 21, the yield
was 5.8 g (89%), a dense oil. Found (%): C, 38.72; H, 8.14.
C21H53NO8P2Si5. Calculated (%): C, 38.96; H, 8.22.
(d, C(3), 3JP,C = 4.9 Hz); 24.06 (s, C(4)); 29.61 (s, C(5)); 174.62
2
(s, C(6)); 62.21 (d, 2 CH2OP, JP,C = 7.1 Hz); 16.12 (d, 2 Me,
3JP,C = 5.6 Hz). 31P{1H} NMR (CDCl3), δ: 21.39 (s).
Acids 24—26, 28, 29 were obtained similarly.
NꢀProlinomethylphosphonic acid (24), the yield was 95%,
m.p. 192 °C. Found (%): C, 34.37; H, 5.59. C6H12NO5P. Calculatꢀ
ed (%): C, 34.46; H, 5.79. 1H NMR (D2O), δ: 3.35 (m, ABX,
1 H, C(1)H2, 2JH,H = 14.4 Hz, 2JP,H = 14.4 Hz, the signals for the
second proton overlaped with the signals of the pyrrolidine
3
3
fragment), 4.20 (dd, 1 H, C(2)H, JH,H = 8.8 Hz, JH,H
=
=
1
= 7.6 Hz). 13C{1H} NMR (D2O), δ: 54.16 (d, C(1), JP,C
The first isomer, the content was 60%. 1H NMR (CDCl3), δ:
3.42 (br.t, C(1)H, 2JP,H = 26.2 Hz); 3.6—3.8 (m, C(2)H); 2.6—2.8
(m, C(3)H2); 1.3—1.7 (m, C(4)H2, C(5)H2); –0.17 (s, 36 H,
= 136.6 Hz); 71.92 (d, C(2), JP,C = 5.3 Hz); 59.45 (s, C(3));
25.22 (s, C(4)); 30.62 (s, C(5)); 174.23 (s, C(6)). 31P{1H} NMR
(D2O), δ: 4.97 (s).
3

1854
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 7, July, 2016
Prishchenko et al.
Methylꢀ(Nꢀprolinomethyl)phosphinic acid (25), the yield was
95%, m.p. 185 °C. Found (%): C, 40.45; H, 6.68. C7H14NO4P. Calꢀ
culated (%): C, 40.58; H, 6.81. 1H NMR (D2O), δ: 3.19 and 3.35
The second isomer, the content was 35%. 1H NMR (CDCl3),
δ: 3.6—3.8 (m, 6 H, 2 C(1)H2 and 2 C(2)H); 2.6—2.8 (m, 4 H,
2 C(3)H2); 1.4—1.7 (m, 8 H, 2 C(4)H2 and 2 C(5)H2); 0.06
(s, 9 H, Me3SiOP); 0.23 (s, 18 H, 2 Me3SiO). 13C{1H} NMR
2
2
(both m, ABX, 2 H, C(1)H2, JH,H = 14.8 Hz, JP,H = 8.8 Hz,
2JP,H = 10.0 Hz); 4.20 (dd, 1 H, C(2)H, 3JH,H = 7.2 Hz, 3JH,H
= 9.6 Hz); 1.37 (d, 3 H, CH3P, 2JP,H = 12.4 Hz). 13C{1H} NMR
(D2O), δ: 57.05 (d, C(1), 1JP,C = 85.7 Hz); 72.11 (d, C(2), 3JP,C
1
=
(CDCl3), δ: 51.66 (d, C(1), JP,C = 109.2 Hz); 66.98 (d, C(2),
3JP,C = 9.6 Hz); 54.49 (d, C(3), 3JP,C = 3.8 Hz); 23.48 (s, C(4));
29.41 (s, C(5)); 173.84 (s, C(6)); 2.05 (s, Me3SiOP); –0.14
(s, Me3SiO). 31P{1H} NMR (CDCl3), δ: 36.62 (s).
=
= 4.2 Hz); 60.25 (s, C(3)); 25.30 (s, C(4)); 30.58 (s, C(5)); 174.14
(s, C(6)); 18.54 (d, MeP, 1JP,C = 98.2 Hz). 31P{1H} NMR (D2O),
δ: 28.42 (s).
This work was financially supported by the Russian
Foundation for Basic Research (Project Nos 14ꢀ03ꢀ00001
and 15ꢀ03ꢀ00002).
Bis[Nꢀ(Oꢀmethylprolino)methyl]phosphinic acid (26), the yield
was 97%, a dense oil. Found (%): C, 48.03; H, 7.16. C14H25N2O6P.
Calculated (%): C, 48.27; H, 7.23. 1H NMR (CDCl3), δ: 2.60
and 2.79 (m, ABX, 4 H, 2 C(1)H2, 2JH,H = 14.2 Hz, 2JP,H = 9.2 Hz,
References
2JP,H = 11.2 Hz); 3.60 (dd, 2 H, 2 C(2)H, 3JH,H = 5.2 Hz, 3JH,H
=
= 8.4 Hz); 3.33 (s, 6 H, 2 MeO). 13C{1H} NMR (CDCl3), δ:
52.73 (d, C(1), 1JP,C = 100.7 Hz); 65.63 (d, C(2), 3JP,C = 8.6 Hz);
54.44 (s, C(3)); 21.81 (s, C(4)); 27.55 (s, C(5)); 171.70 (s, C(6));
51.21 (s, MeO). 31P{1H} NMR (CDCl3), δ: 22.01 (s).
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m.p. 145 °C. Found (%): C, 44.89; H, 6.56. C12H21N2O6P. Calculꢀ
ated (%): C, 45.00; H, 6.61. 1H NMR (D2O), δ: 3.46 (m, ABX, 2 H,
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2
2
2 C(1)H2, JH,H = 15.2 Hz, JP,H = 10.0 Hz, the signals for the
second proton overlap with the signals of the pyrrolidine fragment),
4.13 (dd, 2 H, 2 C(2)H, 3JH,H = 8.2 Hz, 3JH,H = 6.6 Hz). 13C{1H}
NMR (D2O), δ: 56.53 (d, C(1), 1JP,C = 94.6 Hz); 72.90 (d, C(2),
3JP,C = 1.0 Hz); 54.70 (d, C(3), 3JP,C = 1.0 Hz); 25.49 (s, C(4));
30.91 (s, C(5)); 175.53 (s, C(6)). 31P{1H} NMR (D2O), δ: 13.09 (s).
NꢀProlinomethylenediphosphonic acid (29). The yield was
95%, m.p. 187 °C. Found (%): C, 24.69; H, 4.42. C6H13NO8P2.
Calculated (%): C, 24.93; H, 4.53.
1
The first isomer, the content was 55%. H NMR (D2O), δ:
4.29 (t, C(1)H, 2JP,H = 20.0 Hz); 5.1—5.2 (m, C(2)H); 3.95—4.05
(m, C(3)H2); 2.0—2.5 (m, C(4)H2 and C(5)H2). 13C{1H} NMR
1
(D2O), δ: 58.31 (t, C(1), JP,C = 127.7 Hz); 67.54 (t, C(2),
3JP,C = 5.0 Hz); 54.09 (s, C(3)); 22.84 (s, C(4)); 28.06 (s, C(5));
170.20 (s, C(6)). 31P{1H} NMR (D2O), δ: 7.04 (s).
1
The second isomer, the content was 45%. H NMR (D2O),
δ: 4.32 (t, C(1)H, 2JP,H = 20 Hz); 5.1—5.2 (m, C(2)H); 4.1—4.2
(m, C(3)H2); 2.0—2.5 (m, C(4)H2 and C(5)H2). 13C{1H} NMR
1
(D2O), δ: 58.39 (t, C(1), JP,C = 128.5 Hz); 67.21 (t, C(2),
3JP,C = 5.4 Hz); 54.21 (s, C(3)); 22.64 (s, C(4)); 27.78 (s, C(5));
168.97 (s, C(6)). 31P{1H} NMR (D2O), δ: 7.89 (s).
OꢀTrimethylsilyl bis[Nꢀ(Oꢀtrimethylsilylprolino)methyl]phosꢀ
phinate (27). Concentrated hydrochloric acid (50 mL) was quickly
added to phosphinate 26 (7 g, 0.017 mol). The mixture was reflꢀ
uxed for 4 h, then concentrated in vacuo (8 Torr) to dryness using
a water bath. Bis(trimethylsilyl)amine (25 mL) was added to the
residue, which was refluxed until the precipitate was completely disꢀ
solved and ammonia stopped to evolve. Then, the mixture was
diluted with diethyl ether (100 mL) and pentane (50 mL) and cooled
to 0 °C. A precipitate formed was filtered off, the solvent was evapꢀ
orated, the residue was distilled to obtain phosphinate 27, the yield
was 6.4 g (72%), b.p. 190 °C (1.5 Torr). Found (%): C, 46.87;
H, 8.38. C21H45N2O6PSi3. Calculated (%): C, 46.99; H, 8.45.
1
The first isomer, the content was 65%. H NMR (CDCl3),
δ: 3.6—3.8 (m, 6 H, 2 C(1)H2 and 2 C(2)H); 2.6—2.8 (m, 4 H,
2 C(3)H2); 1.4—1.7 (m, 8 H, 2 C(4)H2 and 2 C(5)H2); 0.28
(s, 9 H, Me3SiOP); 0.23 (s, 18 H, 2 Me3SiO). 13C{1H} NMR
1
(CDCl3), δ: 52.03 (d, C(1), JP,C = 110.6 Hz); 67.07 (d, C(2),
3JP,C = 9.0 Hz); 54.90 (d, C(3), 3JP,C = 4.8 Hz); 23.55 (s, C(4));
29.53 (s, C(5)); 173.88 (s, C(6)); 1.47 (s, Me3SiOP), –0.14
(s, Me3SiO). 31P{1H} NMR (CDCl3), δ: 35.96 (s).
Received January 18, 2016;
in revised form February 29, 2016