Synthesis of bis- and tris-organophosphorus substituted amines and amino acids with PCH2N Fragments

Article abstract of DOI:10.1002/hc.20616

The aminomethylation of the derivatives of trivalent organophosphorus acids, containing PH and POSiMe₃ fragments with various bis- and tris(alkoxymethyl)amines and bis(alkoxymethyl)amino acids, is proposed as a convenient method for the synthesis of new bis- and trisphosphorylated amines and amino acids as well as their derivatives with four and five coordinated phosphorus. Also the three-components systems of phosphorous acid, paraformaldehyde, and amines are thoroughly investigated via the treatment of reaction mixtures with bis(trimethylsilyl)amine.

Full text of DOI:10.1002/hc.20616

Heteroatom Chemistry
Volume 21, Number 6, 2010
Synthesis of Bis- and Tris-Organophosphorus
Substituted Amines and Amino Acids with
PCH N Fragments
2
Andrey A. Prishchenko, Mikhail V. Livantsov, Olga P. Novikova,
Ludmila I. Livantsova, and Valery S. Petrosyan
Department of Chemistry, M. V. Lomonosov Moscow State University, Moscow, 119991, Russia
Received 1 April 2010; revised 26 May 2010
amino acids are promising bioactive substances
ABSTRACT: The aminomethylation of the
with various important properties [4,5]. Some of
derivatives of trivalent organophosphorus acids,
these compounds are interesting biomimetics of
containing PH and POSiMe3 fragments with
amino acids and interfere with enzymatic pro-
various bis- and tris(alkoxymethyl)amines and
cesses [6]. Here, we present the convenient meth-
bis(alkoxymethyl)amino acids, is proposed as a
ods for obtaining the bis- and tris-organophosphorus
convenient method for the synthesis of new bis- and
containing aminomethyl compounds which are
trisphosphorylated amines and amino acids as well
based on the aminomethylation reaction of esters
as their derivatives with four and five coordinated
of the trivalent organophosphorus acids and hy-
phosphorus. Also the three-components systems of
drospirophosphoranes with the corresponding bis-
phosphorous acid, paraformaldehyde, and amines are
and tris(alkoxymethyl)amines and the amino acids
thoroughly investigated via the treatment of reaction
esters. Also, it is found out that the formation of
ꢀ
C
mixtures with bis(trimethylsilyl)amine.
2010 Wiley
some by-products is the results of reduction pro-
cesses in the three-components systems of phospho-
rous acid, paraformaldehyde, and amines or amino
acids (cf. [1]).
Periodicals, Inc. Heteroatom Chem 21:430–440, 2010;
View this article online at wileyonlinelibrary.com. DOI
10.1002/hc.20616
INTRODUCTION
Organophosphorus compounds including the sev-
eral PCH2N fragments are of great interest as effec-
tive chelating ligands and extragents [1–3]. Also, the
aminomethylphosphonic acids are the organophos-
phorus analogs of amino acids, hence these com-
pounds as well as organophosphorus substituted
RESULTS AND DISCUSSION
In the present work, we showed that the
aminomethylation of phosphorous acid using
paraformaldehyde and various amines and amino
acids proceeds in the presence of hydrochloric
acid (cf. [1]), and several O-trimethylsilyl sub-
stituted bis- and trisphosphonates were obtained
under treatment on the reaction mixture with
bis(trimethylsilyl)amine. So the primary amines
were easily transformed under these conditions
into bis(phosphonomethyl)amines 1–5 in high yields
Correspondence to: Andrey A. Prishchenko; e-mail:
aprishchenko@yandex.ru.
Contract grant sponsor: Russian Foundation for Basic Re-
search.
Contract grant number: 08-03-00282.
2010 Wiley Periodicals, Inc.
c
ꢀ
430

Synthesis of Bis- and Tris-Organophosphorus Substituted Amines and Amino Acids with PCH2N Fragments 431
(Eq. (1)).
2(Me3Si)2NH
– 2NH3
2 C H 2O, HCl
– 2H2O
[(Me3SiO)2PCH2]2NR
2(HO)2PH + RNH2
[(HO)2PCH2]2NR
O
O
O
1–5
R = Me (1), Et (2), CH2=CHCH2 (3),
(4), PhCH2 (5).
(1)
The similar reaction of the several amino acids provided O-trimethylsilyl substituted
bis(phosphonomethyl)aminoacids 6–9 which were isolated by distillation in good yields (Eq. (2)).
+
(Me3Si)2NH
– NH3
2CH2O, HCl
– 2H2O
2(HO)2PH + H3N(CH2)nCOO–
[(Me3SiO)2PCH2]2N(CH2)nCOOSiMe3
O
[(HO)2PCH2]2N(CH2)nCOOH
O
O
6–9
n = 1 (6), 2 (7), 3 (8), 5 (9).
(2)
It should also be noted that this reaction with glycine gave N-(phosphonomethyl)sarcosine 10, in 20% yield.
Obviously it arises from in situ reaction of aminomethylating intermediate A with phosphorous acid (Eq. (3)),
and formaldehyde in this case reacts as reducing agent (cf. [7]).
+
2CH2O, HCl
– 2H2O
(HO)2P(O)H
– H2O
CH2O
H3NCH2COO–
(HOCH2)2NCH2COOH
HOCH2NCH2COOH
– HCOOH
CH3
A
(Me3Si)2NH
(HO)2PCH2NCH2COOH
(Me3SiO)2PCH2NCH2COOSiMe3
– NH3
O
O
CH3
CH3
10
(3)
Similary, the reaction of an excess of phosphorous acid and paraformaldehyde with ammonium chloride pro-
vided a mixture of bisphosphonate 1 and trisphosphonate 11, which were separated by distillation (Eq. (4)).
(Me3Si)2NH
– NH3
3CH2O, 3 (HO)2P(O)H
N[CH2P(OH)2]3
O
+
N[CH2P(OSiMe3)2]3 +
CH3N[CH2P(OSiMe3)2]2
CH3N[CH2P(OH)2]2
O
NH4Cl
– H2O, – HCOOH, – HCl
O
O
11
1
(4)
The analogous reaction of 3-aminopropionic acid under the same conditions resulted in the formation of a
mixture of expected bisphosphonate 7 and triphosphonate 11 as a by-product in 4:3 ratio. Undoubtedly, the
Heteroatom Chemistry DOI 10.1002/hc

432 Prishchenko et al.
formation of by-product 11 proceeds due to the particular disintegration of starting acid by giving in situ
ammonium chloride (Eq. (5)).
+
HCl
(Me3Si)2NH
– NH3
3 C H 2O, 3(HO)2P(O)H
– H2O
H3N(CH2)2COO–
7 + 11
[(HO)2PCH2]2N(CH2)2COOH + N[CH2P(OH)2]3
NH4Cl
– C2H4, – CO2
O
O
(5)
N,N-Bis(diethoxyphosphorylmethyl)amines 12–15 were synthesized by us in high yields (Eq. (6)) with the
using of three-component system of diethyl phosphite, paraformaldehyde, and primary amine according to
the well-known Kabachnik–Fields reaction [8,9].
RNH2, 2CH2O
[(EtO)2PCH2]2NR
2(EtO)2PH
O
– 2H2O
O
12–15
R = CH2=CHCH2 (12), Bu (13),
(14), PhCH2 (15).
(6)
This method was successfully applied for obtaining the O-trimethylsilyl bisphosphorylated amino acids
16–18 under treatment on the reaction mixture with bis(trimethylsilyl)amine (Eq. (7)).
+
(Me3Si)2NH
– NH 3
2CH2O, 2(EtO) 2P(O)H
– 2 H2O
H3N(CH2)nCOO–
[(EtO)2PCH2]2N(CH2)nCOOSiMe3
[(EtO)2PCH2]2N(CH2)nCOOH
O
O
16–18
n = 1 (16), 2 (17), 3 (18).
(7)
Also the esters 1–6, 8–10, and 16–18 containing trimethylsilyl groups were easily removed with an excess
of methanol to form free bisphosphonic acids or bisphosphorylated amino acids 19–30, isolated as white
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Bis- and Tris-Organophosphorus Substituted Amines and Amino Acids with PCH2N Fragments 433
hygroscopic crystals or thick oils (Eq. (8)). The synthesized acids may be used as water-soluble ligands, and
the precursors of bisphosphorylated peptides.
4 MeOH
[(HO)2PCH2]2NR
1–5
– 4 MeOSiMe3
O
19–23
R = Me (19), Et (20), CH2=CHCH2 (21),
(22), PhCH2 (23).
5 MeOH
[(HO)2PCH2]2N(CH2)nCOOH
6,8,9
– 5 MeOSiMe3
O
24–26
n = 1 (24), 3 (25), 5 (26).
3 MeOH
(HO)2PCH2NCH2COOH
10
– 3 MeOSiMe3
O
CH3
27
5 MeOH
[(EtO)2PCH2]2N(CH2)nCOOH
16–18
– 5 MeOSiMe3
O
28–30
n = 1 (28), 2 (29), 3 (30).
(8)
Also in the present work, we propose the convenient methods for the synthesis of bis- and trisphorylated
amines using the corresponding bis- and tris(alkoxymethyl)amines. So bisphosphonates 12,13,31,32 were
prepared in high yields via the aminomethylation of diethyl phosphite with bis(ethoxymethyl)amines B as
intermediates in the reaction of symmetrical hexahydrotriazines, paraformaldehyde, and an excess of ethanol
(Eq. (9)). This route is especially convenient for the compounds 31,32 containing the fragments of starting
low-boiling amines (cf. [10,11]). It should be noted that recently we had obtained the bisphosphonates
12,13,31,32 as the by-products in low yields [12].
3CH2O, 6EtOH
– 3 H2O
RN
NR
6 ( Et O ) 2P(O)H
– 6 EtOH
3 RN(CH2OEt)2
3 RN[CH2P(OEt)2]2
N
R
O
B
12,13,31,32
R = Me (31), Et (32), CH2=CHCH2 (12), Bu (13).
(9)
The yield of bisphosphinate 33 is rather lower if it was obtained according to the similar scheme. Obviously,
this fact is connected with the hydrolysis of starting O-ethyl methylphosphonous acid by water formed on
the first step of the process (Eq. (10)).
Me
3CH2O, 6EtOH
– 3H2O
MeN
NMe
6Me(EtO)P(O)H
– 6EtOH
3 MeN(CH2OEt)2
MeN CH2P
O
OEt
N
2
Me
33
(10)
Heteroatom Chemistry DOI 10.1002/hc

434 Prishchenko et al.
Several bis(butoxymethyl)amines and esters of amino acids 34–38 were synthesized by the interaction of
symmetrical hexahydrotriazines with paraformaldehyde and an excess of butanol (Eq. (11)), (cf. [13]).
3CH2O, 6BuOH
– 3H2O
RN
NR
3RN(CH2OBu)2
N
R
34–38
R = Me (34), Et (35), CH2COOEt (36), (CH2)2COOEt (37), (CH2)3COOMe (38).
(11)
Amines 34–38 are the valuable key substances for obtaining the bisphosphonates 1,2,39–41 and bisphos-
phoranes 42–46 according to usual scheme in high yields (Eq. (12)).
2(Me3SiO)3P, Z n Cl 2
– 2Me3SiOBu
2(EtO)2P(O)H
– 2BuOH
RN[CH2P(OSiMe3)2]2
O
RN(CH2OBu)2
RN[CH2P(OEt)2]2
O
1,2
39–41
H
P
O
O
O
O
2
O
O
O
O
P
CH2
RN
RN(CH2OBu)2
– 2BuOH
2
42–46
R = Me (1,42), Et (2,43), CH2COOEt (39,44), (CH2)2COOEt (40,45), (CH2)3COOMe (41,46).
(12)
It should be noted the similar reaction of amine 34 with O-isopropyl methylphosphonous acid was accom-
panied by transesterification of the starting acid with butanol and resulted in formation of a mixture of bis-
phosphinates C. However, the hydrolysis of a mixture and followed by treatment of bis(trimethylsilyl)amine
lead to the formation of O-silylated bisphosphinate 47 in high yield. The corresponding acid 48 was obtained
by methanolysis of bisphosphinate 47 as usually (Eq. (13)).
Me
Me
1. HCl 2. (MeSi)2NH
– RCl, – NH3
2Me(i-PrO)2P(O)H
MeN(CH2OBu)2
MeN CH2P
O
MeN CH2P
O
OR
OSiMe3
– 2BuOH
2
2
34
C
47
R = i-Pr, Bu
Me
2MeOH
MeN CH2P
47
– 2MeOSiMe3
OH
O
2
48
(13)
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Bis- and Tris-Organophosphorus Substituted Amines and Amino Acids with PCH2N Fragments 435
In contrast, the more active bis(chloromethyl)amine D reacted smoothly with an excess of O,O-diisopropyl
methylphosphonite under mild conditions forming bisphosphinate 49 in high yield (Eq. (14)).
Me
2PCl3
2MeP(OPr-i)2
– 2i-PrCl
EtN(CH2OBu)2
EtN(CH2Cl)2
EtN CH2P
–2BuOPCl2
OPr-i
2
O
49
D
(14)
The valuable synthon–N,N-bis(methoxymethyl)piperazine 50, was easily prepared via methoxymethylation
of piperazine using a mixture of paraformaldehyde and methanol (Eq. (15)), (cf. [14]).
2CH2O, 2MeOH
HN
MeOCH2N
NH
NCH2OMe
– 2H2O
50
(15)
The synthon 50 used as aminomethylating reagent was applied to some of the PH-acids for obtaining
the bisphosphorylated piperazines 51–53 with four- and five-coordinated phosphorus. It should be noted
that the exotermic reaction of piperazine 50 with tris(trimethylsilyl)phosphite proceeds in the presence of
trimethylsilyl chloride as a catalyst in methylene chloride as a solvent to form bisphosphonate 54 in high
yield (Eq. (16)), (cf. [15,16]).
Me
i-PrO
P(O)H
Me
Me
2(EtO)2P(O)H
– 2MeOH
(EtO)2PCH2N
O
NCH2P(OEt)2
O
PCH2N
O
50
NCH2P
– 2MeOH
OPr-i
i-PrO
O
51
52
H
O
O
O
O
P
2
O
O
O
O
O
O
O
O
2(Me3SiO)3P, M e 3SiCl
–2MeOSiMe3
(Me3SiO)2PCH2N
O
P
50
NCH2P(OSiMe3)2
O
CH2N
P
NCH2
–2MeOH
54
53
(16)
Tris(butoxymethyl)amine 55 was prepared by reaction of hexamethylenetetramine, paraformaldehyde, and
an excess of butanol under conditions similar for obtaining the compounds 34–38 (Eq. (17)).
6CH2O, 12BuOH
(CH2)6N4
4N(CH2OBu)3
–6H2O
55
(17)
We have proposed a facile synthetic route to the new trisphosphorylated amines 11,56,57 using amine 55 as
available reagent for the aminomethylation of some PH-acids and their derivatives. So the trisphosphonates
11,56 and trisphosphorane 57 were synthesized in high yields (Eq. (18)), (cf. [10]).
Heteroatom Chemistry DOI 10.1002/hc

436 Prishchenko et al.
H
P
O
O
O
O
3
O
O
O
2 O
3(EtO)2P(O)H
–3BuOH
CH
N
P
N[CH2P(OEt)2]3
55
–3BuOH
3
O
56
57
3(Me3SiO)3P, Z n Cl 2
–3BuOSiMe3
55
N[CH2P(OSiMe3)2]3
O
11
(18)
N-Cyclohexyl N,N-bis(diethoxyphosphorylmethyl)
The structures of the starting N-alkoxymethyl
amines, organophosphorus substituted amines, and
amino acids 1–57 were confirmed by the 1H, 13C, and
31P NMR spectra which indicated the characteristic
signals of the OC1H2NC2Hn and PC1H2NC2Hn frag-
ments (see Tables 1 and 2). The element analysis
data of synthesized compounds are summarized in
Table 3.
amine (14). A mixture of diethyl phosphite, 15 g; cy-
clohexylamine, 5 g; and paraformaldehyde, 3 g was
stirred in a boiling water bath for 2 h. Then it was
cooled, and 100 mL of diethyl ether and 10 g of potas-
sium carbonate were added under stirring. After 2 h,
the organic layer was separated, the solvent was re-
moved, and the residue was distilled in a vacuum to
obtain 16.9 g of bisphosphonate 14.
Bisphosphonates 12,13,15 was prepared simi-
larly.
EXPERIMENTAL
O-Trimethylsilyl
N,N-bis(diethoxyphosphoryl)
The 1H, 13C, and 31P NMR spectra were registered on
the Varian VXR-400 and Bruker Avance-400 spec-
trometer (400, 100, and 162 MHz, respectively) in
CDCl3 or C6D6 (1–18, 28–47, 49–57), CD3OD or
D2O (19–27, 48). All reactions were carried out
under dry argon. The starting derivatives of triva-
lent organophosphorus acids and symmetrical 1,3,5-
trisubstituted hexahydrotriazines were prepared as
described in [7,17,18].
glycine (16). A mixture of diethyl phosphite, 15
g; glycine, 3.8 g; paraformaldehyde, 3 g; butanol,
100 mL; pyridine, 5 mL; and zinc chloride, 0.1 g
was refluxed for 2 h. The solvent was removed
in a vacuum (8 mmHg), bis(trimethylsilyl)amine,
50 mL was added to the residue, and the mixture
was refluxed until the ammonia release was com-
pleted. Then the solvent was removed, and the
residue was distilled in a vacuum to obtain 19.5 g
bisphosphonate 16.
O-Trimethylsilyl
N,N-bis[bis(trimethylsiloxy)
Bisphosphonates 17,18 were obtained analo-
gously.
phosphorylmethyl]glycine (6) and O-trimethylsilyl N-
[bis(trimethylsiloxy)phosphorylmethyl]sarcosine (10).
A mixture of 16 g of phosphorous acid; glycine, 7.5 g;
water, 10 mL; and concentrated hydrochloric acid,
20 mL was heated to 100◦C, and paraformaldehyde
9 g was added under stirring. The mixture was re-
fluxed for 2 h, then the solvents were evaporated in a
vacuum (8 mmHg). Water, 30 mL was added to the
residue and also was evaporated in a vacuum. The
residue was refluxed with bis(trimethylsilyl)amine,
100 mL until the ammonia release was completed.
Then the solvent was removed, and the residue was
distilled in a vacuum to obtain 40.6 g of bisphos-
phonate 6. The next distillation of the low-boiling
fraction gave 8 g of phosphonate 10.
N-(Dihydroxyphosphorylmethyl)sarcosine (27). A
solution of 10.8 g phosphonate in 10 mL of di-
ethyl ether was added dropwise under stirring at
10◦C to 70 mL of methanol. The resulting mixture
was heated to boil, the solvent was distilled off in
a vacuum, and the residue was kept in a vacuum
(1 mmHg) for 1 h to give 3.5 g of acid 27 as colorless
hydroscopic crystals.
The acids 19–26,28–30,48 were obtained simi-
larly.
N-Methyl
N,N-bis(diethoxyphosphorylmethyl)
amine (31). A mixture of 1,3,5-trimethylhexahydro-
triazine, 7.3 g; paraformaldehyde, 4.5 g; and
ethanol, 60 mL was refluxed for 1 h, and then
diethyl phosphite 50 g was added. The mixture was
refluxed for 2 h, and the solvent was distilled off.
The compounds 1–5,8,9,11 and the mixture of
compounds 7 and 11 in 80:20 ratio were prepared
similarly.
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Bis- and Tris-Organophosphorus Substituted Amines and Amino Acids with PCH2N Fragments 437
TABLE 1 Yields, Products Constants, and NMR Spectral Data (δ, ppm, J, Hz) for the PC1H2NC2Hn Fragmentsa of Phospho-
rylated Amines and Amino Acids 1–33, 39–49, 51–54, 56, 57
Bp (◦C)
Yield (p, mmHg)
δ(H)
C1H2 d JPH
δ(H)
δ
δ
No. (%) (mp, (◦C))
n2D0
1.4390 3.00
C2Hn
3JHH (C1) dd 1JPC 3JPC δ(C2) t 3JPC (C O) s
δ
sb
P
2
1
2
3
4
5
6
7
8
9
74
79
83
80
81
65
59
86
83
20
62d
78
80
84
83
86
89
83
95
96
95
94
95
95
97
95
96
96
95
96
83
85
62
155 (1)
147 (0.5) 1.4405 3.19
159 (1)
168 (1)
9.2
8.8
2.60 s
2.89 k
–
7.2
3.2
–
–
–
7.6
6.8
7.4
–
56.12 161.7 9.4 45.78
51.90 160.1 4.6 50.71
51.98 161.0 5.5 59.78
7.9
8.8
8.7
–
–
–
–
–
4.40
5.23
4.90
5.80
7.13
4.05
4.85
5.13
5.36
4.03
4.10
21.59
22.16
22.68
24.44
21.08
21.95
22.12
5.12
5.95
5.64
6.09
6.48
5.26
5.28
5.76
4.53
21.68
22.10
22.23
21.59
22.22
46.32
46.49
23.37
24.19
24.39
−11.28
−10.42
−9.17
−8.24
−8.16
36.99
37.23
30.76
45.34
45.69
21.85
47.15
47.28
−13.30
1.4508 3.14
1.4690 2.88
9.6 3.50 d
8.4
12.0
10.4
8.4
2.76 m
3.90 s
4.01 s
3.12 t
2.84 t
2.83 t
3.42 s
–
48.37 165.7 5.5 59.99 11.4
180 (0.5) 1.4910 2.98
51.62 161.0 6.5 60.04
53.34 163.5 10.8 56.62
52.18 158.8 4.0 52.58
52.24 159.6 4.6 55.91
52.26 158.8 5.1 56.69
8.0
209 (3)
200 (2)
213 (3)
202 (0.5) 1.4439 3.24
155 (3) 1.4330 2.85
178 (0.5) 1.4435 3.58
158 (1) 1.4580 3.16
168 (1.5) 1.4500 3.13
180 (1)
192 (1)
178 (1)
181 (1)
205 (2)
(209)
(206)
(189)
(234)
(244)
(205)
(168)
(179)
(210)
oil
1.4402 3.29
6.2 171.10
8.9 172.21
9.2 173.53
9.1 173.46
c
3.16
1.4459 3.20
8.4
8.8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
11.2
10.0
53.96e 169.4
–
59.17e 8.6 170.85
–
54.11f 160.5 8.0
–
–
–
–
–
–
–
9.6 3.46 d
9.2 2.76 t
10.0 3.05 m
8.0
10.4
9.2 3.14 t
8.8 2.52 t
6.4
7.2
–
–
–
9.2
6.9
–
7.2
2.5
–
–
–
7.4
8.0
–
50.05 156.8 7.8 60.05
50.60 155.3 7.1 56.92
47.05 161.5 8.5 60.99
49.27 155.5 7.5 60.76
50.91 159.2 10.5 57.16
50.50 153.9 5.7 53.05
49.47 156.2 6.9 55.27
53.47 136.4 4.2 43.59
50.39 137.7 4.3 52.61
51.10 137.2 4.1 60.52
49.07 138.1 4.0 60.95
51.14 136.5 3.9 61.04
52.20 137.4 3.8 55.89
51.48 136.2 4.2 56.37
51.16 135.2 3.2 56.91
8.6
8.4
7.3
8.0
1.4665 3.08
1.5205 2.91
1.4488 3.33
1.4515 3.20
1.4540 2.84
3.72 s
3.30 s
6.2 171.05
8.1 172.41
7.6 173.34
–
–
–
–
–
–
–
–
–
–
–
–
3.42
3.33
3.37
3.35
3.29
3.73
3.56
3.57
3.42
3.11
3.01
2.94
12.7
13.2
12.8 3.75 d
13.0 3.08 m
13.2
13.2
13.2 3.39 t
12.8 3.48 t
12.8
10.4
8.8 2.94 t
8.8 2.61 t
9.6
9.2 2.83 t
3.05 s
3.27 k
3.7
3.5
3.8
4.1
3.9
–
–
–
–
–
4.12 s
4.41 s
3.2 168.03
3.5 176.88
3.0 178.76
5.0 168.29
4.9 171.56
7.2 173.53
7.5 175.14
4.18 s
3.51 s
52.96e 135.3
–
57.30e
–
50.16 160.6 10.4 55.38
49.63 155.4 5.9 52.16
49.56 156.4 7.1 55.50
53.93 157.4 10.4 46.26
50.09 156.3 7.6 51.03
57.78 112.3 10.6 46.85
58.01 110.0 10.6 47.17
51.09 159.9 10.6 56.17
50.40 154.8 6.0 52.94
50.45 156.9 7.1 56.18
58.35 177.7 6.1 44.15
55.37 176.5 2.0 50.16
56.37 179.5 3.5 57.31
56.48 178.7 2.3 53.21
56.68 179.2 1.6 55.35
59.44 116.5 10.3 47.28
59.70 113.6 10.5 47.01
oil
oil
154 (1)
155 (1)
160 (1)
7.2
6.6
–
7.2
–
–
–
7.8
6.7
–
–
–
–
–
–
–
–
–
1.4520 2.97
1.4482 3.12
2.52 s
7.9
8.0
7.4
7.4
–
–
–
–
g
1.4670
–
2.38 s
2.47 s
4.01 s
3.25 k
3.27 k
2.38 s
39
40
41
42
43
44
45
46
47
85
86
83
93
91
91
89
90
78
167 (1)
173 (1)
185 (1.5) 1.4550 3.18
(146)
(154)
oil
oil
oil
139 (1)
1.4505 3.45
1.4470 3.28
9.5
9.0
9.1
3.6
6.7 170.49
8.4 171.73
8.3 173.07
–
–
–
–
–
3.15
4.7
5.8
–
–
3.32
2.4 2.70 m
–
–
–
–
g
g
5.6 171.31h
6.9 172.29
7.0 172.88
g
g
g
3.02 m
2.72 m
2.49 s
2.46 s
3.45 s
2.77 m
1.4545
7.9
7.8
3.0
7.4
7.2
–
–
–
–
–
–
–
–
–
48
49
96
87
(149)
143 (1)
–
3.73
8.4
–
60.13
86.5 4.2 52.39
g
1.4620
54.52 114.1 9.1 51.25
54.79 111.1 9.1 51.30
51
52
89
78
(41)
(104)
–
–
2.76
2.64
2.64
2.90
12.0
9.2
9.2
2.67 s
2.70 s
2.70 s
2.59 s
–
–
–
–
53.88e 170.4
57.48e 113.3
57.48e 113.3
59.09e 189.5
–
–
–
–
54.88e 10.2
55.09e
55.09e
9.0
9.0
53
91
(187)
–
9.6
54.89e 11.7
(Continued)
Heteroatom Chemistry DOI 10.1002/hc

438 Prishchenko et al.
TABLE 1 Continued
Bp ( ◦C)
Yield (p, mmHg)
δ(H)
δ(H)
δ
δ
No. (%) (mp, ( ◦C))
n2D0
C1H2 d JPH C2Hn 3JHH (C1) d d 1JPC 3JPC δ(C2) t 3JPC (C O) s
δ
sb
P
2
54
56
57
90
89
94
(126)
195 (1)
(144)
–
1.4540
–
2.50
12.4 2.65 s
–
–
–
56.43e 171.3
51.82f 155.1
56.98f 178.9
–
8.5
6.1
55.37e 10.6
–
–
–
3.54
21.21
−11.78
3.50
10.8
–
–
–
–
–
–
–
i
aAll signals of alkyl, phenyl, and trimethylsilyl fragments are in the standard area. According to the NMR spectra, the amines 33,47,49,52 are
mixtures of two stereoisomers. The spectral parameters of the major isomer are given first; their ratio for compounds: 33, 60 : 40; 47, 65 : 35;
49, 70 : 30; 52, 65 : 35. In NMR spectra, fragment NCH3 for compounds: 10, δH , 2.42 s, δC 44.05 d, 3JPC 11.5; 27, δH , 3.09 s, δC 43.56 s. In 1H
NMR spectra, fragment COOH for compounds, δH , s: 28, 9.88; 29, 10.75; 30, 10.33. In NMR spectra, fragment PCH3 for compounds: 33, δH
1.34 d and 1.30 d, 2JPH 14.0, δC 13.34 d, 1JPC 91.2 and 13.21 d, 1JPC 91.7; 47, δH 1.34 d, 2JPH 14.4, and 1.27 d, 2JPH 14.0, δC 15.25 d, 1JPC 94.2
and 15.49 d, 1JPC 93.6; 48, δH 1.63 d, 2JPH 14.8, δC 19.71 d, 1JPC 98.5; 49, δH 1.34 d and 1.29 d, 2JPH 14.0, δC 13.86 d, 1JPC 92.2 and 14.14 d,
1JPC 91.2; 52, δH 1.48 d and 1.36 d, 2JPH 13.6 and 1.47 d 2JPH 14.0, δC 13.59 d, 1JPC 93.6 and 13.53 d, 1JPC 93.1.
1
bData of 31P { H} spectra.
cThe mixture with 11 (20%).
dVia Eq. (4)
ed.
f dt.
gOverlapping multiplets.
ht, 4JPC 2.2.
i 3.35–3.42, broad signal.
TABLE 2 Yields, Products Constants, and NMR Spectral Data (δ, ppm, J, Hz) for the OC1H2NC2Hn Fragmentsa of N-
Alkoxymethyl Amines 34–38, 50, 55
Bp (◦C) (p, mmHg)
No.
Yield (%)
(mp ( ◦C))
n2D0
δ(H) C1H2 s
δ (H) C2Hn
3JHH
δ(C1) s
δ(C2) s
δ(C O) s
34
35
36
37
38
50
55
82
80
77
73
79
80
75
102 (8)
112 (7)
128 (1)
136 (1)
143 (1.5)
(44)
1.4425
1.4420
1.4388
1.4418
1.4395
–
4.18
4.16
4.20
4.00
4.02
3.83
4.31
2.52 s
2.78 k
3.70 s
2.89 t
2.63 t
2.60 s
–
–
7.2
–
7.2
7.3
–
86.26
84.31
84.95
85.76
83.15
90.13
83.02
46.28
43.86
44.89
46.83
47.16
49.73
–
–
–
170.90
171.73
171.22
–
105 (0.5)
1.4350
–
–
aAll signals of alkyl fragments are in the standard area.
The residue was distilled in a vacuum to give 46.7 g
of bisphosphonate 31.
Bisphosphonate 2 (yield 84%) and trisphospho-
nate 11 (yield 92%) were prepared similarly.
Bisphosphonates 12,13,32, and bisphosphinate
33 were obtained analogously.
O-Ethyl
N,N-bis(diethoxyphosphorylmethyl)
glycine (39). A mixture of amine 36, 4.1 g; and
diethyl phosphite, 5.5 g was heated at 110–120◦C
in a vacuum (20 mmHg) for 1 h with distillation of
butanol and then distilled in a vacuum to give 5.1 g
of bisphosphonate 39.
The compounds 40–46,56,57 were obtained
analogously. Phosphoranes 42–46,57 were crystal-
lized from a mixture of methylene chloride and
hexane.
N-Methyl N,N-bis[methyl(trimethylsiloxy)phos-
phorylmethyl]amine (47). A mixture of amine 34, 4.8
g, and O-isopropyl methylphosphonite, 6.6 g was
heated at 120◦C in a vacuum (30 mmHg) for 1 h and
then distilled to give a mixture of bisphosphinates
(bp 140–160◦C (1 mmHg), δP 46.2, 46.1, 45.9, 45.0,
44.9, 44.8 ppm, s in equal ratio). Concentrated
hydrochloric acid, 40 mL was added to the mixture
N-Methyl N,N-bis(butoxymethyl)amine (34). A
mixture of 1,3,5-trimethylhexahydrotriazine, 4.6 g;
paraformaldehyde, 3.5 g; and butanol, 35 mL was
refluxed with a Dean-Stark trap until the water re-
lease was completed. Then potassium carbonate, 3 g
was added under stirring, and the mixture was left
for 12 h. The organic layer was separated, the sol-
vent was evaporated, and the residue was distilled in
a vacuum to give 17.8 g of amine 34.
Amines 35–38, 55 were prepared similarly.
N-Methyl N,N-bis[bis(trimethylsiloxy)phospho-
rylmethyl]amine (1). A mixture of amine 34, 4 g;
tris(trimethylsilyl) phosphite, 13 g; and zinc chlo-
ride, 0.1 g was heated at 130◦C for 2 h, and then
distilled to give 8.7 g of bisphosphonate 1, yield
87%.
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Bis- and Tris-Organophosphorus Substituted Amines and Amino Acids with PCH2N Fragments 439
TABLE 3 Elemental Analyses Data of Compoundsa
Calcd.(%)
Found (%)
No.
Empirical Formula
Formula weight
C
H
C
H
1
2
3
4
5
6
8
9
C15H43NO6P2Si4
C16H45NO6P2Si4
C17H45NO6P2Si4
507.79
521.82
533.83
575.91
583.89
623.99
652.04
680.09
399.64
732.14
357.32
373.36
399.40
407.38
447.47
461.50
475.52
219.08
233.11
245.12
287.20
295.18
263.09
291.14
319.19
183.10
375.30
389.32
403.35
331.24
345.27
271.24
403.35
417.37
417.37
359.25
373.28
431.32
445.34
445.34
359.49
215.14
313.32
386.37
354.37
414.33
562.87
467.37
509.32
35.48
36.83
38.25
41.71
43.20
36.57
38.52
40.62
39.07
34.45
43.70
45.03
48.12
50.12
40.26
41.64
42.94
16.45
20.61
24.50
33.46
36.62
18.26
24.75
30.10
26.24
38.40
40.10
41.69
39.89
41.74
39.85
41.69
43.16
43.16
36.77
38.61
38.98
40.45
40.45
36.75
27.92
46.00
43.52
47.45
40.58
38.41
38.55
35.37
8.54
8.69
8.50
8.93
8.11
8.24
8.39
8.74
8.58
8.26
8.18
8.91
8.83
7.67
7.88
8.08
8.27
5.06
5.62
5.34
6.67
5.12
4.22
5.19
6.00
5.51
7.25
7.51
7.75
8.21
8.47
8.55
7.75
7.97
7.97
6.45
6.75
6.31
6.56
6.56
8.69
7.03
9.33
8.35
9.10
6.81
8.60
7.76
5.94
35.19
36.68
37.98
41.54
42.94
36.40
38.68
40.48
38.96
34.07
43.54
44.92
47.89
49.94
40.07
41.55
42.81
16.30
20.50
24.28
33.32
36.49
18.03
24.65
29.93
25.98
38.28
39.78
41.52
39.72
41.64
39.68
41.56
42.98
43.01
36.49
38.57
38.80
40.31
40.26
36.60
27.80
45.85
43.39
47.26
40.42
38.23
38.40
35.05
8.40
8.52
8.39
8.83
8.02
8.03
8.50
8.59
8.42
8.09
7.92
8.78
8.74
7.58
7.69
7.95
7.99
5.12
5.69
5.40
6.73
5.17
4.20
5.22
6.09
5.45
7.03
7.40
7.64
8.12
8.38
8.48
7.68
7.81
7.86
6.37
6.65
6.09
6.49
6.47
8.57
6.92
9.26
8.22
8.95
6.69
8.49
7.64
5.78
C20H51NO6P2Si4
C21H47NO6P2Si4
C19H51NO P Si5
C21H55NO8P2Si5
C23H59NO8P2Si5
8
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
39
40
41
42
43
44
45
46
47
48
49
51
52
53
54
56
57
C13H34NO5PSi
C21 60
H
NO9P3S3i6
C13H29NO6P2
C14H33NO6P2
C16H35NO6P2
C17H31NO6P2
C15H35NO8P2Si
C16H37NO8P2Si
C
17H39NO8P2Si
C3H11NO6P2
C4H13NO6P2
C5H13NO6P2
C8H19NO6P2
C9H15NO6P2
C4H11NO8P2
C6H15NO8P2
C8H NO8P2
19
C4H10NO5P
C12
C13
H
H
H
NO8P2
NO8P2
NO8P2
27
29
C
C
14 31
11H27NO6P2
C12H29NO6P2
C9H23NO4P2
C14H31NO8P2
C
C
15H33NO8P2
15H33NO8P2
C11H23NO8P2
C12H25NO8P2
C14 27
H
NO10P2
15H29NO10P2
15H29NO10P2
C
C
C11H31NO4P2Si2
C5H15NO4P2
C12H29NO4P2
C14H32N2O6P2
C14H32N2O4P2
C14H28N2O8P2
C18H48N2O6P2Si4
C15H36NO9P3
C H NO12P3
15 30
aCompound 7 was obtained as a mixture with amine 11.
and it was heated on a boiling water bath for 3 h
under stirring. Then the solvents were evaporated
in a vacuum (8 mmHg), 50 mL water was added to
the residue, and also evaporated in a vacuum. The
residue was refluxed with bis(trimethylsilyl)amine,
40 mL until the ammonia release was completed.
Then the solvent was removed, and the residue was
distilled to obtain 6.6 g of bisphosphinate 47.
N-Ethyl N,N-bis[methyl(isopropoxy)phosphoryl-
methyl]amine (49). A solution of amine 35, 4.4 g
Heteroatom Chemistry DOI 10.1002/hc

440 Prishchenko et al.
in diethyl ether, 30 mL, was added to a solution
of phosphorus trichloride, 6.5 g in diethyl ether,
15 mL under stirring and cooling at −20◦C. Hexane,
30 mL was added to a mixture, the white crystals of
bis(chloromethyl)amine were isolated and washed
with hexane, 30 mL. Then methylene chloride, 30 mL
was added to the crystals of amine; the mixture was
cooled to −30◦C; and a solution of O,O-diisopropyl
methyl phosphonite, 8.3 g in 20 mL of methylene
chloride was added under stirring. The mixture was
heated and refluxed for 0.5 h; the solvent was re-
moved and the residue was distilled in a vacuum to
give 5.5 g of bisphosphinate 49.
chloride and hexane. The white crystals were kept
in a vacuum (1 mmHg) for 0.5 h to obtain 5 g of
bisphosphonate 54.
REFERENCES
[1] Moedritzer, K.; Irani, R. R. J Org Chem 1966, 31,
1603–1607.
[2] Petrov, K. A.; Chauzov, V. A.; Erokhina, T. S. Usp
Khim 1974, 43, 2045–2085 (in Russian).
[3] Uziel, J.; Jenet, J. P. Zh Org Khim 1997, 33, 1605–
1627 (in Russian).
[4] Kukhar, V. P.; Hudson, H. R. Aminophosphonic and
Aminophosphinic Acids. Chemistry and Biological
Activity; John Wiley and Sons: New York, 2000.
[5] Kolodiazhnyi, O. I. Usp Khim 2006, 75, 254–282 (in
Russian).
[6] Fields, S. C. Tetrahedron 1999, 55, 12237–12273.
[7] Hilgetag, G.; Martini, A. Weygand- Hilgetag.
Organisch-Chemische Experimentierkunst; Khimia:
Moscow, 1968 (in Russian).
/
N,N -Bis(methoxymethyl)piperazine (50). A mix-
ture of piperazine, 8.6 g; paraformaldehyde, 6 g;
and methanol, 100 mL was refluxed for 2 h. Then
potassium carbonate, 7 g was added under stirring,
and the mixture was left for 12 h. The organic layer
was separated, the solvent was evaporated, and the
residue was crystallized from a mixture of diethyl
ether and hexane to give 13.6 g of piperazine 50.
[8] Kabachnik, M. I.; Medved, T. Ya. Dokl Akad Nauk
1952, 83, 689 (in Russian).
[9] Fields, E. K. J Am Chem Soc 1952, 74, 1528.
[10] Petrov, K. A.; Maklyaev, F. L.; Bliznyuk, N. K. Zh
Obsh Khim 1959, 29, 591–594.
/
N,N -Bis(diethoxyphosphorylmethyl)piperazine
(51). A mixture of compound 50, 3.4 g; diethyl
phosphite, 6 g was heated at 100–110◦C until the
distillation of methanol was completed. The residue
was crystallized from a mixture of diethyl ether and
hexane. The white crystals were stored in a vacuum
(1 mmHg) for 0.5 h to obtain 6.9 g of compound
51.
[11] Belsky, F. I.; Goryunova, I. V.; Petrovsky, P. V.;
Medved, T. Ya.; Kabachnik, M. I. Izv AN SSSR Khim
1982, 103–109 (in Russian).
[12] Prishchenko, A. A.; Livantsov, M. V.; Novikova, O. P.;
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[13] Robinson, G. M.; Robinson, R. J Chem Soc 1923, 123,
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Phosphonates; Elsevier: Amsterdam, 2006.
Piperazines 52,53 were prepared similarly.
/
N,N -Bis[bis(trimethylsiloxy)phosphorylmethyl]-
piperazine (54). Trimethylsilyl chloride, 1 mL was
added to a mixture of compound 50, 1.7 g, and
tris(trimethylsilyl) phosphite, 9 g under stirring.
After the completion of the exothermic reaction
the mixture was heated at 70–90◦C for 1 h with
distillation of low-boiling compounds. The residue
was crystallized from a mixture of methylene
Heteroatom Chemistry DOI 10.1002/hc