Synthesis of new types of N,N-disubstituted aminomethylspirophosphoranes

Article abstract of DOI:10.1002/hc.20642

Aminomethylation of several hydrospirophosphoranes and their derivatives, using chloro-, alkoxy-, and amino-substituted methylamines of various structures, is proposed as the convenient method for the synthesis of new N,N-disubstituted aminomethylspiropho

Full text of DOI:10.1002/hc.20642

Heteroatom Chemistry
Volume 21, Number 7, 2010
Synthesis of New Types of N,N-Disubstituted
Aminomethylspirophosphoranes
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 28 April 2010
amines and amino acids are promising polydentate
ABSTRACT: Aminomethylation of several hy-
ligands and bioactive substances.
drospirophosphoranes and their derivatives, using
chloro-, alkoxy-, and amino-substituted methylamines
of various structures, is proposed as the convenient
method for the synthesis of new N,N-disubstituted
RESULTS AND DISCUSSION
In the present paper, we studied the dialky-
laminomethylation of several hydrospirophospho-
ranes, using chloro-, alkoxy-, and amino-substituted
methylamines of various structures. These het-
aminomethylspirophosphoranes. The unique reaction
of aminomethylphosphonites with ethylene glycol also
resulted in the aminomethylspirophosphoranes via
the transesterification followed by the redox pro-
ꢀ
C
erosubstituted methylamines A were used as
cess.
2010 Wiley Periodicals, Inc. Heteroatom Chem
aminomethylating reagents because of their possi-
bilities to generate highly reactive electrophilic car-
boimmonium ions B (cf. [8–11]; (Eq. 1).
21:515–520, 2010; View this article online at wileyonlineli-
brary.com. DOI 10.1002/hc.20642
−
X
[CH2=NR2]+
XCH2NR2
INTRODUCTION
B
A
The functionalized spirophosphoranes incorporat-
ing five-membered ring are of great interest for
their structural investigations as well as the per-
spective biomimetics of amino acids in the vari-
ous biochemical transformations [1–4]. Here, we
present the convenient methods for the synthesis of
N,N-disubstituted aminomethylspirophosphoranes
including alkyl and cycloalkyl fragments, as well as
the moieties of sarcosine and proline, on the basis of
the available hydrospirophosphoranes with reactive
PH fragments and heterosubstituted methylamines
as aminomethylating reagents (cf. [5–7]). The syn-
thesized compounds with the fragments of various
X = Cl, AlkO, Alk2N
(1)
So hydrospirophosphorane C reacted with the most
reactive chloromethylamines in the presence of tri-
ethylamine at 20◦C in methylene chloride to give the
aminomethylspirophosphoranes 1–5 in good yields
(Eq. 2).
H
P
O
O
O
O
O
O
+
−
ClCH2NR2
POCH2CH2O HNEt3
D
C
O
O
O
P
O
O
O
+
+
−
POCH2CH2O HNEt3
CH2NR2 Cl−
- Et3N HCl
CH2NR2
E
1–5
Correspondence to: Andrey A. Prishchenko; e-mail:
aprishchenko@yandex.ru.
Contract grant sponsor: Russian Foundation for Basic
Research.
NR2 = NMe2 (1), NEt2 (2), NPr (3), N(Bu-i) (4),
N
(5)
2
2
Contract grant number: 08-03-00282.
2010 Wiley Periodicals, Inc.
(2)
515
c
ꢀ

516 Prishchenko et al.
The proposed scheme of this reaction involved an electrophilic attack of chloromethylamine on the tertiary
phosphorus of the tautomer D and the elimination of triethylamine hydrochloride from the intermediate E
followed by the rebuilding of the phosphorane structure. Also, we found that the several hydrospirophos-
phoranes reacted smoothly with various N-alkoxymethyl dialkylamines or bis(dialkylamino)methanes un-
der heating at 120◦C via similar scheme to give dialkylaminomethylspirophosphoranes 1–16 in high yields
(Eq. 3).
H
O
O
O
O
O
O
XCH2NR2
P
P
O
O
CH2NR2
1–9
Me
Me
O
O
O
O
Me
H
P
Me
O
O
O
XCH2NR2
P
O
CH2NR2
10, 11
Me
Me
Me
Me
O
O
O
O
Me
Me
H
P
Me
Me
O
O
O
O
XCH2NR2
P
CH2NR2
12–16
X = MeO, EtO, R2N;
NR2 = NMe2 (1, 12), NEt2 (2, 10, 13), NPr (3, 14), N(Bu-i) (4),
(6),
N
(7, 11, 16),
N
(5, 15),
O
N
2
2
(9)
N(Me)CH2COOMe (8),
N
COOMe
(3)
It should be noted that the similar reactions of hydrospirophosphorane C with chlorophospholane F or
bis(trimethylsilyl)amine resulted only in the formation of compounds of three-coordinated phosphorus. So
phosphorane C reacted with chlorophospholane F in the presence of triethylamine at 20◦C to give bisphos-
pholane 17 in a high yield (cf. [12]; Eq. 4).
O
O
O
O
P
POCH2CH2O
ClP
, F
H
P
O
O
O
O
Et3N
O
O
O
O
+
POCH2CH2O−HNEt3
17
− Et 3N HCl
− Et3N
O
O
P
C
O
O
P
O
O
G
(4)
The interaction of phosphorane C with an excess of bis(trimethylsilyl)amine proceeded under boiling of the
reaction mixture and resulted in trimethylsilyl-substituted phospholane 18 in a high yield (Eq. 5).
O
POCH2CH2OSiMe3
H
P
O
O
O
O
O
(Me3Si)2NH
18
− Et3N
O
O
P
C
O
O
SiMe3
H
(5)
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of New Types of N,N-Disubstituted Aminomethylspirophosphoranes 517
The formation of the bulky phosphoranes G and H with the labile P P or P Si bonds was not observed in these
reactions. We found that bisphospholane 17 and phospholane 18, which possessed the similar structures as
the intermediate D, were readily aminomethylated by N-ethoxymethyl dialkylamines via similar schemes. So
bisphospholane 17 slowly reacted with ethoxymethylamines at 20◦C, and this reaction was completed under
heating at 120◦C to give phosphoranes 2, 5, and 6 and phospholane 19 in high yields (Eq. 6).
O
O
O
O
O
O
O
O
O
O
O
O
O
O
+
EtOCH2NR2
+
EtOP
P
P
POCH2CH2O
P
POCH2CH2O
CH2NR2
CH2NR2 OEt
2, 5, 6
19
(6)
O
NR2 = NEt2 (2),
N
(5), N
(6)
The phospholane 18 was aminomethylated via the same way only when heated at 130◦C in the presence of
zinc chloride as a catalyst with distillation of ethoxy(trimethyl)silane to obtain phosphoranes 2, 5, and 6
(Eq. 7).
O
O
O
O
O
O
EtOCH2NR2
P
POCH2CH2OSiMe3
3
CH2NR2
2, 5, 6
(6)
O
NR2 = NEt2 (2),
N
(5), N
(7)
Thus, we developed convenient methods for the dialkylaminomethylation of the hydrospirophosphoranes
and their derivatives, which resulted in the new types of N,N-disubstituted aminomethylspirophosphoranes.
We realized another interesting route for the synthesis of several aminomethylspirophosphoranes via the
interaction of the recently available O,O-diethyl aminomethylphosphonites [13] with ethylene glycol un-
der mild conditions. So, the mixing of the reagents in methylene chloride was accompanied by the rapid
formation of hydrogen to give the spirophosphoranes 3, 5, and 6 in high yields (Eq. 8).
H
O
O
2 HO(CH2)2OH
(EtO)2PCH2NR2
(HOCH2CH2O)2PCH2NR2
POCH2CH2OH
I
CH2NR2
H
J
O
O
O
O
O
O
O
20°C
P
P
2
O
CH2NR2
+
CH2NR2H
3, 5, 6
K
(6)
O
NR2 = NPr2 (3),
N
(5), N
(8)
The proposed scheme of this reaction included the transesterification of starting phosphonites with the
formation of tautomers I and J, and the latter was transformed into the bipolar complex K, which readily
decomposed to give the final spirophosphoranes and hydrogen (cf. [14–16]).
Heteroatom Chemistry DOI 10.1002/hc

518 Prishchenko et al.
TABLE 1 Yields, Products Constants, and NMR Spectral Data (δ ppm, J Hz) for the PC1H2NC2Hn Fragmentsa of
Aminomethylspirophosphoranes 1–16
bp (◦C) (p mm Hg)
No. Yield (%)
(mp (◦C))
nD20
δ (H) C1H2d 2JPH
δ (C1)d
1JPC
δ (C2)d 3JPC
δbPsc
1
2
75
87
89 (1)
112 (1)
(41)
1.4760
–
2.80
2.98
8.6
6.9
60.98
55.16
183.9
180.7
46.75
48.89
10.6
8.1
−9.52 (100)
−7.64 (100)
3
4
5
6
7
8
9
10
74
68
82
82
81
83
74
80
108 (0.5)
125 (1.5)
108 (1)
145 (2)
128 (1.5)
130 (1.5)
168 (2)
98 (0.5)
1.4712
1.4597
1.4878
1.5000
1.5025
1.4801
1.4953
1.4688
3.15
3.36
3.03
2.86
3.27
3.28
7.1
4.5
8.9
9.7
6.8
7.5
4.5d
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
7.2
7.6
56.04
56.79
60.94
60.36
60.53
57.89
54.40
55.63
55.98
56.28
56.13
52.50
54.68
60.98
60.58
61.22
61.31
61.52
60.53
61.84
62.46
55.52
56.45
56.68
57.46
61.67
61.90
61.16
61.71
182.5
182.1
189.4
185.4
171.6
180.8
179.2
182.0
186.6
185.0
184.2
180.7
188.5
172.2
171.1
181.7
175.1
184.0
181.2
181.4
190.3
177.2
190.3
177.1
184.3
187.6
192.2
168.1
181.9
57.52
64.89
56.88
55.21
56.35
43.51
54.40
9.2
4.1
11.1
11.3
6.1
8.6
2.9
6.9
–
–
–
–
–
8.2
8.2
8.9
8.9
8.7
8.7
10.2
12.2
8.3
10.5
9.8
9.0
10.6
9.1
5.0
7.9
−7.41 (100)
−6.10 (100)
−9.63 (100)
−10.62 (100)
−10.15 (100)
−9.63 (100)
−9.37 (100)
−9.50 (25)
3.40d
e
48.91
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
f
−9.45 (20)
f
f
f
f
−9.16 (15)
−9.47 (15)
−9.07 (15)
−8.94 (10)
11
78
133 (1)
1.4995
56.45
56.45
56.81
56.81
57.25
57.25
46.70
47.29
48.83
49.05
57.51
57.89
55.99
56.86
56.98
57.34
−11.44 (25)
−11.79 (20)
−11.34 (15)
−11.23 (15)
−11.54 (15)
−11.91 (10)
−16.25 (65)
−16.54 (35)
−14.20 (70)
−15.00 (30)
−15.94 (55)
−16.86 (45)
−18.62 (60)
−18.52 (40)
−16.72 (70)
−17.36 (30)
12
13
14
15
16
80
60
72
83
79
81 (0.5)
102 (0.5)
115 (1)
113 (1)
139 (1)
1.4674
1.4565
1.4615
1.4812
1.4989
3.15
3.30
aAll signals of alkyl and cycloalkyl groups are in the standard area. In 1H NMR spectra, fragment NCH2C(O) of compound 8, δH = 3.41 d,
4JPH = 2.2; δC = 58.29 d, JPC = 7.5; δC (C O) = 171.36 d, JPC = 2.6. In 13C NMR spectra, fragment NCHC(O) of compound 9: δ(CH) =
3
4
65.13 d, 3JPC = 10.4; δ(C O) = 174.31 d, 3JPC = 2.9.
bThe ratio of isomers, %. This ratio was determined from the 31P NMR spectra.
cData of 31P { H} spectra.
1
dB part of ABX multiplet, 2J(HA HB) = 15.8; A part of ABX multiplet is in the area of overlapping multiplets.
eOverlapping multiplets at the range 2.8–3.3 ppm.
f Overlapping doublets at the range 48.7–48.8.
or CDCl3 (1–18). All reactions were carried out un-
der dry argon in anhydrous solvents. The starting
compounds were prepared as described elsewhere
[8,17,18].
The
structures
of
N,N-disubstituted
aminomethylspirophosphoranes 1–16 and their
precursors 17 and 18 were confirmed by the 1H,
13C, and 31P NMR spectra, which indicated the
characteristic signals of the PC1H2NC2Hn fragments
for phosphoranes (Table 1). The element analysis
data of synthesized compounds are summarized in
Table 2.
5-Dimethylaminomethyl-1,4,6,9-tetraoxa-5-
phosphaspiro[4.4]nonane (1)
(a) To a mixture of 14 g of spirophosphorane C, 9.3 g
of triethylamine, and 50 mL of methylene chloride,
a solution of 8.6 g of N-chloromethyl dimethylamine
in 100 mL of methylene chloride was added dropwise
under stirring at 20◦C. The solvent was distilled off
in a vacuum, 200 mL of diethyl ether was added to
EXPERIMENTAL
The 1H, 13C, and 31P NMR spectra were recorded on a
Varian VXR-400 and Bruker Avance-400 spectrom-
eter (400, 100, and 162 MHz, respectively) in C6D6
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of New Types of N,N-Disubstituted Aminomethylspirophosphoranes 519
TABLE 2 Element Analyses Data of Compounds
Calculated (%)
Found (%)
No.
Empirical Formula
Formula Weight
C
H
C
H
1
2
3
4
5
6
7
8
C7H16NO4P
C9H20NO4P
C11H24NO4P
209.19
237.24
265.29
293.35
249.25
251.21
263.27
267.21
293.25
265.29
291.33
265.29
293.35
321.40
305.35
319.18
242.11
224.27
40.19
45.57
49.80
53.23
48.19
43.03
50.18
40.45
45.05
49.80
53.60
49.80
53.23
56.06
55.07
56.41
29.77
37.49
7.71
8.50
9.12
9.62
8.82
7.22
8.42
6.79
6.87
9.12
9.00
9.12
9.62
10.03
9.24
9.47
5.00
7.64
39.87
45.36
49.68
52.94
47.94
42.98
50.02
40.31
44.91
49.59
53.48
49.54
53.02
55.93
54.96
56.26
29.55
37.13
7.65
8.41
8.87
9.48
8.85
7.38
8.19
6.58
6.72
9.03
8.92
8.99
9.51
9.94
9.12
9.39
4.91
7.52
C13H28NO4P
C10H20NO4P
C9H18NO5P
C11H22NO4P
C9H18NO6P
9
C11H20NO6P
10
11
12
13
14
15
16
17
18
C11H24NO4P
C13H26NO4P
C11H24NO4P
C13H28NO4P
C15H32NO4P
C14H28NO4P
C15H30NO4P
C6H12O6P2
C7H17O4PSi
the residue, and then the mixture was filtrated. The
solvent was distilled off in a vacuum, and the residue
was distilled to give 14.4 g of phosphorane 1.
The phosphoranes 2–5 were obtained analo-
gously.
(b) A mixture of 15.2 g of spirophosphorane
C and 12.2 g of bis(dimethylamino)methane was
heated at 90◦C for 1.5 h and then distilled in a vac-
uum to give 14.9 g of phosphorane 1.
2-[2-(Trimethylsiloxy)ethoxy]-1,3,2-
dioxaphospholane (18)
A mixture of 13 g of spirophosphorane C and 30 g
of bis(trimethylsilyl)amine was heated under reflux
with stirring until the ammonia release was com-
plete. The residue was then distilled to obtain 18 g of
phospholane 18. Yield 93%, b.p. 68◦C under 0.5 mm
Hg, n2D0 = 1.4450. In 13C NMR spectrum, δ (ppm): –
0.42 s (Me3Si), 62.72 d (CH2OSi, 3 JPC = 3.8 Hz), 63.90 d
The phosphoranes 2–16 were prepared similarly.
2
(cyclic CH2, JPC = 8.8 Hz), 64.37 d (CH2OP,2 JPC
=
12.2 Hz). In 31P NMR spectrum, δ (ppm): 135.22 s.
1,2-Bis(1,3,2-dioxaphospholan-2-yloxy)
ethane (17)
5-Diethylaminomethyl-1,4,6,9-tetraoxa-5-
phosphaspiro[4.4]nonane (2)
To a solution of 15.2 g of spirophosphorane C and
13.2 g of triethylamine in 100 mL of benzene, a solu-
tion of 12.7 g of 2-chloro-1,3,2-dioxaphospholane F
in 10 mL of diethyl ether was added dropwise under
stirring at 20◦C. The mixture was left for 48 h, the
mixture was filtrated, and then the solvent was dis-
tilled off. The residue was distilled off in a vacuum
to give 20.1 g of bisphospholane 17. Yield 83%, b.p.
(a) A mixture of 9 g of bisphospholane 17 and 7.3 g
of N-ethoxymethyl diethylamine was heated at 120◦C
for 2 h and then distilled to give 7.7 g of phosphorane
2. Also, 4.5 g of 2-ethoxy-1,3,2-dioxaphospholane 19,
was obtained via distillation of the low-boiling frac-
tion. Yield 89%, b.p. 60◦C under 20 mm Hg, n2D0
1.4392, δP = 133 ppm (cf. [20]).
=
The phosphoranes 5 and 6 were obtained simi-
larly.
1
120◦C under 0.5 mm Hg, n2D0 = 1.4890. In H NMR
spectrum, δ (ppm): 3.55–3.65 m (cyclic CH2, 8H),
(b) A mixture of 5.6 g of phospholane 18, 3.9 g
of N-ethoxymethyl diethylamine, and 0.1 g of zinc
chloride was heated at 130◦C until the distillation
of ethoxy(trimethyl)silane (b.p. 74–76◦C) complete.
The residue was distilled to give 3.4 g of phosphorane
2. Yield 58%.
3.80–3.95 m (bridged CH2, 4H). In 13C NMR spec-
2
trum, δ (ppm): 64.86 d (cyclic CH2, JPC = 8.9 Hz),
62.68 dd (bridged CH2, 2 JPC = 11.9 Hz, 3 JPC = 4.2 Hz).
In 31P NMR spectrum, δ (ppm): 134.46 s.
The constants and NMR spectral data of bispho-
spholane 17 coincided with the data given in refer-
ences [12,19].
The phosphoranes 5 (yield 54%) and 6 (yield
52%) were prepared similarly.
Heteroatom Chemistry DOI 10.1002/hc

520 Prishchenko et al.
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A
mixture of 2.7
g
of
O,O-diethyl-N-
morpholinomethylphosphonite, 1.5 g of ethylene
glycol, and 5 mL of methylene chloride was stirred
at 20◦C until the hydrogen release was complete.
The solvent was removed and then the residue was
distilled to give 2.5 g of phosphorane 6, yield 82%.
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Heteroatom Chemistry DOI 10.1002/hc