Synthesis of N,N-Bis(dialkoxyphosphinoylmethyl)- And N,N-Bis(diphenylphosphinoylmethyl)-?2- and ?3 -amino acid derivatives by the microwave-assisted double Kabachnik-fields reaction

Article abstract of DOI:10.1002/hc.21221

The title compounds were synthesized by the microwave-assisted, mostly solvent-free bis Kabachnik-Fields condensation of ?2-alanine and ?3-aminobutyric acid or their esters with formaldehyde and >P(O)H species, such as dialkyl phosphites and diphenylphosp

Full text of DOI:10.1002/hc.21221

Heteroatom Chemistry
Volume 00, Number 00, 2014
S
ynthesis of
N,N-Bis(dialkoxyphosphinoylmethyl)- and
N,N-Bis(diphenylphosphinoylmethyl)-β- and
γ -amino acid Derivatives by the
Microwave-Assisted Double Kabachnik–Fields
Reaction
1
2
3
2
Erika B a´ lint, Eszter Fazekas, J a´ nos K o´ ti, and Gy o¨ rgy Keglevich
1
MTA-BME Research Group for Organic Chemical Technology, 1521 Budapest, Hungary
2Department of Organic Chemistry and Technology, Budapest University of Technology and
Economics, 1521 Budapest, Hungary
3Gedeon Richter Plc., 1475 Budapest 10, Hungary
Received 28 May 2014; revised 23 July 2014
lated derivatives [1–5] that are of real or potential
biological activity [3,6–8]. With regard to the synthe-
sis, a number of catalytic versions were described in-
cluding microwave (MW)-assisted variations [9,10].
It was suggested that under solvent-free and MW-
assisted conditions, there is no need for any cat-
alyst [11]. α- and β-Amino acids may also be the
starting materials for the Kabachnik–Fields reaction
ABSTRACT: The title compounds were synthe-
sized by the microwave-assisted, mostly solvent-free
bis Kabachnik–Fields condensation of β-alanine and
γ -aminobutyric acid or their esters with formalde-
hyde and >P(O)H species, such as dialkyl phosphites
and diphenylphosphine oxide. ꢀC 2014 Wiley Period-
icals, Inc. Heteroatom Chem. 00:1–10, 2014; View
this article online at wileyonlinelibrary.com. DOI
[12–14].
10.1002/hc.21221
As
a
significant modification, the double
Kabachnik–Fields reaction was also elaborated to
make available bis(phosphonomethyl)amine deriva-
tives [15–18]. The bis(phosphinoylmethyl)amines
are valuable intermediates as they may be converted
to bisphosphine ligands after double deoxygena-
tion [16–18].
INTRODUCTION
The Kabachnik–Fields reaction is an important tool
for the synthesis of α–aminophosphonates and re-
It is also possible to prepare bis(phosphino-
ylmethyl) derivatives from amino acids or their es-
ters by the double Kabachnik–Fields reaction. A few
studies appeared on the synthesis of bis deriva-
tives from α-amino acids or esters [19–22]. The
bis(Kabachnik–Fields) reaction was utilized in the
synthesis of an N,N-bis(dimethoxyphosphinoylme-
thyl)-γ -aminobutyric acid applying the reagents in
an excess, and using tetrahydrofuran as the solvent
Correspondence to: Gy o¨ rgy Keglevich; e-mail: gkeglevich@
mail.bme.hu.
Contract grant sponsor: Hungarian Scientific and Research
Fund.
Contract grant number: OTKA No K83118 and PD111895.
Contract grant sponsor: National Excellence Programme.
´
Contract grant number: TAMOP 4.2.4.A/1-11-1-2012-0001.
Supporting Information is available in the online issue at
www.wileyonlinelibrary.com.
ꢀC
2014 Wiley Periodicals, Inc.
1

2
B a´ lint et al.
SCHEME 1 [23]
SCHEME 2 [24]
SCHEME 3 [24]
SCHEME 4 [25]
(
(
Scheme 1) [23]. Other derivatives, such as N,N-bis-
diethoxyphosphinoylmethyl)-γ -aminobutyric acid
and 3) with 2 equiv of paraformaldehyde and 2
equiv of dialkyl phosphites, such as dimethyl phos-
phite, diethyl phosphite, dibutyl phosphite, and
dibenzyl phosphite, was investigated under MW
conditions. The methyl and ethyl esters of β-
alanine (2 and 3) were liberated from the cor-
responding hydrochloride salts prior to the reac-
tion. The condensations were performed at 100°C
for 1 h in the absence of any solvents, and
the expected N,N-bis(dialkoxyphosphinoylmethyl)-
β-alanine derivatives (4a–d, 5a–d, and 6a–d)
were obtained in yields of 70–99% after column
chromatography (Scheme 5 and Table 1). Using
diphenylphosphine oxide as the P reagent, the re-
actions were carried out in acetonitrile to overcome
the heterogeneity of the reaction mixture. After a
1 h irradiation at 100°C, flash chromatography af-
forded the bis(diphenylphosphinoylmethyl) deriva-
tives 7, 8, and 9 in yields of 61–89% (Scheme 6 and
Table 1).
or β-aminopropionic acid derivatives, were synthe-
sized by somewhat related or different approaches
suggested by Prishchenko (Schemes 2 and 3) [24].
Scheme 2 shows a method comprising a double
nucleophilic substitution, whereas Scheme 3 in-
volves a double Kabachnik–Fields reaction that is
followed by the temporary derivatization of the bis-
substituted aminobutyric and aminopropionic acids
to obtain pure bis(diethoxyphosphinoylmethyl)-
amino acids as the final products [24]. N,N–Bis-
(diphenylphosphinoylmethyl)-γ -aminobutyric acid
and the analogous β-aminopropionic acid were
made available by a special method utilizing the
diphenylphosphine formaldehyde adduct in the dou-
ble N-alkylation of the amino acids (Scheme 4) [25].
In this article, we describe the synthesis of the
bis(phosphinoyl) derivatives of β-alanine and γ –
aminobutyric acid and their esters by the double
Kabachnik–Fields condensation.
In the next round, γ -aminobutyric acid (10) and
its methyl and ethyl esters (11 and 12) were re-
acted with 2 equiv of paraformaldehyde and the
same amount of dialkyl phosphites. After an irra-
diation of 1 h at 100°C, the corresponding products
RESULTS AND DISCUSSION
MW-Assisted Synthesis of β- and γ -Amino Acid
Derivatives
13a–d, 14a–d, and 15a–d were obtained in yields
of 60–97% (Scheme 7 and Table 2). The similar
reaction of diphenylphosphine oxide afforded the
First, the double Kabachnik–Fields reaction of β-
alanine (1) and its methyl and ethyl esters (2
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of N,N-Bis(dialkoxyphosphinoylmethyl)- and N,N-Bis(diphenylphosphinoylmethyl)-β- and γ -amino acid
3
SCHEME 5 Double Kabachnik–Fields reaction of β-alanine derivatives, paraformaldehyde, and dialkyl phosphites.
TABLE 1 Yields of the Bis(>P(O)CH
2
)-β-alanine Deriva-
2
TABLE 2 Yields of the Bis(>P(O)CH )-γ -aminobutyric Acid
Derivatives
tives
Yield
Yield
Yield
Yield
Yield
Yield
Entry Compound (%) Compound (%) Compound (%)
Entry Compound (%) Compound (%) Compound (%)
1
2
3
4
5
4a
4b
4c
4d
7
70
85
77
96
61
5a
5b
5c
5d
8
73
95
90
99
89
6a
6b
6c
6d
9
76
87
77
91
85
1
2
3
4
5
13a
13b
13c
13d
16
79
76
77
81
60
14a
14b
14c
14d
17
86
89
93
88
94
15a
15b
15c
15d
18
74
96
79
97
80
bis(diphenylphosphinoylmethyl) derivatives 16, 17,
and 18 in 60, 89, and 80% yields, respectively. These
reactions had to be also carried out in acetonitrile
due to the heterogeneity (Scheme 8 and Table 2).
It was found that in the reaction of γ -
aminobutyric acid (10) or its ethyl ester (12),
paraformaldehyde, and diphenyl phosphine oxide,
a ring by-product, N–diphenylphosphinoylmethyl)-
The analogous by-products were also found to
have been formed in small quantities (5–-10%) in
the condensation of γ –aminobutyric acid (10) or its
esters (11 and 12), paraformaldehyde, and dialkyl
phosphites. The pyrrolidinone-type by-products may
be formed in two ways. The first possibility is that
2-pyrrolidinone (19), was formed that was isolated
in 18% and 35%, respectively.
SCHEME 6 Double Kabachnik–Fields reaction of β-alanine derivatives, paraformaldehyde, and diphenylphosphine oxide.
SCHEME 7 Double Kabachnik–Fields reaction of γ -aminobutyric acid derivatives, paraformaldehyde, and dialkyl phosphites.
Heteroatom Chemistry DOI 10.1002/hc

4
B a´ lint et al.
SCHEME 8 Double Kabachnik–Fields reaction of γ -aminobutyric acid derivatives, paraformaldehyde, and diphenylphosphine
oxide.
the amino acid is dehydrated to the lactam prior
to the Kabachnik–Fields reaction (Route 1). The
other possibility is that the α–aminophosphine ox-
TABLE 3 Yields of the MW-Assisted and Comparative Ther-
mal Reactions
Yield (%)
1
ide [R O2C(CH2)3NHCH2P(O)Ph2 (20)] or α–amino-
1
Entry
Compound
MW
ꢀ
phosphonate [R O2C(CH2)3NHCH2P(O)(OR)2 (21)]
intermediate formed in the first stage undergoes
cyclization (Route 2). The possibility for Route 1
was investigated by a separate experiment involving
1
2
3
4
5
6
4b
5b
85
95
87
76
89
96
70
81
80
54
63
57
6b
13b
14b
15b
the attempted cyclization of ethyl γ –aminobutyrate
1
(
12) under MW irradiation at 100°C for 1 h.
H
NMR analysis revealed that 18% of the amino
acid ester 12 was cyclized. It is worth mention-
ing that γ –aminobutyric acid (10) was more re-
luctant in respect of cyclization. In the reaction of
paraformaldehyde, and diethyl phosphite carried
out on conventional heating, a small proportion
10 at 100°C for 1 h in a few drops of acetoni-
(
<7%) of the pyrrolidinone-type by-products was
trile (to ensure a homogeneous medium), only a
always present. This confirms that the lactam by-
product may be formed both under MW and con-
ventional heating. The direct cyclization of γ –
aminobutyric acid (10) to 2-pyrrolidinone involves
a 5-h reflux in toluene in the presence of Al2O3 as
the dehydrating agent [28].
In summary, 30 trifunctionalized amines,
comprising bis(dialkoxyphosphinoylmethyl)- or
bis(diphenylphosphinoylmethyl)-β- and γ -amino
acid derivatives, were synthesized under MW and,
in most cases, solvent-free conditions. Among the
compounds, 25 are new and two were characterized
partially earlier. The accelerating effect of the
MW technique was demonstrated by comparative
thermal experiments.
small (<3%) quantity of the pyrrolidinone could
be pointed out by 1H NMR analysis. From the
above data, one can see that Route 2 may be-
come predominant in respect of the formation of
the ring by-product via the α–aminophosphine oxide
1
[
R O2C(CH2)3NHCH2P(O)Ph2 (20)] intermediate. If
1
R = alkyl, the cyclization is more preferred, as com-
1
pared to the case, when R = H.
Comparative Thermal Experiments
Comparative thermal experiments were also per-
formed in a few cases to evaluate the potential of
MW irradiation in the above syntheses. The double
Kabachnik–Fields reactions of β–alanine (1), or γ –
aminobutyric acid (10), or their esters (2, 3 and 11,
12), paraformaldehyde, and diethyl phosphite were
repeated under conventional heating at 100°C for 1 h
in sealed tubes. The yields of the thermal control ex-
periments were 7–39% lower, indicating the positive
role of MW irradiation (Table 3). The acceleration
observed on MW irradiation is the consequence of
the beneficial effect of the local overheatings occur-
ring statistically in the bulk of the mixture [26]. The
detailed study of this effect in organophosphorus re-
actions means a challenge for us [27].
EXPERIMENTAL
General
The 31P, 13C, and H NMR spectra were obtained
in CDCl3 solution on a Bruker AV-300 spectrometer
operating at 121.5, 75.5, and 300 MHz, respectively.
Chemical shifts are downfield relative to 85% H3PO4
and tetramethylsilane. Mass spectra were obtained
using a Thermo LTQ-FT-Ultra mass spectrometer.
The reactions were carried out in a 300 W CEM Dis-
cover focused MW reactor equipped with a pressure
1
It is worth mentioning that in the reac-
tion of γ –aminobutyric acid derivatives (10–12),
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of N,N-Bis(dialkoxyphosphinoylmethyl)- and N,N-Bis(diphenylphosphinoylmethyl)-β- and γ -amino acid
5
controller, applying 20–30 W under isothermal con-
ditions.
The β-alanine and γ -aminobutyric acid esters
were liberated from their hydrochloride salts using
0% Na2CO3 solution (2.0 g of Na2CO3 and 8 mL of
water). Dichloromethane (2 × 10 mL) was used for
the extraction of the free base. The organic phase
was separated and dried (Na2SO4). Evaporation of
the volatile components provided the β-alanine and
γ –aminobutyric acid esters.
N,N-Bis(dibutoxyphosphonylmethyl)-β-alanine
3
1
(4c). Yield: 77% (0.66 g);
P NMR (CDCl3)
1
3
δ: 24.7;
3 3
C NMR (CDCl ) δ: 13.5 (CH ), 18.7
3
(CH CH CH CH ), 32.5 (t, J = 2.9, OCH CH ),
2
2
2
3
CP
2
2
1
3
2
33.3 (CH C O), 50.0 (dd, J = 155.6, J = 5.3,
2
CP
CP
3
3
CH P), 53.0 (t, J = 6.4, CH N), 66.0 (t, J
2
CP
2
1
CP
=
3.5, OCH CH ), 174.0 (C O); H NMR (CDCl ) δ:
2
2
3
3
0.92 (t, J
HH
= 7.4, 12H, CH ), 1.32–1.41 (m, 8H, O
3
CH CH CH ), 1.58–1.66 (m, 8H, OCH CH ), 2.50
2
2
2
2
2
3
3
(t, J = 6.7, 2H, CH C O), 3.13 (t, J = 6.7, 2H,
HH
2
HH
2
CH2N), 3.21(d, JPH = 8.3, 4H, CH2P), 4.00–4.15 (m,
+
8
H, OCH2); [M + H]
= 502.2690, C21H46NO8P2
found
General Procedure for the Preparation of
requires 502.2693.
Bis(>P(O)CH )-β-alanines (4) and
2
Bis(>P(O)CH )-β-alanine Esters (5 and 6)
2
N,N-Bis(dibenzylyoxyphosphonylmethyl)-β-
3
1
alanine (4d). Yield: 96% (1.04 g); P NMR (CDCl3)
A mixture of 1.70 mmol β-alanine or its esters (β-
alanine: 0.15 g, β-alanine methyl ester: 0.18 g, or
β-alanine ethyl ester: 0.20 g), 0.10 g (3.40 mmol) of
paraformaldehyde, and 3.40 mmol of the >P(O)H
species (dimethyl phosphite: 0.31 mL, diethyl phos-
phite: 0.44 mL, dibutyl phosphite: 0.67 mL, and
dibenzyl phosphite: 0.75 mL) was heated at 100°C
in a vial in the MW reactor equipped with a pressure
controller for 1 h. Then, the water formed was re-
moved in a vacuum. Column chromatography (silica
gel 3% methanol in dichloromethane) of the residue
afforded the products (4a–d, 5a–d, 6a–d) as oils. The
following products were thus prepared.
1
3
δ: 25.4; C NMR (CDCl3) δ: 33.4 (CH2C=O), 50.6
1
3
3
(
dd, JCP = 154.7, JCP = 4.7, CH2P), 53.1 (t, JCP =
3
2
1
1
2
.
8
.7, CH2N), 67.8 (t, JCP = 3.2, OCH2), 128.1 (C3),*
3
28.5 (C4), 128.6 (C2),* 135.9 (t, JCP = 2.7, C1),
1
73.9 (C O), *may be reversed; H NMR (CDCl3) δ:
2
.39–2.48 (m, 2H, CH2C O), 3.15 (d, JPH = 8.1, 4H,
3
CH2P), 3.90 (t, JHH = 5.6, 2H, CH2N), 4.91–5.04 (m,
+
H, OCH2), 7.28–7.39 (m, 20H, ArH); [M + H]
found
=
638.2062, C33H38NO8P2 requires 638.2067.
N,N-Bis(dimethoxyphosphonylmethyl)-β-alanine
3
1
Methyl Ester (5a). Yield: 73% (0.43 g); P NMR
1
3
(
4
(
CDCl3) δ: 26.9; C NMR (CDCl3) δ: 32.8 (CH2C O),
1
3
9.2 (dd, JCP = 156.1, JCP = 5.9, CH2P), 51.6
N,N-Bis(dimethoxyphosphonylmethyl)-β-alanine
3
2
COOCH3), 52.4 (t, JCP = 7.7, CH2N), 52.6 (t, JCP
3
1
(
4a). Yield: 70% (0.40 g); P NMR (CDCl3) δ:
1
=
3.4, OCH3), 172.3 (C O); H NMR (CDCl3) δ: 2.53
1
3
2
5.2; C NMR (CDCl3) δ: 33.0 (CH2C O), 49.3 (dd,
3
3
(
t, JHH = 7.0, 2H, CH2C O), 3.14 (t, JHH = 6.9,
1
3
2
JCP = 157.1, JCP = 6.0, CH2P), 52.7 (t, JCP = 3.0,
2
2
3
[
3
H, CH2N), 3.22 (d, JPH = 8.7, 4H, CH2P), 3.68 (s,
3
1
CH2N), 52.8 (t, JCP = 3.5, OCH3), 174.1 (C O); H
2
H, COOCH3), 3.78 (d, 12H, JPH = 10.4, OCH3);
3
NMR (CDCl3) δ: 2.53 (t, JHH = 6.7, 2H, CH2C O),
+
M + H]
= 348.0968, C10H24NO8P2 requires
found
3
2
3
8
.14 (t, JHH = 6.5, 2H, CH2N), 3.22 (d, JPH =
48.0972.
2
.8, 4H, CH2P), 3.79 (d, 12H, JPH = 10.3, OCH3);
+
[
3
M + H]
= 334.0804, C9H22NO8P2 requires
found
N,N-Bis(diethoxyphosphonylmethyl)-β-alanine
34.0815.
31
Methyl Ester (5b). Yield: 95% (0.65 g); P NMR
1
3
3
(
CDCl3) δ: 24.6; C NMR (CDCl3) δ: 16.4 (t, JCP
1
N,N-Bis(diethoxyphosphonylmethyl)-β-alanine
= 2.8, CH2CH3), 32.9 (CH2C=O), 50.0 (dd, JCP =
3
1
3
(
4b). Yield: 85% (0.56 g); P NMR (CDCl3) δ: 25.3;
155.3, JCP = 5.7, CH2P), 51.5 (COOCH3), 52.3 (t,
1
3
3
3
2
δ [24] (CDCl3) 22.1; C NMR (CDCl3) δ: 16.3 (t, JCP
J
= 7.5, CH N), 61.9 (t,
J
CP
= 3.4, CH CH ),
CP
2
1
2
3
1
3
=
2.7, CH2CH3), 33.0 (CH2C O), 50.1 (dd, JCP =
172.4 (C O); H NMR (CDCl3) δ: 1.33 (t, JHH = 7.0,
3
3
3
1
56.6, JCP = 6.0, CH2P), 52.7 (t, JCP = 6.6, CH2N),
12H, CH2CH3), 2.54 (t, JHH = 7.2, 2H, CH2C O),
2
3
2
6
(
5
(
2.3 (t, JCP = 3.3, OCH2), 174.0 (C O); δ [24]
3.16 (t, J
= 7.1, 2H, CH N), 3.20 (d, J = 8.4,
HH
2
PH
1
3
CDCl3) 49.63 (dd, JCP = 155.4, JCP = 5.9, CH2P),
4H, CH2P), 3.67 (s, 3H, COOCH3), 4.09–4.18 (m, 8H,
3
1
+
2.16 (t, JCP = 7.2, CH2N), 173.53 (C O); H NMR
OCH2); [M + H]
= 404.1593, C14H32NO8P2
found
3
CDCl3) δ: 1.29 (t, JHH = 6.8, 12H, CH2CH3), 2.48
requires 404.1598.
3
3
(
t, JHH = 6.3, 2H, CH2C O), 3.11 (t, JHH = 6.1, 2H,
2
CH2N), 3.16 (d, JPH = 8.7, 4H, CH2P), 4.04–4.17 (m,
N,N-Bis(dibutoxyphosphonylmethyl)-β-alanine
3
31
8
H, OCH2); δ [24] (CDCl3) 2.94 (t, JHH = 7.2, 2H,
Methyl Ester (5c). Yield: 90% (0.79 g); P NMR
2
+
13
CH2N), 3.01 (d, JPH = 8.8, 4H, CH2P); [M + H]
(CDCl3) δ: 24.8; C NMR (CDCl3) δ: 13.5 (CH2
found
3
=
390.1447, C13H30NO8P2 requires 390.1441.
CH2CH2CH3), 18.7 (CH2CH2CH2CH3), 32.5 (t, JCP
Heteroatom Chemistry DOI 10.1002/hc

6
B a´ lint et al.
=
=
2.9, OCH2CH2), 32.9 (CH2C=O), 49.9 (dd, 1JCP
N,N-Bis(dibutoxyphosphonylmethyl)-β-alanine
Ethyl Ester (6c). Yield: 77% (0.69 g); 31P
NMR (CDCl3) δ: 24.8; 13C NMR (CDCl3) δ:
13.5 (CH2 CH2CH2CH3), 14.1 (CH2CH3), 18.7
3
154.7, JCP = 5.4, CH2P), 51.5 (COOCH3), 52.2
3
3
(
t, JCP = 7.3, CH2N), 65.6 (t, JCP = 3.5, OCH2),
1
3
1
72.3 (C O); H NMR (CDCl3) δ: 0.90 (t, JHH
7.3, 12H, CH2CH2CH2CH3), 1.30–1.43 (m, 8H,
OCH2CH2CH2), 1.55–1.70 (m, 8H, OCH2CH2), 2.50
3
=
(CH2CH2CH2CH3), 32.6 (t, JCP = 2.9, OCH2CH2),
1
3
33.2 (CH2C O), 49.9 (dd, JCP = 154.8, JCP
3
3
3
(
t, JHH = 7.2, 2H, CH2C=O), 3.13 (t, JHH = 7.2, 2H,
= 5.6, CH2P), 52.3 (t, JCP = 7.3, CH2N), 60.4
2
3
CH2N), 3.17 (d, JPH = 8.3, 4H, CH2P), 3.63 (s, 3H,
(OCH2CH3), 65.7 (t, JCP = 3.5, OCH2CH2), 171.9
+
1
3
COOCH3), 3.96–4.10 (m, 8H, OCH2); [M + H]
(C O); H NMR (CDCl3) δ: 0.92 (t, JHH = 7.3,
found
3
=
516.2845, C22H48NO8P2 requires 516.2848.
12H, CH2CH2CH2CH3), 1.24 (t, JHH = 7.2, 3H,
OCH2CH3), 1.31–1.46 (m, 8H, OCH2CH2CH2), 1.56–
3
1
.71 (m, 8H, OCH2CH2), 2.50 (t, JHH = 7.0, 2H,
N,N-Bis(dibenzylyoxyphosphonylmethyl)-β-
3
alanine Methyl Ester (5d). Yield: 99% (1.10 g); 31P
NMR (CDCl3) δ: 25.4; C NMR (CDCl3) δ: 32.8
CH2C O), 3.13 (t, JHH = 7.3, 2H, CH2N), 3.19 (d,
2
1
3
JPH = 8.2, 4H, CH2P), 3.98–4.17 (m, 10H, OCH2);
+
1
3
[M + H] found = 530.3069, C23H50NO8P2 requires
(
CH2C O), 50.4 (dd, JCP = 155.1, JCP = 6.2, CH2P),
3
530.3062.
5
1.5 (COOCH3), 52.3 (t, JCP = 7.3, CH2N), 67.4 (t,
3
JCP = 3.4, OCH2) 127.9 (C3),* 128.3 (C4), 128.5
3
N,N-Bis(dibenzylyoxyphosphonylmethyl)-β-
(
C2),* 136.2 (t, JCP = 2.9, C1), 172.2 (C O), *may
alanine Ethyl Ester (6d). Yield: 91% (1.03 g); 31P
1
3
be reversed; H NMR (CDCl3) δ: 2.42 (t, JHH = 7.1,
1
3
3
NMR (CDCl3) δ: 25.4; C NMR (CDCl3) δ: 14.1
2
H, CH2C O), 3.12 (t, JHH = 7.0, 2H, CH2N), 3.21
1
2
(OCH2CH3), 32.9 (CH2C O), 50.4 (dd, JCP = 155.0,
(
4
d, JPH = 8.1, 4H, CH2P), 3.57 (s, 3H, COOCH3),
3
3
JCP = 5.8, CH2P), 52.3 (t, JCP = 7.3, CH2N), 60.3
.91–5.07 (m, 8H, OCH2), 7.25–7.38 (m, 20H, ArH);
3
+
(OCH2CH3), 67.4 (t, JCP = 3.4, OCH2) 127.9 (C3),*
[
6
M + H]
= 652.2213, C34H40NO8P2 requires
found
3
1
28.3 (C4), 128.5 (C2),* 136.2 (t, JCP = 2.9, C1), 171.7
52.2224.
1
(
(
2
C O), *may be reversed; H NMR (CDCl3) δ: 1.19
t, JHH = 7.1, 3H, OCH2CH3), 2.41 (t, JHH = 7.2,
3
3
N,N-Bis(dimethoxyphosphonylmethyl)-β-alanine
3
H, CH2C=O), 3.12 (t, JHH = 6.9, 2H, CH2N), 3.21
3
1
Ethyl Ester (6a). Yield: 76% (0.47 g); P NMR
2
(
4
d, JPH = 8.1, 4H, CH2P), 4.04 (q, 2H, C(O)OCH2),
1
3
(CDCl3) δ: 27.0; C NMR (CDCl3) δ: 14.1 (CH2CH3),
.88–5.09 (m, 8H, OCH2), 7.26–7.33 (m, 20H, ArH);
1
3
3
3.1 (CH2C O), 49.2 (dd, JCP = 156.0, JCP = 5.8,
+
[
6
M + H]
= 666.2374, C35H42NO8P2 requires
found
3
2
CH2P), 52.5 (t, JCP = 7.6, CH2N), 52.6 (t, JCP = 3.3,
66.2380.
1
OCH3), 60.5 (OCH2), 171.9 (C O); H NMR (CDCl3)
3
3
δ: 1.24 (t, JHH = 7.4, 3H, OCH2CH3), 2.49 (t, JHH =
3
General Procedure for the Synthesis of N,N-Bis-
(diphenylphosphinoylmethyl)-β-alanine (7) and
N,N-Bis(diphenylphosphinoylmethyl)-β-alanine
Esters (8 and 9)
7
3
1
3
.0, 2H, CH2C O), 3.11 (t, JHH = 7.0, 2H, CH2N),
2
2
.19 (d, JPH = 8.6, 4H, CH2P), 3.75 (d, 12H, JPH =
+
0.4, OCH3), 4.11 (q, 2H, OCH2); [M + H]
=
found
62.1141, C11H26NO8P2 requires 362.1128.
A mixture of 0.85 mmol β-alanine or its es-
ters (β-alanine: 0.08 g, β-alanine methyl ester:
0.09 g, or β-alanine ethyl ester: 0.10 g), 0.05 g
(1.7 mmol) of paraformaldehyde, 0.34 g (1.7 mmol)
of diphenylphosphine oxide in 3 mL of acetonitrile
was heated at 100°C in a closed vial in the MW re-
actor for 1 h. The work-up was similar as above to
provide products 7, 8, and 9 as oils.
N,N-Bis(diethoxyphosphonylmethyl)-β-alanine
Ethyl Ester (6b). Yield: 87% (0.66 g); P NMR
3
1
1
3
(
(
CDCl3) δ: 24.6; δ [24] (CDCl3) 24.2;
C NMR
3
CDCl3) δ: 14.0 (C(O)OCH2CH3), 16.3 (t, JCP = 2.6,
1
CH2CH3), 32.9 (CH2C O), 49.9 (dd, JCP = 155.5,
3
3
JCP = 5.7, CH2P), 52.2 (t, JCP = 7.5, CH2N), 60.2
(
(
C(O)OCH2), 61.9 (t, 2JCP = 3.3, CH2CH3), 171.8
1
3
C=O); δ [24] (CDCl3) 50.40 (dd, JCP = 154.8, JCP
3
=
6.0, CH2P), 52.94 (t, JCP = 8.4, CH2N), 171.73
N,N-bis(diphenylphosphinoylmethyl)-β-alanine
1
3
31
(
C=O); H NMR (CDCl3) δ: 1.26 (t, JHH = 7.1, 3H,
(7). Yield: 61% (0.27 g);
P NMR (CDCl3) δ:
3
13
C(O)OCH2CH3), 1.33 (t, JHH = 7.0, 12H, CH2CH3),
30.1; δ [25] (CDCl3) 30.0; C NMR (CDCl3) δ: 32.3
3
3
3
1
2
7
.53 (t, JHH = 7.1, 2H, CH2C O), 3.14 (t, JHH =
.0, 2H, CH2N), 3.22 (d, 2JPH = 8.5, 4H, CH2P),
(CH2C O), 54.6 (t, JCP = 6.7, CH2N), 55.2 (dd, JCP
3
3
= 82.4, JCP = 6.5, CH2P), 128.6 (d, JCP = 12.0,
3
3
4
.05–4.18 (m, 10H, OCH2); δ [24] (CDCl3) 3.25 (k,
C3),* 131.1 (d, JCP = 9.6, C2),* 131.2 (d, JCP = 97.9,
3
2
1
JHH = 7.8, 2H, CH2N), 3.28 (d, JPH = 9.0, 4H,
C1), 131.9 (C4), 174.5 (C O), *may be reversed; H
+
3
CH2P); [M + H]
= 418.1757, C15H34NO8P2
NMR (CDCl3) δ: 2.47 (t, JHH = 6.6, 2H, CH2C O),
found
3
2
requires 418.1752.
3.23 (t, JHH = 6.5, 2H, CH2N), 3.76 (d, JPH = 4.3,
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of N,N-Bis(dialkoxyphosphinoylmethyl)- and N,N-Bis(diphenylphosphinoylmethyl)-β- and γ -amino acid
7
3
1
1
3
4
H, CH2P), 7.32–7.78 (m, 20H, ArH); δ [25]* (CDCl3)
P NMR (CDCl ) δ: 24.9; δ [23] (CDCl ) 30.7;
3
3
2.53 (t, 2H, CH2), 3.23 (s, 2H, CH2N), 3.79 (s, 4H,
3 2 2 2
C NMR (CDCl ) δ: 22.6 (CH CH CH N), 31.2
+
1
3
CH2P), 7.36–7.73 (m, 20H, ArH); [M + H]
=
(CH C O), 49.4 (dd, J = 158.5, J = 7.3, CH P),
found
2
CP
CP
2
3
2
518.1638, C29H29NO4P2 requires 518.1645.
52.7 (t, J = 3.4, OCH ), 56.0 (t, J = 7.5, CH N),
CP
3
CP
2
1
76.1 (C O); δ [23] (CDCl3) 22.6 (CH2CH2CH2N),
1
3
N,N-Bis(diphenylphosphinoylmethyl)-β-alanine
31.1 (CH C O), 49.3 (dd, J = 158.0, J = 7.3,
2
CP
CP
3
1
2
2
Methyl Ester (8). Yield: 89% (0.40 g); P NMR
CH P), 52.8 (d, J = 7.2, OCH ), 56.0 (t, J
=
2
CP
3
CP
CDCl3) δ: 29.1; 13C NMR (CDCl3) δ: 31.5 (CH2C O),
1
(
2 3
7.5, CH N), 176.1 (C O); H NMR (CDCl ) δ: 1.79
3
3
3
5
1.5 (COOCH3), 53.9 (t, JCP = 6.6, CH2N), 55.6 (dd,
(t, J
= 7.2, 2H, CH CH CH N), 2.41 (t, J
=
HH
2
2
2
HH
1
3
3
3
JCP = 83.3, JCP = 6.8, CH2P), 128.4 (d, JCP = 11.7,
7.4, 2H, CH C O), 2.83 (t, J
= 6.8, 2H, CH N),
2
HH
2
2
3
2
C3),* 131.1 (d, JCP = 9.3, C2),* 131.7 (C4), 131.9
3.16 (d, J = 8.9, 4H, CH P), 3.79 (d, 12H, J
=
PH
2
PH
3
3
(
d, JCP = 88.2, C1), 172.8 (C O), *may be reversed;
10.6, OCH ); δ [23] (CDCl ) 1.74 (q, J
HH
= 7.1, 2H,
3
3
1
3
H NMR (CDCl3) δ: 1.50–1.62 (m, 2H, CH2CH2CH2),
CH CH CH N), 2.36 (t, J
HH
= 7.1, 2H, CH C O),
2
2
2
2
2
3
3
3
1
.88 (t, JHH = 7.4, 2H, CH2C O), 2.98 (t, JHH =
2.78 (t, JHH = 7.1, 2H, CH N), 3.10 (d,
J
PH
=
2
2
6
.4, 2H, CH2N), 3.59 (s, 3H, COOCH3), 3.72 (d,
8.8, 4H, CH P), 3.74 (d, 12H, J = 10.7, OCH );
2
PH
3
2
+
JPH = 5.8, 4H, CH2P), 7.34–7.78 (m, 20H, ArH);
[M + H]
= 348.0971, C H NO P requires
found
10 24
8 2
+
[
M + H]
= 532.1806, C30H32NO4P2 requires
348.0972.
found
532.1811.
N,N-Bis(diethoxyphosphonylmethyl)-γ -amino-
butyric Acid (13b). Yield: 76% (0.52 g); P NMR
N,N-Bis(diphenylphosphinoylmethyl)-β-alanine
Ethyl Ester (9). Yield: 85% (0.40 g); P NMR
31
3
1
13
(
(
(
1
6
(
5
CDCl3) δ: 25.9; δ [24] (CDCl3) 22.2;
C NMR
1
3
(
(
7
6
(
8
(
(
CDCl3) δ: 29.2;
C
NMR (CDCl3) δ: 14.1
3
CDCl3) δ: 16.3 (t, JCP = 2.8, CH2CH3), 22.6
OCH2CH3), 31.6 (CH2C O), 53.8 (t, 3JCP
=
1
CH2CH2CH2N), 31.2 (CH2C O), 50.0 (dd, JCP =
1
3
.0, CH2N), 55.6 (dd, JCP = 83.3, JCP = 7.0, CH2P),
3
3
57.6, JCP = 7.0, CH2P), 55.8 (t, JCP = 7.3, CH2N),
3
0.4 (OCH2CH3), 128.4 (d, JCP = 11.7, C3),* 131.1
2
2.0 (t, JCP = 3.4, OCH2), 175.8 (C O); δ [24]
3
3
d, JCP = 9.4, C2),* 131.7 (C4), 131.9 (d, JCP =
1
3
CDCl3) 49.56 (dd, JCP = 156.4, JCP = 7.1, CH2P),
1
7.6, C1), 172.4 (C O), *may be reversed; H NMR
3
1
5.50 (t, JCP = 7.5), 175.14 (C O); H NMR (CDCl3)
3
CDCl3) δ: 1.15 (t, JHH = 7.2, 3H, OCH2CH3), 2.39
3
3
δ: 1.25 (t, JHH = 7.0, 12H, CH2CH3), 1.71 (t, JHH
3
3
t, JHH = 6.9, 2H, CH2C O), 3.32 (t, JHH = 6.7, 2H,
3
=
7.0, 2H, CH2CH2CH2N), 2.31 (t, JHH = 7.0, 2H,
2
CH2N), 3.76 (d, JPH = 5.81, 4H, CH2P), 3.98 (q, 2H,
3
CH2C O), 2.76 (t, JHH = 6.5, 2H, CH2N), 3.08 (d,
+
C(O)OCH2), 7.33–7.79 (m, 20H, ArH); [M + H]
2
found
JPH = 8.9, 4H, CH2P), 4.01–4.16 (m, 8H, OCH2);
=
546.1960, C31H34NO4P2 requires 546.1958.
3
δ [24] (CDCl3) 2.61 (t, JHH = 6.6, 2H, CH2N), 2.94
2
+
(
d, JPH = 8.8, 4H, CH2P); [M + H]
= 404.1592,
found
General Procedure for the Preparation of
C14H32NO8P2 requires 404.1598.
Bis(>P(O)CH )-γ -aminobutyric Acids (13) and
2
Bis(>P(O)CH )-γ -aminobutyric Acid Esters
2
N,N-Bis(dibutoxyphosphonylmethyl)-γ -amino-
(
14 and 15)
butyric Acid (13c). Yield: 77% (0.68 g); 31P
1
3
NMR (CDCl3) δ: 25.7; C NMR (CDCl3) δ: 13.5
A mixture of 1.7 mmol γ -aminobutyric acid or its es-
ters (γ –aminobutyric acid: 0.18 g, γ –aminobutyric
acid methyl ester: 0.20 g, or γ –aminobutyric
acid ethyl ester: 0.22 g), 0.10 g (3.4 mmol) of
paraformaldehyde, and 3.4 mmol of the >P(O)H
species (dimethyl phosphite: 0.31 mL, diethyl phos-
phite: 0.44 mL, dibutyl phosphite: 0.67 mL, and
dibenzyl phosphite: 0.75 mL) was heated at 100°C
in a vial in the MW reactor equipped with a pressure
controller for 1 h. Then, the water formed was re-
moved in a vacuum. Column chromatography (silica
gel 3% methanol in dichloromethane) of the residue
afforded the products (13a–d, 14a–-d, 15a–d) as
oils. The following products were thus prepared.
(
(
2
CH2 CH2CH2CH3), 18.7 (CH2CH2CH2CH3), 22.9
3
CH2CH2CH2N), 31.5 (CH2C O), 32.5 (t, JCP =
1
3
.8, OCH2CH2), 50.0 (dd, JCP = 156.9, JCP = 6.6,
3
3
CH2P), 55.7 (t, JCP = 6.9, CH2N), 65.8 (t, JCP = 3.5,
1
OCH2CH2), 176.1 (C O); H NMR (CDCl3) δ: 0.93
3
(
8
1
t, JHH = 7.3, 12H, CH2CH2CH2CH3), 1.34–1.45 (m,
H, OCH2CH2CH2), 1.57–1.70 (m, 8H, OCH2CH2),
3
3
.79 (t, JHH = 6.9, 2H, CH2CH2CH2N), 2.40 (t, JHH
3
=
7.3, 2H, CH2C O), 2.85 (t, JHH = 6.0, 2H, CH2N),
2
3
.15 (d, JPH = 8.5, 4H, CH2P), 4.01–4.15 (m, 8H,
+
OCH2); [M + H]
= 516.2844, C22H48NO8P2
found
requires 516.2850.
N,N-Bis(dibenzylyoxyphosphonylmethyl)-γ -
N,N-Bis(dimethoxyphosphonylmethyl)-γ -
aminobutyric Acid (13a). Yield: 79% (0.47 g);
aminobutyric Acid (13d). Yield: 81% (0.90 g); 31P
NMR (CDCl3) δ: 26.5; C NMR (CDCl3) δ: 22.7
1
3
Heteroatom Chemistry DOI 10.1002/hc

8
B a´ lint et al.
1
6.7, 2H, CH2N), 3.10 (d, 2JPH = 8.5, 4H, CH2P),
(
CH2CH2CH2), 31.3 (CH2C O), 50.5 (dd, JCP =
3
3
1
6
1
*
=
57.2, JCP = 7.2, CH2P), 55.8 (t, JCP = 7.0, CH2N),
3.62 (s, 3H, COOCH3), 3.96–4.09 (m, 8H, OCH2);
3
+
7.6 (t, JCP = 3.4, OCH2) 128.0 (C3),* 128.4 (C4),
[M + H]
= 530.2998, C23H50NO8P2 requires
found
3
28.5 (C2),* 136.0 (t, JCP = 2.9, C1), 176.2 (C O),
530.3006.
1
3
may be reversed; H NMR (CDCl3) δ: 1.69 (t, JHH
3
6.9, 2H, CH2CH2CH2), 2.29 (t, JHH = 7.3, 2H,
N,N-Bis(dibenzylyoxyphosphonylmethyl)-γ -
aminobutyric Acid Methyl Ester (14d). Yield: 88%
3
CH2C O), 2.78 (t, JHH = 6.2, 2H, CH2N), 3.12 (d,
2
JPH = 8.3, 4H, CH2P), 4.90–5.01 (m, 8H, OCH2),
31
13
(
1.0 g); P NMR (CDCl3) δ: 26.0; C NMR (CDCl3)
+
7
.23–7.30 (m, 20H, ArH); [M + H]
= 652.2211,
1
found
δ: 22.5 (CH CH CH ), 31.0 (CH C=O), 50.4 (dd, J
2
2
2
2
CP
C34H40NO8P2 requires 652.2224.
3
=
156.4, JCP = 7.1, CH2P), 51.4 (COOCH3), 55.7 (t,
3
JCP = 7.4, CH2N), 67.2–67.5 (m, OCH2), 127.9 (C3),*
3
N,N-Bis(dimethoxyphosphonylmethyl)-γ -amino-
butyric Acid Methyl Ester (14a). Yield: 86% (0.52
g); P NMR (CDCl3) δ: 24.7; C NMR (CDCl3) δ:
128.3 (C4), 128.5 (C2),* 136.2 (t, JCP = 2.9, C1),
1
173.7 (C O), *may be reversed; H NMR (CDCl3) δ:
3
1
13
3
3
1.71 (t, JHH = 7.1, 2H, CH2CH2CH2), 2.27 (t, JHH =
1
3
2
2.5 (CH2CH2CH2), 30.9 (CH2C O), 49.2 (dd, JCP
7.5, 2H, CH2C=O), 2.81 (t, JHH = 6.7, 2H, CH2N),
3
2
=
157.9, JCP = 7.1, CH2P), 51.5 (COOCH3), 52.6
3.17 (d, JPH = 8.6, 4H, CH2P), 4.95–5.20 (m, 8H,
2
3
+
(
t, JCP = 6.9, OCH3), 55.9 (t, JCP = 7.6, CH2N),
OCH2), 7.28–7.32 (m, 20H, ArH); [M + H] found =
1
1
73.8 (C O); H NMR (CDCl3) δ: 1.65–1.82 (m, 2H,
666.2383, C35H42NO8P2 requires 666.2380.
3
CH2CH2CH2), 2.40 (t, JHH = 7.4, 2H, CH2C O),
3
2
2
.82 (t, JHH = 6.7, 2H, CH2N), 3.16 (d, JPH = 9.0,
N,N-Bis(dimethoxyphosphonylmethyl)-γ -amino-
butyric Acid Ethyl Ester (15a). Yield: 74% (0.47 g);
4
H, CH2P), 3.67 (s, 3H, COOCH3), 3.78 (d, 12H,
2
+
3
1
13
JPH = 10.6, OCH3); [M + H]
= 362.1126,
found
3 3
P NMR (CDCl ) δ: 24.7; C NMR (CDCl ) δ: 14.1
C11H26NO8P2 requires 362.1128.
(
(
CH2CH3), 22.5 (CH2CH2CH2), 31.2 (CH2C=O), 49.2
1 3 2
dd, JCP = 157.8, JCP = 7.1, CH2P), 52.5 (t, JCP =
3
3
1
3
2
6
.4, OCH3), 55.9 (t, JCP = 7.7, CH2N), 60.2 (OCH2),
N,N-Bis(diethoxyphosphonylmethyl)-γ -amino-
butyric Acid Methyl Ester (14b). Yield: 89% (0.63
g); P NMR (CDCl3) δ: 26.0; δ [24] (CDCl3) 24.4;
1
3
73.3 (C O); H NMR (CDCl3) δ: 1.20 (t, JHH = 7.1,
3
1
H, OCH2CH3), 1.67–1.79 (m, 2H, CH2CH2CH2),
3
3
1
3
3
.33 (t, JHH = 7.3, 2H, CH2C=O), 2.76 (t, JHH =
C NMR (CDCl3) δ: 16.4 (t, JCP = 2.8, CH2CH3),
2
1
.7, 2H, CH2N), 3.11 (d, JPH = 9.0, 4H, CH2P), 3.73
2
2.6 (CH2CH2CH2), 31.0 (CH2C O), 50.0 (dd, JCP
2
3
(
[
d, 12H, JPH = 10.5, OCH3), 4.11 (q, 2H, OCH2);
=
157.1, JCP = 6.9, CH2P), 51.4 (COOCH3), 55.7 (t,
+
3
2
M + H]
= 376.1276, C12H28NO8P2 requires
JCP = 7.7, CH2N), 61.9 (t, JCP = 3.4, OCH2), 173.8
found
1
3
3
76.1285.
(
C O); δ [24] (CDCl3) 50.45 (dd, JCP = 156.9, JCP
3
=
7.1, CH2P), 56.18 (t, JCP = 8.3, CH2N), 173.07
1
3
(
C O); H NMR (CDCl3) δ: 1.30 (t, JHH = 7.0, 12H,
N,N-Bis(diethoxyphosphonylmethyl)-γ -amino-
butyric Acid Ethyl Ester (15b). Yield: 96% (0.70 g);
CH2CH3), 1.70–1.81 (m, 2H, CH2CH2CH2), 2.37 (t,
3
3
31
13
JHH = 7.4, 2H, CH2C O), 2.81 (t, JHH = 6.6, 2H,
3 3
P NMR (CDCl ) δ: 24.9; C NMR (CDCl ) δ: 14.1
2
3
CH2N), 3.12 (d, JPH = 8.9, 4H, CH2P), 3.64 (s, 3H,
(C(O)OCH CH ), 16.4 (t, J = 2.9, CH CH ), 22.6
2
3
CP
2
3
1
COOCH3), 4.05–4.14 (m, 8H, OCH2); δ [24] (CDCl3)
(CH CH CH ), 31.3 (CH C=O), 50.0 (dd,
J
CP
=
2
2
2
2
2
3
3
3
3
2
.18 (d, JPH = 9.1, 4H, CH2P), 3.27 (k, JHH = 6.7,
156.9, J = 6.9, CH P), 55.8 (t, J = 7.8, CH N),
CP
2
CP
2
+
2
H, CH2N); [M + H]
= 418.1749, C15H34NO8P2
60.2 (C(O)OCH ), 61.8 (t, J = 3.4, CH CH ),173.5
found
2
CP
2
3
1
3
requires 418.1754.
(C O); H NMR (CDCl ) δ: 1.25 (t, J
= 7.1, 3H,
3
3
HH
C(O)OCH2CH3), 1.33 (t, JHH = 7.0, 12H, CH2CH3),
3
1
.75–1.83 (m, 2H, CH2CH2CH2), 2.38 (t, JHH = 7.4,
N,N-Bis(dibutoxyphosphonylmethyl)-γ -amino-
butyric Acid Methyl Ester (14c). Yield: 84% (0.76 g);
P NMR (CDCl3) δ: 25.7; C NMR (CDCl3) δ: 13.5
CH2 CH2CH2CH3), 18.7 (CH2CH2CH2CH3), 22.7
3
2
H, CH2C = O), 2.84 (t, JHH = 6.7, 2H, CH2N),
2
3
1
13
3.15 (d, J = 8.8, 4H, CH P), 4.07–4.17 (m, 10H,
PH
2
+
OCH2); [M + H]
= 432.1919, C16H36NO8P2
(
(
found
3
requires 432.1911.
CH2CH2CH2N), 31.1 (CH2C O), 32.5 (t, JCP = 2.9,
1
3
OCH2CH2), 49.8 (dd, JCP = 156.1, JCP = 6.6, CH2P),
3
5
(
0
1
1.4 (COOCH3), 55.7 (t, JCP = 7.5, CH2N), 65.4–65.7
N,N-Bis(dibutoxyphosphonylmethyl)-γ -amino-
1
m, OCH2CH2), 173.9 (C O); H NMR (CDCl3) δ:
butyric Acid Ethyl Ester (15c). Yield: 79% (0.73
3
31
13
.89 (t, JHH = 7.3, 12H, CH2CH2CH2CH3), 1.29–
g); P NMR (CDCl3) δ: 25.6; C NMR (CDCl3)
δ: 13.5 (CH2 CH2CH2CH3), 14.2 (OCH2CH3), 18.7
(CH2CH2CH2CH3), 22.7 (CH2CH2CH2N), 31.4
.42 (m, 8H, OCH2CH2CH2), 1.54–1.68 (m, 8H,
3
OCH2CH2), 1.74 (t, JHH = 7.2, 2H, CH2CH2CH2N),
3
3
3
2
.34 (t, JHH = 7.4, 2H, CH2C O), 2.78 (t, JHH =
(CH2C=O), 32.6 (t, JCP = 2.9, OCH2CH2), 49.8
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of N,N-Bis(dialkoxyphosphinoylmethyl)- and N,N-Bis(diphenylphosphinoylmethyl)-β- and γ -amino acid
9
1
3
3
2
(
dd, JCP = 156.0, JCP = 6.4, CH2P), 55.7 (t, JCP
(d, JPH = 5.4, 4H, CH2P), 7.33–7.78 (m, 20H, ArH);
3
=
7.3, CH2N), 60.1 (OCH2CH3), 65.5 (t, JCP =
δ [25]* (CDCl3) 1.69 (m, 2H, CH2), 2.15 (t, 2H, CH2),
1
2
3
.5, OCH2CH2), 173.4 (C O); H NMR (CDCl3) δ:
2.97 (t, 2H, CH2N), 3.76 (d, JPH = 3.6, 4H, CH2P),
3
+
0
(
.92 (t, JHH = 7.2, 12H, CH2CH2CH2CH3), 1.23
7.32–7.86 (m, 20H, ArH); [M + H]
= 532.1801,
found
3
t, JHH = 7.0, 3H, OCH2CH3), 1.33–1.42 (m, 8H,
C30H32NO4P2 requires 532.1801.
OCH2CH2CH2), 1.57–1.68 (m, 8H, OCH2CH2), 1.77
3
3
(
7
3
t, JHH = 7.1, 2H, CH2CH2CH2N), 2.35 (t, JHH =
N,N-Bis(diphenylphosphinoylmethyl)-γ -amino-
butyric Acid Methyl Ester (17). Yield: 94% (0.44 g);
P NMR (CDCl ) δ: 29.5; C NMR (CDCl ) δ: 21.8
3 3
3
.3, 2H, CH2C=O), 2.81 (t, JHH = 6.6, 2H, CH2N),
2
31
13
.13 (d, JPH = 8.7, 4H, CH2P), 4.00–4.13 (m, 10H,
+
OCH2); [M + H]
= 544.3165, C24H52NO8P2
(CH CH CH ), 30.7 (CH C=O), 51.3 (COOCH ),
found
2
2
2
2
3
1
3
3
requires 544.3163.
55.7 (dd, J = 84.8, J = 7.8, CH P), 57.3 (t, J
CP
CP
3
2
CP
=
7.2, CH2N), 128.4 (d, JCP = 11.7, C3),* 131.0 (d,
3
3
JCP = 9.2, C2),* 131.7 (C4), 131.8 (d, JCP = 84.8, C1),
N,N-Bis(dibenzylyoxyphosphonylmethyl)-γ -
aminobutyric Acid Ethyl Ester (15d). Yield: 97%
1.1 g); P NMR (CDCl3) δ: 26.4; C NMR (CDCl3)
δ: 14.1 (OCH2CH3), 22.5 (CH2CH2CH2), 31.2
1
1
74.0 (C O), *may be reversed; H NMR (CDCl3) δ:
3
3
1
13
1.50–1.62 (m, 2H, CH CH CH ), 1.88 (t, J
HH
= 7.4,
(
2
2
2
3
2
H, CH2C=O), 2.98 (t, JHH = 6.4, 2H, CH2N), 3.59
2
1
3
(s, 3H, COOCH ), 3.72 (d, J
= 5.8, 4H, CH P),
(
5
(
(
CH2C=O), 50.4 (dd, JCP = 156.4, JCP = 7.0, CH2P),
3
PH
2
+
3
7.34–7.78 (m, 20H, ArH); [M + H]
= 546.1945,
5.7 (t, JCP = 7.4, CH2N), 60.1 (OCH2CH3), 67.3
found
3
C H NO P requires 546.1958.
t, JCP = 3.4, OCH2) 127.8 (C3),* 128.2 (C4), 128.4
31 34
4 2
3
C2),* 136.2 (t, JCP = 2.9, C1), 173.2 (C O), *may be
1
3
N,N-Bis(diphenylphosphinoylmethyl)-γ -amino-
butyric Acid Ethyl Ester (18). Yield: 80% (0.38 g);
P NMR (CDCl ) δ: 29.2; C NMR (CDCl ) δ: 14.2
3 3
reversed; H NMR (CDCl3) δ: 1.21 (t, JHH = 7.1, 3H,
3
OCH2CH3), 1.69 (t, JHH = 7.1, 2H, CH2CH2CH2),
3
1
13
3
3
2
6
4
7
.23 (t, JHH = 7.5, 2H, CH2C=O), 2.79 (t, JHH =
.6, 2H, CH2N), 3.16 (d, 2JPH = 8.9, 4H, CH2P),
.07 (q, 2H, C(O)OCH2), 4.90–5.06 (m, 8H, OCH2),
(OCH CH ), 21.8 (CH CH CH ), 31.1 (CH C=O),
2
3
1
2
3
2
2
2
5
5.8 (dd, JCP = 84.9, JCP = 7.8, CH2P), 57.5 (t,
3
3
+
JCP = 6.8, CH N), 60.0 (OCH CH ), 128.4 (d, J
.23–7.34 (m, 20H, ArH); [M + H]
= 680.2532,
2
2
3
CP
found
3
=
11.7, C3),* 131.1 (d, JCP = 9.2, C2),* 131.6 (C4),
C36H44NO8P2 requires 680.2537.
3
1
32.0 (d, JCP = 97.9, C1), 173.6 (C O), *may be
1
3
reversed; H NMR (CDCl3) δ: 1.22 (t, JHH = 4.6, 3H,
General Procedure for the Synthesis of N,N-Bis-
diphenylphosphinoylmethyl)-γ –aminobutyric
Acid (16) and N,N-Bis(diphenylphosphinoyl-
methyl)-γ –aminobutyric Acid Esters (17 and
OCH CH ), 1.51–1.66 (m, 2H, CH CH CH ), 1.90
2
3
2
2
2
3
3
(
(t, J = 7.6, 2H, CH C=O), 3.00 (t, J = 6.7, 2H,
HH
2
HH
2
CH N), 3.72 (d, J = 6.0, 4H, CH P), 4.05 (q, 2H,
2
PH
2
+
C(O)OCH ), 7.32–7.85 (m, 20H, ArH); [M + H]
2
found
1
8)
= 560.2111, C H NO P requires 560.2114.
3
2
36
4 2
A mixture of 0.85 mmol γ -aminobutyric acid
or its esters (γ –aminobutyric acid: 0.09 g, γ –
aminobutyric acid methyl ester: 0.10 g, or γ -
aminobutyric acid ethyl ester: 0.11 g), 0.05 g (1.7
mmol) of paraformaldehyde, 0.34 g (1.7 mmol) of
diphenylphosphine oxide in 3 mL of acetonitrile was
heated at 100°C in a closed vial in the MW reactor
for 1 h. The work-up was similar as above to provide
products 10, 11, and 12 as oils.
N-Diphenylphosphinoylmethyl)pyrrolodin-2-one
3
1
13
(
19).
P NMR (CDCl3) δ: 30.3; C NMR (CDCl3)
δ: 17.9 (C4), 29.9 (C3=O), 43.3 (d, JCP = 43.3, CH2P),
3
3
4
8.5 (C5N), 128.7 (d, JCP = 11.8, C ),* 130.7 (d, JCP
3
’
3
=
98.4, C
ꢁ
), 130.9 (d, JCP = 9.7, C
ꢁ
),* 132.2 (d,
2
1
3
3
JCP = 2.8, C
ꢁ
), 174.9 (d, JCP = 2.7, C O), *may
4
1
be reversed; H NMR (CDCl3) δ: 1.83–1.92 (m, 2H,
3
3
C4H), 2.20 (t, JHH = 8.4, 2H, C3H), 3.65 (t, JHH
2
=
7.0, 2H, C5H), 4.23 (d, JPH = 5.6, 2H, CH2P),
7
.44–7.88 (m, 10H, ArH); δ [29] (CDCl3) 1.9 (m, 2H,
N,N-Bis(diphenylphosphinoylmethyl)-γ -amino-
3
3
CH2), 2.2 (t, JHH = 6.2, 2H, CH2), 3.6 (t, JHH = 6.9,
3
1
butyric Acid (16). Yield: 60% (0.27 g); P NMR
2
2
1
H, CH2), 4.2 (d, JPH = 5.7, 2H, CH2P), 7.1–8.0 (m,
1
3
(CDCl3) δ: 30.2; δ [25] (CDCl3) 30.0;
C NMR
+
0H, ArH); [M + H]
= 300.1146, C17H19NO2P
found
(
CDCl3) δ: 21.6 (CH2CH2CH2), 31.1 (CH2C=O), 55.4
requires 300.1153.
1
3
3
(
6
dd, JCP = 84.6, JCP = 7.6, CH2P), 57.3 (t, JCP =
3
3
.8, CH2N), 128.5 (d, JCP = 11.8, C3),* 130.9 (d, JCP
3
REFERENCES
=
9.4, C2),* 131.0 (d, JCP = 98.6, C1), 131.9 (C4),
1
1
1
2
75.7 (C O), *may be reversed; H NMR (CDCl3) δ:
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Heteroatom Chemistry DOI 10.1002/hc