The synthesis of N,N-Bis(dialkoxyphosphinoylmethyl)- and N,N-Bis(diphenylphosphinoylmethyl)glycine esters by the microwave-assisted double kabachnik-fields reaction

Article abstract of DOI:10.1002/hc.21126

The condensation of a glycine ester, two equivalents of paraformaldehyde, and the same quantity of a dialkyl phosphite or diphenylphosphine oxide afforded the title compounds as new bis(phospha-Mannich) products under microwave (MW) conditions at 100°C. The dialkoxyphosphinoylmethyl derivatives were synthesized under solvent-free conditions, whereas the diphenylphosphinoylmethyl derivatives were synthesized in acetonitrile solution. Comparative thermal experiments showed the beneficial role of MW in respect of efficiency.

Full text of DOI:10.1002/hc.21126

Heteroatom Chemistry
Volume 24, Number 6, 2013
The Synthesis of
N,N-Bis(dialkoxyphosphinoylmethyl)- and
N,N-Bis(diphenylphosphinoylmethyl)glycine
Esters by the Microwave-Assisted Double
Kabachnik–Fields Reaction
Erika Ba´lint,1 Eszter Fazekas,2 La´szlo´ Drahos,3
and Gyo¨rgy Keglevich2
1MTA-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
3Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1525 Budapest, Hungary
Received 10 July 2013; revised 20 September 2013
INTRODUCTION
ABSTRACT: The condensation of a glycine ester,
two equivalents of paraformaldehyde, and the same
quantity of a dialkyl phosphite or diphenylphosphine
oxide afforded the title compounds as new
bis(phospha-Mannich) products under microwave
(MW) conditions at 100◦C. The dialkoxyphosphinoyl-
methyl derivatives were synthesized under solvent-free
conditions, whereas the diphenylphosphinoylmethyl
derivatives were synthesized in acetonitrile solution.
Comparative thermal experiments showed the ben-
The Kabachnik–Fields reaction of amines, alde-
hydes, and dialkyl phosphites leading to α–
aminophosphonates [1, 2] remains an evergreen re-
action model for three reasons. The resulting α-
aminophosphonic derivatives are important targets
in the development of antibiotics, antiviral species,
antihypertensives, and antitumour agents based on
their effect as inhibitors of GABA receptors, enzyme
inhibitors, and antimetabolites [3–7].
The mechanism of reaction also generated a
considerable interest, in whether imines (Schiff
bases) or α-hydroxyphosphonates are the inter-
mediates of the Kabachnik–Fields reaction [8–11].
The way of accomplishment has also been in fo-
cus. More and more catalytic versions and the
use of microwave (MW) irradiation were described
[12–26]. The senior author of this article (G. Kegle-
vich) suggested that under MW-assisted and solvent-
free conditions, there is no need for any catalyst
[27]. The Kabachnik–Fields condensation was ex-
tended to a wide variety of models including
N-heterocycles and heterocyclic >P(O)H species
[28, 29]. α-Aminoacid esters were also applied as
ꢀC
eficial role of MW in respect of efficiency.
2013
Wiley Periodicals, Inc. Heteroatom Chem. 24:510–
515, 2013; View this article online at wileyonlineli-
brary.com. DOI 10.1002/hc.21126
Correspondence to: Gyo¨rgy Keglevich; e-mail: gkeglevich@
mail.bme.hu.
Contract grant sponsor: Hungarian Scientific and Research
Fund.
Contract grant number: OTKA No K83118.
Contract grant sponsor: National Excellence Programme.
´
Contract grant number: TAMOP 4.2.4.A/1-11-1-2012-0001.
2013 Wiley Periodicals, Inc.
ꢀC
510

The Synthesis of N,N-Bis(dialkoxyphosphinoylmethyl)- and N,N-Bis(diphenylphosphinoylmethyl)glycine Esters 511
SCHEME 1 The double Kabachnik–Fields reaction of glycine esters, paraformaldehyde, and dialkyl phosphites.
SCHEME 2 The double Kabachnik–Fields reaction of glycine esters, paraformaldehyde, and diphenylphosphine oxide.
TABLE 1 Yields of the Bis(>P(O)CH2)glycine Esters
starting materials [30–33]. In another research
line, primary amines were utilized in the double
Kabachnik–Fields reaction resulting in the forma-
tion of bis(phosphonomethyl)amine derivatives [34–
38]. Another special approach was also described for
the synthesis of bis(phospha-Mannich) derivatives
[39]. The bis(diphenylphosphinoylmethyl)amines
may be regarded as precursors of bisphosphine lig-
ands. The bisphosphines formed after double de-
oxygenation from the bis(phosphine oxides) may be
converted to ring platinum complexes that can be
used as catalysts in the hydroformylation of styrene
[36–38].
Entry
Compound
Yield (%)
1
2
3
4
5
6
7
8
1b
1c
2a
2b
2c
2d
3
85
93
70
87
83
94
92
88
4
derivatives 3 and 4 in ca. 90% yields. Because of het-
erogeneity, these reactions had to be carried out in
acetonitrile as the solvent (Scheme 2, Table 1).
With the exception of 2b [35], all other prod-
ucts (1b, 1c, 2a, 2c, and 2d, along with 3 and 4)
In this article, novel N,N-bis(dialkoxyphos-
phinoylmethyl)- and N,N-bis(diphenylphosphinoyl-
methyl)glycine esters are described utilizing the dou-
ble Kabachnik–Fields reaction of glycine esters.
are new and were characterized by 31P, 13C and H
1
nuclear magnetic resonance (NMR), as well as high-
resolution molecular spectroscopy data.
RESULTS AND DISCUSSION
The methyl and ethyl glycine esters liberated from
the corresponding hydrochloride salts were re-
acted with two equivalents of paraformaldehyde
and the same amount of dialkyl phosphites includ-
ing dimethyl phosphite, diethyl phosphite, dibutyl
phosphite, and dibenzyl phosphite under MW and
solvent-free conditions at 100◦C for 1 h. The ex-
pected N,N–bis(dialkoxyphosphinoylmethyl)glycine
esters (1b, 1c, and 2a–d) were obtained in 70%–
94% yield after column chromatography (Scheme 1,
Table 1). The similar reaction of diphenylphosphine
oxide afforded the bis(diphenylphosphinoylmethyl)
Bisadduct 2b was also prepared from N-
(diethoxyphosphinoylmethyl)glycine ethyl ester 5
synthesized separately by its reaction with one equiv-
alent of paraformaldehyde and diethyl phosphite at
100◦C for 1 h. After flash column chromatography,
product 2b was obtained in a yield of 93%, which
was somewhat better than the outcome of the one-
step procedure (87%, Table 1/Entry 4).
Starting from glycine ester hydrochloride in-
stead of the free glycine ester, acetonitrile had
to be used as the solvent due to the heterogene-
ity. After an irradiation of 1 h at 70◦C, a mixture
Heteroatom Chemistry DOI 10.1002/hc

512 Ba´lint et al.
Comparative Thermal Experiments
CO2Et
(EtO)2P(O)H
+
+ (HCHO)n
MW
To evaluate the potential of MW irradiation,
comparative thermal experiments were carried
out in a few instances at 100◦C for 1 h. On
conventional heating, mixtures comprising the
bis(dialkoxyphosphinoylmethyl)glycine ester (1b,
2a, or 2b) as the major component (61%–
91%) and the primary dialkoxyphosphinoylmethyl-
glycine esters [R1O2CCH2NHCH2P(O)(OR2)2] as
the minor components (2%–30%) were formed
(Table 2). A small portion (ca. 9%) of uniden-
tified by-products was also formed. On further
heating, only a minor part of the dialkoxyphos-
phinoylmethylglycine esters was converted to the
corresponding bis products (1b, 2a, and 2b).
After purification by column chromatography,
bis(dialkoxyphosphinoylmethyl)glycines 1b, 2a, and
2b were obtained in preparative yields of 66%, 57%,
and 53%, respectively. The incomplete conversions
in respect of the bis products (1b, 2a, and 2b) and the
13%–34% lower yields of the thermal control exper-
iments clearly indicate the advantage of the MW ac-
complishment. The MW-assisted reactions are gen-
erally more efficient than the variations carried out
under conventional heating [40–42].
.
NH2 HCl
Acetonitrile
°
70 C, 1 h
EtO2CCH2NHCH2P(O)(OEt)2
5 (25%)
+
EtO2CCH2N(CH2P(O)(OEt)2)2
2b (65%)
+
(EtO2)P(O)CH(CO2Et)NHCH2P(O)(OEt)2
6 (10%)
SCHEME 3 The outcome of the Kabachnik–Fields reaction
starting from glycine ester hydrochloride.
containing ca. 50% of the expected product (2b)
[35] besides unidentified by-products was formed.
When the glycine ester hydrochloride was reacted
with one equivalent of formaldehyde and the same
amount of diethyl phosphite, a mixture of N–
(diethoxyphosphinoylmethyl)glycine ethyl ester (5)
In conclusion, eight bis(dialkoxyphosphinoyl-
methyl)- or bis(diphenylphosphinoylmethyl)glycine
esters were synthesized under MW conditions.
Among the compounds synthesized, seven are new.
The potential of the MW irradiation was proved by
comparative thermal experiments.
{δp (CDCl3) 23.7, (δp [32] 22.9), [M + H]+
found
= 254.1160, C9H21NO5P requires 254.1157}, N,N–
bis(diethoxyphosphinoylmethyl)glycine ethyl es-
ter (2b) [35] and 2-(diethoxyphosphinoyl)-N-
(diethoxyphosphinoylmethyl)glycine ethyl ester (6)
{δp (CDCl3) 15.1, [M + H]+
= 390.1457,
EXPERIMENTAL
General
found
C13H30NO8P2 requires 390.1447} was formed.
The ratio of 5, 2b, and
6
was 25:65:10
(Scheme 3). It was somewhat surprising that
despite the equimolar ratio of the compo-
nents, bis(diethoxyphosphinoylmethyl)glycine ester
2b was the major component. The glycine ethyl es-
ter hydrochloride was not too reactive in the pri-
mary Kabachnik–Fields reaction, but once it had
been formed, it further reacted easily with formalde-
hyde and diethyl phosphite.
The 31P, 13C, and 1H NMR spectra were obtained
in CDCl3 solution on a Bruker AV-300 spectrome-
ter operating at 121.5, 75.5, and 300 MHz, respec-
tively. Chemical shifts are downfield relative to 85%
H3PO4 and tetramethylsilane. Mass spectrometric
measurements were performed using a Q-TOF Pre-
mier mass spectrometer (Waters Corporation, Mil-
ford, Massachusetts) in positive electrospray mode.
TABLE 2 Composition of Comparative Thermal Experiments
Composition (%)
Entry
R1O2CCH2NHCH2P(O)(OR2)2
Bis Product
By-product
Isolated Yield of Bis Product (%)
1
5 (R1 = Me, R2 = Et)
2 (R1 = Et, R2 = Me)
30 (R1 = Et, R2 = Et)
84 (1b)
91 (2a)
62 (2b)
11
7
8
66 (1b)
57 (2a)
53 (2b)
2
3a
aAfter an additional heating of 2 h, the mixture contained 21% of phosphonomethylglycine ester and 71% of 2b beside the 8% of the by-product.
Heteroatom Chemistry DOI 10.1002/hc

The Synthesis of N,N-Bis(dialkoxyphosphinoylmethyl)- and N,N-Bis(diphenylphosphinoylmethyl)glycine Esters 513
The reactions were carried out in a 300 W CEM Dis-
N,N-Bis(dimethoxyphosphinoylmethyl)glycine
Ethyl Ester (2a). Yield: 70% (0.41 g); 31P
NMR (CDCl3) δ: 26.1; 13C NMR (CDCl3) δ: 14.1
cover focused MW reactor (CEM Microwave Tech-
nology, Buckingham, UK) equipped with a pres-
sure controller, applying 20–30 W under isothermal
conditions.
The glycine esters were liberated from their hy-
drochloride salts using 20% Na2CO3 solution (2.0 g
of Na2CO3 and 8 mL of water). Dichloromethane was
used for the extraction of the free base. The organic
phase was separated and dried (Na2SO4). Evapora-
tion of the volatile components provided the glycine
esters.
1
3
(OCH2CH3), 49.8 (dd, JCP = 161.7, JCP = 9.8,
2
3
CH2P), 52.8 (d, JCP = 7.0, OCH3), 56.0 (t, JCP
=
6.4, CH2N), 60.5 (OCH2CH3), 170.4 (C O); 1H
3
NMR (CDCl3) δ: 1.24 (t, JHH = 7.1,3H, OCH2CH3),
3.29(d, 2JPH = 10.3, 4H, CH2P), 3.75 (s, 12H, OCH3),
3.79 (s, 2H, CH2N), 4.09–4.19 (m, 2H, OCH2CH3);
[M + H]+
= 348.0973, C10H24NO8P2 requires
found
348.0977.
N,N-Bis(diethoxyphosphinoylmethyl)glycine
Ethyl Ester (2b). Yield: 85% (0.56 g); 31P NMR
(CDCl3) δ: 23.8; δ [35] (CDCl3) 23.4; 13C NMR
General Procedure for the Preparation of
Bis(>P(O)CH2)glycine Esters
A mixture of 1.70 mmol glycine ester (0.15 g of
glycine methyl ester or 0.18 g of glycine ethyl es-
ter), 0.10 g (3.40 mmol) of paraformaldehyde, and
3.40 mmol of the >P(O)H species (0.31 mL of
dimethyl phosphite, 0.44 mL of diethyl phosphite,
0.67 mL of dibutyl phosphite, and 0.75 mL of diben-
zyl phosphite) was heated at 100◦C in a vial in a
CEM Discover Microwave reactor equipped with a
pressure controller for 1 h. Then, the water formed
was removed in vacuum. Column chromatogra-
phy (silica gel 3% methanol in dichloromethane)
of the residue afforded the products (1a, 1b, and
2a–d) as oils. The following products were thus
prepared:
3
(CDCl3) δ: 14.1 (OCH2CH3), 16.4 (d, JCP = 6.1,
CH2CH3), 50.5 (dd, 1JCP = 136.7, 3JCP = 10.2, CH2P),
3
51.8 (OCH3), 55.7 (t, JCP = 6.0, CH2N), 62.1 (d,
2JCP = 7.0, CH2CH3), 171.0 (C=O); δ [35]* (CDCl3)
51.09 (dd, 1JCP = 159.9, 3JCP = 10.6, CH2P), 56.17 (t,
1
3JCP = 6.7, CH2N), 170.49 (C O); H NMR (CDCl3)
δ: 1.28 (t, 3JHH = 7.0, 12H, CH2CH3), 3.26 (d, 2JPH
=
10.3, 4H, CH2P), 3.66 (s, 3H, OCH3), 3.78 (s, 2H,
CH2N), 4.05–4.18 (m, 8H, CH2CH3); δ [35]* (CDCl3)
2
3.45 (d, JPH = 9.5, 4H, CH2P), 4.01 (s, 2H, CH2N),
*Signals of ethyl group are missing; [M + H]+
=
found
404.1605, C14H32NO8P2 requires 404.1603.
N,N-Bis(dibutoxyphosphinoylmethyl)glycine
N,N-Bis(diethoxyphospinonylmethyl)glycine
Ethyl Ester (2c). Yield: 93% (0.79 g); 31P NMR
Methyl Ester (1b). Yield: 85% (0.56 g); 31P NMR
(CDCl3) δ: 23.9; 13C NMR (CDCl3) δ: 13.5 (CH2CH3),
3
(CDCl3) δ: 23.8; 13C NMR (CDCl3) δ: 16.4 (d, JCP
=
3
14.1 (OCH2CH3), 18.7 (CH2CH3), 32.5 (d, JCP
=
1
3
6.1, CH2CH3), 50.5 (dd, JCP = 136.7, JCP = 10.2,
1
3
6.2, OCH2CH2), 50.5 (dd, JCP = 160.2, JCP = 10.1,
CH2P), 51.3 (OCH3), 55.6 (t, 3JCP = 5.8, CH2N), 65.8
(d, 2JCP = 7.2, OCH2), 171.0 (C O); 1H NMR (CDCl3)
3
CH2P), 51.8 (OCH3), 55.7 (t, JCP = 6.0, CH2N),
2
1
62.1 (d, JCP = 7.0, CH2CH3),171.0 (C O); H NMR
3
(CDCl3) δ: 1.28 (t, JHH = 7.0, 12H, CH2CH3), 3.26
3
δ: 0.90 (t, JHH = 7.4, 12H, CH2CH3), 1.29–1.44 (m,
2
(d, JPH = 10.3, 4H, CH2P), 3.66 (s, 3H, OCH3),
8H, CH2CH3), 1.55–1.68 (m, 8H, OCH2CH2), 3.27
3.78 (s, 2H, CH2N), 4.05–4.18 (m, 8H, CH2CH3);
2
(d, JPH = 10.2, 4H, CH2P), 3.66 (s, 3H, OCH3),
[M + H]+
= 390.1448, C13H30NO8P2 requires
found
3.79 (s, 2H, CH2N), 3.99–4.11 (m, 8H, OCH2);
390.1447.
[M + H]+
= 516.2855, C22H48NO8P2 requires
found
516.2855.
N,N-Bis(dibutoxyphosphinoylmethyl)glycine
Methyl Ester (1c). Yield: 93% (0.79 g); 31P NMR
(CDCl3) δ: 23.9; 13C NMR (CDCl3) δ: 13.5 (CH2CH3),
18.7 (CH2CH3), 32.5 (d, 3JCP = 6.2, OCH2CH2), 50.5
N,N-Bis(dibenzylyoxyphosphinoylmethyl)glycine
Ethyl Ester (2d). Yield: 96% (1.06 g); 31P
NMR (CDCl3) δ: 26.1; 13C NMR (CDCl3) δ: 14.1
1
3
(dd, JCP = 160.2, JCP = 10.1, CH2P), 51.3 (OCH3),
55.6 (t, 3JCP = 5.8, CH2N), 65.8 (d, 2JCP = 7.2, OCH2),
3
1
3
171.0 (C O); 1H NMR (CDCl3) δ: 0.90 (t, JHH
=
(OCH2CH3), 49.8 (dd, JCP = 161.7, JCP = 9.8,
2
3
7.4, 12H, CH2CH3), 1.29–1.44 (m, 8H, CH2CH3),
CH2P), 52.8 (d, JCP = 7.0, OCH3), 56.0 (t, JCP =
2
1.55–1.68 (m, 8H, OCH2CH2), 3.27 (d, JPH = 10.2,
6.4, CH2N), 60.5 (OCH2CH3), 170.4 (C O); 1H NMR
3
4H, CH2P), 3.66 (s, 3H, OCH3), 3.79 (s, 2H, CH2N),
3.99–4.11 (m, 8H, OCH2); [M + H]+found = 502.2708,
C21H46NO8P2 requires 502.2699.
(CDCl3) δ: 1.24 (t, JHH = 7.1, 3H, OCH2CH3), 3.29
2
(d, JPH = 10.3, 4H, CH2P), 3.75 (s, 12H, OCH3),
3.79 (s, 2H, CH2N), 4.09–4.19 (m, 2H, OCH2CH3);
Heteroatom Chemistry DOI 10.1002/hc

514 Ba´lint et al.
[M + H]+
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= 652.2239, C34H40NO8P2 requires
found
652.2229.
N-(Diethoxyphosphinoylmethyl)glycine ethyl es-
ter (5) was prepared as bisadduct 2b, but the three
reactants were used in an equimolar quantity. Yield
after flash column chromatography: 73%. 31P NMR
(CDCl3) δ: 23.6; δ[32] (CDCl3) 22.9; [M + H]+
=
found
254.1162, C9H21NO5P requires 254.1157.
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General procedure for the synthesis of N,N-bis-
(diphenylphosphinoylmethyl)glycine esters
A mixture of 0.85 mmol glycine ester (0.08 g of
glycine ethyl ester or 0.09 g of glycine methyl ester),
0.05 g (1.70 mmol) of paraformaldehyde, and 0.34 g
(1.70 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 workup was similar as
above to provide products 3 and 4 as oils.
N,N-Bis(diphenylphosphinoylmethyl)glycine
Methyl Ester (3). Yield: 92% (0.40 g); 31P NMR
(CDCl3) δ: 29.7; 13C NMR (CDCl3) δ: 51.4 (OCH3),
1
3
55.2 (dd, JCP = 84.4, JCP = 7.7, CH2P), 57.6 (t,
3JCP = 6.2, CH2N), 128.4 (d, JCP = 11.7, C2),* 131.1
(d, JCP = 9.3, C3),* 131.6 (d, 1JCP = 98.6, C1), 131.7 (d,
1
4JCP = 2.7, C4), *may be reversed; H NMR (CDCl3)
δ: 3.04 (s, 4H, CH2P), 3.65 (s, 3H, OCH3), 3.95 (s,
2H, CH2N), 7.28–7.53 (m, 12H, ArH), 7.63–7.79 (m,
8H, ArH); [M + H]+
= 518.1650, C29H30NO4P2
found
requires 518.1650.
N,N-Bis(diphenylphosphinoylmethyl)glycine
Ethyl Ester (4). Yield: 88% (0.40 g); 31P NMR
(CDCl3) δ: 29.8; 13C NMR (CDCl3) δ: 14.1 (CH3),
1
3
55.2 (dd, JCP = 84.3, JCP = 7.4, CH2P), 57.8 (t,
3JCP = 6.7, CH2N), 60.4 (OCH2), 128.4 (d, JCP = 11.7,
C2),* 131.1 (d, JCP = 9.3, C3),* 131.6 (d, 1JCP = 98.4,
4
1
C1), 131.7 (d, JCP = 2.7, C4), *may be reversed; H
NMR (CDCl3) δ: 1.21 (t, 3JHH = 7.1, 3H, OCH2CH3),
3.45–3.61 (m, 4H, CH2P), 3.94 (s, 2H, CH2N),
4.06–4.15 (m, 2H, OCH2), 7.29–7.54 (m, 12H, ArH),
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= 532.1808,
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