Microwave-assisted synthesis of α-aminophosphine oxides by the Kabachnik–Fields reaction applying amides as the starting materials

Article abstract of DOI:10.1080/00397911.2019.1584675

A series of acylated α-aminophosphine oxides were synthesized by the microwave-assisted Kabachnik–Fields reaction of a series of carboxylic acid amides, formaldehyde and secondary phosphine oxides. To compensate the lower reactivity of the –NH₂

Full text of DOI:10.1080/00397911.2019.1584675

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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Microwave-assisted synthesis of α-
aminophosphine oxides by the Kabachnik–Fields
reaction applying amides as the starting materials
Anna Tripolszky, Lili Zoboki, Erika Bálint, János Kóti & György Keglevich
To cite this article: Anna Tripolszky, Lili Zoboki, Erika Bálint, János Kóti & György Keglevich
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reaction applying amides as the starting materials , Synthetic Communications, DOI:
0.1080/00397911.2019.1584675
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https://doi.org/10.1080/00397911.2019.1584675
Microwave-assisted synthesis of a-aminophosphine oxides
by the Kabachnik–Fields reaction applying amides as the
starting materials
a
a
a
, J ꢀa nos K oꢀ tib , and Gy o€ rgy
Anna Tripolszky
Keglevich
, Lili Zoboki , Erika B ꢀa lint
a
a
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics,
b
Budapest, Hungary; Gedeon Richter Plc, Budapest, Hungary
ABSTRACT
ARTICLE HISTORY
A series of acylated a-aminophosphine oxides were synthesized by
the microwave-assisted Kabachnik–Fields reaction of a series of car-
boxylic acid amides, formaldehyde and secondary phosphine oxides.
Received 1 February 2019
KEYWORDS
To compensate the lower reactivity of the –NH reagents, they had
2
a-Aminophosphine oxides;
carboxylic acid amides;
Kabachnik–Fields reac-
tion; microwave
to be used in an excess. The solvolytic condensations furnished the
a-aminophosphine oxides in yields of 58–93% after purification by
chromatography.
GRAPHICAL ABSTRACT
Introduction
The Kabachnik–Fields reaction comprising the condensation of amines, oxo compounds
and >P(O)H reagents, e.g. dialkyl phosphites is an important tool towards a-amino-
[
1–3]
[4–7]
phosphonic derivatives
due to their potential as biologically active substrates.
Numerous methods were described for the synthesis of a-aminophosphonates, however,
[
8–16]
the major part of the protocols reported applied a catalyst.
The senior author of
this article, together with a coworker, was who proposed that using the microwave
[
17]
(MW)-assisted solvent-free protocol, there is no need for any catalyst.
Hence, cost
and environmental burdens may be saved. The green chemical approaches deserve spe-
cial attention. In this line, the ionic liquid catalyzed or catalyst-free, solvent-free and
[
18–26]
MW-promoted procedures should be mentioned.
The authors of this paper belong
CONTACT Gy €o rgy Keglevich
gkeglevich@mail.bme.hu
Department of Organic Chemistry and Technology,
Budapest University of Technology and Economics, 1521 Budapest, Hungary.
Supplemental data for this article is available online at on the publisher’s website
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc
ß 2019 Taylor & Francis Group, LLC

2
A. TRIPOLSZKY ET AL.
Scheme 1. Synthetic protocols for acylated a-aminophosphonates.
to those, who tried to extend the scope of the phospha-Mannich reaction to obtain
[
17,26–28]
a-aminophosphine oxides.
The “bis” Kabachnik-Fields reaction leading to
ZN(CH P(O)Y ) (Z ¼ alkyl or aryl, Y ¼ alkoxy or alkyl/aryl) type of species are also of
2
[
2 2
25–31]
interest.
It was a challenge for us to try the phospha-Mannich condensation using a different
kind of carboxylic amides as the –NH component (Scheme 1A). The literature survey
2
showed that mostly urethanes were applied as starting materials in the synthesis of acyl-
[
32–40]
aminophosphonates.
These preparations requested the use of acetic acid, acetic
ꢀ
anhydride or acetyl chloride as the solvent at 25 C to afford the products in yields of
2
2–95%. There are three examples, when acetamide or urea derivatives were the starting
[
41–43]
materials of the Kabachnik–Fields reaction.
These condensations were performed in
ꢀ
toluene, acetic anhydride or acetyl chloride at 40–120 C. As a matter of fact, the
acylated a-aminophosphonates could also be prepared by the acylation of –NH2
derivatives (Scheme 1B). However, the synthesis of the starting materials, unsubstituted
a-aminophosphonates by the Kabachnik–Fields reaction utilizing ammonia or its precur-
[
44–46]
sors is not easy.
It was also obvious for us that the amides exhibit a lower reactivity in the phospha-
Mannich condensation than amines.
Results and discussion
We wished to perform the Kabachnik-Fields reaction of a series of carboxylic acid
amides (acetamide, propionic acid amide, as well as benzoic acid amide), paraformalde-
hyde and secondary phosphine oxides under MW conditions. The phospha-Mannich
condensation of acetamide, paraformaldehyde and diphenylphosphine oxide served as
the model reaction to find the optimum conditions. As earlier, we aimed at the catalyst-
[
17]
and solvent-free protocol.
Experimental data were collected in Table 1. Reacting the
ꢀ
three components at a 1:1:1 molar ratio at 150 C, there was no reaction after a 2 h’s
irradiation (Table 1, entry 1). Increasing the amount of acetamide to 5 equivalents, a
low conversion of 2% was attained (Table 1, entry 2). A further increase to 10 equiva-
lents led to a conversion of 11% (Table 1, entry 3). An increase in the temperature and
ꢀ
reaction time to 180 C and 3.5 h, respectively, brought the real breakthrough, as in this
case the conversion was 61% (Table 1, entry 4). Following this line, applying a tempera-
ꢀ
ture of 200 and 220 C, the conversion was 93 and 99%, respectively (Table 1, entries 5
and 6). One can see that practically a solvolytic-like accomplishment using acetamide in
a 10-fold quantity at a relatively high temperature could compensate the lower reactivity
of the amide. For comparison purpose, the last reaction was also carried out on conven-
tional heating. A conversion of only 57% could be detected (Table 1, entry 7). In the
3
1
realistic temperature range, the proceeding of the condensation was monitored by
P
ꢀ
NMR measurements. The curves obtained for 180, 200 and 220 C can be seen in
Figure 1. Our experiments also revealed that there were no side products, the

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SYNTHETIC COMMUNICATIONS
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Table 1. Optimization of the Kabachnik–Fields reaction of acetamide, paraformaldehyde, and diphe-
nylphosphine oxide.
ꢀ
a
Entry
Quantity of aceatamide (eq.)
T ( C)
t (h)
Conversion (%)
1
2
3
4
5
6
1
5
10
10
10
10
10
150
150
150
180
200
220
220
2
2
2
3.5
3.5
3.5
3.5
–
2
11
61
93
99
57
b
7
a
31
Based on P NMR relative intensities.
b
Thermal control experiment in an oil bath.
Figure 1. Time dependence of the conversion of acetamide, paraformaldehyde, and Ph P(O)H to
2
a-aminophosphine oxide (1a) at a 10:1:1 molar ratio.
corresponding a-aminophosphine oxide (1a) was formed in a neat reaction. After the
work-up procedure including chromatography, product 1a was isolated in a yield
of 72%.
In the next stage of our work, acetamide was also reacted in Kabachnik-Fields reac-
tions utilizing other secondary phosphine oxides, such as bis(4-metylphenyl)phosphine
oxide, bis(3,5-dimetylphenyl)phosphine oxide and dibenzylphosphine oxide at the con-
ditions elaborated above. The corresponding a-aminophosphine oxides (1a-d) were
obtained in yields of 72–93% (Table 2, entries 1-4). Then, propionic acid amide and
benzamide were also converted to the corresponding a-aminophosphine oxides, 2a-d

4
A. TRIPOLSZKY ET AL.
Table 2. Kabachnik–Fields reaction of amides, paraformaldehyde, and secondary phosphine oxides.
ꢀ
Entry
Y
Z
T ( C)
Yield (%)
1
2
3
4
5
6
7
8
9
Me
Ph
4-MeC
220
220
220
220
220
220
220
220
240
240
240
240
72 (1a)
85 (1b)
75 (1c)
93 (1d)
91 (2a)
89 (2b)
66 (2d)
62 (2d)
78 (3a)
78 (3b)
58 (3c)
64 (3d)
6
H
4
3,5-Me
2
6
C H
3
3
3
Bn
Ph
4-MeC
Et
H
6 4
3,5-Me
2
6
C H
Bn
Ph
4-MeC
Ph
10
11
12
H
6 4
3,5-Me
Bn
2
6
C H
and 3a-d, respectively (Table 2, entries 5–8 and 9–12, respectively). As can be seen, the
yields fell in the range of 57–91%, and the phopha-Mannich condensation of benzoic
ꢀ
acid amide required a somewhat higher temperature of 240 C. All compounds prepared
3
1
13
1
are new, and were characterized by P, C and H NMR spectral data, as well
as HRMS.
Conclusions
In summary, an efficient, catalyst-free MW-assisted method was developed for the
selective synthesis of acylated a-aminophosphine oxides by the phospha-Mannich reac-
tion of carboxylic acid amides, paraformaldehyde and secondary phosphine oxides. All
together, 12 new derivatives were prepared in good to high yields, which form a new
family of compounds.
Experimental
General procedure for the synthesis of acylated a-aminophosphine oxides
(
1a–d, 2a–d and 3a–d)
A mixture of 5.0 mmol of the amide (0.29 g of acetamide, 0.37 g of propionamide or
.61 g of benzamide), 0.50 mmol (0.02 g) of paraformaldehyde and 0.50 mmol of the
0
secondary phosphine oxide (0.11 g of diphenylphosphine oxide, 0.12 g of di(p-tolyl)-
phosphine oxide, 0.13 g of bis(3,5-dimetylphenyl)phosphine oxide or 0.12 g of dibenzyl-
ꢀ
ꢀ
phosphine oxide) was heated at 220 C or 240 C in a closed vial in a CEM Discover
microwave reactor equipped with a pressure controller for 3.5 h. The crude product so
obtained was dissolved in dichloromethane, and the excess of amide was removed by
extraction with 3 ꢁ 15 mL of water.

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The combined organic phases were dried (Na SO ). Evaporation of the solvent left a
2
4
residue that was passed through a 1 cm silica gel layer using 10% methanol in dichloro-
methane as the eluent to provide products 1a–d, 2a–d and 3a–d as white crystals. Most
of the aminophosphine oxides were recrystallized from acetone. Characterization data
3
1
1
13
and copies of P, H, and C NMR spectra for the compounds synthesized were
collected in the Supporting Information.
Funding
The authors are indebted to the National Research, Development and Innovation Fund [No
K119202] for financial support.
ORCID
Anna Tripolszky
http://orcid.org/0000-0002-3223-7315
Erika B ꢀa lint
http://orcid.org/0000-0002-5107-7089
J ꢀa nos K oꢀ ti
http://orcid.org/0000-0002-3021-3002
Gy o€ rgy Keglevich
http://orcid.org/0000-0002-5366-472X
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