Synthesis of α-Aminophosphonate Derivatives by Microwave-Assisted Kabachnik-Fields Reaction

Article abstract of DOI:10.1080/10426507.2014.984022

The synthesis of aminophosphonates was studied in aqueous solution using triethyl phosphite and under solvent-free and microwave-assisted conditions using >P(O)H species and starting from primary amines or α-, β- and γ-amino acid derivatives. The synthesis of bisaminophosphonates from suitable bifunctional compounds was also investigated in the presence of the T3P reagent.

Full text of DOI:10.1080/10426507.2014.984022

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis of α-Aminophosphonate Derivatives by
Microwave-Assisted Kabachnik-Fields reaction
a
b
b
b
b
Erika Bálint , Eszter Fazekas , Anna Tripolszky , Réka Kangyal , Mátyás Milen & György
c
Keglevich
a
MTA-BME Organic Chemical Technology Research Group, 1521 Budapest, Hungary
b
Department of Organic Chemistry and Technology, Budapest University of Technology and
Economics, 1521 Budapest, Hungary
c
Egis Pharmaceuticals Plc., Chemical Research Division, 1475 Budapest, Hungary
Accepted author version posted online: 20 Mar 2015.
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To cite this article: Erika Bálint, Eszter Fazekas, Anna Tripolszky, Réka Kangyal, Mátyás Milen & György Keglevich (2015):
Synthesis of α-Aminophosphonate Derivatives by Microwave-Assisted Kabachnik-Fields reaction, Phosphorus, Sulfur, and Silicon
and the Related Elements, DOI: 10.1080/10426507.2014.984022
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SYNTHESIS OF α-AMINOPHOSPHONATE DERIVATIVES BY MICROWAVE-
ASSISTED KABACHNIK-FIELDS REACTION
1
*
2
2
2
2
Erika Bálint, Eszter Fazekas, Anna Tripolszky, Réka Kangyal, Mátyás Milen, and
2
György Keglevich
1
MTA-BME Organic Chemical Technology Research Group, 1521 Budapest, Hungary
2
Department of Organic Chemistry and Technology, Budapest University of Technology and
Economics, 1521 Budapest, Hungary
3
Egis Pharmaceuticals Plc., Chemical Research Division, 1475 Budapest, Hungary
Abstract The synthesis of aminophosphonates was studied in aqueous solution using triethyl
phosphite and under solvent-free and microwave-assisted conditions using >P(O)H species and
starting from primary amines or α-, β- and γ-amino acid derivatives. The synthesis of
bisaminophosphonates from suitable bifunctional compounds was also investigated in the presence
®
of the T3P reagent.
Ar
Ar
HN
O
P
O
P
OEt
OEt
OEt
OEt
HN
HN
O
P
O
Y1
Y2
Y
Y2
OEt
OEt
CH2 NH CH P
CH2
R
N
1
CH2
P
O
P
O
P
OEt
OEt
OEt
OEt
O
HN
Ar
Ar
Keywords Kabachnik–Fields reaction, Microwave, α-Aminophosphonate, Ring platinum
complex
1
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One of the most convenient and widespread method for the synthesis of -aminophosphonates is
the condensation of an amine, oxo compound and >P(O)H species that is called the Kabachik-
1
2,3
Fields reaction. In our research group, these kind of condensations were studied before. In this
paper, our recent results are summarized on the synthesis of novel α-aminophosphonates.
1.) Kabachnik-Fields reactions using triethyl or diethyl phosphite in water
The model reaction investigated was the condensation of benzylamine, benzaldehyde and
4
triethyl phosphite (TEP) or diethyl phosphite (DEP) at room temperature in water. First, we
studied the hydrolysis of TEP to DEP (Scheme 1), and the formation of imine from the aldehyde
(
Scheme 2). It was found that both processes were relatively fast (with reaction times of 1 h and
6
min, respectively).
In the Kabachnik-Fields reaction of benzylamine, benzaldehyde and TEP in water, the
maximum composition of the α-aminophosphonate 1 was 95% after a reaction time of 10 h using
equivalents of the phosphite in the presence of 10% of p-toluenesulfonic acid (Scheme 3).
2
Using DEP as the P-component, the reaction was slower, and the maximum ratio of the α-
aminophosphonate 1 was 76% after 1 day. The condensation was not complete even at a higher
temperature.
Therefore, this reaction was carried out in the absence of water at 100 °C under conventional
heating and also under MW conditions. It was found that the condensation was complete under
both variations, however, under MW irradiation the reaction was much faster. In conclusion, in the
condensation with DEP, there is no need for any solvent, water and catalyst as compared to the
2
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reaction with TEP. In addition, the TEP is malodorous and the use of excess of this reagent means
extra cost. We can say that DEP is preferable to be used in this condensation.
2
.) Double Kabachnik-Fields reactions of primary amines
The condensation of primary amines, two equivalents of paraformaldehyde and two
equivalents of the >P(O)H species, such as dialkyl phosphites, alkyl phenyl-H-phosphinates,
diarylphosphine or oxaphosphorine oxide derivatives was carried out under MW conditions at
5
-7
1
00 °C, in the absence of catalyst and, in most cases, without any solvent (Scheme 4). When
diarylphosphine oxides were used as the P-component, the condensations were performed in
acetonitrile due to the heterogeneity of the reaction mixtures. The corresponding
bis(phosphinoylmethyl)amines (2) were obtained in 55-98% yield.
We wished to study the utilization of these bisphosphinoyl compounds, therefore the
bis(diphenylphosphinoylmethyl)amines (2, Y=Ph) were subjected to double deoxygenation
5
-7
applying phenylsilane (Scheme 5).
The diphosphines (3) obtained were reacted with
dichlorodibenzonitrile platinum to furnish ring platinum complexes (4) in yields of 38–60%.
These complexes (4) showed good activity and chemoselectivity, along with an unexpected
7
regioselectivity as catalyst in the hydroformylation of styrene.
3
.) Double Kabachnik-Fields reactions of amino acid derivatives
The condensation of α-, β- and γ-amino acid derivatives was studied with two equivalents of
paraformaldehyde and two equivalents of dialkyl phosphites or diphenyl phosphine oxide (Scheme
8
-9
6
). The condensations were carried out under MW irradiation at 100 °C for 1 h in the absence of
3
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catalyst and, except of the reaction with diphenylphosphine oxide, without any solvent. The
bis(aminophosphonates) (5) expected were obtained in high yields.
In a few cases, comparative thermal experiments were also performed to evaluate the potential of
the MW technique. The yields of the thermal control experiments were 7-39% lower indicating
the beneficial role of the MW irradiation.
4
.) Synthesis of bis(α-aminophosphonates) from bifunctional compounds
We have also studied the synthesis of bisaminophosphonates starting from bifunctional
10
compounds, such as 1,4-phenylenediamnine and terephthalic aldehyde. First the reaction of
1,4-phenylenediamine, two equivalents of aromatic aldehydes and two equivalents of TEP or DEP was
®
investigated in the presence of propylphosphonic anhydride (the T3P reagent) (Scheme 7). The
condensations were performed in ethylacetate/dichloromethane at room temperature, and it was found
that the reactions took place through the monoaminophosphonates (6) as the intermediates. The
bisaminophosphonates (7) were obtained in 66-87% yields. It was observed that the condensations with
TEP, in most cases, were faster and more efficient, than the reactions with DEP.
Finally, the reation of terephthalic aldehyde was studied with aniline derivatives
1
0
(
Scheme 8). The condensations were also performed at room temperature and resulted in the
formation of the corresponding bis(aminophosphonates) (8) in shorter reaction times, as
compared to the reactions with 1,4-phenylenediamine.
4
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REFERENCES
1
2
3
4
. Keglevich, G.; Bálint E. Molecules 2012, 17, 12821-12835.
. Keglevich, G.; Szekrényi, A. Lett. Org. Chem. 2008, 5, 616-622.
. Prauda, I.; Greiner, I.; Ludányi, K.; Keglevich, G. Synth. Commun. 2007, 37, 317-322.
. Keglevich, G.; Bálint, E.; Kangyal, R.; Bálint, M.; Milen, M. Heteroatom Chem. 2014, 25, 282-
289.
5
. Keglevich, G.; Szekrényi, A.; Szöllősy, Á.; Drahos, L. Synth. Commun.. 2011, 41, 2265-2272.
. Bálint, E.; Fazekas, E.; Pintér, G.; Szöllősy, Á.; Holczbauer, T.; Czugler, M.; Drahos, L.;
Körtvélyesi, T.; Keglevich, G. Curr. Org. Chem. 2012, 16, 547–554.
6
7
. Bálint, E.; Fazekas, E.; Pongrácz, P.; Kollár, L.; Drahos, L.; Holczbauer, T.; Czugler, M.;
Keglevich, G. J. Organomet. Chem. 2012, 717, 75-82.
8
9
1
. Bálint, E.; Fazekas, E.; Drahos, L.; Keglevich, G. Heteroatom Chem. 2013, 24, 510-515.
. Bálint, E.; Fazekas, E.; Mucsi, Z.; Kóti, J.; Keglevich, G., submitted.
0. Milen, M.; Ábrányi-Balogh, P.; Kangyal, R.; Dancsó, A.; Frigyes, D.; Keglevich, G.
Heteroatom Chem., 2014, 25, 245-255.
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OEt
OEt
26 °C, 1 h
EtO
EtO
O
H
EtO P
P
H O
2
(
0.5 ml)
TEP
DEP
Scheme 1
O
C
CH2 NH2
26 °C, 6 min
H
N
+
H O
2
(
0.5 ml)
Scheme 2
OEt
O
C
O
EtO P
OEt
OEt
CH2 NH2
+
OEt
CH2 NH CH P
2
6 °C
H
or
+
H O
2
EtO
O
H
P
EtO
1
Scheme 3
6
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O
P
Y1
MW
00 °C, 1-1.5 h
no solvent or
acetonitrile
Y1
Y2
O
H
CH2
2
1
Y
Y
R NH2
+
2 (HCHO)n
+
2
P
R
O
N
1
CH2
P
Y2
2
O
Y1
Ph
Bn
n
n
c
OMe OEt OBu OBn O
Et Bu
R= Pr, Bu, Hex, Bn, Ph,
-MeC H , 4-MeOC H
4
Y2 OMe OEt OBu OBn
6
4
6
4
O
,
, Ph Ph Ph Bn
Scheme 4
O
Ph
.
.
8
0 °C, 3 days
25 °C, 1 day
Ph
CH2 PPh2
CH2 PPh
CH2
P
PhSiH , N
2
Pt(PhCN) Cl , N
3
2
2
2
2
R
N
R N
PtCl2
.
.
R N
CH2 PPh2
ArH
CH2 PPh
ArH
CH2
P
2
Ph
O
Ph
2
3
4
n
n
c
R= Pr, Bu, Hex, Bn, Ph, 4-MeOC H , 4-MeC H
(38-60%)
6
4
6
4
Scheme 5
O
MW
00 °C, 1 h
no solvent
CO R
CH2 PY2
2
Y
Y
O
H
1
(
H C)
+
2
P
RO C (CH )
N
2
n
+
2 (HCHO)n
2
2 n
CH2 PY2
O
NH2
R = H, Me, Et
n = 1, 2, 3
Y= MeO, EtO, BuO, BnO, Ph
R = H, Me, Et
n = 1, 2, 3
5 (60-99%)
Scheme 6
7
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Ar
Ar
O
P
O
P
2
6 °C, 3-9 h
OEt
OEt
OEt
OEt
NH2
NH2
HN
HN
T3P (2eq.)/EtOAc
O
(EtO) P (2 eq.) or (EtO) P(O)H (2 eq.)
3
2
+
2
Ar
H
CH Cl
2 2
O
P
OEt
OEt
NH2
HN
Ar
6
7
(66-87%)
Scheme 7
Ar
O
Ar
O
OEt
P
2
6 °C, 1.5-5 h
T3P (2eq.)/ EtOAc
EtO)3P (2 eq.) or (EtO)2P(O)H (2 eq.)
OEt
OEt
O
O
HN
P
HN
OEt
(
2
ArNH2
+
CH Cl
2
2
O
OEt
P
N
HN
Ar
OEt
Ar
8
(54-95%)
Scheme 8
8
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