Efficient synthesis of phosphono- and phosphinoxidomethylated N-heterocycles under solvent-free microwave conditions

Article abstract of DOI:10.1080/00397910601033856

Simple N-heterocycles were converted to N-phosphono- and phosphinoxidomethyl derivatives by a solvent-free microwave-assisted condensation of the heterocycle, paraformaldehyde, and diethylphosphite or diphenylphosphine oxide in a convenient and, in most cases, efficient way. In contrast to an earlier report, imidazole proved to be unreactive in this type of phospha-Mannich reaction. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910601033856

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Efficient Synthesis of Phosphono‐ and
Phosphinoxidomethylated N‐Heterocycles
under Solvent‐Free Microwave Conditions
a
b
c d
a
Ibolya Prauda , István Greiner , Krisztina Ludányi
& György Keglevich
a
Department of Organic Chemical Technology , Budapest University of
Technology and Economics , Budapest, Hungary
b
Gedeon Richter Ltd. , Budapest, Hungary
c
Hungarian Academy of Sciences, Chemical Research Center , Budapest,
Hungary
d
Semmelweis University Faculty of Pharmacy, Department of
Pharmaceutics , Budapest, Hungary
Published online: 25 Jul 2007.
To cite this article: Ibolya Prauda , István Greiner , Krisztina Ludányi & György Keglevich (2007) Efficient
Synthesis of Phosphono‐ and Phosphinoxidomethylated N‐Heterocycles under Solvent‐Free Microwave
Conditions, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 37:2, 317-322, DOI: 10.1080/00397910601033856
To link to this article: http://dx.doi.org/10.1080/00397910601033856
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Synthetic Communications , 37: 317–322, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601033856
Efficient Synthesis of Phosphono- and
Phosphinoxidomethylated N-Heterocycles
under Solvent-Free Microwave Conditions
Ibolya Prauda
Department of Organic Chemical Technology, Budapest University of
Technology and Economics, Budapest, Hungary
Istv a´ n Greiner
Gedeon Richter Ltd., Budapest, Hungary
Krisztina Lud a´ nyi
Hungarian Academy of Sciences, Chemical Research Center, and
Semmelweis University Faculty of Pharmacy, Department of
Pharmaceutics, Budapest, Hungary
Gy o¨ rgy Keglevich
Department of Organic Chemical Technology, Budapest University of
Technology and Economics, Budapest, Hungary
Abstract: Simple N-heterocycles were converted to N-phosphono- and phosphinoxi-
domethyl derivatives by a solvent-free microwave-assisted condensation of the hetero-
cycle, paraformaldehyde, and diethylphosphite or diphenylphosphine oxide in a
convenient and, in most cases, efficient way. In contrast to an earlier report,
imidazole proved to be unreactive in this type of phospha-Mannich reaction.
Keywords: a-aminomethylphosphine oxides, a-aminomethylphosphonates, green
chemistry, N-heterocycles, microwave synthesis, solvent-free method
Received in the U.K. March 30, 2006
Address correspondence to Gy o¨ rgy Keglevich, Department of Organic Chemical
Technology, Budapest University of Technology and Economics, Budapest, Hungary.
E-mail: keglevich@mail.bme.hu
3
17

3
18
I. Prauda et al.
One of the widespread methods for the synthesis of a-aminophosphonates,
which form an important class of biologically active compounds, is based
[
1,2]
on the Kabachnik–Fields reaction,
P(O)H reactant, an oxo-compound that is mainly an aldehyde (most fre-
applying a ternary system of a
.
[3]
quently formaldehyde), and a secondary or primary amine. The phospha-
Mannich-type reaction was claimed to have been successfully applied to the
phosphonomethylation of imidazole derivatives under conventional heating
[4]
at 80–1008C for 6–8 h to afford the products in 73–92% yields.
similar reaction of piperidine and morpholine carried out in benzene at
A
reflux for 1.5 h using p-toluenesulfonic acid as the catalyst led to the corres-
[3]
ponding phosphonomethyl derivatives in 70–88% yields. We aimed at
the microwave synthesis of phosphono- and phosphinoxidomethylated N-het-
erocycles under solvent-free conditions and wished to survey the immediate
precedents critically. To the best of our knowledge, to date no similar study
is available in the literature.
A variety of N-heterocycles, such as pyrrolidine, piperidine derivatives,
morpholine, and piperazine derivatives, were converted to the corresponding
diethylphosphonomethyl derivatives (1a–g) in a reaction with paraformal-
dehyde and diethylphosphite without any solvent, under microwaves
(
Scheme 1, I). The optimum set of reaction conditions involved heating at
808C for 30 min in the presence of a catalytic amount of hydrochloric acid.
The method was extended to the synthesis of a few diphenylphosphinoxido-
methyl derivatives (2a, 2c, 2d, and 2f) using pyrrolidine, 4-methylpiperidine,
morpholine or a 4-arylpiperazine, and diphenylphosphine oxide (Scheme 1,
II). From among products 1 and 2, 1c, 1e, 1f, 2c, and 2f are new and were
3
1
13
1
fully characterized by means of P, C, and H NMR, as well as mass spec-
troscopy. The -CH P(O), derivatives (1a–d, f and 2a, c, d, f) were obtained
2
in 70–93% yields (Table 1), in purities of ca. 98–99% after flash-column
chromatography. It is worthy of mention that the yields were higher using
Ph P(O)H as the P-component. Comparison of the yields and d shifts of
2
P
Scheme 1.

Table 1. Synthesis of phosphonomethyl- and phosphinoxidomethyl N-heterocycles (1a–g and 2a, c, d, f) by the Kabachnik–Fields reaction under
microwave conditions
Experimental
Literature
Yield (%) MW/
808C/30 min
dP
(CDCl
Product
3
)
mp (8C)
Conditions
Yield (%)
d
P
mp (8C)
Ref.
a
1
1
1
1
1
1
2
2
2
2
a
b
c
d
e
f
73
70
71
70
54
71
91
93
89
73
25.1
25.0
24.9
23.9
24.4
24.1
26.7
26.6
27.4
27.4
ꢀ858C, 15 min
—
ꢀ79
24.0
23.0
[5,2]
[3]
b
6
D, 1.5 h, C H
6
b
6
D, 1.5 h, C
6
H
ꢀ79
19.0
[3]
c
g
g
j
f
i
a
c
d
f
158–161
130–131
166–168
d
h
e
e
154–156
[6]
f
164 , 158–159
[6,7]
237–238
a
No yield was provided.
PTSA catalyzed.
b
c
Recrystallized from ethyl acetate/isopropanol.
d
Prepared by substitution at P.
e
f
P
No d shift was provided.
Recrystallized from cyclohexane.
g
Recrystallized from ethyl acetate.
Prepared by the Arbusov approach.
h
i
Recrystallized from CH Cl /hexane.
2
2
j
Recrystallized from isopropanol.

3
20
I. Prauda et al.
the products obtained also under conventional methods suggests that the
solvent-free microwave synthesis may be a green alternative to traditional
heating in aromatics, giving comparable or even better yields.
Russian authors claimed that they synthesized imidazolyl -CH P(O)(OEt)
2
2
by the solvent-free condensation reaction of imidazol, paraformaldehyde, and
[4]
diethylphosphite carried out at 80–1008C for 6–8 h. We found that, in this
case, the real product was HOCH P(O)(OEt) , due to the unreactivity of
2
2
imidazole in phospha-Mannich reaction. Neither reproduction of the procedure
nor a solvent-free microwave irradiation of the three components at 908C led
to the desired product. The formaldehyde-diethylphoshite adduct obtained in a
3
1
13
5
4% yield was identified by P and C NMR [d (CDCl ) 24.7; d 15.9
p 3 C
(
J ¼ 5.5), 56.1 (J ¼ 163.7), 62.1 (J ¼ 6.6)], as well as IR and mass spectrometry
21
þ
[n (cm ) 1028, 1234, 3310; (M þ H) ¼ 169] and was found to be identical
[
8]
with an authentic sample. Russian authors identified their product(s) only by
IR and UV, and in the case under discussion, this may have been misleading.
In summary, the Kabachnik–Fields reaction involving N-heterocycles,
paraformaldehyde, and .P(O)H species can be accomplished in an environ-
mentally friendly manner under solvent-free microwave conditions. The
procedure can obviously be extended to other type of phospha-Mannich
reactions. A discrepancy found in the literature was clarified.
EXPERIMENTAL
General
3
1
13
1
The P, C, and H NMR spectra were obtained on a Bruker DRX-500 spec-
trometer operating at 202.4, 125.7, and 500 MHz, respectively. Chemical
shifts are downfield relative to 85% H PO or TMS. The couplings are
3
4
given in Hertz. Mass spectrometry was performed on a ZAB-2SEQ
instrument.
General Procedure for the Preparation of >P(O)CH -N-
2
heterocycles (1a–f; 2a, c, d, f)
A mixture of 4.0 mmol of the N-heterocycle (pyrrolidine, pyrrole, piperidine
derivatives, morpholine, and piperazine derivatives), 0.12 g (4.0 mmol) of
paraformaldehyde, 4.0 mmol of dialkylphosphite or diphenylphosphine
oxide, and 0.1 ml (1.0 mmol) of 37% hydrochloric acid is heated at 808C
(
applying ca. 5 W) in a closed vial in a CEM Discover (300 W) microwave
reactor for 45 min. The crude product was taken up in chloroform and
passed through a 10-cm silica-gel column using 3% methanol in chloroform
to furnish products 1a–f and 2a, c, d, f (Table 1).

Phospha-Mannich Reactions under MW Conditions
321
Products 1a, b, d are known compounds, whereas the following ones
listed below are new.
New Compounds
Diethyl 4-Methyl-piperidinomethylphosphonate (1c)
3
Yield and dp in Table 1; dC (CDCl ) 16.3 ( J ¼ 5.8, OCH CH ), 21.6
3
2
3
1
(
(
CHCH ), 30.0 (CH), 34.1 (CHCH ), 54.2 ( J ¼ 161.9, PCH ), 55.4
3
2
2
3
2
J ¼ 9.9, NCH ), 61.7 ( J ¼ 6.8, OCH CH ); d 0.90 (d, J ¼ 6.0, 3H,
2 2 3 H
CHCH ), 1.31–1.36 (m, 3H, CH, CH ), 1.33 (t, J ¼ 7.1, 6H, OCH CH ),
3
2
2
3
1
.57–1.61 (m, 2H, CHCH ), 2.14–2.22, 3.01–3.05 (m, 4H, NCH ), 2.78
2 2
(
(
d, J ¼ 11.4, 2H, PCH2), 4.12–4.18 (m, 4H, OCH CH );
2
3
M þ H)þ ¼ 250.1559; C H NO P requires 250.1572.
found 11 25 3
Diethyl 4-Hydroxyethyl-piperazinomethylphosphonate (1e)
3
Yield and dp in Table 1; dC (CDCl ) 16.4 ( J ¼ 5.8, OCH CH ), 52.8
3
2
3
1
3
(
NCH CH NCH P), 53.8 ( J ¼ 163.3, PCH ), 54.8 ( J ¼ 10.3,
2
2
2
2
2
NCH CH NCH P), 57.7 (NCH CH O), 59.2 (CH OH), 62.0 ( J ¼ 6.7,
2
2 2 2 2 2 2
OCH CH ); d 1.33 (t, J ¼ 7.1, 6H, OCH CH ), 2.52–2.69 (m, 10H, NCH
2
3
H
2
3
and OH), 2.79 (d, J ¼ 11.7, 2H, PCH ), 3.61 (t, J ¼ 5.4, 2H, CH OH),
2
2
þ
4
requires 281.1630.
.12–4.18 (m, 4H, OCH CH ); (M þ H)
¼ 281.1618; C H N O P
11 26 2 4
2
3
found
Diethyl 4-(4-Chlorophenyl)-piperazinomethylphosphonate (1f)
3
Yield and dp in Table 1; dC (CDCl ) 16.8 ( J ¼ 5.8, OCH CH ), 49.5
3
2
3
1
3
(
NCH CH NCH P), 54.2 ( J ¼ 163.9, PCH ), 54.9 ( J ¼ 10.4, NCH CH
2
2
2
2
2
2
2
NCH P), 62.0 ( J ¼ 6.8, OCH CH ), 117.5 (C
0
), 124.8 (C
0
), 129.2 (C
0
3
),
2
2
3
2
4
1
2
50.1 (C
.84 (d, J ¼ 12.0, 2H, PCH ), 3.17 (t, J ¼ 5.0, 4H, NCH ), 4.13–4.23
0
); d 1.34 (t, J ¼ 7.1, 6H, CH CH ), 2.81 (t, J ¼ 5.0, 4H, NCH ),
2 2
1
H
2
3
2
(
(
m, 4H, CH CH ), 6.82 (d, J ¼ 9.0, 2H, Ar), 7.19 (d, J ¼ 8.9, 2H, Ar);
2
3
M þ H)þ ¼ 347.1277; C H ClN O P requires 347.1291.
found 15 25 2 3
4
-Methyl-piperidinomethyl-diphenylphosphine oxide (2c)
Yield and d in Table 1; d (CDCl ) 21.6 (CH ), 29.9 (CH), 34.1 (NCH CH )
p
C
3
3
2
2
3
1
2
ꢁ
5
6.0 ( J ¼ 6.6, NCH CH ), 58.7 ( J ¼ 81.4, PCH ), 128.4 ( J ¼ 11.2, C
0
) ,
2
2
2
2
ꢁ
3
ꢁ
1
(
may be reversed) , 131.2 ( J ¼ 8.8, C
0
) ; 131.7 (C
0
4
), 132.6 ( J ¼ 97.7,
2 2
3
ꢁ
0
), may be reversed ; d 1.15–1.41 (m, 3H, CH, CH CH N), 1.47–1.58
1 H
C
(
(
(
m, 2H, CH CH N), 2.22–2.43, 2.88–3.00 (m, 4H, NCH CH ), 3.31
2 2 2 2
d, J ¼ 6.6, 2H, PCH2), 7.46–7.54, 7.81–7.88 (m, 10H, Ar);
M þ H)þ ¼ 314.1659; C H NOP requires 314.1674.
found
19 25

3
22
I. Prauda et al.
4-(4-Chlorophenyl)-piperazinomethyl-diphenyl-phosphine oxide (2f)
3
Yield and d in Table 1; d (CDCl ) 49.1 (NCH CH NCH ), 55.2 ( J ¼ 7.9,
p
C
3
2
2
2
1
NCH CH NCH ), 58.3 ( J ¼ 87.8, PCH ), 117.2 (C
0
), 124.5 (C ), 128.9
0
4
2
2
2
2
2
ꢁ
ꢁ
(
(
(
(
(
C
0
), 149.8 (C
0
), 128.5 (J ¼ 11.5, C 00) , 131.2 (J ¼ 8.9, C 00) , 131.8
ꢁ
1
3
1
2
3
4
1
J ¼ 2.7, C 00) 132.3 ( J ¼ 97.9, C 00), may be reversed; dH 2.78–2.96
4
m, 4H, NCH ), 3.06–3.19 (m, 4H, NCH ), 3.28–3.43 (m, 2H, PCH ), 6.79
2
2
2
d, J ¼ 8.4, 2H, Ar), 7.18 (d, J ¼ 8.7, 2H, Ar), 7.43–7.62, 7.79–7.89
m, 10H, Ar); (M þ H)þ ¼ 411.1375; C H ClN OP requires 411.1393.
found
23 25
2
ACKNOWLEDGMENT
This work was supported by the joint funds from the European Union and the
Hungarian State (GVOP-3.2.2-2004-07-0006/3.0). The financial support
from Gedeon Richter Ltd is also acknowledged. I. P. is grateful to the
Hungarian Scientific Research Funds (OTKA PD 050010) for the support.
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