Synthesis of cyclic aminomethylphosphonates and aminomethyl-arylphosphinic acids by an efficient microwave-mediated phospha-mannich approach

Article abstract of DOI:10.1002/hc.20387

Microwave-assisted condensation of 1,3,-2-dioxaphosphinane 2-oxide (1), paraformaldehyde and secondary amines including 5- and 6-membered N-heterocycles at 55°C gave cyclic aminomethylphosphonates (2), whereas an analogous reaction involving dibenzo[c.e][

Full text of DOI:10.1002/hc.20387

Heteroatom Chemistry
Volume 19, Number 2, 2008
Synthesis of Cyclic
Aminomethylphosphonates
and Aminomethyl-Arylphosphinic Acids
by an Efficient Microwave-Mediated
Phospha-Mannich Approach
Gyo¨rgy Keglevich,1 Anna Szekre´nyi,1 Melinda Sipos,1
Krisztina Luda´nyi,2,3 and Istva´n Greiner4
1Department of Organic Chemistry and Technology, Budapest University of Technology and
Economics, H-1521 Budapest, Hungary
2Semmelweis University, Faculty of Pharmacy, Department of Pharmaceutics,
H-1092 Budapest, Hungary
3Hungarian Academy of Sciences, Chemical Research Center, H-1525 Budapest, Hungary
4Richter Gedeon Rt., PO Box 27, H-1475 Budapest 10, Hungary
Received 25 April 2007; revised 17 June 2007
INTRODUCTION
ABSTRACT: Microwave-assisted condensation of
1,3,-2-dioxaphosphinane 2-oxide (1), paraformalde-
hyde and secondary amines including 5- and 6-
membered N-heterocycles at 55◦C gave cyclic amino-
methylphosphonates (2), whereas an analogous re-
action involving dibenzo[c.e][1,2]oxaphosphinane 2-
oxide (3) resulted in the corresponding aminomethyl-
2-(2ꢀ-hydroxybiphenyl)phosphinic acids (4) as a con-
sequence of a hydrolytic ring opening following
The Kabachnik–Fields reaction [1,2] involving the
condensation of a ternary system comprising a
>P(O)H reactant, an aldehyde or ketone, and
a secondary or primary amine is an important
method for the synthesis of compounds of type
of >NC(R1)(R2)P(O)<, such as aminophosphonates
[3–6] that forms an important class of biologically
active compounds. The green chemical aspects of
the Kabachnik–Fields reaction also received consid-
erable attention [4,6].
In our laboratory, the microwave promoted,
solvent-free synthesis of phosphono- and phosphi-
noylmethylated N-heterocycles has been elaborated
[7]. In this paper, we introduce aminomethylphos-
phonic and phosphinic derivatives based or related
on 6-membered P-heterocycles.
ꢁ
C
the condensation.
2008 Wiley Periodicals, Inc. Het-
eroatom Chem 19:207–210, 2008; Published online in
Wiley InterScience (www.interscience.wiley.com). DOI
10.1002/hc.20387
Correspondence to: Gyo¨rgy Keglevich; e-mail: keglevich@mail.
bme.hu.
Contract grant sponsor: Hungarian Scientific Research Fund.
Contract grant number: OTKA T 067679.
Contract grant sponsor: Joint Funds from the European Union
and the Hungarian State.
On the basis of our previous experiences with
cyclic >P(O)H species [8,9], it was a challenge
for us to convert them to the corresponding
aminomethyl derivatives. 1,3,2-Dioxaphosphinane
Contract grant number: GVOP-3.2.2.-2004-07-0006/3.0.
2008 Wiley Periodicals, Inc.
c
ꢀ
207

208 Keglevich et al.
SCHEME 1
2-oxide 1 reacted easily with paraformaldehyde
and secondary amines including pyrrolidine, mor-
pholine, piperidine-, and piperazine derivatives at
55◦C in chloroform under microwave to afford
the corresponding aminomethylphosphonates 2a–
f (Scheme 1). After purification by column chro-
matography, products 2a–f were obtained in 54%–
72% yields and were characterized by 31P, 13C, and
1H NMR, as well as mass spectral data.
In summary, new aminomethyl cyclic phospho-
nates and hydroxybiphenylphosphinic acids were
synthesized by the microwave-assisted conden-
sation of a cyclic or acyclic secondary amine,
paraformaldehyde, and the P(O)H derivative of the
corresponding P-heterocycle.
The next cyclic >P(O)H species was
dibenzo[c.e][1,2]oxaphosphinane oxide
3
that
was reacted with paraformaldehyde and sec-
ondary amines at 80◦C in dry ethanol, again under
microwave. Instead of the desired aminomethyl-
dibenzooxaphosphorine oxides, aminomethyl-2-
(2ꢀ-hydroxybiphenyl)phosphinic acids 4a,b,g,h
were obtained (Scheme 2). Compounds 4 were
formed by opening of the oxaphosphinane ring of
the primary product (e.g., 5) via hydrolysis. The
water bringing about the hydrolytic ring opening is
derived from the primary Mannich condensation.
Products 4a,b,g,h were purified by recrystallization
EXPERIMENTAL
The 31P, 13C, and 1H NMR spectra were obtained on
a Bruker DRX-500 spectrometer operating at 202.4,
125.7, and 500 MHz, respectively. Chemical shifts
are downfield relative to 85% H3PO4 or TMS. Mass
spectrometry was performed on a ZAB-2SEQ instru-
ment. The reactions were carried out in a 300-W
CEM Discover focused microwave reactor under
isotermic conditions.
1
and were identified on the basis of 31P, 13C, and H
NMR, as well as mass spectrometry. Carrying out
the condensation in chloroform instead of ethanol,
the ring opening was somewhat suppressed and
the presence of the aminomethyldibenzooxaphos-
phinane oxide (e.g., 5) could be detected by 31P
NMR and FAB, but it was not possible to prevent
the predominant ring opening. The ratio of 4a and
5 was ca. 75:25 on the basis of relative 31P NMR
intensities.
General Procedure for the Preparation of
Aminomethyl[1,3,2]dioxaphosphinane 2-Oxides
(2a–f)
A mixture of [1,3,2]dioxaphosphinane 2-oxide 1
[10] (0.21 g, 1.7 mmol), paraformaldehyde (0.05 g,
SCHEME 2
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Cyclic Aminomethylphosphonates and Aminomethyl-Arylphosphinic Acids 209
1.7 mmol), and secondary amine (1.7 mmol) in 2 mL
(m, 4H, OCH2); (M + H)+found = 234.1245, C10H21NO3P
requires 234.1259.
of chloroform was stirred at 55◦C in a microwave
reactor for 20 min. Volatile components including
water were removed in vacuo. Column chromatog-
raphy (silica gel, 3% methanol in chloroform) of the
residue afforded the product (2a–f) as an oil.
2f: Yield: 64%; 31P NMR (CDCl3) δ 19.1; 13C
NMR (CDCl3) δ 26.5 (3 J = 8.3, CH2CH2CH2), 49.1
(ArNCH2), 52.6 (1 J = 159.7, PCH2), 54.7 (3 J = 10.0,
CH2NCH2P), 67.0 (2 J = 7.2, OCH2), 117.3 (CHCN),
1
The following products were thus prepared:
124.5 (ClC), 128.9 (ClCCH), 149.7 (NC); H NMR
2a: Yield, 72%; 31P NMR (CDCl3) δ 21.5; 13C NMR
(CDCl3) δ 11.6 (CH3), 26.6 (3 J = 8.4, CH2CH2CH2),
48.6 (3 J = 8.8, NCH2CH3), 49.0 (1 J = 159.7, PCH2),
(CDCl3) δ 2.10–2.10 (m, 2H, CH2CH CH2), 2.65 (t,
2
3 JHH = 5.0, 4H, CH NCH2P), 2.97 (d, 2 JPH = 11.5, 2H,
2
3
PCH2), 3.19 (t, JHH = 5.5, 4H, ArNCH CH2N), 4.35–
2
1
67.2 (2 J = 7.5, OCH2); H NMR (CDCl3) δ 1.08 (t,
4.44 (m, 2H, OCH2), 4.47–4.59 (m, 2H, OCH2),
6.82 (d, JHH = 9.0, 2H, Ar), 7.20 (d, JHH = 9.0, 2H,
Ar); (M + H)+found = 331.0956, C14H21N2O3P requires
331.0978.
J = 7.0, 6H, CH3), 2.06–2.15 (m, 2H, CH2CH CH2),
2
2.69–2.78 (m, 4H, NCH CH3), 3.03 (br d, 2 JPH = 10.0,
2
2H, PCH2), 4.33–4.46 (m, 2H, OCH2), 4.46–4.58 (m,
2H, OCH2); (M + H)+found = 208.1084, C8H19NO3P re-
quires 208.1102.
General Procedure for the Preparation of Amino-
methyl-2-(2ꢀ-hydroxybiphenyl)phosphinic Acids
4a,b,g,h
2b: Yield: 55%; 31P NMR (CDCl3) δ 19.6; 13C
NMR (CDCl3) δ 11.3 (CH3), 19.7 (CH2CH2CH3), 26.2
(3 J = 8.2, CH2CH2CH2), 49.9 (1 J = 157.9, PCH2), 57.0
(3 J = 8.0, NCH2CH2), 66.3 (2 J = 7.3, OCH2); 1H NMR
(CDCl3) δ 0.90 (t, J = 7.5, 6H, CH3), 1.40–1.55 (m,
4H, CH2CH CH3), 2.00–2.18 (m, 2H, CH2CH CH2),
A mixture of dibenzooxaphosphinane oxide 3
(0.20 g, 0.93 mmol), paraformaldehyde (0.03 g,
1.0 mmol), and secondary amine (1.0 mmol) in 2 mL
of ethanol was reacted under microwave conditions
at 80◦C for 1.5 h. Volatile components including wa-
ter were removed in vacuo to give phosphinic acid
(4a,b,g,h) as a solid.
2
2
2
2.54 (m, 4H, NCH CH2), 2.99 (d, JPH = 9.9, 2H,
2
PCH2), 4.30–4.42 (m, 2H, OCH2), 4.45–4.58 (m,
2H, OCH2); (M + H)+found = 236.1398, C10H23NO3P re-
quires 236.1416.
2c: Yield: 49%; 31P NMR (CDCl3) δ 20.9;
The following products were thus prepared:
13C NMR (CDCl3)
δ
23.9 (NCH2CH2), 26.7
4a: Yield, 98%; mp. 176◦C–178◦C after recrys-
tallization from ethyl acetate-pentane; 31P NMR
(CDCl3) δ 15.1; 13C NMR (CDCl3) δ 7.8 (CH3), 47.9
(3 J = 4.4, NCH2CH3), 50.8 (1 J = 91.3, PCH2), 121.2
(Ar),a 122.5 (Ar),a 127.2 (J = 11.3, Ar),b 129.6 (Ar),a
130.9 (Ar),a 131.2 (J = 2.4, Ar),b 131.7 (J = 7.6, Ar),b
132.1 (J = 11.1, Ar),b 134.2 (2 J = 3.0, C2), 135.5
(1 J = 129.2, C1), 141.9 (3 J = 10.3, C7), 154.9 (C8),
atentative assignment for C9, C10, C11 and C12,
btentative assignment for C3, C4, C5, and C6; 1H NMR
(CDCl3) δ 0.97–1.15 (m, 6H, CH3), 2.66–2.76 (m, 2H,
(3 J = 7.9, CH2CH2CH2), 51.2 (1 J = 161.8, PCH2),
56.2 (3 J = 10.7, NCH2CH2), 66.6 (2 J = 7.0, OCH2);
1H (CDCl3) NMR δ 1.75–1.85 (m, 4H, NCH2CH ),
2
2.00–2.16 (m, 2H, CH2CH CH2), 2.65–2.75 (m,
2
2
4H, NCH CH2), 3.05 (d, JPH = 12.0, 2H, PCH2),
2
4.30–4.42 (m, 2H, OCH2), 4.49–4.61 (m, 2H,
OCH2); (M + H)f+ound = 206.0937, C8H17NO3P requires
206.0946.
2d: Yield: 50%; 31P NMR (CDCl3) δ 19.8; 13C
NMR (CDCl3) δ 26.8 (3 J = 8.1, CH2CH2CH2), 54.3
(1 J = 160.6, PCH2), 55.4 (3 J = 10.1, OCH2CH2N),
66.8 (2 J = 7.1, POCH2), 67.1 (OCH2CH2N); 1H NMR
PCH2), 2.93–3.18 (m, 4H, NCH CH3), 7.04 (t, J = 7.5,
2
1H, ArH), 7.11 (d, J = 6.5, 1H, ArH), 7.14 (d, J = 8.5,
1H, ArH), 7.23 (dd, J1 = 7.0, J2 = 5.0, 1H, ArH), 7.33
(t, J = 7.0, 1H, ArH), 7.43 (t, J = 7.5, 1H, ArH), 7.51
(t, J = 7.5, 1H, ArH), 8.08 (dd, J1 = 7.5, J2 = 12.5, 1H,
ArH); (M + H)+found = 320.1402, C17H23NO3P requires
320.1416. Performing the above reaction at 55◦C for
40 min in 2 mL of chloroform led to a mixture of 4a
(75%) and 5 (25%).
(CDCl3) δ 2.03–2.15 (m, 2H, CH2CH CH2), 2.65 (t,
2
2
3 JHH = 4.8, 4H, OCH2CH N), 2.89 (d, JPH = 11.4,
2H, PCH2), 3.71 (t, JHH2 = 4.5, 4H, OCH CH2N),
2
4.29–4.43 (m, 2H, OCH2), 4.47–4.61 (m, 2H,
OCH2); (M + H)f+ound = 222.0880, C8H17NO4P requires
222.0895.
2e: Yield: 54%; 31P NMR (CDCl3) δ 19.8; 13C NMR
(CDCl3) δ 21.7 (CH3), 26.5 (3 J = 8.1, CH2CH2CH2),
30.0 (CH), 34.4 (CHCH2), 54.3 (1 J = 159.6, PCH2),
55.7 (3 J = 9.6, NCH2), 67.3 (2 J = 7.3, OCH2); 1H
NMR (CDCl3) δ. 0.90 (d, J = 6.4, 3H, CH3), 1.18–
5: 31P NMR (CDCl3) δ 33.8; (M + H)+found = 302.
1278, C17H21NO2P requires 302.1310.
4b: Yield, 56%; mp 156◦C–158◦C after crystal-
lization from ethylacetate–hexane; 31P NMR (CDCl3)
δ 14.9; 13C NMR (CDCl3) δ 10.7 (CH3), 16.1 (CH3CH2),
52.0 (1 J = 90.8, PCH2), 55.6 (br signal, NCH2CH2),
121.5 (Ar),a 121.7 (Ar),a 127.4 (J = 11.3, Ar),b 129.7
(Ar),a 131.1 (Ar),a 131.5 (J = 1.8, Ar),b 131.9 (J = 8.0,
1.28 and 1.58–1.64 (m, 4H, CHCH ), 1.29–1.40 (m,
2
1H, CH), 2.02–2.16 (m, 2H, CH2CH CH2), 2.21 (br
2
1
t, J = 11.6, 2H, CH2CH N), 2.89 (d, JPH = 10.2, 2H,
2
PCH2), 2.97 (br d, J = 11.5, 2H, CH2CH N), 4.38–4.56
2
Heteroatom Chemistry DOI 10.1002/hc

210 Keglevich et al.
Ar),b 132.2 (J = 11.5, Ar),b 133.7 (2 J = 3.0, C2), 134.9
(1 J = 130.7, C1), 141.6 (3 J = 10.5, C7), 154.2 (C8),
atentative assignment for C9, C10, C11, and C12,
btentative assignment for C3, C4, C5, and C6; 1H
NMR (CDCl3) δ 0.68–0.85 (m, 6H, CH3), 1.37–1.58
CH3), 0.98–1.80 (m, 8H, CH2), 2.71–3.08 (overlap-
ping signals, 6H, NCH2 + PCH2), 6.98–7.52 (m, 8H,
Ar), 8.03 (dd, J1 = 7.4, J2 = 12.3, 1H, OH), 10.3 (br
s, 1H, OH); (M + H)+found = 376.2018, C21H31NO3P re-
quires 376.2042.
(m, 4H, CH CH3), 2.67–2.98 (overlapping signals,
2
6H, NCH2 + PCH2), 6.98–7.52 (m, 8H, ArH), 8.05
(dd, J1 = 7.5, J2 = 11.5, 1H, OH), 10.40 (br s, 1H,
OH); (M + H)+found = 348.1709, C19H27NO3P requires
348.1729.
ACKNOWLEDGMENT
The assistance of Dr. Helga Szelke and Gyo¨rgyi
Osztrovszky at the beginning of the project is
appreciated.
4g: Yield: 59%; 31P NMR (CDCl3) δ 13.3; 13C NMR
(CDCl3) δ 17.8 (br s, CH3), 46.0 (1 J = 87.3, PCH2),
55.7 (NCH), 121.2 (Ar),a 122.2 (Ar),a 127.1 (J = 11.5,
Ar),b 129.6 (Ar),a 130.8 (Ar),a 131.0 (J = 2.3, Ar),b
131.5 (J = 7.7, Ar),b 131.8 (J = 11.1, Ar),b 134.0
(2 J = 3.0, C2), 135.3 (1 J = 132.1, C1), 141.2 (3 J = 10.3,
C7), 154.2 (C8), atentative assignment for C9, C10, C11,
and C12, btentative assignment for C3, C4, C5, and C6;
1H NMR (CDCl3) δ 1.12– ∼ 1.20 (m, 6H, CH3), 1.21
(d, J = 6.6, 6H, CH3), 2.52–2.64 (septet, J= 7.7, 2H,
CH), 3.54–3.64 (m, 2H, PCH2), 6.98–7.50 (m, 8H, Ar),
8.03 (dd, J1 = 7.6, J2 = 11.5, 1H, OH), 10.43 (br s, 1H,
OH); (M + H)+found = 348.1724, C19H27NO3P requires
348.1729.
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4h: Yield: 61%; mp. 152◦C–154◦C; 31P NMR
(CDCl3) δ 14.5; 13C NMR (CDCl3) δ 13.5 (CH3), 19.8
(CH2CH2), 24.2 (CH2CH2), 51.4 (1 J = 92.3, PCH2),
52.9 (br s, NCH2CH2), 121.1 (Ar),a 122.8 (Ar),a
127.0 (J = 11.2, Ar),b 129.5 (Ar),a 130.7 (Ar),a 131.0
(J = 2.4, Ar),b 131.7 (J = 7.5, Ar),b 132.1 (J = 11.1,
Ar),b 134.3 (2 J = 2.9, C2), 135.6 (1 J = 128.4, C1), 141.9
a
(3 J = 10.3, C7), 155.0 (C8), tentative assignment for
b
C9, C10, C11, and C12, tentative assignment for C3,
1
C4, C5, and C6; H NMR (CDCl3) δ 0.84 (br s, 6H,
Heteroatom Chemistry DOI 10.1002/hc