Synthesis of bis(phosphonatomethyl)-,bis(phosphinatomethyl)-, and bis(phosphinoxidomethyl)amines, as well as related ring bis(phosphine) platinum complexes

Article abstract of DOI:10.1080/00397911.2010.501478

The double Kabachnik-Fields condensation of primary amines with 2 equivalents of the other reagents (formaldehyde and a >P(O)H species, such as dialkyl phosphites, diphenylphosphine oxide, as well as the related dioxaphosphorine and oxaphosphorine derivatives) carried out under microwave conditions afforded the title products in 79-94% yields. The bis(phosphinoxidomethyl)amines were converted, after double deoxygenation, to the corresponding ring platinum complexes. Copyright

Full text of DOI:10.1080/00397911.2010.501478

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Synthesis of Bis(phosphonatomethyl)-,
Bis(phosphinatomethyl)-, and
Bis(phosphinoxidomethyl)amines, as Well
as Related Ring Bis(phosphine) Platinum
Complexes
György Keglevich a , Anna Szekrényi a , Áron Szöllősy b & László
Drahos c
a Department of Organic Chemistry and Technology , Budapest
University of Technology and Economics , Budapest , Hungary
b Department of Inorganic and Analytical Chemistry , Budapest
University of Technology and Economics , Budapest , Hungary
c Hungarian Academy of Sciences , Chemical Research Center ,
Budapest , Hungary
Published online: 25 May 2011.
To cite this article: György Keglevich , Anna Szekrényi , Áron Szöllősy & László Drahos (2011)
Synthesis of Bis(phosphonatomethyl)-, Bis(phosphinatomethyl)-, and Bis(phosphinoxidomethyl)amines,
as Well as Related Ring Bis(phosphine) Platinum Complexes, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 41:15, 2265-2272,
DOI: 10.1080/00397911.2010.501478
To link to this article: http://dx.doi.org/10.1080/00397911.2010.501478
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Synthetic Communications1, 41: 2265–2272, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.501478
SYNTHESIS OF BIS(PHOSPHONATOMETHYL)-,
BIS(PHOSPHINATOMETHYL)-, AND
BIS(PHOSPHINOXIDOMETHYL)AMINES, AS WELL
AS RELATED RING BIS(PHOSPHINE) PLATINUM
COMPLEXES
1
Gyorgy Keglevich, Anna Szekrenyi, Aron Szollosy, and
1
2
´
´
}
¨
¨
3
´
´
Laszlo Drahos
1Department of Organic Chemistry and Technology,
Budapest University of Technology and Economics, Budapest, Hungary
2Department of Inorganic and Analytical Chemistry,
Budapest University of Technology and Economics, Budapest, Hungary
3Hungarian Academy of Sciences, Chemical Research Center,
Budapest, Hungary
GRAPHICAL ABSTRACT
Abstract The double Kabachnik–Fields condensation of primary amines with 2 equivalents
of the other reagents (formaldehyde and a >P(O)H species, such as dialkyl phosphites,
diphenylphosphine oxide, as well as the related dioxaphosphorine and oxaphosphorine deri-
vatives) carried out under microwave conditions afforded the title products in 79–94%
yields. The bis(phosphinoxidomethyl)amines were converted, after double deoxygenation,
to the corresponding ring platinum complexes.
Keywords a-Aminophosphine oxides; a-aminophosphonates; Kabachnik–Fields
reaction; microwave; ring platinum complexes
INTRODUCTION
a-Aminophosphonates (AAPs), the structural analogs of a-aminocarboxylates,
are of great importance mainly from biochemical points of view.[1] AAPs are applied
in the development of inhibitors for GABA receptors, enzyme inhibitors, antibiotics,
antihypertensives, and antitumor agents.[2–5] The most widespread synthesis of
AAPs involves the Kabachnik–Fields (or phospha-Mannich) reaction, which is a
Received April 22, 2010.
Address correspondence to Gyo¨rgy Keglevich, Department of Organic Chemistry and Technology,
Budapest University of Technology and Economics, 1521 Budapest, Hungary. E-mail: gkeglevich@
mail.bme.hu
2265

2266
G. KEGLEVICH ET AL.
three-component condensation of oxo-compounds, amines, and >P(O)H
species, mainly dialkyl phosphites.[6,7] Possibilities for the accomplishment of the
Kabachnik–Fields reaction have been studied in detail.[8,9] The microwave (MW)–
promoted accomplishment of the reaction under discussion was a serious develop-
ment.[10–12] A number of publications appeared in the past decade, suggesting the
use of exotic catalysts, such as a phthalocyanine–AlCl3 complex,[13] magnesium
perchlorate,[14,15] metal triflates,[16] indium triflate,[17] bismuth nitrate,[18] samarium
iodide,[19] indium chloride,[20] and lanthanide triflates.[21] We found, however, that
there is no need to use exotic catalysts to promote the three-component conden-
sation, as it generally takes place under MW conditions without the use of any
solvent.[22] The MW-assisted Kabachnik–Fields reaction was extended to hetero-
cyclic amines or heterocyclic >P(O)H species.[23,24]
In this article, we describe the synthesis of novel bis(phosphonatomethyl)-, bis
(phosphinatomethyl)-, and bis(phosphinoxidomethyl)amines by double Kabachnik–
Fields condensation.
RESULTS AND DISCUSSION
The condensation of n-propylamine or n-butylamine with 2 equivalents of
formaldehyde and 2 equivalents of dialkyl phosphites at 100 ꢀC under MW conditions
gave bis(dialkylphosphonatomethyl)amines 1a, 1b, 2a, and 2b (Scheme 1). The
condensation was extended using 1,3,2-dioxaphosphorine 2-oxide, dibenzo[c.e]
[1,2]oxaphosphorine 2-oxide, and diphenylphosphine oxide to afford bis(phosphona-
tomethyl)amines 3a, bis(phosphinatomethyl)amines 4a and 4b, as well as bis(diphe-
nylphosphinoxidomethyl)amines 5a and 5b, respectively (Schemes 1 and 2). The
condensation can be regarded as a double Kabachnik–Fields (or phospha-Mannich)
reaction.
Scheme 1. The double Kabachnik–Fields reaction leading to different types of products.

DOUBLE KABACHNIK–FIELDS REACTIONS
2267
Scheme 2. The Kabachnik–Fields condensation giving bis(phosphinoxidomethyl)amines.
After column chromatography, and in a few cases by digeration, the products
1
1–5 were obtained in 75–94% yields and were characterized by 31P, 13C, and H
NMR, as well as mass spectroscopic data.
From among the bis(phospha-Mannich) products, compounds 1b, 5a, and 5b
have been described in the literature[25,26] but were prepared by different approaches
involving substitution at the carbon by diethyl phosphite[25] or methylene insertion
into a P-N bond.[26] The double phospha-Mannich condensation represents a novel
method for the synthesis of tertiary amines of (>P(O)CH2)2NR-type.
The bis(diphenylphosphinoxidomethyl)amines 5a and 5b were subjected to a
double deoxygenation according to a standard procedure,[27] and the bis(phosphines)
6a and 6b so obtained were reacted with a half equivalent of dichlorodibenzonitrile
platinum to furnish the corresponding ring bis(phosphine) platinum complexes
(7a and 7b) (Scheme 2).
Recrystallization provided the complexes 7a and 7b in ꢁ39%, yields and
1
they were characterized by 31P, 13C, and H NMR, as well as mass spectroscopic
data.
In the case of chiral phosphorus atoms being present in compounds 4a and 4b,
the complex 1H and 13C NMR spectroscopic patterns of some signals are due to the
1:1 mixture of meso and racemic isomers (not separated), as well as magnetic
nonequivalence.
The complexes 7a and 7b are potential catalysts in homogeneous catalytic
transformations.
Further results in this field, such as stereostructure and catalytic activity of the
complexes, will be published separately.
In summary, a novel and simple method was developed for the synthesis of
bis(phosphonatomethyl)-, bis(phosphinatomethyl)-, and bis(phosphinoxidomethyl)-
amines by double Kabachnik–Fields reaction. The bis(phosphine oxides) were
useful in the preparation of the corresponding ring platinum(II) complexes.
Scheme 3. Synthesis of ring platinum(II) complexes.

2268
G. KEGLEVICH ET AL.
EXPERIMENTAL
1
The 13C, and H NMR spectra were obtained in CDCl3 solution on a Bruker
DRX-500 spectrometer operating at 125.7 and 500.1 MHz, respectively. The 13C and
1H chemical shifts are referred to tetramethylsilane (TMS). 31P NMR spectra were
obtained also in CDCl3 solution on a Bruker AV-300 spectrometer. Chemical shifts
are downfield relative to 85% H3PO4. In some cases the 13C NMR spectra also were
taken at 75.5 MHz to recognize the 13C–31P couplings. The couplings are given in
hertz. Mass spectrometry was performed on a ZAB-2SEQ instrument. The reactions
were carried out in a 300-W CEM Discover focused microwave reactor applying
50 W under isothermal conditions.
General Procedure for the Preparation of Bis(phospha-Mannich)
Adducts
A mixture of 0.10 g (3.40 mmol) of paraformaldehyde, 3.40 mmol of diethyl
phosphite, dimethyl phosphite, dibenzo[c.e][1,2]oxaphosphorine 2-oxide or 1,3,2-
dioxaphosphorine 2-oxide (0.44 ml, 0.31 ml, 0.74 g, and 0.42 g, respectively), and
1.70 mmol of n-propyl- or n-butylamine (0.14 ml and 0.17 ml, respectively) was
heated at 100 ꢀC in a vial in a CEM Discover Microwave reactor equipped with a
pressure controller for 1 h. Volatile components were removed in vacuo. Column
chromatography (silica gel 3% methanol in chloroform) of the residue afforded
the products as oils (1, 2, 3) or as white crystals (4).
Selected Data for 1–4
Compound 1a. Yield: 94%; 31P NMR: d 24.6; 13C NMR: d 11.1 (CH3CH2
CH2), 16.3 (d, 3J ¼ 2.6, CH3CH2O), 20.3 (CH3CH2CH2), 50.0 (dd, 1J ¼ 157.0,
3J ¼ 7.2, PCH2) 58.6 (t, 3J ¼ 7.7, CH3CH2CH2), 61.8 (m, 2J ꢁ 3.4, OCH2); 1H
NMR: d 0.90 (t, 3H, CH3CH2CH2), 1.33 (t, 12H, CH3CH2O), 1.48 (sx, 2H,
2
CH3CH2CH2), 2.77 (t, 2H, CH3CH2CH2), 3.15 (d, JP,H ¼ 8.8, 4H, PCH2), 4.15
found
requires 359.1627.
(dq, JH,H ꢁ JP,H ꢁ 7.1, 8H, OCH2); ðM þ HÞþ
¼ 359:1610; C13H31NO6P2
3
3
Compound 1b. Yield: 89%; 31P NMR: d 25.1 (31P NMR[25] d 22.3); 13C
3
NMR: d 13.6 (CH3CH2CH2CH2), 16.1 (d, J ¼ 2.9, CH3CH2O), 19.6 (CH3CH2CH2
CH2), 29.1 (CH3CH2CH2CH2), 49.8 (dd, 1J ¼ 156.8, 3J ¼ 7.2, PCH2), 56.2 (t, 3J ¼ 7.7,
CH3CH2CH2CH2), 61.5 (m, 2J ꢁ 3.4, OCH2); 1H NMR: d 0.99 (t, 3H, CH3CH2CH2-
CH2), 1.24–1.46 (m, 16H, CH3CH2O and CH3CH2CH2CH2), 2.80 (t, 2H, CH3CH2-
3
CH2CH2), 3.15 (d, 2JP,H ¼ 9.0, 4H, PCH2), 4.14 (dq, JH,H ꢁ JP,H ꢁ 7.1, 8H, OCH2);
ðM þ HÞþfound ¼ 373:1795; C14H33NO6P2 requires 373.1783.
Compound 2a. Yield: 79%; 31P NMR d 27.4; 13C NMR d 11.3 (CH3CH2-
1
3
2
CH2), 20.5 (CH3CH2CH2), 49.4 (dd, J ¼ 157.6, J ¼ 7.0, PCH2), 52.7 (m, J ꢁ 3.4,
3
1
CH3O), 58.9 (t, J ¼ 8.1, CH3CH2CH2); H NMR (CDCl3) d 0.91 (t, 3H, CH3CH2-
2
CH2), 1.50 (sx, 2H, CH3CH2CH2), 2.75 (t, 2H, CH3CH2CH2), 3.16 (d, JP,H ¼ 9.3,
found
P2 requires 303.1001.
4H, PCH2), 4.15 (d, 2JP,H ¼ 10.1, 12H, CH3O); ðM þ HÞþ
¼ 303:1012; C9H23NO6

DOUBLE KABACHNIK–FIELDS REACTIONS
2269
Compound 2b. Yield: 82%; 31P NMR: d 25.9; 13C NMR: d 13.8 (CH3CH2-
1
CH2CH2), 19.9 (CH3CH2CH2CH2), 29.2 (CH3CH2CH2CH2), 49.2 (dd, J ¼ 157.4,
2
3
1
3J ¼ 7.3, PCH2), 52.6 (m, J ꢁ 3.4, CH3O), 56.7 (t, J ¼ 7.9, CH3CH2CH2CH2); H
NMR d 0.90 (t, 3H, CH3CH2CH2CH2), 1.33 (sx, 2H, CH3CH2CH2CH2), 1.43
2
(qui, 2H, CH3CH2CH2CH2), 2.76 (t, 2H, CH3CH2CH2CH2), 3.14 (d, JP,H ¼ 9.2,
found
NO6P2 requires 317.1157.
4H, PCH2), 3.78 (d, JP,H ¼ 10.4, 12H, CH3O); ðM þ HÞþ
¼ 317:1153; C10H25
2
Compound 3a. Yield: 89%; 31P NMR: d 20.6; 13C NMR d 11.1 (CH3CH2-
CH2), 20.2 (CH3CH2CH2), 26.3 (d, 3J ¼ 4.1, OCH2CH2CH2O), 49.4 (dd, 1J ¼
3
3
2
154.2, J ¼ 7.9, PCH2), 58.8 (t, J ¼ 7.0, CH3CH2CH2), 66.6 (m, J ¼ 3.5, OCH2);
1H NMR d 0.91 (t, 3H, CH3CH2CH2), 1.53 (sx, 2H, CH3CH2CH2), 2.07 (m, 4H,
2
OCH2CH2CH2O), 2.82 (t, 2H, CH3CH2CH2), 3.29 (d, JP,H ¼ 9.5, 4H, PCH2),
found
4.32–4.51 (m, 8H, OCH2); ðM þ HÞþ
¼ 327:0986; C11H23NO6P2 requires 327.1001.
Compound 4a. Yield: 92%; mp 159.7–160.7 ꢀC; 31P NMR d 32.72 (50%) and
32.75 (50%); 13C NMR: d 11.2 (CH3 and CH3 ), 20.4 (CH3CH2 and CH3CH2 ), 53.0
0
0
1
3
3
0
and 53.1 (dd, J ¼ 111.0, J ¼ 7.0, PCH2 and PCH2 ), 59.2 and 59.4 (t, J ¼ 7.0,
0
0
CH3CH2CH2 and CH3CH2CH2 ), 120.3 and 120.4 (d, C4 and C4 ), 122.1 (m, C1a
and C1a0), 123.6 (m, C10 and C100), 123.8 and 123.9 (d, J ¼ 116.0, C6a and C6a0),
0
0
0
124.6 (C3 and C3 ), 125.2 (C1 and C1 ), 128.4 (d, J ¼ 14.0, C8 and C8 ), 130.6 (C2
0
0
0
and C2 ), 131.2 (m, C7 and C7 ), 133.4 and 133.5 (C9 and C9 ), 135.6 and 135.8 (m,
1
C10a and 0C10a0), 149.2 (m, C4a and C4a0); H NMR d 0.62 and 0.63 (t, 6H, CH3
0
and CH3 ), 1.03–1.16 (m, 4H, CH3CH2 and CH3CH2 ), 2.66 and 2.86 (dt, 2H,
0
CH3CH2CH2), 2.78 (t, 2H, CH3CH2CH2 ), 3.24, 3.34, 3.48, 3.53 (dd, Jgem ¼ 16.0,
2
0
JPH ¼ 5.0, 4H, PCH2 and PCH2 ), 7.10 (d, J ¼ 8.2 2H, C4H and C4H0), 7.22
(t, J ¼ 7.5, 2H, C3H and C3H0), 7.33 (m, 2H, C2H and C2H0), 7.39 and 7.43
(t, J ¼ 7.5, 2H, C8H and C8H0), 7.61 and 7.66 (t, J ¼ 8.2, 2H, C9H and C9H0), 7.79
and 7.80 (m, 2H, C7H and C7H0), 7.83–7.95 (m, 4H, C1H=C1H0 and C10H=C10H0);
ðM þ HÞþfound ¼ 515:1401; C29H27NO4P2 requires 515.1415.
Compound 4b. Yield: 90%; mp 165.0–165.9 ꢀC; 31P NMR d 32.78 (50%) and
13
0
0
32.80 (50%); C NMR d 14.1 (CH3 and CH3 ), 20.1 (CH3CH2 and CH3CH2 ), 29.5
0
and 30.0 (CH3CH2CH2 and CH3CH2CH2 ), 53.0 and 53.2 (dd, J1 ¼ 111.0, J2 ¼ 7.0,
0
PCH2 and PCH2 ), 57.3 and 57.4 (dd, J1 ¼ J2 ¼ 7.0, CH2CH2CH2 and CH2CH2
CH2 ), 120.4 and 120.5 (d, C4 and C4 ), 122.1 (m, C1a and C1a0), 123.70(m, C10 and
0
0
C
100), 124.0 and 124.1 (d, J ¼ 114.0, C6a and C6a0), 124.7 (C3 and C3 ), 125.3 (C1
0
0
0
and C1 ), 130.7 (C2 and C2 ), 128.5 (d, J ¼ 15.0, C8 and C8 ), 131.3 (m, C7 and
C7 ), 133.4 and 133.5 (C9 and C9 ), 136.0 and 137.7 (m, C10a and C10a0), 149.3 (m,
0
0
1
C4a and C4a0); H NMR (CDCl3) d 0.69 and 0.70 (t, 6H, CH3 and CH3 ), 0.90–
1.10 (m, 8H, CH3CH2CH2 and CH3CH2CH2 ), 2.68 and 2.88 (dt, 2H, CH2CH2N),
0
0
2
2.80 (t, 2H, CH2CH2N0), 3.24, 3.35, 3.48, 3.53 (dd, Jgem ¼ 16.0, JPH ¼ 5.0, 4H,
PCH2 and PCH2 ), 7.10 (d, J ¼ 8.2, 2H, C4H and C4H0), 7.22 (t, J ¼ 7.5, 2H, C3H
0
and C3H0), 7.33 (m, 2H, C2H and C2H0), 7.39 and 7.43 (m, 2H, C8H and C8H0),
7.61 and 7.66 (t, J ¼ 7.5, 2H, C9H and C9H0), 7.79 and 7.80 (m, 2H, C7H and
C7H0), 7.83–7.95 (m, 4H, C1H=C1H0 and C10H=C10H0); ðM þ HÞfþound ¼ 529:1588;
C30H29NO4P2 requires 529.1572.

2270
G. KEGLEVICH ET AL.
General Procedure for the Preparation of Bis(phosphinoxidomethyl)-
amines (5a and 5b)
A mixture of 0.030 g (1.0 mmol) of paraformaldehyde, 0.20 g (1.0 mmol) of
diphenylphosphine oxide, and 0.50 mmol of n-propyl- or n-butylamine (0.04 ml and
0.05 ml, respectively) was heated at 100 ꢀC in a vial in a CEM Discover Microwave
reactor equipped with a pressure controller for 1 h. Column chromatography (silica
gel 3% methanol in chloroform) of the crude mixture followed by digeration with
n-hexane–CH2Cl2 8:2 afforded the products 5a and 5b as white crystals.
Selected Data for 5a and 5b
Compound 5a. Yield: 78%; mp 150–151 ꢀC (mp[26] 154–156 ꢀC); 31P NMR d
29.2 (31P NMR[26] d 29.1); 13C NMR d 11.1 (CH3CH2CH2), 19.6 (CH3CH2CH2),
1
3
3
3
55.9 (dd, J ¼ 85.3, J ¼ 7.9, PCH2), 60.3 (t, J ¼ 7.2, CH3CH2CH2), 128.3 (d, J ¼
2
1
1
0
0
0
0
11.7, C3 ), 131.2 (d, J ¼ 9.1, C2 ), 131.6 (C4 ) 132.2 (d, J ¼ 99.5, C1 ); H NMR d
0.59 (t, 3H, CH3CH2CH2), 1.31 (sx, 2H, CH3CH2CH2), 2.94 (t, 2H, CH3CH2CH2),
¼ 488:1893;
3.71 (d, JP,H ¼ 6.0, 4H, PCH2), 7.30–7.82 (m, 20H, Ar); ðM þ HÞþ
2
found
C29H32NO2P requires 488.1908.
Compound 5b. Yield: 75%; mp 178–179 ꢀC (mp[26] 178–180 ꢀC); 31P NMR d
29.2 (31P NMR[26] d 29.2); 13C NMR d 14.2 (CH3CH2CH2CH2), 20.1 (CH3CH2CH2
CH2), 28.8 (CH3CH2CH2CH2), 56.1 (dd, 1J ¼ 76.4, 3J ¼ 7.7, PCH2), 58.6 (t, 3J ¼ 7.0,
3
2
0
0
0
CH3CH2CH2CH2), 128.6 (d, J ¼ 11.6, C3 ), 131.4 (d, J ¼ 9.1, C2 ), 131.8 (C4 ), 132.5
1
1
0
d J ¼ 100.9 C1 ); H NMR d 0.72 (t, 3H, CH3CH2CH2CH2), 0.98 (sx, 2H, CH3CH2
CH2CH2), 1.24 (qui, 2H, CH3CH2CH2CH2), 2.97 (t, 2H, CH3CH2CH2CH2), 3.72 (d,
¼ 502:2086; C30H34
2JP,H ¼ 5.9, 4H, PCH2), 7.30–7.80 (m, 20H, Ar); ðM þ HÞþ
found
NO2P2 requires 502.2065.
General Procedure for the Preparation of Bis(phosphinomethyl)-
amine-platinum Complexes
To 0.60 mmol of 5a or 5b (0.29 g and 0.30 g, respectively) was added 0.40 ml
(3.0 mmol) of phenylsilane under nitrogen. The mixture was stirred at 80 ꢀC for 3 days.
Then 6 ml of benzene was added to the crude mixture. To a 1-ml aliquot of the sol-
ution containing 0.10 mmol of phosphine 6 was added 0.050 g (0.105 mmol) of dichlor-
odibenzonitrile platinum in 10 ml of benzene, and the mixture was stirred at 26 ꢀC for
1 day. Platinum complex 7 crystallized from the mixture was separated by filtration.
Selected Data for 7a and 7b
Compound 7a. Yield: 38%; 31P NMR d ꢂ 8.5 (JPt–P ¼ 3379); 1H NMR d 0.58
(t, 3H, CH3CH2CH2) 1.29 (sx, 2H, CH3CH2CH2), 2.92 (t, 2H, CH3CH2CH2), 3.71
(d, 4H, JP,H ¼ 6.9, PCH2), 7.30–7.80 (m, 20H, Ar); (M – Cl þH) ¼ 684.
Compound 7b. Yield: 40%; 31P NMR d ꢂ 8.4 (JPt–P ¼ 3399); 1H NMR d 0.78
(t, 3H, CH3CH2CH2CH2), 1.04 (sx, 2H, CH3CH2CH2CH2), 1.29 (qui, 2H, CH3CH2
CH2CH2), 2.55 (t, 2H, CH3CH2CH2CH2), 3.38 (d, 4H, JP,H ¼ 6.9, PCH2), 7.30–7.80

DOUBLE KABACHNIK–FIELDS REACTIONS
2271
(m, 20H, Ar); ðM ꢂ Cl þ HÞfþound ¼ 698:1423; C30H33NClP2Pt requires 698.1404 for
the 35Cl and 194Pt isotopes.
ACKNOWLEDGMENTS
G. K. is grateful to Professor Harry R. Hudson (London Metropolitan
University) for his advice. This project was supported by the Hungarian Scientific
and Research Fund (OTKA K83118).
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