Synthesis of thiazole aminophosphine oxides, aminophosphonic and aminophosphinic acids and Cu(II) binding abilities of thiazole aminophosphonic acids

Article abstract of DOI:10.1016/j.tet.2005.12.016

A series of new aminophosphine oxides, aminophosphonic and aminophosphinic acids derived from thiazole was synthesized by addition of phosphine oxides or silylated phosphorus esters to the corresponding thiazole aldimines. The thiazole aldimines were obta

Full text of DOI:10.1016/j.tet.2005.12.016

Tetrahedron 62 (2006) 2183–2189
Synthesis of thiazole aminophosphine oxides, aminophosphonic
and aminophosphinic acids and Cu(II) binding abilities
of thiazole aminophosphonic acids
a
b
b
Tomasz K. Olszewski,a, Bogdan Boduszek, Sylwia Sobek and Henryk Kozłowski
*
aDepartment of Organic Chemistry, Faculty of Organic Chemistry, Wrocław University of Technology,
´
Wybrzez˙e Wyspianskiego 27, 50-370 Wrocław, Poland
bFaculty of Chemistry, University of Wrocław, F. Joliot-Curie 14, 50-383 Wrocław, Poland
Received 29 October 2005; revised 17 November 2005; accepted 9 December 2005
Available online 10 January 2006
Abstract—A series of new aminophosphine oxides, aminophosphonic and aminophosphinic acids derived from thiazole was synthesized by
addition of phosphine oxides or silylated phosphorus esters to the corresponding thiazole aldimines. The thiazole aldimines were obtained
from 2-thiazole aldehyde and primary amines by a standard procedure. The corresponding phosphine oxides were obtained by alkylation of
diethyl phosphite or ethyl phenylphosphinate with the appropriate Grignard reagents. The silylated phosphorus esters were prepared from
trimethyl phosphite and from methyl- or phenylphosphinic ethyl ester by treatment with bromotrimethylsilane. The coordination ability
towards Cu(II) ions are described for two obtained aminophosphonate ligands.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
more useful in preparation of heterocyclic
aminophosphonates.
Aminophosphonic acids, as phosphorus analogues of
a-aminocarboxylic acids, are of great interest due to a
significant biological activity.1 Some of them are powerful
herbicides and have found a wide commercial application,
as for example, the phosphonomethylglycine (the glypho-
sate).2 Some representatives of aminophosphonates have
demonstrated promising enzyme inhibitory activity, as
for example, HIV protease antagonists3 and collagenase
inhibitors4 and biological activities are often related to their
metal ion binding abilities.1,5 In the last decades, an
intensive synthetic work was performed in the preparation
of aminophosphonates,6 some of them being analogues of
natural amino acids and others being analogues of important
unnatural amino acids.7
Recently, some heterocyclic derivatives of aminomethyl-
phosphonic acid were prepared; for example, the furan
derivatives,8–10 imidazole and pyrazole derivatives,11
thiophene derivatives,12 and pyridine derivatives.13,14 The
prevailing synthetic route used in the preparation of these
heterocyclic aminophosphonate derivatives was Fields’
method,15 and depended generally on addition of dialkyl
phosphites to heterocyclic aldimines. This method was not
suitable as a general synthetic procedure for most
heterocyclic aminophosphonates, because, in some cases,
decomposition of the heterocyclic moieties was observed,
or, due to a cleavage of a C–P bond in the formed
aminophosphonates.13,14,16
During the last few years, a new kind of silicon–
phosphorus based reagent for synthesis of organo-
phosphorus compounds has been developed.17–20 Application
of these reagents enabled the synthesis of heterocyclic
a-aminophosphonate compounds.18 It was found that
silylated phosphorus acid esters were effective reagents for
preparation of heterocyclic, fragile aminophosphonates from
aldimines.21–23
To the best to our knowledge, aminophosphonates
possessing a thiazole moiety are unknown. A basic difficulty
in the synthesis of parent heterocyclic aminophosphonates8
is an inapplicability of known, regular procedures for
synthesis of the typical aminophosphonates. Therefore,
there is a need to search for new methods, which could be
Keywords: Aminophosphonic acids; Heterocyclic derivatives; Grignard
reagent.
In this paper, we wish to report the first synthesis of
aminophosphonic and aminophosphinic acids derived from
*
Corresponding author. Tel.: C48 71 320 2917; fax: C48 71 328 4064;
e-mail: tomasz.olszewski@pwr.wroc.pl
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.12.016

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T. K. Olszewski et al. / Tetrahedron 62 (2006) 2183–2189
thiazole, by exploitation of the recently described methods.
We report, additionally, the synthesis of thiazole amino-
phosphine oxides, which are parent compounds of the
thiazole aminophosphonic and aminophosphinic acids.
Earlier studies have shown that aminophosphonates bearing
imidazole, pyrazole or pyridine moiety were effective
ligands for metal ions, especially Cu(II).24–27 The coordi-
nation properties of thiazole phosphonate ligands using
potentiometric and spectroscopic methods are also reported
here.
24 h. Formed silylated phosphonic and phosphinic inter-
mediates, 3 and 5 (Scheme 1) were then treated with
methanol, as a dealkylating agent, to give the final
aminophosphonic 4a–b and aminophosphinic acids 6a–d.
The silylated phosphoesters were found to be good
nucleophiles toward the imines. The presence of a
bulky trimethylsilyl group in the formed phosphonate or
phosphonite-like ester increases the power of such a
nucleophile due to formation of a stable, three-coordinated
phosphorus moiety with a free electron pair at phosphorus.
Also, lack of the possibility of tautomerization in the formed
three-coordinated, silylated phosphorus ester into less
nucleophilic four-coordinated phosphonate-like ester,
additionally secure a nucleophilic character of the applied
reagent.
2. Results and discussion
2.1. Synthesis of aminophosphonic and aminophosphinic
acids
The syntheses of thiazole aminophosphonic and amino-
phosphinic acids are illustrated in Scheme 1. 2-Thiazole
aldehyde28 1 reacted easily with aliphatic or aromatic
primary amines in dichloromethane to give the correspond-
ing aldimines 2. The aldimines were reacted directly with
silylated phosphorus esters to form the thiazole amino-
phosphonic, or aminophosphinic silylated esters 3 and 5, as
intermediates, which were then deprotected giving the
thiazole aminophosphonic and aminophosphinic acids 4a,b
and 6a–d (Scheme 1).
The use of bromotrimethylsilane (BrTMS) resulted in an
easier silylation process of the alkyl phosphoesters, due to a
higher reactivity of the BrTMS, in comparison with
chlorotrimethylosilane, which is frequently used for
silylation reactions.17,18 Application of BrTMS for depro-
tection of phosphonate esters gave excellent results and
allowed, in our case, to obtain the desired thiazole
aminophosphonic and aminophosphinic acids by a direct
way, in high yield and purity.
The described method presents a substantial improvement
in the synthesis of heterocyclic aminophosphonic and
aminophosphinic acids. After slight modifications, the
present method can also be applied for synthesis of the
monoalkyl esters of aminophosphonic acids, which are not
easily available compounds.22 Such a method is useful for
synthesis of aminophosphonates possessing heterocyclic,
fragile moieties.
Silylated in situ phosphoesters used for addition to the imines
were prepared from trimethyl phosphite (in the case of
preparation of thiazole aminophosphonic acids) or from
methyl-, or phenylphosphinate ethyl ester (in the case of
preparation of thiazole aminophosphinic acids), by treatment
of the corresponding phosphoesters with bromotrimethyl-
silane. Nucleophilic addition of the silylated phosphorus
esters to imines proceeded easily at room temperature for
Scheme 1. Synthesis of thiazole aminophosphonic and aminophosphinic acids.

T. K. Olszewski et al. / Tetrahedron 62 (2006) 2183–2189
2185
Scheme 2. Synthesis of thiazole aminophosphine oxides.
2.2. Synthesis of thiazole aminophosphine oxides
with varied substituents on phosphorus and nitrogen atoms,
was obtained. Some of the thiazole aminophosphine oxides
7 were isolated and purified as oxalate salts. Oxalates were
formed as crystalline solids when the aminophosphines 7
were treated with oxalic acid in acetone solution.
In this paper, we describe a facile approach to new thiazole
aminophosphine oxides, which are parent compounds to the
thiazole aminophosphonic and aminophosphinic acids 4 and
6. The method is based on addition of phosphinous acids
(also called phosphine oxides, due to existence of such
tautomeric a form) to thiazole aldimines 2. Such addition of
phosphine oxides to thiazole aldimines occurred readily in
boiling toluene, to give the expected products, that is, the
thiazole aminophosphine oxides 7a–f (Scheme 2). As a
result, a series of new thiazole aminophosphine oxides 7,
Phosphine oxides 9a–b used in the presented synthetic
procedure, were prepared from H-phosphinates (methyl- or
phenylphosphinate ethyl esters) and Grignard reagents,
according to a literature method 29 (Scheme 3). In turn, the
diphenyl phosphine oxide (diphenylphosphinous acid, 10)
was simply obtained from chlorodiphenylphosphine and
aqueous HCl, following the literature method.30
The synthesized thiazole aminophosphine oxides 7a–d were
mixtures of diastereoisomers (as shown by their NMR
spectra). 31P NMR shifts of the thiazole aminophosphine
oxides depend largely on electronegativity of the substituent
attached to the phosphorus atom. For example, the 31P
signals of diphenyl derivatives 7e,f are placed between 30
and 32 ppm, compared to the corresponding signals of
methyl-phenylphosphine derivatives 7c,d, which are
observed in the range of 41–44 ppm, and the n-butylphenyl-
phosphine oxides 7a,b, which are in the 42–46 ppm,
respectively.
2.3. Complexation of Cu(II) ions by 4a and 4b
Coordination properties of the obtained products were
measured for thiazole aminophosphonic acids 4a and 4b,
Scheme 3. Synthesis of phosphine oxides.
Table 1. Stability constants of proton (log K) and copper(II) complexes (log b)
4a
8.67
4.83
—
12.75
9.10
—
—
14.45
—
3.65
—
—
4b
7.56
4.72
—
—
8.09
—
—
13.17
—
—
—
—
Imid-Bu27
Imid-Ph27
Pyrid-Bu26
Pyrid-Ph26
log K(HL)
10.22
6.05
4.30
18.27
14.74
35.04
28.93
20.67
11.16
3.53
9.06
5.89
4.07
16.59
13.23
32.11
25.77
18.10
—
3.36
6.34
7.67
—
10.14
5.20
1.72
16.50
—
31.35
26.81
20.90
—
9.04
5.21
3.82
—
log K(H2L)
log K(H3L)
log b(CuHL)
log b(CuL)
log b(CuH2L2)
log b(CuHL2)
log b(CuL2)
log b(CuHK1L2)
pK(CuHL)
—
29.11
25.01
19.38
—
—
—
pK(CuH2L2)
pK(CuHL2)
pK(CuL2)
6.11
8.26
9.51
4.54
5.91
—
4.10
5.63
—
—
—

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T. K. Olszewski et al. / Tetrahedron 62 (2006) 2183–2189
Table 2. Spectroscopic parameters for Cu(II) complexes formed by studied
ligands
which were soluble in aqueous solutions. The thiazole
aminophosphinic acids 6 and aminophosphine oxides 7
were not appropriate for potentiometric studies, due to
precipitation of the ligands in a higher pH range. Both
ligands (4a, 4b) behave as H2L acids. Two protonation
constants of 4a log KZ8.67 and 4.83 may be assigned to
amino and phosphonate functions, respectively. Similar
log K values are observed for 4b, 7.56 and 4.71. The
protonation constant of benzylamino substituted nitrogen
(4b) is distinctly lower than that of N-butylamino derivative
(Table 1), while the basicities of the phosphonate function
are rather similar to each other. The analogous derivatives
with the imidazole27 or pyridine26 moiety behave in a
similar way, although the basicities of amino groups of
thiazole derivatives are much lower than those of imidazole,
or pyridine aminophosphonates (Table 1). This indicates
a much higher degree of electron withdrawing abilities of
thiazole when compared to imidazole, or pyridine rings.
Ligands
UV–vis
3 (dm3 molK1
cmK1
EPR
gII
l (nm)
AII
)
L1-4a
L2-4b
CuHL
CuL
CuL2
CuL
CuL2
693
643
612
667
634
48
76
86
86
84
140
155
187
155
190
2.347
2.290
2.222
2.281
2.231
of AIIZ155 and 190 G support such a coordination
mode.24–27 In the CuHL, species observed for 4a the
coordination mode {Nthiazole, PO23K} seems to be the most
likely. The d–d trasition at 693 nm support the one nitrogen
coordination (Table 2).26 Thus, thiazole and amino
nitrogen are basic for the metal ion coordination although
the presence of the phosphonate function modulates the
binding ability of the aminophosphonic acid distinctly. The
thiazole moiety with its least basic nitrogen donor is a very
effective chelating agent for Cu(II) ions although both
pyridine and imidazole derivatives are more powerful
ligands.
According to the calculations based on potentiometric data,
4a and 4b form two major complexes CuL and CuL2
(Table 1, Fig. 1). The stability constants of the 4a
complexes are distinctly higher than those of 4b due to
the higher basicity of the amino function of the ligand. The
d–d transitions observed around 640–660 and 610–630 nm
indicate the involvement of two or four nitrogen donors in
the binding of Cu(II) ion in CuL and CuL2, respectively,
(Table 2).24–27 Also, EPR parameters, especially the values
3. Conclusions
New thiazole aminophosphine oxides, thiazole amino-
phosphonic and aminophosphinic acids were synthesized
in a simple way, from the corresponding aldimines and
secondary phosphine oxides, or silylated phosphorus
esters. It was demonstrated that thiazole aminophosphonic
acids are effective ligands for complexation of Cu(II)
ions.
(a)
100
80
60
40
20
0
CuL
CuL
2
Cu(II)
CuHL
4. Experimental
NMR spectra were recorded on a Bruker Avance TM DRX
spectrometer, in D2O, 10% D2O/D2SO4, or CDCl3
solutions, respectively. IR spectra were recorded on a
Perkin Elmer 1600 FTIR spectrophotometer. MS analyses
were determined on a Finnigan TSQ 700 instrument
(electrospray ionization on mode: ESI CQ1MS) in
Department of Chemistry, University of Wrocław. Melting
points were determined using an Electrothermal 9200
apparatus and a Boetius hot-stage apparatus and were
uncorrected. Elemental analyses were done in Department
of Chemistry, University of Wrocław. All commercially
available materials were used as received from the supplier
(Aldrich Company).
2
4
6
8
10
pH
(b)
100
CuL
CuL
2
Cu(II)
80
60
40
20
0
4.1. Synthesis of reagents
Ethyl methylphosphinate (8b) was prepared from methyl-
dichlorophosphine, as described in the literature.31
4.1.1. n-Butylphenylphosphine oxide32 (9a). To a 2.0 M
solution of n-BuMgCl (10.0 mL, 20.0 mmol) in dry diethyl
ether (20 mL) ethyl phenylphosphinate (1.70 g, 10.0 mmol)
was added dropwise at 0 8C with stirring. Then, the reaction
mixture was refluxed for 2 h, cooled (ice bath) and aqueous
2
4
6
8
10
pH
Figure 1. Species distribution curves for the complexes formed in the
(a) Cu(II)-4a; (b) Cu(II)-4b system as a function of pH. CCu(II)Z1.0!
10K3 mol dmK3, CLZ4.0!10K3 mol dmK3
.

T. K. Olszewski et al. / Tetrahedron 62 (2006) 2183–2189
2187
25% H2SO4 (30 mL) was slowly added. The organic layer
was separated and discarded. The remaining aqueous layer
was extracted with CH2Cl2 (5!30 mL). The combined
organic extracts were shaken with the solid K2CO3 and
dried over anhydrous Na2SO4. After evaporation of the
filtrate, the crude n-butylphenylphosphine oxide 9a was
3.4 Hz), 4.82 (d, 1H, CH–P, JZ16.6 Hz), 2.89–2.68 (m, 2H,
NHCH2), 1.38–1.26 (m, 2H, CH2CH2), 1.08–1.01 (m, 2H,
CH2CH2), 0.57–0.48 (m, 3H, CH3). 31P NMR; dP (D2O/
D2SO4; 121.5 MHz): 6.91 (s). IR, nmax (KBr): 3439 (NH);
3109; 2964; 2837; 2811; 2681; 2328; 1616; 1558; 1492;
1466; 1385; 1225; 1185 (P]O); 1076; 984; 926; 850; 748;
642; 567 cmK1. MS; (ESICQ1MS): 273.2 (100, MCCNa).
Anal. Calcd for C8H15N2O3PS, requires C, 38.39; H, 6.04;
N, 11.19; found: C, 38.34; H, 6.18; N, 11.10%.
1
obtained as colorless oil. Yield: 66% (1.2 g). H NMR; dH
(CDCl3; 300 MHz): 8.13–6.59 (dt, 1H, P–H, JH–PZ463 Hz,
JZ3.7 Hz), 7.61–7.36 (m, 5H, PhH), 1.93–1.83 (m, 2H,
PCH2(CH2)2CH3), 1.54–1.13 (m, 4H, CH2(CH2)2CH3),
0.92–0.87 (m, 3H, CH3). 31P NMR; dP (CDCl3;
121.5 MHz): 29.66 (s).
4.2.2. Thiazole-2-yl-methyl-(N-benzylamino)phosphonic
acid (4b). A white solid. Yield: 0.50 g (70%), mp 185–
187 8C. 1H NMR; dH (D2O/10% D2SO4; 300 MHz): 7.56 (d,
1H, thiazole-4, JZ3.3 Hz), 7.40 (d, 1H, thiazole-5, JZ
3.3 Hz), 6.99–6.89 (m, 5H, PhH), 4.86 (d, 1H, CH–P, JZ
18.7 Hz), 3.94 (s, 2H, NHCH2Ph). 31P NMR; dP (D2O/
D2SO4; 121.5 MHz): 6.06 (s). IR, nmax (KBr): 3492, 3407
(NH); 3040; 2886; 2614; 2486, 2398; 1662; 1576; 1456;
1466; 1382; 1277; 1187 (P]O); 1118; 937; 864; 743; 636;
555; 490, 460 cmK1. MS; (ESICQ1MS): 307.2 (100,
MCCNa). Anal. Calcd for C11H13N2O3PS, requires C,
46.48; H, 4.61; N, 9.85; found: C, 46.40; H, 4.75; N, 9.81%.
4.1.2. Methylphenylphosphine oxide33 (9b). The title
compound was prepared using PhMgCl (2.0 M solution in
diethyl ether, 16.0 mL, 32.0 mmol) and ethyl methyl-
phosphinate 8b (1.7 g, 16.0 mmol). The procedure for
preparation of 9a was exactly followed and 9b obtained as
1
colorless oil. Yield: 54% (1.2 g). H NMR; dH (CDCl3;
300 MHz): 8.24–6.65 (dq, 1H, P–H, JH–PZ476.3 Hz, JZ
3.8 Hz), 7.64–7.29 (m, 5H, PhH), 1.77 (dd, 3H, P–CH3, JZ
13.9, 3.8 Hz). 31P NMR; dP (CDCl3; 121.5 MHz): 22.30 (s).
Aldimines 2 were prepared from 2-formylthiazole (1) and
primary amines, according to the following procedure:
aldehyde 1 (0.47 g, 2.5 mmol) was dissolved in dry CH2Cl2
(25 mL) and an appropriate amine was added (2.5 mmol).
The mixture was stirred for 24 h at room temperature and
dried over anhydrous Na2SO4, filtered and the filtrate
evaporated to give the crude imines 2, which were used
directly in a next step.
4.2.3. Thiazole-2-yl-methyl-(N-butylamino)-phenyl-
phosphinic acid (6a). A white solid. Yield: 0.57 g (74%),
mp 157–160 8C. 1H NMR; dH (D2O/10% D2SO4;
300 MHz): 8.61 (d, 1H, thiazole-4, JZ3.3 Hz), 8.57 (d,
1H, thiazole-5, JZ3.3 Hz), 8.00–7.82 (m, 5H, PhH), 5.23
(d, 1H, CH–P, JZ19.6 Hz), 3.59–3.51 (m, 2H, NHCH2),
2.07–1.97 (m, 2H, CH2CH2), 1.75–1.62 (m, 2H, CH2CH2),
1.19 (t, 3H, CH3, JZ7.3 Hz). 31P NMR; dP (D2O/D2SO4;
121.5 MHz): 19.62 (s). MS; IR, nmax (KBr): 3394 (NH);
3060; 2961; 2777; 1591; 1487; 1441; 1316; 1216 (P]O);
4.2. General procedure for preparation of 2-thiazole
aminophosphonic acids 4a–b and aminophosphinic
acids 6a–d
1131; 990; 938; 750; 718; 695; 547; 505 cmK1
.
(ESICQ1MS): 333.3 (100, MCCNa). Anal. Calcd for
C14H19N2O2PS, requires C, 54.18; H, 6.17; N, 9.03; found:
C, 54.15; H, 6.21; N, 8.97%.
To a solution of crude imine 2 (2.5 mmol) in dichloro-
methane (25 mL) trimethyl phosphite was added (0.32 g,
2.5 mmol), followed by bromotrimethylsilane (1.6 g,
10 mmol). The mixture was stirred for 24 h at room
temperature and evaporated under reduced pressure. The
resulted oil was treated with methanol (5 mL) and
refrigerated for several hours. The products (thiazole
aminophosphonic acids 4a–b) separated as white solids
and were collected by filtration, washed with diethyl ether
and dried.
4.2.4. Thiazole-2-yl-methyl-(N-benzylamino)-phenyl-
phosphinic acid (6b). A white solid. Yield: 0.53 g (63%),
mp 217–220 8C. 1H NMR; dH (D2O/10% D2SO4;
300 MHz): 8.50 (d, 1H, thiazole-4, JZ3.3 Hz), 7.30 (d,
1H, thiazole-5, JZ3.3 Hz), 8.20–8.03 (m, 10H, PhH), 5.22
(d, 1H, CH–P, JZ18.7 Hz), 4.71 (s, 2H, NHCH2Ph). 31P
NMR; dP (D2O/D2SO4; 121.5 MHz): 19.64 (s). IR, nmax
(KBr): 3620; 3446 (NH); 3047; 2963; 2930; 2848; 2730;
2603; 1617; 1476; 1437; 1366; 1169 (P]O); 1131; 1026;
Phosphinic acids 6a–d were obtained in the following way:
the ethyl phenylphosphinate (8a) (0.45 g, 2.5 mmol), or
ethyl methylphosphinate (8b) (0.28 g, 2.5 mmol), was
added to solution of crude imine 2 in dry CH2Cl2
(25 mL). Bromotrimethylsilane (1.2 g, 7.5 mmol) was then
added and the whole mixture was stirred for 24 h, at room
temperature. After this, the mixture was evaporated, the
resulted oil treated with 5 mL MeOH and refrigerated for
several hours. The separated products were filtered and
dried to give the aminophosphinic acids 6a–d as white
solids.
997; 918; 891; 743; 732; 695; 645; 602; 566; 510 cmK1
.
MS; (ESICQ1MS): 345.3 (100, MCC1). Anal. Calcd for
C17H17N2O2PS, requires C, 59.29; H, 4.98; N, 8.13; found:
C, 59.18; H, 5.02; N, 8.09%.
4.2.5. Thiazole-2-yl-methyl-(N-butylamino)-methyl-
phosphinic acid (6c). A white solid. Yield: 0.41 g (67%),
mp 168–172 8C. 1H NMR; dH (D2O/10% D2SO4;
300 MHz): 8.59 (d, 1H, thiazole-4, JZ3.3 Hz), 8.57 (d,
1H, thiazole-5, JZ3.3 Hz), 5.26 (d, 1H, CH–P, JZ
17.6 Hz), 3.56–3.50 (m, 2H, NHCH2), 1.79–1.70 (m, 2H,
CH2CH2), 1.40–1.32 (m, 2H, CH2CH2), 1.17 (t, 3H, CH3,
JZ7.3 Hz), 1.02 (d, 3H, PCH3, JZ14.3 Hz). 31P NMR; dP
(D2O/D2SO4; 121.5 MHz): 29.80 (s) ppm. IR, nmax (KBr):
3313 (NH); 3243; 2951; 2908; 2878; 1587; 1487; 1421;
1198 (P]O); 1123; 995; 928; 755; 708; 695; 504 cmK1
4.2.1. Thiazole-2-yl-methyl(N-butylamino)phosphonic
acid (4a). A white solid. Yield: 0.40 g (65%), mp 220–
224 8C. H NMR; dH (D2O/10% D2SO4; 300 MHz): 7.67
1
(d, 1H, thiazole-4, JZ3.4 Hz), 7.55 (d, 1H, thiazole-5, JZ

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T. K. Olszewski et al. / Tetrahedron 62 (2006) 2183–2189
MS; (ESICQ1MS): 271.3 (100, MCCNa). Anal. Calcd for
C9H17N2O2PS, requires C, 43.54; H, 6.90; N, 11.28; found:
C, 43.45; H, 7.01; N, 11.21%.
PCH2(CH2)2)], 0.97–0.92 (m, 3H, CH3). 31P NMR; dP
(D2O; 121.5 MHz): 43.02 (s) and 42.31 (s), in a ratio 1:0.83
(two diastereomers). IR, nmax (KBr): 3491; 3415 (NH);
2965; 2810; 1668; 1481; 1449; 1408; 1183 (P]O); 792;
744; 690; 541; 531; 491 cmK1. MS; (ESICQ1MS): 407.5
(100, MCCNa). Anal. Calcd for C21H25N2OPS$2!
(COOH)2, requires C, 53.19; H, 5.18; N, 4.96; found: C,
53.08; H, 5.34; N, 4.75%.
4.2.6. Thiazole-2-yl-methyl-(N-benzylamino)methyl-
phosphinic acid (6d). A white solid. Yield: 0.50 g (72%),
mp 210–214 8C. 1H NMR; dH (D2O/10% D2SO4;
300 MHz): 8.50 (d, 1H, thiazole-4, JZ3.3 Hz), 8.25 (d,
1H, thiazole-5, JZ3.3 Hz), 8.20–8.03 (m, 5H, PhH), 4.90
(d, 1H, CH–P, JZ17.7 Hz), 4.64 (s, 2H, NHCH2Ph), 1.10
(d, 3H, PCH3, JZ14.3 Hz). 31P NMR; dP (D2O/D2SO4;
121.5 MHz): 30.45 (s) ppm. IR, nmax (KBr): 3386 (NH);
3045; 2960; 2928; 2863; 1604; 1485; 1326; 1181 (P]O);
1154; 938; 887; 733; 649; 596; 561; 504 cmK1. MS; (ESIC
Q1MS): 305.3 (100, MCCNa). Anal. Calcd for
C12H15N2O2PS, requires C, 51.06; H, 5.36; N, 9.92;
found: C, 50.99; H, 5.43; N, 9.87%.
4.3.3. Thiazole-2-yl-methyl(N-butylamino)-methyl-
phenylphosphine oxide, oxalate (7c). A crystalline solid.
Yield: 0.67 g (62%), mp 132–135 8C. H NMR; dH (D2O;
1
300 MHz): 7.67–7.47 (m, 7H, thiazole-4, thiazole-5, PhH),
5.63 (d, 0.5H, CH–P, JZ12.6 Hz), 5.59 (d, 0.5H, CH–P, JZ
12.6 Hz), 3.95–3.90 (m, 2H, NHCH2), 1.54–1.49 (m, 4H,
CH2CH2), 1.57 (d, 1.5H, PCH3, JZ13.0 Hz), 1.47 (d, 1.5H,
PCH3, JZ13.0 Hz), 0.87–0.84 (m, 3H, CH3). 31P NMR; dP
(D2O; 121.5 MHz): 44.21 and 43.83 (s), in a ratio 1:0.90
(two diastereomers). IR, nmax (KBr): 3465; 3389 (NH);
3090; 2951; 2803; 1656; 1471; 1408; 1204; 1186 (P]O);
780; 739; 678; 541; 491 cmK1. MS; (ESICQ1MS): 331.4
(100, MCCNa). Anal. Calcd for C15H21N2OPS$2!
(COOH)2, requires C, 46.72; H, 5.16; N, 5.74; found: C,
46.58; H, 5.24; N, 5.70%.
4.3. General procedure for preparation of 2-thiazole
aminophosphine oxides (7a–f)
To a solution of crude imine 2 (2.5 mmol) in dry toluene
(25 mL), the appropriate phosphine oxide (9 or 10) was
added (2.5 mmol). The mixture was stirred overnight at
room temperature and then refluxed for 2 h to complete the
reaction. After evaporation of the solvent, crude thiazole
aminophosphine oxides were obtained as solids, or thick
oils. Compounds 7e and 7f (solids) were purified by
crystallization from toluene–hexane solution. Compounds
7a–d (oils) were purified as oxalate salts, obtained by the
following procedure: the crude product (w2.5 mmol) was
dissolved in acetone (10 mL) and treated with acetone
solution of oxalic acid (10 mL, containing 0.61 g
(COOH)2$2H2O). After cooling, the separated crystals
were collected by filtration and dried on air to give oxalates
7a–d, as white, crystalline solids.
4.3.4. Thiazole-2-yl-methyl(N-benzylamino)-methyl-
phenylphosphine oxide, oxalate (7d). A crystalline solid.
Yield: 0.65 g (57%), mp 142–145 8C. H NMR; dH (D2O;
1
300 MHz): 7.50–7.21 (m, 12H, thiazole-4, thiazole-5,
2!PhH), 4.64 (d, 0.5H, CH–P, JZ12.6 Hz), 4.60 (d,
0.5H, CH–P, JZ12.6 Hz), 4.04–4.00 (m, 2H, NHCH2Ph),
1.60 (d, 1.5H, PCH3, JZ12.9 Hz), 1.45 (d, 1.5H, PCH3, JZ
12.9 Hz). 31P NMR; dP (D2O; 121.5 MHz): 41.22 and 40.31
(s), in a ratio 1:0.88 (two diastereomers). IR, nmax (KBr):
3466; 3398 (NH); 2954; 2812; 1675; 1443; 1440; 1194
(P]O); 801; 756; 692; 547 cmK1. (ESICQ1MS): 365.4
(100, MCCNa). Anal. Calcd for C18H19N2OPS$2!
(COOH)2, requires C, 50.58; H, 4.44; N, 5.36; found: C,
50.55; H, 4.48; N, 5.23%.
Oxalates 7a–d, treated with an excess of aqueous sodium
bicarbonate and extracted with methylene chloride give the
pure thiazole aminophosphine oxides, as thick oils.
4.3.5. Thiazole-2-yl-methyl(N-butylamino)-diphenyl-
phosphine oxide (7e). A white solid. Yield: 0.59 g (65%),
mp 110–112 8C. 1H NMR; dH (CDCl3; 300 MHz):
7.88–7.18 (m, 12H, thiazole-4, thiazole-5, 2!PhH), 5.03
(d, 1H, CH–P, JZ12.6 Hz), 2.67–2.51 (m, 2H, NHCH2),
1.42–1.20 (m, 4H, CH2CH2), 0.85 (t, 3H, CH3, JZ7.5 Hz).
31P NMR; dP (CDCl3; 121.5 Hz): 30.93 (s). IR, nmax (KBr):
3445; 3275 (NH); 3054; 2923; 2868; 1627; 1592; 1484;
1435; 1379; 1182 (P]O); 1116; 999; 829; 722; 690; 644;
554; 507 cmK1. (ESICQ1MS): 393.4 (100, MCCNa).
Anal. Calcd for C20H23N2OPS, requires C, 64.85; H, 6.26;
N, 7.56; found: C, 64.80; H, 6.34; N, 7.49%.
4.3.1. Thiazole-2-yl-methyl(N-butylamino)-butylphenyl-
phosphine oxide, oxalate (7a). A crystalline solid. Yield:
0.79 g (67%), mp: 104–106 8C. 1H NMR; dH (D2O;
300 MHz): 7.70–7.37 (m, 7H, thiazole-4, thiazole-5, PhH),
5.63 (d, 0.5H, CH–P, JZ11.6 Hz), 5.58 (d, 0.5H, CH–P, JZ
11.6 Hz), 3.98–3.76 (m, 4H, NHCH2, PCH2), 1.59–1.20
[(m, 8H, NHCH2(CH2)2 and PCH2(CH2)2)], 0.97–0.80
(m, 6H, 2!CH3). 31P NMR; dP (D2O; 121.5 MHz): 46.61
(s) and 45.83 (s), in a ratio 1:0.80 (two diastereomers). IR,
nmax (KBr): 3489; 3410 (NH); 3110; 2956; 2806; 1742;
1662; 1479; 1445; 1403; 1174 (P]O); 786; 741; 696; 551;
482 cmK1. MS; (ESICQ1MS): 373.4 (100, MCCNa).
Anal. Calcd for C18H27N2OPS$2!(COOH)2, requires C,
49.81; H, 5.89; N, 5.28; found: C, 49.80; H, 5.94; N, 5.25%.
4.3.6. Thiazole-2-yl-methyl(N-benzylamino)-diphenyl-
phosphine oxide (7f). A white solid. Yield: 0.58 g
(58%), mp 138–141 8C. H NMR; dH (CDCl3; 300 MHz):
1
4.3.2. Thiazole-2-yl-methyl(N-benzylamino)-butylphenyl-
phosphine oxide, oxalate (7b). A crystalline solid. Yield:
0.73 g (58%), mp 120–122 8C. 1H NMR; dH (D2O;
300 MHz): 7.48–7.19 (m, 12H, thiazole-4, thiazole-5,
2!PhH), 4.73 (d, 0.5H, CH–P, JZ14.6 Hz), 4.69 (d,
0.5H, CH–P, JZ14.6 Hz) 4.05–3.99 (m, 2H, NHCH2Ph),
2.41–2.36 (m, 2H, PCH2), 1.50–1.45 [(m, 4H,
7.84–7.15 (m, 17H, thiazole-4, thiazole-5, 3!PhH), 4.98
(d, 1H, CH–P, JZ12.3 Hz), 3.95–3.90 (m, 2H, NHCH2Ph).
31P NMR; dP (CDCl3; 121.5 Hz): 31.45 (s). IR, nmax (KBr):
3434 (NH); 3054; 2923; 2855; 2606; 2206; 1634; 1497;
1436; 1380; 1315; 1187 (P]O); 1166; 1124; 1073; 1038;
1021; 917; 857; 799; 699; 555; 507; 489 cmK1. (ESIC
Q1MS): 427.5 (100, MCCNa). Anal. Calcd for

T. K. Olszewski et al. / Tetrahedron 62 (2006) 2183–2189
2189
Aminophosphinic Acids; Wiley: Chichester, 2000;
pp 579–621.
C23H21N2OPS, requires C, 68.30; H, 5.23; N, 6.93; found:
C, 68.23; H, 5.36; N, 6.87%.
5. Bal, W.; Bertini, I.; Kozlowski, H.; Monnani, R.; Scozzafava, A.;
Siatecki, Z. J. Inorg. Biochem. 1990, 40, 227–235.
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4.4. Potentiometric and spectroscopic studies of Cu(II)
complexes with 4a and 4b
4.4.1. Potentiometric measurements. The purities and
exact concentrations of the stock solutions of the ligands
were confirmed pH-metrically by the Gran method.34 The
concentration of the Cu(II) stock solution was measured
gravimetrically via precipitation of the quinolin-8-olate.
7. Kukhar, V. P.; Solodenko, V. P. Phosphorus, Sulfur and
Silicon 1994, 92, 239–264.
8. Boduszek, B. Phosphorus, Sulfur and Silicon 1995, 104, 63–70.
9. Cottier, L.; Descotes, G.; Lewkowski, J.; Skowronski, R.
Phosphorus, Sulfur and Silicon 1996, 116, 93–100.
10. Cottier, L.; Descotes, G.; Grabowski, G.; Lewkowski, J.;
Skowronski, R. Phosphorus, Sulfur and Silicon 1996, 118,
181–188.
The stability constants both for protons and Cu(II)
complexes of the studied ligands were determined by pH-
metric titration of 1.5–2.0 cm3 samples at the pH range
2.5–11.0. The ligand concentration 2.5–3.0 mmol dmK3
;
11. Boduszek, B. Phosphorus, Sulfur and Silicon 1996, 113,
209–218.
metal to ligand molar ratios 1:2, 1:4, 1:6; ionic strength
adjusted to 0.1 mol dmK3 with KNO3; duplicate pH titration
calibrated in concentration;35 temperature 25 8C.
12. Hubert, C.; Quassaid, B.; Moghadam, G. E.; Koenig, M.;
Garrigues, B. Synthesis 1994, 51–55.
13. Boduszek, B. Tetrahedron 1996, 52, 12483–12494.
14. Boduszek, B. Phosphorus, Sulfur and Silicon 1997, 122, 27–32.
15. (a) Fields, E. K. J. Am. Chem. Soc. 1952, 74, 1528–1531. (b)
Tyka, R. Tetrahedron Lett. 1970, 677–680.
The pH was measured with MOLSPIN automatic titration
system with a microcombined glass-calomel electrode
calibrated daily. Titration data were used to calculate the
stability constants (bpqrZ[MpHrLq]/[M]p[H]r[L]q) with a
SUPERQUAD computer program.36 Standard deviations
quoted refer to random errors only.
16. Boduszek, B.; Latajka, R.; Walkowiak, U. Pol. J. Chem. 2001,
75, 63–69.
17. Evans, D. A.; Hurst, K. M.; Takacs, J. M. J. Am. Chem. Soc.
1978, 100, 3467–3477.
18. Afarinkia, K.; Rees, C. W.; Cadogan, J. I. G. Tetrahedron
1990, 46, 7175–7196.
4.4.2. Spectroscopic measurements. The absorption
spectra were recorded on a Beckman DU 650 spectro-
photometer. The EPR spectra were recorded, in 1:2 ethane-
1,2-diol/water (v/v), on a Bruker ESP 300E spectrometer at
the X-band (9.3 GHz) at 120 K. The concentrations used in
the spectroscopic measurements were similar to those given
for potentiometric titrations. The results of potentiometric
and spectroscopic studies are collected in Tables 1 and 2.
19. Wozniak, L.; Chojnowski, J. Tetrahedron 1989, 45,
2465–2524.
20. Chojnowski, J.; Cypryk, M.; Michalski, J. J. Organomet.
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21. Boduszek, B.; Vegh, D.; Korenova, A.; Uher, M. Pol. J. Chem.
2001, 75, 1271–1275.
22. Boduszek, B. Pol. J. Chem. 2001, 75, 663–672.
23. Boduszek, B.; Olszewski, T. Pol. J. Chem. 2002, 76,
1619–1623.
Acknowledgements
24. Boduszek, B.; Dyba, M.; Jezowska-Bojczuk, M.; Kiss, T.;
Kozłowski, H. J. Chem. Soc., Dalton Trans. 1997, 973–976.
25. Chruscinski, L.; Młynarz, P.; Malinowska, K.; Ochocki, J.;
Boduszek, B.; Kozłowski, H. Inorg. Chim. Acta 2000, 303,
47–53.
Support of the Faculty of Chemistry Wrocław University of
Technology, is kindly acknowledged.
This work was financially supported by KBN (Poland);
grant no. 3 TO9A 068 28.
26. Lipinski, R.; Chruscinski, L.; Młynarz, P.; Boduszek, B.;
Kozłowski, H. Inorg. Chim. Acta 2001, 322, 157–161.
27. Sobek, S.; Boduszek, B.; Kozlowski, H. Inorg. Chim. Acta
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