Nucleophilic addition to dimethylvinylphosphine sulfide as a convenient route to polydentate ligands containing the 2-dimethylphosphinoethyl unit

Article abstract of DOI:10.1016/j.tet.2005.03.012

The synthesis of a range of new phosphine-containing polydentate ligands has been achieved by addition of sulfur and nitrogen nucleophiles to dimethylvinylphosphine sulfide, followed by reduction of the resulting phosphine sulfides with lithium aluminium hydride.

Full text of DOI:10.1016/j.tet.2005.03.012

Tetrahedron 61 (2005) 4595–4600
Nucleophilic addition to dimethylvinylphosphine sulfide as a
convenient route to polydentate ligands containing the
2-dimethylphosphinoethyl unit
a
b
b
D. Vaughan Griffiths,a, Helen J. Groombridge, Peter M. Mahoney, Stephen P. Swetnam,
*
Garry Waltonb and David C. Yorkb
aDepartment of Chemistry, Queen Mary, University of London, London E1 4NS, UK
bDepartment of Chemistry, University of Keele, Newcastle, Staffs ST5 5BG, UK
Received 8 November 2004; revised 15 February 2005; accepted 3 March 2005
Available online 23 March 2005
Abstract—The synthesis of a range of new phosphine-containing polydentate ligands has been achieved by addition of sulfur and nitrogen
nucleophiles to dimethylvinylphosphine sulfide, followed by reduction of the resulting phosphine sulfides with lithium aluminium hydride.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
appropriately substituted alkyl halides by the dimethylpho-
sphide anion. However, this latter material is particularly
unpleasant to handle and it often proved necessary to purify
the resulting ligand via temporary formation of the
corresponding sulfide or oxide in order to obtain material
of sufficient purity for subsequent testing.
Metal complexes containing phosphine ligands have a wide
range of uses including both medical and industrial
applications. Phosphines are known to coordinate well to
a range of metals and their inclusion in polydentate ligands
can facilitate complex formation in some circumstances.
However, the tendency of alkyl substituted phosphines to
oxidise in air makes it difficult to prepare pure samples of
some complex phosphine-containing polydentate ligands
and this has often inhibited the synthesis of polydentate
ligands containing trialkylphosphine centres in favour of
those containing diphenylphosphino groups.
We now report a convenient route to a range of new
polydentate ligands containing the dimethylphosphino
group based on the use of dimethylvinylphosphine sulfide
1 as the precursor for the 2-dimethylphosphinoethyl unit.
Previous workers4 have reported the use of this compound
in the synthesis of a number of polyphosphine ligands. We
have exploited the susceptibility of the dimethylvinyl-
phosphine sulfide to nucleophilic attack to include the use of
both sulfur and nitrogen nucleophiles, thus offering scope
for the synthesis of a wide range of new polydentate
phosphine ligands such as those shown in Scheme 1 and
Figure 1.
Our interest in phosphine-containing polydentate
ligands developed from our work on 99mTc-based radio-
pharmaceutical imaging agents.1 Here, the ligand must be
prepared in a high state of purity and the overall complex
must have an appropriate lipophilicity if it is to exhibit a
useful biodistribution. In this context the presence of phenyl
substituents on the phosphorus is highly undesirable due to
the high lipophilicity of the resulting systems while the
incorporation of a terminal dimethylphosphino group is
often highly desirable. In some cases, such as the bis-
phosphines we have prepared as potential myocardial
imaging agents2,3 incorporation of the dimethylphosphino
group was achieved by nucleophilic substitution of
2. Results and discussion
In general, the nucleophilic additions to dimethylvinyl-
phosphine sulfide 1 were carried out in ethanol and while the
addition of the more nucleophilic thiolate anions could be
achieved at room temperatures, addition of aliphatic amines
usually required an extended period of heating under reflux.
Aromatic amines were found to be unreactive towards 1
under these conditions, but they did react rapidly if first
converted into their amide anions by the action of
Keywords: Phosphine; Polydentate; Ligand.
*
Corresponding author. Tel.: C44 20 7882 5389; fax: C44 20 7882 7794;
e-mail: d.v.griffiths@qmul.ac.uk
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.012

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D. V. Griffiths et al. / Tetrahedron 61 (2005) 4595–4600
The phosphine sulfides produced in these studies were very
stable, often crystalline solids, which could be readily
purified. Reduction of these materials with reducing agents
such as lithium aluminium hydride gave the corresponding
phosphine ligands in good yield and in a high state of purity.
Additional support of the structure of the polydentate
phosphine ligands produced in this way was obtained by
adding sulfur, which led to regeneration of the phosphine
sulfide precursors.
It should be noted that some of the phosphine ligands were
found to readily co-distil with the dioxane used as the
solvent in the reduction step. This could result in significant
loss of the phosphine ligand from the distillation flask unless
particular care was taken during the distillation. An
alternative approach was to convert the phosphine ligand
into its hydrochloride salt before removing the dioxane. The
phosphine was then regenerated and recovered via extrac-
tion into diethyl ether. Fortunately, in general, this was
unnecessary, as a dioxane solution of the phosphine ligand
was suitable for our purposes.
Scheme 1.
We have also prepared other dialkylvinylphosphine sulfides
for use in ligand synthesis. Thus, for example, diethyl-
vinylphosphine sulfide was prepared by an analogous route
to that used for the dimethyl analogue 1 and used to prepare
the bisphosphine 12c.
Preliminary work has also been carried out on the use of
alkyldivinylphosphine sulfides such as 16,5 for the
preparation of polydentate ligands containing a trialkyl-
phosphine site at a non-terminal position.
We have already established that it is possible to react 16
with N,N,N0-trimethylethylenediamine to give 17 (N0Z
NMeCH2CH2NMe2) and that this can be converted into 18
(N0ZN00ZNMeCH2CH2NMe2) in a subsequent step
(Scheme 2). The stepwise addition of two different
nucleophiles to the divinylphosphine sulfide 16 should
therefore provide a route for the preparation of a wide range
of new unsymmetrical (N0sN00) polydentate ligand
systems. This is currently being investigated.
Figure 1.
Scheme 2.
n-butyllithium. Thus, for example, the lithium salt of
methylaniline readily added to 1 to give the phosphine
sulfide 4.
3. Conclusions
The susceptibility of dialkylvinylphosphine sulfides, such as
1, to nucleophilic attack by both sulfur and nitrogen
nucleophiles can be exploited to provide a convenient
route for the synthesis of a wide range of new phosphine-
containing polydentate ligands via the initial formation of
the corresponding air-stable phosphine sulfide precursors.
The range of ligands that are accessible by this approach can
also be extended by the stepwise addition of two
nucleophilic units to an alkyldivinylphosphine sulfide such
as 16.
In some cases reported here, reaction of more than one
dimethylvinylphosphine sulfide molecule with the nucleo-
phile is possible, although in general we found that this
could be avoided if the nucleophile was kept in excess. This
approach enabled the preparation of the phosphine sulfide 2
to be achieved from the thiolate of ethane-1,2-dithiol
without significant formation of the bis(phosphine sulfide)
8, and likewise the formation of the phosphine sulfide 3a
rather than 10 from the reaction of 1 with methylamine.

D. V. Griffiths et al. / Tetrahedron 61 (2005) 4595–4600
4597
4. Experimental
4.1.4. 2-(2-Dimethylphosphinoethylsulfanyl)ethanethiol
(5). The following reduction procedure and subsequent
work-up was carried out in an inert atmosphere of nitrogen
using degassed solvents. To a suspension of lithium
aluminium hydride (2.2 g, 56 mmol) in dry dioxane
(200 cm3) was added 2-(2-dimethylphosphinothioylethyl-
sulfanyl)ethane-thiol 2 (6 g, 28 mmol), and the mixture
heated under reflux for 24 h (N.B. After a short initiation
period a vigorous exothermic reaction often occurs which
may necessitate cooling the reaction mixture). The
mixture was allowed to cool and 25% aqueous dioxane
(10 cm3) was added dropwise. Aqueous sodium hydroxide
(5 cm3, 2 M) was then added followed by water (7 cm3).
The resulting mixture was filtered through a glass sinter and
the solvent was removed under reduced pressure (50 8C at
40 mmHg). The residue, which contained a little solid, was
redissolved in dry dioxane, filtered, and the solvent then
removed under reduced pressure (50 8C at 40 mmHg) to
give the phosphine 5 (ca. 4.5 g, 86%) containing a small
quantity of solvent. dP (CDCl3) K50.2; dH (60 MHz,
CDCl3) 0.94 (6H, d, JPHZ2 Hz, PMe2), 1.40–1.68 (2H,
m, b-CH2), 1.70 (1H, br s, SH), 2.38–2.78 (6H, m, CH2); dC
(CDCl3) 13.8 (d, JPCZ13 Hz, PMe2), 24.7 (CH2), 28.5 (d,
JPCZ18 Hz, a-CH2), 32.1 (d, JPCZ13 Hz, b-CH2), 36.1
(CH2).
4.1. General
NMR spectra were recorded in CDCl3 (on JEOL GSX270,
FX100, PMX60 and Bruker AMX 600 spectrometers), dm,
doublet of multiplets. Melting points were taken in open
capillaries on an electrically heated Buchi SMP-20 melting
point apparatus and are uncorrected. Elemental analyses
were obtained on a Carlo Erba 1106 Elemental Analyser.
4.1.1. Dimethylvinylphosphine sulfide (1). Dimethyl-
vinylphosphine sulfide was prepared by a previously
reported procedure.4
4.1.2. Diethylvinylphosphine sulfide. Diethylvinyl-
phosphine sulfide was obtained from diethylphosphino-
thioylbromide by the procedure used to prepare the
corresponding dimethyl analogue 1 and isolated as a
colourless oil, (0.93 g, 20% overall yield after 3 steps), bp
44 8C, 0.05 mmHg, (lit.6 bp 98–99 8C, 1.5 mmHg). dP
(CDCl3) 48.5; dH (270 MHz, CDCl3), 0.81 (6H, td, JP–H
19.3 Hz, JH–HZ7.4 Hz, CH2Me), 1.57 (4H, dq, JP–H
11.4 Hz, JH–HZ7.4 Hz, CH2), 5.99 (3H, m, CHZCH2); dC
(CDCl3), 5.77 (d, JP–CZ4.2 Hz, CH2Me), 23.9 (d, JP–C
Z
Z
Z
56.1 Hz, CH2–P), 129.1 (d, JP–CZ69.5 Hz, P–CH), 135.3 (s,
CHZCH2). EI-MS: 148 ([M]C, 37%), 147 (92), 120 (84),
92 (100), 63 (52), 57 (35). ESI-HRMS: Found [MCNa]C
171.0368, [C6H13PSCNa]C requires 171.19772.
4.1.5. N-(20-Dimethylphosphinothioylethyl)methylamine
(3a). Dry methylamine was passed into ethanol (100 cm3)
until it no longer readily dissolved. Dimethylvinyl-
phosphine sulfide 1 (8 g, 66 mmol) was added and the
mixture was heated at 80 8C overnight in a Teflon-lined
(Berghof) autoclave. Volatile components were removed
under reduced pressure (60 8C at 18 mmHg) and the residue
distilled under vacuum, bp 100 8C at 0.1 mmHg, to give the
pure phosphine sulfide 3a as a colourless low melting solid
(6 g, 60%), mp 35–36 8C (Found: C, 39.8; H, 9.53; N, 9.3.
C5H14NPS requires C, 39.7; H, 9.3; N, 9.3%). dP (CDCl3)
35.2; dH (270 MHz, CDCl3) 1.77 (6H, d, JPHZ13 Hz,
P(S)Me2), 1.82 (1H, br s, NH), 2.10 (2H, dt, JPHZ12 Hz,
4.1.3. 2-(2-Dimethylphosphinothioylethylsulfanyl)-
ethanethiol (2). 1,2-Dimercaptoethane (20 g, 213 mmol)
was added to a solution of sodium ethoxide, prepared by
adding sodium (1.5 g, 65 mmol) to ethanol (300 cm3). The
mixture was stirred for 1 h at room temperature and then
cooled in ice before dimethylvinylphosphine sulfide 14 (8 g,
66 mmol) was added. The mixture was allowed to warm to
room temperature and left to stir overnight. The solvent and
excess dithiol were removed under reduced pressure and
water (250 cm3) was added. The mixture was acidified by
addition of hydrochloric acid and extracted with chloroform
(3!200 cm3). The chloroform extracts were dried with
anhydrous MgSO4, filtered and the solvent evaporated to
give the phosphine sulfide 2 (12 g, 85%) as a colourless oil,
containing a small quantity of the bis(phosphine sulfide) 8.
The phosphine sulfide 2 was further purified by distillation
(bp 155–160 8C at 0.001 mmHg), although care was needed
since some decomposition occurred at higher temperatures.
JHHZ7 Hz, a-CH2), 2.44 (3H, s, NMe), 2.97 (2H, dt, JPH
14 Hz, JHHZ7 Hz, b-CH2); dC (CDCl3) 21.2 (d, JPC
Z
Z
55 Hz, P(S)Me2), 33.6 (d, JPCZ53 Hz, a-CH2), 35.4 (Me),
45.2 (b-CH2); IR (n max cmK1, thin film): 3472, 3287,
2974, 2936, 2905, 2851, 2797, 1474, 1451, 1420, 1289,
1115, 945, 918, 856, 744.5, 713.6, 575.
4.1.6. N-(20-Dimethylphosphinoethyl)methylamine (6a).
N-(20-Dimethylphosphinothioylethyl)methylamine 3a (3 g,
26 mmol) was reduced cleanly to the corresponding
phosphine 6a using the method previously given for the
preparation of 5. Because the resulting N-(20-dimethyl-
phosphinoethyl)methylamine 6a tended to co-distil when
efforts were made to remove the reaction solvent, it was
generally used as a solution in dioxane in subsequent
studies. The dioxane could be removed carefully at 53 8C at
100 mmHg but this resulted in significant loss of product
from the reaction flask.7 dP (CDCl3) K55.5; dH (270 MHz,
CDCl3) 0.95 (6H, d, JPHZ2 Hz, PMe2), 1.50 (2H, br t,
JHHZ8 Hz, a-CH2), 2.08 (1H, br s, NH), 2.35 (3H, s, NMe),
2.62 (2H, dt, JPHZ7.5 Hz, JPHZ8 Hz, b-CH2); dC (CDCl3)
13.5 (d, JPCZ13 Hz, PMe2), 32.0 (d, JPCZ10 Hz, a-CH2),
35.6 (NMe), 48.2 (d, JPCZ17 Hz, b-CH2).
dP (CDCl3) 36.0; dH (270 MHz, CDCl3) 1.77 (6H, d, JPH
13 Hz, P(S)Me2), 2.10–2.20 (2H, m, a-CH2), 2.72–2.95
(6H, m, b-CH2 and SCH2CH2S); dC (CDCl3) 21.1 (d, JPC
Z
Z
54 Hz, P(S)Me2), 24.4 (CH2), 24.8 (d, JPCZ2 Hz, b-CH2),
34.3 (d, JPCZ49 Hz, a-CH2), 36.0 (CH2).
On prolonged exposure to the air the thiol 2 (RZCH2CH2-
SH) oxidised to the corresponding disulfide 9, a colourless
waxy solid (Found: C, 33.52; H, 6.5. C12H28P2S6 requires C,
33.8; H, 6.6%). dP (CDCl3) 36.2; dH (270 MHz, CDCl3) 1.78
(12H, d, JPHZ13 Hz, P(S)Me2), 2.12–2.22 (4H, m, a-CH2)
2.92 (8H, br s, SCH2CH2S) 2.87–2.97 (4H, m, b-CH2); dC
(CDCl3) 21.3 (d, JPCZ54 Hz, P(S)Me2), 25.2 (d, JPC
Z
2 Hz, b-CH2), 31.6 (CH2), 34.6 (d, JPCZ50 Hz, a-CH2),
38.3 (CH2).

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D. V. Griffiths et al. / Tetrahedron 61 (2005) 4595–4600
4.1.7.
N,N-Bis(20-dimethylphosphinothioylethyl)-
dimethylethylenediamine (5 g, 57 mmol) and dimethyl-
vinylphosphine sulfide (14 g, 117 mmol) in ethanol
(75 cm3) was heated under reflux for approximately
1 week and monitored by 31P NMR spectroscopy. After
this time the reaction mixture was cooled to afford a
crystalline solid which was isolated by filtration. The bulk of
the solvent was then removed under reduced pressure (60 8C
at 18 mmHg) to give a further quantity of the crystalline
product. Recrystallisation of this material from ethyl acetate
gave the pure product 12a (15 g, 80%) as a colourless solid,
mp 120 8C, (Found: C, 43.6; H, 9.2; N, 8.51. C12H30N2P2S2
requires C, 43.9; H, 9.2; N, 8.53%). dP (CDCl3) 36.0; dH
(270 MHz, CDCl3) 1.77 (12H, d, JPHZ13 Hz, P(S)Me2),
2.07 (4H, dm, JPHZ12 Hz, a-CH2), 2.26 (6H, s, NMe), 2.53
(4H, s, CH2), 2.82 (4H, dm, JPHZ13 Hz, b-CH2); dC
methylamine (10). A mixture of N-(20-dimethylphos-
phinothioylethyl)-methylamine 3a (11 g, 73 mmol) and
dimethyl-vinylphosphine sulfide 1 (9 g, 75 mmol) in ethanol
(150 cm3) was heated under reflux for 24 h. The mixture
was cooled in ice and the resulting precipitate was isolated
by filtration. The solid was then recrystallised from ethanol
to give the pure product 10 (11.5 g, 58%), mp 189 8C,
(Found: C, 39.9; H, 8.8; N, 4.9. C9H23NP2S2 requires C,
39.8; H, 8.54; N, 5.2%), dP (CDCl3) 36.0; dH (270 MHz,
CDCl3) 1.77 (12H, d, JPHZ13 Hz, P(S)Me2), 2.09 (4H, dt,
JPHZ12 Hz, JPHZ7 Hz, a-CH2), 2.27 (3H, s, NMe), 2.82
(4H, dt, JPHZ13 Hz, JPHZ7 Hz, b-CH2); dC (CDCl3) 21.5
(d, JPCZ54 Hz, P(S)Me2), 31.7 (d, JPHZ53 Hz, a-CH2),
41.6 (NMe), 50.8 (b-CH2).
(CDCl3) 21.3 (d, JPCZ55 Hz, P(S)Me2), 31.5 (d, JPC
53 Hz, a-CH2), 41.9 (NMe), 51.1 (b-CH2), 54.8 (CH2).
Z
4.1.8. N,N-Bis(20-dimethylphosphinoethyl)methylamine
(11). N,N-Bis(20-dimethylphosphinothioylethyl)methyl-
amine 10 (5 g, 18 mmol) was cleanly reduced to the
phosphine 11 (3.5 g, 91%) using the procedure previously
given for the preparation of 5, allowing for the presence of
two phosphine sulfide centres in the molecule. dP (CDCl3)
K53.6; dH (60 MHz, CDCl3) 0.96 (12H, d, JPHZ2 Hz,
PMe2), 1.42 (4H, m, a-CH2), 2.15 (3H, s, NMe), 2.42 (4H,
m, b-CH2); dC (CDCl3) 14.0 (d, JPCZ13 Hz, PMe2), 29.4
4.1.12.
N,N0-Bis(20-dimethylphosphinoethyl)-N,N0-
dimethylethylenediamine (13a). N,N0-Bis(20-Dimethyl-
phosphinothioylethyl)-N,N0-dimethyl-ethylenediamine 12a
(6 g, 18 mmol) was cleanly reduced to the phosphine 13a
(4.0 g, 83%) using the procedure previously indicated for
the preparation of 11. dP (CDCl3) K53.8; dH (60 MHz,
CDCl3) 0.95 (12H, d, JPHZ2 Hz, PMe2), 1.48 (4H, m,
a-CH2), 2.17 (6H, s, NMe), 2.40 (4H, br s, CH2), 2.42 (4H,
m, b-CH2); dC (CDCl3) 13.8 (d, JPCZ13 Hz, PMe2), 29.0
(d, JPCZ10 Hz, a-CH2), 41.9 (NMe), 54.4 (d, JPCZ19 Hz,
b-CH2), 54.6 (CH2).
(d, JPCZ10 Hz, a-CH2), 41.4 (s, NMe), 53.7 (d, JPC
19 Hz, b-CH2).
Z
4.1.9. N-(20-Dimethylphosphinothioylethyl)dimethyl-
amine (3b). Dry dimethylamine was passed into ethanol
(100 cm3) until it no longer readily dissolved. Dimethyl-
vinylphosphine sulfide 1 (10 g, 83 mmol) was added and the
mixture was heated at 80 8C overnight in a Teflon-lined
(Berghof) autoclave. The crystalline product was filtered off
and purified by vacuum sublimation (100 8C at 0.1 mmHg)
to give the pure product 3b as a colourless solid (10 g, 73%),
mp 79–80 8C (lit.8 mp 125–129 8C)9 (Found: C, 43.50; H,
9.8; N, 8.4. C6H16NPS requires C, 43.6; H, 9.8; N, 8.50%).
4.1.13. N,N0-Bis(20-dimethylphosphinothioylethyl)-N,N00-
diethylpropylenediamine (12b). A mixture of N,N -
dimethylpropylene-1,3-diamine (5 g, 38 mmol) and
dimethylvinylphosphine sulfide 1 (10.5 g, 87 mmol) in
ethanol (125 cm3) was heated under reflux for 48 h in an
atmosphere of dry nitrogen. The solvent was removed under
reduced pressure to give an orange oil which was
recrystallised in ethyl acetate. This yielded the pure
bis(phosphine sulfide) 12b (7.9 g, 56%) as a colourless
solid, mp 79 8C, (Found: C, 48.9; H, 9.9; N, 7.5.
C15H36N2P2S2 requires C, 48.6; H, 9.8; N, 7.56%). dP
dP (CDCl3) 35.8; dH (270 MHz, CDCl3) 1.77 (6H, d, JPH
Z
13 Hz, P(S)Me2), 2.07 (2H, dm, JPHZ12 Hz, a-CH2), 2.56
(6H, s, NMe2), 2.68 (2H, dm, JPHZ12 Hz, b-CH2); dC
(CDCl3) 21.3 (d, JPCZ54 Hz, P(S)Me2), 32.6 (d, JPC
53 Hz, a-CH2), 45.1 (NMe2), 53.2 (b-CH2).
Z
(CDCl3) 36.1; dH (270 MHz, CDCl3) 1.03 (6H, t, JHH
7 Hz, Me), 1.58–1.69 (2H, m, CH2), 1.76 (12H, d, JPH
Z
Z
13 Hz, P(S)Me2), 1.98–2.08 (4H, dm, JPHZ12 Hz, a-CH2),
2.45 (4H, t, JHHZ7 Hz, NCH2), 2.53 (4H, q, JHHZ7 Hz,
CH3CH2), 2.83–2.93 (4H, dm, JPHZ12 Hz, b-CH2); dC
(CDCl3) 11.9 (Me), 21.4 (d, JPCZ55 Hz, P(S)Me2), 24.8
(CH2), 31.5 (d, JPCZ53 Hz, a-CH2), 47.0 (b-CH2), 47.1
(CH2), 51.3 (CH2). EI-MS: 371 ([MCH]C 99%), 355 (15),
339 (6), 251 (8), 325 (4), 178 (21), 166 (7). ES-HRMS:
Found [MCH]C 371.18762 C15H36N2P2S2 requires
371.18732.
4.1.10. N-(20-Dimethylphosphinoethyl)dimethylamine
(6b). N-(20-Dimethylphosphinothioylethyl)dimethylamine
3b (3 g, 26 mmol) was cleanly reduced to the corresponding
phosphine 6b using the method previously given for the
preparation of 5. Because the resulting N-(20-dimethyl-
phosphinothioylethyl)dimethylamine tended to co-distil
when efforts were made to remove the reaction solvent, it
was generally used as a solution in dioxane in subsequent
studies. The dioxane could be removed under reduced
pressure (53 8C at 100 mmHg) but this resulted in
significant loss of product. dP (CDCl3) K53.8; dH
(60 MHz, CDCl3) 0.96 (6H, d, JPHZ2 Hz, PMe2), 1.44
(2H, m, a-CH2), 2.17 (6H, s, NMe2), 2.32 (4H, m, b-CH2);
4.1.14.
N,N0-Bis(20-dimethylphosphinoethyl)-N,N0-
diethyl-propylenediamine (13b). N,N0-Bis(20-dimethyl-
phosphinothioylethyl)-N,N0-diethyl-propylenediamine 12b
(1.9 g) was reduced to the phosphine 13b using the
procedure previously indicated for the preparation of 11.
However, to obtain a pure sample of the bisphosphine 13b
the reduction mixture was evaporated prior to
hydrolysis. This caused the pure bisphosphine (0.52 g,
33%) to separated from the remaining creamy oil. dP
(CDCl3) K53.8; dH (270 MHz, CDCl3) 0.95–1.03 (18H, m,
dC (CDCl3) 14.1 (d, JPCZ12 Hz, PMe2), 30.2 (d, JPC
Z
10 Hz, a-CH2), 45.2 (s, NMe2), 56.3 (d, JPCZ19 Hz,
b-CH2).
4.1.11. N,N0-Bis(20-dimethylphosphinothioylethyl)-N,N00-
dimethylethylenediamine (12a). A mixture of N,N -

D. V. Griffiths et al. / Tetrahedron 61 (2005) 4595–4600
4599
JPHZ2 Hz, Me, PMe2), 1.46 (4H, m, a-CH2) 1.56 (2H, m,
CH2), 2.40 (4H, m, b-CH2), 2.49–2.56 (8H, m, NCH2,
CH2CH3); dC (CDCl3) 11.4 (Me), 13.7 (d, JPCZ12 Hz,
PMe2), 24.2 (CH2), 28.5 (d, JPCZ10 Hz, a-CH2), 46.5
(CH2), 49.3 (d, JPCZ19 Hz, b-CH2), 50.8 (CH2).
14 (7 g, 21 mmol) was cleanly reduced to the phosphine
15 (4.83 g, 86%) using the procedure previously indicated
for the preparation of 11 and isolated as a colourless viscous
oil which solidified on standing. dP (CDCl3) K53.1; dH
(60 MHz, CDCl3) 0.92 (12H, d, JPHZ2 Hz, PMe), 1.45 (4H,
m, a-CH2), 2.35 (4H, m, b-CH2), 2.40 (8H, br s, CH2); dC
(CDCl3) 14.0 (d, JPCZ12 Hz, PMe), 29.2 (d, JPCZ10 Hz,
b-CH2), 52.8 (NCH2), 55.1 (d, JPCZ19 Hz, a-CH2).
4.1.15. N,N0-Bis(20-diethylphosphinothioylethyl)-N,N00-
diethylpropylenediamine (12c). A mixture of N,N -
diethylpropylene-1,3-diamine (1.83 g, 14 mmol) and
diethylvinylphosphine sulfide (4.8 g, 32 mmol) in ethanol
(45 cm3) was heated under reflux in an atmosphere of dry
nitrogen for 72 h. After cooling, the solvent was removed
under reduced pressure and the crude product recrystallised
from diethyl ether/cyclohexane. The pure bis(phosphine
sulfide) 12c (2.75 g, 46%) was isolated as a colourless solid,
mp 56 8C, (Found: C, 53.4; H, 10.5; N, 6.9. C19H44N2P2S2
requires C, 53.50; H, 10.4; N, 6.6%). dP (CDCl3) 52.2; dH
(270 MHz, CDCl3) 1.01 (6H, t, JHHZ7 Hz, N–CH2CH3),
1.18 (12H, dt, JPHZ19 Hz, JHHZ7.5 Hz, P(S)CH2CH3),
1.63 (2H, m, CH2), 1.86 (8H, dm, JPHZ12 Hz, PCH2CH3),
1.90–2.00 (4H, m, a-CH2), 2.49 (4H, m, N–CH2), 2.53
(4H, q, JHHZ7 Hz, N–CH2CH3), 2.83 (4H, m, b-CH2);
dC (CDCl3), 6.7 (d, JPCZ5 Hz, P(S)CH2CH3), 12.1
(N-CH2CH3), 24.2 (d, JPCZ52, P(S)CH2CH3), 24.9
(CH2), 26.8 (d, JPCZ48 Hz, a-CH2), 46.9 (bCH2), 47.3
(CH2), 51.5 (CH2). EI-MS: 427 ([MCH]C, 99%), 399 (10),
305 (30), 279 (39), 232 (10), 220 (5), 206 (69), 183 (20), 149
(68). ES-HRMS: Found [MCH]C 427.24935
C19H44N2P2S2 requires 427.24992.
4.1.19. N-(20-Dimethylphosphinothioylethyl)-N,N00,N00-
trimethylethylenediamine (3c). A mixture of N,N ,N -
trimethylethylenediamine (8.5 g, 83 mmol) and dimethyl-
vinylphosphine sulfide 1 (10 g, 83 mmol) in ethanol
(100 cm3) was heated under reflux for 3 days. Evaporation
of the solvent gave the title product as a yellow oil, in a good
state of purity. A pure sample of the product 3c (9.6 g, 51%)
was obtained by distillation (bp 114 8C at 0.1 mmHg),
(Found: C, 48.6; H, 10.2; N, 12.35. C9H23N2PS requires C,
48.6; H, 10.4; N, 12.6%). dP (CDCl3) 36.4; dH (270 MHz,
CDCl3, 30 8C), 1.57 (6H, d, JPHZ13 Hz, P(S)Me), 1.87
(2H, dm, JPHZ12 Hz, b-CH2), 2.05 (6H, s, NMe2), 2.08
(3H, s, NMe), 2.22 (2H, m, CH2NMe2), 2.32 (2H, m,
CH2NMe), 2.64 (2H, dm, JPHZ13 Hz, a-CH2); dC (CDCl3),
21.4 (d, JPCZ55 Hz, P(S)Me), 32.1 (d, JPCZ52 Hz,
a-CH2), 42.0 (N-Me), 45.8 (N-Me2), 51.6 (CH2), 55.3
(CH2), 57.3 (CH2). EI-MS: 223 ([MC H]C 99%), 207 (6),
189 (10), 178 (12), 164 (48), 150 (3). ES-HRMS: Found
[MCH]C 223.13982 C9H23N2PS requires 223.13977.
4.1.20. N-(20-Dimethylphosphinoethyl)-N,N0,N0-tri-
methyl-ethylenediamine (6c). N-(20-Dimethylphos-
phinothioylethyl)-N,N0,N0-trimethyl-ethylenediamine 3c
(3.7 g, 17 mmol) was reduced cleanly to the phosphine 6c
using the method previously given for the preparation of 5
and isolated as a colourless oil (2.2 g, 69%), dP (CDCl3)
K53.4; dH (270 MHz, CDCl3) 0.96 (6H, d, JPHZ2 Hz,
PMe), 1.46–1.53 (2H, m, a-CH2), 2.21 (3H, s, NMe), 2.24
(6H, s, NMe2), 2.41–2.53 (6H, m, CH2); dC (CDCl3) 13.4 (d,
JPCZ13 Hz, PMe), 28.8 (d, JPCZ11 Hz, a-CH2), 41.5
(NMe), 45.2 (NMe), 54.2 (d, JPCZ19 Hz, b-CH2), 54.5
(CH2), 56.8 (CH2).
4.1.16. N,N0-(20-Diethylphosphinoethyl)-N,N0-diethyl-
ethylenediamine
(13c).
N,N0-Bis(20-diethylphos-
phinothioylethyl)-N,N0-diethyl-propylenediamine 12c
(1.45 g, 3 mmol) was cleanly reduced to the bisphosphine
13c (0.63 g, 51%) using the procedure previously indicated
for the preparation of 11. dP (CDCl3) K25.7; dH (600 MHz,
CDCl3) 0.95 (6H, t, JHHZ7.5 Hz, NCH2CH3), 0.99 (12H,
dt, JPHZ14 Hz, JHHZ7.5 Hz, PCH2CH3), 1.35 (8H, q,
JHHZ7.5 Hz, PCH2CH3), 1.46 (4H, m, JPHZ6.5 Hz,
a-CH2), 1.53 (2H, quintet, JHHZ7.2 Hz, CH2), 2.37 (4H,
‘t’, JHHZ7.2 Hz, CH2CH2CH2), 2.46 (4H, q, JHHZ7.5 Hz,
N–CH2), 2.51 (4H, dm, JPHZ12 Hz, b-CH2); dC (CDCl3)
9.1 (d, JPCZ13 Hz, PCH2CH3), 11.6 (N-CH2CH3), 18.6 (d,
JPCZ13 Hz, PCH2CH3), 23.4 (d, JPCZ16 Hz, a-CH2), 24.8
(CH2), 46.6 (CH2), 49.8 (d, JPCZ20 Hz, b-CH2), 50.7
(CH2).
4.1.21. N-(20-Dimethylphosphinothioylethyl)methyl-
amino-benzene (4). To a solution of N-methylaniline (1 g,
9.3 mmol) and dimethylvinylphosphine sulfide 1 (1.25 g,
10.4 mmol) in dry toluene (50 cm3), at room temperature
and under an atmosphere of dry nitrogen, was added a
solution of n-butyl lithium in pentane (5.5 cm3, 1.7 M). The
resulting cloudy orange solution was stirred for 30 min and
ethanol (20 cm3) was then slowly added. The mixture was
acidified with hydrochloric acid (2 M) and then extracted
with chloroform. The aqueous layer was basified by the
addition of aqueous sodium hydroxide (2 M) and re-
extracted with chloroform. The latter chloroform extracts
were dried with MgSO4 and the solvent removed under
reduced pressure to give a solid. This was recrystallised
from diethyl ether to yield the phosphine sulfide 4 as a
colourless solid (1.2 g, 56%) (Found: C, 57.9; H, 8.15; N,
6.2. C11H18NPS requires C, 58.1; H, 8.0; N, 6.2%). dP
4.1.17. N,N0-(20-Dimethylphosphinothioylethyl)pipera-
zine (14). Piperazine (1.8 g, 21 mmol) and dimethylvinyl-
phosphine sulfide 1 (5.1 g, 42 mmol) were dissolved in
ethanol (150 cm3) and the mixture heated under reflux for
6 days. After cooling the product was filtered off and dried
to give the pure product 14 as a colourless solid (5 g, 73%),
mp 212 8C, (Found: C, 44.3; H, 8.7; N, 8.4. C12H28N2P2S2
requires C, 44.1; H, 8.65; N, 8.6%). dP (CDCl3) 36.0; dH
(270 MHz, CDCl3) 1.77 (12H, d, JPHZ13 Hz, P(S)Me),
2.06 (4H, dt, JPHZ12 Hz, JHHZ7 Hz, a-CH2), 2.51 (8H, br
m, NCH2), 2.77 (4H, dt, JPHZ14 Hz, JHHZ7 Hz, b-CH2);
dC (CDCl3) 21.5 (d, JPCZ54 Hz, P(S)Me), 31.9 (d, JPC
Z
53 Hz, a-CH2), 51.8 (b-CH2), 52.9 (NCH2).
(CDCl3) 34.6; dH (270 MHz, CDCl3) 1.67 (6H, d, JPH
Z
11 Hz, P(S)Me), 2.06 (2H, dm, JPHZ12 Hz, a-CH2), 2.90
(3H, s, NMe), 3.72 (2H, dm, JPHZ14 Hz, b-CH2), 6.65–
6.71 (3H, m, ArH), 7.15–7.22 (2H, m, ArH); dC (CDCl3)
4.1.18. N,N0-(20-Dimethylphosphinoethyl)piperazine
(15). N,N0-(20-Dimethylphosphinothioylethyl)piperazine

4600
D. V. Griffiths et al. / Tetrahedron 61 (2005) 4595–4600
21.4 (d, JPCZ55 Hz, P(S)Me), 30.6 (d, JPCZ50 Hz,
a-CH2), 38.6 (NMe), 46.9 (b-CH2), 113.0 (C-2,6), 117.3
(C-4), 129.4 (C-3,5), 148.4 (C-1). EI-MS: 227 ([MCH]C,
22%), 152 (5), 132 (100), 120 (81), 104 (63), 94 (58), 77
(65), 65 (15), 51 (12), 42 (23). ES-HRMS: Found [MCH]C
228.0970 C11H19NPS requires 228.0976.
References and notes
1. Pinkerton, T. C.; Desilets, C. D.; Hoch, D. J.; Mikelsons, M. V.;
Wilson, G. M. J. Chem. Educ. 1985, 62, 965–973.
2. Kelly, J. D.; Chiu, K. W., Latham, I. A.; Griffiths, D. V.;
Edwards, P.G. Eur. Pat. Appl. 1989, 52, pp EP 311352; Chem.
Abstr. 1990 112(17), 154491d.
4.1.22. N-(20-Dimethylphosphinoethyl)methylamino-
benzene (7). N-(20-Dimethylphossphinoethyl)methyl-
aminobenzene 4 (0.5 g, 2.6 mmol) was reduced cleanly to
the phosphine 7 using the method previously given for the
preparation of 5 and isolated as a colourless oil (0.13 g,
26%), dP (CDCl3) K54.9; dH (270 MHz, CDCl3) 0.96 (6H,
d, JPHZ2 Hz, PMe), 1.51–1.56 (2H, m, a-CH2), 2.81 (3H, s,
NMe), 3.34–3.38 (6H, m, CH2), 6.63–6.69 (3H, m, ArH),
7.17–7.20 (2H, m, ArH); dC (CDCl3) 13.4 (d, JPCZ14 Hz,
PMe), 28.1 (d, JPCZ13 Hz, a-CH2), 37.5 (NMe), 49.2 (d,
JPCZ21 Hz, b-CH2),), 112.0 (C-2,6), 115.8 (C-4), 128.7
(C-3,5), 148.4 (C-1)
3. Kelly, J. D.; Higley, B.; Archer, C. M.; Canning, L. R.; Chiu,
K. W.; Edwards, B.; Forster, A. M.; Gill, H. K.; Latham, I. A.;
Webbon, P.; Edwards, P. G.; Imran, I.; Griffiths, D. V.; York,
D. C.; Mahoney, P. M.; Tonkinson, D. J.; Dilworth, J. R.; Lahiri,
A. In Nicolini, M., Bandoli, G., Mazzi, U., Eds.; Technetium
and Rhenium in Chemistry and Nuclear Medicine; Cortina
International: Verona, 1990; Vol. 3, pp 405–412.
4. King, R. B.; Cloyd, J. C., Jr. J. Am. Chem. Soc. 1975, 97, 53–60.
5. Prepared by the reaction of vinylmagnesium bromide with
dichloroethylphosphine sulfide, the latter being prepared by the
reaction of tetraethyl lead with thiophosphoryl chloride.
6. Kutyrev, G. A.; Cherkasov, R. A.; Pudovik, A. N. J. Gen. Chem.
USSR 1974, 44, 979.
7. Use of lower boiling ethers as the solvent for the reduction gave
unacceptably long reaction times.
Acknowledgements
8. Field, L. D.; Luck, I. J. Tetrahedron Lett. 1994, 35, 1109.
9. Although this higher melting material gave similar NMR data to
that reported here, no details of the purification procedure used
were given and no combustion analysis data were provided.
The authors wish to thank Amersham plc for financial
support for PMM, SPS, GW and DCY and EPSRC for
financial support for HJG. They also wish to thank the
EPSRC mass spectrometry service at Swansea.