Preparation of new phosphine oxide synthons: Synthesis of an analogue of muscarinic antagonists

Article abstract of DOI:10.1055/s-1999-2899

Protected primary phosphine oxides may be obtained by reaction of ethyl (diethoxyalkyl)phosphinates with organometallic reagents. These products, stable to chromatography or distillation, may be further elaborated into new, functional unsymmetrical second

Full text of DOI:10.1055/s-1999-2899

LETTER
1633
Preparation of New Phosphine Oxide Synthons: Synthesis of an Analogue of
Muscarinic Antagonists
Roger G. Hall,* Peter Riebli
Novartis Crop Protection AG, Basel, Switzerland
E-mail: roger_graham.hall#cp.novartis.com
Received 26 July 1999
The reaction of dialkyl phosphites with organometallic re-
Abstract: Protected primary phosphine oxides may be obtained by
agents has been described. Hays5 demonstrated that sym-
reaction of ethyl (diethoxyalkyl)phosphinates with organometallic
metrical secondary phosphine oxides can be obtained
from the reaction of diethyl phosphite with three equiva-
reagents. These products, stable to chromatography or distillation,
may be further elaborated into new, functional unsymmetrical sec-
ondary and tertiary phosphine oxides. A close analogue of muscar- lents of alkyl Grignard reagent, followed by acidic work-
inic antagonists has been prepared using this methodology.
up.
Key words: functional phosphine oxides, synthons, muscarinic an-
tagonists
We reasoned that synthons 1 might undergo a similar re-
action, using only two equivalents of organometallic re-
agent. Thus reaction of 1 (R= H, CH3) with two
equivalents of Grignard or organolithium reagent 6 leads
to phosphine oxides 2 in good to excellent yields (Table).
The acetal or ketal functionality is stable under the reac-
We have previously reported1 the synthesis of phosphinic
acid synthons 12 and demonstrated their application in the
preparation of novel α, β and γ - amino phosphinic acids.
Such molecules are close analogues of natural amino ac-
ids, and as such have potentially useful biological proper-
ties. In addition to novel therapeutic agents,3 such
phosphinic acids have found application as tools for prob-
ing receptor sub-types.4 The strategy, Scheme 1, relies on
the use of the diethoxy - methyl (R = H) or - ethyl function
(R = CH3) as a P-H protecting group; selective transfor-
mations are performed on the exposed P-H. Functional
group modifications can then be optionally performed on
group R1, thereafter a deprotection step regenerates a P-H
function which can be further derivatised as required.
tion conditions. The formation of unwanted by-products
(EtO)2C(R)-P(O)(R1)2 can be minimised by inverse addi-
tion of the organometallic reagent to the phosphinates 1,
Scheme 2.
Scheme 1
Whilst the biological properties of phosphinic acids are by
now well documented, that of phosphine oxides remains
relatively unexplored. This could well be due to the fact
that no general method exists for the synthesis of highly
functional, unsymmetrical phosphine oxides. We have
now developed such a method by converting synthons 1
into phosphine oxide synthons and report our findings
here.
Scheme 2
Synlett 1999, No. 10, 1633–1635 ISSN 0936-5214 © Thieme Stuttgart · New York

1634
R. G. Hall, P. Riebli
LETTER
Compounds 2 can be viewed as protected primary phos-
phine oxides. Primary phosphine oxides are known to be
unstable and decompose via disproportionation . Buckler7
reported that either in solution or in the solid state, prima-
ry phosphine oxides decompose into primary phosphines
and phosphinic acids. However, such protected species 2
are stable and may be isolated by chromatography or dis-
tillation.
Phosphine oxides 2 can be further elaborated via P-H
chemistry. For example 2d undergoes alkylation leading
to compounds 3; these tertiary phosphine oxides can in
turn be deprotected under acidic conditions yielding sec-
ondary phosphine oxides 4, Scheme 3.
Scheme 5
Scheme 3
We have developed a synthesis of stable, protected prima-
ry phosphine oxides. These synthons can be elaborated
using straightforward transformations into functional, un-
symmetrical phosphine oxides of potential biological in-
terest.
We next sought to apply this methodology to prepare nov-
el phosphine oxides with potentially interesting biological
properties. A number of interesting secondary and tertiary
alcohols were identified as targets, where the C-OH could
be mimicked by a P=O functionality. Hexahydro-sila-
diphenidol 5 is a potent anticholinergic agent which ex-
hibits selective antagonism to muscarinic receptors.8 The
carbon analogue 6 shows a different selectivity profile to
receptor sub-types, Scheme 4.
Acknowledgement
We would like to acknowledge the technical support of S. N. Ben-
nett, K. Jones, N. Blair and N. Squirrel.
References and Notes
(1) Dingwall, J. G.; Ehrenfreund, J.; Hall, R. G. Tetrahedron
1989, 45, 3787.
(2) R = H, Gallagher, M. J.; Honnegar, H. Aus. J. Chem. 1980,
33, 287 ; R = CH3, Baylis, E. K.; Tetrahedron Lett. 1995, 36,
9385.
(3) Froestl, W.; Mickel, S. J.; Hall, R. G.; von Sprecher, G.; Strub,
D.; Baumann, P. A.; Brugger, F.; Gentsch, C.; Jaekel, J.; Olpe,
H-R.; Rihs, G.; Vassout, A.; Waldmeier, P.C.; Bittiger, H.; J.
Med. Chem. 1995, 38, 3297.
Scheme 4
(4) Bowery, N. G.; Bittiger, H.; Olpe, H-R. (editors), GABA-B
receptors in Mammalian Function, Wiley 1990.
(5) Hays, H. R. J. Org. Chem. 1968, 33, 3690.
The synthesis of the phosphine oxide analogue 7 is shown
below, Scheme 5. Reaction of cyclohexyl (diethoxymeth-
yl)phosphine oxide 2i with bromobenzene under palladi-
um catalysis gave the tertiary phosphine oxide 8 in good
yield. Acid deprotection liberated the P-H function for the
Michael addition to ethyl acrylate to give 9. Elaboration of
the ester function via reduction to the alcohol, tosylation
and displacement with piperidine gave the target molecule
7 as a racemic mixture.
(6) Typical procedure : Ethyl diethoxymethyl phosphinate (5.0
gm, 25.5 mmol) is dissolved in 75 ml dry tetrahydrofuran and
this solution is cooled to -40oC under argon. To this stirred
solution is added dropwise 50 ml of methyl lithium (1.0 M
solution in diethyl ether) whilst maintaining the temperature
below -40oC. After the addition is complete, the reaction
mixture is allowed to stand at room temperature for 12 hours.
Hydrochloric acid (50 ml, 0.1M) is then carefully added and
the mixture extracted with dichlormethane (3 X 100 ml). The
organic extracts are combined, dried over magnesium sulfate,
and the solvent removed. The crude material is purified by
vacuum distillation to give methyl diethoxymethyl phosphine
Synlett 1999, No. 10, 1633–1635 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Preparation of New Phosphine Oxide Synthons: Synthesis of an Analogue of Muscarinic Antagonists
1635
oxide as a colourless liquid, b. p. 85o / 0.02 mm. 1H NMR
(7) Buckler, S. A.; Epstein, M. Tetrahedron 1962, 18, 1221.
(CDCl3) : 1.3 (t, J = 9Hz, 6H), 1.6 (d.d, J = 20Hz, 5.4Hz, 3H),
3.8 (m, 4H), 4.3 (m, 0.5H), 4.9 (d.d, J = 12.5Hz, 1.8Hz, 1H),
9.6 (m, 0.5H). 31P NMR : 26.6ppm (CDCl3) J P-H = 468.6 Hz.
13C NMR (CDCl3) : 10.1 (d, J = 97Hz), 15.5, 66.5 (dd, J =
9Hz), 101.2 (d, J = 184Hz). IR (CCl4) : 2980, 2940, 2890,
2340, 1300, 1200, 1120, 1060, 965. Anal. Calcd. for C6H15O3P
: C 43.4%; H 9.1%. Found : C 44.0%; H 9.1%. All new
compounds gave satisfactory spectroscopic data.
(8) Waelbroeck, M.; Tastenoy, M.; Camus, J., Christophe, J.;
Strohmann, C.; Linoh, H.; Zilch, H.; Tacke, H.; Mutschler, E.;
Lambrecht, G. Br. J. Pharmacol. 1989, 98, 197.
Article Identifier:
1437-2096,E;1999,0,10,1633,1635,ftx,en;L10599ST.pdf
Synlett 1999, No. 10, 1633–1635 ISSN 0936-5214 © Thieme Stuttgart · New York