A simple and efficient preparation of (arylphosphinyl)methylphosphonates

Article abstract of DOI:10.1081/SCC-120012983

A simple and efficient preparation of (arylphosphinyl)methylphosphonates is described whereby the phosphinylmethylphosphonate group is introduced via the Pd(O) mediated phosphinylation of an aryl halide or triflate with diethyl (ethoxyphosphinyl)methylphosphonate.

Full text of DOI:10.1081/SCC-120012983

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A SIMPLE AND EFFICIENT PREPARATION OF
(ARYLPHOSPHINYL)-METHYLPHOSPHONATES
George P. Luke a & William C. Shakespeare b
a Neurogen Corporation , 35 Northeast Industrial Road, Branford, CT, 06405, U.S.A.
b ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, MA, 02139-4234, U.S.A.
Published online: 16 Aug 2006.
To cite this article: George P. Luke & William C. Shakespeare (2002) A SIMPLE AND EFFICIENT PREPARATION OF
(ARYLPHOSPHINYL)-METHYLPHOSPHONATES, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 32:19, 2951-2957, DOI: 10.1081/SCC-120012983
To link to this article: http://dx.doi.org/10.1081/SCC-120012983
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 19, pp. 2951–2957, 2002
A SIMPLE AND EFFICIENT
PREPARATION OF (ARYLPHOSPHINYL)-
METHYLPHOSPHONATES
*
George P. Luke and William C. Shakespeare
ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street,
Cambridge, MA 02139-4234, USA
ABSTRACT
A simple and efficient preparation of (arylphosphinyl)methyl-
phosphonates is described whereby the phosphinylmethylphos-
phonate group is introduced via the Pd(0) mediated
phosphinylation of an aryl halide or triflate with diethyl
(ethoxyphosphinyl)methylphosphonate.
Phosphinylmethylphosphonate (PMP) groups have been incorporated
into a variety of biologically active molecules, often as stable pyrophosphate
mimetics. Among the numerous PMP containing molecules are
nucleoside PMPs,[1] isoprenoid PMPs[2] and amino acid PMPs.[3]
a-Halo(phenylphosphinyl)methylphosphonates have been shown to be inhi-
bitors of Naþ-phosphate cotransport in renal brush border membrane.[4]
Furthermore, antiresorptive compounds have incorporated PMPs.[5] From
a synthetic standpoint, PMPs are useful reagents for the preparation of vinyl
phosphonates or vinyl phosphinates via the olefination of an aldehyde.[6] As
*Corresponding author. Current address: Neurogen Corporation, 35 Northeast
Industrial Road, Branford, CT 06405, USA. E-mail: gluke@nrgn.com
2951
DOI: 10.1081/SCC-120012983
Copyright & 2002 by Marcel Dekker, Inc.
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2952
LUKE AND SHAKESPEARE
part of our efforts to develop novel mediators of signal transduction path-
ways, we were interested in incorporating an (arylphos-
phinyl)methylphosphonate (arylPMP) moiety into some of the molecules
we were investigating. We required an efficient and mild method for intro-
ducing this functionality so as to allow for the rapid preparation of a variety
of analogs. This communication describes our successful efforts to develop
such a method.
ArylPMPs have previously been prepared by the Michaelis–Arbuzov-
type reaction of a dialkyl (or diaryl) arylphosphonite with a dialkyl halo-
methylphosphonate[4a,7] or, conversely, by the Michaelis–Arbuzov reaction
of an alkyl (aryl)halomethylphosphinate with a trialkyl phosphite.[8]
Alternatively, arylPMPs may be obtained following methodology employed
for the preparation of (alkylphosphinyl)methylphosphonates whereby the
lithium anion of a dialkyl methylphosphonate is condensed with an alkyl
arylphosphonochloridate.[2b,3,9] The aforementioned methodology does not
lend itself well to the rapid and efficient preparation of a variety of arylPMPs
possessing differentially functionalized aryl rings since the PMP group is
introduced in a step-wise fashion. That is, an appropriately functionalized
arylphosphonite, (aryl)halomethylphosphinate, or arylphosphonochloridate
must first be prepared before the phosphonate group can be introduced.
Furthermore, the reaction conditions employed in some of the previously
described methods are incompatible with some of the additional functionality
present in the molecules that we were investigating. An attractive alternative
approach would introduce the complete PMP onto the functionalized aryl
ring in one step under mild conditions.
Dialkyl arylphosphonates have previously been prepared by the
Pd(0) mediated phosphonylation of aryl halides[10] or triflates[11] using a
dialkyl phosphite. Analogously, alkyl alkylphenylphosphinates have been
prepared by the Pd(0) mediated phosphinylation of aryl halides using an
alkyl alkylphosphonite.[12] It seemed reasonable then that arylPMPs might
efficiently be prepared in an analogous manner using readily available
diethyl (ethoxyphosphinyl)methylphosphonate (2).[13] This, in fact, turned
out to be the case, and the results of our investigation, using some simple
aryl halides or triflates (1a–i) to prepare arylPMPs 3a–i, are summarized in
Table 1.
The reactions were carried out in acetonitrile at 80–100ꢀC in a sealed
tube using 1.05–1.1 eq of 2, 3.0eq of either Et 3N or N-methylmorpholine
(NMM) and 0.025–0.05 eq of Pd(PPh3)4.[14] As can be seen, the reaction
appears to be fairly general, and yields range from good to excellent.
Entries a–c suggest that bromide, iodide and triflate all appear to be
comparable leaving groups. Entries d–i demonstrate the compatibility of
some simple substituents under the reaction conditions. Entry i is particularly

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(ARYLPHOSPHINYL)METHYLPHOSPHONATES
2953
Table 1. Pd(0) Mediated Reactions of Some Simple Aryl Halides
or Triflates with Diethyl (Ethoxyphosphinyl)methylphosphonate (2)
Time
(h)
Yielda
(%)
Entry
X
R
a
b
c
d
e
f
g
h
i
Br
I
OTf
I
Br
I
I
I
I
H
H
H
3
3
3
3
3
2.5
6
6
6
79
74
72
77
61
98
82
67
55
p-CO2Me
p-NO2
p-NO2
m-OMe
p-OMe
Br
aYield of purified product. All products were purified by flash chro-
matography on silica gel and were homogeneous by TLC and HPLC.
interesting in that arylPMP 3i possesses an aryl bromide, which lends itself to
further functionalization, including additional transition metal mediated
reactions.[15] All reactions proceeded smoothly, and the diethoxyphosphonyl
group of 2 did not appear to adversely affect the course of the reaction.
In summary, we have demonstrated a facile preparation of arylPMPs
via the Pd(0) mediated phosphinylation of aryl bromides, iodides or triflates
using diethyl (ethoxyphosphinyl)methylphosphonate (2). The method com-
pliments well existing methodology for the preparation of arylPMPs. The
reaction conditions are mild, a variety of functional groups are tolerated,
and the complete PMP group is installed in one step, thereby allowing for
the rapid preparation of arylPMP analogs incorporating a variety of
functionalized aryl groups.
REFERENCES
1. (a) Trowbridge, D.B.; Kenyon, G.L. Adenosine 50-Bis(dihydroxy-
phosphinylmethyl)phosphinate, the a,b : b,g-Bismethylene Analog of
Adenosine 50-Triphosphate. J. Am. Chem. Soc. 1970, 92(7), 2181–2182;

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2954
LUKE AND SHAKESPEARE
(b) Shirokova, E.A.; Shipitsin, A.V.; Victorova, L.S.; Dyatkina, N.B.;
Goryunova, L.E.; Beabealashvilli, R.Sh.; Hamilton, C.J.; Roberts,
S.M.; Krayevsky, A.A. Modified Nucleoside 50-Triphosphonates as a
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E.A.; Dyatkina, N.B.; Goryunova, L.E.; Beabealashvilli, R.Sh.;
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Nucleoside 50-Triphosphates: Synthesis, Properties Towards DNA
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2. (a) McClard, R.W.; Fujita, T.S.; Stremler, K.E.; Poulter, C.D. Novel
Phosphonylphosphinyl (P–C–P–C) Analogues of Biochemically Inter-
esting Diphosphates. Syntheses and Properties of P–C–P–C-Analogues
of Isopentenyl Diphosphate and Dimethylallyl Diphosphate. J. Am.
Chem. Soc. 1987, 109(18), 5544–5545; (b) Biller, S.A.; Forster, C.;
Gordon, E.M.; Harrity, T.; Scott, W.A.; Ciosek, Jr., C.P. Isoprenoid
(Phosphinylmethyl)phosphonates as Inhibitors of Squalene Synthetase.
J. Med. Chem. 1988, 31(10), 1869–1871.
3. Flohr, A.; Aemissegger, A.; Hilvert, D. a-Functionalized Phosphonyl-
phosphinates: Synthesis and Evaluation as Transcarbamoylase Inhibi-
tors. J. Med. Chem. 1999, 42(14), 2633–2640.
4. (a) McKenna, C.E.; Pham, P.-T.T.; Rassier, M.E.; Dousa, T.P.
a-Halo[(Phenylphosphinyl)methyl]phosphonates as Specific Inhibitors
of Naþ-Gradient-Dependent Naþ-Phosphate Cotransport Across
Renal Brush Border Membrane. J. Med. Chem. 1992, 35(26),
4885–4892; (b) Bau, R.; Pham, P.-T.T.; Duncan, G.D.; McKenna,
C.E. Absolute Configuration of (þ)-[Fluoro(hydroxyphenylphosphi-
nyl)methyl]phosphonic Acid, a Specific Inhibitor of Naþ-Gradient-
Dependent Naþ-Phosphate Cotransport Across Renal Brush Border
Membrane, by X-ray Crystallographic Analysis of Its (À)-Quinine
Salt. J. Med. Chem. 1995, 38(9), 1575–1578.
5. (a) Ebetino, F.H.; Degenhardt, C.R.; Jamieson, L.A.; Burdsall, D.C.
Recent Work on the Synthesis of Phosphonate-Containing,
Bone-Active Heterocycles. Heterocycles 1990, 30(2), 855–862; (b)
McOsker, J.E. Methods for the Treatment of Osteoporosis. WO
92/14474, September 3, 1992; (c) Geddes, A.D.; Boyce, R.W. Methods
for the Treatment of Osteoporosis Using Bisphosphonates and
Parathyroid Hormone. WO 93/11786, June 24, 1993.
6. (a) Gilmore, W.F.; Park, J.S. Base-Catalyzed Reactions of Phos-
phonomethylphosphinates, Bis(phosphonomethyl)phosphinates, and
Bis(phosphonomethyl)phosphinic Amides with Aldehydes. In
Phosphorus Chemistry; ACS Symposium Series 171; American Chemical

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©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
(ARYLPHOSPHINYL)METHYLPHOSPHONATES
2955
Society: Washington, DC, 1981; pp 611–614; (b) Prashad, M.
Phosphonate vs. Phosphinate Elimination During Olefination of
Aldehydes. Tetrahedron Lett. 1993, 34(10), 1585–1588 and references
cited therein.
7. Gloyna, D.; Lachman, U.; Henning, H.G. Preparation of Methylene-
P(O) Compounds With Different Phosphorous Substituents. J. Prakt.
Chem. 1975, 317(5), 840–852.
8. Gobel, R.; Richter, F.; Weichmann, H. Synthesis and Reactivity of
Methylene Bridged Diphosphonyl Compounds. Phosphorus, Sulfur
Silicon Relat. Elem. 1992, 73(1–4), 67–80.
9. Vu, C.B. Unpublished results.
10. Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T. A Novel Synthesis of
Dialkyl Arenephosphonates. Synthesis 1981, 56–57.
11. Petrakis, K.S.; Nagabhushan, T.L. Palladium-Catalyzed Substitutions
of Triflates Derived from Tyrosine-Containing Peptides and Simpler
Hydroxyarenes Forming 4-(Diethoxyphosphinyl)phenylalanines and
Diethyl Arylphosphonates. J. Am. Chem. Soc. 1987, 109(9),
2831–2833.
12. Xu, Y.; Zhang, J. Palladium-Catalyzed Synthesis of Functionalised
Alkyl Alkylarylphosphinates. Synthesis 1984, 778–782.
13. Diethyl (ethoxyphosphinyl)methylphosphonate (2) can readily be pre-
pared in multi-ten-gram quantities in three steps from commercially
available materials. (a) Baxter, A.D.; Taylor, R.J.; Collingwood, S.P.
Intermediates for Dinucleotide and Oligonucleotide Analogues. US
Patent 5,952,478, September 14, 1999; (b) Baillie, A.C.; Wright, B.J.;
Wright, K. Pesticidally Active Salts and Compositions Containing
Them and Processes for Their Manufacture and Use. EP0009348,
April 2, 1980.
14. A representative experimental is given for 3d: A mixture of methyl
4-iodobenzoate (1d) (160 mg, 0.607 mmol), diethyl (ethoxyphosphinyl)-
methylphosphonate (2) (163 mg, 0.668 mmol), NMM (0.20 mL,
1.82 mmol) and Pd(PPh3)4 (34 mg) in acetonitrile (2 mL) were
stirred at 90ꢀC in a sealed tube under an atmosphere of Ar for 3 h.
The reaction mixture was then concentrated, and the residue parti-
tioned between 0.5 N aq HCl and CH2Cl2. The layers were separated,

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2956
LUKE AND SHAKESPEARE
and the aqueous layer was reextracted three times with CH2Cl2.
The combined extracts were washed with saturated aq NaCl, dried
over MgSO4, and concentrated. The crude product was purified by
flash chromatography on silica gel. Gradient elution from 10%
MeOH–CH2Cl2 to 25% MeOH–CH2Cl2 afforded 177 mg (77%)
of 3d as a colorless oil. 1H NMR (300 MHz, CDCl3) ꢀ 8.16–8.13
(m, 2H), 7.97–7.90 (m, 2H), 4.24–4.05, 4.04–3.97 (m, 6H), 3.95 (s,
3H), 2.73–2.59 (m, 2H), 1.33 (t, J ¼ 7.1 Hz, 3H), 1.30(t, J ¼ 7.1 Hz,
3H), 1.18 (t, J ¼ 7.1 Hz, 3H); 31P NMR (121 MHz, 1H-decoupled,
CDCl3) ꢀ 33.1 (d, J ¼ 7 Hz), 19.1 (d, J ¼ 7 Hz); Electrospray mass
spectrum (50: 50 acetonitrile : water þ 0.1% NH4OH): m/z 379
[M þ H]. Anal. Calcd. for C15H24O7P2: C, 47.62; H, 6.39. Found: C,
47.59; H, 6.32.
Products 3a–c: 1H NMR (300 MHz, CDCl3) ꢀ 7.89–7.82 (m, 2H),
7.59–7.46 (m, 3H), 4.21–3.95 (m, 6H), 2.69–2.56 (m, 2H), 1.35
(t, J ¼ 7.1 Hz, 3H), 1.30(t, J ¼ 7.1 Hz, 3H), 1.18 (t, J ¼ 7.1 Hz, 3H);
1
31P NMR (121 MHz, H-decoupled, CDCl3) ꢀ 33.8 (d, J ¼ 8 Hz), 19.6
(d, J ¼ 8 Hz); Electrospray mass spectrum (50: 50 acetonitrile:
water þ 0.1% NH4OH): m/z 321 [M þ H]. Anal. Calcd. for
C13H22O5P2: C, 48.75; H, 6.92. Found: C, 48.72; H, 6.90.
1
Products 3e,f: H NMR (300 MHz, CDCl3) ꢀ 8.33 (dd, J ¼ 8.7, 2.6 Hz,
2H), 8.09 (dd, J ¼ 11.7, 8.7 Hz, 2H); 4.27–3.96 (m, 6H), 2.73–2.60
(m, 2H), 1.36 (t, J ¼ 7.1 Hz, 3H), 1.31 (t, J ¼ 7.1 Hz, 3H), 1.22
(t, J ¼ 7.1 Hz, 3H); 31P NMR (121 MHz, 1H-decoupled, CDCl3) ꢀ
31.5, 18.6; Anal. Calcd. for C13H21NO7P2: C, 42.75; H, 5.80; N,
3.83. Found: C, 42.67; H, 5.70; N, 3.77.
Product 3g: 1H NMR (300 MHz, CDCl3) ꢀ 7.49–7.37 (m, 3H);
7.16–7.13 (m, 1H), 4.26–3.95 (m, 6H), 3.88 (s, 3H), 2.86–2.60
(m, 2H), 1.36 (t, J ¼ 7.1 Hz, 3H), 1.34 (t, J ¼ 7.1 Hz, 3H), 1.23
(t, J ¼ 7.1 Hz, 3H); 31P NMR (121 MHz, 1H-decoupled, CDCl3) ꢀ
35.2, 19.4; Electrospray mass spectrum (50: 50 acetonitrile :
water þ 0.1% NH4OH): m/z 351 [M þ H]. Anal. Calcd. for
C14H24O6P2: C, 48.00; H, 6.91. Found: C, 47.84; H, 6.85.
1
Product 3h: H NMR (300 MHz, CDCl3) ꢀ 7.81 (dd, J ¼ 12.0, 8.7 Hz,
2H), 7.02 (dd, J ¼ 8.7, 2.9 Hz, 2H), 4.23–3.91 (m, 6H), 3.88 (s, 3H),
2.78–2.53 (m, 2H), 1.35 (t, J ¼ 7.1 Hz, 3H), 1.33 (t, J ¼ 7.1 Hz, 3H), 1.23
(t, J ¼ 7.1 Hz, 3H); 31P NMR (121 MHz, 1H-decoupled, CDCl3) ꢀ 34.8,
19.8; Electrospray mass spectrum (50: 50 acetonitrile : water þ 0.1%
NH4OH): m/z 351 [M þ H]. Anal. Calcd. for C14H24O6P2: C, 48.00;
H, 6.91. Found: C, 47.95; H, 6.90.
Product 3i: 1H NMR (300 MHz, CDCl3) ꢀ 7.77–7.62 (m, 4H), 4.21–3.92
(m, 6H), 2.67–2.53 (m, 2H), 1.33 (t, J ¼ 7.0Hz, 3H), 1.31 (t, J ¼ 7.0Hz,

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(ARYLPHOSPHINYL)METHYLPHOSPHONATES
2957
3H), 1.20(t, J ¼ 7.0Hz, 3H); 31P NMR (121 MHz, 1H-decoupled,
CDCl3) ꢀ 33.0(d, J ¼ 7 Hz), 19.2 (d, J ¼ 7 Hz); Anal. Calcd. for
C31H21BrO5P2: C, 39.12; H, 5.30. Found: C, 39.00; H, 5.26.
15. The authors wish to thank Dr. Raji Sundaramoorthi for the
preparation of 3i.
Received in the USA October 4, 2001

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