Arylation of allylphosphonates and application to the preparation of phosphonomethyl-coumarin, -quinolinone and -benzoxepinone skeletons

Article abstract of DOI:10.1016/j.tetlet.2015.02.038

An efficient and selective synthesis of Z-(het)arylallylphosphonates is described. The versatile Pd-assisted process also allowed polyarylation sequences leading to star-shaped and binaphthyl derivatives. The methodology could be extended to the preparati

Full text of DOI:10.1016/j.tetlet.2015.02.038

Tetrahedron Letters 56 (2015) 1679–1681
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Arylation of allylphosphonates and application to the preparation of
phosphonomethyl-coumarin, -quinolinone and -benzoxepinone
skeletons
a,
Abderrahmen Abdelli a,b, Anne Gaucher a, Mohamed Lotfi Efrit b, Hedi M’rabet b, , Damien Prim
⇑
⇑
a Université de Versailles Saint Quentin-en-Yvelines, Institut Lavoisier de Versailles—UMR CNRS 8180, 45, avenue des Etats-Unis, 78035 Versailles, France
b Université de Tunis El Manar, Faculté des Sciences de Tunis, Laboratoire de synthèse Organique et Hétérocyclique, 2092 Tunis, Tunisia
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and selective synthesis of Z-(het)arylallylphosphonates is described. The versatile Pd-assisted
process also allowed polyarylation sequences leading to star-shaped and binaphthyl derivatives. The
methodology could be extended to the preparation of new phosphonomethyl-coumarin, -quinolinone,
and -benzoxepinone architectures in high yields.
Received 12 January 2015
Revised 5 February 2015
Accepted 10 February 2015
Available online 16 February 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Allylphosphonate
Coumarin
Quinolinone
Benzoxepinone
Introduction
OAc
P(OR')3
FeCl3
Phosphonates are an important class of organic compounds that
exhibit various bioorganic and medicinal properties such as
antimicrobial, antimalarial, or enzyme inhibition.1 The modulation
of such properties can be envisioned through the installation of
(i)
CO2R
Ar
CO2R
Ar
OH
PO(OR')2
(ii)
CO2R
P(OR')3
various substituents in a, b, c-positions to the phosphonate group.
+
Ar
In this context, 2-phosphonomethyl acrylates emerged as powerful
intermediates, taking advantage of the twice-activated double
bond induced by the presence of both phosphonomethylene and
carboxylate groups. The installation of various (hetero)nucle-
ophiles can thus take place through Michael-type additions leading
Ar
Ar
ArH, PivOH
[Pd], [Ag],
CO2R
CO2R
PO(OR)2
(ii)
CO2R
PO(OR)2
Ph
Ph
Ph
to
aryl groups in
c
-substituted-2-phosphonomethyl acrylates.2 The installation of
PO(OR)2
major
minor
c-position of the phosphonate backbone is also of
high interest giving access to cinnamylphosphonate derivatives.
3-Aryl-2-phosphonomethyl acrylates are usually considered as
precursors of 3-phosphono-2-alkylpropionoic acid derivatives in
model catalytic hydrogenation reactions.3 The preparation of
3-aryl-2-phosphonomethyl acrylates rely mainly on Baylis Hillman
strategy. Allylic acetates derived therefrom undergo addition of
phosphorous-based nucleophiles to give stereoselectively the (Z)-
3-aryl-2-phosphonomethyl acrylates (Scheme 1i).4 3-Substituted-
2-phosphonomethyl acrylates can also be prepared by treatment
Scheme 1. Main access to 3-aryl-2-phosphonomethyl acrylates.
of Baylis–Hillman adduct with FeCl3 and trialkyl phosphites
(Scheme 1ii).5 Although limited to phenyl or dichlorophenyl aro-
matics, appealing arylation under Pd-catalyzed oxidative process
has also been described recently (Scheme 1iii).6
We have been deeply involved in the construction of allylphos-
phonates bearing additional carboxylate groups and on further
development of methods that rely on addition reactions.2 We were
interested in the installation of aromatics at the allylphosphonates
1 core through Pd-catalyzed arylation and whether the normal
Heck-reaction course could be glanced to the construction of var-
ious fused heterocycles by using the carboxylate function located
⇑
Corresponding authors. Tel.: +33 1 39 25 44 54; fax: +33 1 39 25 44 52.
E-mail addresses: mrabet.fst@gmail.com (H. M’rabet), damien.prim@uvsq.fr (D.
Prim).
http://dx.doi.org/10.1016/j.tetlet.2015.02.038
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

1680
A. Abdelli et al. / Tetrahedron Letters 56 (2015) 1679–1681
in position 1. In this context, the preparation of coumarin, quinoli-
none, and benzoxepinone skeletons7 bearing a phosphonomethyl
group is illustrated.
The few examples that describe a palladium catalyzed arylation
of allylphosphonate reported the formation of vinylphosphonate as
final product9 or a mixture of vinyl and arylallylphosphonate6 after
the b-elimination process.
Interestingly, products 2–7 were isolated as unique products of
the transformation. As shown in Scheme 3, selective b-Ha elimina-
tion takes place leading the formation of the functionalized styrene
rather than the vinylphosphonate and accounts for the
stereochemistry observed. As already stated by Kim,10 stabilization
of the carbopalladate-intermediate by the phosphonate group
plausibly controls the b-H elimination process. Indeed, hydrogens
Results and discussion
We started to examine the arylation of allylphosphonate 1
through Heck-type reaction. Among the Pd source precursor, base,
solvent, and additives tested, the catalytic combination using,
Pd(OAc)2, PPh3, K2CO3, nBu4NBr in DMF–H2O was found superior.
The optimal Pd/L ratio and reaction temperature were determined
as 1/2 and 75 °C, respectively. Under these conditions, cin-
namylphosphonate 2 could be obtained in 61% yield for 6h reaction
courses. The yields could be further increased to 71% by using
iodobenzene instead of the bromo analogue. Such optimized con-
ditions avoided degradation of the starting phosphonate and
appearance of side products rending tedious the silica gel purifica-
tion step (Scheme 2).
The E configuration relative to the ethoxycarbonyl group was
undoubtedly evidenced by NOESY two dimensional NMR
spectroscopy.8 The arylation process could be extended to various
aromatics and heteroaromatics (Fig. 1). Indeed, ortho-tolyl,
1-naphthyl, and 2-thienyl fragments could be successfully
installed in nearly 60% yield each. Further, we were able to couple
three allylphosphonates moieties at a central benzene ring using
1,3,5-tribromobenzene as starting electrophile affording an
appealing star-shaped architecture.
located
a to the phosphonate group within the pseudo metallacy-
cle are difficult to adapt the mandatory syn-position with respect
to the palladium center. As a consequence the easier b-Ha elimina-
tion takes place affording the expected styrene product.
We next examined the Pd-promoted installation of ortho-sub-
stituted iodoarenes and focused especially on iodophenol and
iodobenzylalcohol. At first, iodophenol reacted under the afore-
mentioned catalytic conditions at room temperature to cleanly
afford the expected arylallylphosphonate 8 in a fair 62% yield.
Attempts to increase the yield by reacting both starting material
at 70 °C unexpectedly led to the formation of coumarin derivative
9. The preparation of such coumarin has been described by two
synthetic methods. The first was done through multistep processes
characterized by the installation of the ‘P-based’ group in the last
step of the sequence by reacting triethyl phosphite with 3-(iodo)
and 3-(chloromethyl)coumarins.11 The second pathway started
from 3-(diethoxyphosphoryl)propionic acid. Further exposure to
the action of oxalyl chloride and salicylaldehyde under basic con-
ditions led to the designed coumarin (Scheme 4).12
Under the same reactions conditions, 2 equivalents of allylphos-
phonate 1 reacted with 1,8-diiodonaphthalene to form symmetri-
cal functionalized biaryl 7 in 68% yield. The latter plausibly arose
from a sequential installation of the naphthyl group in position 3
of the starting allylphosphonate leading on a mono coupled
intermediate and a further Pd-promoted homocoupling reaction
affording the binaphthyl unit.
Hb
Ar
EtO
EtO
EtO
EtO
CO2Et
Ha
CO2Et
Hb
P
P
Ar
Ha
O
O
Pd(II)LX
Pd(II)LX
Pd(OAc)2, PPh3,
X
CO2Et
CO2Et
K2CO3,nBu4NBr
+
CO2Et
CO2Et
O
DMF-H2O
PO(OEt)2
PO(OEt)2
O
nOe
2
OEt
OEt
OEt
Ar
P
Ar
P
1
OEt
61%
X = Br,
2-7
vinylphosphonate
not observed
X = I, 71%
Scheme 2. Phenylation of allylphosphonate 1.
Scheme 3. Phosphonate-assisted regioselective b-elimination process.
CO2Et
PO(OEt)2
OH
CO2Et
CO2Et
CO2Et
CO2Et
r.t.
n= 0
S
PO(OEt)2
PO(OEt)2
8
62%
O
PO(OEt)2
PO(OEt)2
5
4
62%
3
59%
60%
CO2Et
OH
n
PO(OEt)2
O
PO(OEt)2
I
EtO2C
70°C
n= 0
PO(OEt)2
EtO2C
9 72%
O
P
CO2Et
OEt
OEt
CO2Et
PO(OEt)2
EtO
EtO
PO(OEt)2
O
P
O
O
(EtO)2OP
70°C
n= 1
CO2Et
7 68%
CO2Et
6 69%
PO(OEt)2
10
79%
Figure
1. Pd-catalyzed
installation
of
various
(hetero)aromatics
to
Scheme 4. Selective access to phosphonomethyl-hydroxystyrene, -coumarin, and –
allylphosphonates.
benzoxepinone structures.

A. Abdelli et al. / Tetrahedron Letters 56 (2015) 1679–1681
1681
In conclusion, we succeeded in the selective preparation of ary-
lallylphosphonates. The Pd-assisted process is versatile allowing
the installation of various aromatic and heteroaromatic groups at
the allylphosphonate core. Polyarylation could also be obtained
leading to star-shaped benzene derivatives. The styrene fragment
is selectively obtained in a E configuration through phosphonate-
driven regiodiscrimination of the b-H elimination. The
methodology could be further extended to the preparation of
new phosphonomethyl-coumarin, -quinolinone, and -benzox-
epinone architectures in high yields.
HO
n
n
O
Ar
Ar
EtO
EtO
EtO
EtO
CO2Et
Hb
O
70°C
P
P
Ha
Hb
Ha
O
O
Pd(II)LI
Pd(II)LI
r.t.
8
9-10
Scheme 5. Intermediates involved in the formation of heterocyclic derivatives.
Acknowledgments
CO2Et
NH2
The authors are grateful to the Tunisian Ministry of Higher
Education and Scientific Research, to the University of Tunis El
Manar, to the CNRS and the University of Versailles-St Quentin-
en-Yvelines for financial support.
PO(OEt)2
CO2Et
x
NH2
r.t.
PO(OEt)2
O
I
CO2Et
PO(OEt)2
H
N
Supplementary data
PO(OEt)2
Supplementary data (experimental details as well as charac-
terization data and copies of NMR spectra) associated with this
article can be found, in the online version, at http://dx.doi.org/10.
1016/j.tetlet.2015.02.038.
70°C
11
76%
Scheme 6. Preparation of phosphonomethyl-quinolinone.
Similarly, lactone 10 was obtained in a high 79% yield under
similar reaction conditions. Interestingly, the formation of both
six- and seven-membered heterocycles have been obtained regard-
less of the ring size leading to novel phosphonomethyl-substituted
fused-heterocycles.
References and notes
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2. Mrabet, H.; Zantour, H. Phosphorus, Sulfur Silicon Relat. Elem. 2004, 179, 25–33;
Abdelli, A.; M’rabet, H.; Efrit, M. L.; Gaucher, A.; Prim, D. J. Sulfur Chem. 2014, 35,
674–682. and references cited therein.
3. Wang, D.-Y.; Hu, X.-P.; Hou, C.-J.; Deng, J.; Yu, S.-B.; Duan, Z.-C.; Huang, J.-D.;
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8. Data and stereochemistry in accordance with previous reports. See Refs. 4,6
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The formation of fused heterocycles 9–10, most probably arises
from a similar pathway involving the stabilized intermediate
which is first produced through the carbopalladation process. The
latter might then evolve depending on the reaction temperature
and on the nucleophile. At room temperature, the Pd-intermediate
leads to the arylallylphosphonate 8 in the iodophenol series
(Scheme 5). In contrast, at 70 °C the intermediate is transformed
into a lactone moiety which enforced one conformation and gave
the corresponding heterocycles 9 and 10 after b-Hb elimination
step regardless of the hydroxyl precursor. Although isomerization
from the E to Z olefin after classical b-H elimination cannot be fully
ruled out, we exclusively isolated the E configuration for com-
pounds 2–5 under the same conditions, which corroborates our
hypothesis illustrated in Scheme 5.
Encouraged by these results, we tried to extend our method-
ology to lactam analogues. Thus iodoaniline was next reacted with
allylphosphonate 1 in the presence of Pd(OAc)2, PPh3, K2CO3, and
nBu4NBr in DMF–H2O. Disappointingly, at room temperature, the
expected arylallylphosphonate could not be isolated both reactants
being almost completely recovered. In contrast, increasing the
reaction temperature to 70 °C led to the formation of 2-quinoli-
none 11 in 76% yield (Scheme 6).
10. Lee, H. S.; Kim, K. H.; Kim, S. H.; Kim, J. N. Adv. Synth. Catal. 2012, 354, 2419–
2426.
11. Rashamuse, T. J.; Musa, M. A.; Klein, R.; Kaye, P. T. J. Chem. Res. 2009, 5, 302–
305.
12. Janecki, T.; Bodalski, R. Synthesis 1989, 7, 506–610.