Efficient palladium-catalyzed cross-coupling of β-chloroalkylidene/ arylidene malonates using microwave chemistry

Article abstract of DOI:10.1021/jo049132r

A general method for the synthesis of β-aryl/ alkylarylidene malonates is reported. The key step involves the coupling of an arylboronic acid to a β-chloroalkyl/ arylidene malonate, in the presence of K₂CO ₃ and 1 mol % of the air-stable palladium catalyst (POPd) under microwave irradiation, to afford β-aryl/alkylarylidene malonates in good yields. The combination of mild reaction conditions, air stable catalyst, microwave-enhanced chemistry, and high levels of functional group compatibility make this an attractive synthetic approach to this class of compounds.

Full text of DOI:10.1021/jo049132r

SCHEME 1. Syn th esis of â-Ar yl/a lk yla r ylid en e
Ma lon a tes 1
Efficien t P a lla d iu m -Ca ta lyzed
Cr oss-Cou p lin g of â-Ch lor oa lk ylid en e/
a r ylid en e Ma lon a tes Usin g Micr ow a ve
Ch em istr y
Rajamohan R. Poondra,† Peter M. Fischer,‡ and
Nicholas J . Turner*,†
School of Chemistry, University of Edinburgh,
King’s Buildings, West Mains Road,
Edinburgh EH9 3J J , U.K., and Cyclacel Ltd.,
J ames Lindsay Place, Dundee DD1 5J J , U.K.
n.j.turner@ed.ac.uk
since they are readily prepared in high yield and on a
large scale from acyl malonates. We reasoned that 2
should possess high chemical reactivity in the Suzuki
reaction and hence be amenable to coupling with a wide
range of arylboronic acids. Finally, an additional aspect
of our planned approach involved the use of microwave-
enhanced synthesis to facilitate the coupling reactions.6
The requisite â-chloro-alkyl/arylidene malonates 2
were prepared according to the literature procedure
involving initial treatment of diethyl malonate with an
acyl chloride to yield the 2-acyl malonate (yields 90-
95%)7 followed by chlorination with POCl3/Bu3N to yield
the vinyl chlorides (yields 45-60%) (Scheme 1).8
Received May 24, 2004
Abstr a ct: A general method for the synthesis of â-aryl/
alkylarylidene malonates is reported. The key step involves
the coupling of an arylboronic acid to a â-chloroalkyl/
arylidene malonate, in the presence of K2CO3 and 1 mol %
of the air-stable palladium catalyst (POPd) under microwave
irradiation, to afford â-aryl/alkylarylidene malonates in good
yields. The combination of mild reaction conditions, air
stable catalyst, microwave-enhanced chemistry, and high
levels of functional group compatibility make this an attrac-
tive synthetic approach to this class of compounds.
An initial screen of some typical palladium catalysts
[e.g., Pd(OAc)2, Pd(Ph3P)4, tris(dibenzylideneacetone)-
dipalladium (0)] for their ability to mediate the coupling
of vinyl chloride 2 (R ) Me) with phenylboronic acid gave
low yields of the coupled product (10-15%). We therefore
turned our attention to the commercially available9 and
air-stable palladium(II) complex [(t-Bu)2P(OH)]2PdCl2
(abbreviated as POPd). This catalyst contains phosphi-
nous acid ligands on the palladium that are generated
by tautomerization of RR′P(O)H to less stable phosphi-
nous acids in the presence of transition metals. Since the
original introduction of these catalysts by Li,10 they have
become widely used for cross-coupling reactions11 and
appear to be particularly effective for coupling aryl and
vinyl chlorides. Thus, Li12 demonstrated the coupling of
1-chlorocyclopentene to arylboronic acids using POPd. Of
interest to us was the performance of this catalyst not
only with vinyl chlorides 2 but also under microwave
heating conditions.
Among the various reactions involving palladium-
mediated coupling of sp2-carbon atoms with organome-
tallic compounds to form carbon-carbon bonds, the
Suzuki reaction has attracted much interest due to a
number of attractive features including high yields, mild
reaction conditions, and tolerance of a wide variety of
functional groups.1 In view of the proven versatility of
this reaction, we contemplated its use in the preparation
of â-aryl/alkylarylidene malonates 1, precursors for the
synthesis of a wide range of derivatives including sub-
stituted quinolones,2 flavones,3 and other heterocycles4
possessing biological activity.
Previous approaches to â-aryl/alkylarylidene mal-
onates 1 have relied largely upon Knoevenagel condensa-
tion of diethyl malonate with the corresponding ketone.
However, this reaction is limited in scope and generally
only proceeds well for methyl ketones and cyclohexanone
derivatives.5 Our proposed alternative strategy centered
on the palladium-catalyzed cross-coupling reaction be-
tween â-chloroalkylidine/arylidene malonates 2 and aryl-
boronic acids 3 to yield the desired products 1 (Scheme
1). Vinyl chlorides 2 appeared to be attractive precursors
Initial optimization studies were carried out using a
variety of different bases (Na2CO3, K2CO3, Cs2CO3, and
K3PO4), and all were found to be effective for the cross-
coupling of â-chloroalkyl/arylidene malonates with phen-
† University of Edinburgh School of Chemistry.
‡ Cyclacel Ltd.
(1) (a) Miyaura, N.; Suzuku, A. Chem. Rev. 1995, 95, 2457-2483.
(b) Suzuki, A. J . Organomet. Chem. 1999, 576, 147-168. (c) Hassan,
J .; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002,
102, 1359-1470.
(2) Hormi, O. E. O.; Peltonen, C.; Heikkila¨, L. J . Org. Chem. 1990,
55, 2513-2515.
(3) Hormi, O. E. O.; Moisio, M. R.; Sund, B. C. J . Org. Chem. 1987,
52, 5272-5274.
(4) Khalil, Z. H.; Yanni, A. S.; Khalaf, A. A.; Abdel-Hafez, A. A.;
Abdo, R. F. Bull. Chem. Soc. J pn. 1988, 61, 1345-1349.
(5) (a) Lehnert, W. Tetrahedron 1973, 29, 635-638. (b) Iio, H.; Isobe,
M.; Kawai, T.; Goto, T. J . Am. Chem. Soc. 1979, 101, 6076-6080.
(6) For a recent example of microwave-assisted Suzuki couplings,
see: Wu, T. Y. H.; Schultz, P. G.; Ding, S. Org. Lett. 2003, 5, 3587-
3590.
(7) Rathke, M. W.; Cowan, P. J . J . Org. Chem. 1985, 50, 2622-2624.
(8) (a) Hormi, O. E. O. Org. Synth. 1988, 66, 173. (b) Hormi, O. E.
O. Synth. Commun. 1986, 16, 997.
(9) POPd is commercially available from CombiPhos Catalysts Inc.
(http://www.combiphos.com).
(10) (a) Li, G. Y. Angew. Chem., Int. Ed. 2001, 40, 1513-1516. (b)
Li, G. Y.; Zheng, G.; Noonan, A. F. J . Org. Chem. 2001, 66, 8677-
8681.
(11) (a) Yang, W.; Wang, Y.; Corte, J . R. Org. Lett. 2003, 5, 3131.
(b) Wolf, C.; Lerebours, R. J . Org. Chem. 2003, 68, 7077-7084.
(12) Li, G. Y. J . Org. Chem. 2002, 67, 3643-3650.
10.1021/jo049132r CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/02/2004
6920
J . Org. Chem. 2004, 69, 6920-6922

TABLE 1. Syn th esis of â-Ar yl/a lk yla r ylid en e Ma lon a tesa
a
The reactions of â-chloromalonates with arylboronic acids in the presence of POPd were carried out in 100 °C in THF using Explorer
PLS. A trace of bis-aryl product was observed. c Yields in parentheses are for control experiments involving heating the reaction at 100
b
°C for 36 h under non-microwave conditions.
ylboronic acid. We were rapidly able to identify reaction
conditions under which clean and rapid coupling of the
model substrate (2, R ) Me) occurs with phenylboronic
acid 3, using the air-stable palladium catalyst POPd.
electron-rich (entries 3, 4, 7, and 14), electron-deficient
(entries 2, 6, and 9) and sterically demanding (entries 5,
10, and 12) systems. As has been observed before, the
Suzuki reaction was found to be compatible with -NH2
and -OH functionality in the arylboronic acid leading
to functionalized products 6 and 7 that could be deriva-
tized further (Scheme 2).
Optimized conditions were vinyl chloride 2 (1 equiv),
arylboronic acid 3 (1.5 equiv), K2CO3 as base (3.0 equiv),
and 1 mol % of POPd in THF. Reactions were irradiated
with microwave heating for 30 min at 100 °C followed
by workup and silica chromatography to yield the cor-
responding â-aryl/alkylarylidene malonates in good yields
(Table 1). The Suzuki arylation reaction was found to
work with a wide range of arylboronic acids including
In view of the known ability of POPd to mediate Suzuki
couplings of aryl chlorides,10,11 the product 8 from entry
1 was subjected to a further Suzuki reaction with
o-nitrophenylboronic acid leading to the biphenyl deriva-
tive 9 in 77% yield (Scheme 3).
J . Org. Chem, Vol. 69, No. 20, 2004 6921

SCHEME 2
malonates 1 from readily available precursors, using the
air-stable palladium catalyst POPd. A wide range of
arylboronic acids, bearing a variety of functional groups,
can be tolerated in the reaction. The use of microwave-
assisted heating permits the reaction time to be reduced
to as little as 30 min enabling a number of different
analogues to be prepared in a short period of time.
Exp er im en ta l Section
Gen er al P r ocedu r e for th e Reaction of â-Ch lor oar yliden e/
a lk ylid en e Ma lon a tes w ith Ar ylbor on ic Acid s. POPd (1 mol
%), â-chloroalkylidene/arylidene malonate (1.00 mmol), arylbo-
ronic acid (1.50 to 2.00 mmol), and K2CO3 (3.00 mmol) were
weighed in a microwave tube, equipped with a magnetic stirrer
bar, and sealed with a silicon septum. THF (2 to 3 mL) was
injected into the tube via a syringe, and the reaction mixture
was subjected to microwave irradiation for 30 min at 100 °C.The
reaction vessel was allowed to cool to room temperature and the
crude reaction mixture transferred to a separating funnel and
diluted with hexane (50 mL) and H2O (15 mL). The layers were
separated; the organic layer was washed with H2O (20 mL) and
brine (20 mL), dried over MgSO4, and filtered; and solvents were
removed from the filtrate by rotary evaporation. The resulting
residue was chromatographed on silica gel using ethyl acetate/
hexane as eluents to afford â-aryl/alkylarylidene malonates.
SCHEME 3
SCHEME 4
Ack n ow led gm en t. We are grateful to CEM Corp.,
U.K., for provision of Discover and Explorer microwave
synthesizers.
Finally, as an illustration of the further application of
the â-aryl/alkylarylidene malonates reported in this
paper, treatment of 10 with polyphosphoric acid resulted
in cyclization to the 2-carboxyethylindenone 11 in 50%
yield (Scheme 4).
In conclusion, we have developed an efficient and
versatile route for the synthesis of â-aryl/alkylarylidene
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and spectral data for all transformations and compounds
described. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O049132R
6922 J . Org. Chem., Vol. 69, No. 20, 2004