Controlled mono and double Heck reactions in water catalyzed by an oxime-derived palladacycle

Article abstract of DOI:10.1016/j.tetlet.2004.01.024

The mono and β,β-diarylation of α,β-unsaturated carbonyl compounds with electron-deficient and electron-rich aromatic iodides in water is described. These reactions are catalyzed by the p- hydroxyacetophenone oxime-derived palladacycle 1 by controlling the stoichiometry of the aryl iodide and the alkene as well as the loading of the palladium catalyst. This one-pot protocol is performed in refluxing water and (dicyclohexyl)methylamine as base under thermal or microwave conditions and in the absence of an inert atmosphere.

Full text of DOI:10.1016/j.tetlet.2004.01.024

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1833–1836
Controlled mono and double Heck reactions in water catalyzed by
an oxime-derived palladacycle
*
ꢀ
Luis Botella and Carmen Najera
Departamento de Quꢀımica Orgꢀanica and Instituto de Sꢀıntesis Orgꢀanica (ISO), Universidad de Alicante, Apartado 99,
03080 Alicante, Spain
Received 2 December 2003; revised 7 January 2004; accepted 7 January 2004
ꢀ
Dedicated to Professor Jose Vicente on occasion of his 60th birthday
Abstract—The mono and b,b-diarylation of a,b-unsaturated carbonyl compounds with electron-deficient and electron-rich aromatic
iodides in water is described. These reactions are catalyzed by the p-hydroxyacetophenone oxime-derived palladacycle 1 by con-
trolling the stoichiometry of the aryl iodide and the alkene as well as the loading of the palladium catalyst. This one-pot protocol is
performed in refluxing water and (dicyclohexyl)methylamine as base under thermal or microwave conditions and in the absence of
an inert atmosphere.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The use of water as solvent in organic reactions is an
important goal for the development of environmentally
and technologically safe industrial-scale processes.1
Palladium-promoted reactions in aqueous media have
important advantages concerning catalyst separation
from the organic products and increasing selectivity and
efficiency. The well-known palladium-catalyzed alkenyl-
ation reaction of aromatic halides and other aromatic
substrates, the so-called Heck–Mizoroki reaction, has
emerged as one of the most powerful synthetic tools in
organic synthesis. However, it has not been extensively
studied in aqueous media.2 Beletskaya and co-workers
used in their seminal work ligand-free palladium(II)
salts for the Heck reaction in pure water or in aqueous
organic solvents in the presence of inorganic bases for
hydrophilic materials.3 In addition, palladium(II) ace-
tate is the catalyst of choice in phosphane-free4 or in the
presence of a phosphane under phase-transfer catalysis
(PTC)5 in aqueous environments. Moreover, palladium
on carbon under PTC in the presence of a reducing
agent has been shown as an appropriate catalyst for the
arylation of styrene in water.6 Recently, a di-2-pyr-
idylmethylamine-based palladium chloride complex7
and a cyclopalladated ferrocenylimine8 have been found
to be good phosphane-free catalyst for Heck reactions in
water. Several groups have been working in the devel-
opment of water-soluble ligands, such as sulfonated aryl
phosphanes.9 The presence of water has been found to
be beneficial when this alkenylation reaction was carried
out in organic solvents, such as N-methylpyrrolidone
(NMP)10 and also to promote the formation of palla-
dium nanoparticles.11
The classical intermolecular Heck reaction is mainly
limited to the monoarylation of terminal alkenes.2 The
synthesis of multisubstituted alkenes by b,b-diarylation
has been scarcely investigated.12 In the pioneering work
of Heck and co-workers was described the diarylation of
methyl acrylate with an excess of iodobenzene by using
Pd(OAc)2 and P(o-tol)3 under acetonitrile reflux for 21 h
to give 3,3-diphenylacrylate in 78% yield.13 Acrylonitrile
suffers easily b,b-diarylation when a montmorillonite
anchored
ethylsilyldiphenylphosphanepalladium(II)
dichloride complex is used as catalyst.14 Recent exam-
ples about b,b-diarylation of n-butyl acrylate have been
carried out in ionic liquids with benzothiazole carbene15
and bisimidazole16 derived palladium(II) complexes.
Controlled mono and diarylation of acrylates can be
performed under high pressure conditions.17 However,
the development of an efficient process for the control of
the mono and diarylation of terminal alkenes in water
would be desirable. We have recently shown that oxime-
derived palladacycles are versatile precatalysts in Heck,
Suzuki, Stille, Sonogashira, sila-Sonoghasira, Ullmann
Keywords: Alkenes; Diarylations; Heck reaction; Palladacycle; Palla-
dium catalysis.
* Corresponding author. Tel.: +34-96-5903728; fax: +34-96-5903549;
e-mail: cnajera@ua.es
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.024

1834
L. Botella, C. Nꢀajera / Tetrahedron Letters 45 (2004) 1833–1836
and Rossi reactions in organic solvents.18 Moreover,
these type of palladacycles were active in neat water for
Suzuki couplings of aryl and alkyl boronic acids with
aryl bromides and chlorides as well as with allylic and
benzylic chlorides.19 We report now that an oxime-
derived palladacycle is an appropriate precatalyst for the
controlled mono and b,b-diarylation of terminal alkenes
under very simple reaction conditions in neat water.
pound 4aa 2 equiv of iodobenzene and 3 equiv of
(dicyclohexyl)methylamine under water reflux were the
best reaction conditions, being necessary to increase the
amount of catalyst 1 to 1 mol % in order to obtain good
conversions (Scheme 1 and Table 1, entries 9–11). Other
bases such as triethylamine or diisopropylamine failed
and Pd(OAc)2 gave very poor conversions or no reac-
tion under microwave conditions (Table 1, entries 12
and 13).
For the Heck reactions in water we studied different
bases using 10ꢀ2 mol % Pd of complex 1, which was a
very efficient catalyst in the Suzuki reaction carried out
in aqueous media.19 The monoarylation reaction of tert-
butyl acrylate (2a) with 1 equiv of p-chloroiodobenzene
under water reflux was studied in the presence of
different secondary and tertiary amines, such as
diisopropylamine,20 dicyclohexylamine or (dicyclo-
hexyl)methylamine,21 and triethylamine (Scheme 1 and
Table 1, entries 1–4). The reaction was faster (3 h) (Table
1, entry 4) in the presence of Cy2NMe giving product
3ab in a high TON of 59,000 (Table 1, entry 5). When
the reaction was carried out under microwave irradia-
tion22 at 120 W and 120 ꢁC,23 the monoarylation took
place in only 10 min with similar TON but much higher
TOF (up to 42,000) (Table 1, entry 6). When Pd(OAc)2
was used instead of palladacycle 1 either under thermal
or microwave conditions, similar results were achieved
(Table 1, compare entries 4 and 7 or 6 and 8, respec-
tively). For the diarylation process of 2a to give com-
The scope of the mono and diarylation reactions under
water reflux was studied with different a,b-unsaturated
carbonyl compounds and activated and deactivated
iodides using palladacycle 1 as catalyst and (di-
cyclohexyl)methylamine as base (Scheme 1 and Table 2).
For tert-butyl acrylate (2a) the mono and diarylation
reaction with activated aryl iodides (Table 2, entries 3–6)
provide compounds 3 and 4 using a lower catalyst
loading than iodobenzene (Table 2, entries 1 and 2) or
deactivated aryl iodides (Table 2, entries 7 and 8). In the
case of diarylation with p-chloroiodobenzene, diisopro-
pylamine has to be used as base because (dicyclo-
hexyl)methylamine gave also the corresponding
homocoupling product 4,40-dichlorobiphenyl as
byproduct (Table 2, entry 4). When Pd(OAc)2 was used
as catalyst the monoarylation works nicely also with
p-methoxyiodobenzene (Table 2, entry 9). However, the
diarylation failed with p-fluorobenzene24 after 23 h
reaction time (Table 2, entry 10) and in the case of
ArI (1 equiv)
Ar
Ar
Z
1
3
N OH
Pd
Z
HO
Cy2NMe, H2O
ArI (2 equiv)
/
2
Cl
2
Z
reflux
Ar
1
4
Scheme 1.
Table 1. Mono and diarylation of tert-butyl acrylate: reaction conditions study
Entry
ArI (equiv)
Cat. (mol % Pd)
Amine
Reaction
conditionsa
Time
Yield (%)b TON
TOF (hꢀ1
)
1
4-ClC6H4I (1)
4-ClC6H4I (1)
4-ClC6H4I (1)
4-ClC6H4I (1)
4-ClC6H4I (1)
4-ClC6H4I (1)
4-ClC6H4I (1)
4-ClC6H4I (1)
PhI (2)
1 (1.1 · 10ꢀ2
)
i-Pr2NH
Et3N
Cy2NH
Thermal
Thermal
Thermal
Thermal
Thermal
lm
Thermal
lm
Thermal
Thermal
lm
24 h
14 h
63c
89 (83)c
94c
96 (94)c
59c
91 (87)c
83c
5727
239
636
2
1 (10ꢀ2
1 (10ꢀ2
)
8900
9400
8727
59,000
7000
7545
8167
58
3
)
6 h
3 h
1567
2909
2458
42,000
2515
49,000
4
4
1 (1.1 · 10ꢀ2
)
)
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NH
d
5
1 (10ꢀ3
)
24 h
10 min
3 h
6
1 (1.3 · 10ꢀ2
7
Pd(OAc)2 (1.1 · 10ꢀ2
Pd(OAc)2 (1.2 · 10ꢀ2
1 (1)
)
)
8
10 min
14 h
13 h
98 (88)c
58e
9
10
11
12
13
PhI (2)
PhI (2)
1 (1)
1 (1)
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
65 (66)e
31e
66
31
5
186
10 min
14 h
10 min
PhI (2)
PhI (2)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Thermal
lm
13e
13
1
e
—
––
––
a Reaction conditions see typical procedure.
b Determined by GC based on the ArI using decane as an internal standard. In parenthesis yields after purification.
c For compound 3ab.
d A 2 · 10ꢀ5 M solution (0.5 mL) of palladacycle 1 in N,N-dimethylacetamide (DMAc) was added.
e For compound 4aa.

L. Botella, C. Nꢀajera / Tetrahedron Letters 45 (2004) 1833–1836
Table 2. Mono and diarylation reactions in water with aryl iodides
1835
Entry
Olefin
Cat. (mol % Pd)
Time (h)
Product
Ar
No.
Z
Yield (%)a
1
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2c
2c
2d
2d
1 (10ꢀ2
1 (1)
)
3
13
3
3aa
4aa
3ab
4ab
3ac
4ac
3ad
4ad
3ad
4ac
4ad
3ba
4ba
3ca
4ca
3da
4da
CO2-t-Bu
CO2-t-Bu
CO2-t-Bu
CO2-t-Bu
CO2-t-Bu
CO2-t-Bu
CO2-t-Bu
CO2-t-Bu
CO2-t-Bu
CO2-t-Bu
CO2-t-Bu
CONMe2
CONMe2
CN
Ph
Ph
87
91
94
89
85
92
87
75
84
0
2
3
1 (1.1 · 10ꢀ2
)
)
4-ClC6H4
b
4
1 (10ꢀ1
1 (10ꢀ2
1 (10ꢀ1
)
)
)
22
22
14
14
14
14
23
14
14
14
9
4-ClC6H4
4-FC6H4
4-FC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-FC6H4
4-MeOC6H4
Ph
5
6
7
1 (1.2 · 10ꢀ2
1 (1)
8
9
Pd(OAc)2 (2 · 10ꢀ2
)
10
11
12
13
14
15
16
17
Pd(OAc)2 (10ꢀ1
Pd(OAc)2 (1)
)
34
96
77
94c
86
69d
41e
1 (10ꢀ1
1 (1)
)
Ph
Ph
1 (1)
1 (10ꢀ1
1 (8.6 · 10ꢀ3
1 (0.5)
)
23
23
8
CN
COMe
COMe
Ph
Ph
)
Ph
a Yield after flash chromatography (hexane/EtOAc).
b Diisopropylamine was used as base.
c A Z=E:1/4 mixture was obtained.
d 5% of 4da and 5% of 5da were isolated.
e 53% of 5da was isolated.
p-methoxyiodobenzene a lower yield than using pallada-
cycle 1 was observed (Table 2, compare entries 8 and
11). In the case of N,N-dimethylacrylamide (2b) and
acrylonitrile (2c) the mono and diarylation with iodo-
benzene could also be controlled (Table 2, entries 12–
15). Surprisingly, for acrylonitrile the diarylation25 is
more favorable than the monoarylation and in this case
the amount of catalyst has to be higher for the later
process (Table 2, entries 14 and 15). When methyl vinyl
ketone was used as alkene in the monoarylation process
also 10% of a 1/1 mixture of diarylation products 4da
and 5da was obtained (Table 2, entry 16). The diaryla-
tion of this ketone gave a ca. 1/1 mixture of products 4da
and 5da. Saturated ketone 5da results by in situ conju-
gated addition on the unsaturated ketone 3da.26 On the
other hand, both mono and diarylation processes in neat
water failed when aryl bromides instead of aryl iodides
were used.
cycles after subsequent addition of the substrates and
water (1 mL).
In conclusion, oxime-derived palladacycle
1
or
Pd(OAc)2 are appropriate catalysts for the monoaryl-
ation of a; b-unsaturated carbonyl compounds in water
using (dicyclohexyl)methylamine as base either under
thermal or microwave conditions, whereas for diaryl-
ation reactions thermal conditions have to be used and
palladacycle 1 is the catalyst of choice.
Typical experimental procedure: A 15 mL Ace pressure
tube was charged with the aryl iodide (2 mmol), the
alkene (3 mmol), (dicyclohexyl)methylamine (0.642 mL,
3 mmol), the catalyst (0.01–1 mol % Pd) and water
(3 mL) for monoarylation reactions. For diarylation
the following amounts were used, aryl iodide (1 mmol),
the alkene (0.5 mmol), (dicyclohexyl)methylamine
(0.321 mL, 1.5 mmol), the catalyst (0.01–1 mol % Pd, see
Tables 1 and 2) and water (2 mL). The mixture was
heated at 120 ꢁC and monitorized by GLC. The reaction
mixture was cooled and poured in EtOAc (40 mL). The
organic phase was washed with 2 M HCl (2 · 30 mL) and
water (2 · 30 mL), dried (Na2SO4), and the solvent
evaporated to afford the corresponding crude olefin
which was purified by recrystallisation or flash chro-
matography (hexane/EtOAc) to afford pure compounds
3 or 4.27
Ph
O
Ph
O
Ph
Ph
5da
4da
The catalyst 1 remains active upon addition of more
substrates in both mono and diarylation processes. In
the case of the monoarylation of tert-butyl acrylate with
p-chloroiodobenzene (see conditions in Table 2, entry 3)
total conversion was observed during four subsequent
cycles. Each cycle was performed in situ by addition of
the reagents and water (1 mL) and considered complete
after 3 h reaction time (monitorized by GLC). For the
diarylation reaction between both substrates (Table 2,
entry 4) using higher catalyst 1 loading (1 mol % Pd) also
total conversion after 13 h was obtained during four
References and notes
1. (a) Li, C.-J.; Chan, T.-H. Organic Reactions in Aqueous
Media; Wiley: New York, 1997; (b) Aqueous-Phase Orga-
nometallic Catalysis, Concepts and Applications; Cornils,
B., Herrmann, W. A., Eds.; Wiley-VCH: Weinheim, 1998;
(c) Grieco, P. A. Organic Synthesis in Water; Blackie

1836
L. Botella, C. Nꢀajera / Tetrahedron Letters 45 (2004) 1833–1836
ꢀ
18. (a) Alonso, D. A.; Najera, C.; Pacheco, M. C. Org. Lett.
Academic & Professional: London, 1998; (d) Lubineau,
A.; Auge, J. In Modern Solvents in Organic Synthesis;
Knochel, P., Ed.; Springer: Berlin, 1999.
ꢀ
2000, 2, 1823–1826; (b) Alonso, D. A.; Najera, C.;
Pacheco, M. C. Adv. Synth. Catal. 2002, 344, 172–183;
ꢀ
(c) Alonso, D. A.; Najera, C.; Pacheco, M. C. J. Org.
ꢀ
Chem. 2002, 67, 5588–5594; (d) Alonso, D. A.; Najera, C.;
Pacheco, M. C. Tetrahedron Lett. 2002, 43, 9365–9368; (e)
2. (a) Heck, R. F. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991,
Vol. 4; (b) Beleskaya, I. P.; Chepranov, A. V. Chem. Rev.
€
ꢀ
Alonso, D. A.; Najera, C.; Pacheco, M. C. Adv. Synth.
Catal. 2003, 345, 1146–1158.
2000, 100, 3009–3066; (c) Larhed, M.; Hallberg, A. In
Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E.-I., de Meijere, A., Eds.; Wiley:
New York, 2002; pp 1133–1178.
ꢀ
19. (a) Botella, L.; Najera, C. Angew. Chem., Int. Ed. 2002, 41,
179–183; (b) Botella, L.; Najera, C. J. Organomet. Chem.
ꢀ
3. Bumagin, N. A.; More, P. G.; Beletskaya, I. P. J.
Organomet. Chem. 1989, 371, 397–401.
4. (a) Bradley, D.; Williams, G.; Lombard, H.; Holzapfel, C.
W. Synth. Commun. 2001, 31, 2077–2081; (b) Zhao, H.;
Cai, M.-Z.; Hu, R.-H.; Song, C.-S. Synth. Commun. 2001,
31, 3665–3669.
5. Jeffery, T. Tetrahedron Lett. 1994, 35, 3051–3054.
6. Mukhopadhyay, S.; Rothenberg, G.; Joshi, A.; Baidossi,
M.; Sasson, Y. Adv. Synth. Catal. 2002, 344, 348–354.
2002, 663, 46–57.
20. Our group has used diisopropylamine as base for the Heck
monoarylation reaction in water using a di-2-pyridyl-
methylaminepalladium(II) dichloride derived complex as
catalyst.7
21. (Dicyclohexyl)methylamine and dicyclohexylamine were
the bases of choice in the Heck arylation of disubstituted
alkenes catalyzed by palladium(II) acetate in DMAc to
€
give trisubstituted derivatives: Gortler, C.; Buchwald, S.
L. Chem. Eur. J. 1999, 5, 3107–3112.
ꢀ
ꢀ
€
7. Najera, C.; Gil-Molto, J.; Karlstrom, S.; Falvello, L. R.
Org. Lett. 2003, 5, 1451–1454.
22. The monoarylation of styrenes, acrylic acid, and methyl
acrylate with aryl iodides in a microwave oven under
argon in water as solvent catalyzed by Pd(PPh3)2Cl2
(5 mol %) in the presence of potassium carbonate as base
and n-Bu4NBr as phase-transfer catalyst has been recently
described: Wang, J. X.; Liu, Z.; Hu, Y.; Wei, B.; Bai, L.
Synth. Commun. 2002, 32, 1607–1614.
23. Microwave reactions were performed with a CEM Dis-
cover Synthesis Unit (CEM Corp., Matthews, NC) in glass
vessels (10 mL) sealed with a septum under magnetic
stirring.
8. Hou, J.-J.; Yang, L.-R.; Cui, X.-L.; Wu, Y.-J. Chinese J.
Chem. 2003, 21, 717–719.
9. (a) Casalnuovo, A. L.; Calabrese, J. C. J. Am. Chem. Soc.
^
1990, 112, 4324–4330; (b) Genet, J.-P.; Blart, E.; Savignac,
M. Synlett 1992, 715–717; (c) Uozumi, Y.; Watanabe, T.
J. Org. Chem. 1999, 64, 6921–6923; (d) Thorpe, T.; Brown,
S. M.; Crosby, J.; Fitzjohn, S.; Muxworthy, J. P.;
Williams, J. M. J. Tetrahedron Lett. 2000, 41, 4503–
4505; (e) Amengual, R.; Genin, E.; Michelet, V.; Savignac,
^
M.; Genet, J.-P. Adv. Synth. Catal. 2002, 344, 393–398.
10. (a) Zhang, H.-C.; Daves, G. D., Jr. Organometallics 1993,
12, 1499–1500; (b) Hiroshige, M.; Hauske, J. R.; Zhou, P.
Tetrahedron Lett. 1995, 36, 4567–4570; (c) Zhao, F.;
Shirai, M.; Arai, M. J. Mol. Catal. (A) 2000, 154, 39–44.
11. Gittins, D. I.; Caruso, F. Angew. Chem., Int. Ed. 2001, 40,
3001–3004.
24. Similar result has been observed in ionic liquids as solvents
with bisimidazole palladium complexes.16
25. The Heck reaction of acrylonitrile with iodobenzene in the
presence of tri-n-butylamine at 100 ꢁC with montmoril-
lonite-ethylsilyldiphenylphosphane palladium(II) dichlor-
ide as catalyst gave 3,3-diphenylacrylonitrile (4ca)
exclusively.14
€
12. Brase, S.; de Meijere, A. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-I., de Mei-
jere, A., Eds.; Wiley: New York, 2002; pp 1179–1208.
13. Cortese, N. A.; Ziegler, C. B., Jr.; Hrnjez, B. J.; Heck, R.
F. J. Org. Chem. 1978, 43, 2952–2958.
14. Choudary, B. M.; Sarma, R. M.; Rao, K. K. Tetrahedron
1992, 48, 719–726.
26. Saturated compounds of the type 5da have been obtained
mainly in the diarylation of a,b-unsaturated ketones
with palladium(II) acetate and triphenylphosphane in
acetonitrile and in the presence of formic acid
and triethylamine: Cacchi, S. Synthesis 1984, 1, 575–
577.
ꢁ
ꢀ
27. This work has been supported by the Direccion General
15. Calo, V.; Nacci, A.; Monopoli, A.; Lopez, L.; di Cosmo,
A. Tetrahedron 2001, 57, 6071–6077.
ꢀ
de Investigacion of the Spanish Ministerio de Ciencia
ꢀ
16. Park, S. B.; Alper, H. Org. Lett. 2003, 5, 3209–3212.
17. Sugihara, T.; Takebayashi, M.; Kaneko, C. Tetrahedron
Lett. 1995, 36, 5547–5550.
y Tecnologıa (MCyT) (BQU2001-0724-CO2-01). L.B.
thanks the Generalitat Valenciana for a predoctoral
fellowship.