Palladium-catalysed direct regioselective synthesis of cyclic ketals from electron-rich olefins and aryl bromides in ionic liquids

Article abstract of DOI:10.1002/adsc.200606151

The Heck reaction comprises one of the most important carbon-carbon coupling reactions in organic synthesis. The popularity of the reaction is attributable to the broad availability of aryl halides and to the tolerance of the reaction for a wide variety o

Full text of DOI:10.1002/adsc.200606151

FULL PAPERS
DOI: 10.1002/adsc.200606151
Palladium-Catalysed Direct Regioselective Synthesis of Cyclic
Ketals from Electron-Rich Olefins and Aryl Bromides in Ionic
Liquids
Zeynab Hyder,a Jun Mo,a and Jianliang Xiaoa,*
a
Liverpool Centre for Materials and Catalysis, Department of Chemistry, University of Liverpool, Liverpool, L697ZD,
United Kingdom
Fax : (+44)-151–794–3589; e-mail: J.Xiao@liv.ac.uk
Received: March 28, 2006; Accepted: May 29, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The Heck reaction comprises one of the performed with palladium catalysis using ionic liquid
most important carbon-carbon coupling reactions in as solvent with no need for any halide scavengers,
organic synthesis. The popularity of the reaction is providing an alternative to the use of aryl triflates.
attributable to the broad availability of aryl halides The ionic liquid is found to direct the reaction path-
and to the tolerance of the reaction for a wide varie- way towards exclusive a-arylation via a cationic
ty of functional groups. Reported herein is a direct route.
method for the highly regioselective preparation of
5-membered and 7-membered cyclic ketals in re-
spectable to good yields from aryl bromides (1a–k) Keywords: Heck reaction; ionic liquids; ketals; palla-
and electron-rich olefins (2a and b). The reaction is dium; regioselectivity
Introduction
thus far has enabled very regioselective arylation to
be performed. Early research by Hallberg and Larhed
The formation of carbon-carbon bonds is one of the and co-workers revealed that the regioselectivity of
most significant reactions in synthetic chemistry. the palladium-catalysed arylation of enol ethers is
Among the many established methods for doing this, sensitive to structure of the enol ether, the arylating
the palladium-catalysed arylation and vinylation of agent used, and the reaction medium.[3] Control of
olefins by aryl and vinyl halides or their derivatives, these factors allows control of regioselectivity for ary-
known as the Heck reaction, is one of the most im- lation at the olefinic a- or b-carbons of the enol
portant.[1,2] The Heck reaction generally works well ether. It was also suggested that electron-rich aryl sys-
with olefins possessing electron-withdrawing substitu- tems favour a-arylation whereas electron-poor aryls
À
À
ents, such as CO2R and CN, i.e., electron-deficient favour b-arylation. A significant advance was made
olefins. When aryl halides are used, electron-rich ole- by Cabri, recording a/b-regioselectivities of >99/1
fins, such as acyclic enol ethers, silanes, and enol with acyclic enol ethers such as butyl vinyl ether in
amides, often suffer from poor a/b-regioselectivity, DMF; the key finding was to use bidentate ligands
producing a mixture of linear and branched re- and stoichiometric amounts of silver or thallium salts
gioisomers (Scheme 1). This problem thus hampers as halide scavengers, or replace the arylating halides
the applicability in synthetic chemistry.
with triflates.[4,5] The chemistry has since been applied
Whilst the use of electron-rich olefins in Heck ary- to a number of synthetic efforts.[1] A drawback to the
lation reactions is limited, progress made in this area chemistry is that triflates are base-sensitive, thermally
labile, and are rarely commercially available, and the
inorganic salt additives are costly and toxic. Hence,
there is a need for an alternative route that allows for
the use of aryl halides and circumvents the need for
the halide scavengers, while maintaining regioselectiv-
ity.
Scheme 1. Formation of regioisomers in the Heck reactions.
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The regioselective reactions observed with triflates shown by Santelli and co-workers.[10] As will be seen,
or halide scavengers can be rationalised by the mech- ionic liquids as solvent allow aryl bromides to be di-
anism shown in Scheme 2, in which two reaction path- rectly employed to give the a-products. Apart from
ways are suggested. Path A portrays the dissociation this advantage, there is a growing need to replace
of one neutral ligand, while path B is characterised by toxic and/or volatile organic solvents with eco-friendly
the dissociation of halide anions generating a cationic media. In this context, room temperature ionic liquids
Pd(II)-olefin complex, which is believed to be the key such as those based on imidazolium salts have been
species that gives rise to the a-regioselectivity.[4,5] Tri- recognised as a promising alternative to hazardous or-
flates or halide scavengers are expected to facilitate ganic solvents, due to the low vapour pressure and
the formation of the cationic palladium species and tuneable physiochemical properties.[11]
hence the a-arylated products. In our research into
catalysis in ionic liquids,[6] we thought that the forma-
tion of such ionic species might also be promoted by Results and Discussion
ionic liquid as solvent because this would be favoured
by electrostatic interactions.[6a] Indeed, we have found Following the successful arylation by aryl halides of
that several classes of electron-rich olefins can be ary- vinyl ethers and other electron-rich olefins in the
lated highly regioselectively in imidazolium ionic liq- ionic liquid [bmim]
[BF4],[6a–c,j] we were delighted to
G
uids by directly using aryl halides with no need for a find that the hydroxyalkyl vinyl ether 2a could also be
halide scavenger.[6a–c,j] Similar results have also been arylated highly regioselectively, and the resulting
reported by other groups by using ionic liquid sol- products can cyclise to give cyclic ketals under the
vents.[7] Herein, we report that the Heck arylation of same conditions. To the best of our knowledge, this is
hydroxyalkyl vinyl ethers by aryl bromides can be car- the first time when a hydroxyalkyl vinyl ether is selec-
ried out in the ionic liquid 1-butyl-3-methylimidazoli- tively a-arylated by an aryl bromide without recourse
um tetrafluoroborate ([bmim]
esting cyclic ketal compounds in a highly selective vinyl ether 2a was carried out with a variety of aryl
manner. These ketals can be useful as intermediates bromides in [bmim][BF4], with all the reactions af-
A
AHCTREUNG
in the synthesis of anti-HIV agents or as protected fording the cyclic ketals that arise from the a-arylated
precursors for carbonyls.[8]
2a. In a typical reaction, a mixture of 1, 2a, NEt3,
Hallberg and Larhed and co-workers were the first Pd
A
ACHTREUNG
to report the highly regioselective arylation of hy- a certain period of time under an inert atmosphere,
droxyalkyl vinyl ethers to synthesise cyclic ketals, and standard work-up afforded the product 3. The re-
using aryl triflates in DMF.[9] Aryl bromides and io- sults obtained are summarised in Table 1. All the re-
dides were also used; but these required the addition actions finished in>99/1 regioselectivity in favour of
of TlOAc and tend to afford slow arylation.[9] When the branched products with good to excellent yields.
aryl halides are used without the halide scavenger, hy- As can be seen, the reactions all completed within
droxyalkyl vinyl ethers can be arylated highly regiose- 24 h, regardless of the nature of the substituents on
lectively in DMF to give the b-arylated products by the aryl rings, e.g., compare entry 2 with entry 9. A
using a tetradentate phosphine-palladium catalyst as notable example is the coupling of 1c, which provides
Scheme 2. The suggested neutral and cationic pathways of the Heck reaction.
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Cyclic Ketals from Electron-Rich Olefins and Aryl Bromides in Ionic Liquids
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Table 1. Regioselective arylation of hydroxy vinyl ether 2a.[a]
[a]
Reaction conditions: 1.0 mmol 1, 2.0 mmol 2a, 3 mol% Pd(OAc)2, 6 mol% DPPP, and 1.5 mmol NEt3 in 2 mL [bmim]
[BF4] at 1158C; 100% conversion and>99/1 regioselectivity for all, as determined by H NMR; isolated yields.
A
1
a protected ketone and thus enables further elabora- cyclise to give 3 with no need for an acid to be added.
tion on the more reactive aldehyde. As aforemen- HOAc is sometimes necessary for the reactions in
tioned, similar coupling of aryl halides has been conventional solvents.[9]
shown to be feasible in DMF by Hallberg and Larhed
Under the same reaction conditions, the hydroxy-
and co-workers, but it requires stoichiometric TlOAc. alkyl vinyl ether 2b could also be arylated highly re-
In its absence, a mixture of a- and b-regioisomers was gioselectively, and the resulting products cyclise to
obtained.[9] In contrast, no halide scavenger is re- give the 7-membered cyclic ketals 4. The results ob-
quired here, and the reaction appears to be faster. It tained are summarised in Table 2. As can be seen, the
is also interesting to point out that the ionic liquid reaction is completed within 32 h, affording the cyclic
[bmim][BF4] allows the internal arylated product to ketals in good isolated yields.
G
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Table 2. Regioselective arylation of 1,4-butanediol vinyl ether 2b.[a]
[a]
Reaction conditions: 1.0 mmol 1, 2.0 mmol 2b, 3 mol% Pd(OAc)2, 6 mol% DPPP, and 1.5 mmol NEt3 in 2 mL [bmim]
[BF4] at 1158C; 100% conversion and>99/1 regioselectivity for all, as determined by H NMR; isolated yields.
A
1
The arylation of 2 presumably proceeds via the cat-
ionic pathway B (Scheme 2), and we believe that it is
the unique ionic property of the ionic liquid that
makes this possible. In accordance with the findings
made by Hallberg and Larhed,[9] the reaction first
leads to the arylation of 2, giving rise to an a-arylated
vinyl ether. This is followed by cyclisation to give the
cyclic ketals 3 or 4 (Scheme 3). Unlike the reaction in
Scheme 3. A possible sequence leading to the cyclic ketals.
The regioselective Heck arylation of 2a can also be
DMF, however, no additional Brçnsted acid is needed
for the cyclisation in [bmim][BF4]. In the latter, the
AHCTREUNG
reaction might be promoted by the ammonium salt
+
HNEt3 generated in the Heck coupling step or by
the Lewis acidic C2-H proton of the imidazolium performed in the ionic liquid [bmim][PF6]. [bmim]
U
cation. Hallberg and Larhed showed that NH4Br pro- [PF6] is known to readily form a triphasic system with
motes the cyclisation.[9] There may also exist a possi- water and non-polar solvents, which makes possible
bility of Pd(II)-catalysed cyclisation followed by pro- the recycle of catalyst.[12] As is shown in Scheme 4,
tonolysis to release the ketal.
when diethyl ether was used to extract the product
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Cyclic Ketals from Electron-Rich Olefins and Aryl Bromides in Ionic Liquids
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acetate and hexane (5/95 to 30/70) containing 2% (in
volume) triethylamine as eluant. The isolated yields of the
products are given in Table 1 and Table 2, and the analytical
details of the products are found in the Supporting Informa-
tion.
Recycle of the Palladium Catalyst and Ionic Liquid in
the Heck Arylation
An oven-dried, two-necked round-bottom flask containing a
stir bar was charged with 2-bromonaphthalene 1j
Scheme 4. Catalyst and ionic liquid recycle in the arylation
of 2a.
(1.0 mmol), Pd
A
[bmim][PF6] (3 mL) under nitrogen at room temperature.
AHCTREUNG
Following degassing three times, 2-hydroxy vinyl ether 2a
(2.0 mmol) and NEt3 (1.5 mmol) were injected. The flask
was placed in an oil bath, and the mixture was stirred and
heated at 1158C. After a reaction time of 24 h, the flask was
removed from the oil bath and cooled to room temperature.
The resulting mixture was extracted with diethyl ether (5”
10 mL), and the rest of the mixture was washed with water
(3”10 mL). The recovered catalyst and ionic liquid were
ready for a next run. The diethyl ether was then washed
with water until neutrality, dried (Na2SO4), filtered, and
concentrated under vacuum. The cyclic ketal 3j was isolated
out of the crude product by flash chromatography on silica
gel using a mixture of ethyl acetate and hexane (10/90) con-
taining 2% (in volume) triethylamine as eluant. The isolated
yields of the products are given in Scheme 4.
and water to extract the ammonium bromide salt, the
catalyst and the ionic liquid [bmim][PF6] can be recy-
A
cled and reused for 8 times without significant loss of
their catalytic effect under the chosen conditions.
Conclusions
In summary, we have developed an efficient method
for the internal arylation of hydroxyalkyl vinyl ethers
by aryl bromides by using Pd-DPPP catalysis in the
ionic liquids [bmim]
N
N
sulting products cyclise in situ to give cyclic ketals in
good to excellent isolated yields, and the catalyst and
ionic liquid can be recycled. Although the detailed re-
action mechanism remains to be clarified, the Pd-
DPPP catalysis described here is typical of the Heck
reaction proceeding via the cationic pathway. As a
Acknowledgements
solvent made entirely of ions, the ionic liquid pro- We thank the ESPRC for financial support and Johnson Mat-
they for the loan of palladium.
motes this pathway and hence renders the addition of
halide scavengers totally unnecessary.
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An oven-dried, two-necked round-bottom flask containing a
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