HeckReactionandCinnamicAcid.pdf

The Heck Reaction and Cinnamic Acid

Synthesis by Heterogeneous Catalysis

PALLADIUM ON CARBON CATALYST GIVES IMPROVED PRODUCTION

By Valerie M. Wall, Amihai Eisenstadt, David J. Ager

and Scott A. Laneman

NSC Technologies, Mount Prospect, Illinois, U.S.A.

The Heck reaction for the construction of carbon-carbon bonds, using

palladium catalysts, is one of the most valuable strategies in organic chemistry

and appears frequently in the literature, usually as homogeneous catalysis.

In this review the progress made to date with this reaction is examined, together

with the most discussed aspects of the Heck reaction, including a description

of its mechanism and the conditions required for success. Some limitations to

the homogeneous reaction are mentioned with reasons for proceeding with

heterogeneous catalysts, in particular with palladium/carbon. Examples of

various heterogeneous Heck reactions are presented and work that we are under-

taking to develop methods for the production of cinnamic acids, useful as

substrates for the synthesis of “unnatural” amino acids, is discussed. Finally,

we present some results from our work using palladium/carbon catalysts for

heterogeneous Heck reactions.

The Heck reaction is considered to be one of

the more useful strategies in organic synthesis

for the construction of carbon-carbon bonds.

First discovered by Heck in 1968 (1), the reac-

tion involves the palladium-catalysed coupling

of aryl or alkenyl halides with alkenes, see

Scheme I. It has since been expanded to include

organometallic reagents (such as Grignard,

organolithium and organoselenium reagents),

aryl triflates, aryl diazonium salts, and boronic

acids and esters as substrates.

The reaction has been comprehensively

reviewed (2–7); indeed, a literature search for

the “Heck Reaction” showed 11 “hits” for the

initial period to 1980, 69 for 1981–1990, 279

for 1990–1995, and from 1995 to May 1999

this figure has increased to 419 (8).

The mechanism of the Heck reaction has been

the subject of intense study and the one that is

generally accepted is depicted in Scheme II

(3, 5–7). The catalytic cycle can be considered

in four stages:

(a) oxidative addition,

(b) co-ordination/insertion,

(d) regeneration of the Pd(0) species to com-

plete the catalytic cycle.

Traditionally, the Heck coupling reaction has

been catalysed by PdL 4 , PdCl 2 L 2 or Pd(OAc) 2

with two equivalents of added ligand (L).

Ligands employed in the Heck reaction include

1,10-phenanthroline derivatives (9, 10) and car-

benes (11, 12), but mono- and bidentate phos-

phines, such as PPh 3 or P( o -tolyl) 3 , are more

Scheme I

R = aryl, alkenyl; R 1 = aryl, alkyl, OR,

CO 2 R, etc; X = I, Br, OTf (triflate)

Platinum Metals Rev. , 1999, 43 , (4), 138 – 145

138

Scheme II

General mechanism for the

palladium-catalysed

Heck reaction

(a)

oxidative addition

(b)

co-ordination/insertion

(c)

-hydride elimination/

dissociation and

(d) regeneration of the Pd(0)

species

typical (4). The combined electronic and steric

properties of the ligand affect both the stabil-

ity of the intermediates as well as the activity

and selectivities of the palladium catalyst. For

the homogeneous reaction, the presence of lig-

ands is necessary on all complexes for oxidative

addition to occur, except on the most reactive

aryl iodides. It is noteworthy that the success of

cyclopalladated, phosphine-free, nitrogen-based

ligands in the Heck arylation has been reported

(13); these ligands have thermal and air stabil-

ity and in certain cases can deliver turnover num-

bers in excess of one million.

Whatever the chosen combination of palla-

dium complex and ligand, the catalytically active

species is assumed to be the 14-electron com-

plex Pd(0)L 2 ( 1 in Scheme II) (5, 6). Oxidative

addition of the alkyl or aryl halide can then

occur, at (a), to afford the trans -RPdXL 2 species,

2 , followed by loss of one of the ligands to cre-

ate a vacant site where alkene co-ordination can

occur, at (b). The co-ordinated alkene forms an

unstable s -bonded complex, and the desired

product is delivered after a b -hydride elimina-

tion, at (c). One problem that can arise with

couplings of unsymmetrical alkenes is that of

regioselectivity. This factor is considered to be

under steric control as the R group adds to the

less substituted carbon of the double bond of

the incoming alkene (3, 14). The regioselectiv-

ity of the Heck reaction has been demonstrated

to be highly dependent on the alkene substituents

and also on whether mono- or bidentate ligands

are chosen (5, 15, 16). The factors contribut-

ing to electronic control for a - or b -arylation

have been described and are discussed below

(15, 17).

The Role of the Counter Ion

The general mechanism of the Heck reaction

as shown in Scheme II has been modified inde-

pendently by Ozawa and Hayashi (18) and by

Cabri and Candiani (5) to define the role played

by the counter ion, X. Thus, the co-ordina-

tion/insertion process (b) in Scheme II can be

viewed as a combination of two separate path-

ways: (i) and (ii), as shown in Scheme III. In

pathway (i) of this model, X remains co-ordi-

nated throughout the cycle. This can occur when

X = halide and the alkene co-ordinates upon

the dissociation of one of the other ligands (L).

Alternatively, if the Pd-X bond is more labile,

as in the case where X is triflate, OTf, the lig-

ands remain bound, and alkene insertion occurs

at the site vacated by X, which results in a

cationic palladium complex (ii)a by pathway

(ii). Further studies have indicated that the reac-

tivities of the cationic complex (ii)a and

the neutral complex (i)a are dependent upon

the electronic nature of the alkene substrate.

Electron-rich alkenes react faster with cat-

ionic palladium complexes and conversely, the

Platinum Metals Rev. , 1999, 43 , (4)

139

Scheme III

The two possible reaction pathways showing the part played by the counter ion, X. In pathway

(i) if X = halide, the X remains co-ordinated to the palladium, and the ligand L dissociates;

while in (ii) if the Pd-X bond is more labile, such when if X = OTf, both ligands,

L, remain bound, with alkene insertion occurring at the site vacated by X

reaction of electron-deficient substrates is faster

when neutral palladium complexes are used (5,

15, 16). Also, the introduction of halide-remov-

ing agents, such as AgNO 3 or TlOAc allows

replacement of the strong Pd-X bond with a

more labile one. The effect of the leaving group

and of the alkene substituents on the coupling

reaction has been elucidated by Cabri and

Candiani by using the expanded co-ordina-

tion/insertion cycle, see Scheme III (5).

Åkermark and co-workers have also investi-

gated the effect of counter ions on the regio-

selectivity of the Heck reaction (16). The reac-

tion of a cationic Pd species with electron-rich

alkenes mainly results in a -substitution, whereas

b -substitution is the predominant reaction with

electron-poor substrates (16).

a wide range of both organic and inorganic bases

(NaOAc, NaHCO 3 and K 2 CO 3 ), in addition

to Proton Sponge ® (1,8-bis(dimethylamino)-

naphthalene) and Ag(I)/Tl(I) salts, have been

found effective (5). Common reaction tem-

peratures are between 60 to 150ºC, though this

range can vary considerably depending on the

reactants: some reactions of aryl iodides can be

carried out at room temperature, while aryl chlo-

rides are essentially unreactive at temperatures

below 120ºC. Most alkenyl and aryl halides,

however, do react at room temperature under

high pressure or with Jeffery’s phase-transfer

conditions ( vide infra ). Tertiary phosphines are

usually employed to maintain the stability of the

catalyst. (It is noted, however, that these phos-

phines can also react under the standard Heck

conditions to form a phosphonium salt (19). In

some cases, Pd-catalysed transfer of aryl groups

from the triarylphosphine to the substrate is

observed (3)).

Reaction Conditions

and General Trends

Conventionally, the Heck reaction is performed

by the combination of an appropriate alkenyl or

aryl halide (Scheme I) with a slight excess of the

alkene and a base, usually an amine in the pres-

ence of the Pd(OAc) 2 /triarylphosphine cata-

lyst system under an inert atmosphere. The most

commonly employed base is triethylamine, but

Substrates/Substituents

Used in the Heck Reaction

Aryl, heterocyclic, benzylic, and vinylic iodides

and bromides have been used as substrates (3,

4). A wide variety of substituents can be present

Platinum Metals Rev. , 1999, 43 , (4)

140

in the aryl halide, but with two limitations: (a)

halides in possession of b -hydrogens cannot

be used as they undergo elimination, and (b)

the utilisation of chloro- and fluoroarenes has

not been generally successful since these com-

pounds demonstrate considerably lower reac-

tivities than do their iodo and bromo counter-

parts (3, 5, 7). No examples of Heck reactions

which use aryl or alkenyl fluorides as substrates

have been documented to date, while tradi-

tionally, chlorides (other than benzylic chlo-

rides) require harsh conditions.

the preparation of aryl amines in high yield with

sodium tert -butyrate as base. The palladium-

catalysed P-C coupling reaction between selected

aryl iodides and primary and secondary phos-

phines has been described and yields for this

novel route to water-soluble phosphines are as

high as 98 per cent (24).

Solvents

A wide variety of solvents has also been inves-

tigated for use in the Heck reaction. Among the

more commonly used are dipolar aprotic sol-

vents, such as DMF, DMSO, N -methylpyrroli-

done (NMP) and acetonitrile. Other solvents

which can be used are methanol, hexamethyl-

phosphoramide, N , N -dimethylacetamide and

even water. In particular, the coupling of cyclic

alkenes and aryl iodides in high temperature

water was investigated, the reactions being per-

formed over 3 hours at 175 to 225°C and at

pressures £ 100 bar (25).

When fluorinated palladium complexes are

used as the catalyst, reactions can be performed

in supercritical carbon dioxide and with lower

catalyst loadings and temperatures (75 to 80ºC)

than are usually required for the Heck reaction,

giving yields of up to 96 per cent (26). One

unusual line of study made use of vodka as the

solvent and a commercial animal worm medi-

cine as the base (27)!

Heck couplings can also be performed under

phase-transfer conditions by the procedure devel-

oped by Jeffery, where the addition of quater-

nary ammonium salts, such as tetraalkylam-

monium chloride, bromide or hydrogen sulfate

caused an enhancement in both the reactivity

and the selectivity compared to the standard

Heck reaction (28–30). However, in general,

the combination of catalyst/base/salt must be

fine-tuned to obtain optimum conditions (31).

The Use of Aryl Chloride as Substrates

The use of aryl chlorides for industrial appli-

cation would be attractive as they are readily

available in bulk quantity and are much less

expensive than the equivalent iodo and bromo

compounds. Progress has recently been made

in this area and it has been established that the

Heck coupling of aryl chlorides can proceed,

with yields of 70 to 85 per cent in the presence

of sterically hindered, electron-rich phosphines,

in particular P( t -Bu) 3 and P(cyclohexyl) 3 . The

improved reactivities arise from the easier oxida-

tive addition of the aryl chloride to the more

electron-rich palladium centre (20). Other

examples of the use of aryl chlorides have been

given in a comprehensive review (21).

Selective coupling catalysed by Pd(OAc) 2

occurs at the iodo position when both bromo

and iodo substituents are present (22). The

bromo group can be subsequently reacted with

additional alkene if a triarylphosphine is added

to the Pd(OAc) 2 catalyst.

The utilisation of aryl and vinyl triflates as sub-

strates in the Heck reaction is now becoming

more frequent (5, 16, 18) and a selection of

alternate reactants have also been evaluated.

Coupling reactions with aryl diazonium salts

can be achieved at room temperature; these

include the reaction of endocyclic enecarba-

mates with aryl diazonium salts in place of ArX

(Ar = aryl), and allowed the production of some

pyrrolidine alkaloids and a novel C-aryl aza-

sugar (23).

The Heck reaction of various aryl bromides

with secondary amines has been employed for

Products from the Heck Reaction

The preparation of E -benzylidenesuccinate

diesters via the Heck coupling of aryl halides

and itaconic diesters has been reported.

Subsequent asymmetric hydrogenation of the

Heck product produces chiral 2-benzylsuccinic

acid derivatives, which are highly desirable

Platinum Metals Rev. , 1999, 43 , (4)

141

chiral building blocks (19).

The “unnatural” amino acid, 2,6-dimethyl- L -

tyrosine, was synthesised via Heck coupling of

the aryl component 3,5-dimethyl-4-iodo-phenyl

acetate and 2-acetamidoacrylate in acetonitrile

under reflux, to afford the coupling product in

85 per cent yield. An asymmetric hydrogena-

tion followed by hydrolysis then gives the desired

amino acid in 87 per cent yield (32).

loadings of between 0.02 and 0.18 per cent (34).

· Palladium catalysts supported on glass beads

in ethylene glycol have also been successfully

applied to the Heck reaction, with moderate

yields (27 to 75 per cent) and very low levels

of palladium leaching (35).

· Heterogeneous catalysts comprising poly-

mer-supported palladium and clay-supported

Pd-Ph 2 P-Si have been employed for the cou-

pling reaction (17, 36). However, drawbacks to

the Pd-Ph 2 P-Si systems include the large num-

ber of steps required in the preparation and the

use of costly phosphorus and silicon reagents.

· A palladium-copper-exchanged montmoril-

lonite K10 clay catalyst has been described,

which can catalyse the preparation of stilbene

from aryl halides and styrenes with yields as high

as 93 per cent (37).

· Another polymer-bound palladium catalyst,

(polymer)-phenyl-(1,10-phenanthroline)-pal-

ladium(0), has been found to couple various

substituted iodobenzenes and acrylamide suc-

cessfully, to produce cinnamamides (38). This

polymeric catalyst showed no decrease in activ-

ity after 10 recycles. In one example, the poly-

meric complex yielded the desired product,

whereas the equivalent homogeneous system

showed no reaction after 24 hours at 130ºC.

· Another novel heterogeneous catalyst sys-

tem, consisting of palladium-grafted molecular

sieves, has proved very successful for C-C bond

formation (39). For example, n -butyl acrylate

and 4-bromoacetophenone were coupled to

afford the cinnamic acid in 99 per cent yield

after 60 minutes (120ºC) with a turnover num-

ber (TON) of 5000 using 2 mol% of catalyst.

· Other attempts include the use of a palla-

dium species entrapped in various zeolites (40)

and supported Pd(0)/MO x catalysts, where MO x

= MgO, ZnO, CaO, TiO 2 , SiO 2 and Al 2 O 3 (41).

· A different approach has been taken by

Novartis AG, where palladium-catalysed cou-

pling occurred between terminal acetylenes and

alkenes with aryl iodides which were linked to

a polystyrene resin (42).

· Furthermore, a palladium/carbon (Pd/C)

catalyst has been employed for arylation reac-

tions of enol ethers (15, 43).

Heterogeneous Catalysis

in Heck Coupling Reactions

As palladium has a high susceptibility to poi-

soning, relatively large amounts of palladium

(1–5 mol%) must be employed to achieve

acceptable conversions. Thus, the use of het-

erogeneous catalysis is a very attractive indus-

trial alternative to homogeneous catalysis, due

to the ease of recovery (filtration) and recycling

of the metal.

Most examples of the Heck reaction in the lit-

erature are of homogeneous catalysis and

describe the use of organopalladium complexes

(usually with phosphine ligands, as previously

mentioned). However, in recent years, as indi-

cated by the quantity of reports in the literature,

there has been a growing interest in the het-

erogeneous variant of the Heck reaction. There

is still controversy as to the mechanism of this

reaction: whether it is still homogeneous, even

with a heterogeneous catalyst, and has just a

simple dissolution of metal from the catalyst

support. Examples of some systems, which have

been used with varying degrees of success, are

described below.

· The regiochemistry of the Heck reaction

catalysed by a supported palladium reagent has

previously been shown to depend on the char-

acteristics of the support material: acidic sup-

ports mainly resulting in linear product and basic

materials predominantly giving branched prod-

uct. Consequently, a catalyst system was devel-

oped where the regioselectivity of the Heck ary-

lation could be modified by the application of

an electrical potential to the catalyst (palla-

dium/graphite) (33).

· A palladium/porous glass catalyst has also

been used for Heck couplings, with palladium

Platinum Metals Rev. , 1999, 43 , (4)

142

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