Mizoroki-Heck reactions catalyzed by dichloro{bis[1- (dicyclohexylphosphanyl)piperidine]}palladium: Palladium nanoparticle formation promoted by (water-induced) ligand degradation

Article abstract of DOI:10.1002/adsc.201100646

The palladium-based dichlorobis[1-(dicyclohexylphosphanyl)piperidine] complex - [(P{(NC₅H₁₀)(C₆H₁₁) ₂})₂Pd(Cl)₂] is readily prepared in quantitative yield from the reaction of [Pd(cod)(Cl)₂] (cod=cycloocta-1,5-diene) with two equivalents of 1-(dicyclohexylphosphanyl) piperidine in toluene under N₂ within only a few minutes at room temperature. This complex is a highly active Heck catalyst with excellent functional group tolerance, which reliably operates at low catalyst loadings. Various activated, non-activated, deactivated, functionalized, sterically hindered, and heterocyclic aryl bromides, which may contain nitro, chloro or trifluoromethane groups, nitriles, acetales, ketones, aldehydes, ethers, esters, lactones, amides, anilines, phenols, alcohols, carboxylic acids, and heterocyclic aryl bromides, such as pyridines and derivatives, as well as thiophenes and aryl bromides containing methylsulfanyl groups have been successfully coupled with various (also functionalized) alkenes in excellent yields and selectivities (the E-isomers are typically exclusively formed) at 140 °C in the presence of 0.05 mol % of the catalyst in DMF. Even though lower catalyst loadings could be used for many electronically activated, non-activated and some electronically deactivated aryl bromides without noticeable loss of activity, the great advantage of the reaction protocol presented here lies in its reliability and general applicability, which allows its direct adoption to other aryl bromides without the neccessity of its modification. Experimental observations indicated that palladium nanoparticles are the catalytically active form. Consequently, whereas comparable levels of activity were observed for dichloro-bis(aminophosphine) complexes of palladium, a dramatic drop in activity was found for their phosphine-based analogue [(P(C₆H ₁₁)₃)₂Pd(Cl)₂]. Copyright

Full text of DOI:10.1002/adsc.201100646

FULL PAPERS
DOI: 10.1002/adsc.201100646
Mizoroki–Heck Reactions Catalyzed by Dichloro{bis[1-(dicyclo-
U
hexylphosphanyl)piperidine]}palladium: Palladium Nanoparticle
Formation Promoted by (Water-Induced) Ligand Degradation
Miriam Oberholzer,a Roman Gerber,a and Christian M. Frecha,*
a
Institute of Inorganic Chemistry, University of Zꢀrich, Winterthurerstrasse 190, CH-8057 Zꢀrich, Switzerland
Fax : (+41)-44-635-6802; phone: (+41)-44-635-4692; e-mail: chfrech@aci.uzh.ch
Received: August 11, 2011; Revised: September 30, 2011; Published online: February 23, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100646.
Abstract: The palladium-based dichlorobis[1-(dicy- cellent yields and selectivities (the E-isomers are typ-
clohexylphosphanyl)piperidine]
[(P{(NC5H10)(C6H11)2})2Pd(Cl)2] is readily prepared of 0.05 mol% of the catalyst in DMF. Even though
in quantitative yield from the reaction of lower catalyst loadings could be used for many elec-
[Pd(cod)(Cl)2] (cod=cycloocta-1,5-diene) with two tronically activated, non-activated and some elec-
complex
–
ically exclusively formed) at 1408C in the presence
N
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
equivalents of 1-(dicyclohexylphosphanyl)piperidine tronically deactivated aryl bromides without noticea-
in toluene under N2 within only a few minutes at ble loss of activity, the great advantage of the reac-
room temperature. This complex is a highly active tion protocol presented here lies in its reliability and
Heck catalyst with excellent functional group toler- general applicability, which allows its direct adoption
ance, which reliably operates at low catalyst loadings. to other aryl bromides without the neccessity of its
Various activated, non-activated, deactivated, func- modification. Experimental observations indicated
tionalized, sterically hindered, and heterocyclic aryl that palladium nanoparticles are the catalytically
bromides, which may contain nitro, chloro or tri- active form. Consequently, whereas comparable
fluoromethane groups, nitriles, acetales, ketones, al- levels of activity were observed for dichloro-bis(ami-
dehydes, ethers, esters, lactones, amides, anilines, nophosphine) complexes of palladium, a dramatic
phenols, alcohols, carboxylic acids, and heterocyclic drop in activity was found for their phosphine-based
aryl bromides, such as pyridines and derivatives, as analogue [(P
well as thiophenes and aryl bromides containing
methylsulfanyl groups have been successfully cou- Keywords: aminophosphines; C C bond formation;
ACHTGNURTNEN(UNG C6H11)3)2Pd(Cl)2].
À
pled with various (also functionalized) alkenes in ex- Heck cross-coupling; nanoparticles; palladium
Introduction
ample, the case for species [Pd
[Pd(PPh3)2A
(OAc)2].[3] Other systems, such as
The Mizoroki–Heck reaction belongs to an indispen- [Pd(OAc)2], serve as sources of palladium nanoparti-
ACHTUNGTERN(NUNG PPh3)4] or
G
AHCTUNGTRENNUNG
CHTUNGTRENNUNG
sable set of palladium-catalyzed cross-coupling reac- cles.[4] In the case of pincer-type complexes, which
tions and is nowadays the method of choice for the ar- have been introduced in the late 1990s as Heck cata-
ylation of alkenes (Scheme 1).[1] Various types of pal- lysts,[5–7] nanoparticles are generally considered to be
ladium complexes have been reported to promote the their catalytically active form, even though the often
vinylation of aryl halides, of which many follow the proposed controversial Pd(II)/Pd(IV) cycles still
“classical” Pd(0)/Pd(II) mechanism,[2] as it is, for ex- cannot be excluded completely as being operative.[8]
In contrast, recent experimental and computational
investigations indicated that pincer-type Pd(IV) inter-
mediates are thermally accessible and hence, are to
be considered as reactive intermediates in reactions
performed with aryl halides in polar, non-protic sol-
vents and at elevated temperatures.[9,10]
Scheme 1. General scheme of a Heck cross-coupling reac-
tion between an aryl bromide and an olefin.
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Although recent developments led to a considera- particles (nanoparticles were shown to be the catalyti-
ble increase in the activity of Heck catalysts, of which cally active form in the Suzuki reaction) as well as
some efficiently couple sterically hindered substrates being able to operate via homogeneous mechanisms,
or occasionally even aryl chlorides (in the absence of as it was recently demonstrated in Negishi cross-cou-
aryl bromide units) under mild reaction conditions, a pling reactions.[11] Consequently, whereas a similar
typical protocol for this reaction still requires pro- catalytic activity will be found for the aminophos-
longed reaction times and relatively high catalyst phine-based system when compared to their phos-
loadings. Moreover, in most cases only few reactions phine-based analogues in a homogeneous mechanism,
with rather simple substrates and coupling partners a significantly improved catalytic activity was expect-
have been tested. In addition, modified reaction con- ed to be obtained when palladium nanoparticles are
ditions (reaction temperatures, catalyst loadings, addi- the true catalytically active form. Experimental obser-
tives, e.g.) are often reported for different substrates, vations strongly indicate that palladium nanoparticles
which strongly limit their application in organic syn- are involved in the catalytic cycle of the Heck reac-
thesis or industrial processes. Furthermore, the cata- tion performed with complexes of type [(P-
lyst syntheses are often time consuming, difficult, and/
CAHUTGTNNERG{NU (NC5H10)3ÀnACHTUGNTRNE(NUGN C6H11)n})2Pd(Cl)2] (n=0–2) under the
or require the use of expensive starting materials and chosen reaction conditions and thus, provide a simple
many of these catalysts suffer from poor thermal sta- explanation why comparable catalytic activities were
bility, low functional group tolerance and/or sensitivi- found for the aminophosphine-based systems while a
ty towards both, air and moisture, and hence require dramatic drop in activity was found for their phos-
inconvenient inert-atmosphere techniques for their phine-based analogues.
successful use, which demonstrates the clear need for
more efficient and definitely more generally applica-
ble systems.
Results and Discussion
We report herein the catalytic activity of dichloro-
bis[1-(dicyclohexylphosphanyl)piperidine]palladium,
Catalyst preparation
[(P
ACHTUNGTRENNUNG{(NC5H10)ACHTUNGTRENNUNG(C6H11)2})2Pd(Cl)2] (1), in the arylation
of olefins performed with a wide variety of activated, Treatment of toluene suspensions of [Pd(Cl)2ACHTUNGTRENNUNG(cod)]
non-activated, deactivated and sterically hindered, (cod=cycloocta-1,5-diene) with two equivalents of 1-
functionalized as well as heterocyclic aryl bromides (dicyclohexylphosphanyl)piperidine under N2 at 258C
and various different types of olefins, which reliably exclusively and quantitatively yielded within few mi-
operates at low catalyst loadings and thus, demon- nutes the dichlorobis[1-(dicyclohexylphosphanyl)-
strates its general applicability in this process. We piperidine]
show that 1 is a highly efficient and extremely versa- [(PACTHUGNTRENNU{NG (NC5H10)ACHTGNUTRENNUNG
complex
of
palladium,
namely
(C6H11)2})2Pd(Cl)2] (1) (Scheme 2).[11a]
tile Heck catalyst with an excellent functional group
À
tolerance, which exclusively activates Caryl Br bonds
when bromochlorobenzenes were applied. Excellent
conversions and product yields were typically ob-
tained within a few hours of reaction time. Moreover,
the E-isomer of the arylated olefins is often exclusive-
ly formed. Even though extremely low catalyst load-
ings could be used for many of the cross-coupling re-
actions performed without loss of activity or reliabili-
ty, all the reactions examined have been described
with a single catalyst under uniform reaction condi-
tions (at 1408C in DMF and K2CO3 as solvent and
base and in the presence of 0.05 mol% of catalyst),
which allows a direct adoption of the reaction proto-
col presented here to other aryl bromides without the
Scheme 2. Synthesis of dichloro
AHCTUNGTRENNpGUN hanyl)piperidine]}palladium (1).
ACHTUNGTNER{NUNG bis[1-(dicyclohexylphos-
neccessity of its modification. Overall, 1 is nowadays Catalysis
one of the most effective and versatile catalyst for the
vinylation of aryl bromides and thus, a real alternative Complex 1 is a highly active, reliable, and versatile
to the currently applied Heck catalysts. Heck catalyst with excellent functional group toler-
Aminophosphine-based complexes of the type ance, that successfully couples a large variety of aryl
[(P{(NC5H10)3ÀnA(C6H11)n})2Pd(Cl)2] (n=0–2) were as- bromides which may contain nitro, chloro or trifluoro-
A
CHTUNGTRENNUNG
sumed to be ideal Heck catalysts, because they methane groups, nitriles, acetales, ketones, aldehydes,
proved to promote (in contrast to phosphine-based ethers, esters, lactones, amides, anilines, phenols, alco-
systems) efficiently the formation of palladium nano- hols, carboxylic acids, and heterocyclic aryl bromides,
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Mizoroki–Heck Reactions Catalyzed by DichloroACTHNUGRTENUNG{bis[1-(dicyclohexylphosphanyl)piperidine]}palladium
Table 1. Heck cross-coupling reactions between aryl bromides and styrene, catalyzed by 1.[a]
[a]
Reaction conditions: 1.0 mmol aryl bromide, 1.5 mmol olefin (relative to bromide), 2.0 mmolK2CO3, 2.5 mL DMF, cata-
lyst (0.05 mol%) added in solution (THF), reaction performed at 1408C. The conversions and product ratios (trans/gem/
cis) are determined by GC/MS, based on aryl bromide, isolated yields are given in brackets.
The product ratio refers to (trans-trans/trans-gem/trans-cis).
[b]
[c]
3.0 mmol of K2CO3 were used.
such as pyridines and derivatives, as well as thio- NEt3 and pyridine is not practical due to their ligating
phenes and aryl bromides containing methylsulfanyl properties and inhibits the catalysis efficiently. A simi-
groups with various (also functionalized) alkenes in lar effect was found by a change of solvent: while
excellent yields – generally within few hours at 1408C only a slightly lower catalytic activity was noticed in
in DMF and K2CO3 as solvent and base in the pres- NMP, replacement of DMF by (non-polar) p-xylene,
ence of only 0.05 mol% of catalyst. Exemplary cross- for example, leads to a dramatic drop of activity.
coupling reactions were performed with styrene Almost no catalytic activity was obtained when the
(Table 1) and its derivatives, such as 1-ethenyl-4- Heck reactions were performed in DMSO or n-buta-
methylbenzene, 1-ethenyl-4-methoxybenzene, 1-eth- nol. Finally, lowered reaction temperatures retard the
enyl-3-nitrobenzene, 1-ethenyl-3-chlorobenzene, 4- conversions significantly. However, when styrene was
ethenylphenyl acetate, 1-(benzyloxy)-4-ethenyl-2-me- allowed to react at 1408C in DMF and K2CO3 as sol-
thoxybenzene, and 1-ethenyl-2-methoxybenzene as vent and base in the presence of 0.05 mol% of cata-
well as 4-vinylpyridine (Table 2). Further reactions lyst with electronically activated non-ortho-substituted
have been performed with N,N-dimethylprop-2-enam- aryl bromides, the desired product was quantitatively
ide, 4-acryloylmorpholine (Table 3), and butyl prop-2- formed within 2 h (Table 1). Exemplary reactions
enoate (Table 4). Notably, the base, solvent and reac- have been performed with 1-bromo-4-nitrobenzene,
tion temperature strongly influence the conversion 1-bromo-4-fluorobenzene,
1-bromo-3-(trifluorome-
rates and yields: whereas best results were observed thyl)benzene, 1-(4-bromophenyl)ethanone, (4-
with K2CO3, for example, the use of K3PO4, sodium bromophenyl)ACTHNUGNRTE(NUG phenyl)methanone, and 3-bromoben-
acetate or potassium tert-butoxide is not appropriate zaldehyde as well as 1-bromo-3-(diethoxymethyl)ben-
and led to very low conversion rates and yields – zene, and 1-bromo-3-chlorobenzene, of which the
among other reasons, due to fast deposition of inac- latter exclusively yielded 1-chloro-3-[(E)-2-phenyl-
tive palladium black. Also the use of amines, such as ethenyl]benzene. Essentially the same conversion
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Table 2. Heck cross-coupling reactions between aryl bromides and derivatives of styrene, catalyzed by 1.[a]
[a]
Reaction conditions: 1.0 mmol aryl bromide, 1.5 mmol olefin (relative to bromide), 2.0 mmolK2CO3, 2.5 mL DMF, cata-
lyst (0.05 mol%) added in solution (THF), reaction performed at 1408C. The conversions and product ratios (trans/gem/
cis) are determined by GC/MS, based on aryl bromide, isolated yields are given in brackets.
Isolated as phenol.
[b]
[c]
3.0 mmol of K2CO3 were used.
rates and yields were achieved when non-activated (4-bromophenyl)methanol and 4-bromobenzoic acid,
aryl bromides were applied. Examples include reac- which were successfully converted into 4-[(E)-2-phe-
tions performed with bromobenzene and 1-bromo-4- nylethenyl]aniline, 4-[(E)-2-phenylethenyl]phenol, {4-
tert-butylbenzene. Slow but quantitative product for- [(E)-2-phenylethenyl]phenyl}methanol and 4-[(E)-2-
mation (24 h were required for full conversion) was phenylethenyl]benzoic acid, respectively. The product
noticed for the conversion of 5-bromo-2-benzofuran- yields were in all the reactions higher than 82%, of
1(3H)-one into 5-[(E)-2-phenylethenyl]-2-benzofuran- which the E-isomer was formed in >90%. The same
1(3H)-one. However, an excellent performance was yields but prolonged reaction times were noticed
also observed when aryl bromides with an increased when sterically hindered aryl bromides were applied:
electron density on the aryl unit were applied. Exem- For example, when 1-bromonaphthalene, 1-bromo-2-
plary reactions have been performed with 1-bromo-4- methylbenzene, methyl 2-bromobenzoate or 2-bromo-
methoxybenzene, 4-bromo-N,N-dimethylaniline as 1,3,5-trimethylbenzene were used as substrates, the
well as with 1-bromo-3,5-dimethoxybenzene, which respective coupling products were cleanly formed and
cleanly yielded the respective coupling products in could have been isolated in excellent yields. More-
almost quantitative yields. Further reactions have over, also heterocyclic aryl bromides were successfully
been performed with 4-bromoaniline, 4-bromophenol, used as substrates. Examples include reactions with 3-
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Mizoroki–Heck Reactions Catalyzed by DichloroACTHNUGRTENUNG{bis[1-(dicyclohexylphosphanyl)piperidine]}palladium
Table 3. Heck cross-coupling reactions between aryl bromides and N,N-dimethylprop-2-enamide, and 4-acryloylmorpholine,
catalyzed by 1.[a]
[a]
Reaction conditions: 1.0 mmol aryl bromide, 1.5 mmol olefin (relative to bromide), 2.0 mmolK2CO3, 2.5 mL DMF, cata-
lyst (0.05 mol%) added in solution (THF), reaction performed at 1408C. The conversions and product ratios (trans/gem/
cis) are determined by GC/MS, based on aryl bromide, isolated yields are given in brackets.
Isolated as the aldehyde.
[b]
[c]
3.0 mmol of K2CO3 were used.
bromopyridine and 3-bromoquinoline, which undergo were required for the latter. Essentially the same con-
clean and quantitative conversion into 3-[(E)-2-phe- version rates, product yields and selectivities were ob-
nylethenyl]pyridine and 3-[(E)-2-phenylethenyl]qui- tained when 4-ethenylphenyl acetate, 1-ethenyl-3-
noline within 8 h. The coupling products were isolated chlorobenzene, 1-ethenyl-4-methylbenzene, and 1-eth-
in almost quantitative yields. An excellent perfor- enyl-4-methoxybenzene – a styrene derivative with an
mance was also obtained when sulphur-containing increased electron density on the aryl unit – were
substrates were applied: For example, whereas 94% used as coupling partners. Exemplary reactions have
conversion of 2-bromothiophene into the respective been performed with electronically activated aryl bro-
coupling product was achieved in 8 h, 64% conver- mides, such as 1-bromo-4-fluorobenzene, 1-bromo-4-
sion into 3-[(E)-2-phenylethenyl]thiophene was ach- nitrobenzene, 1-(4-bromophenyl)ethanone, electroni-
ieved in 6 h with 3-bromothiophene as substrate. A cally deactivated 1-bromo-3,5-dimethoxybenzene, N-
similar performance was generally noticed when de- (4-bromophenyl)acetamide, 4-bromophenol as well as
rivatives of styrene were used as coupling partners sterically hindered 1-bromonaphthalene, 1-bromo-2-
(Table 2). For example, when 1-ethenyl-3-nitroben- methylbenzene, and 2-bromo-1,3,5-trimethylbenzene.
zene was used as coupling partner, complete and The same yields but retarded conversions have been
almost exclusive formation of the E-isomers was typi- noticed when the cross-coupling reactions were per-
cally achieved within 2 h. Exemplary reactions were formed with electron-rich olefins, such as 1-(benzy-
performed with bromobenzene, 1-bromo-3-chloroben- loxy)-4-ethenyl-2-methoxybenzene or sterically hin-
zene, and N-(4-bromophenyl)acetamide. High conver- dered olefins, like 1-ethenyl-2-methoxybenzene. Ex-
sions were also achieved when sterically hindered aryl emplary reactions have been performed with 1-(4-bro-
bromides, such as 1-bromo-2-methylbenzene or 4- mophenyl)ethanone, 3-bromobenzaldehyde 4-bromo-
bromo-3-methoxybenzaldehyde were coupled with 1- phenol, 1-bromo-2-methylbenzene, and 2-bromo-
ethenyl-3-nitrobenzene, which afforded 1-methyl-2- 1,3,5-trimethylbenzene. Further retardation was no-
[(E)-2-(3-nitrophenyl)ethenyl]benzene and 3-me- ticed with 4-vinylpyridine as coupling partner. For ex-
thoxy-4-[(E)-2-(3-nitrophenyl)ethenyl]benzaldehyde,
ample, reactions performed with 1-bromo-3-(trifluoro-
respectively, in 98 and 78% yields. However, whereas methyl)benzene, N-(4-bromophenyl)acetamide, 1-
formation of the former was complete after 2 h, 24 h bromo-4-methoxybenzene, 1-bromonaphthalene and
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Table 4. Heck cross-coupling reactions between aryl bromides and butyl prop-2-enoate, catalyzed by 1.[a]
[a]
Reaction conditions: 1.0 mmol aryl bromide, 1.5 mmol olefin (relative to bromide), 2.0 mmolK2CO3, 2.5 mL DMF, cata-
lyst (0.05 mol%) added in solution (THF), reaction performed at 1408C. The conversions and product ratios (trans/gem/
cis) are determined by GC/MS, based on aryl bromide, isolated yields are given in brackets.
3.0 mmol of K2CO3 were used.
[b]
1-bromo-2-methylbenzene quantitatively yielded the mobenzonitrile, 4-bromo-3-methoxybenzonitrile, 4-
coupling products within 6 h. It should be emphasized bromophenol, 4-bromobenzoic acid, 3-bromoquino-
À
that the Caryl Br bonds are exclusively activated when line and 2-bromothiophene, which in all the reactions
bromochlorobenzenes were applied. For example, examined exclusively yielded the E-isomers in excel-
when 2-bromo-1,4-dichlorobenzene was coupled with lent yields. For example, when N,N-dimethylprop-2-
1-ethenyl-4-methoxybenzene or 1-ethenyl-3-chloro- enamide was coupled with 3-bromobenzaldehyde,
benzene full conversion into 1,4-dichloro-2-[(E)-2-(4- (2E)-3-(3-formylphenyl)-N,N-dimethylprop-2-enamide
methoxyphenyl)ethenyl]benzene and 1,4-dichloro-2- was exclusively and quantitatively formed in 2 h. The
[(E)-2-(3-chlorophenyl)ethenyl]benzene was achieved isolated yield was 97%. Furthermore, whereas full
after 32 and 48 h, respectively. Similarly, 4-[(E)-2-(4- conversions of 1-bromo-4-nitrobenzene, 1-(4-bromo-
chloro-2-methylphenyl)ethenyl]pyridine was exclu- phenyl)ethanone, and ethyl 4-bromobenzoate into
sively and quantitatively formed within 16 h when 1- (2E)-N,N-dimethyl-3-(4-nitrophenyl)prop-2-enamide,
bromo-4-chloro-2-methylbenzene was coupled with 4- (2E)-3-(4-acetylphenyl)-N,N-dimethylprop-2-enamide,
vinylpyridine. Finally, when 2-bromo-1,3-dichloroben- and ethyl 4-[(1E)-3-(dimethylamino)-3-oxoprop-1-en-
zene was coupled with 1-ethenyl-4-methylbenzene, 1-yl]benzoate, respectively, were achieved within 1
80%
methylphenyl)ethen
24 h, while only ~4% of 1-chloro-2,3-bis[(E)-2-phe- anophenyl)-N,N-dimethylprop-2-enamide. The same
nylethenyl]benzene was detectable. yields but a slightly reduced catalytic activity were no-
conversion
into
1,3-dichloro-2-[(E)-2-(4- hour, a slightly prolonged reaction time (4 h) was re-
AHCTUNGTRENGNyUN l]benzene was achieved after quired for the quantitative formation of (2E)-3-(4-cy-
An excellent performance and thus, clean, quantita- ticed when sterically hindered aryl bromides were
tive and highly selective product formations within used as substrates. An excellent performance was also
short reaction times was generally observed when noticed with heterocyclic substrates, such as 2-bromo-
N,N-dimethylprop-2-enamide and 4-acryloylmorpho- thiophene and 3-bromoquinoline, which were smooth-
line were used as coupling partners (Table 3). Exem- ly converted into (2E)-N,N-dimethyl-3-thiophen-2-
plary reactions have been performed with electroni- ylprop-2-enamide and (2E)-N,N-dimethyl-3-quinolin-
cally activated, non-activated or deactivated aryl bro- 3-ylprop-2-enamide within only 4 and 2 h, respective-
À
mides, such as 1-bromo-4-nitrobenzene, 4-bromoben- ly. Exclusive Caryl Br bonds activation and thus, quan-
zonitrile, 1-(4-bromophenyl)ethanone, ethyl 4-bromo- titative formation of (2E)-3-(4-chloro-2-methylphen-
benzoate, 3-bromobenzaldehyde, 9-bromoanthracene, yl)-N,N-dimethylprop-2-enamide was observed in 16 h
and 1-(benzyloxy)-4-bromobenzene as well as with when 1-bromo-4-chloro-2-methylbenzene was applied.
sterically hindered, functionalized and heterocyclic The same performance was generally observed with
substrates, such as 1-bromo-2-methylbenzene, 2-bro- 4-acryloylmorpholine as coupling partner.
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Mizoroki–Heck Reactions Catalyzed by DichloroACTHNUGRTENUNG{bis[1-(dicyclohexylphosphanyl)piperidine]}palladium
Essentially the same performance was noticed with its formation could have been excluded. Indeed, ther-
butyl prop-2-enoate as coupling partner (Table 4). For mal treatment of DMF solutions of butyl prop-2-
example, when ethyl 4-bromobenzoate or 1-bromo-3- enoate (in the presence of K2CO3 but in the absence
(trifluoromethyl)benzene was coupled with butyl of aryl bromide and catalyst) afforded – among others
prop-2-enoate, ethyl 4-[(1E)-3-butoxy-3-oxoprop-1- – the same by-product, whose identity is unknown as
en-1-yl]benzoate and butyl (2E)-3-[3-(trifluorome- yet.
thyl)phenyl]prop-2-enoate were cleanly and quantita-
tively formed within only 30 min. Moreover, butyl
(2E)-3-(3-chlorophenyl)prop-2-enoate was exclusively Tandem Heck/Cyclization Reactions with 2-
and quantitatively formed in 30 min when 1-bromo-3- Iodophenols
chlorobenzene was used as substrate. A slightly re-
tarded conversion was noticed for 4-bromobenzoni- Impressively, when 4-bromophenol, an electronically
trile and 3-bromobenzaldehyde: Whereas full conver- deactivated aryl bromide was coupled with butyl
sion of the former into butyl (2E)-3-(4-cyanophenyl)- prop-2-enoate; full conversion into butyl (2E)-3-(4-
prop-2-enoate was achieved in 1 hour, 2 h were re- hydroxyphenyl)prop-2-enoate was achieved within
quired for the quantitative formation of butyl 3-for- only 30 min. In contrast, when 2-bromophenol was
mylbenzoate. The same yields but further retardations applied, only 15% conversion into butyl (2E)-3-(2-hy-
were noticed when non-activated and deactivated aryl droxyphenyl)prop-2-enoate was achieved within 24 h.
bromides, such as bromobenzene, 1-bromo-4-meth- Moreover, among other products, 20% of 2H-chro-
ACHTUNGTRENNUNGoxybenzene, 4-bromo-N,N-dimethylaniline or 1- men-2-one (coumarine) had formed, most probably
bromo-3,5-dimethoxybenzene were coupled with via cyclization of butyl (2E)-3-(4-hydroxyphenyl)-
butyl prop-2-enoate. Interestingly, even though com- prop-2-enoate. 2H-Chromen-2-ones, however, are im-
plete conversion of N-(4-bromophenyl)acetamide into portant synthetic targets, as they are integral parts in
butyl 4-(acetylamino)cinnamate was obtained and various complex natural products with pharmacologi-
thus, a product yield of 95% was achieved after 2 h, it cal activities, such as anticancer and anti-HIV activi-
is worth mentioning that GC/MS analysis of the reac- ty,[12] and also have been used as photostable laser
tion mixture (after 30 min) indicated the reversible dyes, luminescent probes, and triplet sensitizers.[13]
formation of potassium (1Z)-3-(acetyl{4-[(1E)-3- Apart from classical synthetic paths involving Perkin,
butoxy-3-oxoprop-1-en-1-yl]phenyl}amino)-1-butoxy-
Knoevenagel or Pechmann reactions, which suffer
prop-1-en-1-olate, a Michael-type product between from significant drawbacks, such as the need of harsh
potassium acetyl{4-[(1E)-3-butoxy-3-oxoprop-1-en-1- reaction conditions, multi-step procedures, inconven-
yl]phenyl}azanide, the deprotonated form of the Heck ient work-up procedures and stoichiometric amounts
product {butyl (2E)-3-[4-(acetylamino)phenyl]prop-2- of Lewis or inorganic acids, transition metal-catalyzed
enoate]} and butyl prop-2-enoate. However, when procedures have been developed to broaden their
sterically hindered substrates, such as 1-bromo-2- synthetic accessibility.
methylbenzene, 2-bromobenzonitrile or 1-bromo-2-
Nevertheless, many of these methods are limited in
methoxybenzene were coupled with butyl prop-2- scope and involve the functionalization of pre-formed
enoate retarded conversions were generally observed coumarine units or alkyne-based cyclizations,[14] this is
in the Heck reaction. Moreover, their conversion into why we were intrigued by the possibility to get a
butyl (2E)-3-(2-methylphenyl)prop-2-enoate, butyl direct synthetic access to 2H-chromen-2-one via
(2E)-3-(2-cyanophenyl)prop-2-enoate and butyl (2E)- Heck/lactonization sequences (Scheme 3) from 2-io-
3-(2-methoxyphenyl)prop-2-enoate, respectively, was dophenols and ethyl prop-2-enoate, for which higher
accompanied by the formation of a by-product (as in- conversion rates and cleaner product formations were
dicated by GC/MS analysis of the reaction mixtures). expected to be obtained when compared to reactions
Anyhow, since the by-product was in all these reac- performed with 2-bromophenols and butyl prop-2-
tions the same, the involvement of aryl bromides in enoate.[15] This was tested by thermal treatment of 2-
Scheme 3. 2H-Chromen-2-one formation via Heck/lactonization reaction sequences performed with 2-iodophenol and 3-io-
dobiphenyl-4-ol and ethyl prop-2-enoate at 1408C in DMF and K2CO3 as solvent and base in the presence of 0.05 mol% of
1.
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Miriam Oberholzer et al.
FULL PAPERS
iodophenol with an equimolar amount of ethyl prop- acid). Notably, benzofurans and their analogues con-
2-enoate in DMF and K2CO3 as solvent and base in stitute a large family of compounds with biological
the presence of 0.05 mol% of 1. Indeed, the respec- and pharmaceutical activity and hence, are important
tive 2H-chromen-2-one was exclusively formed in synthetic targets, which are typically prepared via oxi-
almost quantitative yield within 24 h. Moreover, ethyl dative cyclization of o-vinylphenols,[18] dehydrative
(2E)-3-(2-hydroxyphenyl)prop-2-enoate and ethyl cyclization of a-phenoxy ketones,[19] cyclization of o-
(2Z)-3-(2-hydroxyphenyl)prop-2-enoate, the respec- ynylphenol,[20] copper- or palladium-catalyzed O-ary-
tive Heck products were clearly identified as inter- lation of o-halobenzyl ketones[21] or intramolecular
mediate products, of which both isomers are fully con- McMurry couplings and Wittig reactions.[22] Palladi-
verted into coumarine by a non-catalytic, thermally-in- um-catalyzed syntheses of benzofuran and its deriva-
duced cyclization.[16] The same reactivity pattern and tives from 3-(2-hydroxyaryl)prop-2-enoates or 3-(2-
hence, formation of 6-phenyl-2H-chromen-2-one was hydroxyaryl)prop-2-enoic acids, however, have not
obtained when 3-iodobiphenyl-4-ol was applied. On been described so far and hence, are novel, offering a
the other hand, when Heck/cyclization reactions were new synthetic approach for this important class of
examined with electronically activated 1-(4-hydroxy- compounds from simple and readily available starting
3-iodophenyl)ethanone or methyl 4-hydroxy-3-iodo- materials. Further investigations are ongoing.
benzoate, not 6-acetyl-2H-chromen-2-one and methyl
2-oxo-2H-chromene-6-carboxylate, but 1-(1-benzofur-
an-5-yl)ethanone and methyl 1-benzofuran-5-carbox- Catalytic Performance
ylate were formed instead (Scheme 4). The substitu-
ent on the aryl unit apparently determines the reactiv- DichloroACTHNUTRGNEUNG{bis[1-(dicyclohexylphosphanyl)piperidine]}-
ity pattern of the alkyl 3-(2-hydroxyaryl)prop-2- palladium (1) belongs nowadays to the most active,
enoate intermediate and hence, the product forma- versatile, and convenient Heck catalysts reported,
tion: whereas for non-activated (and most probably enable a wide variety of aryl bromides, which may
also for deactivated) alkyl 3-(2-hydroxyaryl)prop-2- contain nitro, chloro or trifluoromethane groups, ni-
enoates an intramolecular lactonization process and triles, acetales, ketones, aldehydes, ethers, esters, lac-
consequently the formation of 2H-chromen-2-ones is tones, amides, anilines, phenols, alcohols, carboxylic
favoured, an intermolecular nucleophilic attack of hy- acids, as well as heterocyclic aryl bromides, such as
droxide anions (hydroxide ions are generated from pyridines and derivates, or thiophenes and aryl bro-
À
the equilibrium between HCO3 , OHÀ and CO2)[17] on mides with methylsulfanyl groups to be selectively
the carbonyl carbon atom and hence, the formation of coupled with various (also functionalized) olefins in
the respective 3-(2-hydroxyaryl)prop-2-enoates occur very high conversion rates and yields with only
when electronically activated 2-iodophenols were ap- 0.05 mol% of catalyst within a few hours in DMF at
plied. Subsequent formation of palladium olefin com- 1408C. Demonstration of such a broad functional
plexes of type A promotes an intramolecular cycliza- group tolerance and applicability of a single catalyst
tion and thus, the formation of intermediates of type under uniform reaction conditions is unprecedented.
B. Decarboxylation of B, promoted by the presence With this regard, it is important to note that although
of electron-withdrawing groups and subsequent re- catalyst loadings between 0.002 and 0.01 mol% could
ductive elimination yield the respective benzofuran. be used for most of the reactions performed with
The catalyst is most probably regenerated by reduc- electronically activated, non-activated and even some
tion of CO2 (and the formation of dianionic oxalic electronically deactivated aryl bromides without loss
Scheme 4. Palladium-catalyzed benzofuran formation via Heck/cyclization reaction sequences performed with (electronically
activated) 1-(4-hydroxy-3-iodophenyl)ethanone and methyl 4-hydroxy-3-iodobenzoate and ethyl prop-2-enoate at 1408C in
DMF and K2CO3 as solvent and base in the presence of 0.1 mol% of 1.
634
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Adv. Synth. Catal. 2012, 354, 627 – 641

Mizoroki–Heck Reactions Catalyzed by DichloroACTHNUGRTENUNG{bis[1-(dicyclohexylphosphanyl)piperidine]}palladium
of activity or reliability, catalyst loadings between 0.01 95% and reaction times between 36 h and one week.
and 0.05 mol% were required when sterically hin- This demonstrates on one hand the excellent catalytic
dered substrates were applied. Therefore, all the reac- activity of 1 but on the other hand also its long active
tions have been examined in the presence of lifetime and thus, the potential application of 1 in the
0.05 mol% of catalyst, as a universally applicable re- preparation of pharmaceutically active com-
action protocol is more attractive (than substrate-op- pounds.[23,24]
timized reaction conditions) for synthetic chemists or
industrial applications as this allows its direct adap- formed with aryl bromides more efficient than report-
tion to other substrates without the necessity of its ed for [Pd
(OAc)2],[25] [(PCNHCP)Pd(Cl)][Cl],[26]
modification. This is also the reason why all the reac- ({C6H3-2,6-[CH2P(i-Pr)2]2Pd(TFA)} (TFA=trifluoro-
tions have been described with 1, even though a
acetate),[5] [(C5H3N-2,6-(NHCMe)Pd(Br)]+,[6c] [(C6H4-
higher level of activity was often found for dichloro- 2-(CH2P
{bis[1,1’,1’’-(phosphanetriyl)tripiperidine]}palladium {OP(OAr)2}Pd(Cl)]2
Overall, 1 is in nearly all the coupling reactions per-
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
(t-Bu)2)Pd
E
[(C6H2-3,5-(t-Bu)2-2-
[28]
E
G
(2) when electronically activated or non-activated aryl PCP pincer complex ({C6H3-2,6-[OP
bromides or bromopyridines were used as substrates. Complex 1 is even more active than the very recently
The overall improved catalytic activity of 1 when reported systems like [(CNHCN)Pd
(fppz)] (fppzH=2-
compared with 2 {and dichloro-bis[1,1’-(cyclohexyl- [3-(trifluoromethyl)-1H-pyrazol-5-yl]pyridine) and
phosphanediyl)dipiperidine]palladium (3)} was attrib- trans-di(m-aceto)bis[2-diphenylphospino-2’-methylbi-
(iPr)2]2}Pd(Cl)).[6o]
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
uted to its higher stability, which results in a retarded phenyl]dipalladium.[29,30] On the other hand, the re-
palladium nanoparticle formation. Even though this cently published aminophosphine-based pincer com-
also leads to prolonged induction periods, the nano- plex [C6H3-2,6-{NHP(piperidinyl)2}2Pd(Cl)] shows a
particles are more active because their growth is higher performance when sterically hindered aryl bro-
slower and hence, their size smaller, which makes the mides were used as substrates.[7b] In contrast, 1 is
ratio between palladium on the outer rim and on the more efficient when electronically deactivated aryl
inside of the particles more favourable. Consequently, bromides (4-bromoanisole, e.g.) were applied or 4-vi-
whereas electronically activated and non-activated nylpyridine was used as coupling partner. However,
substrates or bromopyridines were more efficiently apart from comparisons with literature data, which al-
converted into the respective coupling products with ready indicated an improved catalytic activity and
2, significantly improved conversion rates and yields functional group tolerance of the aminophosphine-
were observed with 1 when electronically deactivated based system when compared to the above mentioned
or sterically hindered aryl bromides were applied. For catalysts, a comparative study with 1, [Pd
example, while full conversion of 1-bromo-3- [(C6H4-2-(CH2P(t-Bu)2)Pd(OAc)]2 was performed
(trifluoromethyl)benzene or 3-bromoquinoline into 1- with a series of randomly chosen aryl bromides and
ACHTUNGRTENN(UNG OAc)2] and
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
[(E)-2-phenylethenyl]-3-(trifluoromethyl)benzene and olefins at 1408C in DMF and K3CO3 as solvent and
3-[(E)-2-phenylethenyl]quinoline was achieved in 1 base in the presence of 0.05 mol% (relative to palladi-
and 7 h, respectively, with 1, only 30 min and 4 h were um) of catalyst. Indeed, this study impressively dem-
required to quantitatively form the cross-coupling onstrated that the aminophosphine-based catalyst is
products with 2. On the other hand, whereas 82% of superior to palladium acetate and Herrmannꢂs system
4-bromoaniline was converted into 4-[(E)-2- – at least under the reaction conditions applied.
phenylethenyl]aniline after 4 h with 1, only ~18% of Whereas almost complete product formations for the
G
the coupling product was achieved with 2. Similarly, cross-coupling of 1-bromo-4-methoxybenzene with
while 96% conversion of 2-bromotoluene into 1- styrene, and 4-bromobenzonitrile, 3-bromobenzalde-
methyl-2-[(E)-2-phenylethenyl]benzene was obtained hyde or 1-bromonaphthalene with butyl prop-2-
after 5 h with 1, only 60% conversion was achieved enoate were found for all examined catalysts, a signif-
with 2.
icantly higher catalytic activity of 1 when compared
The exceptional high catalytic performance of 1 in to [PdAHCTUNGTRENNUNG
(OAc)2] was generally noticed when sterically
the Heck reaction was demonstrated further in exem- hindered aryl bromides were applied: for example,
plary “large-scale” reactions, where bromobenzene while conversions of >90% into the respective cou-
(52.7 mL; 0.5 mol), 1-bromonaphthalene (70 mL; 0.5 pling products were achieved with 1 and ({C6H4-2-
mol) and electronically deactivated 4-bromoanisole [CH2PACHTNUGTRENNUG(t-Bu)2]PdACHTUNGTREN(NGUN OAc)}2) when 1-bromo-2-methyl-
(62.5 mL; 0.5 mol) were coupled with styrene (86 mL; benzene or 2-bromo-1,3,5-trimethylbenzene were cou-
0.75 mol) in 300 mL of DMF at 1408C in the presence pled with styrene, only 64 and 6% conversion into 1-
of K2CO3 (138 g; 1 mol) and only 0.0001 mol% methyl-2-[(E)-2-phenylethenyl]benzene and 1,3,5-tri-
(1 ppm) of catalyst. Impressively, 1,1’-(E)-ethene-1,2- methyl-2-[(E)-2-phenylethenyl]benzene, respectively,
diyldibenzene,
1-[(E)-2-phenylethenyl]naphthalene, was noticed when palladium acetate was applied. On
and 1-methoxy-4-[(E)-2-phenylethenyl]benzene all the other hand, whereas an almost quantitative con-
were exclusively formed in yields between 80 and version of ethyl 4-bromobenzoate into ethyl 4-[(E)-2-
Adv. Synth. Catal. 2012, 354, 627 – 641
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635

Miriam Oberholzer et al.
FULL PAPERS
phenylethenyl]benzoate
was
achieved
with Mechanistic Investigations
[PdACHTUNGTRENNUNG(OAc)2] and the aminophosphine-based palladium
system, only 66% of the coupling product was formed Although detailed mechanistic investigations have not
when Herrmannꢂs system was used as catalyst. Simi- been performed, the following experimental observa-
À
larly, while complete C C bond formations were tions clearly indicate the involvement of palladium
achieved with palladium acetate and 1 when 6-bromo- nanoparticles in the catalytic cycle of the Heck reac-
N-ethyl-N-phenylpyridin-2-amine was coupled with 4- tion. (i) Sigmoidal-shaped kinetics with induction pe-
vinylpyridine, 81% conversion into N-ethyl-N-phenyl- riods (typically between 10 and 20 min) were ob-
6-[(E)-2-pyridin-4-ylethenyl]pyridin-2-amine was ob- served in all the coupling reactions examined
tained
Moreover, a significantly improved catalytic activity mixtures of aryl bromide, olefin and catalyst led to
was found for 1 when compared to both, [Pd(OAc)2] decreased induction periods (due to faster catalyst
and ({C6H4-2-[CH2P(t-Bu)2]}Pd
(OAc)]2), when 5- degradation and thus,[33] faster palladium nanoparticle
with
(OAc)]2). (Figure 1).[32] (ii) The addition of water to reaction
({C6H4-2-[CH2PACTHUNGTRENNU(G t-Bu)2]}PdACTHUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
bromo-2-benzofuran-1(3H)-one or heterocyclic sub- formation) but was often found to be accompanied by
strates, such as 2-bromothiophene or 3-bromoquino- lowered product yields – most probably due to the
line were coupled with styrene: while the coupling formation of inactive palladium black.[34] (iii) The ad-
products were almost quantitatively formed with 1, dition of a large excess of metallic mercury to reac-
conversions between 50 and 75% have been obtained tion mixtures of aryl bromide, olefin and catalyst effi-
when palladium acetate or Herrmannꢂs system were ciently stopped catalysis and no product formation at
applied. Overall, the comparative study clearly dem- all was observed when Hg(0) was added at the begin-
onstrated that the aminophosphine-based palladium ning of the reaction.[35] Essentially the same observa-
complex 1 is indeed superior to both, palladium ace- tions were made when poly(4-vinylpyridine) (PVPy)
tate and Herrmannꢂs system – under the reaction con- (2% cross-linked with divinylbenzene) was used in-
ditions applied. In addition to the improved catalytic stead.[36] (iv) No product formation at all was ob-
activity of 1 in the Heck cross-coupling reaction fur- tained when 0.1 equiv. (relative to catalyst) of CS2
ther, great advantages when compared to palladium was present in the reaction mixtures. (v) Neither the
acetate and Herrmannꢂs system were noticed: 1 ex- conversion rates nor the product yields were affected
hibit an excellent functional group tolerance and by the presence of about 20 mol% (relative to aryl
hence, shows in contrast to Pd
[CH2P(t-Bu)2]}Pd(OAc)]2) a consistently high catalytic >0.1 mol% are not appropriate and lead to the fast
(OAc)2] and ({C6H4-2- bromide) of NBu4Br.[38] (vi) Catalyst concentrations
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
activity with all the aryl bromides tested, allowing the deposition of inactive palladium black. (vii) Whereas
conversion rates and yields of coupling reactions with comparable catalytic activities were observed for 1
other substrates to be much better predicted than it is and
the case for palladium acetate and Herrmannꢂs ne]}palladium (2), a reduced catalytic activity was no-
system. Finally it may be mentioned that comparisons ticed for dichlorobis[1,1’-(cyclohexylphosphanediyl)di-
with [Pd2A(dba)3]/P(t-Bu)3 (dba=dibenzylideneace- piperidine]palladium (3). A significant drop in activity
tone). for example, are not possible, as the Heck reac- was found for their phosphine-based analogue
tions are typically performed with aryl chlorides.[31]
[(P(C6H11)3)2Pd(Cl)2] (4), the most stable system of
Apart from the excellent catalytic activity and func- this series – another piece of evidence that dichloro-
tional group tolerance of dichlorobis[1-(dicyclohexyl- {bis[1-(dicyclohexylphosphanyl)piperidine]}palladium
dichloroACTHNGUTRENNU{G bis[1,1’,1’’-(phosphanetriyl)tripiperidi-
AHCTUNGTRENNUNG
C
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
phosphanyl)piperidine]palladium (1) in the Heck re- (1) is a pre-catalyst that is transformed into palladium
action, a further advantage of 1 (or aminophosphine- nanoparticles.[39] Indeed, their presence could be veri-
based systems in general) when compared to water-in- fied by analysis of the reaction mixture by a transmis-
soluble phosphine-based ligand systems includes their sion electron microscopy (TEM) equipped with an
sensitivity towards protons: It was recently demon- energy dispersive X-ray (EDX) analysator (Figure 2).
strated that dichloroACHTUNRGTNE{NUG bis[1-(dicyclohexylphosphanyl)-
piperidine]}palladium (1) degrades in the presence of
water in air at elevated temperatures into dicyclohex- Conclusions
ylphosphinate and other, insoluble, palladium-con-
taining products.[11a] In a similar way, treatment of 1 In conclusion, complex 1 is an extremely efficient,
with aqueous hydrochloric acid in air and thus, under versatile and reliable Heck catalyst with an excellent
work-up conditions led to a rapid catalyst degradation functional group tolerance, which enables us to selec-
and the formation of products which are easily sepa- tively and quantitatively couple a large variety of
rated from the coupling products – an often ignored electronically activated, non-activated, deactivated
but very important issue for the preparation of phar- and/or sterically hindered aryl bromides, which may
maceutically active compounds, e.g.
contain nitro, chloro or trifluoromethane groups, ni-
triles, acetales, ketones, aldehydes, ethers, esters, lac-
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Mizoroki–Heck Reactions Catalyzed by DichloroACTHNUGRTENUNG{bis[1-(dicyclohexylphosphanyl)piperidine]}palladium
Figure 1. Kinetics of the Heck reaction of 1-bromo-4-methoxybenzene with styrene in the presence and in the absence of ad-
ditives, catalyzed by 0.05 mol% of dichloroACTHNUTRGENUG{N bis[1-(dicyclohexylphosphanyl)piperidine]}palladium (1) at 1408C in DMF.
pyridines and derivatives, or thiophenes and aryl bro-
mides with methylsulfanyl groups that have been suc-
cessfully coupled with various olefins under uniform
reaction conditions, generally within only few hours
of reaction time in DMF and K2CO3 as solvent and
base at 1408C in the presence of only 0.05 mol% of
catalyst. Even though catalyst loadings between 0.002
and 0.01 mol% would be sufficient to achieve similar
conversions for many of the substrates tested, the
great advantage of the reaction protocol described
here lies in its general applicability, which allows a
direct adoption to other aryl bromides without the
neccessity of its modification. Overall, the demonstra-
tion of such a broad applicability in the Heck reaction
of a single catalyst under uniform reaction conditions
is unprecedented. Moreover, the coupling products of
all the reactions examined were cleanly formed and
hence, could have been isolated in good to excellent
yields. All the experimental observations indicate that
palladium nanoparticles are the catalytically active
form of the dichloro-bis(aminophosphine) complexes
1–3 and thus, provide a simple explanation why ami-
nophosphine-based complexes of palladium are supe-
rior to their phosphine-based systems when aryl bro-
mides are used as substrates.
Figure 2. TEM image showing palladium nanoparticles (as
indicated by EDX analysis) from the cross-coupling reaction
of 1-bromo-4-methoxybenzene with styrene, catalyzed by
0.05 mol% of dichloroACTHNUTRGENUG{N bis[1-(dicyclohexylphosphanyl)piperi-
dine]}palladium (1) at 1408C in DMF.
tones, amides, anilines, phenols, alcohols, carboxylic
acids, as well as heterocyclic aryl bromides, such as
Adv. Synth. Catal. 2012, 354, 627 – 641
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637

Miriam Oberholzer et al.
FULL PAPERS
(m, 16H), 1.98–1.29 (m, 24H); 13C{1H} NMR (CD2Cl2): d=
Experimental Section
3
1
219.0 (d, JP, C =10.5 Hz), 215.9 (d, JP, C =41.0 Hz), 209.5 (d,
2JP, C =10.9 Hz), 56.9, 47.2 (overlapping signals), 28.3, 26.8
(overlapping signals), 25.4, 23.1; IR (ATR): A1n(CO) =2007
cmÀ1; elemental analysis: calcd. for C27H40MoN4O4P: C
50.09, H 7.01, N 9.74; found: C 49.92, H 6.99, N 9.69.
General
All synthetic operations for the catalyst preparation were
carried out in oven-dried glassware using a combination of
glovebox (M. Braun 150B-G-II) and Schlenk techniques
under a dinitrogen atmosphere. Solvents were reagent grade
or better and freshly distilled under N2 atmosphere by stan-
dard procedures. All chemicals were purchased from Al-
drich Chemical Co. and used as received.
Data for 2: 31P{1H} NMR (CD2Cl2): d=131.2 [s, P-
1
(NC5H10)
G
3.33–2.79 (m, 12H), 2.46–1.38 (m, 29H); 13C{1H} NMR
(CD2Cl2): d=219.3 (d, 3JP, C =8.7 Hz), 216.7 (d, JP, C
37.6 Hz), 210.7 (d, 2JP, C =9.7 Hz), 57.0, 50.3, 35.7 (d, J=
29.2 Hz), 28.6, 27.6 (overlapping signals), 27.1 (overlapping
signals), 26.4, 25.4, 23.5; IR (ATR): A1n(CO) =2006 cmÀ1; ele-
mental analysis: calcd. for C25H41MoN3O4P: C 52.26, H 7.19,
N 7.31; found: C 52.42, H 7.39, N, 7.51.
Analysis
1H, 13C{1H}, and 31P{1H} NMR data were recorded at 500.13,
125.76 and 202.46 MHz, respectively, on a Bruker DRX-500
spectrometer or at 300.1, 121.5 and 75.4 MHz, respectively,
on a Varian Gemini spectrometer. Chemical shifts (d) are
expressed in parts per million (ppm), coupling constants (J)
are in Hz. The 1H and 13C NMR chemical shifts are reported
relative to tetramethylsilane; the resonance of the residual
Data for 3: 31P{1H} NMR (CD2Cl2): d=105.3 [s, P-
(C6H11)2]; 1H NMR (CD2Cl2): d=8.79 (broad s,
ACHUNTGRENN(UG (NC5H10)ACHTUNGTRENNGUN
1H), 3.20–2.79 (m, 8H), 2.02–0.89 (m, 34H); 13C{1H} NMR
(CD2Cl2): d=219.6 (d, 3JP, C =7.4 Hz), 216.1 (d, JP, C
33.8 Hz), 210.8 (d, 2JP, C =8.7 Hz), 57.3, 51.8, 39.1 (d, J=
14.0 Hz), 28.6 (overlapping signals), 27.7 (overlapping sig-
nals), 26.8, 25.5, 23.4; IR (ATR): A1n(CO) =2006 cmÀ1; ele-
mental analysis: calcd. for C26H42MoN2O4P: C 54.45, H 7.38,
N 4.88; found: C 54.19, H 7.30, N 4.79.
1
protons of the solvent was used as internal standard for H
(d=7.15 benzene, 5.32 dichloromethane) and all deuterium
solvent peaks for 13C (d=128.0 benzene, 53.8 dichlorome-
thane). All measurements were carried out at 298 K. Abbre-
viations used in the description of NMR data are as follows:
s, singlet; d, doublet; t, triplet; m, multiplet; br, broad. Ele-
mental analyses were performed on a Leco CHNS-932 ana-
lysator at the University of Zꢀrich, Switzerland. TEM-EDX
analysis was performed on a Tecnai G2 Spirit 120 kV (FEI,
Eindhoven, Netherlands) using an Oxford X-Max 80 EDX
Detector (Oxford Instruments, Oxfordshire, UK) at the
center for microscopy and image analysis at the University
of Zꢀrich, Switzerland
Data for 4: IR (ATR): A1n(CO) =2005 cmÀ1.[42]
General Procedure for Heck Cross-Coupling
Reactions
A round-bottomed flask was charged under N2 with the ap-
propriate olefin (1.5 mmol), aryl bromide (1.0 mmol), pow-
dered K2CO3 [347825; potassium carbonate – reagent grade,
ꢀ98%, powder, À325 mesh (Sigma–Aldrich), 2.0 mmol],
and 2.5 mL of DMF [33120; N,N-dimethylformamide –
puriss. p. a., ACS reagent, reag. Ph. Eur., ꢀ99.8% (GC)
(Sigma–Aldrich)]. The mixture was vigorously stirred and
heated to 1408C. Then the catalyst was added by syringe as
a solution (0.05 mol%, 0.1 mL of a 5ꢃ10À3 M THF solution).
Samples were periodically taken from the reaction mixture,
quenched with 1M aqueous HCl (or 1M NaOH when basic
functional groups are present), extracted with ethyl acetate,
and analyzed by GC/MS. At the end of catalysis, the reac-
tion mixtures were allowed to cool to room temperature,
quenched with 1M aqueous HCl (or 1M NaOH when basic
functional groups are present in the coupling products), and
extracted with ethyl acetate (3ꢃ25 mL). The combined ex-
tracts were dried (MgSO4) and evaporated to dryness. The
crude material was purified by flash chromatography on
silica gel, as necessary.
(C6H11)2]2}Pd(Cl)2) (1)[11a]
Preparation of ({PACHTUNGTRNNEUG[(NC5H10)ACHTUGNTRENNUGN
100 mg (0.35 mmol) of [Pd
10 mL of toluene. After the addition of toluene solutions
(10 mL) containing two equivalents of P(NC5H10)(C6H11)2,
ACHTUNGRTEN(NUNG cod)(Cl)2] were suspended with
G
ACHTUNGTRENNUNG
the reaction mixture was stirred for 10 min. Removal of the
volatiles under reduced pressure and the addition of pen-
tane, followed by filtration afforded the yellow, analytically
pure palladium complex 1 in almost quantitative yield.
31P{1H} NMR (C6D6): d=80.0 [s,
PACHTUGNERTNU(NG (NC5H10)ACTHNUGTREN(NNUG C6H11)2];
1H NMR (C6D6): d=3.21 (broad s, 8H), 3.62 (broad s, 4H),
3.32–2.28 (m, 4H), 1.95–1.16 (m, 48H); 13C{1H} NMR
(C6D6): d=51.8 (t, J=49.5 Hz), 35.9 (t, J=50.3 Hz), 30.4,
28.6, 27.5–27.2 (overlapping signals), 25.0.
Preparation of cis-
[(PACHTUNGTRENNUNG{(NC5H10)nACHTUNGTRENNUNG(C6H11)3Àn})CATHUNGTREN(NUGN NC5H10)Mo(CO)4] (1–3)
Acknowledgements
200 mg (0.52 mmol) of [Mo(CO)4ACHTUNGRTENUNG(NC5H10)2]2 were suspend-
ed in 5 mL of CH2Cl2. After the addition of an equimolar
amount of appropriate ligand (dissolved in CH2Cl2), the re-
action mixture was stirred for 15 min at 508C. Removal of
the volatiles under reduced pressure and the addition of
pentane, followed by filtration afforded the pale yellow, ana-
lytically pure molybdenum complexes 1–3 in almost quanti-
tative yields.
Financial support by the University of Zurich and the Swiss
National Science Foundation (SNSF) and the center for mi-
croscopy and image analysis at the University of Zꢀrich,
Switzerland for TEM-EDX measurements are acknowledged.
Data for 1: 31P{1H} NMR (CD2Cl2): d=140.6 [s, P-
1
A
638
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 627 – 641

Mizoroki–Heck Reactions Catalyzed by DichloroACTHNUGRTENUNG{bis[1-(dicyclohexylphosphanyl)piperidine]}palladium
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with an H2O content of up to 0.1% (~2.5 mL
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H2O relative to catalyst! In this respect it is worth men-
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with “anhydrous” DMF [227056; N,N-dimethylform-
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hexylphosphanyl)piperidine and tricyclohexylphosphine
are almost identical as are also their s-donor strengths
(as indicated by the CO stretching frequency of com-
A
with a water content of up to 0.005%, which corre-
spond to a ~30-fold excess relative to catalyst – still
enough for its degradation. The price difference of
these solvents, however, justifies the use of the former.
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reactions, where nanoparticles were found to be the
catalytically active form: J. L. Bolliger, C. M. Frech,
Adv. Synth. Catal. 2010, 352, 1075.
[35] For a comprehensive review article about the problem
of distinguishing true homogeneous catalysis from solu-
ble or other metal-particle heterogeneous catalysis
under reducing conditions see: J. A. Widegren, R. G.
Finke, J. Mol. Catal. A 2003, 198, 317, and references
cited therein.
(NC5H10)Mo(CO)4],[40] which is
plexes of type cis-ACHTNUTRGENNG[U (PR3)ACHTUNGTRENNUGN
indicative for the electron density at the metal cen-
ters).[41] Thus, a similar catalytic activity is expected to
be obtained for 1–4 when molecular mechanisms are
operative. In contrast, significantly different catalytic
activities are expected to be obtained when palladium
nanoparticles are involved in the catalytic cycle. Conse-
quently, the dramatic difference in activity of the di-
chloro-bis(aminophosphine)complexes 1–3 when com-
pared with their phosphine-based analogue was attrib-
uted to the significantly slower nanoparticle formation
(or when for the latter a molecular mechanism was op-
erative).
[40] A. L. Morris, J. T. York, J. Chem. Educ. 2009, 86, 1408.
[41] See Experimental Section.
[42] J. E. Cortꢇs-Figueroa, L. Santiago, M. S. Leꢈn, M. P. De
Jesffls, J. Coord. Chem. 1997, 41, 249.
[36] PVPy is a palladium trap, which can effectively inhibit
catalysis when nanoparticles are the catalytically active
form of a catalyst. Nevertheless, it should be mentioned
Adv. Synth. Catal. 2012, 354, 627 – 641
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