Dehydrative cross-coupling reactions of allylic alcohols with olefins

Article abstract of DOI:10.1002/chem.201404026

The direct dehydrative activation of allylic alcohols and subsequent cross-coupling with alkenes by using palladium catalyst containing a phosphoramidite ligand is described. The activation of the allyl alcohol does not require stoichiometric additives, thus allowing clean, waste-free reactions. The scope is demonstrated by application of the protocol to a series allylic alcohols and vinyl arenes, leading to variety of 1,4-diene products. Based on kinetic studies, a mechanism is proposed that involves a palladium hydride species that activates the allyl alcohol to form the allyl intermediate.

Full text of DOI:10.1002/chem.201404026

DOI: 10.1002/chem.201404026
Communication
&
Cross-Coupling
Dehydrative Cross-Coupling Reactions of Allylic Alcohols with
Olefins
Yasemin Gumrukcu, Bas de Bruin,* and Joost N. H. Reek*[a]
use of at least one (pre- or in situ) stoichiometrically activated
Abstract: The direct dehydrative activation of allylic alco-
reagent.[8] For instance, nickel-catalyzed coupling of ethylene
hols and subsequent cross-coupling with alkenes by using
and allylic ethers produces the corresponding 1,4-dienes only
palladium catalyst containing a phosphoramidite ligand is
in the presence of triethylsilyltrifluoromethanesulfonate
described. The activation of the allyl alcohol does not re-
(Et3SiOTf) and triethylamine.[9] An iridium-catalyzed coupling
quire stoichiometric additives, thus allowing clean, waste-
protocol was reported that used potassium trifluoroborate
free reactions. The scope is demonstrated by application
substituted alkenes that were coupled to secondary allylic al-
of the protocol to a series allylic alcohols and vinyl arenes,
cohols, nBu4NHSO4 being used as an activator.[10] Herein, we
leading to variety of 1,4-diene products. Based on kinetic
report the first example of a Pd-catalyzed dehydrative alkene–
studies, a mechanism is proposed that involves a palladi-
allyl cross-coupling reaction between non-activated allylic alco-
um hydride species that activates the allyl alcohol to form
hols and vinyl arenes, in the absence of any stoichiometric acti-
the allyl intermediate.
vators (Scheme 1). The catalyst is a simple Pd catalyst, 1, based
on an accessible and scalable ligand, making this a versatile
and clean cross-coupling reaction.
Palladium-catalyzed cross-coupling reactions are commonly ap-
plied in the synthesis of natural products and complex biologi-
cally active compounds.[1] These catalytic processes are power-
ful methods to generate various synthetic building blocks in
an efficient and selective manner, and as such, find wide appli-
cation in the fine chemical and pharmaceutical industries.[2]
Scheme 1. Direct dehydrative cross-coupling of allylic alcohols with vinyl
arenes using a simple, accessible catalyst.
Among the latest developments are cross-coupling reactions
involving non-activated (and preferably abundant) substrates,
leading to low-waste processes with high atom economy.[3] To
Catalyst 1 (Figure 1) was developed previously in our group
this end, allylic alcohols, which are abundant structural motifs
for CÀC and CÀN bond-forming reactions by using allylic alco-
in renewables, are attractive substrates for direct use in allylic
alkylation reactions, producing only water as a side product.[4]
However, the CÀO bonds of allyl alcohols are rather difficult to
activate, and consequently, activators are typically used in (su-
per)stoichiometric amounts for the in situ activation of the
substrates. The use of activators obviously leads to waste pro-
duction, dodging any potential benefits of the direct use of
allyl alcohols.[5] Recently, our research group[6] and those of
others[7] reported catalyst systems that allow the direct activa-
tion of allylic alcohols in alkylation and amination reactions
without the need for stoichiometric activators. Coupling of sev-
eral aliphatic and aromatic allylic alcohols with a variety of dif-
ferent nucleophiles has been reported. However, thus far,
cross-coupling of allylic alcohols with olefins is limited to the
hols, affording linear alkylated and aminated products in high
yields and selectivity.[6] Notably, the activity of 1 was higher in
the presence of 1,3-diethylurea (3 mol%), the high activity
being attributed to the hydrogen bond assisted activation of
the allylic alcohol to form the p-allyl Pd complex. This was the
starting point of the current study.
Initial experiments were focused on the cross-coupling of
cinnamyl alcohol (2) with styrene (3a), with solvent, ligand,
and temperature being varied (Table 1). Under the standard re-
action conditions, previously optimized for allylic alkylation re-
actions (toluene, 808C, 3 mol% 1,3-diethylurea), we were de-
lighted to find the coupled product being formed in 31% yield
[a] Y. Gumrukcu, Prof. Dr. B. de Bruin, Prof. Dr. J. N. H. Reek
Van’t Hoff Institute for Molecular Sciences
University of Amsterdam
Science Park 904, 1098 XH, Amsterdam (The Netherlands)
Fax: (+31)20 525 5604
E-mail: b.debruin.@uva.nl
j.n.h.reek@uva.nl
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404026.
Figure 1. Schematic representation of catalyst 1 and the phosphoramidite
ligand, L, used in this study.
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much lower compared to the use of ligand L (see Figure 1 for
the structure of L; 100% after only 5 h; see Table 1, entries 14,
18, and 19).
Table 1. Pd-catalyzed cross-coupling of cinnamyl alcohol (2) and styrene
(3a): optimization of the reaction conditions and catalyst.[a]
Next, we briefly explored if Pd nanoparticles, possibly
formed under catalytic conditions, may be the active species.
For this purpose, a variety of commercially available Pd nano-
particles were used, as well as a series of Pd0 and PdII precur-
sors known to produce Pd nanoparticles under typical reaction
conditions (Table 2). Catalysis with the commercial BASF and
Lindlar’s nanoparticles did not show any formation of the 1,4-
diene product (Table 2, entries 1 and 2). The use of Pd(OAc)2
Entry
Solvent
Temp
[8C]
Time
[h]
Ligand
Yield[b]
[%]
1
2
3
4
5
6
7
8
toluene
heptane
1,4-dioxane
DMF
ClCH2CH2Cl
MeCN
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
80
80
80
80
80
60
60
60
60
60
60
14
14
14
3
3
3
3
5
14
14
14
18
18
L+1,3-diethylurea
L+1,3-diethylurea
L+1,3-diethylurea
L+1,3-diethylurea
L+1,3-diethylurea
L+1,3-diethylurea
L+1,3-diethylurea
L+1,3-diethylurea
L+1,3-diethylurea
L
L+1,3-diethylurea[c]
L+1,3-diethylurea[d]
L+1,3-diethylurea[e]
L
31
10
73
0
0
0
41
36
100
71
56
47
33
100
trace
trace
0
13
46
80
90
Table 2. Pd-catalyzed cross-coupling of cinnamyl alcohol (2) and styrene
(3a): control experiments with various Pd complexes and nanoparticles.[a]
100
120
120
120
120
120
120
100
120
100
120
120
9
10
11
12
13
14[f]
15
16
17
18
19
Entry
Temp
[8C]
Time
[h]
Catalyst
Yield
[%][b]
1
2
3
4
5
6
7
8
120
120
80
120
120
120
120
120
18
18
26
18
18
14
14
14
Pd-np-BASF (0.5% Pd)
Lindlar’s cat. (5% Pd)
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2/nBu4NCl
[Pd(dba)2]
0
0
0
0
0
0
0
44
monophos
monophos
xanthphos
PPh3
P(OtBu)3
[Pd2(dba)3]
[(h3-allyl)Pd(cod)]BF4
[a] Reaction conditions: cinnamyl alcohol (0.1 mmol), styrene (0.3 mmol),
3 mol% [(h3-allyl)Pd(cod)]BF4, 3 mol% 1,3-diethylurea (entries 1–9),
6 mol% ligand, 0.2m. [b] Yields are determined by 1HNMR spectroscopy
relative to the substrate and reaction intermediates. [c] 3 mol%.
[d] 6 mol%. [e] 10 mol%. [f] 0.12 mmol styrene added.
[a] Reaction conditions: Cinnamyl alcohol (0.1 mmol), styrene (0.3 mmol),
3 mol% Pd precursor or nanoparticle as catalyst, 1,4-dioxane, 0.2m.
[b] Yields are determined by 1H NMR spectroscopy relative to the sub-
strate and reaction intermediates.
(Table 1, entry 1). The solvent has a large influence on the yield
of the reaction: by using N,N-dimethylformamide (DMF), 1,2-di-
chloroethane, CH3CN, toluene, and heptane, a low yield was
obtained; the highest yield (73% after 60 h) was obtained
when 1,4-dioxane was used (Table 1, entries 1–6). Further im-
provement of the reaction yield (100% after 14 h) was ach-
ieved by raising the reaction temperature to 1208C (Table 1,
entries 7–9). For the alkylation reaction, we previously found
an increase in reaction rate with increasing concentration of
urea additives. Interestingly, increasing the amount of 1,3-di-
ethylurea for the dehydrative cross-coupling reaction lowered
the yield significantly (from 71% (no urea) to 33% (10 mol%
urea) after 3 h; Table 1, entries 10–14). This negative effect sug-
gests that the activation of the allyl alcohol may be different
for this reaction compared to the previous reactions report-
ed.[6] Urea most likely competes for coordination with the
alkene substrate, thus perhaps leading to the inhibition of the
catalyst.
failed to generate the desired product, even in the presence of
a nanoparticle stabilizer, nBu4NCl, and at elevated tempera-
tures (Table 2, entries 3–5). Also the use of a Pd0 complex as
a precursor, [Pd(dba)2] and [Pd2(dba)3] (dba=dibenzylideneace-
tone), did not lead to formation of the diene product (Table 2,
entries 6 and 7). Only the use of [(h3-allyl)Pd(cod)]BF4 as a cata-
lyst resulted in the formation of the product in 44% yield, thus
suggesting that the allyl fragment at the Pd center plays a cru-
cial role. To further rule out the role of nanoparticles, we per-
formed selective poisoning experiments, which are commonly
applied to discriminate homogeneous and heterogeneous cat-
alyst species.[11] The addition of polyvinylpyridine (PVP; after
3 h), which is a selective poison for homogeneous catalysts,[12]
directly terminated the reaction. These experiments together
strongly indicate that Pd particles do not play a role in the cur-
rent reaction (see the Supporting Information for details). On
the basis of the combined results, we concluded that the
cross-coupling reaction proceeds via well-defined homogene-
ous Pd complexes, a conclusion that is also in line with the ki-
netic studies (see below).
Next, we explored some common phosphoramidite and
phosphine ligands that were used in combination with the
same Pd precursor, [(h3-allyl)Pd(cod)]BF4 (cod=1,5-cycloocta-
diene). The reaction with the monophos-based complex pro-
duced the expected product only in trace amounts, both at
100 and 1208C (Table 1, entries 15–16). The complex based on
bidentate ligand xanthphos did not show any formation of the
product (Table 1, entry 17). Some product formation was ob-
served by using triphenylphosphine (13%) or tri(tert-butyl)-
phosphite (46%), but the yields obtained after 18 h were
Once catalyst 1 was identified as an effective catalyst and
the reaction conditions were optimized, we explored the sub-
strate scope for the dehydrative cross-coupling reaction
(Table 3). The coupling of cinnamyl alcohol with styrene, which
was used as the model reaction, gave full conversion and af-
forded the product 4a in 90% yield upon isolation (Table 3,
entry 1). Substituted styrene derivatives, either with electron-
donating or electron-withdrawing groups, were also efficiently
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coupled to cinnamyl alcohol, generating the corresponding
1,4-dienes as the only products with full conversions. The
yields upon isolation were only moderate for these products
owing to losses during purification.[13] The use of electron-rich
p-methoxy and p-methylstyrene afforded the products 4b and
4c in 58% and 65% yields upon isolation, respectively,
(Table 3, entries 2 and 3); m-methylstyrene resulted in product
4d being isolated in 70% yield (Table 3, entry 4). The electron-
deficient substrates, p-fluoro and p-chlorostyrene, led to the
corresponding products being isolated in 55% (4e) and 66%
(4 f) yield, respectively (Table 3, entries 5 and 6).
The cross-coupling reaction was further extended to aliphat-
ic allylic alcohols, which are generally more challenging to acti-
vate than cinnamyl alcohol. Also, for these substrates, the reac-
tion with styrene derivatives resulted in the formation of the
corresponding 1,4-diene products, significantly broadening the
scope of this reaction (Table 4). The catalytic reaction of 2-
hexen-ol (5a) and p-methoxystyrene (3b) afforded product 6a
in 47% yield upon isolation as a single product (Table 4,
entry 1). Application of methyl-substituted allylic alcohols
(either at the 1- or the 3-position) generated two regioisomers.
These two products can be ex-
Table 3. Cross-coupling of cinnamyl alcohol with styrene derivatives[a]
Entry
Alkene
Product
Yield
[%][b]
1
2
3
4
5
90
58
65
70
55
6
66
[a] Reaction conditions: cinnamyl alcohol (0.1 mmol), styrene derivative
(0.12 mmol), 3 mol% catalyst 1, 1,4-dioxane, 0.2m, 1208C, 14 h. [b] Yield
of isolated product.
Table 4. Cross coupling of aliphatic allyl alcohols with styrene derivatives.[a]
plained by an isomerization of
the p-allyl intermediate involving
b-hydrogen elimination (see
below). The coupling reaction of
styrene with prenol, 5b, pro-
Entry
1
Alcohol
Alkene
Product
Yield
duced products 7a and 7b in
a 10:23 isomeric ratio and 30%
[%][b]
yield upon isolation (Table 4,
47
entry 2). Importantly, the cou-
pling of p-methoxystyrene, 3b,
with 5b resulted in a reaction
2
3
4
30 (19:23)
yield and product distribution
that was similar to that found
with the coupling with styrene
(8a and 8b; Table 4, entry 3).
The coupling of 3b with 5c,
32 (10:21)
which is an isomer of 5b, led to
the same products (8a and 8b)
but in a different product ratio
(1:1 compared to 10:21; Table 4,
38 (1:1)
entries 3 and 4). In line with this,
the coupling of 3b with the re-
gioisomeric alcohols, geraniol,
5d, and linalool, 5e, resulted in
products 9a and 9b in different
5
6
40 (10:8)
ratios (10:8 and 10:2, Table 4, en-
tries 5 and 6) and in moderate
yields upon isolation. This clearly
indicates that the regioselectivity
of the reaction depends on the
42 (10:2)
isomeric form of the starting al-
cohol.
To get insight in the reaction
[a] Reaction conditions: cinnamyl alcohol (0.1 mmol), styrene derivative (0.12 mmol), 3 mol% catalyst 1, 1,4-di-
oxane, 0.2m, 1208C, 14 h. [b] Yield of isolated product.
mechanism for these dehydra-
tive cross-coupling reactions, we
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performed kinetic studies (with cinnamyl alcohol and styrene
as model substrates) by monitoring the reaction progress in
time with 1H NMR spectroscopy. These experiments show
a zero order reaction rate dependence on the cinnamyl alcohol
concentration and a positive order dependence in [styrene]
(see the Supporting Information for details). Moreover, we ob-
served bis(cinnamyl)ether (2a) as a reaction intermediate,
which was consumed during the course of the reaction. In
a separate experiment, 2a was directly used as substrate for
the cross-coupling reaction with styrene. The reaction rate in
this experiment was identical to that of the coupling reaction
with cinnamyl alcohol, suggesting that under catalytic condi-
tions there is a fast equilibrium between cinnamyl alcohol and
the bis(cinnamyl)ether.
Most likely, according to kinetic experiments (zero order in [al-
lylic alcohol] and a positive order in [styrene]), the rate-deter-
mining step involves either coordination of styrene to the cata-
lyst, 1b, or the subsequent migration to the allyl fragment. No-
tably, the oxidation state of the Pd center remains the same (+
II) throughout the entire catalytic cycle.
Activation of the allyl alcohol by hydride species [(L)2PdH] to
form allyl intermediate 1b, which is the key step of the pro-
posed catalytic cycle, likely proceeds via the steps shown in
Scheme 3. Coordination and insertion of the C=C bond of the
substrate leads to a b-hydroxy-alkyl intermediate. Subsequent
b-hydroxy elimination[14] and intramolecular deprotonation of
the acidic allylic CÀH bond[15] by the hydroxo ligand then leads
to formation of 1b with elimination of water.
Based on these kinetic data, we propose the mechanism for
the dehydrative cross-coupling reactions shown in Scheme 2.
Starting from the p-allyl complex 1b, coordination and the
subsequent insertion of styrene gives intermediate 1c and 1d,
respectively. Subsequent b-hydride elimination and decoordi-
Scheme 3. Proposed allylic alcohol activation steps involving a Pd hydride
species. For clarity, we have neither indicated the charge of the Pd center
(cationic throughout the cycle), nor included the counterion (BF4À).
Other allyl alcohols most likely react in a similar manner as
the cinnamyl alcohol. The formation of two isomers when
methyl-substituted allyl alcohols are used is easily explained by
an isomerization process of the allyl moiety from allyl inter-
mediate 10 to allyl intermediate 11, involving b-hydride elimi-
nation at the methyl substituent (Scheme 4). This process is
likely preceded by formation of a s-allyl intermediate. Both the
linear and branched products derive from insertion of the vinyl
arene into the PdÀC bond of the allyl moiety at the least hin-
dered position. The linear product arises directly from 10,
while the branched product arises from isomerized allyl inter-
mediate 11. b-Hydride elimination following the vinyl arene in-
sertion step generates the observed products and regenerates
the Pd hydride intermediate.
Scheme 2. Proposed mechanism for the cross-coupling reactions of cinnam-
yl alcohol with vinyl arenes. For clarity, we have neither indicated the charge
of the Pd center (cationic throughout the cycle), nor included the counterion
(BF4À).
As noted, the linear to branched ratios depend on the iso-
meric form of the starting alcohol. The branched aliphatic alco-
nation gives product 4a and re-
active Pd hydride intermediate
1 f. After coordination of the
substrate to this species, the p-
allyl complex resting state 1b
can form. From p-allyl complex
1b, allyl ether 2a can be formed
after nucleophilic attack of the
cinnamyl alcohol. This reaction is
likely slow compared to the
product-forming pathway (as
formation of the ether is minor
compared to product formation,
and the ether in turn serves also
as substrate), and as such it does
Scheme 4. Proposed isomerization mechanism for the linear and branched products. For clarity, we have neither
not appear in the rate equation. indicated the charge of the Pd center (cationic throughout the cycle), nor included the counterion (BF4À).
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Experimental Section
Preparation of catalyst 1
Catalyst 1 was prepared by mixing phosphoramidite ligand, L,
(0.2 mmol) and [(h3-allyl)Pd(cod)]BF4 precursor (0.1 mmol) in 5 mL
dry dichloromethane. After stirring the mixture for 15 min at room
temperature, the solvent was evaporated under vacuum. Co-evap-
oration with dry toluene afforded catalyst 1 quantitatively.
General procedure for dehydrative cross-coupling reactions
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226, 101–110.
Cinnamyl alcohol, 2, (0.1 mmol), styrene, 3a, (0.12 mmol) and cata-
lyst 1 were added to a flame-dried Schlenk flask. The Schlenk flask
was flushed with argon before the solvent (1,4-dioxane, 0.5 mL)
was added and then placed into the preheated oil bath (80–
1208C). After the reaction was stopped the product was isolated in
pure form by column chromatography.
Acknowledgements
This research has been performed within the framework of the
CatchBio program. The authors gratefully acknowledge the
support of the Smart Mix Program of the Netherlands Ministry
of Economic Affairs and the Netherlands Ministry of Education,
Culture and Science.
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polarities, thus entailing
column chromatography.
a separation problem for purification by
´
´
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Keywords: alkenes
palladium · phosphoramidite
·
allylic alcohols
·
cross-coupling
·
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Received: June 19, 2014
Published online on August 11, 2014
Chem. Eur. J. 2014, 20, 10905 – 10909
www.chemeurj.org
10909
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