Mizoroki–Heck Cross-Coupling of Acrylate Derivatives with Aryl Halides Catalyzed by Palladate Pre-Catalysts

Article abstract of DOI:10.1002/ejic.201901075

The Mizoroki–Heck (MH) reaction involving aryl halides with various acrylates and acrylamides has been studied using air and moisture-stable imidazolium-based palladate pre-catalysts. These pre-catalysts can be converted into Pd-NHC species (NHC = N-heterocyclic carbene) under catalytic conditions and are capable of facilitating the Mizoroki–Heck reaction of aryl halides with various acrylates. The effects of solvent, catalyst loading, temperature and bases on the reaction outcome have been investigated. Various coupling partners were tolerated under the optimal reaction conditions catalyzed by palladate 1, [SIPr·H][Pd(η³-2-Me-allyl)Cl₂]. The efficiency of the optimized synthetic methodology was tested on various aryl halides and substituted acrylates as well as acrylamides. The MH reaction yielded the coupled products in good to excellent isolated yields (up to 98%).

Full text of DOI:10.1002/ejic.201901075

A Journal of
Accepted Article
Title: Mizoroki-Heck cross-coupling of acrylate derivatives with aryl
halides catalyzed by palladate pre-catalysts
Authors: Mohammad Islam, Fady Nahra, Nikolaos Tzouras, Assem
Barakat, Steven Patrick Nolan, and Abdullah Al Majid
This manuscript has been accepted after peer review and appears as an
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content of this Accepted Article.
To be cited as: Eur. J. Inorg. Chem. 10.1002/ejic.201901075
Link to VoR: http://dx.doi.org/10.1002/ejic.201901075

10.1002/ejic.201901075
European Journal of Inorganic Chemistry
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Mizoroki-Heck cross-coupling of acrylate derivatives with aryl
halides catalyzed by palladate pre-catalysts
Mohammad Shahidul Islam,[a] Fady Nahra,[b,c] Nikolaos V. Tzouras,[b] Assem Barakat,[a] Catherine S. J.
Cazin,*[b] Steven P. Nolan,*[a,b] and Abdullah Mohammed Al-Majid*[a]
Abstract: The Mizoroki-Heck (MH) reaction involving aryl halides
with various acrylates and acrylamides has been studied using air
and moisture-stable imidazolium-based palladate pre-catalysts.
These pre-catalysts can be converted into Pd-NHC species (NHC =
N-heterocyclic carbene) under catalytic conditions and are capable
of facilitating the Mizoroki-Heck reaction of aryl halides with various
acrylates. The effects of solvent, catalyst loading, temperature and
bases on the reaction outcome have been investigated. Various
coupling partners were tolerated under the optimal reaction
conditions catalyzed by palladate 1, [SIPr·H][Pd(ƞ3-2-Me-allyl)Cl2].
The efficiency of the optimized synthetic methodology was tested on
various aryl halides and substituted acrylates as well as acrylamides.
The MH reaction yielded the coupled products in good to excellent
isolated yields (up to 98%).
precursors in medicinal industry, as UV absorbers or as
molecular devices.[7-9]
In this regard, the design and implementation of new palladium
pre-catalysts have significantly improved the efficiency of
various cross-coupling reactions.[3,10-11] Pd-NHC catalysts are
among the most used nowadays for various cross-coupling
reactions, including carbon-nitrogen,[11a] carbon-carbon,[11b] and
carbon-sulfur[11c] bond formations as well as arylation of
ketones.[11d] Using these NHC-based palladium complexes,
several advances in the Mizoroki-Heck reactions have been
reported albeit to a lesser extent than other cross-coupling
reactions.[12]
Recently, palladate-NHC complexes, of the formula
[NHC·H]Pd(ƞ3-R-allyl)Cl2], have been described as bench-stable
and highly efficient pre-catalysts for several cross-coupling
reactions,[13] including a preliminary proof-of-concept in the
Mizoroki-Heck (MH) reaction.[13a] Their ease of access (one step
from commercially available materials) and ease of activation
(no need for additives or any prior activation as long as the
reactions are conducted under slightly basic conditions) make
them highly useful tool for the synthetic community.
Introduction
Palladium-catalyzed cross-coupling reactions are one of
the most effective synthetic approaches for the construction of
carbon-carbon bonds, sparking an ever-growing demand for the
development of new and more active catalysts, which can
operate under mild conditions.[1,2] Among these couplings, the
Mizoroki-Heck reaction has emerged as a highly useful synthetic
tool,[3] widely used in the medicinal,[4] fine-chemical[5] and
polymer chemistry sectors,[6] as well as in the synthesis of
natural products.[7] An interesting use of this strategy can be
found in a the report by Jiang and co-workers on the synthesis
of a retinoid x receptor antagonist, diazepinylbenzoic acid,
where the Mizoroki-Heck reaction was a determining step of the
synthetic strategy.[8] The direct cross-coupling of an
alkene/acrylate with an aryl/alkyl halide provides rapid access to
functionalized building blocks that are of great importance as
In this report, we describe the investigation/optimization of the
Mizoroki-Heck reaction starting from various aryl halides and
substituted acrylates as well as acrylamides, using NHC-based
palladate complexes, [NHC·H]Pd(ƞ3-R-allyl)Cl2], as pre-catalysts.
Results and Discussion
Based
on
our
previous
work,[13a]
1,
3-bis
(2,6-
diisopropylphenylimidazolidene (SIPr) was chosen as the
optimal NHC ligand for the palladate precursors. In this manner,
initial optimization was conducted using [SIPr·H][Pd(ƞ3-2-Me-
allyl)Cl2] (Pd-1) and [SIPr·H][Pd(ƞ3-cin)Cl2] (Pd-2). These pre-
catalysts were synthesized using our previously reported
procedure that makes use of simply grinding the corresponding
palladium precursors, [Pd(ƞ3-2-Me-allyl)(µ-Cl]2 or [Pd(ƞ3-cin)(µ-
Cl]2, with the imidazolium salt (SIPr·HCl).[13b] These two
palladates were initially tested in the Mizoroki-Heck reaction
involving 4-bromoanisole 1a and n-butyl acrylate 2a as standard
substrates (Scheme 1).
[a]
[b]
Prof. S. P. Nolan,* M. S. Islam, Dr. A. Barakat, Prof. A. M. Al-Majid
Department of Chemistry, College of Science
King Saud University, P.O. Box 2455
Riyadh 11451, Saudi Arabia
amajid@ksu.edu.sa
Dr. F. Nahra, N. V. Tzouras, Prof. C. S. J. Cazin, Prof. S. P. Nolan
Department of Chemistry and Centre for Sustainable Chemistry
Ghent University
Initially, the coupling reaction was conducted with 0.5
mol% of palladate (Pd-1 or Pd-2) in THF at 50 oC and at 100 oC
with 1.5 equiv. of K2CO3 as base (Table 1, entries 1-3). A 47%
Krijgslaan 281, S-3, 9000 Ghent, Belgium
Steven.nolan@ugent.be
https://www.nolan.ugent.be/
o
NMR conversion was observed at 100 C when Pd-1 was used
[c]
Dr. F. Nahra
Separation and Conversion Technology Unit
VITO (Flemish Institute for Technological Research)
Boeretang 200, B-2400 Mol, Belgium
(Table 1, entry 2). The use of Pd-2 gave lower conversions even
after increasing the catalyst loading to 1 mol% (Table 1, entries
3-4). Increasing the temperature, catalyst loading and base did
not lead to any improvement in the reaction outcome (Table 1,
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejic.201901075
European Journal of Inorganic Chemistry
FULL PAPER
entries 5-6). Upon conducting the reaction in DMF using Pd-1 as
catalyst, a 76% NMR conversion to 3a was obtained (Table 1,
entry 7). Of note, 2.0 equiv. of K2CO3 was used for the
remainder of the optimisation as it proved optimum.
Table 2. Catalyst loading and time optimisation.
Entries
Pd-1 (mol%)
Temp (oC)
100
Time (h)
20
Conv. (%)[b]
1[c]
2
0.5
1.0
1.3
1.4
1.4
1.5
2.0
1.4
1.4
1.4
1.4
36
76
88
99
99
96
90
51
73
98
-
100
20
3
110
20
4
110
20
5
100
20
6
110
20
Scheme 1. Selected palladate-catalyzed Mizoroki-Heck reaction using 4-
bromoanisole 1a and n-butyl acrylate 2a.
7
110
20
8
110
08
9
110
16
10
11
110
24
80
20
Table 1. Initial catalyst system screening.
Entries
Catalyst (mol%)
K2CO3
(equiv.)
Temp
(oC)
Conversion
(%)[b]
[a] Reaction Conditions: [SIPr·H][Pd(3-2-Me-allyl)Cl2] (Pd-1), K2CO3 (138 mg,
1 mmol), DMF (1 mL), 1a (0.5 mmol), 2a (0.5 mmol), at the indicated
temperature for the indicated time. [b] Conversion was determined by NMR
based on 4-bromoanisole disappearance. Value calculated from an average of
two reactions.
1[c]
2
Pd-1 (0.5)
Pd-1 (0.5)
Pd-2 (0.5)
Pd-2 (1.0)
Pd-1 (0.5)
Pd-1 (1.0)
Pd-1 (1.0)
Pd-2 (1.0)
1.5
1.5
1.5
1.5
2.0
2.0
2.0
2.0
50
-
100
100
110
110
110
110
110
47
25
32
48
40
76
10
Varying the solvent did not bring further improvement to
the reaction conversion (Table 3). However, an interesting
solvent choice, DMF/H2O, arose as an alternative reaction
media. Attempts to improve the conversion by varying the
solvent ratio proved moderately successful; only an optimal 81%
NMR conversion was achieved using a 2:1 DMF/H2O mixture at
3
4
5
6
o
100 C (Table 3, entry 11). Interestingly, when the reaction was
performed in acetone, two MH products were formed with 96%
total NMR conversion (74% mono-substituted and 22% di-
substituted). The isolated yields of both products were 65% and
18% for the mon-substituted (3a) and the di-substituted (3’a) MH
products, respectively.
7[d]
8[d]
[a] Reaction Conditions: [SIPr·H][Pd(3-2-Me-allyl)Cl2] (Pd-1), K2CO3, THF (1
mL), 1a (0.5 mmol), 2a (0.5 mmol) at the indicated temperature for 20 h. [b]
Conversion was determined by NMR based on 4-bromoanisole
disappearance. Value calculated from an average of two reactions. [c]
Reaction time was 16 h. [d] 1 mL of DMF was used.
Next, the MH reaction of 4-bromoanisol and n-butyl
acrylate was explored using several inorganic and organic bases
and the findings are presented in Table 4. Among the tested
inorganic bases (Na2CO3, NaOH, Cs2CO3, Li2CO3, KOH and
K2CO3), K2CO3 was found to be the most effective, yielding 99%
conversion to the desired product 3a (Table 4, entries 1-7).
Organic bases such as NEt3, NHEt2 and DBU were also tested
and found to be almost ineffective in this reaction (Table 4,
entries 8-10). The use of 2.0 equiv. of K2CO3 was shown to be
essential for achieving full conversion (Table 4, entries 11-12). In
an attempt to reduce the reaction temperature, the MH coupling
was conducted at 80 oC using LiCl and TBAI as additives (Table
4, entries 13-14). Even though, the addition of TBAI gave a high
conversion at this temperature, the obtained NMR spectra of the
crude clearly shower multiple products.
Next, the catalyst loading and time were investigated at
100-110 C. The catalyst loading was gradually increased from
o
0.5 mol% to 2.0 mol%, showing maximum NMR conversions
(99%) at 100 oC and 110 oC with 1.4 mol% of Pd-1 (Table 2,
entries 1-7). It should be noted that 20 h were needed for full
conversion; shorter reaction times led to a significant decrease
in conversion (Table 2, entries 8-10). Lowering the temperature
from 100 oC to 80 oC was also detrimental to the reaction
outcome, affording no conversion to the desired product (Table
2, entry 11).
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10.1002/ejic.201901075
European Journal of Inorganic Chemistry
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9
NHEt2
DBU
110
110
110
110
80
07
10
03
11[c]
12[d]
13
K2CO3
81
K2CO3
92
10
Table 3. Solvent and temperature screening.
K2CO3+LiCl (1 eq.)
K2CO3+TBAI (1 equiv.)
Entries[a]
Solvent
Temp (oC)
100
100
110
110
80
Conversion (%)[b]
14
80
95 (Not clean)
1
2
Acetone
74:22 (3a/3’a)
[a] Reaction Conditions: [SIPr·H][Pd(3-2-Me-allyl)Cl2] (Pd-1) (4.4 mg, 1.4
mol%), base (2.0 equiv.), DMF (1 mL), 1a (0.5 mmol), 2a (0.5 mmol), at the
indicated temperature for 20 h. [b] Conversion was determined by NMR based
on 4-bromoanisole disappearance. Value calculated from an average of two
reactions. [c] 1.5 equivalents were used. [d] 1.75 equivalents were used.
EtOH
-
3
H2O
15
4
DMSO
02
During the initial investigation, the optimal amount of n-
butyl acrylate was also investigated, demonstrating that using
the acrylate in excess significantly reduces the conversion.
Therefore, 1 equivalent of acrylate 2a was selected as the
optimal amount to be used (see Supporting Information).
5
DMF/H2O (1:1)
DMF/H2O (2:1)
DMF/H2O (4:1)
DMF/H2O (1:2)
DMF/H2O (1:4)
DMF/H2O (1:1)
DMF/H2O (2:1)
DMF/H2O (4:1)
DMF/H2O (1:2)
DMF/H2O (1:4)
not clean
6
80
not clean
7
80
not clean
Based on the above findings, the best conversion for the
Mizoroki–Heck reaction of 4-bromoanisol and n-butyl acrylate
8
80
not clean
o
9
80
08
59
was obtained at 100 C in DMF using 1.4 mol% of Pd-1 in the
presence of 2.0 eq. K2CO3. These optimized conditions were
then applied to various aryl halides (1a-h) and acrylates (2a-e)
(Scheme 2).
10
11
12
13
14
100
100
100
100
100
81
>99 (multiple products)
59 (multiple products)
58 (multiple products)
[a] Reaction Conditions: [SIPr·H][Pd(3-2-Me-allyl)Cl2] (Pd-1) (4.4 mg, 1.4
mol%), K2CO3 (138 mg, 1 mmol), solvent (1 mL), 1a (0.5 mmol), 2a (0.5
mmol), at the indicated temperature for 20 h. [b] Conversion was determined
by NMR based on 4-bromoanisole disappearance. Value calculated from an
average of two reactions.
Table 4. Base screening.
Entries[a]
Base
Temp (oC)
Conv. (%)[b]
1
2
3
4
5
6
7
8
Na2CO3
NaOH
Cs2CO3
Li2CO3
KOH
110
110
110
110
110
110
100
110
42
43
70
10
05
99
>99
16
Scheme 2. Substrate scope for the MH reaction with acrylate 2a-b.
K2CO3
K2CO3
NEt3
The reactions proceeded smoothly with n-butyl acrylate (2a) and
tert-butyl acrylate (2b), with the latter affording higher yields in
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10.1002/ejic.201901075
European Journal of Inorganic Chemistry
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most cases (Scheme 2). Para- and meta-methoxy-substituted
aryl halides were well tolerated under our reaction conditions,
affording 96%, 98%, 84% and 96% isolated yields for 3a, 3b, 3g
and 3h, respectively. In order to compare the palladate reactivity
with its neutral Pd-NHC analogue, 3a and 3b were again
synthesized using 1.4 mol% of [Pd(SIPr)(3-2-Me-allyl)Cl]
instead of palladate Pd-1, affording 72% and 78%, respectively.
This interesting result highlights the better efficiency of
palladates compared to their neutral Pd-NHC counterparts, in
accordance with our previous observations.[13] As for ortho-
substituted bromoanisole, only moderate yields were obtained
even after prolonged reaction times (40 h, 49% and 51% for 3e
and 3f, respectively). 4-bromotoluene was also tolerated,
affording excellent isolated yields with both acrylates (93% and
97% for 3i and 3j, respectively). Ortho-substituted bromo and
iodo anilines were also successfully coupled with both acrylates,
affording moderate to good yields of 3k and 3l. In this case, it
should be noted that higher yields were obtained when tert-butyl
acrylate was used. It should be noted that arylchlorides do not
lead to substantial yields of product using this protocol. The
issue of low reactivity in this MH reaction is something we are
examining at present. In order to confirm the reliability and
robustness of this MH procedure, the reaction was scaled up
tenfold, i.e. 5 mmol of 4-bromoanisole and 5 mmol n-butyl
acrylate, to afford 3a in 97% isolated yield. It should be
mentioned that in all cases where we did not obtain high yields
of the desired product, unconsumed starting materials were
observed.
observed (Scheme 3); mono-coupled MH product 4 (major) and
bis-coupled product 4’ (minor) (with yield ratios: 65%:17% for
4a/4’a; 68%:14% for 4b/4’b; 64%:24% for 4g/4’g; 56%:26% for
4h/4’h). The mechanism for the formation of compound 4’ is
shown in Scheme 4; after the 1st MH reaction affords product 4,
a double bond migration leads to intermediate 4”, which is then
subjected to a second MH coupling to afford the observed
product 4’. It should be noted that the addition of excess aryl
halide and/or the increase in catalyst loading in an attempt to
afford full conversion toward the bis-coupled product 4’, did not
lead to any significant improvement.
In the remaining cases (4c-f and 4i-j), moderate to good yields
were obtained of the desired mono-coupled products. As
observed previously, the coupling of ortho-substituted
bromoanisole with both methacrylates performed poorly,
affording 32 and 30% isolated yields of 4e and 4f, respectively,
even after prolonged reaction times (40 h).
Next, methacrylates 2c and 2d were used as coupling
partners (Scheme 3). Similar to what was previously observed,
aryl bromides and iodides were coupled with both methacrylates,
although only moderate isolated yields were observed in this
case.
Scheme 4. Proposed mechanism for the formation of the bis-coupled product
4’.
Next, we turned our attention to acrylamides as potential
coupling partners. Acrylamide scaffolds are typically present in
various anticancer agents,[14] and therefore, selective and
efficient access to this class of compounds would be highly
interesting. In this context, our newly optimized method was
applied for the coupling of aryl halides (1a-f) with acrylamide
(2e) to afford moderate to good yields of the coupled product 5a-
e (Scheme 5).
Scheme 3. Substrate scope for the MH reaction with methacrylate 2c-d.
Interestingly, when the coupling was performed with para or
meta-substituted bromoanisoles, two coupled products were
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10.1002/ejic.201901075
European Journal of Inorganic Chemistry
FULL PAPER
Scheme 5. Substrate scope for the MH reaction with acrylamide 2e.
Keywords: Mizoroki-Heck • Coupling • Palladate • aryl halide •
acrylate
Conclusions
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Sarlah, Angew. Chem. Int. Ed. 2005, 44, 4442-4489; e) J. Magano, J. R.
Dunetz, Chem. Rev. 2011, 111, 2177-2250; f) S. Würtz, F. Glorius, Acc.
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Stevens, F. Naud, M. Studer, S. P. Nolan, Org. Lett. 2003, 5, 1479-
1482; h) P. Ruiz-Castillo, S. L. Buchwald, Chem. Rev. 2016, 116,
12564–12649
In conclusion, the use of an easily accessible SIPr-based
palladate as pre-catalyst in the Mizoroki-Heck coupling reaction
was successfully demonstrated. Palladate pre-catalyst Pd-1
successfully promoted the coupling of aryl halides with acrylate
and methacrylate derivatives as well as acrylamide to afford the
desired coupled products (3, 4 and 5) in moderate to good yields,
in the presence of an inexpensive and mild base (i.e. K2CO3). It
should be noted that, contrarilyy to previous applications
involving palladates, Pd-1 no prior activation under the
described conditions is required. In some cases, the bis-coupled
products 4’ were observed, indicating that at some point an
isomerization of the double bond in 4 occurs; this implies that
three sequential reactions are occurring in the reaction mixture.
Further investigation into this reaction is ongoing in our
laboratories.
[2]
Science of Synthesis: N-Heterocyclic Carbenes in Catalytic Organic
Synthesis, vol 1 & 2 (Eds.: S. P. Nolan, C. S. J. Cazin) Thieme,
Stuttgart, 2016.
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Experimental Section
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General procedure for the Mizoroki-Heck reaction: In air, a vial was
charged with [SIPr·H][Pd(ƞ3-2-Me-allyl)Cl2] (Pd-1) (4.4 mg, 1.4 mol%),
K2CO3 (2.0 equiv.), DMF (1 mL) and
a magnetic stir bar. The
[9]
J. H. Kim, H. Lee, Chem. Mater. 2002, 14, 2270-2275.
corresponding aryl halide (0.5 mmol) was added followed by the
corresponding acrylate (1.0 equiv.), and the vial was then sealed with a
screw cap. The reaction was left to stir for 20 h at 100 °C. Afterwards,
distilled water (2 mL) was added and the products were extracted with
diethyl ether (3x3 mL). Finally, the products were isolated by flash
column chromatography. The isolated yields are average of two runs. All
the related supporting data are given in the Supporting Information.
[10] a) E. A. B. Kantchev, C. J. O'Brien, M. G. Organ, Angew. Chem. Int. Ed.
2007, 46, 2768-2813; b) G. C. Fortman, S. P. Nolan, Chem. Soc. Rev.
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2015, 7, 4021-4024; b) F. Izquierdo, C. M. Zinser, Y. Minenkov, D. B.
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Mizoroki-Heck reaction scale up: Following the general procedure,
[SIPr·H][Pd(ƞ3-2-Me-allyl)Cl2] (Pd-1) (44 mg, 1.4 mol%), K2CO3 (1.38 g,
2.0 equiv.), DMF (10 mL) were charged into oven dried 20 ml screwed
cap vial. 4-bromoanisol (0.93 g, 5 mmol) and n-butyl acrylate (0.64 g, 5
mmol) were added subsequently and the vial was closed and heated to
100 oC for 20 h. the reaction residue was purified by column
chromatography 100-200 mesh silica gel and EtOAc/n-hexane (3:97) to
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1
afford 3a in 1.13 g (97%) as a yellow liquid. H NMR (400 MHz, CDCl3):
δ (ppm) = 7.63 (d, J = 16.4 Hz, 1H, CH=CH), 7.47 (d, J = 8.8 Hz, 2HAr),
6.90 (d, J = 8.8 Hz, 2HAr), 6.31 (d, J = 16.4 Hz, 1H, CH=CH), 4.19 (t, J =
7.2 Hz, 2H, OCH2), 3.84 (s, 3H, OCH3), 1.64 – 1.70 (m, 2H, CH2), 1.40 –
1.46 (m, 2H, CH2), 0.96 (t, J = 7.6 Hz, 3H, CH3). 13C {1H} NMR (100 MHz,
CDCl3): δ (ppm) = 167.6 (C=O), 161.4 (OCAr), 144.3 (CH=CH), 129.8
(CAr), 127.3 (CAr), 115.9 (CH=CH), 114.5 (CAr), 64.4 (OCH2), 55.5 (OCH3),
30.9 (CH2), 19.3 (CH2), 13.9 (CH3).
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Acknowledgements
The authors gratefully acknowledge support from the Distinguish
Scientist Fellowship Program (DSFP) at KSU.
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10.1002/ejic.201901075
European Journal of Inorganic Chemistry
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Cross-coupling
Mohammad Shahidul Islam , Fady
Nahra, Nikolaos V. Tzouras, Assem
Barakat, Steven P. Nolan,* and Abdullah
Mohammed Al-Majid*
Page No. – Page No.
The Mizoroki-Heck reaction involving aryl halides with various acrylates and
acrylamides has been studied using air and moisture-stable imidazolium-based
palladate pre-catalysts.
Mizoroki-Heck cross-coupling of
acrylate derivatives with aryl halides
catalyzed by palladate pre-catalysts
This article is protected by copyright. All rights reserved.