Selective Heck reaction of electron-rich aryl bromides with cyclic alkenones

Article abstract of DOI:10.1016/j.tetlet.2015.02.045

A simple and efficient protocol for the Heck reaction of cyclic alkenones with electron-rich aryl bromides has been developed. A ligand combination of X-Phos and tri-tert-butylphosphonium hydrogen tetrafluoroborate in the presence of Pd(PPh₃)

Full text of DOI:10.1016/j.tetlet.2015.02.045

Accepted Manuscript
Selective Heck reaction of electron-rich aryl bromides with cyclic alkenones
Tarak Nath Gowala, Jagadish Pabba
PII:
S0040-4039(15)00316-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.02.045
TETL 45914
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 January 2015
13 February 2015
14 February 2015
Please cite this article as: Gowala, T.N., Pabba, J., Selective Heck reaction of electron-rich aryl bromides with cyclic
alkenones, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.02.045
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Graphical Abstract
Selective Heck reaction of electron-rich aryl
bromides with cyclic alkenones
Leave this area blank for abstract info.
Tarak Nath Gowala and Jagadish Pabba ∗
Pd(PPh3)2Cl2 (5 mol%)
X-Phos (10 mol%), P(tBu)3.HBF4 (20 mol%)
Na
2CO3
(3 eq), DMSO, 100 oC, 12 h
n
45 - 86%
n

1
Tetrahedron Letters
journal homepage: www.els evier.com
Selective Heck reaction of electron-rich aryl bromides with cyclic
alkenones
Tarak Nath Gowala a and Jagadish Pabba a, ∗
a Syngenta Biosciences Private Limited, Santa Monica Works, Corlim, Goa, India 403110
ARTICLE INFO
ABSTRACT
Article history:
Received
A simple and efficient protocol for the Heck reaction of cyclic alkenones with electron-rich aryl
bromides has been developed. A ligand combination of X-Phos and tri-tert-butylphosphonium
hydrogen tetrafluoroborate in the presence of Pd(PPh3)2Cl2 and Na2CO3 in DMSO was found to
be efficient and selective for electron-rich aryl bromides with high substrate scope for cyclic
alkenones.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Heck reaction
electron-rich aryl bromide
cyclic alkenone
The Heck reaction is one of the most efficient palladium
catalyzed carbon-carbon bond forming reactions.1 Though Heck
reaction with diverse range of olefins is very popular in organic
synthesis, α,β-unsaturated ketones like cyclic alkenones are
challenging substrates due to the unfavorable stereo-chemical
orientation required for syn β-hydride elimination in the final step
of traditional Heck reaction pathway.2-5 There are a few literature
reports describing protocols for the Heck reaction of cyclic
alkenones with aryl iodides,2,3,5-7 aryl boronic acids under
oxidative conditions8 and other not readily available substrates.6,9
Heck reaction of cycloalkenones with readily available substrated
like aryl bromides10-13 is also not very well explored.
for such Heck reactions providing coupling product 3 in a
moderate yield of 40% (entry 2, Table 1).
Scheme 1
Table 1
1
2
3
Considering that addition of ammonium or phosphonium salts
sometimes improves yields of Heck reactions,1a,3,11,14 we then
explored the Heck reaction of cyclopentenone 1 with 2,4-
dimethoxybromobenzene together with ammonium and
phosphine additives (Table 1). Heck coupling product yield was
improved moderately (by about 25%) with tri-tert-
butylphosphonium hydrogen tetrafluoroborate (entry 9, Table 1)
while other ammonium salts did not improve the yield
significantly (entries 10-11, Table 1). Other protocols postulated
to involve Pd-colloids15 for efficient Heck coupling like Jeffrey’s
conditions16 (entry 13, Table 1) and de Vries protocol17 (entry 14,
Table 1) were also found to be unsuccessful.
Electron-rich aryl halides are known to be poor substrates in the
Heck reactions.1e,6 Development of efficient reaction conditions
for the Heck reaction with difficult substrates like cyclic
alkenones and electron-rich aryl halides is of interest. To our best
knowledge, a generic and efficient protocol for the Heck reaction
of electron-rich aryl halides with cyclic alkenones is not known
in literature. We report in this paper a simple and efficient
protocol for the Heck reaction of cyclic alkenones selective for
electron-rich aryl bromides.
We started with the catalyst screening by choosing the substrates
as
cyclopentenone (cyclic alkenone)
1
and 2,4-
Table 1: Catalyst screening with K2CO3 in N,N-
dimethylacetamide at 135 oC for 15
atmosphere.
dimethoxybromobenzene (electron-rich aryl bromide) 2 (Scheme
1). K2CO3 and N,N-dimethylacetamide were chosen as base and
solvent, respectively. Trials with a few palladium catalysts with
different ligand combinations (Table 1) suggested that
Pd(PPh3)2Cl2 together with X-Phos (2-dicyclohexylphosphino-
h
under nitrogen
Entry
Catalyst
Ligand
Additive
Yield
1
Pd(OAc)2
X-Phos
-
20
2′,4′,6′-triisopropylbiphenyl) ligand forms a good catalyst system
———
∗ Corresponding author. Tel.: +91-832-249-0537; fax: +91-832-249-0525; e-mail: jagadish.pabba@syngenta.com

2
Tetrahedron
40
tPBu3.HBF4 (1.15 mmol), Base (6.90 mmol), solvent (5 ml), 12 h, N2
2
3
Pd(PPh3)2Cl2
Pd3(dba)2
X-Phos
X-Phos
X-Phos
XantPhos
S-Phos
-
atmosphere.
-
20
It is worthwhile to note that the reaction is sensitive to the
quantity of phosphine additive improving the yield to 96% (entry
6, Table 3) when the phosphine was used in a stoichiometric
ratio. Based on the temperature screening and the best suited
additive loading, we fixed 0.2 equivalents of phosphine additive
in the presence of Pd(PPh3)2Cl2, X-Phos, and Na2CO3 in DMSO
4
Pd(dppf)Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(OAc)2
-
-
30
5
15
6
-
10
7
DavePhos
X-Phos
X-Phos
X-Phos
X-Phos
P(o-tol)3
-
<10
50
8
PPh3 (0.5 eq)
PBu3.HBF4 (0.5 eq)
Bu4NBr (0.5 eq)
Et4NCl (0.5 eq)
Bu4NBr (1.0 eq)
Bu4NBr (1.0 eq)
0
as solvent at 100 C (entry 1, Table 3) as our standard reaction
conditions for validating Heck reaction between cycloalkenones
and aryl bromides.
9
65
10
11
12a
13b
14c
52
45
Table 3: Additive screening
25
Entry
Ligand
X-Phos
X-Phos
X-Phos
-------
Additive
Temp.
100 oC
120 oC
100 oC
100 oC
80 oC
Yield (%)
Pd(OAc)2
traces
<10
mmol),
1
2
3
4
5
6
7
PtBu3.HBF4 (0.2 eq)
PtBu3.HBF4 (0.2 eq)
------
86
Pd(OAc)2
66
Reaction
conditions:
2,4-Dimethoxybromobenzene
(2.30
cyclopentenone (2.76 mmol), Catalyst (0.11 mmol), Ligand (0.22 mmol),
K2CO3 (6.90 mmol), DMA (5 ml), 135 oC, 15 h. a) Catalyst (0.02 mol%),
NaOAc (2.0 eq), Ligand (0.05 mol%) and Bu4NBr (1.0 eq)) in DMA (5 ml) at
130 oC, 12 h. b) Catalyst (0.05 mol%), NaHCO3 (2.5 eq), and Bu4NBr (1.0
eq)) in DMF (5 ml) at 100 oC, 12 h. c) Catalyst (0.05 mol%), and NaOAc (1.2
eq) in NMP (5 ml) at 130 oC, 12 h.
62
PtBu3.HBF4 (0.2 eq)
PtBu3.HBF4 (0.5 eq)
PtBu3.HBF4 (1.0 eq)
-------
68
X-Phos
X-Phos
-------
80
80 oC
96
<5
100 oC
We further optimized the reaction conditions by varying base,
solvent and temperature (Table 2). To our delight a combination
of Pd(PPh3)2Cl2, X-Phos and tri-tert-butylphosphonium hydrogen
Reaction conditions: 2,4-Dimethoxybromobenzene
2
(2.30 mmol),
cyclopentenone 1 (2.76 mmol), Pd(PPh3)2Cl2 (0.11 mmol), X-Phos (0.22
mmol), Additive (shown in table), Na2CO3 (6.90 mmol), DMSO (5 ml),
under nitrogen atmosphere, 12 h.
o
tetrafluoroborate in the presence of Na2CO3 in DMSO at 80 C
further enhanced the yield of Heck coupling product to 80%. It is
notable that DMSO is the most suitable solvent for this
transformation as demonstrated by the consistently high yields
with different bases with an additional advantage of lower
reaction temperature.
We then investigated the scope of aryl bromide substrates. A
range of electron-rich and electron-poor aryl bromides were
tested for Heck reaction with cylcopentenone 1 under our
standard reaction conditions. Results shown in the Scheme 2
suggest that these reaction conditions generally provide medium
to high yield of Heck coupling products with electron-rich aryl
bromides (5a-5c, 5f-5r).
Table 2: Solvent and base screening
Entry
1
Base
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOAc
Na2CO3
Cs2CO3
Ag2CO3
KF
Solvent
DMA
Temp
135 0C
100 0C
110 0C
80 0C
80 0C
135 0C
80 0C
80 0C
80 0C
80 0C
80 0C
80 0C
80 0C
80 0C
80 0C
80 0C
Yield%
Scheme 2
65
3
Pd(PPh ) Cl (5 mol%)
2
2
t
2
1,4-dioxan
toluene
acetonitrile
1,2-dichloroethane
DMF
5
3.
4
X-Phos (10 mol%), P(Bu) HBF (20 mol%)
Na CO
(3 eq), DMSO, 100 oC, 12 h
2
3
3
5
4
10
1
5
4
5
15
OMe
MeO
6
50
R2
MeO
7
DMSO
70
5a, 68%
5b, 58%
5d, 35%
5e, 0%
5c, 54%
R2 = 2-CF3, 3-CF3, 2-CN
2-NO2, 4-NO2
8
NMP
30
OMe
OMe
OMe
O
O
MeO
MeO
9
DMSO
20
OMe
MeO
5f, 86%
OMe
10
11
12
13
14
15
16
DMSO
DMSO
80
5g, 56%
5h, 52%
5i, traces
5j, 58%
15
Me
OMe
5k, 48%
5q,56%
Me
MeO
MeO
MeO
MeO
DMSO
15
Me
Me
t-Bu
OMe
DMSO
70
5l, 45%
5m, 77%
5n,52%
5o, 59%
5p, 54%
K3PO4
KOtBu
iPr2NEt
DMSO
10
DMSO
5
70
S
Me
N
MeS
O
2
MeO
C
2
5r, 62%
5s, 52%
5t, 48%
5u, <5%
DMSO
Whereas, electron poor aryl bromides bearing electron
withdrawing groups such as CF3, CN, NO2 and CO2Me (5e, 5u)
are not suitable substrates under these reaction conditions, in
Reaction conditions: 2,4-Dimethoxybromobenzene
2
(2.30 mmol),
cyclopentenone 1 (2.76 mmol), catalyst (0.11 mmol), ligand (0.22 mmol),

3
each case we isolated homo coupled products with minor
amounts of corresponding debrominated products. Simple
bromobenzene without any other substituent resulted in 35%
yield of the corresponding coupling product (5d).
undergo aryl-palladium insertion thus resulting in self coupling
or reduction products.
Scheme 4
Proposed hypothetical mechanism for the selective heck reaction of electron
rich aryl halides with cyclic alkenones
Steric hindrance seems to be detrimental as demonstrated by the
example of arylbromide with two ortho substituents (5i) which
gave only traces of coupling product. Electron-rich bicyclic
heteroaryl bromides (5s and 5t) also reacted under these
conditions providing medium yield (~50%) of coupling products.
P(tBu)3
Heck reaction protocol specific for electron-rich aryl bromides
reported here is complementary to the known methods for heck
coupling of aryl bromides with cyclic alkenones developed by
Santelli and coworkers12 which in our experience was found to be
selective for electron-poor aryl bromides. Our attempts at Heck
reaction of electron-rich substrates (5a, 5b and 5f) with
cyclopentenone 1 under Santelli and coworker’s conditions
oxidative
addition
aryl-palladium
insertion
P(tBu)3
(Bu3)P-Pd0-Ln
t
Pd0-Ln
t
( Bu)3P
o
(Pd(OAc)2, DMF, KF, 130 C, 20 h) resulted in poor yields. A
beta trans-elimination
closely related protocol for heck coupling of aryl bromides with
cyclic alkenones described by Wu et al.11 does not seem to
differentiate the electron-rich and electron-poor aryl bromides
while the catalyst system reported in this work does differentiate
between the electron-rich and electron-poor aryl bromides (5a,
5p and 5u).
:B
Scheme 3
t
(Bu)3P
P(tBu)3
Pd(PPh3)2Cl2 (5 mol%)
X-Phos (10 mol%), P(tBu)3.HBF4 (20 mol%)
Na2CO3 (3 eq), DMSO, 100 oC, 12 h
n
n
7
In summary, we developed a simple method for a selective Heck
reaction of two difficult coupling partners of electron-rich aryl
2
6
bromides and cyclic alkenones with diverse scope.
A
combination of X-Phos with tri-tert butylphosphonium hydrogen
tetrafluoroborate as ligands improved the Heck coupling yields.
This method could provide access to some of the difficult to
obtain building blocks which can be used for further
derivatisation with potential applications in medicinal- and agro-
chemistry.
7a, 86%
7b, 74%
7d, 0%
7c, 65%
7e, 50%
7f, 59%
7g, 48%
We next examined the substrate scope for cyclic alkenones
(Scheme 3). Different ring sizes varying from five to seven
membered cyclic alkenones reacted well with aryl bromides (7a-
7c) to provide Heck coupling products in 65-86% yield with 2,4-
dimethoxybromobenzene. Lactone group (7e and 7f) was also
Acknowledgments
tolerated, but resulted in
a slight reduction in yield.
We thank Dr. Guillaume Berthon for his comments and inputs
and Dr. Sudhindra Deshpande for analytical support. This work
has been completed as a part of the PhD Thesis (T. Gowala)
affiliated to the University of Mangalore with guidance from Dr.
Jagadish Pabba at Syngenta Goa Research & Technology Centre.
T. Gowala thanks Dr. Bhanu Manjunath, Director, Syngenta
Biosciences Private Limited for his support.
Cyclohexenone substrate (7d) with two methyl substituents next
to the double bond did not react with 2,4-dimethoxy-aryl bromide
again demonstrating the influence of steric hindrance on the
reactivity. Aromatic alkenone like Chromone was also tolerated
providing the corresponding coupling product (7g) in 48% yield.
Overall, the Heck coupling protocol reported here has a large
scope of cyclic alkenones.
References and notes
With regard to the mechanism, we hypothesize that the reaction
path way is similar to the standard Heck reaction as shown in
Scheme 4 involving oxidative addition, aryl-palladium insertion,
and a base induced “formal” beta trans-elimination (as postulated
for α,β-unsaturated carbonyl compounds).18 We speculate that
oxidative addition occurs rapidly under the described catalytic
system without any discrimination of electron-rich and electron-
poor aryl bromides. The observed selectivity for the electron-rich
aryl bromides may be due to more favorable aryl-palladium
insertion onto the cyclic alkenone for electron-rich aryl bromides
facilitated by higher nucleophilicity (probably enhanced by the
presence of electron rich phosphine ligands tri-tert-
butylphosphine and/or X-Phos on palladium) of the aryl group in
the oxidative addition product. While, electron-poor aryl halides
could not be activated sufficiently under these conditions to
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tetrafluoroborate (0.53 mmol). The reaction mixture was degassed
with nitrogen for 10 min and treated with Pd(PPh3)2Cl2 (0.13
mmol) and X-Phos (0.26 mol), and stirred at 100 0C for 12 h. The
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water, and extracted with AcOEt (3 x 50 ml). The combined
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Na2SO4, and evaporated. Flash chromatography on silica gel
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Scheme 1: Heck reaction between cyclopent-2-en-1-one and 2,4-dimethoxy-1-bromobenzene.
Scheme 2: Substrate scope of arylbromides for the Heck reaction with cyclopent-2en-1-one.
Scheme 3: Substrate scope of cyclic alkenones for the Heck reaction with 2,4-dimethoxy-1-
bromobenzene.
Scheme 4: Proposed hypothetical mechanism for the selective Heck reaction of electron rich aryl
bromides with cyclic alkenones.