The first ligand-modulated oxidative Heck vinylation. Efficient catalysis with molecular oxygen as palladium(0) oxidant

Article abstract of DOI:10.1039/b311492a

The discovery of the first ligand-supported Pd(II) catalysed oxidative Heck reaction with molecular oxygen as reoxidant and the scope with diverse arylboronic acids and olefins using only 1-2% of catalyst are reported.

Full text of DOI:10.1039/b311492a

The first ligand-modulated oxidative Heck vinylation. Efficient catalysis
with molecular oxygen as palladium(0) oxidant†
Murugaiah M. S. Andappan, Peter Nilsson and Mats Larhed*
Box 574, Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, BMC, Uppsala,
SE-75123, Sweden. E-mail: mats@orgfarm.uu.se; Fax: 46 18 4714474; Tel: 46 18 4714667
Received (in Cambridge, UK) 18th September 2003, Accepted 22nd October 2003
First published as an Advance Article on the web 11th November 2003
The discovery of the first ligand-supported Pd(II) catalysed
oxidative Heck reaction with molecular oxygen as reoxidant
and the scope with diverse arylboronic acids and olefins using
only 1–2% of catalyst are reported.
were due to the poor percentage of conversion and also the
concurrent formation of biphenyl through the homocoupling of
PhB(OH)2, which was negligible with dmphen ligand. The nitrile
solvents, MeCN and EtCN, gave the highest yields (entries 8–11).
The polar, aprotic solvent DMSO afforded only poor to moderate
yields, even after prolonged time (entries 4–6). Toluene gave a
slightly depressed yield (entry 7). N-Methylmorpholine (NMM)
was identified as an effective base and 2 equiv. proved to be
optimal. Et3N was also effective (entry 16), but the inorganic base
LiOAc gave a poor result. While the acid 1a readily coupled to the
olefin, the corresponding boronic ester was surprisingly inert under
the reaction conditions.
The immediate impact of the dmphen ligand-support was that the
reaction could be performed with 1 mol% of Pd(II), down from 10
mol% in the absence of the ligand.3d Having identified an efficient
catalytic system, we then investigated the scope of arylboronic and
olefinic substitution. The results from preparative coupling of
olefins (2a–d) with a diverse set of boronic acids, bearing sensitive
nitro, keto, bromo, and iodo functionalities (1a–m), are sum-
marised in Table 2. The standard conditions identified from Table
1 (entry 11) were employed, even though individual cases were
optimised for high yield, with regard to Pd(OAc)2 amount (1 or 2
mol%), solvent and temperature. The reactions were diastereo- and
regioselective, except that of the styrene derivative (last entry).
The transition metal (Pd, Rh, Ru and Ir)1 catalysed cross-coupling
of organoboronic acids and olefins is rapidly growing as a versatile
synthetic methodology. The multifarious advantages of arylboronic
acid over other arylpalladium precursors (triflates, halides, etc.)
include 1) the availability of vast numbers of arylboronic acids, 2)
the stability to air and moisture, 3) the low toxicity and 4) the easy
removal of boron-derived byproducts unlike that of other organo-
metalloids.2 The Pd(II)-mediated vinylic substitution of organo-
boronic acids, known as the oxidative Heck reaction, was first
reported by Heck1 with stoichiometric amounts of Pd(II) more than
two decades ago. However, this reaction has been developed very
little, barring a few recent reports. The first catalytic protocol was
reported by Cho et al. using AcOH as solvent3a followed by a mild
method by Du et al. using DMF as solvent with Cu(OAc)2 as
reoxidant.3b We recently developed a microwave-accelerated
procedure for the fast generation of oxidative Heck products,3c and
Jung et al. reported the utility of molecular oxygen as an efficient
reoxidant of Pd(0), though with relatively high amount of Pd(II) (10
mol%).3d
The complete absence of ligand-supported oxidative Heck
protocols limits the development of selective and efficient
applications in organic synthesis. The presence of ligands might not
only invoke the stability of the catalyst by preventing the
aggregation of Pd(0), prompting smaller amounts of catalyst, but
also aid in control over the regio- and stereoselectivity with
electron-rich and prochiral olefins respectively. In particular, the
nitrogen ligands are known to facilitate the efficient reoxidation of
Pd(0) by molecular oxygen.4 In general, nitrogen-based ligands are
very cheap, air and moisture stable compared to their phosphine
counterparts. To start with, we undertook studies on the viability of
ligands in the oxidative Heck reaction with more-common electron-
poor olefins, which are reported herein.
A set of 19 optimisation experiments were performed to discover
proper conditions in terms of Pd(II) source, solvent, ligand, base,
temperature and time with PhB(OH)2 (1a) and n-butyl acrylate (2a)
as model reactants (Table 1). Molecular oxygen was used
throughout as reoxidant for catalyst regeneration because of its eco-
friendly advantages. The oxidatively stable phenanthroline-class
ligand, 2,9-dimethyl-1,10-phenanthroline (dmphen), known to
provide high yields in internal arylation with aryl triflates,5
performed generally well. In contrast, the exclusion of the ligand
did not afford any product (entry 18). Bipyridyl and monodentate
pyridine6 were ineffective (entries 14, 15). The phosphines, Ph3P
and BINAP, which are susceptible to oxidation,7 gave moderate
yields (entries 12, 13). The inferior yields with phosphine ligands
Table 1 Ligand-based optimisation of oxidative Heck protocola
Yieldb
(%)
Entry Solvent
Ligand [L/Pd] Base
T/°C t/h
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
DMSO
DMSO
—
—
LiOAc
LiOAc
50
70
24
24
24
24
30
24
12
12
12
12
6
24
24
24
6
12
12
12
12
36
0c
1,4-Dioxane dmphen [1.0] 2,6-Lutidine 70
0d
27
25
69
78
95
97
97
96
44
47
0
DMSO
DMSO
DMSO
Toluene
EtCN
dmphen [1.0] LiOAc
dmphen [4.0] LiOAc
dmphen [1.0] NMM
dmphen [1.0] NMM
dmphen [1.2] NMM
dmphen [1.0] NMM
dmphen [1.2] NMM
dmphen [1.2] NMM
Ph3P [2.5]
BINAP [1.2]
bipy [1.2]
pyridine [4.0]
dmphen [1.2] Et3N
dmphen [1.2] LiOAc
70
70
50
80
70
50
50
50
50
50
50
50
50
50
50
50
EtCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
NMM
NMM
NMM
—
0
90
20
0
22e
—
NMM
dmphen [1.2] NMM
a 1a (2.0 mmol), 2a (1.0 mmol), Pd(OAc)2 (1 mol%), ligand (L) and base
(2.0 mmol) in MeCN (2.5 mL) were stirred under O2 atm. b Isolated yield
with purity 495% (GC-MS). c Pd(II): Pd(phen)Cl2. d Pd(II):
Pd(MeCN)2Cl2. e Additive: LiBr (5 equiv.).
† Electronic Supplementary Information (ESI) available: Experimental and
analytical data. See http://www.rsc.org/suppdata/cc/b3/b311492a/
218
C h e m . C o m m u n . , 2 0 0 4 , 2 1 8 – 2 1 9
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

Table 2 Vinylation of diverse arylboronic acids with olefinsa
The general trend was that the electron-rich arylboronic acids
were the superior substrates affording high yields without any
byproduct. The m-substituted electron-poor arylboronic acids (1e–
f, 1h–j) afforded moderate to good yields, while those with p-
substitution8 were inert towards vinylation and only furnished
homocoupling products in small amounts (e.g. 1g). The fluoride
salt additives like CsF and TBAF, which are known to generate
highly-nucleophilic “ate” complexes with ArB(OH)2, made no
difference in the latter case.9 This large disparity in the reactivity
might indicate that the insertion of electron-poor aryl groups in a
chelation-controlled cationic Pd(II) p-intermediate is a sluggish
process. This is in contrast to ligand-free oxidative Heck condi-
tions, where the p-complex might be neutral.10,11 The addition of
LiBr decelerated the reaction rate with non-functionalised 1a,
which supports the role of the cationic pathway (entry 19, Table
1).12 The formation of the branched isomer (17%) in the last entry
(Table 2) may also be interpreted based on the cationic mechanism.
The sterically-hindered boronic acids, 1k–l, gave moderate to good
yields. The reactions with 1h-j are highly chemoselective as no
competitive Pd(0)-catalysed Heck vinylation and Suzuki coupling
were noticed.
Yieldd
95
R–PhB(OH)2 Olefinb Productc
Cond. t/h (%)
3,4-dioxy
methylene 1b 2a
A
6
4-methyl
1c
2a
2a
A
B
3
6
73
92
4-methoxy
1d
A
B
6
70
3-nitro
1e
In conclusion, ligand modulated oxidative Heck chemistry was
developed with 1) arylboronic acids as latent aryl halides, 2) low
catalyst loading with an inexpensive ligand and 3) molecular
oxygen as a “green reoxidant”. This protocol should serve as the
foundation for the future development of regio- and stereocon-
trolled chemistry. Our further efforts are directed towards the above
goal,13 and overcoming limitations pertaining to the eletron-poor
arylboronic acids.
2a
12 40
24 77
3-acetyl
1f
2b
2a
A
A
4-acetyl
1g
12
0
The authors thank Prof. Anders Hallberg for valuable sugges-
tions and the Swedish Research Council for financial support.
3-iodo
1h
2a
2a
A
B
12 43
12 45e
Notes and references
3,5-dibromo
1i
1 Pd: H. A. Dieck and R. F. Heck, J. Org. Chem., 1975, 40, 1083. Rh: K.
Fagnou and M. Lautens, Chem. Rev., 2003, 103, 169. Ru: E. J.
Farrington, J. M. Brown, C. F. J. Barnard and E. Roswell, Angew.
Chem., Int. Ed., 2002, 41, 169. Ir: T. Koike, X. Du, T. Sanada, Y. Danda
and A. Mori, Angew. Chem., Int. Ed., 2003, 42, 89.
2 S. Kotha, K. Lahiri and D. Kashinath, Tetrahedron, 2002, 58, 9633.
3 (a) C. S. Cho and S. Uemura, J. Organomet. Chem., 1994, 465, 85; (b)
X. Du, M. Suguro, K. Hirabayashi, A. Mori, T. Nishikata, N. Hagiwara,
K. Kawata, T. Okeda, H. F. Wang, K. Fugami and M. Kosugi, Org. Lett.,
2001, 3, 3313; (c) A. M. S. Murugaiah, P. Nilsson and M. Larhed, Mol.
Div., 2003, in press; (d) Y. C. Jung, R. K. Mishra, C. H. Yoon and K. W.
Jung, Org. Lett., 2003, 5, 2231.
4 R. A. Sheldon, I. Arends, G. J. Ten Brink and A. Dijksman, Acc. Chem.
Res., 2002, 35, 774; B. A. Steinhoff, S. R. Fix and S. S. Stahl, J. Am.
Chem. Soc., 2002, 124, 766.
5 W. Cabri, I. Candiani, A. Bedeschi and R. Santi, J. Org. Chem., 1993,
58, 7421. Arylation of electron-poor olefins with Pd(0)/dmphen was
reported unsuccessful in this article.
6 Pyridine has been shown to accelerate a related oxidation by the “in situ”
formation of Py2Pd(OAc)2: B. A. Steinhoff and S. S. Stahl, Org. Lett.,
2002, 23, 4179.
7 C. W. Lee, J. S. Lee, N. S. Cho, K. D. Kim, S. M. Lee and J. S. Oh, J.
Mol. Catal., 1993, 80, 31.
8 The following arylboronic acids with electronically deactivating groups
at the p-position were investigated: CF3, Br, CHO, COCH3.
9 N. Miyaura, J. Organomet. Chem., 2002, 653, 54.
12 67
12 73
12 43f
3-bromo
1j
2c
B
2,4,6-trimethyl
1k
2a
2a
B
B
2-methoxy
1l
6
6
77g
77
1-naphthyl
1m
2c
B
B
1a
2d
12 83h
10 For example, under ligand free conditions [Pd(OAc)2/LiOAc/DMSO/
O2], the product from the reaction of 1g was isolated in 80% yield
(unpublished result).
11 M. Larhed and A. Hallberg, Handbook of Organopalladium Chemistry
for Organic Synthesis, ed. E. Negishi, John Wiley & Sons, Inc., New
York, 2002, vol. 1, p. 1133.
12 This is in agreement with the results obtained in internal vinylation of
aryl triflates with dmphen as ligand. See ref. 5.
13 Preliminary investigation has established excellent internal regiocontrol
in the arylation of electron-rich olefins.
a Condition A: ArB(OH)2 (2.0 mmol), alkene (1.0 mmol), Pd(OAc)2 (2.3
mg, 1 mol%), dmphen (2.6 mg, 1.2 mol%), and NMM (0.22 mL, 2.0 mmol)
in MeCN (2.5 mL) were stirred under O2 atm at 50 °C, except as noted; B:
L/Pd(II): 2.4/2 mol%. b 2a: n-Butyl acrylate; 2b: styrene; 2c: 1-octen-3-one;
2d: 4-ethoxystyrene. c New compounds gave satisfactory 1H and 13C NMR,
IR, and combustion analysis. d Isolated yield with purity 495% (GC-MS or
1H NMR). e L/Pd(II): 6.0/5.0 mol%. f Solvent: DMF, 100 °C. g Solvent:
EtCN, 80 °C. h b : a = 83 : 17.
C h e m . C o m m u n . , 2 0 0 4 , 2 1 8 – 2 1 9
219