Ru-catalyzed 1,4-addition of arylboronic acids to acrylic acid derivatives in the presence of phenols

Article abstract of DOI:10.1039/c3cc43095b

[Ru(p-cymene)Cl₂]₂-catalyzed 1,4-addition reactions between arylboronic acids and butyl acrylate and acrylamide in the presence of phenols were investigated, good to excellent yields were obtained. The addition of phenols remarkably promoted the protonolysis and inhibited the β-H elimination of the 1,4-addition intermediates, and also efficiently suppressed the protonolysis of arylboronic acids. The Royal Society of Chemistry 2013.

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Ru-catalyzed 1,4-Addition of Arylboronic Acids to Acrylic Acid
Derivatives in the Presence of Phenols
Lei Zhang,a,b Xiaomin Xie,b Zhiyong Peng,b Lei Fu,a* Zhaoguo Zhangb*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
5
Recently, we reported a simple and efficient Ru-catalyzed
[Ru(p-cymene)Cl2]2-catalyzed 1,4-addition reactions between
arylboronic acids and butyl acrylate and acrylamide in the
presence of phenols were investigated, good to excellent yields
45 conjugate addition reaction of arylboronic acids to enones
under neutral conditions, in which vinyl ketones gave 1,4-
addition products with excellent yields and no β-H elimination
product.9
10 were obtained. The addition of phenols remarkably promoted
the protonolysis and inhabited the β-H elimination of the 1,4-
addition intermediates, and also efficiently suppressed the
protonolysis of arylboronic acids.
In transition metal-catalyzed addition reactions, it is believed
50 that after the insertion of the C-C double bond of an α,β-
unsaturated compound into the C-M bond of an ArMX, the
resulted metal complex (I) will be in equilibrium to its
enolized complex (II) (Scheme 1). When α,β-unsaturated
compounds used are ketones or aldehydes, enolization is more
55 favorable than when they are esters. Complex II can be
hydrolized (or protonolized) in the presence of a proton
source, while complex I does not form O-bound intermediate
II easily 10 and can undergo β-H elimination under basic
conditions.
Transition metal-catalyzed 1,4-conjugate addition of
15 organometallic reagents to α,β-unsaturated carbonyl
compounds is a powerful tool for C-C bond formation
1
reactions.
Among various organometallic reagents,
organoboron compounds had been extensively investigated
due to their readily availability, stability and low toxicity.2
20 Since Miyaura and co-workers’ pioneering work in Rh-
catalyzed 1,4-addition of arylboronic acids to enones, 3 the
4 5
Rh(I)-2a, and Pd(II)-catalyzed6 conjugate addition has been
,
60 β-H elimination occurs easily when the transition metal
possesses a vacant coordination site. In order to suppress the
β-H elimination product, some ligands are added to prevent
the metal from unsaturately coordinated. So we examined the
reaction of 4-(t-butyl)phenylboronic acid 1a (1.05 mmol) and
65 butyl acrylate 2a (1.0 mmol) in the presence of [RuCl2(p-
cymene)]2 (2.0 mol %) in dioxane-H2O (3.0 mL, V/V = 20:1)
at 90 °C in the presence of a ligand. When PPh3, bipyridine,
and dppp were employed as the ligands, the yields of 3aa
were 43%, 0%, and 0%, respectively. In the presence of PPh3
70 and DPPP as ligands, protonolysis product of t-
butylphenylboronic acid was the major byproduct. We also
tried organic acids as additives, hoping that the presence of an
acid to stimulate the protonolysis of the enolate of the 1,4-
addition intermediate (II in scheme 1). As a result, in the
75 presence of 10 mol% of benzoic acid, the yield was 57%
together with some t-butylbenzene; while in the presence of
20 mol% of acetic acid, the yield decreased to 12% with the
generation of a large amount of t-butylbenzene (70%) as the
byproduct. Apparently, the protonolysis of arylboronic acid
80 becomes more favorable under acidic conditions. However,
the β-H elimination became overwhelming even in the
presence of a weak base, as a result, addition of 10 mol% of
NaOAc to the reaction, no desired 1,4-addition product was
detected; only Heck-type product was obtained.
extensively investigated and well developed. It was
noteworthy that the substrates in these catalytic reactions were
25 limited to enones and enals, unsaturated esters were rarely
employed as the reagents because of their easy β-H
elimination.7 Meanwhile, Ru(II)-catalyzed conjugate addition
has been sporadically reported8 and there has been no example
for the Ru(II)-catalyzed 1,4-addition of arylboronic acids to β-
30 unsubstituted acrylates. Herein, we report the first Ru(II)-
catalyzed conjugate addition of arylboronic acids to α,β-
unsaturated esters and amides, using 2,6-di-t-butylphenol as a
versatile additive.
35 Scheme 1 Competition between protonolysis and β-H elimination of the
1,4-addition intermediates
aSchool of Pharmacy, and School of Chemistry and Chemical
Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road,
40 Shanghai 200240, China. E-mail: zhaoguo@sjtu.edu.cn
†Electronic Supplementary Information (ESI) available: Experiment
details of substrates synthesis, NMR and HPLC data. See
DOI: 10.1039/b000000x/
85 Because both oxygen-based ligands and the acidity of the
reaction condition play a crucial role in controlling the
protonolysis of arylboronic acids and the β-H elimination
process,11 neutral or weak acidic oxygen-based ligand, such as
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DOI: 10.1039/C3CC43095B
widely-used pentane-2,4-dione and rarely-used phenols, were
tested. When pentane-2,4-dione was used as ligand, the
reaction gave 3aa in only 20% yield, most of 1a and 2a was
investigated. The results are summarized in Table 2. The
para- and meta- substituted arylboronic acids 1c-o can
efficiently react with 2a to afford the corresponding addition
remained (Table 1, entry 7). When phenol was used as the 40 products in good to excellent yields (Table 2). The catalytic
5
ligand in our catalytic system, the reaction produced 1,4-
addition product 3aa in 90% yield (Table 1, entry 8). Other
phenols were also tested, and 2,6-di(t-butyl)phenol performs
best (For more details, see supporting information, Table 1).
reactions tolerated various functional groups, such as OCF3,
Cl, F, Br, COCH3, CO2CH3 and CHO on the phenyl rings of
arylboronic acids 1. These results indicate that the catalytic
reaction is not sensitive to the electronic properties of the
This result prompted us to explore the possibility of using 45 substituent, but it is susceptible to the position of the
10 oxygen-based ruthenium complexes as catalysts for the 1,4-
addition reaction. As a result, if the catalyst was pre-formed
with [Ru(p-cymene)Cl2]2 and 1 to 2 equivalents of PhONa, the
reaction gave 1,4-addition product in not more than 30% yield
substituents on the phenyl rings. For example, 3-
methylphenylboronic acid (1c) afforded 3ca in 85% yield
(Table 2, entry 3) whereas 2-methylphenylboronic acid (1b)
gave 3ba in only 35% yield even if 2.5 eq. of 1b was used
together with varying amount of Heck-type product. 50 (Table 2, entry 2). As mentioned before, this reaction is
15 Replacing the catalyst with [Ru(benzene)Cl2]2, the yield was
decreased from 94% to 85% (Table 1, entry 10 vs entry 11);
other ruthenium catalysts are inefficient, [Ru(COD)Cl2]n and
RuCl3.xH2O are totally inert (Table 1, entries 13 and 14). This
sensitive to the acidity of the reaction condition, when acrylic
acid as substrate, almost all of the arylboronic acids were
protonolyzed. Likewise, the catalytic reaction is very sensitive
to the steric hindrance with the alkenes 2, no reaction took
reaction was not susceptible to the temperature, when the 55 place with α- or β-substituted acrylic substrates under the
20 reaction was carried out at 120 °C, the yield was almost equal
to that at 90 °C; while at 50 °C the yield was slightly
decreased even with longer reaction time. Other solvents, such
as THF, acetone, toluene, methanol and DMF, decreased the
yields with varying degrees in our catalytic system. If the
25 reaction was carried out in a dry solvent, the yield was
remarkably decreased (See supporting information, Table 1).
On the basis of these optimization studies, we employed
[RuCl2(p-cymene)]2 (2 mol %) as the catalyst, 2,6-di-(t-
butyl)phenol (10 mol %) as the additive, in dioxane/H2O = 20
30 : 1 (V/V) , 90 °C and 12 h as the standard reaction conditions
for the following catalytic conjugate addition reactions.
standard reaction conditions.
Table 2 Ru-catalyzed 1,4-addition reaction of arylboronic acids 1 with
alkenes 2a
Entry
1
2
3
4
Ar
E
Product
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
3oa
3eb
3ec
Yieldb (%)
94
p-t-BuC6H4 (1a)
o-MeC6H4 (1b)
m-MeC6H4 (1c)
p-MeC6H4 (1d)
C6H5 (1e)
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
30c
85
Table 1 Ru-catalyzed 1,4-addition reaction of 1a and 2aa
88
91
86
90
92
88
84
74
90
87
81
83
58
ND
5
6
p-FC6H4 (1f)
7
8
9
p-CF3C6H4 (1g)
p-ClC6H4 (1h)
p-CF3OC6H4 (1i)
p-CH3OC6H4 (1j)
p-BrC6H4 (1k)
p-CH3COC6H4 (1l)
p-CO2CH3C6H4 (1m)
p-CHOC6H4 (1n)
m-CHOC6H4 (1o)
C6H5 (1e)
10
11
12
13
14
15
16
17
Entry Catalyst
1
Additive
None
PPh3
Bipyridine
DPPP
Benzoic acid
HOAc
Pentane-2,4-dione
Phenol
2,6-Dimethylphenol
2,6-Di-t-butylphenol
2,6-Di-t-butylphenol
2,6-Di-t-butylphenol
2,6-Di-t-butylphenol
2,6-Di-t-butylphenol
Yield (%)b
75c
43
ND
ND
57
12
20
90
92
94
85
ND
ND
ND
[RuCl2(p-cymene)]2
2
3
4
5
6
7
8
9
10
11
12
13
14
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[Ru(benzene)Cl2]2
RuCl2(PPh3)3
C6H5 (1e)
aAll the reactions were carried out with 1 (1.0 mmol), 2 (1.0 mmol),
ruthenium complex (2.0 mol %), 2,6-di-t-butylphenol (10.0 mol %), in
dioxane/water = 20 : 1 (v/v) (3 mL) at 90 °C under N2 for 12 h. bIsolated
yield (Heck-type product is less than 3%). 2.5 eq. of aryboronic acid
was used.
c
60
[RuCl2(COD)]n
RuCl3·xH2O
It is still a puzzle what the role phenols play in the catalytic
1,4-addition reaction, but it is clear that phenols do not serve
only as ligands, as depicted earlier that the pre-formed
catalyst from [Ru(cymene)Cl2]2 and varying amounts of
aAll the reactions were carried out with 1 (1.05 mmol), 2 (1.00 mmol),
ruthenium complex (2.0 mol %) and an additive (10 mol%) in a mixed
solvent [dioxane/H2O = 20/1 (v/v), 3 mL] at 90 °C under N2 for 12 h.
bYields were determined by GC (signal-integration method with
durene as an internal standard, Heck-type product was less than 2%).
cWith 20% of Heck-type product. dND: not detected.
65 NaOPh performed worse than [Ru(cymene)Cl2]2 and phenol.
Further experiments showed that phenols do not only serve as
a pH adjusting agent either. If the reaction was run in buffered
solutions (citric acid/sodium hydroxide, potassium dihydrogen
phosphate/disodium hydrogen phosphate, and sodium
70 tetraborate/hydrochloric acid) with a pH varying from 5.0 to
9.0, the yields varying from 78% to 31% acompanying with
35 Under the optimized reaction conditions, a wide range of
arylboronic acids and acrylates or acrylamides were
2
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