S. W. Reilly et al. / Tetrahedron Letters 55 (2014) 6738–6742
6739
2-cyclopentenone to examine five-membered rings, (entry 2)
which also produced a high yield with PhB(OH)2. 3-Methylcycloh-
exenone (entry 3) reacted much slower, which was attributed to
the methyl group at the b-position creating steric hindrance. All
acyclic Michael acceptors screened in Table 2 demonstrated excel-
lent yields with PhB(OH)2 including the enal cinnamaldehyde
(entry 6). High yields were also obtained with chalcone (entry 8),
a Michael acceptor with medicinal significance due to its cytotoxic,
anticancer, and other therapeutic characteristics.16 Since consistently
high yields were obtained at 80 °C with a,b-unsaturated enones and
enals, this temperature was adopted for further studies.
The scope of reaction with aryl boronic acids was examined
(Table 3). Utilizing previously optimized conditions of 1.2 equiv
of PhB(OH)2, initial catalytic trials with substituted-aryl boronic
acids with 2-cyclohexenone produced low yields (Table 3, entries
6 and 8) Upon careful observation of the 1H NMR spectra and
GC–MS data, deborylated aryl compounds could be observed, indi-
cating deborylation of boronic acid. This observation is consistent
with the previously reported literature, stating hydrolysis of
boronic acids occurs as a competing side reaction under basic
conditions and/or elevated temperatures.17 Previous reports had
overcome this loss of boronic acid by increasing the boronic acid
equivalents, which resulted in higher yields of product.18 There-
fore, 2.5 equiv of all aryl boronic acids were evaluated and found
to produce excellent higher yields. Many of the boronic acids with
electron rich substituents generated yields >97% in 1 h (entries 1, 2,
and 4). A high yield was obtained using naphthalene boronic acid
(entry 5), which is noteworthy due to naphthalene’s importance
in the production of plastic, dyes, and insecticides.19 It has been
reported that aryl boronic acids with ortho-substituents drastically
slow the rate of 1,4-addition,6 which held true for 2,4,6-trimethyl-
phenyl boronic acid (entry 3). However, 2-methylphenyl and
2-methoxyphenyl boronic acid (entries 2 and 9) resulted in high
yields in just 1 h. While longer reaction times were required to
obtain high yields with boronic acids containing strong electron
withdrawing substituents (entries 6 and 8), no yield was obtained
when using 1,3-dibromophenyl boronic acid (entry 7). Boronic
acids containing moderate electron withdrawing groups, (entries
9 and 10), produced yields of >99% in just 1 h.
Scheme 1. Equilibrium of amine adduct and iodo-bridged dimer.
Table 1
Catalyst optimization of Michael addition of PhB(OH)2
O
O
2 mol % cat.
1.2 eq. PhB(OH)2
50oC
Ph
Entry Solvent
Cat.
mol %
NHMe2
Time
(h)
Yielda
1
2
3
4
5
6
7
8
9
10:1 MeOH/H2O
1
1
1
1
–
1
1
1
1
1
1
—
1
1
1
1
1
1
1
1
1
1
1
0
10:1 MeOH/H2O
10:1 MeOH/H2O
10:1 MeOH/H2O
10:1 MeOH/H2O
H2O
MeOH
EtOH
10:1 EtOH/H2O
1:1 MeOH/H2O
10:1 Dioxane/
H2O
0.6
3.0
11.0
12.0
3.0
3.0
3.0
3.0
3.0
3.0
>98
>98
>98
0
>98
>98
>98
>98
>98
>98
10
11
12
10:1 Dioxane/
H2O
—
—
48
0
13
14
15
16
17
18
H2O
—
—
—
3.0
—
3.0
3.0
20
20
20
16
1
0
51
0
0
0
10:1 EtOH/H2O
10:1 EtOH/H2O
10:1 EtOH/H2O
CH2Cl2
[Rh(COD)Cl]2
—
1
1
1
Benzene
1
10
Nitrogen heterocycles such as pyrazole and pyridine are some of
the most common heterocycles in biologically- and medicinally-
active compounds.20 Pyrimidine is an important pharmacophore
and plays a vital role in the synthesis of nucleic acids and the HIV
drug zidovudine.21 5-Fluorouracil (5-FU) is an important chemo-
therapy agent and has shown inhibitory effects on human gastric
carcinoma cell growth.22 Sulfur heterocycles such as thiophenes,
can be coupled to produce polythiophene electron acceptors which
have attracted considerable attention due to their outstanding elec-
trical, optical, and magnetic properties.23 Polysubstituted furans are
also important building blocks throughout synthetic chemistry, and
widely seen throughout pharmaceutical and natural products.24
The scope of reaction with heterocyclic boronic acids was examined
with 2-cyclohexenone as the Michael acceptor (Table 4).
Deborylation products were also observed in the early screen-
ings of heterocyclic boronic acid, therefore 2.5 equiv of boronic
acid were employed. With this increase, higher yields were
obtained for many 1,4-addition products. It was found that longer
reaction times were required compared to many of the aryl boronic
acids to produce moderate to high yields for most of the heterocy-
cles screened in Table 4. With the extended reaction times, a yield
of 77% was obtained with furan-3-boronic acid (entry 1).
Thiophene-3-boronic acid (entry 2) produced moderate conver-
sion, while no conversion was observed when using uracil-5-boro-
nic acid (entry 3). Nitrogen heterocycles, 3-pyrazole boronic acid
and 4-pyridine boronic acid, were successfully coupled to 2-cyclo-
hexenone in high yields (entries 4 and 5). Pyrimidine boronic acid
a
Yields were determined by 1H NMR and identified by GC–MS.
3 mol % was found to be a good compromise that gave excellent
yields and reproducibility. In the absence of the Rh complex, no
product was formed (entry 5). A variety of protic and aprotic sol-
vents were also screened. The reaction proceeded in a variety of
‘green’ protic solvents.15 Limited conversion was observed in
purely aprotic solvents such as benzene or methylene chloride
(entries 17 and 18). Conveniently, a 1:1 MeOH/H2O mixture (entry
10) was found to give high yields comparable with 10:1 solvent
mixtures, and was, therefore, chosen for catalytic trials. It should
be noted, with extended reaction times, bi-phenyl was observed
in the GC–MS spectra in minor amounts (<3%, entries 12–16).
Once the reaction conditions were optimized, the catalyst load-
ing was lowered to 1 and 0.1 mol % (Table 2, entry 1). Even at
reduced loading, moderate conversion was seen within 1 h though
not at the level seen with 2 mol %. Therefore, all remaining reac-
tions were carried out with 2 mol % of the catalyst.
After optimization, the scope of a,b-unsaturated carbonyl com-
pounds was examined (Table 2). While good to moderate yields
(P77%) were obtained at 50 °C (entries 5 and 7) and even at room
temperature (entry 1), low yields were observed for several sub-
strates at these temperatures (entries 4 and 6). Therefore a higher
temperature of 80 °C was evaluated and found to produce consis-
tently higher yields. The screening of cyclic enones also included