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X. Zhou et al. / Tetrahedron Letters 55 (2014) 5137–5140
Table 1
that the hydroxy group of the resulting intermediate o-hydroxy-
chalcone tosylhydrazone 2a as a nucleophile could intramolecu-
larly attack the diazo intermediate to afford correspondingly 2H-
chromene 3a (Scheme 1). In an initial demonstration of this
hypothesis, we chose to evaluate substrate 1a for the preparation
of 2-phenyl 2H-chromenes 3a according to the conditions
described by Valdes18 (K2CO3/dioxane, 110 °C for 24 h). However,
the corresponding ring closure product 2H-chromene 3a was not
detected. Unexpectedly, the conjugate reduction product o-hydro-
xyl dihydrochalcone 4a was obtained in 78% yield. With the
Optimization of conjugate reduction of chalcone 1b with tosylhydrazinea
O
O
H NNHTs
2
base, solvent
1b
4b
Entry
Solvent (equiv)
Base
Yieldb (%)
1
2
3
4
5
6
7
8
9
K2CO3 (1.5)
NaOH (1.5)
tBuOK (1.5)
K3PO4 (1.5)
AcONa (1.5)
Et3N (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (2.0)
K2CO3 (1.0)
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Pyridine
Toluene
DMSO
73
41
46
56
58
52
50
48
54
49
72
66
encouraging initial result, herein, we will describe
approach for transition metal-free conjugate reduction of
unsaturated ketones with tosylhydrazine as a hydrogen source.
To explore the general reactivity of conjugate reduction of
a novel
a,b-
a,b-
unsaturated ketones with tosylhydrazine as a hydrogen source, we
selected chalcone 1b as the model substrate and the results are
listed in Table 1. As shown, initial studies were carried out in the
above reaction condition (K2CO3/Dioxane, 110 °C for 24 h), gratify-
ingly, the model substrate 1b was reduced via 1,4-reduction path-
way and afforded the 1,4-adduct 4b in 73% yield without the
formation of pyrazoles (Table 1, entry 1).22 To get optimum reac-
tion conditions, firstly, a variety of bases were examined, we found
10
11
12
Acetonitrile
Dioxane
Dioxane
a
Reaction conditions: chalcone 1b (1.0 mmol), tosylhydrazine (1.1 mmol), K2CO3
(1.5 mmol) , dioxane (2 mL), 110 °C, 24 h, under N2.
b
Isolated yield based on 1b.
t
that strong bases such as NaOH and BuOK were inefficient and
afforded the desired product in poor yields (Table 1, entries 2
and 3). However, other bases such as K3PO4, AcONa, and Et3N
can only afford moderate yields (Table 1, entries 4–6). Next, under
the same condition (Table 1, entry 1), we screened various solvents
(Table 1, entries 7–10), all the reactions proceeded smoothly to
afford the desired product, however, only moderate yields were
obtained. Finally, the amounts of base were screened, interestingly,
we found that increasing the amounts of base to 2.0 equiv is insig-
nificant to activity and a similar yield was obtained (Table 1, entry
11 vs 1), while the yield of dihydrochalcone was decreased to 66%
when the amounts of base were reduced to 1.0 equiv (Table 1,
entry 12). The influence of the reaction temperature and time were
also investigated and it was confirmed that reactions run at 110 °C
gave the best results. Based on the result of the above systemati-
cally screening experiments, the optimized conditions for the con-
present protocol and gave the corresponding conjugate reduction
products up to 81% yields which can undergo additional transfor-
mations by metal-catalyzed cross-couplings (Table 2, 1i–l). More-
over, substrates with the dimethylamino group proceeded
smoothly to afford the conjugate reduction products in moderate
yields (Table 2, 1m–o). The steric effect on the reactivity was not
significant by the ortho-substituents on the aromatic ring, when
we introduced a substituent on the ortho position of the aromatic
ring, the yields of products are slightly lower than those which
possess a para substituent group such as methyloxyl or bromo
(Table 2, 1p–t). The reaction of substrate 1u, bearing a furyl ring
proceeded smoothly to afford the desired product 4u in 55% yield
(Table 2, 1u). Furthermore, we found substrates with nitro group
which are sensitive to ordinary hydrogenation conditions,
remained intact in this process and afforded the conjugate reduc-
tion product in 58% yield (Table 2, 1v). Notably, the diketene sub-
strate 1w was a suitable substrate under the modified conditions,
giving the double conjugate reduction product 4w in 46% yield
(Table 2, 1w). As for substrates, bearing ketones derived from ali-
phatic aldehydes such as 1x and 1y, only moderate yields were
obtained along with the minor formation of pyrazole as by-prod-
ucts (Table 2, 1x and 1y). Unexpectedly, substrates derived from
aliphatic ketones were unsuitable in the present protocol, giving
the corresponding pyrazoles.22
jugate reduction of
a,b-unsaturated ketones with tosylhydrazine
were obtained as follows: 1.1 equiv of tosylhydrazine and 1.5 equiv
of K2CO3 in dioxane at 110 °C for 24 h under N2.
Under the above optimum reaction conditions, the substrate
scope and limitation of the conjugate reduction were then
explored. As summarized in Table 2, a variety of chalcones with
diverse substitution patterns of electron donating groups in both
the rings smoothly underwent the transformation and gave their
corresponding products ranging from 48% to 81% (Table 2, 1b–u).
For instance, chalcones with various groups in both the rings such
as methyl and methoxyl were successfully reduced to their corre-
sponding products in good yields (Table 2, 1b–h). It was interesting
that the chlorine on the aromatic rings was tolerated under this
In summary, we have developed a novel approach for the tran-
sition metal-free conjugate reduction of
a,b-unsaturated ketones
to the corresponding saturated ketones with tosylhydrazine as a
hydrogen source under mild condition. The method is versatile
NNHTs
OH
O
3a
X
O
2a
H2NNHTs
K2CO3,
Dioxane
OH
√
O
1a
78%
OH
4a
Scheme 1. Conjugate reduction reaction of chalcone 1a using tosylhydrazine as a hydrogen source.
Zhou, Xiaomeng
