Transition metal free chemoselective reduction of α,β-unsaturated ketones to saturated ketones using tosyl hydrazide as a hydrogen donor

Article abstract of DOI:10.1002/cjoc.201400684

An efficient, inexpensive and simple method for the reduction of various α,β-unsaturated ketones to corresponding saturated ketones using tosyl hydrazide as a hydrogen donor in DMF using calcium oxide powder has been reported. A variety of enones underwen

Full text of DOI:10.1002/cjoc.201400684

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DOI: 10.1002/cjoc.201400684
Transition Metal Free Chemoselective Reduction of
α,β-Unsaturated Ketones to Saturated Ketones Using
Tosyl Hydrazide as a Hydrogen Donor
Yarabally R Girish,a Kanchipura R Raghavendra,a Dasappa Nagaraja,b
Kothanahally S Sharath Kumara and Sheena Shashikanth*,a
a Deparment of Studies in Chemistry, Manasagangothri, University of Mysore, Mysore 570006, India
b Department of PG Studies in Chemistry, Government Science College, Chitradurga 577501, India
An efficient, inexpensive and simple method for the reduction of various α,β-unsaturated ketones to corre-
sponding saturated ketones using tosyl hydrazide as a hydrogen donor in DMF using calcium oxide powder has
been reported. A variety of enones underwent reduction without forming undesirable side products. High chemose-
lectivity, broad functional group tolerance and good yields are the noteworthy features of this protocol.
Keywords α,β-unsaturated carbonyl compounds, tosyl hydrazide, transition metal free, saturated ketones
Introduction
Scheme 1 Synthesis of α,β-saturated ketones
The chemoselective reduction of double bond of
α,β-unsaturated carbonyl compounds is of great interest
in organic synthesis.[1] Several research groups have
been working on the development of an efficient, selec-
tive and inexpensive protocols for the reduction of
α,β-unsaturated carbonyl compounds. In this direction,
Satoshi et al.[2] have reported the iridium catalyzed re-
duction of chalcones to saturated ketones using alcohols
as a hydrogen source. In addition, Pincer-Pd[3] (Scheme
1, reaction 1) complex and many other transition metals
like rhodium,[4] ruthenium,[5] cobalt,[6] indium,[7] tita-
nium[8] and few other catalysts[9] have been used for the
reduction of isolated double bonds. Scrap automobile
catalyst has been used to facilitate the conjugate reduc-
tion of isolated double bonds to saturated carbonyl
compounds.[10] In further, Nandy and his group[11] re-
ported reduction of isolated double bond by using am-
monium formate as the hydrogen donor with catalytic
amount of 10% Pd/C in methanol/THF at reflux tem-
perature. In 2002, Kosal and his co-workers[12] have
reported chemoselective reduction of α,β-unsaturated
carbonyl compounds using Cp2TiCl2 derivative in the
presence of Zn dust as a catalyst. Interestingly, reduc-
tion of α,β-unsaturated carbonyl compounds has been
achieved using biocatalyst Penicillium citrinum CBMAI
1186.[13] In addition to above methods several research
groups have showed different approaches for the syn-
thesis of saturated ketones.[14]
Previous work
O
O
Pincer-Pd-complex
R1
R2
(1)
(2)
R1
R2
K2CO3 (10 mol %)
n-BuOH
O
O
K2CO3
R1
R2
+ H2NNHTs
R1
R2
Dioxane
110 oC, 24 h
R2
O
SO2NHNH2
O
Pd
R3
(3)
+
R2
R3
R1
R1
Present work
O
DMF, 100 oC
O
CaO (100 mg)
R2
R1
+ H2NNHTs
(4)
R2
R1
However, all the literature reported methods have
one or the other disadvantages like prolonged heating,
low yields, using expensive noble metals and harsh re-
action conditions, so there is an urgent need for the de-
velopment of a new protocol which circumvents these
difficulties. On the other hand, tosyl hydrazide has been
used in various palladium catalyzed reactions to make a
C－C bond.[15] Haukaas et al.[16] have reported enanti-
oselective synthesis of 2-deoxy and 2,3-dideoxyhexoses
*
E-mail: shashis1956@gmail.com; Tel.: 0091-0821-2419668
Received October 11, 2014; accepted November 27, 2014; published online XXXX, 2014.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400684 or from the author.
Chin. J. Chem. 2015, XX, 1—4
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1

Girish et al.
COMMUNICATION
using NSBH/Et3N as a diimide precursor. Zhou and his
co-workers[17] have reported synthesis of saturated ke-
tones from chalcones using tosyl hydrazide as hydrogen
donor in the presence of base at reflux temperature
(Scheme 1, reaction 2), and Chen and his co-workers[18]
reported conjugate addition of tosyl hydrazides to
α,β-unsaturated ketones (Scheme 1, reaction 3).
ATR-Fourier transform infrared (FTIR) spectra were
recorded using a Thermo Nicolet FTIR spectrometer
(Model 5700, Madison, WI) fitted with a single bounce
attenuated total reflectance (ATR) accessory with a
ZnSe crystal of range 400－4000 cm−1
General procedure for the synthesis of saturated ke-
tones (2a)
All the literature reported methods require an addi-
tional hydrogen source for hydrogenation of unsaturated
carbonyl compounds in the presence of inner transition
metals. Since tosyl hydrazide could be used as a hydro-
gen source,[19] which is stable in air and can be prepared
easily in one step from readily available tosyl chloride
and hydrazine hydrate,[20] these qualities make this re-
agent as an alternate hydrogen source. Tosyl hydrazide
has been tested on the α,β-unsaturated carbonyl system
for the various transformations.[21] By keeping all these
facts in mind, we tried tosyl hydrazide as a hydrogen
source for the reduction of α,β-unsaturated ketones to
saturated carbonyl compounds (Scheme 1, reaction 4).
We have been engaged from the past few years in the
development of novel synthetic protocols for the syn-
thesis of various heterocycles using different cata-
lysts.[22] As continuation of our research work, we
herein report a simple, efficient, economical and effec-
tive method for the chemoselective reduction of
α,β-unsaturated carbonyl compounds using tosyl hy-
drazide as hydrogen source.
All reactions were performed on a 0.50 mmol scale
relative to chalcones. (E)-1-(4-Methoxyphenyl)-3-phe-
nylprop-2-en-1-one (1a) (1 mmol), 4-methylbenzene-
sulfonyl hydrazide (1.2 mmol), CaO (100 mg) and 3 mL
of DMF were taken in a round bottom flask equipped
with a stirrer. The reaction mixture was agitated at 100
℃ for 0.45 h. Following, to the reaction mixture was
added water (2 mL), and extracted with ethyl acetate (10
mL×3). The combined organic phases were washed
with brine (5 mL×2), dried over anhydrous Na2SO4
and concentrated in vacuum. The residue was subjected
to column chromatography with hexanes/EtOAc (V∶
V＝5∶0.1) as eluent to obtain the desired 2k (87%
yields). The remaining substituted saturated carbonyl
compounds were prepared in the similar manner.
Results and Discussion
Initially we have selected (E)-1-(4-methoxyphenyl)-
3-phenylprop-2-en-1-one (1a) as a model substrate for
the synthesis of pyrazoles 4a. Interestingly the reaction
produced mixture of saturated ketone 2a and saturated
tosyl imine 3a (Table 1, Entry 2) instead of pyrazole
product 4a (Scheme 2). By inspiring with these findings
we went on to optimize the reaction conditions to get an
exclusively saturated ketone product which looks inter-
esting. For the optimization study, initially we examined
a variety of inorganic bases. In the presence of strong
bases such as NaOH and Cs2CO3, reaction yielded the
product in low yields (Table 1, Entries 7, 9). Whereas
the bases like Na2CO3, K2CO3 gave improved yields
(Table 1, Entries 5, 6 and 8). In further, we screened the
Experimental
Reactions were monitored by TLC using precoated
sheets of silica gel G/UV-254 of 0.25 mm thickness
(Merck 60F254) using UV light for visualization. The
melting points were determined on a Selaco melting
point apparatus and uncorrected. 1H and 13C NMR spec-
tra were recorded on an NMR spectrometer operating at
400 and 100 MHz, respectively, using the residual sol-
vent peaks as reference relative to SiMe4. Mass spectra
were measured with Micromass Q-Tof (HRESI-MS).
Scheme 2 Synthesis of 1-(4-methoxyphenyl)-3-phenylprop-2-one (2a)
NNHTs
O
O
SO2NHNH2 DMF, 100 oC
CaO (100 mg)
+
+
MeO
MeO
MeO
2a
1a
3a
Me
H
N
N
OMe
4a
Not formed
2
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Chin. J. Chem. 2015, XX, 1—4

Transition Metal Free Chemoselective Reduction of α,β-Unsaturated Ketones to Saturated Ketones
reaction using various acid and base catalysts under
solvent and solvent free conditions, among which CaO
was found to be very effective (Table 1, Entry 15) for
the transformation of α,β-unsaturated carbonyl com-
pounds to saturated ketones (Table 1, Entries 10－16).
ring was survived throughout the reaction and gave the
corresponding saturated ketones up to 83% yields (Ta-
ble 2, Entries 1, 3, 8, 9). In addition, substrates with the
halogen group proceeded smoothly to afford the desired
product in moderate yields (Table 2, Entries 4－7). The
reaction of substrates bearing thiophene ring underwent
smoothly to afford the desired products in good yields
(Table 2, Entries 8－14).
Table 1 Optimization of conjugate reduction of chalcone 1a
with tosylhydrazinea
DMF, 100 oC
SO2NHNH2
O
Table 2 Synthesis of different substituted saturated ketones
from α,β-unsaturated carbonyl compoundsa
CaO (100 mg)
+
OMe
SO2NHNH2
1a
DMF, 100 oC
O
O
O
CaO (100 mg)
+
R1
R2
R1
R2
1
2
OMe
2a
Entry
R1
R2
2 Time/h Yieldb/%
Yieldb/%
1
2
3
4
5
6
7
8
9
4-OMeC6H4
4-NH2C6H4
4-OMeC6H4
C6H5
C6H5
2a
1
95[23]
Entry Solvent
Base
Time/h Temp./℃
2a 3a
2,4-Cl2C6H3
4-BrC6H4
4-BrC6H4
2b 2.25
2c 1.25
2d 1.5
78
83[25]
55[26]
45
1
DCM
EtOH
EtOH
EtOH
EtOH
MeOH
EtOH
EtOH
EtOH
EtOH
DMF
－
CaO
CaO
24
8
r.t
80
－
－
45 55
20 80
3
4
CaCO3
－
12
24
1.5
1.75
18
6
80
4-OMeC6H4 3,4-(OMe)2C6H3 2e
3
2
65[27]
80
trace
87
－
－
4-OMeC6H4
4-BrC6H4
4-FC6H4
2f
5
K2CO3
80
4-BrC6H4
2g 1.75
60
6
K2CO3
80
65 35
10 90
70 30
30 70
65 35
90 10
60 40
90
2-Thiophenyl 3,4-(OMe)2C6H3 2h 1.75
85
7
NaOH
80
2-Thiophenyl
4-OMeC6H4
C6H5
2i
2
82[28]
70[24]
78
8
Na2CO3
Cs2CO3
ZrO2-Al2O3
ZrO2-β-Cd
ZrO2-β-Cd
ZrO2-β-Cd
ZrO2-Al2O3
CaO
80
10 2-Thiophenyl
11 2-Thiophenyl
12 2-Thiophenyl
13 2-Thiophenyl
2j 1.5
9
3
80
4-MeC6H4
4-FC6H4
4-EtC6H4
2k 1.75
10
11
12
13
14
15
16
17
18
6
80
2l
2
85
4
100
80
2m 1.75
83
4
14 2-Thiophenyl Benzo[1,3]dioxole 2n
4
90
a Reaction conditions: 1 (1 mmol), tosyl hydrazide (1.2 mmol),
CaO (100 mg) in DMF (3 mL), refluxed at 100 ℃ until comple-
tion of reaction. b Isolated yields.
－
0.5
3
100
100
100
100
80
－
40 50
DMF
DMF
THF
1
90
－
ZrO2-β-Cd
CaO
1
50 50
60 30
70 30
Table 3 Catalyst recycle studies
0.75
4
Catalyst
Time/min
Yield/%
95
EtOH
CaO
70
a Reaction conditions: 1a (1 mmol), TsNHNH2 (1.2 mmol), CaO
1
2
3
4
5
45
45
45
55
60
(100 mg) in DMF (3 mL), 100 ℃. b Isolated yields.
93
93
With the optimized reaction condition in hand, we
next explored the generality of the protocol by using
different funtionalized chalcones in the presence of to-
syl hydrazide and CaO powder in DMF and the results
are summarized in Table 2. Thus, α,β-unsaturated car-
bonyl compounds bearing electron-donating and elec-
tron-withdrawing substitutents on aromatic ring under-
went reaction smoothly; producing the corresponding
saturated ketones in good to excellent yields (Table 3,
Entries 1－14). Interestingly, α,β-unsaturated carbonyl
compounds bearing thiophene ring also gave the corre-
sponding product in excellent yields (Table 3, Entries 8
－14).
90
88
Recycling study of the catalyst
We also investigated reusability of catalyst under
DMF using model chalcone 1a with tosyl hydrazine in
presence of 100 mg CaO powder. After completion of
the reaction, the mixture was dissolved in ethyl acetate
(10 mL) and the catalyst was filtered off. The powder
CaO was treated with ethanol, acetone, and then washed
with distilled water. It was then dried in an oven at 80
℃ for 2 h and used for the next catalytic cycle. Powder
CaO was found to be reusable up to five catalytic cycles
It was found that the methoxy group on the aromatic
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Girish et al.
COMMUNICATION
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Conclusions
In conclusion, we have developed a simple, efficient,
inexpensive and excellent method for the conversion of
different substituted α,β-unsaturated carbonyl com-
pounds into corresponding saturated ketones in the
presence of tosyl hydrazide and powder CaO in DMF.
The present work does not demand harsh and prolonged
reaction conditions. The reaction goes to completion in
the absence of noble metal catalysts and easy workup
procedure makes this process as a benign protocol.
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Acknowledgement
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Yarabally R Girish and Kothanahally S Sharath
Kumar are thankful to the University Grant Commis-
sion-Basic Science Research (Order no DV-5/662/
RFSMS/2012-13), New Delhi, India for financial sup-
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