FeCl3·6H2O-catalyzed selective conjugate reduction of alkylidene-β-keto esters and alkylidene-1,3-diketones

Article abstract of DOI:10.1016/j.tetlet.2018.07.041

FeCl₃·6H₂O/triethylsilane composite catalyst system is successfully developed for the selective conjugate reduction of carbon-carbon double bond of Michael acceptor-alkylidene-β-keto esters and alkylidene-1,3-diketones under mild rea

Full text of DOI:10.1016/j.tetlet.2018.07.041

Tetrahedron Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
FeCl3Á6H2O-catalyzed selective conjugate reduction of alkylidene-b-keto
esters and alkylidene-1,3-diketones
⇑
Lakshmi V.R. Babu Syamala, Trimbak B. Mete, Ramakrishna G. Bhat
Department of Chemistry, Indian Institute of Science Education and Research (IISER)-Pune, Dr. Homi Bhabha Road, Pashan, Pune 411008, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
FeCl3Á6H2O/triethylsilane composite catalyst system is successfully developed for the selective conjugate
reduction of carbon-carbon double bond of Michael acceptor-alkylidene-b-keto esters and alkylidene-
1,3-diketones under mild reaction conditions to afford the corresponding saturated b-keto esters and
1,3-diketones. The process involves the iron-catalyzed hydrosilylation, followed by in situ hydrolysis of
silyl enol ether. The optimal reaction conditions include 20 mol% of FeCl3Á6H2O and triethylsilane in
dichloromethane at room temperature. A broad range of substrates undergoes the reduction in 1, 4-selec-
tive manner to afford the corresponding saturated compounds in excellent yields.
Received 16 June 2018
Revised 14 July 2018
Accepted 16 July 2018
Available online xxxx
Keywords:
Conjugate reduction
Alkylidene keto ester
Lewis acid
Ó 2018 Published by Elsevier Ltd.
Triethylsilane
Introduction
exploring the use of first-row transition elements [8] such as Ti,
Zn, Cu, Fe, Ni and the early transition element such as Mo [9].
Composite reducing systems comprising of hydrosilanes and
transition metal catalysts have been highly successful reduction
strategies in organic synthesis [1]. The chemoselective reduction
of one functionality over another without any side reactions is
always a challenge in both chemical and pharmaceutical indus-
tries. However, organosilanes, unlike organometallic reagents are
usually unreactive and inert towards various organic substrates
[2]. Trialkylsilanes are known to be poor reducing agents and these
organosilanes can be activated by appropriate Lewis acids in order
to explore their effective use in organic synthesis [2,3]. Alterna-
tively, transmetallation has also been explored to activate the less
reactive organosilanes to carry out organic transformations [4].
Hydrosilylation strategy has been successfully explored for the
reduction of olefins, carbonyls and imines [6–9]. The conjugate
reduction of
a, b-unsaturated ketones and esters are complex
and commonly suffers from the competitive 1, 2-reduction. Usu-
ally, it can lead to multiple reduction products via 1, 2-reduction,
1, 4-reduction and complete competitive reductions. The chemos-
elective conjugate reduction is an important and challenging task
in organic synthesis [10]. The chemoselective reduction of a partic-
ular functional group without reducing other sensitive moieties is
desirable and demanding.
Interestingly, most of the work on hydrosilylation has been
focused on the reduction of ketones or
a, b-unsaturated ketones
Nowadays, the selective conjugate reduction of
a
, b-unsaturated
[8b–8d,11]. Also, most of the hydrosilylation methods require the
use of base or acid for the final hydrolysis of silylated
intermediates [8d]. Surprisingly, there are no reports on the
selective reduction/hydrosilylation reaction on the alkylidene b-
keto esters. It would be interesting to explore the novel catalyst
system comprising of simple and commercially available metal
catalyst. It is also desirable to develop a protocol without the
need for any ligands and additives/co-catalysts. Among the
transition metal catalysts, iron is believed to be ideal in many
ways, as it is environmentally benign, easily available and less
expensive. Herein, we report the versatility of FeCl3Á6H2O/Et3SiH
system for the selective conjugate reduction of the carbon-
carbon double bond of alkylidene-b-keto esters, alkylidene-1,3-
diketones and –Meldrum’s adducts under mild reaction conditions.
ketones has become one of the important functional group trans-
formations for the synthesis of natural products and biologically
active compounds under environmentally friendly conditions. It’s
known in the literature that Et3SiH/EtMe2SiH coupled with the
suitable transition metal reagents lead to the conjugate reduction
of a, b-unsaturated ketones and esters [5]. Metals such as Ir, Rh,
Pd and other metal complexes have been explored for the hydrosi-
lylation reaction for achieving the conjugate reduction [6,7].
Likewise, the hydrosilylation methods for the reduction of
a,
b-unsaturated ketones and esters have also been achieved by
⇑
Corresponding author.
E-mail address: rgb@iiserpune.ac.in (R.G. Bhat).
https://doi.org/10.1016/j.tetlet.2018.07.041
0040-4039/Ó 2018 Published by Elsevier Ltd.
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2
Lakshmi V.R. Babu Syamala et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Table 2
Results and discussion
Screening of solvents for optimizing the reaction.a
At the outset, we commenced our work with a model reaction
of benzylidene methylacetoacetate 1a with various Lewis acids in
presence of triethylsilane in DCM at room temperature. Compound
1a did not react with Et3SiH (1 equiv.) in presence of different
Lewis acids (entry 1–6 and 8, Table 1). Surprisingly, metal salts
which are known to catalyze hydrosilylation of enones did not cat-
alyze effectively the reduction of alkylidene b-keto ester 1a. It is
interesting and unusual that the alkylidene b-keto esters did not
react under the reaction conditions even though they are more
reactive than enones. The reaction of compound 1a with anhy-
drous FeCl3 and Et3SiH in DCM at room temperature led to multiple
products (entry 9, Table 1). Interestingly, catalytic amount of
FeCl3Á6H2O (10 mol%) under the reaction condition afforded the
desired product 2a (64%) along with corresponding alcohol 3a
(1, 2-reduction product) in 13% yield (entry 10, Table 1).
Gratifyingly, FeCl3Á6H2O (20 mol%, 0.2 equiv.) reacted smoothly
under the reaction conditions to afford the conjugate reduction
product 2a in 85% yield along with a significantly lower amount
of alcohol 3a in 6% yield (entry 11, Table 1).
The treatment of compound 1a with FeCl2Á4H2O (entry 12,
Table 1) under the reaction conditions led to just a trace amount
of desired product 2a. Likewise, compound 1a did not react with
Et3SiH (1.02 equiv.) in presence of other Lewis acids (entry 13–
18, Table 1). The reaction did not work in the absence of any cata-
lyst (entry 20, Table 1).
Encouraged by this initial success, we screened various solvents
for optimizing the reaction conditions. Non-polar solvents such as
chloroform, benzene and toluene afforded the conjugate reduction
product 2a in poor yield (entry 2–4, Table 2). While solvents such
as ethyl acetate and acetone afforded the product 2a in trace
amounts. The protic solvent such as methanol afforded the mixture
Entry
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
DCM
8
85 + 6c
54 + 11
28 + 8
25 + 6
Trace
30 + 15c
Trace
NR
CHCl3
Toluene
Benzene
EtOAc
MeOH
Acetone
THF
ACN
DMF
DMSO
12
12
12
24
12
24
24
24
24
24
9
10
11
NR
NR
NR
a
Reactions were screened on 1a (1 mmol) with Et3SiH (1.02 equiv.) and
FeCl3Á6H2O (20 mol%) in various solvents.
b
Isolated yield after column chromatography.
c
Yield of alcohol 3a after column chromatography NR = No Reaction.
of 2a and 3a. While aprotic polar solvents proved to be disadvan-
tageous. DCM proved to be the optimum solvent for the desired
transformation (entry 1, Table 2).
In order to explore the most suitable and optimum silyl reduc-
ing agent, we screened the reaction with triethoxysilane and triph-
enylsilane in presence of FeCl3Á6H2O (see Table 3). The reaction of
benzylidene methylacetoacetate 1a with triethoxylsilane (1.02
equiv.) in DCM, FeCl3Á6H2O (20 mol%) led to an inseparable mix-
ture of products (entry 2, Table 3). While, the triphenylsilane
afforded the mixture of 2a and 3a (see entry 3, Table 3).
Triethylsilane proved to be the most suitable reducing agent by
affording the corresponding conjugate reduction product 2a in 85%
yield. Based on different screening experiments FeCl3Á6H2O (20
mol%), Et3SiH (1.02 equiv.) in DCM at room temperature proved
to be the optimum reaction condition.
Table 1
Screening of Lewis acid (LA) catalysts for optimizing the reaction conditions.a
Having optimum reaction conditions in hand, we planned to
explore the substrate scope for the generality of the method. Var-
ious alkylidene methyl acetoacetates (1b-1l) under the optimum
reaction conditions afforded the corresponding 1, 4-conjugate
reduction products (2b-2l) in good to excellent yields (see
Scheme 1). This method proved to be highly chemoselective as it
afforded selectively 1, 4-conjugate addition products and we
observed only a trace amount of 1, 2-addition products (alcohol).
The substrate containing both electron-donating and weak
Entry
LA (Catalyst)a
Time (h)
Yieldc (%)
1
2
3
4
5
6
7
8
CuCl2Á2H2O
MnCl2Á6H2O
NiCl2Á6H2O
Cu(OAc)2
24
24
24
24
24
24
24
24
4
Trace
NR
NR
NR
Zn(OAc)2
NR
CuSO4Á5H2O
NR
Cu(I)Br
27 + 12d
CoCl2Á6H2O
FeCl3
NR
Table 3
Screening of silane reducing agents for optimizing the reduction reaction.a
9
Multiple products
10
11
12
13
14
15
16
17
18
19
20
FeCl3Á6H2O
FeCl3Á6H2Ob
FeCl2Á4H2O
CeCl3Á7H2O
SnCl2Á2H2O
MgBr2Á6H2O
Cu(NO3)2Á3H2O
Ni(acac)2
12
8
64 + 13d
85 + 6d
Trace
NR
24
24
24
24
24
24
24
24
24
15
NR
NR
NR
NR
Trace
NR
Entry
Silane
Time (h)
Yieldb (%)
Fe(acac)3
85 + 6c
Fe(ClO4).3XH2O
No Catalyst
1
2
3
Et3SiH
(EtO)3SiH
Ph3SiH
8
12
8
Inseparable Mixture
66 + 15c
a
Reactions were performed with 0.1 equiv. (10 mol%) of Lewis acids (LA) and
Et3SiH (1.02 equiv.) in DCM.
a
Reactions were screened on 1a (1 mmol) with silane (1.02 equiv.) and
b
FeCl3Á6H2O (20 mol%) in DCM.
20 mol% of catalyst was used.
Isolated yield of the product after column chromatography.
Yield of alcohol 3a. NR = No Reaction.
b
c
Isolated yield.
Yield of alcohol 3a.
c
d
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Lakshmi V.R. Babu Syamala et al. / Tetrahedron Letters xxx (2018) xxx–xxx
3
Scheme 3. Substrate scope of Meldrum’s adducts for reduction under optimized
reaction conditionsa,b aReactions were performed on 7a–7c (1 mmol, 1 equiv.) with
.
FeCl3Á6H2O (20 mnol%) and Et3SiH (1 equiv.) in DCM at rt. bIsolated yield after
column chromatography.
However, substrates with electron withdrawing group 4e
afforded the desired product 5e along with 1, 2-addition product
6e in a smaller quantity (Scheme 2).
To expand the scope of the methodology further we synthesized
a few alkylidene Meldrum’s acid derivatives (7a–7c). These com-
pounds under the optimum reaction conditions afforded the corre-
sponding 1, 4-conjugate addition products (8a–8c) exclusively in
almost quantitative yields (Scheme 3). The method proved to be
highly selective for the 1,4-conjugate reduction.
Scheme 1. Substrate scope of alkylidene b-ketoesters for reduction under
optimized reaction conditionsa,b aReactions were performed on 1a-1l (1 mmol, 1
.
equiv.) with FeCl3Á6H2O (20 mol%) and Et3SiH (1.02 equiv.) in DCM at rt. bIsolated
yield.
Conclusions
In conclusion,
a novel reducing system comprising of
electron withdrawing groups, and heteroaryl derived substrate
reacted smoothly under the reaction conditions. Substrates with
strong electron withdrawing groups (p-CN- and p-NO2-Phenyl)
did not react under the reaction conditions. Also attempts towards
FeCl3Á6H2O/triethylsilane is successfully developed for the highly
selective conjugate reduction of the carbon-carbon double bond
of alkylidene b-keto esters and alkylidene 1,3-diketones under
the mild reaction conditions. The chemoselective reduction
afforded exclusively 1, 4-conjugate reduction products as major
products and the method did not require the use of any base/acid
for the desilylation. A broad range of alkylidene derivatives
underwent smooth reduction under practical reaction conditions.
the reduction of a, b-unsaturated ketones such as cyclohexenone
and benzylidene acetone were unsuccessful as reactions led to
the mixture of products (1,2- and 1,4-reduction and complete
reduction products).
Later, we turned our attention towards acetyl acetone
derivatives. The alkylidene acetylacetone derivatives (4a–4e)
under optimum reaction conditions afforded the corresponding 1,
4-conjugate reduction products (5a–5e) chemoselectively in good
to excellent yields (See Scheme 2).
Acknowledgments
R. G. B. thanks DST-SERB (EMR/2015/000909), Govt. of India for
the generous research grant. Authors also thank Indian Institute of
Science Education and Research (IISER), Pune for the financial sup-
port. L.V. R. B. S. and T. B. M thanks CSIR-UGC and IISER-P for the
fellowship. Authors also thank Dr. Chennakesava Reddy for the
useful discussions.
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