The Employment of Sodium Hydride as a Michael Donor in Palladium-catalyzed Reductions of α, β-Unsaturated Carbonyl Compounds

Article abstract of DOI:10.1002/adsc.201801676

Sodium hydride was employed as a Michael donor under the catalysis of PdCl₂ for 1,4-conjugate reductions of α, β-unsaturated carbonyl compounds, which features operational simplicity, mild conditions and high atom-economy. The merits of NaH as a reductant were demonstrated by the one-pot or cascade reactions for the syntheses of complex molecules. (Figure presented.).

Full text of DOI:10.1002/adsc.201801676

Title: The Employment of Sodium Hydride as a Michael Donor in
Palladium-catalyzed Reductions of α, β-Unsaturated Carbonyl
Compounds
Authors: Shilei Zhang, Ye Liu, Yujian Mao, Yanwei Hu, Jingjing Gui,
Liang Wang, and Wei Wang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801676
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10.1002/adsc.201801676
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
The Employment of Sodium Hydride as a Michael Donor in
Palladium-catalyzed Reductions of α, β-Unsaturated Carbonyl
Compounds
Ye Liu,+,a Yujian Mao,+,a Yanwei Hu,+,a Jingjing Gui,a Liang Wang,b,* Wei Wang,c,d
and Shilei Zhanga,*
a Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, 199
Ren’ai Road, Suzhou, Jiangsu, 215123, China
Fax: (+86)-512–6588-0959; e-mail: zhangshilei@suda.edu.cn
b College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao, Shandong, 266109,
China
E-mail: liangwang0532@yeah.net
c State Key Laboratory of Bioengineering Reactor, and Shanghai Key Laboratory of New Drug Design, School of
Pharmacy, East China University of Science & Technology, Shanghai 200237, China
d Department of Pharmacology and Toxicology, and BIO5 Institute, University of Arizona, 1703 E. Mabel St., P. O. Box
210207, Tucson, AZ 85721-0207, USA
+ These authors contribute equally to this work.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
hazardous hydrogen gas or the lack of atom economy
donor under the catalysis of PdCl2 for 1,4-conjugate for the hydride reagents. In this context, it’s highly
Abstract. Sodium Hydride was employed as a Michael
reductions of α, β-unsaturated carbonyl compounds, which
features operational simplicity, mild conditions and high
atom-economy. The merits of NaH as a reductant were
demonstrated by the one-pot or cascade reactions for the
syntheses of complex molecules.
desirable to develop a more convenient, safer and
atom-economic method for these transformations.
Keywords: sodium hydride; palladium catalysis; Michael
donor; 1,4-conjugate reduction; α, β-unsaturated carbonyl
compounds
As one of the most significant organic
transformations, 1,4-conjugate additions provide
convenient and powerful tools for the construction of
C-C and C-X (X=O, N, P, S, Si, B) bonds,
represented by numerous coupling reactions that use
various nucleophiles as donors and electron-deficient
alkenes as acceptors.[1] Among these reactions, 1,4-
conjugate reductions of α, β-unsaturated carbonyl
compounds have distinguished themselves as
important synthetic protocols for construction of the
corresponding saturated products.[2-6] Apart from the
general approaches of the reduction of double-bonds
through transition-metal catalysed hydrogenation
using H2 or other hydrogen sources,[2] a number of
hydride reagents such as NaBH4,[3] [(Ph3P)CuH]6
Scheme 1. NaH was used as a base or reductant.
Compared with the other widely utilized strong
bases, structurally simple sodium hydride (NaH)
seems to be special because of the release of
hydrogen gas via deprotonation of substrates
(Scheme 1a). It should be noted that this process is
accompanied by energy loss along with some
[5]
(Stryker’s reagent),[4] RxSiH4-x and Hantzsch ester
(1,4-dihydropyridine ester)[6] also work well for
this purpose. However, these well-established
methods frequently suffer from either the use of
1
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10.1002/adsc.201801676
Advanced Synthesis & Catalysis
potential dangers in experiments. In contrast, the
employment of NaH as a reducing reagent by
incorporating hydride into the products could
significantly improve its versatility and atom
economy. Although NaH was documented as a
reductant a long time ago,[7] it was not until recently
this underdeveloped chemistry received considerable
interest again from synthetic communities.[8-11] For
example, Chiba et al. discovered that NaH-iodide
composites could be endowed with unprecedented
hydride donor reactivity for several transformations,
such as hydrodecyanation, the reduction of amides to
aldehydes, the dearylation of arylphosphine oxides,
hydrodehalogenation, amide-directed C-H sodiation
and nucleophilic amination of methoxy arenes.[9]
as catalysts, which only led to lower yield (Table 1,
Entry 10), or even no conversion (Table 1, Entry 11).
Next, the optimization of catalyst loading indicated
that neither increasing nor decreasing the amount of
PdCl2 could improve the yields (Table 1, Entries 12
and 13). Similarly, attempts to optimize the reaction
by adjusting the NaH loading failed to achieve
superior results (Table 1, Entries 14 and 15). Finally,
the reaction media was examined (Table 1, Entries
16-21), and DMA was shown to be the solvent of
choice, delivering 5a in 94% yield (Table 1, Entry
20).
Table 1. Optimization of the reaction conditions.[a]
Studer group reported
a
similar radical
hydrodehalogenation using NaH as a reagent.[10] Very
recently, we demonstrated that NaH could be
switched to a nucleophilic reductant with the addition
of Pd(OAc)2 as a promoter, the reactivity of which
was engineered into a reductive debenzylation and
deallylation of aryl ethers and esters (Scheme 1b).[11]
In further studies, we found that the reductive system
could also be applied to the 1,4-conjugate reductions
of α, β-unsaturated carbonyl compounds (Scheme 1c).
To the best of our knowledge, this is the first example
of using a simple alkali metal hydride as a
nucleophile in Michael-type reactions. It is
particularly noteworthy that the 1,4-conjugate adduct
1 is a reactive carbanionic intermediate, which allows
further reaction with electrophiles to furnish product
2a in a cascade or one-pot fashion, or directly give 2b
by treatment with acid. In contrast, the traditional
step-by-step synthesis of 2a not only requires at least
two equivalents of base but also suffers from
potential contamination by the side product 3
(Scheme 1d). Generally, our protocol has the
advantages of atom-economy and environmental
benignity over the traditional reduction methods[2-6]
since the latter usually cannot be involved into the
cascade process,[4,12] or need to deal with the waste
issues generated from the hydride source used.
Herein, we would like to report our new discovery of
the reduction of α, β-unsaturated carbonyl
compounds by the NaH/[Pd] system and the relevant
one-pot or cascade reactions that provide an efficient
method for the preparation of useful synthetic
building blocks.
Initially, the feasibility of 1,4-conjugate reductions
of α, β-unsaturated carbonyl compounds using NaH
as a reductant was investigated with 3-benzylidene-1-
phenylindolin-2-one 4a as the model substrate. At the
outset, the addition reaction was conducted in the
absence of catalyst, and no conversion was observed
(Table 1, Entry 1). When Pd(OAc)2 was added as a
promoter, the desired product 5a was rapidly
generated in 84% yield (Table 1, Entry 2).
Encouraged by this result, a series of other palladium
catalysts were then evaluated (Table 1, Entries 3-9),
and PdCl2 was identified as the optimal one (Table 1,
Entry 3). The other transition metallic catalysts, such
as rhodium and ruthenium salts, were also screened
Yield
Entry Catalyst
Solvent Time
(%)[b]
0
1
DMF
DMF
DMF
DMF
DMF
10 h
-
2
3
4
5
Pd(OAc)2
PdCl2
50 min
30 min
25 min
10 h
84
88
87
8
Pd(TFA)2
Pd/C
[(η3-
6
DMF
40 min
75
C3H5)PdCl]2
7
Pd(MeCN)2Cl2 DMF
30 min
50 min
10 h
10 h
10 h
50 min
40 min
40 min
30 min
10 h
62
76
7
8
9
10
11
Pd2(dba)3
Pd(PPh3)4
RhCl3·3H2O
RuCl3·nH2O
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CHCl3
THF
36
NR
82
88
80
88
NR
59
30
8
12[c]
13[d]
14[e]
15[f]
16
17
PdCl2
2 h
18
PdCl2
dioxane 4 h
CH3CN 8 h
19
PdCl2
20
PdCl2
DMA
40 min
94
42
0
21
PdCl2
PdCl2
toluene 2 h
22[g]
DMA
10 h
[a]Reaction conditions unless specified: 4a (0.2 mmol),
NaH (0.4 mmol) and catalyst (0.01 mmol) in solvent (1.5
ml) at room temperature under N2 atmosphere. [b]Isolated
yield. [c]1 mol% PdCl2. [d]10 mol% PdCl2. [e]1.5 equiv of
NaH. [f]2.5 equiv of NaH. [g]LiH instead of NaH was used.
With the optimal reaction conditions in hand, the
generality of the hydride addition reaction was then
investigated with a variety of 2-indolinone-based
substrates bearing electronically and sterically diverse
substituents subjected to this reduction. To our
delight, all the substrates were tolerant of the
NaH/PdCl2 system, furnishing the desired products 5
in good to excellent yields (Table 2). Remarkably, the
electronic nature of aromatic groups R1 (Table 2,
Entries 1-10) had a trivial impact on the process,
2
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10.1002/adsc.201801676
Advanced Synthesis & Catalysis
although the phenyl group bearing m-CF3 exhibited a
slightly detrimental effect on the conversion (Table 2,
Entry 10). In addition, the substrates incorporating
hetero-aromatic groups, such as 3-pyridyl, 2-thienyl
and 2-furyl as well as 4-quinolyl were also examined,
wherein electron-poor heterocycles were found to be
favourable to the reaction (Table 2, Entries 14 and
17). Remarkably, the conjugate reductions also
proceeded smoothly when R1 was replaced by
aliphatic groups, providing the desired products 5r-5t
in moderate to good yields (Table 2, Entries 18-20).
At last, the high tolerance of this transformation was
further proved by altering the R1, R2, R3 and R4
groups on the substrates, with all cases providing 5u-
x in good yields (Table 2, Entries 21-24).
mediated conjugate reduction, providing the desired
products 7a-i in good to high yields. As it’s known
that NaH is a hard metal hydride reagent containing
ionic metal-H bonds,[13] which should favour the 1,2-
reduction[7g] over 1,4-reduction in the case of α, β-
enone. However, in our examples, no 1,2-reduction
product was observed when ketone group was present
in the substrates, demonstrating the robustness and
chemospecificity of our protocol.
Having established the efficient 1,4-conjugate
reductions of α, β-unsaturated carbonyl compounds,
we next focused our studies on one-pot reactions to
further improve the atom-economy of our method. As
shown in Scheme 2, the sodium salt 5a-Na generated
in situ from 4a could react with various electrophiles
to provide the pharmaceutically interesting 3,3’-
disubstituted oxindole derivatives. A number of
Table 2. Substrate scope of oxindole-based alkenes.[a]
alkylating
reagents,
such
as
(bromomethyl)cyclopropane, MeI and BnBr, were
employed to deliver products 8-10 bearing all-carbon
quaternary stereocenter in high yields. Similarly, 5a-
Na could also serve as a Michael donor, exampled by
the reaction using methyl acrylate to construct
oxindole 11 in moderate yield. Additionally, the
hydroxyl group was installed readily at the C3-
position of the oxindole via oxidation with H2O2 as
an oxidant to furnish the desired product 12 in good
yield, which further highlighted the synthetic
applicability of our protocol.
Yield
Entry
5
R1
R2
R3
R4
(%)[b]
94
93
90
92
89
86
91
81
88
76
90
89
76
86
84
75
98
85
72
81
1
2
3
4
5
6
7
8
5a Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
6-
CF3
5b 4-MeC6H4
5c 2-MeOC6H4
5d 3-MeOC6H4
5e 4-MeOC6H4
Table 3. 1,4-Conjugate reduction of 2-benzylidene-
substituted propane-1,3-dicarbonyl compounds.[a,b]
5f
4-F3COC6H4
5g 2-FC6H4
5h 4-FC6H4
5i
5j
5k 2-Naphthyl
5l 1-Naphthyl
5m 9-Anthracenyl
5n 3-Pyridyl
5o 2-Thienyl
5p 2-Furyl
4-MeO2CC6H4
3-F3CC6H4
9
10
11
12
13[c]
14
15
16
17
18
19
20
5q 4-quinolyl
5r Cyclohexyl
5s
5t
Isopropyl
Phenylpropyl
21[c]
22[c]
5u Ph
H
Me
83
5v Ph
H
Me
Me
Me
Ph
Ph
5-Ph 87
23[c,d] 5w Ph
H
H
96[e]
95
24[f]
5x Me
[a]Reaction conditions unless specified:
4 (0.2 mmol),
[a]Reaction conditions unless specified:
6 (0.2 mmol),
NaH (0.4 mmol) and PdCl2 (0.01 mmol) in DMA (1.5
ml) at room temperature under N2 atmosphere.
[b]Isolated yield. [c]Stirred at 60 °C. [d]15 mol % PdCl2.
[e]A mixture of separable diastereomers is formed in a
ratio of 58:42. [f]Stirred at 45 °C.
NaH (0.4 mmol) and PdCl2 (0.01 mmol) in DMA (1.5
ml) at room temperature under N2 atmosphere.
[b]Isolated yield. [c]Stirred at 50 °C. [d]50 mol % PdCl2.
[e]10 mol % PdCl2.
Subsequently, the generality of this method were
further investigated (Table 3). A number of 2-
Cascade reactions have been intensively studied as
versatile strategies for the construction of complex
molecular architectures due to their high efficiency.
Thus, ester group was introduced in the ortho position
benzylidene-substituted
propane-1,3-dicarbonyl
compounds were subjected to the NaH/PdCl2-
3
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10.1002/adsc.201801676
Advanced Synthesis & Catalysis
of chalcone or cinnamate to capture the in-situ
generated carbanion of 14 in the pattern of
Dieckmann condensation (Scheme 3). To our delight,
the desired 1,3-dicarbonyl products 15a and 15b were
generated efficiently. Similarly, the relatively less
reactive α, β-unsaturated esters and amide could also
undergo the sequential Michael addition/Dieckmann
condensation to afford the desired products 15c and
15d in good yields.
A mixture of PdCl2 (1.8 mg, 0.01 mmol, 5 mol%) and
sodium hydride (60% in oil) (16 mg, 0.4 mmol, 2
equiv) in DMA (1.0 mL) was stirred at room
temperature under N2 for 5 min until the mixture
turned black. Compound 4 (0.2 mmol) in DMA (0.5
mL) was added through syringe, then the reaction
was stirred at rt. After the reaction was completed
monitored by TLC, a saturated aqueous NH4Cl
solution was added to quench the reaction. The
resulting mixture was extracted with EtOAc, and the
combined organic layers were washed with water and
brine and dried over sodium sulfate and concentrated
under reduced pressure. The crude product was
purified by column chromatography to give desired
prouct 5.
Acknowledgements
This work was supported by National Natural Science
Foundation of China (21202112, 21738002 and 21776148), Ph.D.
Programs Foundation of the Ministry of Education of China
(20123201120019), Suzhou Science and Technology Project
(Grant No. ZXY201435), PAPD (A Project Funded by the
Priority Academic Program Development of Jiangsu Higher
Education Institutions). We are also grateful to the financial
supports from the Natural Science Foundation of Shandong
Province (ZR2016BM07), Key Research & Development Project
of Shandong (2018GSF118224).
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could act as a Michael donor for 1,4-conjugate
reduction of various α, β-unsaturated carbonyl
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Advanced Synthesis & Catalysis
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Advanced Synthesis & Catalysis
COMMUNICATION
The Employment of Sodium Hydride as a Michael
Donor in Palladium-catalyzed Reductions of α, β-
Unsaturated Carbonyl Compounds
Adv. Synth. Catal. Year, Volume, Page – Page
Ye Liu, Yujian Mao, Yanwei Hu, Jingjing Gui,
Liang Wang,* Wei Wang, and Shilei Zhang*
6
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