Facile synthesis of α, β-unsaturated esters through a one-pot copper-catalyzed aerobic oxidation-Wittig reaction

Article abstract of DOI:10.1016/j.tetlet.2017.09.020

An efficient one-pot synthesis of α, β-unsaturated esters through the aerobic oxidation – Wittig tandem reaction of alcohols and phosphorous ylide is developed. This new method operates under mild reaction conditions, and uses CuI/TEMPO (TEMPO = 2,2,6,6-tetramethylpiperidine-N-oxyl) as co-catalyst and air (O₂) as the oxidant. It tolerates a wide range of functionalized benzylic alcohol and aliphatic alcohols.

Full text of DOI:10.1016/j.tetlet.2017.09.020

Accepted Manuscript
Facile synthesis of α, β-unsaturated esters through a one-pot copper-catalyzed
aerobic oxidation-Wittig reaction
Cheng Ren, Zhenyu Shi, Weijie Ding, Zhiqing Liu, Huile Jin, Xiaochun Yu,
Shun Wang
PII:
S0040-4039(17)31137-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.09.020
TETL 49290
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 July 2017
10 September 2017
12 September 2017
Please cite this article as: Ren, C., Shi, Z., Ding, W., Liu, Z., Jin, H., Yu, X., Wang, S., Facile synthesis of α, β-
unsaturated esters through a one-pot copper-catalyzed aerobic oxidation-Wittig reaction, Tetrahedron Letters
(2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.09.020
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Facile synthesis of α, β-unsaturated esters
through a one-pot copper-catalyzed aerobic
oxidation-Wittig reaction
Cheng Ren, Zhenyu Shi, Weijie Ding, Zhiqing Liu, Huile Jin, Xiaochun Yu*and Shun Wang*

1
Tetrahedron Letters
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Facile synthesis of α, β-unsaturated esters through a one-pot copper-catalyzed
aerobic oxidation-Wittig reaction
Cheng Rena, Zhenyu Shia, Weijie Dinga, Zhiqing Liua, Huile Jina, Xiaochun Yua, *and Shun Wanga, *
a College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, Zhejiang Province 325035, People’s Republic of China
ARTICLE INFO
ABSTRACT
Article history:
Received
An efficient one-pot synthesis of α, β-unsaturated esters through the aerobic oxidation - Wittig
tandem reaction of alcohols and phosphorous ylide is developed. This new method operates
under mild reaction conditions, and uses CuI/TEMPO (TEMPO = 2,2,6,6-tetramethylpiperidine
-N-oxyl) as co-catalyst and air (O2) as the oxidant. It tolerates a wide range of functionalized
benzylic alcohol and aliphatic alcohols.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Aerobic oxidation reaction
Alcohol
Phosphonium ylide
Copper catalyst
Carbon-carbon double bond
Introduction
developed. For example, TMEDAO2 (N,N,N’,N’- tetramethyl
ethylenediamine dioxide) could be used as co-oxidant in a
tandem TPAP catalyzed oxidation Wittig protocols, but the
sequential addition protocol was needed, and 2 equivalent of
ylides was used for some cases.14 Gold/palladium bimetallic
nanoparticles were also utilized as a catalyst in oxidation
Horner-Wadsworth-Emmons reaction, where 1.5 equivalent of
triethyl phosphonoacetate and 3.0 equivalent of base were
needed.15 Diruthenium complex catalyzed aerobic oxidation
Wittig reaction was reported, where the catalyst is not
commercially available and complicated procedures were
required to prepare it.16 Therefore, more attention should be
devoted to development of novel catalysts which have excellent
catalytic activity, green oxidant, low cost and mild conditions.
The formation of carbon-carbon double bond through Wittig
reaction1 is one of the most important processes for the
production of functional organic compounds, such as drugs, dye
and spice etc.2 It is well known that classical Wittig reaction
usually utilizes aldehydes as the starting materials (Scheme 1-a),
in which aldehydes are generally prepared from the oxidation of
alcohols. In comparison to aldehydes, alcohols are cheaper, less
toxic and easier to handle. Therefore, the direct one-pot tandem
oxidation–Wittig reaction of alcohols with ylides is an appealing
approach to construct carbon-carbon double bonds. There are
increasing research activities in developing various oxidants
(Swern3, Dess-Martin4, IBX5, BaMnO4 , MnO27, PhI(OAc)2 with
6
TEMPO (cat.)8, NMO with catalytic amount of TPAP9, PCC10,
SO3·Py11, and so on) for the tandem oxidation-Wittig reaction of
alcohol with ylides (Scheme 1-b). These methods require large
excess or at least full equivalent amounts of oxidants. The
subsequent removal of oxidant does not only complicate the
synthetic procedure, but also increases the final cost, which
seriously limits their large-scale application. Moreover, some
used oxidants themselves are hazardous and difficult to handle.
a. Classical Wittig reaction
+
Ph3P=CHCO2Et
RCHO
RCH=CHCO Et
2
b. Large excess amounts of oxidant were employed for the tandem reaction of
alcohols with ylide
Swern, BaMnO4,
Dess-Martin,
PhI(OAc)2 + TEMPO
+
RCH=CHCO Et
2
RCH2OH
Ph3P=CHCO2Et
MnO2, NMO + TPAP,
IBX, PCC, SO3 Py, etc.
To avoid the use of excessive amounts of oxidants, there is
significant interest in the design of new catalysts and use of green
oxidants. Chang12 and J. Park13 both reported the aerobic
oxidation–Wittig reaction of alcohol with ylide by using
ruthenium as catalyst and O2 as oxidant (Scheme 1-c). These two
catalytic systems exhibit impressive safety. However, the
Chang’s method required stoichiometric Cs2CO3 and had poor
yields when aliphatic alcohols were used, and the J. Park’s
method typically used pure O2. Certainly the high cost of the
catalyst also hampers its massive commercial application.
Recently, several catalytic oxidation-olefination methods were
c. Trasition metal cataylzed tandem reaction of alcohols with ylide
Cat. Ru, Pd-Au
Ph3P=CHCO2Et
+
RCH2OH
RCH=CHCO Et
2
air or O2
d. This work: copper catalyzed aerobic oxidation-Wittig reaction of alcohols
with ylide
Cat. Cu
Ph3P=CHCO2Et
+
RCH2OH
RCH=CHCO Et
2
air
Scheme 1

2
Copper has been known as an effective catalyst for aerobic
alcohol oxidations.17 Yet, an efficient and practical Cu-catalyzed
aerobic oxidation-Wittig tandem method has not been reported.
In this article, a high yield one-pot synthesis of α, β-unsaturated
esters through the aerobic oxidation-Wittig tandem reaction are
developed which uses CuI as the catalyst and O2 in air as the
green oxidant (Scheme 1-d).
Results and Discussion
The optimization of copper catalytic system was accomplished
through investing the reaction of p-nitrobenzyl alcohol 2a with
phosphonium ylide 1, and the results are summarized in Table 1.
We found that the reaction could not be effectively carried out
without the addition of TEMPO (Entry 1), base (Entry 2),
Table 1. Condition screening by exploring the bases, ligands and solvent.
Entrya
Ligand
Base (mol%)
T/oC
Solvent
3a(%)b
1c
2
Bipy
Bipy
Bipy
-
t-BuOK(20)
none
65
65
65
65
65
65
65
65
65
65
65
65
65
65
65
65
65
65
65
65
65
r.t.
40
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN/H2O
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
Xylene
Toluene
CH2Cl2
THF
9
31
78
40
22
84
30
35
51
86
70
74
72
68
70
93
67
46
40
74
78
35
70
3
t-BuOK(20)
4
BuOK (20)
5
Bipy
Bipy
Bipy
Bipy
Bipy
Bipy
TMEDA
DMAP
Phen
TMDP
Bipy
Bipy
Bipy
Bipy
Bipy
Bipy
Bipy
Bipy
Bipy
KOH(20)
6
Pyrrolidine (20)
TEA (20)
7
8
DABCO (20)
Pyridine
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Pyrrolidine (2)
Pyrrolidine (2)
Pyrrolidine (2)
Pyrrolidine (2)
Pyrrolidine (2)
Pyrrolidine (2)
Pyrrolidine (2)
Pyrrolidine (2)
Pyrrolidine (2)
Pyrrolidine (2)
Pyrrolidine (2)
Pyrrolidine (2)
Pyrrolidine (2)
Pyrrolidine (2)
Dioxane
DMF
Xylene
Xylene
a The mixture of 1 (1.2 mmol, 1.2 equiv.), 2 (1.0 mmol), CuI (5 mol%), TEMPO (5 mol%), ligand (5 mol%), and Base in Solvent (1.5 mL) was stirred in a sealed
100 mL Schlenk tube with a air balloon for 24 h, monitored by TLC, and then isolated by column chromatography.
b Isolated yields.
c without the addition of TEMPO
or ligand (Entry 4). To improve this transformation
2,2′-bipyridine (Bipy) was used as ligand in the presence of CuI
(5 mol%) and cocatalyst TEMPO (5 mol%). Selected bases such
as t-BuOK, KOH, pyrrolidine, Et3N, DABCO (1,4-diazabicyclo
[2.2.2] octane), and pyridine were screened. Pyrrolidine was
found to be the best one, giving the highest isolated yield (86%)
of the product (Entry 10), even though only 2 mol% of the
pyrrolidine was used. Next, N,N,N',N'-tetramethylethane
-1,2-diamine (TMEDA ), 4-dimethylaminopyridine (DMAP),
1,10-phenanthroline (Phen), and 4,4′-trimethylenedipyridine
(TMDP) were also tested as the ligands for this catalytic system.
While all of these ligands appear to be effective showing good
yield of 2a (Entries 11-14), Bipy was proved to be the best (Entry
10). Then, various types of Cu compounds (CuCl, Cu(OAc)2,
CuBr, CuSO4, CuO) were tested as the catalyst. CuI was found to
be the best one (See Surpporting information Table 1).
temperature had great influence on the Wittig reaction, but had
little effect on the aerobic oxidation of alcohols. Because a lot of
aldehyde were observed by TLC and GC-MS analysis with the
decrease of the temperature, while the yield of 3a was reduced
greatly (Entries 22, 23).
Using the above optimized conditions various alcohols were
subsequently employed in the one-pot aerobic oxidation-Wittig
reaction with ylide 1 in order to examine the application scope of
this method. Results summarized in Table 2 illustrate that the
expected α, β-unsaturated esters are formed with a moderate to
excellent E/Z selectivity and yield. Substituent electronic effect
was not significant in the tandem reactions, in which various
electron-donating (4-CH3- (3k), and 4-CH3O- (3g)) or
electron-withdrawing groups (4-NO2- (3a), 4-Cl- (3b), 4-F- (3e),
and 4-Br-(3f)) substituted benzylic alcohols all reacted efficiently
with phosphorous ylide 1 to form α, β-unsaturated esters with an
excellent isolated yield. Substituent steric effect was not
significant either, and more hindered ortho-substituted alcohols
such as (2-chlorophenyl)methanol (3d) and (2-methoxyphenyl)
methanol (3j) all reacted smoothly and produced products with a
high yield. Those with reactive functional groups such as fluoro,
chloro, bromo and nitro were also compatible with the reaction
conditions, and no other byproduct was detected by GC-MS.
Naphthalen-2-yl, naphthalen-1-ylsubstituted methanol reacted
The effect of solvent was also investigated. All commercial
solvents (DMSO, xylene, Toluene, CH2Cl2, THF, dioxane, and
DMF) were used directly without any pretreatment (Entries
15-21). In comparison, xylene is the best one, in which 93%
isolated yield of 3a was obtained. It should be noted that all the
reactions were conducted under air condition. Moreover, no over
oxidized product (p-nitrobenzoic acid or p-nitrobenzoate) was
detected by GC-MS analysis of the crude reaction mixtures
during the optimized process. And we found the reaction

3
efficiently with ylide 1 to form alkenes with an excellent yield
and a very high steroselectivity (3n, 3o).
Other aliphatic alcohols (3w-3ab) were also examined under
the optimized reaction conditions. Similarly, reactions of these
aliphatic alcohols were inferior under air condition, and
considerable amounts of unidentified byproducts were generated.
These products could not be separated successfully. However, if
the reactions were carried out under O2 atmosphere, the yield of
the target products could be increased greatly.
Our catalytic system was also applicable for the alcohols
containing heteroatom (N, S, O) (3p-3t) aromatic ring. It is
particularly notable that the reaction of pyridine-3-ylmethanol
with ylide 1 in our copper-catalyzed system was much more
efficient than those using RuAlO(OH)13 as the catalyst, which
generated α, β-unsaturated ester with a 44% yield, and 90% yield
of the product was achieved using our catalytic system.
Meanwhile, larger scale reactions were also possible. For
example, under the optimized conidition 3a was synthesised on
gram scale (10 mmol) with 88% isolated yield.
For 3-phenylprop-2-en-1-ol(3u), the reaction was as efficient
as benzylic alcohol, forming the product with a 86% yield. The
reaction of 3-phenylprop-2-yn-1-ol(3v) was inferior, no target
product was obtained under air condition. However, the reactions
were improved greatly when the tandem reactions were
conducted under O2 atmosphere, in which the products were
obtained with 85% isolated yield. The two isomeric products of
ethyl 5-phenylpent-2-en-4-ynoate (3v) could be separated by
column chromatography, and its E/Z ratio was calculated by
weight of the isomers.
It should be mentioned that secondary alcohol such as
1-phenylethan-1-ol was also examined at the optimized reaction
conditions. We found that 1-phenylethan-1-ol could be oxidized
into acetophenone efficiently, but the Wittig reaction of the
ketone with ylide
1 failed, where no corresponding α,
β-unsaturated ester was formed. This outcome may be attributed
to the fact that acetophenone was not so reactive to react with
stabilized ylide in the Wittig reaction.
Table 2. Reactions of ethyl (triphenylphosphoranylidene) acetate and benzylic or aliphatic alcohols. a
a All reactions were carried out with 1.2 mmol of ylide 1, 1.0 mmol of alcohol 2, CuI (5 mol%), 2,2’-bipyridine (5 mol%), TEMPO (5 mol%), and pyrrolidine (2
mol%) in xylene (1.5 mL) was stirred in 100 mL Schlenk tube with an air or O2 balloon at 65oC for 24 h.
b isolated yield in parenthesis under O2 atmosphere.
c The E/Z ratio was determined by 1H NMR.

4
Commun. 1999, 1337-1338; c) Taylor, R. J. K.; Reid, M.; Foot,
J.; Raw, S. A. Acc. Chem. Res. 2005, 38, 851-869.
8. Vatèle, J. M. Tetrahedron Lett. 2006, 47, 715-718.
9. MacCoss, R. N.; Blaskus, E. P.; Ley, S. V. Tetrahedron Lett.
2003, 44, 7779-7781.
Conclusions
In conclusion, this study presents a new, green, and efficient
Cu-catalyzed system for the aerobic oxidation-Wittig tandem
reaction. The reaction can be readily carried out with an air or O2
balloon under mild conditions. Using mild reaction conditions
enables the Wittig tandem aerobic oxidation reaction to tolerate a
wide range of functionalized alcohol partners as well as the
aliphatic alcohols. Relying on environmentally benign oxidant
and abundant transition metal catalysts makes this simple and
practical method more appealing.
10. Bressette, A. R.; Glover, L. C. Synlett. 2004, 738-740.
11. Crisóstomo, F. R. P.; Carrillo, R.; Martín, T.; García-Tellado, F.;
Martín, V. S. J. Org. Chem. 2005, 70, 10099-10101.
12. Kim, G.; Lee, D. G.; Chang, S. Bull. Korean Chem. Soc., 2001,
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13. Lee, E. Y.; Kim, Y.; Lee, J. S.; Park, J. Eur. J. Org. Chem. 2009,
2943-2946.
14. Read, C. D. G.; Moore, P. W.; Williams, C. M. Green Chem.
2015, 17, 4537-4540.
15. Miyamura, H.; Suzuki, A.; Yasukawa, T.; Kobayashi, S. Adv. Synth.
Catal. 2015, 357, 3815.
Acknowledgments
16. Dutta, I. D.; Sarbajna, A.; Pandey, P.; Rahaman, S. M. W.; Singh,
K.; Bera, J. K. Organometallics. 2016, 35, 1505-1513.
17. For reviews on copper catalyzed oxidation of alcohol, please see:
a) Ryland, B. L.; Stahl, S. S. Angew. Chem., Int. Ed. 2014, 53,
8824-8838; b) Cao, Q. Dornan, L. M.; Rogan, L.; Hughes, N. L.;
Financial supports from the National Natural Science
Foundation of China (Nos. 21302143 and 51572198), Natural
Science Foundation of Zhejiang Province (Nos. LY13B020006,
and LZ17E020002) are greatly appreciated.
−4543
; c) Markó,
Muldoon, M. L. Chem. Commun. 2014, 50, 4524
I. E.; Giles, P. R.; Tsukazaki, M.; Chellé-Regnaut, I.; Gautier, A.;
Dumeunier, R.; Philippart, F.; Doda, K.; Mutonkole, J. L.; Brown,
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References and notes
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584-592.
Supplementary Material
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
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appropriate editorial office.
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5
Highlights
Facile
synthesis
of
α,
β-unsaturated esters through a
one-pot copper-catalyzed aerobic
oxidation-Wittig reaction
Cheng Ren, Zhenyu Shi, Weijie Ding, Zhiqing Liu,
Huile Jin, Xiaochun Yu* and Shun Wang*
College of Chemistry and Materials Engineering, Wenzhou University,
Chashan University Town, Wenzhou, Zhejiang Province 325035, People’s
Republic of China.
The highlights were elucidated as below:
1. Developed a green and efficient one-pot
aerobic oxidation-Wittig tandem.
2. The reaction is catalyzed by CuI.
3. Air or O2 is used as the economic and green
oxidant.
4. A diverse range of α, β-unsaturated esters were
synthesized in high yield.