Copper-catalyzed three-component reactions of phenols, acyl chlorides and Wittig reagents for the synthesis of β-aryloxyl acrylates

Article abstract of DOI:10.1039/c4nj02010c

The synthesis of aryloxyl acrylates has been achieved through a new three-component synthetic method involving the assembly of phenols, acyl chlorides and Wittig reagents in the presence of a copper catalyst using glucose as a green ligand. β-Aryloxyl acrylates have been prepared with high diversity and in good to excellent yields involving the cascade formation of a new CC bond and a C(sp²)-O bond.

Full text of DOI:10.1039/c4nj02010c

NJC
View Article Online
View Journal
LETTER
Copper-catalyzed three-component reactions
of phenols, acyl chlorides and Wittig reagents
for the synthesis of b-aryloxyl acrylates†
Cite this:DOI: 10.1039/c4nj02010c
Received (in Montpellier, France)
11th November 2014,
Yi Zhang, Yunyun Liu and Jie-Ping Wan*
Accepted 5th December 2014
DOI: 10.1039/c4nj02010c
www.rsc.org/njc
The synthesis of aryloxyl acrylates has been achieved through a new
three-component synthetic method involving the assembly of phenols,
acyl chlorides and Wittig reagents in the presence of a copper catalyst
using glucose as a green ligand. b-Aryloxyl acrylates have been pre-
pared with high diversity and in good to excellent yields involving the
2
Q
cascade formation of a new C C bond and a C(sp )–O bond.
b-Aryloxyl acrylates and analogous compounds constitute a
class of important organic compounds. They have been broadly
involved as either main building blocks or key intermediates in
the synthesis of numerous useful organic products.1 In addition,
the polar CQC bond in these acrylates is a potential highly
reactive site that can be used for the rational design of new
synthetic reactions. According to the known literature, b-aryloxyl
acrylates have been prepared by employing several different
synthetic approaches such as the oxa-Michael addition of phenols
to propiolates (eqn (1), Scheme 1),2 the copper-catalyzed O-arylation
of enonates (eqn (2), Scheme 1),3 and the coupling of phenols
with haloacrylates.4 While these methods constitute the main
current options towards the synthesis of b-aryloxyl acrylates,
Scheme 1 Different routes to aryloxyl acrylates.
these two-component protocols suffer from the common limita- structural diversity and complexity.5 Owing to their exceptional
tion of low product diversity since only the two reaction partners step economy and low chemical/energy consumption, MCRs have
allow structural variation. In this regard, devising a diversity now been well recognized as an important sustainable synthetic
oriented synthetic tactic is of significant urgency in the field of strategy.6 Therefore, following our long-standing interest in the
b-aryloxyl acrylate chemistry.
chemistry of MCRs,7 and in order to develop diversity oriented
Multicomponent reactions (MCRs) employ three or more synthetic methodologies toward the synthesis of b-aryloxyl acrylates,
reactants to assemble the desired products in one vessel with one we report herein a three-component protocol for the synthesis
set of reaction conditions fixed in one operation. The unique of structurally diverse products using simple starting materials
advantages of MCRs lie in their power to furnish multiple chemical consisting of phenols, Wittig reagents and acyl chlorides via the
transformations (bond cleavage and formation) in one-pot, and functionalization of the sp2C (CO)–Cl bond.8 The construction
the rapid generation of chemical products with significant of the desired product consists of a Wittig reaction/phenol
vinylation cascade using CuBr as catalyst and glucose as a
naturally green ligand9 (eqn (3), Scheme 1).
At the beginning, the investigation started from running the
model reaction of phenol 1a, Wittig reagent 2a and acetyl chloride
3a. It was found that the presence of a copper catalyst, CuBr, a
ligand 1,10-phenanthroline (L1) and Et3N/Cs2CO3 as the base
Key Laboratory of Functional Small Organic Molecules, Ministry of Education,
College of Chemistry and Chemical Engineering, Jiangxi Normal University,
Nanchang 330022, P. R. China. E-mail: wanjieping@gmail.com
† Electronic supplementary information (ESI) available: General information,
experimental procedure, characterization data, 1H and 13C NMR spectra for all
products. See DOI: 10.1039/c4nj02010c
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2014
New J. Chem.

View Article Online
Letter
NJC
Table 1 Results on optimizing reaction conditionsa
Table 2 Synthesis of different b-aryloxyl acrylates 4a
R1
R2
R3
Product
Yieldb (%)
Entry
Cat. (mol%)
Ligand
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
No
No
L1
L2
L3
L4
L5
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
No
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
22
30
47
52
35
30
21
40
37
31
Trace
Trace
40
36
34
65
30
H
4-Me
4-Cl
4-CO2Me
2-Cl
2-I
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
Me
Me
Me
Me
Et
n-Pr
n-Pr
Me
Me
Me
Me
i-Bu
i-Bu
i-Bu
Me
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
65
49
58
48
60
56
40
45
43
63
55
46
43
41
44
45
47
4-Cl
4-Cl
CuI
CuO
9
4-Br
H
4-Me
4-CO2Me
3-COMe
H
4-Cl
4-Br
4-Cl
Et
10
11c
12
13
14
15
16
17
18
19d
20e
Cu(OAc)2
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
Me
Me
Me
Me
Me
Me
Me
t-Bu
K2CO3
NaOH
t-BuONa
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Toluene
Dioxane
DMF
35
58
55
a
General conditions: 1 (0.30 mmol), 2 (0.45 mmol), 3 (0.45 mmol), Et3N
(0.45 mmol), CuBr (0.03 mmol), L3 (0.06 mmol) and Cs2CO3 (0.6 mmol)
DMF
b
in CH2Cl2 (2 mL), DMF (2 mL), stirred at 90 1C for 8 h. Yield of
isolated product based on 1.
It can be seen from the results that the protocol was generally
tolerable to the synthesis of b-aryloxyl acrylates 4 employing a
variety of different starting materials. Because of the ease of
availability, the phenol component displayed the best diversity
in providing the desired products, and substituents with either
electron-withdrawing and electron-donating properties in differ-
a
General conditions: 1a (0.30 mmol), 2a (0.45 mmol), 3a (0.45 mmol),
Et3N (0.45 mmol), Cu catalyst (0.03 mmol), ligand (0.06 mmol) and base
(0.6 mmol) in an additional solvent (2 mL) together with CH2Cl2 c(2 mL),
b
stirred at 90 1C for 8 h. Yield of isolated products based on 1a. In the
absence of Et3N. Reaction at 100 1C. Reaction at 80 1C.
d
e
additive could promote the reaction to produce the desired product ent sites were tolerated to give acrylate products in moderate to
4a, albeit in a low yield (entries 1 and 2, Table 1). The result good yield. Most notably, based on the multicomponent fashion,
inspired us to conduct a systematic optimization of the reaction the easy variation of the acyl chloride component allowed the
conditions. Initially, a class of different ligands, including the cyclic generation of expanded higher diversity in the ester b-site of the
ketoester L2, D-glucose L3, triphenyl phosphine L4 and the products than most methods previously reported on the synthesis
enaminone-based ligand L5 were employed. Among these ligands, of analogous products. What’s more, the products were all
D-glucose L3 exhibited the best effect in assisting the reaction obtained with excellent stereoselectivity, as the product was
(entries 3–6, Table 1). Subsequently, different cuprous and cupric obtained with either the E or Z-configuration only in every entry.10
catalysts as well as an entry without using a copper catalyst were
As an additional example, the entry using resorcinol 5 as the
examined, and no better copper catalyst was identified for the phenol substrate was also examined in the presence of reaction
model reaction (entries 7–10, Table 1). A control experiment in the partners 2b and 3a. The result from the entry showed that the
absence of either Et3N or Cs2CO3 did not give the desired product bisacrylate 6 was the only isolable product under the standard
in an isolable amount probably because Et3N was required for the reaction conditions (eqn (4)). However, attempts at employing
in situ generation of the allene intermediate while Cs2CO3 was the pyrocatechol and hydroquinone failed to provide the expected
base required to assist copper catalysis.1b,c During further examina- products probably because of their tendency to be present as
tion using different bases (entries 13–15, Table 1) and solvents hydroquinone isomers.
(entries 16–18, Table 1), Cs2CO3 and DMF turned out to be the
most favorable base and reaction medium, respectively. Finally,
variation of the reaction temperature proved that 90 1C was the
appropriate temperature (entries 19 and 20, Table 1).
Following the definition of the optimal conditions, an array of
different substrates for each component containing various sub-
structures have been employed for the synthesis of the desired
products 4. The results from this section were shown in Table 2.
(4)
New J. Chem.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2014

View Article Online
NJC
In conclusion, we have developed a copper-catalyzed three-
Letter
Stewart, M. Shevlin, A. D. G. Yamagata, A. W. Gibson,
S. P. Keen and J. P. Scott, Org. Lett., 2012, 14, 5440; (d) M.-J.
Fan, G.-Q. Li, L.-H. Li, S.-D. Yang and Y.-M. Liang, Synthesis,
2006, 2286.
3 Z.-F. Xu, C.-X. Cai, M. Jiang and J.-T. Liu, Org. Lett., 2014,
16, 3436.
4 V. Rosnati and A. Saba, Tetrahedron Lett., 1981, 22, 167–168.
5 For reviews on MCRs, see: (a) B. H. Rotstein, S. Zaretsky, V. Rai
and A. K. Yudin, Chem. Rev., 2014, 114, 8323; (b) A. Domling,
component reaction of phenols, Wittig reagents and acyl chlorides
as a new methodology towards the synthesis of b-aryloxyl acrylates.
When compared with known synthetic processes, the advantages of
the present method lie in the simplicity and ease of availability
of all three substrates involved in the process. More notably, the
product diversity produced by varying the acyl chloride component
allowed the synthesis of a class of new b-aryloxyl acrylates. There-
fore, the present method can be a useful option for the synthesis of
b-aryloxyl acrylate products.
¨
W. Wang and K. Wang, Chem. Rev., 2012, 112, 3083;
´
(c) B. B. Toure and D. G. Hall, Chem. Rev., 2009, 109, 4439;
(d) J.-P. Wan and Y. Liu, Synthesis, 2010, 3943; (e) J.-P. Wan and
Y. Liu, RSC Adv., 2012, 2, 9763; ( f ) Y. Liu, H. Wang and
J.-P. Wan, Asian J. Org. Chem., 2013, 2, 374; (g) J.-P. Wan,
Y. Lin and Y. Liu, Curr. Org. Chem., 2014, 18, 687.
6 (a) R. C. Cioc, E. Ruijter and R. V. A. Orru, Green Chem.,
2014, 16, 2958; (b) M. S. Singh and S. Chowdhury, RSC Adv.,
2012, 2, 4547.
Experimental
General procedure for the synthesis of b-aryloxyl acrylates 4 and 6
In a 25 mL round bottom flask, ylide 2 (0.45 mmol) was
dissolved in CH2Cl2 (2 mL). Acyl chloride 3 (0.45 mmol), Et3N
(0.45 mmol), phenol 1 (0.3 mmol), CuBr (0.03 mmol), L3
(0.06 mmol), Cs2CO3 (0.6 mmol) and DMF (2 mL) were then
added to the vessel. For the synthesis of 6, all reagents except
phenol and DMF were doubled. The resulting mixture was
stirred at 90 1C for 8 h (TLC). The reaction was allowed to stand,
cool down to room temperature and 10 mL of water added.
The heterogeneous mixture was extracted with ethyl acetate
(3 Â 10 mL). The combined organic layers were dried overnight
with anhydrous Na2SO4. The solution was then collected by
filtration and the solvent removed under reduced pressure.
The residue was subjected to silica gel column chromatography
to give the pure desired product using mixed petroleum ether
and ethyl acetate (VPET : VEA = 60: 1).
7 (a) J.-P. Wan, H. Wang, Y. Liu and H. Ding, Org. Lett., 2014,
16, 5160; (b) J.-P. Wan, Y. Lin, Q. Huang and Y. Liu, J. Org.
Chem., 2014, 79, 7232; (c) J.-P. Wan, Y. Zhou and S. Cao,
J. Org. Chem., 2014, 79, 9872; (d) J.-P. Wan, Y. Lin, Y. Jing,
M. Xu and Y. Liu, Tetrahedron, 2014, 70, 7874; (e) J.-P. Wan,
Y. Lin, K. Hu and Y. Liu, Beilstein J. Org. Chem., 2014, 10, 287;
( f ) J.-P. Wan, Y. Zhou, Y. Liu, Z. Fang and C. Wen, Chin.
J. Chem., 2014, 32, 219; (g) J.-P. Wan, R. Zhou, Y. Liu and
M. Cai, RSC Adv., 2013, 3, 2477; (h) J.-P. Wan, Y. Zhou,
K. Jiang and H. Ye, Synthesis, 2014, 46, 3256.
8 For known synthetic examples involving acyl chloride C–Cl bond
functionalization, see: (a) R. Murashige, Y. Hayashi, S. Ohmori,
A. Torii, Y. Aizu, Y. Muto, Y. Murai, Y. Oda and M. Hashimoto,
Tetrahedron, 2011, 67, 641; (b) W. Sun, Y. Wang, X. Wu and
X. Yao, Green Chem., 2013, 15, 2356; (c) J. Chen, Y. Peng, M. Liu,
J. Ding, W. Su and H. Wu, Adv. Synth. Catal., 2012, 354, 2117;
(d) X. Pan and D. P. Durran, Org. Lett., 2014, 16, 2728;
(e) B. Huang, L. Yin and M. Cai, New J. Chem., 2013, 37, 3137.
9 For example involving glucose-based ligand in copper-
catalyzed coupling reactions, see: (a) D. Cheng, F. Gan,
W. Qian and W. Bao, Green Chem., 2008, 10, 171;
(b) S. K. Guchhait, A. L. Chandgude and G. Priyadarshani,
J. Org. Chem., 2012, 77, 4438; (c) A. K. Jha and N. Jain,
Tetrahedron Lett., 2013, 54, 4738; (d) K. G. Thakur and
G. Sekar, Chem. Commun., 2011, 47, 6692.
The work is financially supported by the National Natural
and Science Foundation of China (no. 21102059) and a research
project from the Department of Education of Jiangxi Province
(GJJ13245).
Notes and references
1 (a) G. W. Stewart, M. Shevlin, A. D. G. Yamagata, A. W. Gibson,
S. P. Keen and J. P. Scott, Org. Lett., 2012, 14, 5440; (b) J.-P. Wan,
H. Wang, Y. Liu and H. Ding, Org. Lett., 2014, 16, 5160;
(c) Y. Liu, H. Wang and J.-P. Wan, J. Org. Chem., 2014,
79, 10599; (d) J. Dai, K. Krohn, S. Draeger and B. Schulz, Eur.
J. Org. Chem., 2009, 1564; (e) W. H. Miles, E. J. Fialcowitz and
E. S. Halstead, Tetrahedron, 2001, 57, 9925.
10 For the assignment of the olefin configuration, see:
S. E. Kharrat, P. Laurent and H. Blancou, J. Org. Chem.,
2006, 71, 6742.
2 (a) Y. Sarrafi, M. Sadatshahabi, K. Alimohammadi and
M. Tajbakhsh, Green Chem., 2011, 13, 2851; (b) W. J. Kinart
and A. Kinart, Appl. Organomet. Chem., 2007, 21, 373; (c) G. W.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2014
New J. Chem.