Copper-catalyzed highly efficient ester formation from carboxylic acids/esters and formates

Article abstract of DOI:10.1039/c4ob00193a

A highly efficient copper-catalyzed protocol for the synthesis of esters has been developed from formates. This protocol is applicable to reactions with either esters or acids as the substrates, and shows broad substrate scopes and high yields. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00193a

Organic &
Biomolecular Chemistry
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Copper-catalyzed highly efficient ester formation
from carboxylic acids/esters and formates†
Jun Liu,a Changdong Shao,a Yanghui Zhang,*a,b Guangfa Shia and Shulei Pana
Cite this: Org. Biomol. Chem., 2014,
12, 2637
Received 24th January 2014,
Accepted 6th March 2014
DOI: 10.1039/c4ob00193a
www.rsc.org/obc
A highly efficient copper-catalyzed protocol for the synthesis of
In recent years, the use of non-noble transition metals,
esters has been developed from formates. This protocol is appli- such as Mn,7 Co,8 Fe,9 Cu,10 and Ni,11 as catalysts has gained
cable to reactions with either esters or acids as the substrates, and extensive attention, and a rapidly growing number of the reac-
shows broad substrate scopes and high yields.
tions enabled by these metals have been reported. Compared
to their 4d and 5d analogues, these elements are relatively
cheap and more abundant in the Earth’s crust.12 In addition,
many of these metals, such as Fe and Cu, are less toxic,
making them environmentally benign catalysts. It should be
The ester functionality represents one of the most common
functional groups and is omnipresent in organic molecules.1
Traditionally, esters can be synthesized via Fisher esterification
with carboxylic acids and alcohols in the presence of acid cata-
lysts or transesterification with esters and alcohols.2 As both
esterification and transesterification are equilibrium reactions,
the use of an excess of one of the reagents or the removal of
one of the products (normally water or alcohol) during the
reaction is required for achieving desirable yields.3 Alter-
natively, esters can be prepared from alcohols and highly
active acylating reagents such as acyl halides and acid an-
hydrides. These reactions require the addition of dehydration
reagents or the preparation of acylating reagents, and generate
a large amount of undesired by-products.4 In addition to these
conventional methods, a variety of alternative methods are
available for the synthesis of esters.2
Due to the ubiquity and importance of esters, developing
new methods for the synthesis of esters is still of great interest
and the subject of extensive studies. Over the past few years,
various novel reactions have been discovered and some of
them have become advantageous alternatives to traditional
esterification methods.5 In this context, transition metal-
catalyzed esterification has gained considerable attention.6 It
should be mentioned that these transition metal-catalyzed
esterifications often involve arylation of carboxylic acids,
which is distinct from the formation of ester bonds in
traditional esterification reactions.
Table 1 Survey of reaction conditions
Entry
2a
Solvent
Oxidant
Yield (%)a
1
2
3
4
5
6
7
8
4.0 equiv.
4.0 equiv.
4.0 equiv.
4.0 equiv.
4.0 equiv.
4.0 equiv.
4.0 equiv.
4.0 equiv.
4.0 equiv.
4.0 equiv.
4.0 equiv.
4.0 equiv.
4.0 equiv.
3.0 equiv.
2.0 equiv.
1.0 equiv.
3.0 equiv.
3.0 equiv.
3.0 equiv.
1.4-Dioxane
CH3CN
DMA
DMSO
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
(NH4)2SO8
Oxone
AcOOH
DCP
DTBP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
—
15
NR
NR
5
27
20
<3
17
78
91
9
10
11
12
13
14
15
16
17
18
19
94
54b
<3c
93 (85d)
66
49
24
TBHP
TBHP
<3e
67f
a The yields were determined by 1H NMR analysis of crude products
using CHCl2CHCl2 as the internal standard. DBPT tert-butyl
peroxide, TBHP = tert-butyl hydroperoxide, DCP = dicumyl peroxide,
DCE 1,2-dichloroethane. Reaction conditions: 1a (0.5 mmol),
Cu(OTf)2 (10 mol%), oxidant (2.0 equiv.), solvent (1.0 mL), 130 °C,
12 h, all of the reactions were run under air. b Cu(OTf)2 = 5 mol%.
c Cu(OTf)2 = 1 mol%. d Isolated yield. e No Cu(OTf)2. f 110 °C.
aDepartment of Chemistry, Tongji University, 1239 Siping Road, Shanghai, 200092,
P. R. China
bKey Laboratory of Yangtze River Water Environment, Ministry of Education, Siping
Road 1239, Shanghai, 200092, P. R. China. E-mail: zhangyanghui@tongji.edu.cn
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob00193a
=
=
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Table 2 Copper-catalyzed esterification of benzoic acids with various
formatesa
Entry
1
Substrate
Product
Yield
82%
2
3
51%b
47%
4
0%
a Reaction conditions: 1a (0.5 mmol), 2 (3.0 equiv.), Cu(OTf)2 (10 mol
%), TBHP (2.0 equiv.), DCE (1.0 mL), 130 °C, 12 h. b Isopropyl formate
as a solvent.
of esters, we herein report a novel copper-catalyzed reaction for
the synthesis of esters from acetates and formates.
The research was prompted by the observation that pentyl
benzoate was formed when benzoic acid was allowed to react
with 4 equivalents of pentyl formate in the presence of
2 equivalents of K2S2O8 and 10% Cu(OTf)2 in 1,4-dioxane
(Table 1). While polar solvents such as CH3CN, DMA, and
DMSO suppressed the formation of the ester, the yield was
improved to 27% with non-polar DCE as the solvent. Gratify-
ingly, the yield increased to 78% when K2S2O8 was replaced
with DCP, and was further improved to 91% and 94% in the
presence of DTBP or TBHP. The use of 10% Cu(OTf)2 proved to
be necessary to achieve excellent yield, as the yield decreased
significantly when the amount of the catalyst was reduced to
5 mol% and 1 mol%. 3 Equivalents of formate were enough
and necessary for the reaction to give a high yield. Further-
more, the reactions gave the desired products in low yields in
the absence of TBHP or Cu(OTf)2, and lowering the tempera-
ture to 110 °C decreased the yield to 67%.
Scheme 1 Copper-catalyzed pentylation of various carboxylic acids.
Reaction conditions: 1 (0.5 mmol), 2a (3.0 equiv.), Cu(OTf)2 (10 mol%),
TBHP (2.0 equiv.), DCE (1.0 mL), 130 °C, 12 h.
noted that iron-catalyzed transesterification has been develo-
ped recently.13
Copper-catalyzed organic reactions have been the subject of
extensive exploration, especially over the past decade, and a
variety of reactions have been discovered, including C–N, C–O,
and C–C bond formation reactions.14 However, copper-
catalyzed reactions for the preparation of esters are rare.15
Although Cu(NO3)2 16 and [Cu2(O2CPh)4]17-catalyzed transester-
ification reactions have been reported, the substrates of these
reactions were limited to acetate/formate or methanol, and
one of the substrates (either acetate/formate or methanol) was
used as the solvent. During the preparation of this manuscript,
the Jiao group described an elegant Cu-catalyzed esterification
reaction of 1,3-diones for the synthesis of α-ketoesters.18
Inspired by the great advantages of copper and the importance
Having identified the optimal protocol for the pentylation
of benzoic acid, we explored the substrate scope with regard to
aromatic carboxylic acids. The protocol proved to tolerate
various functionalities and to be compatible with a wide array
of benzoic acids. As summarized in Scheme 1, ortho-, meta-,
and para-methylbenzoic acids were all transformed into the
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Table 3 Copper-catalyzed transesterification of benzoates with pentyl formatea
Entry
1
Substrate
Yield
91%
Entry
4
Substrate
Yield
86%
2
3
72%
92%
5
74%
a Reaction conditions: 3a (0.5 mmol), 2a (3.0 equiv.), Cu(OTf)2 (10 mol%), TBHP (2.0 equiv.), DCE (1.0 mL), 130 °C, 12 h.
corresponding esters in high yields under the reaction con- had no impact on the yields as the steric hindrance of the
ditions. Halides, including fluoride, chloride, bromide, and alkyl groups did not have negative effects on the yields. Benzyl,
iodide, were all well-tolerated, and the reactions gave good which is a common protecting group in organic synthesis, and
yields. Methoxy and various electron-withdrawing groups vinyl benzoate were also transesterificated in medium and
including trifluoromethyl, nitro, and carbonyl were compatible good yields, respectively. This phenomenon, the protocol is
with the reaction conditions. It should be noted that that applicable to both acids and esters, is very intriguing and
hydroxyl group remained intact during the reaction, and the makes this reaction a versatile method for the synthesis of
presence of a bulky phenyl group did not affect the yield. In esters starting from both esters and acids.
addition, a range of disubstituted benzoic acids underwent the
In summary, owing to the importance of esters and the
esterification reaction effectively. Notably, the esterification existing drawbacks of the current reactions, developing
protocol also proved effective for aliphatic carboxylic acids. efficient methods for the synthesis of esters is still the subject
Finally, the benzyl group and the double bond were tolerated of extensive exploration. In this report, we disclose a novel and
during the reaction.
highly efficient protocol for the synthesis of esters. In this pro-
Next, we probed the substrate scope of this protocol with tocol, cheap and less toxic copper was employed as the cata-
respect to formates. In the conventional esterification reac- lyst. Notably, both carboxylic acids and esters can react with
tions of carboxylic acids and alcohols, the reaction rates pri- formates and can be transformed into the desired esters effec-
marily depend on the steric hindrance of alcohols, and the tively under identical conditions. This reaction demonstrates
reactivities of alcohols decrease with an increase of their sizes. broad substrate scopes and high yields. Mechanistic studies
This tendency was observed in this esterification reaction. As and further studies of this type of reaction are underway in our
shown in Table 2, while the formate with a primary alcohol laboratory.
reacted with benzoic acid in high yield, the yields decreased
substantially for the formates with secondary alcohols and no
desired product was formed in the reaction of tert-butyl
formate. It should be mentioned that an excessive amount of
isopropyl formate had to be used to achieve an acceptable
yield, presumably due to the low boiling point of isopropyl
Acknowledgements
formate.
The work was supported by the National Natural Science Foun-
Notably, under identical conditions, esters also reacted dation of China (no. 21372176), Tongji University 985 Phase III
with formates to give transesterification products effectively. funds, Pujiang Project of Shanghai Science and Technology
As shown in Table 3, a range of benzoates underwent a trans- Commission (11PJ1409800), and the Program for Professor
esterification reaction with pentyl formate to afford pentyl of Special Appointment (Eastern Scholar) at Shanghai
benzoate in good yields. Interestingly, the size of benzoates Institutions of Higher Learning.
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