Diethylene Glycol Serving as Ethyne Equivalent: A Sustainable Approach toward 2,3-Disubstituted Furan

Article abstract of DOI:10.1021/acs.orglett.5b01521

In the presence of tert-butyl peroxide (TBHP), the copper-catalyzed annulation of 1,3-dicarbonyl compound with diethylene glycol was developed leading to 2,3-disubstituted furan. Diethylene glycol serves as a cheap and environmentally friendly equivalent of ethyne, with the release of H₂O and alcohol as clean wastes. The procedure involves a sequential O- and C- functionalization of β-ketoester by diethylene glycol.

Full text of DOI:10.1021/acs.orglett.5b01521

Letter
pubs.acs.org/OrgLett
Diethylene Glycol Serving as Ethyne Equivalent: A Sustainable
Approach toward 2,3-Disubstituted Furan
Jin-Tao Yu,† Bo Shi,‡ Haibo Peng,† Song Sun,† Haoke Chu,† Yan Jiang,† and Jiang Cheng*,†
†School of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, Jiangsu Province Key
Laboratory of Fine Petrochemical Engineering, Changzhou University, Changzhou 213164, P. R. China
‡Jiangsu Key Laboratory of Technologies for Polyamine, Polyol and Derived Polymers, Jiangsu Feixiang Group of Companies, Suzhou
215026, P. R. China
S
* Supporting Information
ABSTRACT: In the presence of tert-butyl peroxide (TBHP),
the copper-catalyzed annulation of 1,3-dicarbonyl compound
with diethylene glycol was developed leading to 2,3-
disubstituted furan. Diethylene glycol serves as a cheap and
environmentally friendly equivalent of ethyne, with the release
of H2O and alcohol as clean wastes. The procedure involves a sequential O- and C- functionalization of β-ketoester by diethylene
glycol.
ustainable chemistry is spurring the chemist to develop
Smany important new types of C−C and C−hetero bond-
forming reaction using alcohols because these represent
renewable starting materials derived from biomass.1 With
these considerations in mind, we recently tested the feasibility
of annulating 1,3-ketones with alcohols to construct the
framework of furans (Scheme 1), which are ubiquitous natural
and synthetic substances.2
Fe(acac)2 all failed to work (Table 1, entries 1−4). To our
delight, however, 2-phenyl-3-(ethoxycarbonyl)furan 3a was
isolated in 60% yield by using Cu(OTf)2 as a catalyst (Table
Table 1. Selected Results for Screening the Optimized
a
Reaction Conditions
Scheme 1. Design Plan
b
entry
catalyst
oxidant
solvent
yield (%)
c
1
I2
TBHP
<1
<1
<5
<1
60
<1
40
c
2
Bu4NI
TBHP
c
3
FeCl2
TBHP
c
4
Fe(acac)2
Cu(OTf)2
Cu(OAc)2
Cu(NO3)2·3H2O
TBHP
c
5
TBHP
c
6
TBHP
c
7
TBHP
d
c
e
e,
f
e,g
8
Cu(BF4)2
TBHP
64 (71) (62) (49)
d
9
Cu(BF4)2
BPO
50
38
37
<5
59
<5
<1
d
10
11
12
13
14
15
Cu(BF4)2
DTBP
Conceptually, the procedure may start with the α-alkylation
of a 1,3-dicarbonyl compound by the alcohol.3 Then α-
functionalization of the second hydroxy takes place by O-
functionalization of the 1,3-ketone to construct the framework
of a 2H-furan.4 Finally, the elimination of ROH will provide the
2,3-disubstituted furan. During the reaction, the waste is H2O
and ROH. Thus, an alcohol serves as a cheap, safe,
reproducible, and environmentally friendly equivalent of
ethyne.
Our study started by using the model reaction below.
Phenylacetoacetic acid ethyl ester (0.5 mmol) and TBHP (tert-
butyl hydroperoxide, 70% aqueous, 1.0 mmol) in neat
diethylene glycol (1 mL) under N2 were heated at 120 °C
for 5 h. Disappointingly, catalysts such as I2, Bu4NI, FeCl2, and
d
c
h
Cu(BF4)2
TBHP
PhCl
d
c
h
Cu(BF4)2
TBHP
THF
d
c
h
Cu(BF4)2
TBHP
Cy-H
c
TBHP
d
Cu(BF4)2
a
Reaction conditions: 1a (0.5 mmol), catalyst (10 mol %), oxidant
(1.0 mmol) (TBHP = tert-butyl hydroperoxide, DTBP = di-tert-butyl
peroxide, BPO = benzoyl peroxide), 2 (1.0 mL), at 120 °C under N2
b
c
for 5 h, sealed tube. Isolated yield. TBHP (70% in water).
d
e
f
g
h
Cu(BF4)2 (45% in water). 100 °C. Air. O2. 2.0 mL.
Received: May 25, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01521
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
After the optimal reaction conditions were identified, we
studied the scope of the 1,3-dicarbonyl compounds that could
be used, as shown in Table 2. As expected, all substrates reacted
smoothly under the standard procedure. Importantly, the
reaction was not limited to phenylacetoacetic acid ester, as
ketone, amide, and thioester analogues all worked under the
standard procedure. For example, 3c, 3o, 3p, and 3q were
isolated in 35%, 46%, 46%, and 60% yields, respectively. The
presence of bromo and chloro groups in the phenyl ring of
phenylacetoacetic acid ester appeared to be tolerated well.
These provide handles for further functionalization. The methyl
in the ortho- position of the phenyl had no effect on the
reaction since 3j was isolated in 64% yield. Notably,
heteroarylacetoacetic acid esters took part in the annulation
reaction, providing 3l and 3m in 43% and 60% yields,
respectively. Acetoacetic acid ethyl ester proved to be a good
reaction partner with a 59% yield of isolated 3n. In the case of
1-phenylbutane-1,3-dione, two isomers were isolated in a ratio
of 1.7:1 and a total yield of 60%.
Table 2. Scope of Substrates
Notably, ethylene glycol, 2-methoxyethanol, and ethyl ether
also served as equivalents of ethyne, providing the annulation
products in 54%, 40%, and 38% yields, respectively (Scheme 2).
However, glycerin failed to work in this procedure.
Scheme 2. Scope of Glycol and Its Derivatives
To obtain insights into the mechanism, more experiments
were conducted. Recently, vinyl acetate and its analogues could
serve as an ethyne equivalent in the annulation reactions.5
Thus, we subjected 2-(vinyloxy)ethanol to the standard
procedure. However, the annulation product was only isolated
in 26% yield, which ruled out the possibility of having a vinyl
alcohol ether as a reaction intermediate (eq 1, Scheme 3).
Moreover, adding the radical scavenger TEMPO (2,2,6,6-
tetramethyl-1-piperidinyloxyl) inhibited the reaction, and the
Scheme 3. Preliminary Mechanism Study
a
Reaction conditions: 1 (0.5 mmol), Cu(BF4)2 (45% in water, 10 mol
%), TBHP (70% in water, 1.0 mmol), 2 (1.0 mL), at 100 °C under N2
b
c
for 5 h, sealed tube. 26 h. 10 h.
1, entry 5). Cu(OAc)2 did not work in the procedure, while
Cu(NO3)2·3H2O provided the annulation product in 40% yield
(Table 1, entries 6 and 7). Cu(BF4)2 (45% in water) was found
to be the best choice producing a 64% yield of 3a (Table 1,
entry 8). The yield could be further increased to 71% by
operating at 100 °C (Table 1, entry 8). Conducting the
reaction under air or O2 significantly decreased the yield (Table
1, entry 8). BPO (benzoyl peroxide) and DTBP (di-tert-butyl
peroxide) worked to some extent (Table 1, entries 9 and 10).
Solvents such as PhCl, THF, or cyclohexane all decreased the
reaction efficiency (Table 1, entries 11−13). No reaction took
place in the absence of either copper or peroxide (Table 1,
entries 14 and 15).
B
DOI: 10.1021/acs.orglett.5b01521
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(2) For reviews, see: (a) Brown, R. C. D. Angew. Chem., Int. Ed. 2005,
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T. W. In Heterocyclic Chemistry in Drug Discovery; Li, J. J., Eds.; Wiley:
New York, 2013; pp 119−196. (f) Yeung, K.-S.; Peng, X.-S.; Wu, J.;
Fan, R.; Hou, X.-L. Five-Membered Ring Systems: Furans and
Benzofurans. Progress in Heterocyclic Chemistry; Elsevier: New York,
2013; Vol. 25, pp 183−215. (g) Cadierno, V.; Crochet, P. Adv. Org.
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adduct of TEMPO radical with β-ketoester was isolated,
indicating that a radical pathway may be involved in this
transformation (eq 2). The potential intermediates 4 and 5
were prepared and subjected to the standard procedure.
However, the yield of 3aa was quite low (eqs 3 and 4).
Thus, the path described in Scheme 1 was not possible.
On the basis of these experimental results, the tentative
pathway of these reactions is outlined in Scheme 4. In step 1,
Scheme 4. Plausible Reaction Pathway
(3) Alkylation of ketone with alcohol: (a) Li, Z.; Yu, R.; Li, H. Angew.
Chem., Int. Ed. 2008, 47, 7497. (b) Chan, L. K. M.; Poole, D. L.; Shen,
D.; Healy, M. P.; Donohoe, T. J. Angew. Chem., Int. Ed. 2014, 53, 761.
(c) Bibby, C. E.; Grigg, R.; Price, R. J. Chem. Soc., Dalton Trans. 1977,
872.
(4) O-Functionalization of ketone: (a) Trost, B. M.; Xu, J.; Schmidt,
T. J. Am. Chem. Soc. 2009, 131, 18343. (b) House, H. O.; Auerbach, R.
A.; Gall, M.; Peet, N. P. J. Org. Chem. 1973, 38, 514. (c) Laclef, S.;
Exner, C. J.; Turks, M.; Videtta, V.; Vogel, P. J. Org. Chem. 2009, 74,
8882. (d) Trost, B. M.; Xu, J. J. Org. Chem. 2007, 72, 9372. (e) Yoo,
W.-J.; Li, C.-J. J. Org. Chem. 2006, 71, 6266.
(5) (a) Webb, N. J.; Marsden, S. P.; Raw, S. A. Org. Lett. 2014, 16,
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Org. Chem. 2015, 80, 620.
the α-functionalization of the substrate 2 takes place at the O
atom in the β-ketoester to produce intermediate 7, along with
the loss of 1 equiv of H2O. In this case, a radical pathway may
be involved as confirmed by the radical scavenger experiment,
and copper took part in the single-electron-transferring (SET)
process to fulfill this transformation.6 After that, the C-
functionalization occurs at the α′-position of intermediate 7
to afford intermediate 8. Finally, the elimination of 1 equiv of
HOCH2CH2OH in intermediate 8 constructs the framework of
furan.
(6) For the copper-catalyzed O-functionalization of dicarbonyl
compounds via α-C−H bond activation of ethers, see: Kumar, G. S.;
Pieber, B.; Reddy, K. R.; Kappe, C. O. Chem. - Eur. J. 2012, 18, 6124.
In conclusion, a copper-catalyzed annulation of 1,3-
dicarbonyl compound with diethylene glycol was developed,
leading to 2,3-disubstituted furans. The procedure features the
application of alcohols as renewable starting materials. Thus, it
represents a sustainable pathway to access 2,3-disubstituted
furans.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures along with copies of spectra. The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.5b01521.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jiangcheng@cczu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21272028 and 21202013), “Innovation & Entrepreneur-
ship Talents” Introduction Plan of Jiangsu Province, Qing Lan
Project of Jiangsu Province, Jiangsu Key Laboratory of
Advanced Catalytic Materials &Technology (BM2012110),
and the Priority Academic Program Development of Jiangsu
Higher Education Institutions (PAPD) for financial support.
REFERENCES
■
(1) (a) Schranck, J.; Tlili, A.; Beller, M. Angew. Chem., Int. Ed. 2013,
52, 7642. (b) Zakzeski, J.; Bruijnincx, P. C. A.; Jongerius, A. L.;
Weckhuysen, B. M. Chem. Rev. 2010, 110, 3552.
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DOI: 10.1021/acs.orglett.5b01521
Org. Lett. XXXX, XXX, XXX−XXX