An efficient methodology to substituted furans via oxidation of functionalized α-diazo-β-ketoacetates

Article abstract of DOI:10.1016/j.tetlet.2010.11.166

DMDO oxidation of functionalized α-diazo-β-ketoacetates, formed by zinc triflate catalyzed Mukaiyama-aldol condensation of methyl diazoacetoacetate with aldehydes, occurred in quantitative yield to form dihydrofuranols that undergo acid catalyzed dehydrat

Full text of DOI:10.1016/j.tetlet.2010.11.166

Tetrahedron Letters 52 (2011) 2093–2096
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Tetrahedron Letters
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An efficient methodology to substituted furans via oxidation of functionalized
a-diazo-b-ketoacetates
⇑
Phong Truong, Xinfang Xu, Michael P. Doyle
Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 14 January 2011
DMDO oxidation of functionalized a-diazo-b-ketoacetates, formed by zinc triflate catalyzed Mukaiyama-
aldol condensation of methyl diazoacetoacetate with aldehydes, occurred in quantitative yield to form
dihydrofuranols that undergo acid catalyzed dehydration under mild conditions to generate 3-methoxy-
furan-2-carboxylates in good yield.
Dedicated to Harry Wasserman on the
occasion of his 90th birthday
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Diazoacetate
Vicinal-tricarbonyl
Dimethyldioxirane
Oxidation
Furan
1. Introduction
The advantages of this procedure are the ease of preparation and
handling of the diazoacetoacetate reactants, the quantitative oxida-
The vicinal tricarbonyl (VTC) moiety is an important functional
unit in organic synthesis. This is mainly due to the highly electro-
philicnatureof thecentralcarbonylcarbon, whichcanundergobond
formation with a variety of nucleophiles.1 The first VTC compound
was synthesized in 1890,2 and since then there have been a large
number of methods developed for their preparation.3 In what have
been an insightful contributions to the synthetic developments that
utilize this chemistry, Wasserman and coworkers demonstrated
multiple applications of the VTC system in the synthesis of b-lac-
tams,4 alkaloids,5 pyrroles,6 and indolizidines.7
In one application Wasserman used VTC compounds in a novel
synthetic route directed to the synthesis of substituted furans
(Scheme 1, Eq. 1),8 an important class of compounds due to their
abundance in natural products and biologically relevant molecules.
In this methodology, the VTC unit was prepared by oxidation of
phosphorus ylides that were synthesized from enolates of acyl phos-
phoranylidine carboxylates. Subsequent dehydration using PTSA
yielded 3-hydroxy-furan-2-carboxylates in moderate yields. Herein,
we report an improved approach for the synthesis of substituted
tion under neutral conditions, and the conversion of the VTC com-
pounds to alkoxy-furans under mild conditions.
2. Results and discussion
Our synthesis begins with commercially available aldehydes A
and methyl
transfer to methyl acetoacetate.10
clude B are stable under a wide range of conditions.11 TBSO-
functionalized -diazo-b-ketodicarbonyl compounds were
obtained by a convenient one-pot Mukaiyama-aldol reaction of
a-diazoacetoacetate B that is easily prepared by diazo
a
-Diazoacetoacetates that in-
a
1
aldehydes A and methyl
a-diazoacetoacetate B in high yield
(Scheme 2).9 The TBSO-functionalized condensation products (1)
were easily hydrolyzed with 4 N HCl in THF to form the
corresponding alcohol products 2 in high yields (Table 1).
With a variety of functionalized
a-diazo-b-ketodicarbonyl 2 in
hand, we next sought to oxidize the diazo group to a carbonyl
group. We initially began with t-butyl hypochlorite as an oxidant,
since several reports have shown that t-butyl hypochlorite
furans that utilize the oxidation of functionalized
a-diazo-b-
can generate VTC compounds from
a-diazo-b-dicarbonyl com-
pounds.12 In our hands, however, the use of t-butyl hypochlorite
acetoacetates, formed by zinc triflate catalyzed Mukaiyama-aldol
condensation of alkyl diazoacetoacetates with aldehydes,9 to gener-
ate VTC systems using dimethyldioxirane (DMDO) (Scheme 1, Eq. 2).
afforded the desired product in moderate yield along with other
unidentified by-products. As Saba reported that
a-diazo-b-
dicarbonyl compounds were oxidized to VTC derivatives using
dimethyldioxirane (DMDO) in high yield,13 we subjected diazo
substrates 2 to DMDO.14 This process resulted in the quantitative
oxidation of the full range of diazo compounds 2. The oxidized
⇑
Corresponding author. Tel.: +1 11 301 405 1788; fax: +1 11 301 314 2779.
E-mail address: mdoyle3@umd.edu (M.P. Doyle).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.166

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P. Truong et al. / Tetrahedron Letters 52 (2011) 2093–2096
O
O
O
O
OH
COOR3
O
O
O
R1
COOR3
R1
R2
R1
R2
R1
O3 or
Oxone
OR3
OR3
PTA
(Eq. 1)
PPh3
O
Benzene, reflux
R2
O
R3
OH
OH
OH
68-95%
PTA
COOMe
R
O
O
Benzene, reflux
O
O
OH
COOMe
O
H
R
R
DMDO
Acetone
H
H
R
OH
OMe
OMe
(Eq. 2)
N2
O
O
OH
H
OH
O
PTA
COOMe
R
100%
Methanol, reflux
H
OMe
Scheme 1.
Table 2
Oxidation of
O
Zn(OTf)2
2,6-lutidine
TBSOTf
O
O
OTBS
O
O
a
-diazoacetoacetates 2 to a vicinal tricarbonyl with DMDOa
+
R
H
OMe
R
OMe
CH2Cl2,
-78 °C to rt
O
O
O
O
N2
1
N2
OH
DMDO (3eq.)
O
A
B
R
Acetone
0 °C to rt.
16hr
OMe
COOMe
OMe
4N HCl
THF
N2
O
R
O
OH
R
OH
2
3
4
OH
O
O
Entry
R
Productb
drc
R
OMe
1
2
3
4
5
6
7
8
9
n-Heptyl
t-Butyl
C6H5
2-NO2C6H4
4-NO2C6H4
4-ClC6H4
3,5-(CH3)2C6H3
1,4,6-(CH3)3C6H2
2-Napthyl
4a
4b
4c
4d
4e
4f
4g
4h
4i
33:67
26:74
30:70
36:64
35:65
34:66
32:68
15:85
29:71
2
N2
Scheme 2.
Table 1
Hydrolysis of compound 1 via Scheme 2a
a
b
c
Reaction performed in acetone at 0 °C with dimethyldioxirane as oxidant.
Quantative yield of products 4 were obtained.
Entry
R
Product
Yieldb (%)
Determined by 1H NMR of the crude product 4.
1
2
3
4
5
6
7
8
9
n-Heptyl
t-Butyl
C6H5
2-NO2C6H4
4-NO2C6H4
4-ClC6H4
3,5-(CH3)2C6H3
2,4,6-(CH3)3C6H2
2-Napthyl
2a
2b
2c
2d
2e
2f
2g
2h
2i
90
90
95
91
92
88
93
85
95
OH
O
O
COOMe
R1
R
PTA
COOMe
a
Benzene, reflux
Reaction performed in THF at room temperature using 4 N HCl for hydrolysis.
Isolated yield.
H
H
OH
O
b
4
5
Isolated Yield (%)
R = C6H5
R = 2-NO2-C6H4
51
40
compounds 3 are in equilibrium with dihydrofuranols 4 (Table 2)
and existed as a mixture of diastereomers. The diastereomer ratios
of 4, obtained from their 1H NMR spectra, were approximately 1:2
for most of the compounds. Compound 4h had the highest dr ratio
(1:5.6) due to the steric effect mesityl group. Compounds 4 were
easily isolated by evaporation of acetone and taken to the next step
without further purification.
Scheme 3.
relatively low yield. However, changing the reaction solvent to
methanol resulted in the expected conversion of hemiketal 4 to
3-methoxyfuran-2-carboxylates 6 (Table 3). This modification also
allowed for ease in purification since the 3-hydroxyfuran-2-
carboxylates 5 were otherwise difficult to purify.
A proposed mechanism for the formation of 3-methoxyfuran-2-
carboxylates 6 is given in Scheme 4. Hemiketal formation at posi-
tion 3 is proposed to precede formation of vinyl ether A, which
The hemiketal form of furanone 4 then underwent acid cata-
lyzed dehydration to form 3-hydroxyfuran-2-carboxylates
5
(Scheme 3) by the same procedure as that employed by
Wasserman and Lee.8 However, reactions in refluxing benzene
together with catalytic PTSA resulted in product decomposition,
and isolation of 5 by silica gel chromatography occurred in a

P. Truong et al. / Tetrahedron Letters 52 (2011) 2093–2096
2095
Table 3
Acid catalyzed dehydration for the synthesis of 3-methoxy-2-carboxylate furansa
OH
O
O
COOMe
R1
R
PTA
COOMe
Methanol, reflux
H
H
OMe
O
4
6
Entry
1
R
Product
COOMe
Yieldb (%)
O
n-Heptyl
6a
6b
90
91
OMe
O
COOMe
2
3
t-Butyl
OMe
O
COOMe
C6H5
6c
80
86
OMe
O
COOMe
4
5
6
2-NO2-C6H4
4-NO2-C6H4
4-Cl-C6H4
6d
NO2
OMe
O2N
O
COOMe
6e
6f
92
75
OMe
Cl
O
COOMe
OMe
O
COOMe
7
8
9
3,5-(CH3)2-C6H3
1,4,6-(CH3)3-C6H2
2-Napthyl
6g
6h
6i
75
60c
85
OMe
O
COOMe
OMe
O
COOMe
OMe
a
b
c
Reaction was refluxed in methanol with p-toluenesulfonic acid monohydrate (PTSA) overnight.
Isolated yield.
Combined yield of product and impurity from reaction mixture, which is unable to be separated by general silica gel chromatography.
subsequently undergoes acid catalyzed dehydration to generate
furan 6. By replacing methanol with a different alcohol, the poten-
tial for further modifications in product formation at position 3 is
suggested in this mechanism.
3. Conclusion
In summary, we have developed an efficient method for the
synthesis of 3-methoxyfuran-2-carboxylates and developed an

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P. Truong et al. / Tetrahedron Letters 52 (2011) 2093–2096
OH
O
O
OH
O
Dehydration
[-H2O]
R
R
COOMe
Me
PTSA
R
COOMe
Me
MeThanol
COOMe
6
4
O
O
O
A
OH
O
OH
R
O
[-H2O]
R
COOMe
Me
COOMe
H2O
O
O
Me
Scheme 4. Proposed mechanism.
2. De Neufville, R.; von Pechmann, H. Chem. Ber. 1890, 23, 3375–3387.
3. Rubin, M.; Gleiter, R. Chem. Rev. 2000, 100, 1121–1164.
improved methodology for the preparation of 3-hydroxyfuran-
2-carboxylates. We also have opened up the possibility of derivati-
zation at C3 position by the use of different nucleophile. Application
of this methodology is currently on the way for preparing the side
chain of roseophilin.
4. (a) Wasserman, H. H.; Han, W. T. Tetrahedron Lett. 1984, 25, 3743–3746; (b)
Wasserman, H. H.; Han, W. T. Tetrahedron Lett. 1984, 25, 3747–3750; (c)
Wasserman, H. H.; Han, W. T. J. Am. Chem. Soc. 1985, 5, 1444–1446.
5. (a) Wasserman, H. H.; Kuo, G. H. Tetrahedron Lett. 1989, 30, 873–876; (b)
Wasserman, H. H.; Amici, R.; Frechette, R.; Van Duzer, J. Tetrahedron Lett. 1989,
30, 869–872; (c) Wasserman, H. H.; Lombardo, L. J. Tetrahedron Lett. 1989, 30,
1725–1728; (d) Wasserman, H. H.; Amici, R. J. Org. Chem. 1989, 54, 5843–5844.
6. (a) Wasserman, H. H.; Fukuyama, J.; Murugesan, N.; van Duzer, J.; Lombardo, L.;
Rotello, V.; McCarthy, K. J. Am. Chem. Soc. 1989, 111, 371–372; (b) Wasserman,
H. H.; Cook, J. D.; Fukuyama, J. M.; Rotello, V. M. Tetrahedron Lett. 1989, 30,
1721–1724.
Acknowledgments
We are grateful to the National Institutes of Health (GM46503)
for their support of this research. We wish to thank Dr. Lei Zhou for
his early efforts in this research.
7. Wasserman, H. H.; Cook, J. D.; Vu, C. B. J. Org. Chem. 1990, 55, 1701–1702.
8. Wasserman, H. H.; Lee, G. M. Tetrahedron Lett. 1994, 35, 9783–9786.
9. Doyle, M.; Zhou, L. Org. Lett. 2010, 12, 796–799.
10. Regitz, M.; Maas, G. Diazo Compounds: Properties and Synthesis; Academic Press:
Orlando, FL, 1986.
Supplementary data
11. Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic
Synthesis with Diazo Compounds; Wiley: New York, 1998. Chapter 1.
12. (a) Gleiter, R.; Schang, P. Angew. Chem., Int. Ed. 1980, 19, 715–716; (b) Detering,
J.; Martin, H. D. Angew. Chem., Int. Ed. 1988, 27, 695–698.
Supplementary data (general synthetic methods, HRMS, 1H and
13C NMR of reaction products) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2010.11.166.
13. Saba, A. Synth. Commun. 1994, 24, 695–699.
14. Adam, W.; Bialas, J.; Hadjiarapoglou, L. P. Chem. Ber. 1991, 24, 2377–2378.
Procedure for the preparation of DMDO.
References and notes
1. (a) Rubin, M. D. Chem. Rev. 1975, 75, 177–202; (b) Wasserman, H. H.; Parr, H.
Acc. Chem. Res. 2004, 37, 687–701.