Synthesis of 1-methyl-3-oxo-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid methyl ester

Article abstract of DOI:10.3390/10111413

A simple and efficient method for the preparation of 1-methyl-3-oxo-7- oxabicyclo[2.2.1]hept-5-en-2-carboxylic acid methyl ester (1) is described. The first step is a highly regioselective Diels-Alder reaction between 2-methylfuran and methyl-3-bromopropiolate. A remarkably difficult ketal hydrolysis reaction was effected by treatment with HCl, a simple reagent that was shown to be more efficient, in this case, than commonly used more elaborate methods.

Full text of DOI:10.3390/10111413

Molecules 2005, 10, 1413-1418
molecules
ISSN 1420-3049
http://www.mdpi.org
Synthesis of 1-Methyl-3-oxo-7-oxabicyclo[2.2.1]hept-5-ene-2-
carboxylic Acid Methyl Ester
Valquiria Aragão 1,*, Mauricio Gomes Constantino 1, Adilson Beatriz 2 and Gil Valdo José da
Silva 1
1
Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto,
Universidade de São Paulo, Avenida dos Bandeirantes, 3900, 14040-901, Ribeirão Preto, SP, Brazil
Tel. (+55) 16 3602 3879; Fax (+55) 16 3633 8151.
2
Departamento de Química, Centro de Ciências Exatas e Tecnologia, Universidade Federal de Mato
Grosso do Sul, Avenida Senador Filinto Müller, 1555, 79070-90, Campo Grande, MS, Brazil.
* Author to whom correspondence should be addressed; E-mail: varagao@usp.br
Received: 25 August 2005; in revised form: 22 September 2005 / Accepted: 23 September 2005 /
Published: 30 November 2005
Abstract: A simple and efficient method for the preparation of 1-methyl-3-oxo-7-
oxabicyclo[2.2.1]hept-5-en-2-carboxylic acid methyl ester (1) is described. The first step is
a highly regioselective Diels-Alder reaction between 2-methylfuran and methyl-3-bromo-
propiolate. A remarkably difficult ketal hydrolysis reaction was effected by treatment with
HCl, a simple reagent that was shown to be more efficient, in this case, than commonly used
more elaborate methods.
Keywords: 1-Methyl-3-oxo-7-oxabicyclo[2.2.1]hept-5-en-2-carboxylic acid methyl ester,
ketal hydrolysis, Diels-Alder reaction.
Introduction
7-Oxabicyclo[2.2.1]hept-5-ene derivatives are important intermediates and the base-induced
opening of the oxygen bridge of these types of compounds has been used in the stereoselective
syntheses of a number of shikimic acid derivatives and other natural products [1-3]. These systems
have also acquired increasing importance as starting materials (“naked sugars”) for the synthesis of
numerous sugars, C-nucleosides, etc. [3-5].

Molecules 2005, 10
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Figure 1
O
O
CO2Me
1
In this paper we describe a short and efficient synthesis of methyl 1-methyl-3-oxo-7-
oxabicyclo[2.2.1]hept-5-en-2-carboxylic acid methyl ester (1, Figure 1), starting with a Diels-Alder
reaction between 2-methylfuran (2) and methyl 3-bromopropiolate (3) (Scheme 1).
Scheme 1
O
O
CO2Me
benzene
OMe
Br
MeONa
H3O
82%
O
1
+
OMe
reflux
53%
MeOH
87%
CO2Me
CO2Me
Br
4a
5a
3
2
In spite of its apparent simplicity, each of the three steps of this synthesis has a remarkable aspect
due to the special properties of these compounds.
Results and Discussion
2-Methylfuran (2) is commercially available, whereas the dienophile, methyl-3-bromopropiolate
(3) had to be prepared by the reaction of methyl propiolate with N-bromosuccinimide in acetone with
silver nitrate as catalyst (86% yield) [6]. The methyl propiolate was previously prepared by
esterification of propiolic acid with methanol/sulfuric acid (2 days, 65% yield).
The Diels-Alder reaction between the diene 2 and dienophile 3 (benzene, 24 h reflux, Scheme 2)
resulted in a 15.7:1 mixture of the regioisomers 4a and 4b, respectively, which were separated by
column chromatography and analyzed by nuclear magnetic resonance (NMR), with the assignment of
all hydrogens, carbons and coupling constant values being accomplished using a combination of
1H-NMR, 13C-NMR, gsHMQC and gsHMBC. A remarkable aspect of this reaction is the high
regioselectivity observed.
Scheme 2
CO2Me
O
O
benzene
Br
CO2Me
Br
+
O
+
reflux
53%
CO2Me
15.7
Br
2
:
1
3
4a
4b
The treatment of adduct 4a with sodium methoxide in methanol at room temperature gave ketal 5a,
the endo product, as expected for a kinetic protonation process [7]. Compound 5a was isolated by
column chromatography in 87% yield.

Molecules 2005, 10
1415
The next step was the hydrolysis of ketal 5a. Leroy, in his paper concerning the synthesis of
analogous compounds [3], emphasized the difficulties of the ketal hydrolysis step. After some attempts
he found that the H+ form of the perfluorosulfonic acid resin Nafion®-501, (Nafion-H), led to the
corresponding ketone in 68-83% yield. However, this reagent is expensive and requires long reaction
times (4 days).
We investigated several reagents and reaction conditions such as oxalic or sulfuric acid on wet
silica gel, lithium tetrafluoroborate in wet acetonitrile, Amberlyst®-15 in wet acetone, but none led to
the desired hydrolysis. The treatment of 5a with PPTS (pyridinium p-toluenesulfonate) gave less than
10% of 1, and required a large (tenfold) excess of PPTS and 16 hours at reflux [8]. Finally, we found
that in conc. HCl solution in methanol (room temperature, 7 hours), ketal 5a was converted to ketone 1
in 82% yield. The unusual lack of reactivity of 5a can be attributed to the retarding inductive effect of
the 7-oxa bridge on the formation of cationic intermediates at C-3.
Scheme 3
H
H
O
O
O
O
OMe
OMe
OMe
HCl
OMe
CO2Me
3
MeOH
OMe
OMe
CO2Me
CO2Me
CO2Me
MeOH
5a
However, the double bond of 5a also seems to play a stabilizing effect on the intermediate
carbocation (possibly through conjugation forming a non-classical ion, as shown in Scheme 3),
because after reduction of the double bond (H2/Pd), the hydrolysis occurred readily providing a
complex mixture from which only 7% of the corresponding ketone could be isolated (Scheme 4).
Scheme 4
OH
O
O
OMe
O
O
HCl
other products
+
+
OMe
MeOH
CO2Me
CO2Me
CO2Me
6
7 (7 %)
8 (6 %)
Further support for a favorable role of the double bond in the hydrolysis was provided by the fact
that we found that lactone 10 [9] (which was prepared from 5a as shown in Scheme 5 to confirm its
stereochemistry) did not undergo any transformation when treated with conc. HCl solution for 4 days.
Scheme 5
O
O
O
OMe
OMe
I
OMe
OMe
OMe
NaHCO3
NaOH
87%
OMe
KI3
CO2Me
CO2H
O
49%
5a
O
9
10

Molecules 2005, 10
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Conclusions
The desired product title compound 1 was obtained in 38% overall yield in a short and efficient 3-
step synthesis. The high regioselectivity of the Diels-Alder reaction gives an important contribution to
the efficiency of the process. Also remarkable are the stereoselectivity of the ester 5a formation, and
the hydrolysis of the resistant ketal with a very simple reagent, while more sophisticated methods
proved to be inefficient.
Acknowledgements
The autors wish to thank the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP),
the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and the Coordenação de
Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for financial support.
Experimental
General
Melting points were determined on a Reichert Kofler block melting point apparatus and are
1
uncorrected. H-NMR and 13C-NMR spectra were measured using a Bruker DPX-400 instrument (at
400 MHz and 100 MHz, respectively); deuteriochloroform was used as solvent and tetramethylsilane
as an internal standard. IR spectra were measured with a Perkin-Elmer Spectrum RX IFTIR System.
TLC was performed on precoated silica gel 60 F254 plates (0.25 mm thick, Merck), and silica gel 60
(70-230 mesh, Merck) was used for column chromatography.
(1S*,4R*)-3-Bromo-1-methyl-7-oxabicyclo[2.2.1]hepta-2,5-diene-2-carboxylic acid methyl ester (4a)
and (1R*,4S*)-3-bromo-4-methyl-7-oxabicyclo[2.2.1]hepta-2,5-diene-2-carboxylic acid methyl ester
(4b)
2-Methylfuran (2, 0.986 g, 12.02 mmol), methyl 3-bromopropiolate (3, 1.96 g, 12.02 mmol) and
dry benzene (4 mL) were mixed and stirred at room temperature for 12 h. Another portion of 2-methyl-
furan (2, 0.493 g, 6.01 mmol) was added and the resulting mixture was then heated at reflux for 12 h.
The solvent was removed under vacuum and the residue was purified by chromatography on a silica
gel column, eluting with hexane/ethyl acetate (9:1) to yield 1.46 g (50 %) of 4a and 0.093 g (3.2 %) of
4b. Compound 4a: 1H-NMR δ: 1.82 (s, 3H), 3.72 (s, 3H), 5.14 (d, 1H, J = 1.8 Hz), 6.92 (d, 1H, J = 5.3
Hz), 7.07 (dd, 1H, J1 = 5.3 Hz, J2 = 1.8 Hz); 13C-NMR δ: 16.8 (CH3), 52.0 (CH3), 88.4 (CH), 94.4 (C),
142.5 (CH), 144.8 (C), 147.4 (CH), 150.3 (C), 163.9 (C=O); IR (thin film) cm-1: 2933, 1722, 1607,
1442, 1306, 1260, 1099; MS m/z (relative intensity): 189 [M+ - 56] (7%), 82 (12%), 59 (24%), 51
1
(36%), 43 (100%), 15 (84%); Compound 4b: H-NMR δ: 1.74 (s, 3H), 3.79 (s, 3H), 5.62 (d, 1H, J =
2.0 Hz), 6.90 (d, 1H, J = 5.3 Hz), 7.20 (dd, 1H, J1 = 5.3 Hz, J2 = 2.0 Hz); 13C-NMR δ: 15.6 (CH3), 51.8
(CH3), 83.7 (CH), 95.1 (C), 144.1 (C), 144.5 (CH), 145.2 (CH), 153.2 (C), 162.9 (C=O).

Molecules 2005, 10
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(1S*,2R*,4R*)-3,3-Dimethoxy-1-methyl-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid methyl ester
(5a)
A solution of compound 4a (1.01 g, 4.12 mmol) in methanol (6 mL) was added dropwise to a 1M
solution of sodium methoxide in methanol (20 mL), cooled with an ice bath. The reaction mixture was
stirred for 2 h and then allowed to warm slowly to room temperature. The mixture was cooled again to
4 °C and then treated with 1:1 aqueous hydrochloric acid solution until pH 5. The methanol was
removed under vacuum and the products were extracted with ethyl ether. The combined organic
extracts were washed with saturated brine and dried over anhydrous MgSO4. The solvent was removed
under vacuum and the residue was purified by chromatography in a silica gel column, eluting with
hexane/ethyl acetate (7:3), yielding 0.818 g (87%) of 5a as a yellow solid; m.p. 60-62 °C; 1H-NMR δ:
1.54 (s, 3H), 2.90 (s, 1H), 3.14 (s, 3H), 3.40 (s, 3H), 3.63 (s, 3H), 4.66 (d, 1H, J = 1.8 Hz), 6.36 (dd,
1H, J1 = 5.8 Hz, J2 = 1.8 Hz), 6.61 (d, 1H, J = 5.8 Hz); 13C-NMR δ: 18.2 (CH3), 50.7 (CH3), 51.0
(CH3), 51.7 (CH3), 59.0 (CH), 84.0 (CH), 87.6 (C), 113.0 (C), 131.2 (CH), 140.8 (CH), 169.7 (C=O);
IR (thin film) cm-1: 2953, 2837, 1738; 1436, 1316, 1142, 1060; MS m/z (relative intensity): 146 [M+ -
82] (12%), 115 (31%), 82 (8%), 69 (11%), 59 (9%), 28 (100%), 15 (22%).
(1S*,2R*,4R*)-1-Methyl-3-oxo-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid methyl ester (1)
Conc. hydrochloric acid solution (1.0 mL) was added dropwise at room temperature to a solution
of compound 5a (103.5 mg; 0.454 mmol) in methanol (1.5 mL). The reaction mixture was stirred for 7
h. The resultant mixture was treated with water (1 mL) and extracted with ethyl ether. The organic
extracts were washed with saturated NaHCO3 solution, then dried over anhydrous MgSO4 and the
1
solvent was removed under vacuum, yielding 67.5 mg (82%) of a colorless oil; H-NMR δ: 1.74 (s,
3H), 3.15 (s, 1H), 3.74 (s, 3H), 4.76 (d, 1H, J = 2.0 Hz), 6.40 (dd, 1H, J1 = 5.6 Hz, J2 = 2.0 Hz), 6.75
(d, 1H, J = 5.6 Hz); 13C-NMR δ: 18.4 (CH3), 52.6 (CH3), 55.1 (CH), 83.5 (CH), 87.9 (C), 129.4 (CH),
144.3 (CH), 167.8 (C=O), 199.4 (C=O); IR (thin film) cm-1: 2956, 2840, 1732, 1436, 1303, 1205,
1023.
(1S*,2R*,4R*)-3,3-Dimethoxy-1-methyl-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid methyl ester (6)
A solution of compound 5a (161 mg, 0.707 mmol) in methanol (1 mL) was placed in a 150 mL
stainless steel pressure reactor. After addition of 5% Pd/C (25 mg), the resulting mixture was stirred
under a hydrogen atmosphere at 6 atm and room temperature for 3 h. The reaction mixture was filtered
through silica gel and the residue was washed with ethyl acetate. The organic extracts were dried over
anhydrous MgSO4 and the solvent was removed under vacuum, yielding 126 mg (78%) of a colorless
oil; 1H-NMR δ: 1.40 (ddt, 1H, J1 = J2 = 12.5 Hz, J3 = 5.0 Hz, J4 = 2.0 Hz), 1.48 (s, 3H), 1.77 (ddt, 1H,
J1 = J2 = 12.5 Hz, J3 = 5.8 Hz, J4 = 4.5 Hz), 1.92 (ddd, 1H, J1 = 12.5 Hz, J2 = 9.6 Hz, J3 = 5.0 Hz),
2.80 (d, 1H, J = 2.0 Hz), 2.80 (ddd, 1H, J1 = 12.5 Hz, J2 = 9.6 Hz, J3 = 4.5 Hz), 3.19 (s, 3H), 3.33 (s,
3H), 3.70 (s, 3H), 4.37 (d, 1H, J = 5.8 Hz); 13C-NMR δ: 23.3 (CH3), 24.9 (CH2), 30.0 (CH2), 49.1
(CH3), 51.0 (CH3), 51.6 (CH3), 59.8 (CH), 83.1 (CH), 86.7 (C), 109.7 (C), 169.4 (C=O); IR (thin film)
cm-1: 2951, 2837, 1734, 1213, 1151, 1071.

Molecules 2005, 10
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(1S*,2R*,4R*)-3,3-Dimethoxy-1-methyl-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid (9)
Compound 5a (102.1 mg, 0.448 mmol) was stirred with 5% NaOH solution (2.6 mL) cooled with
an ice bath for 4.5 h or until complete dissolution of 5a. The resultant mixture was diluted with water
(8.5 mL) and washed with light petroleum (8.5 mL). The aqueous phase was cooled to 4 °C, treated
with 1:1 aqueous HCl to pH 2 and then the product was extracted with chloroform. The organic
extracts were dried over anhydrous MgSO4 and the solvent was removed under vacuum, yielding 82.8
mg (87%) of a white solid; m.p. 176-178 °C; 1H-NMR δ 1.65 (s, 3H), 2.96 (s, 1H), 3.27 (s, 3H), 3.44
(s, 3H), 4.74 (d, 1H, J = 1.8 Hz), 6.45 (dd, 1H, J1 = 5.8 Hz, J2 = 1.8 Hz), 6.57 (d, 1H, J = 5.8 Hz); 13C-
NMR δ: 18.4 (CH3), 51.0 (CH3), 51.3 (CH3), 58.4 (CH), 84.0 (CH), 88.2 (C), 112.9 (C), 132.1 (CH),
140.7 (CH), 172.8 (C=O); IR (thin film) cm-1: 2937, 2825, 1700, 1559, 1278, 1143, 1054; MS m/z
(relative intensity): 133 [M+ - 81] (37%), 87 (100%), 82 (75%), 69 (35%), 43 (49%).
(1S*,2S*,3S*,6R*,7R*)-2-Iodo-9,9-dimethoxy-7-mehyl-4,8-dioxatricyclo[4.2.1.03,7]nonan-5-one (10)
0.5 M aqueous NaHCO3 solution (0.75 mL) and a solution of I2 (63.5 mg, 0.25 mmol)/KI (124.5
mg, 0.75 mmol) in water (0.5 mL) were added to a solution of compound 9 (26.7 mg; 0.125 mmol) in
THF (0.75 mL). The reaction mixture was protected from light and stirred at room temperature for 20
h. The mixture was extracted with ethyl ether, the organic extracts were washed with aqueous Na2S2O5
and saturated NaHCO3 solutions, then dried over anhydrous MgSO4 and the solvent was removed
1
under vacuum, yielding 20.7 mg (49%) of a white solid; m.p. 199-201 °C; H-NMR δ: 1.65 (s, 3H),
2.96 (s, 1H), 3.25 (s, 3H), 3.28 (s, 3H), 4.22 (s, 1H), 4.52 (s, 1H), 4.73 (s, 1H); 13C-NMR δ: 17.1
(CH3), 21.8 (CH), 49.7 (CH3), 51.7 (CH3), 53.8 (CH), 87.5 (CH), 91.5 (CH), 91.9 (C), 109.5 (C), 171.0
(C=O); IR (thin film) cm-1: 2958, 2835, 1798, 1302, 1248, 1124, 1021.
References and Notes
1. For a review, see: Vogel, P.; Cossy, J.; Plumet, J.; Arjona O. Tetrahedron 1999, 55, 13521-13642.
2. Gustafsson, J.; Sterner, O. J. Org. Chem. 1994, 59, 3994-3997 and references cited therein.
3. Leroy, J. Tetrahedron Lett. 1992, 33, 2969-2972.
4. Kozikowski, A. P.; Floyd, W. C.; Kuniak, M. P. J. Chem. Soc., Chem. Commum. 1977, 582-583.
5. Moore, J. A.; Partain, E. M. J. Org. Chem. 1983, 48, 1105-1106.
6. Leroy, J. Synthetic Commun. 1992, 22, 567-572.
7. We have observed that, if the protonation is effected at room temperature by slow addition of HCl,
a considerable amount of the presumed exo epimer 5b is obtained along with 5a. When performed
at 0 °C, with rapid addition of HCl, no detectable amount of 5b is observed.
8. Monti, H; Léandri, G.; Klos-Ringuet, M.; Corriol, C. Synthetic Commun. 1983, 13, 1021-1026.
9. Petragnani, N.; Ferraz, H. M. C. Synthesis 1978, 6, 476-478.
Sample Availability: Samples of compounds 1, 2, 3, 5a, 6, 9 and 10 are available from MDPI.
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