Regioselective preparation of 7-oxanorborna-2,5-diene-2,3-dicarboxylic acid derivatives by the diels-alder reaction: A selective access to furans by retro-diels-alder reaction

Article abstract of DOI:10.1055/s-0033-1338802

Hydrolysis of 1-substituted 7-oxanorborna-2,5-diene-2,3-dicarboxylates occurred regioselectively at the ester group in the 3-position to give monocarboxylic acids from which diesters containing two different alkoxy groups and amido esters were selectively

Full text of DOI:10.1055/s-0033-1338802

2018▌
PAPER
paper
Regioselective Preparation of 7-Oxanorborna-2,5-diene-2,3-dicarboxylic Acid
Derivatives by the Diels–Alder Reaction: A Selective Access to Furans by
Retro-Diels–Alder Reaction
7-Oxanorborna-2,5-diene Derivatives
Nisrine Sultan,a Régis Guillot,b Luis Blanco,a Sandrine Deloisy*a
a
Laboratoire de Synthèse Organique et Méthodologie, Institut de Chimie Moléculaire et des Matériaux d'Orsay (ICMMO, UMR 8182-CNRS),
Bât. 420, Univ. Paris-Sud 11, 91405 Orsay Cedex, France
Fax +33(1)69156278; E-mail: sandrine.deloisy@u-psud.fr
b
Service de Cristallographie, ICMMO (UMR 8182-CNRS), Bât. 420, Univ. Paris-Sud 11, 91405 Orsay Cedex, France
Received: 21.12.2012; Accepted after revision: 18.04.2013
Most ONDs have been prepared by Diels–Alder reactions
Abstract: Hydrolysis of 1-substituted 7-oxanorborna-2,5-diene-
of furan derivatives with symmetrical dialkyl acetylenedi-
2,3-dicarboxylates occurred regioselectively at the ester group in
carboxylates.2,3c,e,5,13,15 Cycloaddition of nonsymmetrical
the 3-position to give monocarboxylic acids from which diesters
alkynes with 2-substituted furans might provide increased
containing two different alkoxy groups and amido esters were selec-
tively prepared. Hydrogenation of these oxanorbornadiene deriva- molecular diversity of the products prepared via ONDs. In
tives followed by
a retro-Diels–Alder reaction gave the
a few cases, such as those of 4,4-diethoxybut-2-
ynal,3b,d,f,16 ethyl 4,4,4-trifluorobutynoate,17 or methyl 3-
(phenylsulfonyl)prop-2-ynoate,18 the cycloaddition deliv-
ers one regioisomer exclusively or predominantly, but a
mixture of regioisomers is generally obtained. For exam-
ple, the reaction of 2-methylfuran with ethynyl phenyl
corresponding furans as single regioisomers.
Key words: Diels–Alder reactions, hydrolyses, esters, amides, re-
gioselectivity, furans, heterocycles
Various 7-oxanorborna-2,5-dienes (ONDs) bearing one sulfone in dichloromethane at room temperature for four
or two electron-withdrawing groups on a carbon–carbon days gave a 53:47 mixture of the two regioisomeric prod-
double bond are versatile intermediates for the prepara- ucts,19 whereas cycloaddition of the same furan with
tion of aromatic, ethylenic, and heterocyclic products. For methyl 4-(cyclohexylamino)-4-oxobut-2-ynoate in re-
instance, treatment of ONDs under acidic conditions gives fluxing toluene for three hours gave a 3:2 mixture of the
the corresponding phenols,1 whereas aromatic com- corresponding products.12f The reactions of 2-ethylfuran
pounds are obtained by deoxygenation.2 Ethylenic3,4 and with ethynyl 4-tolyl sulfone (CH2Cl2, r.t., 9 d), methyl 4-
heterocyclic compounds5–11 are synthesized by reactions anilino-4-oxobut-2-ynoate (toluene, reflux, 8 h), and
of electron-deficient carbon–carbon double bonds of methyl 3-(dimethoxyphosphoryl)prop-2-ynoate (toluene,
ONDs with nucleophiles or 1,3-dipolar reactants, fol- 80 °C, 1 d) gave, respectively, 51:49, 77:23, and 63:37
lowed by a retro-Diels–Alder reaction. Moreover, retro- mixtures of the corresponding cycloadducts.17
Diels–Alder reactions performed after selective hydroge-
Here, we describe a selective monohydrolysis of unsym-
nation of electron-rich carbon–carbon double bonds of
metrical oxanorbornadienedicarboxylates to give half es-
ONDs give substituted furans regioselectively.1e,12–14 Fur-
ters that can be converted into diesters containing two
thermore, the presence of a substituent on the bridgehead
different alkoxy groups or into amido esters. Because se-
carbon atom of the dialkyl oxanorbornadiene-2,3-dicar-
lective monohydrolyses of symmetrical dimethyl and di-
boxylate framework permits regioselective reactions,
ethyl 7-oxanorborna-2,5-diene-2,3-dicarboxylate have
such as cycloadditions of azomethine ylides5a,b or nucleo-
been reported to occur under enzymatic or chemical con-
philic additions of thiols.3e
ditions,20,21 we expected to be able to achieve regioselec-
ONDs can be synthesized by Diels–Alder reactions of the tive syntheses of diesters and amido esters.
corresponding furans with alkynes. The reactions of
ONDs generally give the same ethylenic or heterocyclic
product as those formed by reactions of the parent alkyne
The 7-oxanorborna-2,5-diene-2,3-dicarboxylates 7–11
were prepared by treatment of furan (1), 2-ethylfuran (2),
or 2-benzylfuran (3) with dimethyl acetylenedicarboxyl-
ate (4), diethyl acetylenedicarboxylate (5), or diisobutyl
with nucleophiles or 1,3-dipolar reactants. However, the
chemoselectivity can differ3f and, generally, the three-step
acetylenedicarboxylate (6). Reactions were performed in
sequence via the OND is more selective,3d,f,5a,b sometimes
solution in toluene or in the absence of a solvent (Table 1).
faster,6c,7b and generally provides better yields5b,c than the
Under the usual conditions for such reactions, an excess of
the acetylenedicarboxylate was used to avoid the forma-
corresponding sequence starting from alkyne.
tion of products resulting from Diels–Alder reactions be-
tween the OND and the furan reagent. After heating at 80
or 110 °C for four hours, solutions of 3:1 mixtures of di-
methyl acetylenedicarboxylate (4) and the 2-alkylfurans 2
or 3 in toluene gave the expected cycloadducts 8 and 9 in
SYNTHESIS 2013, 45, 2018–2028
Advanced online publication: 29.05.2013
DOI: 10.1055/s-0033-1338802; Art ID: SS-2012-T0944-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

PAPER
7-Oxanorborna-2,5-diene Derivatives
2019
Table 1 Preparation of 7-Oxanorbornadienes 7–11a
R1
CO2R2
CO2R2
CO2R2
O
R1
+
O
1–3
CO2R2
7–11
4–6
Entry
Furan
R1
Alkyne
R2
Ratio furan/alkyne Temp (°C)
Time
Product
Yieldb (%)
1
2
3
4
5
6
1
2
2
3
2
2
H
4
4
4
4
5
6
Me
Me
Me
Me
Et
1.5:1c
1:3
80
80
14 h
4 h
2 d
4 h
7 d
1 d
7
8
63d
96
Et
Et
Bn
Et
Et
1:1e
1:3
35
8
98f
88
110
35
9
1:1e
1:1.2
10
11
99f
60
i-Bu
80
a Unless otherwise noted, reactions were performed in toluene solution.
b In general, the product was purified by chromatography on silica gel.
c Reaction performed in a vacuum-sealed tube after freeze–pump–thaw cycles.
d Isolated by distillation.
e Reaction performed in the absence of a solvent.
f Isolated by evaporation of residual reactants under vacuum.
excellent yields after chromatography on silica gel (en- The resulting carboxylic acids were coupled with amines
tries 2 and 4).
or alcohols in the presence of 4-(4,6-dimethoxy-1,3,5-tri-
azin-2-yl)-4-methylmorpholin-4-ium chloride (DMTMM),22
to give the corresponding amido esters or diesters with
different alkoxy groups, respectively (Scheme 1, Table 2).
By using a slight excess of the freshly prepared diisobutyl
diester 6 (6/2 = 1.2:1), the adduct 11 was obtained in a me-
dium yield after one day at 80 °C (entry 6). The reaction
of dimethyl acetylenedicarboxylate (4) with furan (1) was
performed in a vacuum-sealed tube to prevent loss of the
volatile 1. Moreover, furan (1) was introduced in excess
because, at 80 °C, it exists partially in the gas phase and
might be less available. After 14 hours, adduct 7 was iso-
lated by distillation (entry 1). Interestingly, cycloadduct 8
and the corresponding diethyl ester 10 were easily pre-
pared by keeping equimolar mixtures of ethylfuran (2)
with dimethyl acetylenedicarboxylate (4) or diethyl acet-
ylenedicarboxylate (5), respectively, with no solvent, at
35 °C for several days (entries 3 and 5). Under these very
mild conditions, products of adequate purity were ob-
tained by evaporation of the residual starting materials un-
der low pressure.
R1
CO2R2
O
CO2R2
7–11
NaOH
H2O, THF, 0 °C
R1
CO2R2
O
CO2H
12–16
R4OH (solvent)
DMTMM (2 equiv)
NMM (1.2 equiv), r.t.
R3NH2 (1.1 equiv)
DMTMM (1.1 equiv)
THF, r.t.
Treatment of the diesters 7–11 with a mixture of aqueous
sodium hydroxide and tetrahydrofuran at 0 °C gave the
corresponding monocarboxylic acids 12–16 selectively
(Scheme 1 and Table 2). These reactions were generally
carried out with a 0.5 M solution of sodium hydroxide un-
til the starting diester disappeared. The monoacid 12 was
obtained from the symmetrical diester 7 by using a 0.25 M
solution of sodium hydroxide, because the use of more-
concentrated sodium hydroxide solutions resulted in hy-
drolyses of both ester functions. 1H and 13C NMR spectra
of the monoacids 13–16 showed the presence of a single
regioisomer in each case.
R1
R1
CO2R2
CO2R2
O
O
CO2R4
24–27
CONHR3
17–23
Scheme 1 Selective two-step syntheses of OND amido esters 17–23
and diesters 24–27
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2018–2028

2020
N. Sultan et al.
PAPER
Table 2 Preparation of Monocarboxylic Acids 12–16, Amido Esters 17–23, and Diesters 24–27
Monocarboxylic acida
Time (min)
Amido esterb
Yield (%) R3
Time (h)
4.5
Diesterc
Yieldd (%) R4
Substrate R1
R2
Yieldd (%)
7
8
H
Me
Me
30
35
12e
13
76
78
Ph
Ph
Bn
Cy
Ph
Ph
Ph
17
18
19
20
21
22
23
11
67
33
64
36
51
75
Et
3.5
4.5
4
Etf
24
25
26
69
70
55
Bn
i-Bu
9
10
11
Bn
Et
Me
Et
25
50
14
15
16
87
74
89
3.5
3.5
6g
Me
27
70
Et
i-Bu
120
a Unless otherwise noted, reactions were performed with 0.5 M aq NaOH.
b Generally, reactions were performed with amine (1.1 equiv) and DMTMM.
c Unless otherwise noted, the reaction time was 16 h.
d Isolated yield after column chromatography (silica gel).
e 0.25 M aq NaOH was used.
f Reaction time 5 h.
g After the indicated time, additional portions of the amine and DMTMM (0.4 equiv each) were added, and the reaction was continued for a
further 1 h.
Slight excesses of amine (aniline, benzylamine, or cyclo-
Table 3 Preparation of Furan Derivatives 33–37 via the Oxanor-
hexylamine) and DMTMM were used to prepare the ami- bornenes 28–32
do esters 17–23, which were isolated in good to low yields
after chromatography on silica gel. By using the appropri-
R1
R1
O
R1
CO2R2
CO2R2
COR5
CO2R2
COR5
H2
Pd
heat
ate alcohol as the solvent in the presence of DMTMM (2
O
equiv) and 4-methylmorpholine (1.2 equiv), diesters 24–
COR5
O
27 were obtained in good yields after chromatography on
19–21, 24, 27
28–32
33–37
silica gel. Note that diesters 24 and 27 are the two regio-
isomers that would be formed by cycloaddition of 2-ethyl-
furan (2) with ethyl methyl acetylenedicarboxylate.
Substrate R1 R2 R5
Oxanorbornenea Yieldc Furanb Yieldc
(%)
(%)
The structure of the amido ester 22 was determined by X-
ray diffraction analysis of a single crystal (Figure 1).23
This confirmed unambiguously that hydrolysis of the di-
ester 10 occurred selectively at the ester group distal to the
small ethyl group on the bridgehead carbon atom. We be-
lieve that the same regioselectivity occurs in the monohy-
drolysis reactions of diesters 8, 9, and 11. A similar
regioselective hydrolysis has been claimed to occur in the
19
20
21
24
27
Et Me NHBn 28
Et Me NHCy 29d
Bn Me NHPh 30e
87
95
93
85
90
33
34
35
36
37
94
62
96f
88
94
Et Me OEt
Et Et OMe
31g
32e
a Reaction conditions: H2, 5% Pd/BaSO4, PE, r.t., 40 min (unless oth-
erwise noted).
case of
a dimethyl oxanorbornadienedicarboxylate
bearing a bulky (dansylamino)methyl group in the 1-posi-
b Reaction conditions: decalin, 190 °C, 75 min.
c Isolated yield after column chromatography (silica gel).
d Reaction time 90 min.
tion.3e
The structure of compound 22 contains pyramidalized
ethylenic carbons at C2 and C3. The dihedral angle of the
bond between the ester carbonyl carbon and carbon C2
with bond C3–C4 is 171.6°, whereas that between the
bond between the amide carbonyl carbon and carbon C3
with bond C1–C2 is 169.9°; the dihedral angle between
carbons C1, C2, C3, and C4 is only 0.34°. Clearly, ester
and amide groups are slightly shifted on the endo face,
making the exo face more accessible. A strong hydrogen
bond between the hydrogen of the NH group and the oxy-
gen atom of the ester carbonyl group is another feature of
this structure; the H···O distance is 1.97 Å and the angle
N–H···O is 154.6°.
e Solvent PE–THF.
f See experimental section.
g Reaction time 55 min.
To highlight the importance of the OND products, we pre-
pared various furan derivatives regioselectively by a short
sequence involving hydrogenation and a retro-Diels–
Alder reaction12 (Table 3).
Reduction of amido esters 19, 20, and 21 and diesters 24
and 27 with dihydrogen in the presence of palladium/bar-
ium sulfate occurred at the more electron-rich carbon–
Synthesis 2013, 45, 2018–2028
© Georg Thieme Verlag Stuttgart · New York

PAPER
7-Oxanorborna-2,5-diene Derivatives
2021
In summary, we have developed a simple three-step se-
quence that permits regioselective preparation of amido
esters and of diesters with different alkoxy groups by cou-
pling amines or alcohols, respectively, with monoesters of
1-substituted 7-oxanorborna-2,5-diene-2,3-dicarboxylic
acids. The main feature of this sequence is the selective
hydrolysis of the diesters derived from these diacids,
which occurs on the ester group in 3-position, even in the
presence of a small ethyl group on the bridgehead carbon
atom. The starting diesters are easily obtained by Diels–
Alder reactions of 2-substituted furans with symmetrical
acetylenedicarboxylates. This highly selective synthesis
of oxanorbornadiene derivatives permits the selective
preparation of furans with various electron-withdrawing
groups by hydrogenation followed by a retro-Diels–Alder
reaction.
Figure 2 ORTEP structure of furan 34;23 ellipsoids are drawn at the
30% probability level
carbon double bond. Note that the reaction time for dies-
ters must be carefully controlled to avoid the formation of
oxanorbornanes. The resulting norbornenes 28–32 were
converted selectively into furans 33–37 by heating in
decalin. In each case, a single regioisomer was obtained.
1H and 13C NMR spectra were recorded on Bruker AC250 (250 and
62.9 MHz, respectively), Bruker DRX300 (300 and 75.5 MHz, re-
spectively), and Bruker AM360 (360 and 90.6 MHz, respectively)
spectrometers. Chemical shifts (δ) are given in ppm relative to sol-
vent signals as internal standards (CHCl3: δ = 7.27 ppm; CDCl3: δ =
77.00 ppm). Assignments were aided by JMOD pulse sequences
and heteronuclear two-dimensional experiments (HSQC). Positive
(ES+) and negative (ES–) electrospray mass spectra and high-reso-
lution mass spectra were recorded with a Bruker Daltonics Mi-
crOTOF-Q spectrometer or a Waters LCT spectrometer (Gif-sur-
Yvette, France). Positive chemical ionization (CI+) and electron im-
pact (EI) mass spectra were recorded with a Thermo Scientific DSQ
spectrometer. IR spectra were recorded by using an FT-IR Perkin-
Elmer (Spectrum One) spectrophotometer or an FT-IR Bruker (Ver-
tex 70) spectrophotometer with an ATR accessory.
The structure of furan 34 was confirmed by X-ray diffrac-
tion analysis (Figure 2).23
This sequence is significant, because direct reaction of
methyl 4-(cyclohexylamino)-4-oxobut-2-ynoate with 2-
methylfuran followed by hydrogenation and retro-Diels–
Alder reaction gives a mixture of two regioisomeric prod-
ucts that are active against carcinomas and model carcino-
ma cell lines, but it is necessary to separate the
regioisomeric products.12f Furan 34, obtained in a pure
form after the retro-Diels–Alder reaction, is an analogue
of one of these regioisomers. Moreover, diesters 36 and
37 are the two regioisomers that should be obtained as
mixtures from a similar sequence of reactions starting
from 2-ethylfuran and ethyl methyl acetylenedicarboxyl-
ate.
X-ray diffraction data for 22 and 34 were collected by using a Kap-
pa X8 APPEX II Bruker diffractometer with graphite-monochro-
mated Mo Kα radiation (λ = 0.71073 Å). The temperature of the
crystal was maintained at 100 K (± 1 K) by means of a 700-series
Cryostream cooling device. The data were corrected for Lorentz po-
larization and absorption effects. The structures were solved by di-
rect methods using SHELXS-9724 and refined against F2 by full-
matrix least-square techniques using SHELXL-9724 with anisotro-
pic displacement parameters for all nonhydrogen atoms. Hydrogen
atoms were located on a difference Fourier map and introduced into
calculations as a riding model with isotropic thermal parameters.
All calculations were performed by using the crystal structure crys-
tallographic software package WINGX.25
Diisobutyl Acetylenedicarboxylate (6)
A soln of DMAD (4) (1.00 g, 0.87 mL, 7.04 mmol), i-BuOH (2.40
g, 2.99 mL, 39.3 mmol), and a catalytic amount of PTSA (126 mg,
0.66 mmol) in cyclohexane (10 mL) was refluxed for 3 d while the
MeOH that formed was removed with a 5 Å MS trap maintained at
16 °C. The mixture was then cooled to r.t. and, after addition of
Et2O (60 mL), the organic layer was washed sequentially with 0.1
M aq NaHCO3 (2 × 20 mL) and H2O (20 mL), dried (Na2SO4), and
concentrated under reduced pressure. The crude residue was puri-
fied by column chromatography [silica gel, hexane–Et2O (98:2)] to
give a yellowish oil; yield: 1.53 g (95%); Rf = 0.35 (hexane–Et2O,
94:6). Spectroscopic data were in agreement with those reported.26
1H NMR (360 MHz, CDCl3): δ = 0.97 [d, J = 6.8 Hz, 12 H,
OCH2CH(CH3)2], 2.01 [nonuplet,
J
=
6.8 Hz,
2
H,
OCH2CH(CH3)2], 4.03 [d, J = 6.8 Hz, 4 H, OCH2CH(CH3)2].
Figure 1 ORTEP structure of compound 22;23 ellipsoids are drawn
at the 30% probability level
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2018–2028

2022
N. Sultan et al.
PAPER
Diethyl 1-Ethyl-7-oxabicyclo[2.2.1]hepta-2,5-diene-2,3-dicar-
boxylate (10)
the next step. Caution: Extraction after acidification to pH ≈ 1 re-
sulted in isolation of small amounts of the corresponding diacid.
A mixture of 2-ethylfuran (2; 1.92 g, 2.11 mL, 20.0 mmol) and
EtO2CC≡CCO2Et (5; 3.40 g, 3.20 mL, 19.9 mmol) was stirred at
35 °C for 7 d. Evaporation of the residual reactants at 40 °C under
vacuum (0.1 Torr) for 2 h gave an almost pure orange-yellow oil;
yield: 5.27 g (99%); Rf = 0.32 (PE–Et2O, 2:1).
3-(Methoxycarbonyl)-7-oxabicyclo[2.2.1]hepta-2,5-diene-2-
carboxylic Acid (12)
Treatment of dimethyl diester 7 (130 mg, 0.62 mmol) with 0.25 M
aq NaOH gave a brown oil; yield: 92 mg (76%); Rf = 0.18 (CH2Cl2–
MeOH, 8:2).
1H NMR (360 MHz, CDCl3): δ = 3.99 (s, 3 H, OCH3), 5.79 (t, J =
1.8 Hz, 1 H, H-1, or H-4), 5.83 (t, J = 1.9 Hz, 1 H, H-4, or H-1), 7.20
(dd, J = 5.3, 1.9 Hz, 1 H, H-5, or H-6), 7.28 (dd, J = 5.3, 1.8 Hz, 1
H, H-6, or H-5).
IR (neat): 2982, 2940, 1725, 1712, 1639, 1559, 1465, 1370, 1310,
1267, 1231, 1197, 1095, 1041, 919, 733 cm–1.
1H NMR (250 MHz, CDCl3): δ = 1.04 (t, J = 7.5 Hz, 3 H, CH2CH3),
1.30 (t, J = 7.1 Hz, 3 H, OCH2CH3), 1.35 (t, J = 7.0 Hz, 3 H,
OCH2CH3), 2.12–2.29 (m, 2 H, CH2CH3), 4.23 (q, J = 7.0 Hz, 2 H,
OCH2CH3), 4.31 (q, J = 7.1 Hz, 2 H, OCH2CH3), 5.65 (d, J = 1.9
Hz, 1 H, H-4), 6.99 (d, J = 5.0 Hz, 1 H, H-6), 7.20 (dd, J = 5.0, 1.9
Hz, 1 H, H-5).
13C NMR (90.6 MHz, CDCl3): δ = 8.4 (CH2CH3), 13.5 (2 OCH2CH3),
21.4 (CH2CH3), 60.4 (OCH2CH3), 60.6 (OCH2CH3), 82.6 (C-4),
97.7 (C-1), 144.24 and 144.25 (C-5 and C-6), 150.7 and 155.3 (C-2
and C-3), 161.8 (CO2), 164.3 (CO2).
Spectroscopic data were in agreement with those reported.7b
4-Ethyl-3-(methoxycarbonyl)-7-oxabicyclo[2.2.1]hepta-2,5-di-
ene-2-carboxylic Acid (13)
Treatment of dimethyl diester 8 (1.19 g, 5.00 mmol) with 0.5 M aq
NaOH gave a yellow solid; yield: 876 mg (78%); mp 87 °C; Rf =
0.24 (CH2Cl2–MeOH, 8:2).
IR (neat): 3400–2500, 2974, 2941, 2884, 1729, 1713, 1641, 1613,
1559, 1440, 1324, 1277, 1206, 916, 733 cm–1.
1H NMR (250 MHz, CDCl3): δ = 1.02 (t, J = 7.5 Hz, 3 H, CH2CH3),
2.33 (q, J = 7.5 Hz, 2 H, CH2CH3), 3.97 (s, 3 H, OCH3), 5.71 (d, J =
2.0 Hz, 1 H, H-1), 6.92 (d, J = 5.1 Hz, 1 H, H-5), 7.21 (dd, J = 5.1,
2.0 Hz, 1 H, H-6), 12.50 (br s, 1 H, CO2H).
13C NMR (62.9 MHz, CDCl3): δ = 9.2 (CH2CH3), 22.9 (CH2CH3),
53.8 (OCH3), 83.8 (C-1), 98.2 (C-4), 144.5 (C-5), 144.9 (C-6),
152.5 and 161.8 (C-2 and C-3), 163.1 (CO2Me), 167.3 (CO2H).
MS (ES+): m/z (%) = 193 (12), 289 (100) [M + Na]+, 290 (15), 305
(21), 555 (0.5) [2M + Na]+.
HRMS (ES+): m/z [M + Na]+ calcd for C14H18NaO5: 289.1046;
found: 289.1039.
Diisobutyl 1-Ethyl-7-oxabicyclo[2.2.1]hepta-2,5-diene-2,3-di-
carboxylate (11)
A soln of 2-ethylfuran (2; 213 mg, 234 μL, 2.22 mmol) and diiso-
butyl acetylenedicarboxylate (6; 600 mg, 2.65 mmol) in toluene
(2.4 mL), previously filtered over basic Al2O3, was stirred at 80 °C
for 1 d. The solvent was evaporated under vacuum and the crude
product was purified by column chromatography [silica gel, PE–
Et2O (19:1)] to give a yellow oil; yield: 430 mg (60%); Rf = 0.40
(PE–Et2O, 9:1).
MS (CI/NH3): m/z (%) = 97 (5), 181 (6), 225 (67) [M + H]+, 226 (9),
242 (100) [M + NH4]+, 243 (13).
HRMS (ES+): m/z [M + Na]+ calcd for C11H12NaO5: 247.0577;
found: 247.0580.
IR (neat): 2965, 2876, 1721, 1711, 1640, 1468, 1377, 1314, 1277,
1261, 1229, 1197, 1138, 1079, 920 cm–1.
4-Benzyl-3-(methoxycarbonyl)-7-oxabicyclo[2.2.1]hepta-2,5-di-
ene-2-carboxylic Acid (14)
Treatment of dimethyl diester 9 (400 mg, 1.33 mmol) with 0.5 M aq
NaOH gave an orange oil; yield: 332 mg (87%); Rf = 0.24 (EtOAc).
1H NMR (250 MHz, CDCl3): δ = 0.94 [d, J = 6.6 Hz, 6 H,
OCH2CH(CH3)2], 0.97 [d, J = 6.6 Hz, 6 H, OCH2CH(CH3)2], 1.05
(t, J = 7.5 Hz, 3 H, CH2CH3), 2.00 [nonuplet, J = 6.6 Hz, 2 H, 2
OCH2CH(CH3)2], 2.13–2.28 (m, 2 H, CH2CH3), 3.95 [d, J = 6.6 Hz,
2 H, OCH2CH(CH3)2 on C-3], 3.97 (dd, J = 11.1, 6.6 Hz) and 4.08
(dd, J = 11.1, 6.6 Hz) [AB part of an ABX system, 2 H,
OCH2CH(CH3)2 on C-2], 5.66 (d, J = 1.9 Hz, 1 H, H-4), 6.99 (d, J =
5.2 Hz, 1 H, H-6), 7.20 (dd, J = 5.2, 1.9 Hz, 1 H, H-5).
IR (neat): 3500–2600, 3031, 2955, 1729, 1714, 1635, 1561, 1497,
1436, 1274, 1079, 984, 703 cm–1.
1H NMR (250 MHz, CDCl3): δ = 3.59 (d, J = 15.4 Hz) and 3.67 (d,
J = 15.4 Hz) (AB system, 2 H, CH2Ph), 3.89 (s, 3 H, OCH3), 5.72
(d, J = 1.9 Hz, 1 H, H-1), 7.02 (d, J = 5.1 Hz, 1 H, H-5), 7.19 (dd,
J = 5.1 et 1.9 Hz, 1 H, H-6), 7.21–7.34 (m, 5 H, Ph), 8.65 (br s, 1 H,
CO2H).
13C NMR (90.6 MHz, CDCl3): δ = 8.9 (CH2CH3), 19.00 [2
13C NMR (62.9 MHz, CDCl3): δ = 35.6 (CH2Ph), 53.4 (OCH3), 83.6
(C-1), 97.2 (C-4), 126.8 (CAr-p), 128.2 and 129.6 (CAr-o, CAr-m),
136.0 (CArCH2), 144.5 and 144.6 (C-5, C-6), 153.3 and 160.4 (C-2,
C-3), 162.3 (CO2CH3), 166.7 (CO2H).
OCH2CH(CH3)2],
19.01
[OCH2CH(CH3)2],
19.05
[OCH2CH(CH3)2], 22.0 (CH2CH2), 27.7 [2 OCH2CH(CH3)2], 71.2
[OCH2CH(CH3)2], 71.4 [OCH2CH(CH3)2], 83.3 (C-4), 98.4 (C-1),
144.76 and 144.77 (C-5 and C-6), 150.9 and 156.1 (C-2 and C-3),
162.4 (CO2), 165.1 (CO2).
MS (CI/NH3): m/z (%) = 159 (36), 243 (62), 287 (49) [M + H]+, 288
MS (CI/NH3): m/z (%) = 69 (98), 322 (11), 323 (100) [M + H]+, 324
(11), 304 (100) [M + NH4]+, 305 (17).
(19), 340 (77) [M + NH4]+, 341 (15).
HRMS (ES+): m/z [M + Na]+ calcd for C16H14NaO5: 309.0733;
found: 309.0728.
HRMS (ES+): m/z [M + Na]+ calcd for C18H26NaO5: 345.1672;
found: 345.1666.
3-(Ethoxycarbonyl)-4-ethyl-7-oxabicyclo[2.2.1]hepta-2,5-di-
ene-2-carboxylic Acid (15)
Treatment of diethyl diester 10 (1.02 g, 3.83 mmol) with a 0.5 M aq
soln of NaOH gave a caramel-colored oil; yield: 803 mg (88%);
Rf = 0.34 (CH2Cl2–MeOH, 8:2).
7-Oxabicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylic Acid
Monoesters 12–16; General Procedure
0.5 M or 0.25 M aq NaOH (2.0 equiv) was added to a 0.12 M soln
of the starting diester (2 mmol) in THF at 0 °C. When the conver-
sion of the diester was complete (TLC; silica gel) at 0 °C, the mix-
ture was washed with Et2O (2 × 20 mL) and then acidified to pH ≈
3 with aq HCl. The monoacid was extracted with CHCl3 (3 × 30
mL) and after each separation the pH was readjusted to ≈ 3. The sep-
arated organic soln was immediately concentrated under vacuum,
and the residue was taken up with fresh CHCl3 (50 mL). The organic
phases were combined, dried (Na2SO4), and concentrated under
vacuum to give the crude acid that was used without purification in
IR (neat): 3400–2500, 2981, 2940, 2880, 2670, 1729 (br), 1639,
1613, 1560, 1425, 1373, 1320, 1276, 1203, 1036, 919, 698 cm–1.
1H NMR (250 MHz, CDCl3): δ = 1.00 (t, J = 7.4 Hz, 3 H, CH2CH3),
1.40 (t, J = 7.1 Hz, 3 H, OCH2CH3), 2.20–2.42 (m, 2 H, CCH2CH3),
4.26–4.53 (m, 2 H, OCH2CH3), 5.68 (br s, 1 H, H-1), 6.91 (d, J =
5.1 Hz, 1 H, H-5), 7.19 (br d, J = 5.1 Hz, 1 H, H-6), 10.63 (br s, 1
H, CO2H).
Synthesis 2013, 45, 2018–2028
© Georg Thieme Verlag Stuttgart · New York

PAPER
7-Oxanorborna-2,5-diene Derivatives
2023
13C NMR (62.9 MHz, CDCl3): δ = 9.1 (CH2CH3); 13.7 (OCH2CH3),
22.8 (CCH2CH3), 63.4 (OCH2CH3), 83.6 (C-1), 98.1 (C-4), 144.5
and 144.7 (C-5, C-6), 152.9 and 162.2 (C-2, C-3), 162.0 (CO2CH3),
166.7 (CO2H).
HRMS (ES+): m/z [M + Na]+ calcd for C15H13NNaO4: 294.0737;
found: 294.0745.
Methyl 1-Ethyl-3-(phenylcarbamoyl)-7-oxabicyclo[2.2.1]hepta-
2,5-diene-2-carboxylate (18)
From monoacid 13 (115 mg, 0.51 mmol). Flash chromatography
[PE–EtOAc (4:1)] gave a yellow-green oil; yield: 103 mg (67%);
Rf = 0.33 (PE–EtOAc, 4:1).
MS (CI/NH3): m/z (%) = 239 (100) [M + H]+, 240 (14), 256 (73) [M
+ NH4]+, 257 (10).
HRMS (ES–): m/z [M – H]– calcd for C12H13O5: 237.0768; found:
237.0774.
IR (neat): 3301, 3087, 2973, 2881, 1693, 1661, 1621, 1601, 1557,
1497, 1446, 1328, 1303, 1252, 1201, 994, 931, 757 cm–1.
4-Ethyl-3-(isobutoxycarbonyl)-7-oxabicyclo[2.2.1]hepta-2,5-di-
ene-2-carboxylic Acid (16)
Treatment of diisobutyl diester 11 (380 mg, 1.18 mmol) with 0.5 M
aq NaOH gave a yellow oil; yield: 280 mg (89%); Rf = 0.15 (PE–
EtOAc, 2:1).
1H NMR (360 MHz, CDCl3): δ = 1.05 (t, J = 7.5 Hz, 3 H, CH2CH3),
2.28–2.40 (m, 2 H, CH2CH3), 3.91 (s, 3 H, OCH3), 5.79 (d, J = 1.8
Hz, 1 H, H-4), 6.93 (d, J = 5.0 Hz, 1 H, H-6), 7.13 (br t, J = 7.6 Hz,
1 H, HAr-p), 7.28 (dd, J = 5.0, 1.8 Hz, 1 H, H-5), 7.35 (br t, J = 7.6
Hz, 2 H, HAr-m), 7.66 (br d, J = 7.6 Hz, 2 H, HAr-o), 10.48 (br s, 1
H CONH).
13C NMR (90.6 MHz, CDCl3): δ = 9.2 (CH2CH3), 22.9 (CH2CH3),
52.6 (OCH3), 84.1 (C-4), 98.4 (C-1), 119.7 (CAr-o), 124.4 (CAr-p),
128.9 (CAr-m), 137.8 (CArNH), 144.1 (C-6), 144.6 (C-5), 147.7 (C-
3), 159.9 (C-2), 163.4 and 166.4 (CONH, CO2).
IR (neat): 3500–2600, 2969, 2941, 2876, 1727 (br), 1636, 1559,
1381, 1316, 1276, 1201, 1142, 994, 918, 879, 699 cm–1.
1H NMR (360 MHz, CDCl3): δ = 1.03 [d, J = 6.5 Hz, 6 H,
CH(CH3)2], 1.05 (t, J = 7.4 Hz, 3 H, CH2CH3), 2.10 [nonuplet, J =
6.7 Hz, 1 H, OCH2CH(CH3)2], 2.29–2.45 (m, 2 H, CH2CH3), 4.10
(dd, J = 10.8, 6.5 Hz) and 4.21 (dd, J = 10.8, 6.8 Hz) [AB part of an
ABX system, 2 H, OCH2CH(CH3)2], 5.73 (d, J = 2.0 Hz, 1 H, H-1),
6.92 (d, J = 5.2 Hz, 1 H, H-5), 7.24 (dd, J = 5.1, 2.0 Hz, 1 H, H-6),
12.53 (br s, 1 H, CO2H).
13C NMR (90.6 MHz, CDCl3): δ = 9.1 (CH2CH3), 18.92
[OCH2CH(CH3)2], 18.96 [OCH2CH(CH3)2], 23.0 (CH2CH3), 27.5
[OCH2CH(CH3)2], 73.4 [OCH2CH(CH3)2], 83.7 (C-1), 98.2 (C-4),
144.5 and 144.9 (C-5, C-6), 152.8 and 161.9 (C-2, C-3), 162.6
[CO2CH2CH(CH3)2], 167.0 (CO2H).
MS (CI/NH3): m/z (%) = 300 (100) [M + H]+, 301 (18).
HRMS (ES+): m/z [M + Na]+ calcd for C17H17NNaO4: 322.1050;
found: 322.1049.
Methyl 3-[(Benzylcarbamoyl)carbonyl]-1-ethyl-7-oxabicyc-
lo[2.2.1]hepta-2,5-diene-2-carboxylate (19)
From monoacid 13 (351 mg, 1.57 mmol). Flash chromatography
[PE–EtOAc (4:1)] gave a yellow oil; yield: 160 mg (33%); Rf = 0.37
(PE–EtOAc, 2:1).
MS (CI/NH3): m/z (%) = 97 (8), 223 (7), 267 (100) [M + H]+, 268
IR (neat): 3313, 3032, 2971, 2881, 1713, 1694, 1650, 1622, 1539,
1454, 1438, 1362, 1318, 1272, 1252, 1207, 1081, 928, 701 cm–1.
(16), 284 (36) [M + NH4]+, 285 (5).
HRMS (ES–): m/z [M – H]– calcd for C14H17O5: 265.1081; found:
265.1086.
1H NMR (360 MHz, CDCl3): δ = 1.01 (t, J = 7.6 Hz, 3 H, CH2CH3),
2.22–2.36 (m, 2 H, CH2CH3), 3.78 (s, 3 H, OCH3), 4.47 (dd, J =
15.1, 6.0 Hz) and 4.57 (dd, J = 15.1, 6.0 Hz) (AB part of an ABX
system, 2 H, NHCH2), 5.72 (d, J = 2.1 Hz, 1 H, H-4), 6.90 (d, J =
5.0 Hz, 1 H, H-6), 7.25 (dd, J = 5.0, 2.1 Hz, 1 H, H-5), 7.27–7.34
(m, 5 H, Ph), 8.59 (br s, 1 H CONH).
13C NMR (62.9 MHz, CDCl3): δ = 9.2 (CH2CH3), 22.7 (CH2CH3),
43.6 (NCH2Ph), 52.4 (OCH3), 84.1 (C-4), 98.2 (C-1), 127.4 (CAr-p),
127.6 and 128.6 (CAr-o, CAr-m), 137.6 (CArCH2), 144.0 and 144.6
(C-5, C-6), 147.6 (C-3), 161.9 and 162.1 and 165.8 (C-2, CONH,
CO2).
Amido Esters 17–23; General Procedure
The freshly distilled amine (1.1 equiv) was added to a stirred 0.2 M
soln of the diacid monoester (1 mmol) in THF, followed, after 5
min, by anhyd solid DMTMM (1.1 equiv). The mixture was stirred
for the appropriate time (Table 2) under argon at r.t., then H2O (20
mL) was added and the product was extracted with Et2O (3 × 30
mL). Each separated organic phase was washed successively with
sat. aq Na2CO3 (2 × 10 mL), H2O (10 mL), 1 M aq HCl (10 mL),
and H2O (10 mL). The organic phases were combined, dried
(Na2SO4), and concentrated under vacuum to give a crude product
that was purified by column chromatography [silica gel, PE–
EtOAc (4:1 to 2:1)].
MS (ES+): m/z (%) = 91 (100), 173 (28), 218 (63), 240 (31), 314
(14) [M + H]+, 336 (26) [M + Na]+, 352 (63) [M + K]+.
HRMS (ES+): m/z [M + Na]+ calcd for C18H19NNaO4: 336.1206;
found: 336.1191.
Methyl 3-(Phenylcarbamoyl)-7-oxabicyclo[2.2.1]hepta-2,5-di-
ene-2-carboxylate (17)
From monoacid 12 (177 mg, 0.90 mmol). Flash chromatography
[PE–EtOAc (2:1)] gave a yellow oil; yield: 26 mg (11%); Rf = 0.55
(PE–EtOAc, 2:1).
Methyl 3-(Cyclohexylcarbamoyl)-1-ethyl-7-oxabicyc-
lo[2.2.1]hepta-2,5-diene-2-carboxylate (20)
From monoacid 13 (576 mg, 2.57 mmol). Chromatography [PE–
THF (4:1)] gave a yellow oil; yield: 504 mg (64%); Rf = 0.23 (PE–
Et2O, 1:1).
IR (neat): 3294, 3095, 2953, 1692, 1662, 1620, 1599, 1559, 1496,
1446, 1330, 1304, 1268, 1243, 1211, 881, 754, 701 cm–1.
1H NMR (250 MHz, CDCl3): δ = 3.92 (s, 3 H, OCH3), 5.81 (t, J =
1.9 Hz, 1 H, H-1, or H-4), 5.96 (t, J = 1.9 Hz, 1 H, H-4, or H-1), 7.13
(br t, J = 7.6 Hz, 1 H, HAr-p), 7.20 (dd, J = 5.2, 1.9 Hz, 1 H, H-5, or
H-6), 7.30 (dd, J = 5.2, 1.9 Hz, 1 H, H-6, or H-5), 7.35 (br t, J = 7.6
Hz, 2 H, HAr-m), 7.69 (br d, J = 7.6 Hz, 2 H, HAr-o), 11.07 (br s, 1
H CONH).
13C NMR (90.6 MHz, CDCl3): δ = 53.0 (OCH3), 85.1 and 85.7 (C-
1, C-4), 119.9 (CAr-o), 124.6 (CAr-p), 129.0 (CAr-m), 137.9 (CArNH),
142.8 and 143.4 (C-5, C-6), 146.6 (C-3), 159.3 (C-2), 163.4 and
165.3 (CONH, CO2).
IR (neat): 3315, 3073, 2933, 2855, 1719, 1699, 1650, 1619, 1544,
1451, 1437, 1372, 1327, 1300, 1274, 1251, 1205, 1154, 1081, 1031,
993, 930, 893, 801, 733, 710 cm–1.
1H NMR (250 MHz, CDCl3): δ = 1.01 (t, J = 7.4 Hz, 3 H, CH2CH3),
1.17–1.50 (m, 5 H, HCy), 1.53–1.80 (m, 3 H, HCy), 1.80–2.00 (m, 2
H, HCy), 2.29 (dq, J = 14.8, 7.4 Hz) and 2.32 (dq, J = 14.8, 7.4 Hz)
(AB part of an ABM3 system, 2 H, CH2CH3), 3.80–3.88 (m, CHN)
and 3.85 (s, OCH3) (4 H), 5.68 (d, J = 2.0 Hz, 1 H, H-4), 6.89 (d, J =
5.2 Hz, 1 H, H-6), 7.24 (dd, J = 5.2, 2.0 Hz, 1 H, H-5), 8.20 (br d,
J = 6.7 Hz, 1 H, CONH).
13C NMR (90.6 MHz, CDCl3): δ = 9.3 (CH2CH3), 22.8 (CCy), 24.4
(CCy), 25.5 (CH2CH3), 32.5 and 32.7 (CCy), 48.1 (NCH), 52.3
MS (CI/NH3): m/z (%) = 272 (100) [M + H]+, 273 (16).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2018–2028

2024
N. Sultan et al.
PAPER
(OCH3), 84.2 (C-4), 98.1 (C-1), 144.0 and 144.7(C-5, C-6), 146.8
(C-3), 161.2 (C-2), 162.6 and 165.9 (CON, CO2).
Isobutyl 1-Ethyl-3-(phenylcarbamoyl)-7-oxabicyclo[2.2.1]hep-
ta-2,5-diene-2-carboxylate (23)
From monoacid 16 (260 mg, 0.98 mmol) treated under the general
conditions for 6 h, then stirred for 1 h after introduction of addition-
al aniline (0.4 equiv) and DMTMM (0.4 equiv). Chromatography
[PE–EtOAc (4:1)] gave a yellow oil; yield: 250 mg (75%); Rf = 0.52
(PE–EtOAc, 4:1).
MS (EI): 55 (38), 57 (34), 81 (80), 91 (27), 96 (100), 98 (68), 119
(49), 128 (22), 135 (52), 148 (24), 149 (27), 150 (79), 151 (38), 165
(29), 166 (58), 179 (43), 180 (92), 181 (56), 191 (25), 192 (28), 207
(32), 210 (32), 216 (23), 217 (38), 246 (54), 247 (20), 248 (53), 249
(28), 305 (35) [M]+.
HRMS (ES+): m/z [M + Na]+ calcd for C17H23NNaO4: 328.1519;
found: 328.1508.
IR (neat): 3302, 3091, 2969, 2876, 1684, 1660, 1599, 1559, 1498,
1446, 1326, 1302, 1249, 1197, 992, 921, 756 cm–1.
1H NMR (360 MHz, CDCl3): δ = 1.01 [d, J = 6.8 Hz, 6 H,
CH(CH3)2], 1.07 (t, J = 7.4 Hz, 3 H, CH2CH3), 2.06 [nonuplet, J =
6.7 Hz, 1 H, OCH2CH(CH3)2], 2.31 (dq, J = 14.8, 7.4 Hz) and 2.40
(dq, J = 14.8, 7.4 Hz) (AB part of an ABM3 system, 2 H, CH2CH3),
4.04 (dd, J = 10.6, 6.5 Hz) and 4.14 [dd, J = 10.6, 6.3 Hz) (AB part
of an ABX system, 2 H, OCH2CH(CH3)2], 5.79 (d, J = 1.8 Hz, 1 H,
H-4), 6.91 (d, J = 5.1 Hz, 1 H, H-6), 7.13 (br t, J = 7.2 Hz, 1 H, HAr-
p), 7.28 (dd, J = 5.1, 1.8 Hz, 1 H, H-5), 7.34 (br t, J = 7.5 Hz, 2 H,
HAr-m), 7.66 (br d, J = 7.5 Hz, 2 H, HAr-o), 10.58 (br s, 1 H, CONH).
13C NMR (62.9 MHz, CDCl3): δ = 9.2 (CH2CH3), 18.88
[CH(CH3)2], 18.94 [CH(CH3)2], 22.9 (CH2CH3), 27.4
[OCH2CH(CH3)2], 72.0 [OCH2CH(CH3)2], 84.0 (C-4), 98.2 (C-1),
119.6 (CAr-o), 124.2 (CAr-p), 128.7 (CAr-m), 137.7 (CArNH), 144.0
and 144.6 (C-5, C-6), 147.9 (C-3), 159.8 (C-2), 163.2 and 166.0
(CONH, CO2).
Methyl 1-Benzyl-3-(phenylcarbamoyl)-7-oxabicyclo[2.2.1]hep-
ta-2,5-diene-2-carboxylate (21)
From monoacid 14 (210 mg, 0.73 mmol). Flash chromatography
[PE–EtOAc (2:1)] gave a yellow solid; yield: 96 mg (36%); mp
118 °C [CHCl3–Et2O (1:1), at –20 °C]; Rf = 0.40 (PE–EtOAc, 2:1).
IR (neat): 3300, 3147, 3086, 3065, 3035, 2954, 2927, 1729, 1695,
1601, 1558, 1496, 1446, 1303, 1260, 1201, 988, 756, 704 cm–1.
1H NMR (250 MHz, CDCl3): δ = 3.65 (s, 2 H, CH2Ph), 3.88 (s, 3 H,
OCH3), 5.80 (d, J = 2.0 Hz, 1 H, H-4), 7.02 (d, J = 5.0 Hz, 1 H, H-
6), 7.14 (br t, J = 7.2 Hz, 1 H, HAr-p of NHPh), 7.20–7.40 (m, 8 H,
H-5, HAr of CH2Ph, HAr-m of NHPh), 7.62 (br d, J = 8.7 Hz, 2 H,
HAr-o of NHPh), 10.30 (br s, 1 H, CONH).
13C NMR (90.6 MHz, CDCl3): δ = 35.9 (CH2Ph), 52.5 (OCH3), 84.2
(C-4), 97.4 (C-1), 119.7 (CAr-o of NHPh), 124.4 (CAr-p of NHPh),
126.7 (CAr-p of CH2Ph), 128.2 and 128.8 and 129.6 (CAr-o and CAr-
m of CH2Ph, and CAr-m of NHPh), 136.5 (CArCH2), 137.6 (CArNH),
144.3 (C-6), 144.6 (C-5), 147.7 (C-3), 159.7 (C-2), 162.4 and 166.0
(CONH, CO2).
MS (CI/NH3): m/z (%) = 341 (7), 342 (100) [M + H]+, 343 (22).
HRMS (ES+): m/z [M + Na]+ calcd for C20H23NNaO4: 364.1519;
found: 364.1505.
Diesters 24–27; General Procedure
MS (CI/NH3): m/z (%) = 176 (37), 275 (100), 276 (15), 362 (71) [M
Distilled 4-methylmorpholine (1.2 equiv) was added to a stirred 0.2
M soln of the acid (0.5 mmol) in the appropriate alcohol, followed
after 5 min by anhyd solid DMTMM (2.0 equiv). After stirring for
the indicated time (Table 2) under argon at r.t., the alcohol was
evaporated under vacuum and the residue was taken up in Et2O (20
mL). The organic phase was washed successively with sat. aq
Na2CO3 (10 mL), H2O (10 mL), and sat. aq NaCl (5 mL). The aque-
ous phases were extracted with Et2O (2 × 10 mL) and the organic
phases were combined, dried (Na2SO4), and concentrated under
vacuum. The crude product was purified by column chromatogra-
phy [silica gel, PE– Et2O (1:1)].
+ H]+, 363 (18), 379 (10) [M + NH4]+.
HRMS (ES+): m/z [M + Na]+ calcd for C22H19NNaO4: 384.1206;
found: 384.1202.
Ethyl 1-Ethyl-3-(phenylcarbamoyl)-7-oxabicyclo[2.2.1]hepta-
2,5-diene-2-carboxylate (22)
From monoacid 15 (457 mg, 1.92 mmol). Chromatography [PE–
Et2O (3:1)] gave yellow crystals; yield: 305 mg (51%); mp: 101 °C;
Rf = 0.45 (PE–Et2O, 1:1).
IR (KBr): 3254, 3139, 3040, 2977, 2933, 1682, 1657, 1615, 1597,
1560, 1497, 1446, 1329, 1298, 1252, 1234, 1196, 1008, 901, 770,
714 cm–1.
3-Ethyl 2-Methyl 1-Ethyl-7-oxabicyclo[2.2.1]hepta-2,5-diene-
2,3-dicarboxylate (24)
From monoacid 13 (56 mg, 0.25 mmol). Colorless oil; yield: 43 mg
(69%); Rf = 0.40 (PE–Et2O, 1:1).
1H NMR (300 MHz, CDCl3): δ = 1.05 (t, J = 7.4 Hz, 3 H,
CCH2CH3), 1.40 (t, J = 7.1 Hz, 3 H, OCH2CH3), 2.31 (dq, J = 14.8,
7.4 Hz) and 2.40 (dq, J = 14.8, 7.4 Hz) (AB part of an ABM3 system,
2 H, CCH2CH3), 4.29 (dq, J = 10.9, 7.1 Hz) and 4.46 (dq, J = 10.9,
7.1 Hz) (AB part of an ABX3 system, 2 H, OCH2CH3), 5.79 (d, J =
2.0 Hz, 1 H, H-4), 6.93 (d, J = 5.1 Hz, 1 H, H-6), 7.13 (br t, J = 7.6
Hz, 1 H, HAr-p), 7.30 (dd, J = 5.1, 2.0 Hz, 1 H, H-5), 7.34 (br t, J =
7.6 Hz, 2 H, HAr-m), 7.66 (br d, J = 7.6 Hz, 2 H, HAr-o), 10.56 (br s,
1 H, CONH).
13C NMR (90.6 MHz, CDCl3): δ = 9.3 (CCH2CH3), 14.0
(OCH2CH3), 23.0 (CCH2CH3), 62.1 (OCH2CH3), 84.1 (C-4), 98.4
(C-1), 119.8 (CAr-o), 124.5 (CAr-p), 128.9 (CAr-m), 137.8 (CArNH),
144.2 and 144.7 (C-5, C-6), 148.0 (C-3), 160.0 (C-2), 163.1 and
166.0 (CONH, CO2).
IR (neat): 2980, 2954, 1712 (broad), 1639, 1562, 1436, 1368, 1316,
1272, 1231, 1139, 919, 734 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.02 (t, J = 7.5 Hz, 3 H,
CCH2CH3), 1.29 (t, J = 7.3 Hz, 3 H, OCH2CH3), 2.10–2.26 (m, 2 H,
CCH2CH3), 3.83 (s, 3 H, OCH3), 4.22 (q, J = 7.3 Hz, 2 H,
OCH2CH3), 5.64 (d, J = 1.8 Hz, 1 H, H-4), 6.99 (d, J = 5.3 Hz, 1 H,
H-6), 7.18 (dd, J = 5.3, 1.8 Hz, 1 H, H-5).
13C NMR (90.6 MHz, CDCl3): δ = 8.9 (CCH2CH3), 14.0
(OCH2CH3), 21.9 (CCH2CH3), 52.0 (OCH3), 61.1 (OCH2CH3), 83.2
(C-4), 98.3 (C-1), 144.6 and 144.7 (C-5, C-6), 151.7 and 155.6 (C-
2, C-3), 162.3 (CO2), 165.3 (CO2).
MS (ES+): m/z (%) = 218 (24), 240 (15), 336 (100) [M + Na]+, 337
(17).
MS (CI/NH3): m/z (%) = 253 (100) [M + H]+, 254 (12), 270 (34) [M
+ NH4]+.
HRMS (ES+): m/z [M + Na]+ calcd for C18H19NNaO4: 336.1206;
found: 336.1191.
HRMS (ES+): m/z [M + Na]+ calcd for C13H16NaO5: 275.0890;
found: 275.0880.
X-ray Crystal Data:23 C18H19NO4, M = 313.34, monoclinic, space
group P21/c, Z = 4, a = 8.3840(6) Å, b = 16.4306(11) Å, c =
11.4385(8) Å, V = 1524.79(18) Å3, d = 1.365 g/cm3, R1 = 0.0376,
wR2 = 0.1025, 4463 independent reflections were collected
(Rint=0.0226).
3-Benzyl 2-Methyl 1-Ethyl-7-oxabicyclo[2.2.1]hepta-2,5-diene-
2,3-dicarboxylate (25)
From monoacid 13 (51 mg, 0.23 mmol). Colorless oil; yield: 50 mg
(70%), Rf = 0.60 (PE–Et2O, 1:1).
Synthesis 2013, 45, 2018–2028
© Georg Thieme Verlag Stuttgart · New York

PAPER
7-Oxanorborna-2,5-diene Derivatives
2025
IR (neat): 3033, 2972, 2952, 1710 (broad), 1638, 1559, 1456, 1436,
1381, 1314, 1271, 1228, 1137, 1079, 928, 699 cm–1.
Methyl 3-(Benzylcarbamoyl)-1-ethyl-7-oxabicyclo[2.2.1]hept-
2-ene-2-carboxylate (28)
From amido ester 19 (159 mg, 0.51 mmol), hydrogenated for 40
min in PE. Isolated by chromatography [PE–Et2O (65:35)] as a col-
orless oil; yield: 138 mg (87%); Rf = 0.25 (PE–Et2O, 1:1).
1H NMR (250 MHz, CDCl3): δ = 1.02 (t, J = 7.5 Hz, 3 H, CH2CH3),
2.18 (q, J = 7.5 Hz) and 2.20 (q, J = 7.5 Hz) (2 H, CH2CH3), 3.63 (s,
3 H, OCH3), 5.19 (s, 2 H, OCH2Ph), 5.68 (d, J = 1.8 Hz, 1 H, H-4),
6.99 (d, J = 5.2 Hz, 1 H, H-6), 7.20 (dd, J = 5.2, 1.8 Hz, 1 H, H-5),
7.30–7.41 (m, 5 H, Ph).
13C NMR (90.6 MHz, CDCl3): δ = 8.9 (CH2CH3), 21.9 (CH2CH3),
51.9 (OCH3), 66.9 (CH2Ph), 83.2 (C-4), 98.4 (C-1), 128.2 and 128.5
(CAr-o, CAr-m), 128.3 (CAr-p), 135.1 (CAr-CH2), 144.6 (C-5, C-6),
151.0 and 156.3 (C-2, C-3), 162.1 (CO2), 165.3 (CO2).
IR (neat): 3319, 3064, 3030, 2955, 2879, 1721, 1699, 1657, 1614,
1546, 1455, 1436, 1364, 1330, 1273, 1255, 1176, 1081, 1014, 988,
936, 752, 699 cm–1.
1H NMR (360 MHz, CDCl3): δ = 0.97 (t, J = 7.4 Hz, 3 H, CH2CH3),
1.51 (ddd, J = 10.8, 8.6, 3.4 Hz, 1 H, H-6endo), 1.59 (ddd, J = 11.1,
8.5, 3.4 Hz, 1 H, H-5endo), 1.69 (ddd, J = 10.8, 8.7, 3.3 Hz, 1 H, H-
6exo), 1.92 (dq, J = 14.8, 7.4 Hz, 1 H, A part of an ABM3 system,
MS (CI/NH3): m/z (%) = 69 (5), 315 (57) [M + H]+, 332 (100) [M +
CH2CH3), 2.13 (dddd, J = 11.1, 9.4, 5.0, 3.5 Hz, 1 H, H-5exo), 2.31
(dq, J = 14.8, 7.4 Hz, 1 H, B part of an ABM3 system, CH2CH3),
3.79 (s, 3 H, OCH3), 4.45 (dd, J = 14.9, 5.4 Hz) and 4.59 (dd, J =
14.9, 6.0 Hz, 2 H,) (AB part of an ABX system, NHCH2), 5.33 (d,
J = 5.0 Hz, 1 H, H-4), 7.28–7.37 (m, 5 H, Ph), 8.62 (br s, 1 H,
CONH).
13C NMR (62.9 MHz, CDCl3): δ = 9.2 (CH2CH3), 24.7 (CH2CH3),
27.8 (C-5), 29.5 (C-6), 43.5 (NCH2Ph), 52.3 (OCH3), 80.0 (C-4),
93.4 (C-1), 127.4 (CAr-p), 127.7 and 128.6 (CAr-o, CAr-m), 137.8 and
138.2 (CArCH2, C-3), 152.0 (C-2), 161.9 and 166.3 (CONH, CO2).
MS (ES+): 91 (21), 256 (18) [MH – CH2=CH2 – MeOH]+, 288 (100)
[MH – CH2=CH2]+, 289 (14), 310 (17), 316 (7) [M + H]+, 338 (85)
[M + Na]+, 339 (13).
HRMS (ES+): m/z [M + H]+ calcd for C18H22NO4: 316.1543; found:
316.1530.
NH4]+, 333 (20).
HRMS (ES+): m/z [M + Na]+ calcd for C18H18NaO5: 337.1046;
found: 337.1040.
3-Isobutyl 2-Methyl 1-Ethyl-7-oxabicyclo[2.2.1]hepta-2,5-di-
ene-2,3-dicarboxylate (26)
From monoacid 13 (55 mg, 0.25 mmol). Colorless oil; yield: 38 mg
(55%); Rf = 0.58 (PE–Et2O, 1:1).
IR (neat): 2967, 2878, 1710 (broad), 1640, 1559, 1465, 1436, 1380,
1317, 1270, 1231, 1200, 1138, 1079, 919, 791 cm–1.
1H NMR (360 MHz, CDCl3): δ = 0.94 [d, J = 6.8 Hz, 6 H,
CH(CH3)2], 1.03 (t, J = 7.5 Hz, 3 H, CH2CH3), 1.89–2.01 [m, 1 H,
CH2CH(CH3)2], 2.13–2.26 (m, 2 H, CH2CH3), 3.83 (s, 3 H, OCH3),
3.95 [d, J = 6.5 Hz, 2 H, OCH2CH(CH3)2], 5.65 (d, J = 2.0 Hz, 1 H,
H-4), 6.99 (d, J = 5.2 Hz, 1 H, H-6), 7.18 (dd, J = 5.2, 2.0 Hz, 1 H,
H-5).
13C NMR (90.6 MHz, CDCl3): δ = 8.9 (CH2CH3), 18.9 [CH(CH3)2],
22.0 (CH2CH3), 27.7 [CH2CH(CH3)2], 52.2 (OCH3), 71.3
[OCH2CH(CH3)2], 83.3 (C-4), 98.5 (C-1), 144.74 and 144.77 (C-5,
C-6), 151.3 and 155.7 (C-2, C-3), 162.4 (CO2), 165.5 (CO2).
Methyl 3-(Cyclohexylcarbamoyl)-1-ethyl-7-oxabicyc-
lo[2.2.1]hept-2-ene-2-carboxylate (29)
From amido ester 20 (197 mg, 0.65 mmol), hydrogenated for 1.5 h
in PE. Isolated by chromatography [PE–Et2O (4:1)] as a yellow oil;
yield: 188 mg (95%); Rf = 0.23 (PE–Et2O, 1:1).
MS (CI/NH3): m/z (%) = 69 (100), 281 (64) [M + H]+, 298 (45) [M
IR (neat): 3317, 3073, 2934, 2856, 1721, 1699, 1651, 1613, 1547,
1462, 1452, 1437, 1373, 1363, 1340, 1315, 1272, 1254, 1195, 1176,
1087, 1011, 988, 891, 806, 755 cm–1.
+ NH4]+, 299 (6).
HRMS (ES+): m/z [M + Na]+ calcd for C15H20NaO5: 303.1208;
found: 303.1198.
1H NMR (360 MHz, CDCl3): δ = 0.91 (t, J = 7.4 Hz, 3 H, CH2CH3),
1.12–1.40 (m, 5 H, HCy), 1.40–1.72 (m, 6 H, H-5, H-6, H-6′ and 3
HCy), 1.77–1.92 (m, 3 H, A part of an ABM3 system of CH2CH3 and
2 HCy), 2.00–2.09 (m, 1 H, H-5′), 2.25 (dq, J = 15.0, 7.4 Hz, 1 H, B
part of an ABM3 system, CH2CH3), 3.71–3.82 (m, CHN) and 3.78
(s, OCH3) (4 H), 5.21 (d, J = 5.0 Hz, 1 H, H-4), 8.15 (br d, J = 7.5
Hz, 1 H, CONH).
13C NMR (90.6 MHz, CDCl3): δ = 9.1 (CH2CH3), 24.28 and 24.30
(CH2Cy), 24.6 (CH2Cy), 25.4 (CH2CH3), 27.7 (C-5), 29.4 (C-6), 32.3
and 32.6 (CH2Cy), 47.8 (NCH), 52.2 (OCH3), 79.8 (C-4), 93.2 (C-1),
137.4 (C-3), 152.5 (C-2), 160.8 and 166.2 (CON, CO2).
2-Ethyl 3-Methyl 1-Ethyl-7-oxabicyclo[2.2.1]hepta-2,5-diene-
2,3-dicarboxylate (27)
From monoacid 15 (145 mg, 0.61 mmol). Colorless oil; yield: 107
mg (70%); Rf = 0.40 (PE–Et2O, 1:1).
IR (neat): 2978, 1731, 1713, 1644, 1560, 1436, 1369, 1312, 1264,
1231, 1197, 1138, 1095, 1080, 1041, 900, 709 cm–1.
1H NMR (250 MHz, CDCl3): δ = 1.03 (t, J = 7.5 Hz, 3 H,
CCH2CH3), 1.34 (t, J = 7.1 Hz, 3 H, OCH2CH3), 2.09–2.31 (m, 2 H,
CCH2CH3), 3.77 (s, 3 H, OCH3), 4.30 (dq, J = 10.9, 7.1 Hz) and 4.33
(dq, J = 10.9, 7.1 Hz) (AB part of an ABX3 system, 2 H, OCH2CH3),
5.65 (d, J = 2.0 Hz, 1 H, H-4), 6.99 (d, J = 5.2 Hz, 1 H, H-6), 7.19
(dd, J = 5.2, 2.0 Hz, 1 H, H-5).
13C NMR (90.6 MHz, CDCl3): δ = 9.0 (CCH2CH3), 14.1
(OCH2CH3), 22.0 (CCH2CH3), 52.0 (OCH3), 61.4 (OCH2CH3), 83.3
(C-4), 98.4 (C-1), 144.7 and 144.8 (C-5 and C-6), 151.0 and 156.4
(C-2, C-3), 162.9 (CO2), 164.9 (CO2).
MS (ES+): 248 (3), 280 (12), 302 (17), 303 (3), 308 (5) [M + H]+,
330 (100) [M + Na]+, 331 (33), 637 (7) [2M + Na]+.
HRMS (ES+): m/z [M + Na]+ calcd for C17H25NNaO4: 330.1676;
found: 330.1690.
Methyl 1-Benzyl-3-(phenylcarbamoyl)-7-oxabicyclo[2.2.1]hept-
2-ene-2-carboxylate (30)
From amido ester 21 (327 mg, 0.91 mmol), hydrogenated for 40
min in 7:3 PE–THF. Isolated by chromatography [PE–Et2O (3:1)]
as a yellow solid; yield: 307 mg (93%); mp: 108 °C; Rf = 0.42 (PE–
Et2O, 1:1).
MS (ES+): m/z (%) = 179 (22), 275 (100) [M + Na]+, 276 (13).
HRMS (ES+): m/z [M + Na]+ calcd for C13H16NaO5: 275.0890;
found: 275.0892.
IR (ATR): 3298, 3199, 3142, 3089, 3034, 2988, 2955, 2940, 2917,
2878, 1695, 1661, 1598, 1552, 1495, 1446, 1346, 1272, 1247, 1079,
982, 757, 706 cm–1.
1H NMR (360 MHz, CDCl3): δ = 1.61 (ddd, J = 11.4, 8.7, 3.7 Hz, 1
H, H-6endo), 1.70 (ddd, J = 11.2, 8.7, 3.5 Hz, 1 H, H-5endo), 1.84 (ddd,
J = 11.4, 9.4, 3.7 Hz, 1 H, H-6exo), 2.19 (dddd, J = 11.2, 9.4, 5.0, 3.6
Hz, 1 H, H-5exo), 3.34 (d, J = 15.2 Hz) and 3.56 (d, J = 15.2 Hz) (2
Oxanorbornenes 28–32; General Procedure
A preparation of 5% Pd on BaSO4 (8 mg for 1 mmol) was added to
a 0.1 M soln of the oxanorbornadiene in PE or a PE–THF mixture,
and the mixture was stirred under H2. The solids were separated by
filtration over Clarcel Flo-M and the filtrate was concentrated to
give the crude oxanorbornene, which was purified column chroma-
tography (silica gel).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2018–2028

2026
N. Sultan et al.
PAPER
H, AB system, CH2Ph), 3.86 (s, 3 H, OCH3), 5.44 (d, J = 5.0 Hz, 1
H, H-4), 7.10 (br t, J = 7.6 Hz, 1 H, HAr-p of NHPh), 7.23–7.34 (m,
7 H, HAr of CH2Ph, HAr-m of NHPh), 7.60 (br d, J = 7.6 Hz, 2 H,
HAr-o of NHPh), 10.28 (br s, 1 H, CONH).
MS (ES+): m/z (%) = 181 (20) [MH – CH2=CH2 – EtOH]+, 227 (6)
[MH – CH2=CH2]+, 249 (15) [MNa – CH2=CH2]+, 255 (10) [M +
H]+, 277 (100) [M + Na]+.
HRMS (ES+): m/z [M + Na]+ calcd for C13H18NaO5: 277.1046;
13C NMR (62.9 MHz, CDCl3): δ = 27.7 (C-5), 30.3 (C-6), 37.9
(CH2Ph), 52.5 (OCH3), 80.1 (C-4), 92.9 (C-1), 119.7 (CAr-o of
NHPh), 124.3 (CAr-p of NHPh), 126.6 (CAr-p of CH2Ph), 128.2 and
128.9 and 129.7 (CAr-o and CAr-m of CH2Ph, CAr-m of NHPh), 136.9
(CArCH2), 137.7 (CArNH), 138.2 (C-3), 152.3 (C-2), 159.5 and
166.4 (CONH, CO2).
found: 277.1039.
Furans 33–37; General Procedure
A 0.1 M soln of the oxanorbornene in a mixture of cis- and trans-
decalin (previously filtered over basic Al2O3) was heated for 75 min
at 190 °C under argon then cooled. The furan was generally isolated
by column chromatography (silica gel).
MS (ES+): 304 (6), 336 (13) [MH – CH2=CH2]+, 358 (17) [MNa –
CH2=CH2]+, 386 (100) [M + Na]+, 387 (24).
Methyl 4-(Benzylcarbamoyl)-2-ethyl-3-furoate (33)
From amido ester 28 (93 mg, 0.30 mmol). Isolated by chromatogra-
phy [PE then PE–Et2O (1:1)] as a yellowish solid; yield: 80 mg
(94%); mp: 67–68 °C; Rf = 0.24 (PE–Et2O, 1:1).
HRMS (ES+): m/z [M + Na]+ calcd for C22H21NNaO4: 386.1363;
found: 386.1352.
3-Ethyl 2-Methyl 1-Ethyl-7-oxabicyclo[2.2.1]hept-2-ene-2,3-di-
carboxylate (31)
From diester 24 (239 mg, 0.95 mmol) hydrogenated for 55 min in
PE. Isolated by chromatography [toluene–PE–THF (48:49:3)] as a
colorless oil; yield: 206 mg (85%); Rf = 0.18 (toluene–PE–THF,
47:47:6).
IR (ATR): 3282, 3225, 3132, 3087, 2951, 2921, 1688, 1646, 1578,
1556, 1445, 1398, 1298, 1220, 1197, 1135, 1108, 1051, 927, 728,
694 cm–1.
1H NMR (360 MHz, CDCl3): δ = 1.25 (t, J = 7.4 Hz, 3 H, CH2CH3),
2.99 (q, J = 7.4 Hz, 2 H, CH2CH3), 3.86 (s, 3 H, OCH3), 4.61 (d, J =
5.4 Hz, 2 H, NCH2Ph), 7.24–7.38 (m, 5 H, Ph), 8.07 (s, 1 H, H-5),
9.81 (br s, 1 H, CONH).
13C NMR (90.6 MHz, CDCl3): δ = 12.0 (CH2CH3), 22.5 (CH2CH3),
43.2 (NCH2Ph), 52.1 (OCH3), 109.3 (C-3), 122.4 (C-4), 127.0 and
127.5 (CAr-o, CAr-m), 128.4 (CAr-p), 138.5 (CArCH2), 147.9 (C-5),
161.5 and 166.1 and 166.7 (C-2, CONH, CO2).
IR (neat): 2981, 2954, 2883, 1716 (broad), 1635, 1464, 1436, 1372,
1331, 1304, 1272 (broad), 1176, 1123, 1092, 1075, 1034, 1005,
936, 879, 792 cm–1.
1H NMR (360 MHz, CDCl3): δ = 1.02 (t, J = 7.5 Hz, 3 H,
CCH2CH3), 1.30 (t, J = 7.2 Hz, 3 H, OCH2CH3), 1.50 (ddd, J = 11.5,
8.6, 3.6 Hz, 1 H, H-6endo), 1.60 (ddd, J = 11.3, 8.6, 3.7 Hz, 1 H, H-
5endo), 1.72 (ddd, J = 11.5, 9.1, 3.6 Hz, 1 H, H-6exo), 1.94 (dq, J =
14.8, 7.5 Hz, 1 H, A part of an ABM3 system, CCH2CH3), 2.08
(dddd, J = 11.3, 8.8, 4.8, 3.8 Hz, 1 H, H-5exo), 2.18 (dq, J = 14.8, 7.5
Hz, 1 H, B part of an ABM3 system, CCH2CH3), 3.83 (s, 3 H,
OCH3), 4.23 (q, J = 7.2 Hz, 2 H, OCH2CH3), 5.21 (d, J = 4.7 Hz, 1
H, H-4).
13C NMR (90.6 MHz, CDCl3): δ = 8.8 (CCH2CH3), 13.9
(OCH2CH3), 24.0 (CCH2CH3), 27.0 (C-5), 29.0 (C-6), 51.9 (OCH3),
60.9 (OCH2CH3), 78.5 (C-4), 93.1 (C-1), 141.2 and 146.4 (C-2, C-
3), 161.8 (CO2), 165.0 (CO2).
MS (ES+): m/z (%) = 310 (100) [M + Na]+, 311 (16).
HRMS (ES+): m/z [M + Na]+ calcd for C16H17NNaO4: 310.1050;
found: 310.1039.
Methyl 4-(Cyclohexylcarbamoyl)-2-ethyl-3-furoate (34)
From amido ester 29 (93 mg, 0.30 mmol). Isolated by chromatogra-
phy [PE then PE–Et2O (4:1)] as a white solid; yield: 53 mg (62%);
mp 83–84 °C (Et2O); Rf = 0.20 (PE–Et2O, 1:1).
IR (neat): 3296, 3165, 3093, 2932, 2855, 1720, 1701, 1650, 1640,
1583, 1559, 1447, 1400, 1319, 1295, 1262, 1220, 1197, 1172, 1140,
1110, 1050, 992, 940, 890, 840, 784, 753 cm–1.
1H NMR (360 MHz, CDCl3): δ = 1.25 (t, J = 7.5 Hz, 3 H, CH2CH3),
1.26–1.49 (m, 5 H, HCy), 1.57–1.67 (m, 1 H, HCy), 1.71–1.80 (m, 2
H, HCy), 1.93–2.02 (m, 2 H, HCy), 2.98 (q, J = 7.5 Hz, 2 H, CH2CH3),
3.90–3.99 (m, CHN) and 3.91 (s, OCH3) (4 H), 8.02 (s, 1 H, H-5),
9.31 (br d, J = 6.0 Hz, 1 H, CONH).
13C NMR (90.6 MHz, CDCl3): δ = 12.0 (CH2CH3), 22.6 (CH2Cy),
24.5 (CH2Cy), 25.6 (CH2CH3), 32.6 (CH2Cy), 47.8 (NCH), 52.1
(OCH3), 109.3 (C-3), 122.8 (C-4), 147.7 (C-5), 160.5 and 166.2 and
166.6 (C-2, CONH, CO2).
MS (ES+): m/z (%) = 249 (19) [MNa – CH2=CH2]+, 277 (100), 270
(34) [M + Na]+.
HRMS (ES+): m/z [M + Na]+ calcd for C13H18NaO5: 277.1046;
found: 277.1035.
2-Ethyl 3-Methyl 1-Ethyl-7-oxabicyclo[2.2.1]hept-2-ene-2,3-di-
carboxylate (32)
From diester 27 (145 mg, 0.57 mmol) hydrogenated for 40 min in
85:15 PE–THF. Isolated by chromatography [toluene–PE–THF
(48:49:3)] as a colorless oil; yield: 131 mg (90%), Rf = 0.37 (tolu-
ene–PE–THF, 46:46:8).
MS (EI): 98 (20), 165 (11), 166 (37), 180 (10), 181 (100), 182 (11),
247 (27), 279 (18) [M]+.
HRMS (ES+): m/z [M + Na]+ calcd for C15H21NNaO4: 302.1363;
IR (neat): 2981, 2955, 2883, 1716 (broad), 1635, 1463, 1437, 1369,
1327, 1304, 1273, 1259, 1235, 1176, 1126, 1092, 1074, 1018, 984,
891 cm–1.
found: 302.1366.
1H NMR (360 MHz, CDCl3): δ = 1.03 (t, J = 7.5 Hz, 3 H,
CCH2CH3), 1.34 (t, J = 7.1 Hz, 3 H, OCH2CH3), 1.51 (ddd, J = 11.5,
8.6, 3.5 Hz, 1 H, H-6endo), 1.60 (ddd, J = 11.1, 8.6, 3.7 Hz, 1 H, H-
5endo), 1.71 (ddd, J = 11.5, 9.4, 3.6 Hz, 1 H, H-6exo), 1.94 (dq, J =
14.6, 7.5 Hz, 1 H, A part of an ABM3 system, CCH2CH3), 2.08
(dddd, J = 11.1, 9.4, 4.8, 3.5 Hz, 1 H, H-5exo), 2.19 (dq, J = 14.6, 7.5
Hz, 1 H, B part of an ABM3 system, CCH2CH3), 3.78 (s, 3 H,
OCH3), 4.29 (dq, J = 10.8, 7.1 Hz) and 4.34 (dq, J = 10.8, 7.1 Hz)
(2 H, AB part of an ABM3 system, OCH2CH3), 5.20 (d, J = 4.8 Hz,
1 H, H-4).
13C NMR (90.6 MHz, CDCl3): δ = 8.9 (CCH2CH3), 14.0
(OCH2CH3), 24.0 (CCH2CH3), 27.1 (C-5), 29.0 (C-6), 51.8 (OCH3),
61.1 (OCH2CH3), 78.5 (C-4), 93.1 (C-1), 140.6 and 147.1 (C-2, C-
3), 162.3 (CO2), 164.6 (CO2).
X-ray crystal data:23 C15H21NO4, M = 279.33, triclinic, space group
P1, Z = 4, a = 9.2922(7) Å, b = 10.0908(8) Å, c = 16.3214(13) Å,
V = 1437.57(19) Å3, d = 1.291 g/cm3, R1 = 0.0897, wR2 = 0.2049,
14922 independent reflections were collected (Rint = 0.0291).
Methyl 2-Benzyl-4-(phenylcarbamoyl)-3-furoate (35)
From amido ester 30 (221 mg, 0.61 mmol). When the reaction mix-
ture was allowed to stand overnight at –20 °C, the product crystal-
lized and was separated and washed with PE; yield: 162 mg (79%).
Column chromatography [silica gel, PE then PE–Et2O (7:3)] of the
residual liquid gave a second crop of the product as a white solid;
yield: 35 mg (17%); total yield: 197 mg (96%); mp 124–125 °C;
Rf = 0.39 (PE–Et2O, 1:1).
Synthesis 2013, 45, 2018–2028
© Georg Thieme Verlag Stuttgart · New York

PAPER
7-Oxanorborna-2,5-diene Derivatives
2027
IR (ATR): 3253, 3195, 3134, 3087, 2950, 1697, 1661, 1621, 1561,
1491, 1442, 1395, 1332, 1283, 1250, 1181, 1133, 1070, 943, 877,
761, 745, 725, 695 cm–1.
1H NMR (360 MHz, CDCl3): δ = 3.96 (s, 3 H, OCH3), 4.34 (s, 2 H,
CH2Ph), 7.13 (br t, J = 7.4 Hz, 1 H, HAr-p of NHPh), 7.21–7.40 (m,
7 H, HAr of CH2Ph, HAr-m of NHPh), 7.77 (br d, J = 7.8 Hz, 2 H,
HAr-o of NHPh), 8.18 (s, 1 H, H-5), 11.55 (br s, 1 H, CONH).
13C NMR (62.9 MHz, CDCl3): δ = 35.0 (CH2Ph), 52.5 (OCH3),
110.3 (C-3), 120.0 (CAr-o of NHPh), 123.4 (C-4), 123.9 (CAr-p of
NHPh), 126.9 (CAr-p of CH2Ph), 128.4 and 128.6 and 128.8 (CAr-o
and CAr-m of CH2Ph, CAr-m of NHPh), 136.4 (CArCH2), 138.5
(CArNH), 149.2 (C-5), 159.2 and 163.5 and 166.4 (C-2, CONH,
CO2).
References
(1) (a) Vogel, P.; Willhalm, B.; Prinzbach, H. Helv. Chim. Acta
1969, 52, 584. (b) McCulloch, A. W.; Stanovnik, B.; Smith,
D. G.; McInnes, A. G. Can. J. Chem. 1969, 47, 4319.
(c) Osman, M. A.; Huynh-Ba, T. Mol. Cryst. Liq. Cryst.
1983, 92, 57. (d) Duval, O.; Lynch, M. A.; Richomme, P.;
Mavoungou Gomès, L. Heterocycles 1996, 43, 1901.
(e) Chambers, R. D.; Roche, A. J.; Rock, M. H. J. Chem.
Soc., Perkin Trans. 1 1996, 1095. (f) Maggiani, A.; Tubul,
A.; Brun, P. Tetrahedron Lett. 1998, 39, 4485. (g) Zhu, G.-
D.; Staeger, M. A.; Boyd, S. A. Org. Lett. 2000, 2, 3345.
(h) Shinohara, H.; Sonoda, M.; Atobe, S.; Masuno, H.;
Ogawa, A. Tetrahedron Lett. 2011, 52, 6238.
(2) Xing, Y. D.; Huang, N. Z. J. Org. Chem. 1982, 47, 140.
(3) (a) Mahajna, M.; Quistad, G. B.; Casida, J. E. Chem. Res.
Toxicol. 1996, 9, 241. (b) Blanco, L.; Bloch, R.; Bugnet, E.;
Deloisy, S. Tetrahedron Lett. 2000, 41, 7875. (c) Soret, A.;
Blanco, L.; Deloisy, S. Lett. Org. Chem. 2006, 3, 648.
(d) Albert, S.; Soret, A.; Blanco, L.; Deloisy, S. Tetrahedron
2007, 63, 2888. (e) Hong, V.; Kislukhin, A. A.; Finn, M. G.
J. Am. Chem. Soc. 2009, 131, 9986. (f) Albert, S.; Blanco,
L.; Deloisy, S. ARKIVOC 2009, (xiii), 78.
MS (ES+): m/z (%) = 304 (2) [MH – MeOH]+, 336 (7) [M + H]+, 358
(100) [M + Na]+, 359 (24).
HRMS (ES+): m/z [M + Na]+ calcd for C20H17NNaO4: 358.1050;
found: 358.1040.
4-Ethyl 3-Methyl 2-Ethylfuran-3,4-dicarboxylate (36)
From diester 31 (96 mg, 0.38 mmol). Isolated by chromatography
[PE then PE–Et2O (7:3)] as a colorless oil; yield: 76 mg (88%); Rf =
0.41 (PE–Et2O, 3:2).
(4) Functionalization can also be performed by an
intramolecular reaction, see: Choony, N.; Kuhnert, N.;
Sammes, P. G.; Smith, G.; Ward, R. W. J. Chem. Soc.,
Perkin Trans. 1 2002, 1999.
(5) For syntheses of pyrrolines by reaction with azomethine
ylides, see: (a) Soret, A.; Guillot, R.; Rousseau, G.; Blanco,
L.; Deloisy, S. Synlett 2007, 1284. (b) Soret, A.; Müller, C.;
Guillot, R.; Blanco, L.; Deloisy, S. Tetrahedron 2011, 67,
698; see also ref. 3c.
(6) For syntheses of isoxazoles by reaction with nitrile oxides,
see: (a) Cristina, D.; De Amici, M.; De Micheli, C.;
Gandolfi, R. Tetrahedron 1981, 37, 1349. (b) Reinhoudt, D.
N.; Kouwenhoven, C. G. Recl. Trav. Chim. Pays-Bas 1976,
95, 67. (c) Fišera, L.; Považanec, F.; Zálupský, P.; Kováč, J.;
Pavlovič, D. Collect. Czech. Chem. Commun. 1983, 48,
3144.
(7) For synthesis of 1,2,3-triazoles by reaction with azides, see:
(a) Fišera, L.; Pavlovič, D. Collect. Czech. Chem. Commun.
1984, 49, 1990. (b) van Berkel, S. S.; Dirks, A. J.; Debets,
M. F.; van Delft, F. L.; Cornelissen, J. J. L. M.; Nolte, R. J.
M.; Rutjes, F. P. J. T. ChemBioChem 2007, 8, 1504; see also
refs. 6a–c.
IR (neat): 3148, 2983, 2949, 1724 (broad), 1597, 1557, 1443, 1367,
1310, 1294, 1257, 1200, 1139, 1097, 1046, 1019, 764 cm–1.
1H NMR (250 MHz, CDCl3): δ = 1.25 (t, J = 7.6 Hz, 3 H,
CCH2CH3), 1.34 (t, J = 7.1 Hz, 3 H, OCH2CH3), 2.91 (q, J = 7.6 Hz,
2 H, CCH2CH3), 3.86 (s, 3 H, OCH3), 4.30 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 7.77 (s, 1 H, H-5).
13C NMR (90.6 MHz, CDCl3): δ = 12.0 (CCH2CH3), 14.1
(OCH2CH3), 20.8 (CCH2CH3), 51.6 (OCH3), 60.6 (OCH2CH3),
111.9 (C-3), 118.9 (C-4), 145.2 (C-5), 162.1 and 163.49 and 163.54
(C-2, CO2, CO2).
MS (ES+): m/z (%) = 249 (100) [M + Na]+, 250 (11).
HRMS (ES+): m/z [M + Na]+ calcd for C11H14NaO5: 249.0733;
found: 249.0729.
3-Ethyl 4-Methyl 2-Ethylfuran-3,4-dicarboxylate (37)
From diester 32 (106 mg, 0.42 mmol). Isolated by chromatography
[PE then PE–Et2O (7:3)] as a colorless oil; yield: 90 mg (94%); Rf =
0.42 (PE–Et2O, 3:2).
IR (ATR): 2982, 2938, 1716 (broad), 1552, 1463, 1439, 1415, 1287,
1258, 1195, 1177, 1137, 1095, 1075, 1048, 988, 803, 758 cm–1.
1H NMR (360 MHz, CDCl3): δ = 1.24 (t, J = 7.6 Hz, 3 H,
CCH2CH3), 1.35 (t, J = 7.1 Hz, 3 H, OCH2CH3), 2.90 (q, J = 7.6 Hz,
2 H, CCH2CH3), 3.83 (s, 3 H, OCH3), 4.32 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 7.75 (s, 1 H, H-5).
13C NMR (62.9 MHz, CDCl3): δ = 11.9 (CCH2CH3), 13.9
(OCH2CH3), 20.8 (CCH2CH3), 51.6 (OCH3), 60.6 (OCH2CH3),
112.2 (C-3), 118.6 (C-4), 145.1 (C-5), 162.5 and 162.9 and 163.3
(C-2, CO2, CO2).
(8) For syntheses of pyrazoles by reactions with nitrile imines,
see refs. 6a–c; by reactions with ethyl diazoacetate, see ref.
7a.
(9) Isoxazolines can be synthesized by reaction with nitrones:
Louaisil, N.; Soret, A.; Blanco, L.; Deloisy, S. unpublished
results.
(10) For syntheses of 3H-pyrazoles by reaction with 2-diazo-
propane, see ref. 6a.
(11) For syntheses of pyrroles by reaction of mesoionic
compounds and double fragmentation, see: Matsukubo, H.;
Kato, H. J. Chem. Soc., Perkin Trans. 1 1976, 2565.
(12) (a) Alder, K.; Rickert, H. F. Ber. Dtsch. Chem. Ges. B 1937,
70, 1354. (b) Hofmann, K. J. Am. Chem. Soc. 1944, 66, 51.
(c) Williams, H.; Kaufmann, P.; Mosher, H. S. J. Org.
Chem. 1955, 20, 1139. (d) Duval, O.; Mavoungou Gomès, L.
Bull. Soc. Chim. Fr. 1987, 131. (e) Mann, J.; Holland, H. J.;
Lewis, T. Tetrahedron 1987, 43, 2533. (f) Austin, D. J.;
Nguyen, V.-A. A.; Pupowicz, D.; Deisseroth, A.; Wang, T.;
Lerma, E. US 7304092, 2007.
MS (ES+): m/z (%) = 249 (100) [M + Na]+, 250 (11).
HRMS (ES+): m/z [M + Na]+ calcd for C11H14NaO5: 249.0733;
found: 249.0727.
Acknowledgment
We thank the International Relations Office of the University of
Paris-Sud 11 for the financial support given to N.S.
(13) For a similar indirect transformation, see: Fry, A. J.;
Sherman, L. R.; Beaulieu, A. R.; Sherwin, C. J. Org. Chem.
1990, 55, 389.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2018–2028

2028
N. Sultan et al.
PAPER
(14) For an example of a direct synthesis by retro-Diels–Alder
reaction, see: Tanaka, A.; Harigaya, Y.; Nishino, N.;
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(15) (a) Wei, K.; Gao, H.-T.; Li, W.-D. Z. J. Org. Chem. 2004,
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(d) Raheem, M.-A.; Tam, W. Synth. Commun. 2013, 43,
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(16) Gustafsson, J.; Sterner, O. J. Org. Chem. 1994, 59, 3994.
(17) Hinkel, F.; Blanco, L.; Deloisy, S. unpublished results.
(18) Lautens, M.; Fillion, E. J. Org. Chem. 1997, 62, 4418.
(19) Arjona, O.; Iradier, F.; Medel, R.; Plumet, J. Heterocycles
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(22) Kunishima, M.; Kawachi, C.; Morita, J.; Terao, K.; Iwasaki,
F.; Tani, S. Tetrahedron 1999, 55, 13159.
(23) Crystallographic data for compounds 22 and 34 have been
deposited with the accession numbers CCDC 858773 and
858773, respectively, and can be obtained free of charge
from the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; Fax: +44(1223)336033;
E-mail: deposit@ccdc.cam.ac.uk; Web site:
www.ccdc.cam.ac.uk/conts/retrieving.html.
(24) Sheldrick, G. M. SHELX97 [Includes SHELXS97,
SHELXL97 and CIFTAB]: Programs for Crystal Structure
Analysis (Release 97-2); Institüt für Anorganische Chemie
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(26) Hirahata, W.; Hanaoka, H.; Tanimoto, M. US 20110269927,
2011.
Synthesis 2013, 45, 2018–2028
© Georg Thieme Verlag Stuttgart · New York