Synthesis of 7-azabicyclo[2.2.1]heptane derivatives by transformation of tropinone

Article abstract of DOI:10.1002/jhet.5570430607

The bromination (CuBr₂, AcOEt/CHCl₃) plus Favorskii rearrangement (EtONa, EtOH) of N-carbethoxytropinone (4), readily available from tropinone (3), affords mixtures of exo- and endo-isomers of 2,7-dicarbethoxy-7-azabicyclo[2.2.1]heptane (1b) in variable and moderate chemical yield (maximum 37%). The bromination (Br₂, HBr/AcOH) reaction of compound 4 gives ethyl trans-2,4-dibromo-3-oxo-8-azabicyclo[3.2.1] octane-8-carboxylate (5) in 99% yield, a product that on Favorskii rearrangement (EtONa/EtOH) affords ethyl 2,2-diethoxy-3-oxo-8-azabicyclo[3.2.1]octane-8- carboxylate in moderate yield (6) (52%).

Full text of DOI:10.1002/jhet.5570430607

Nov-Dec 2006
1455
Synthesis of 7-Azabicyclo[2.2.1]heptane Derivatives by
Transformation of Tropinone
Elena Gómez-Sánchez* and José Marco-Contelles
Laboratorio de Radicales Libres, IQOG (CSIC), C/Juan de la Cierva 3,
28006-Madrid, Spain
Tel.: +33-91-5622900 (Ext. 371); fax: +34-91-5644853.; e-mail: iqoc21@iqog.csic.es
Received November 17, 2005
CO2Et
N
N
1. CuBr2
2. EtONa,
EtOH
CO2Et
ClCO2Et
92%
37%
O
The bromination (CuBr2, AcOEt/CHCl3) plus Favorskii rearrangement (EtONa, EtOH) of N-
carbethoxytropinone (4), readily available from tropinone (3), affords mixtures of exo- and endo-isomers
of 2,7-dicarbethoxy-7-azabicyclo[2.2.1]heptane (1b) in variable and moderate chemical yield (maximum
37%). The bromination (Br2, HBr/AcOH) reaction of compound 4 gives ethyl trans-2,4-dibromo-3-oxo-8-
azabicyclo[3.2.1]octane-8-carboxylate (5) in 99% yield, a product that on Favorskii rearrangement
(EtONa/EtOH) affords ethyl 2,2-diethoxy-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate in moderate
yield (6) (52%).
J. Heterocyclic Chem., 43, 1455 (2006).
Introduction.
[4]. Finally, epiboxidine has been synthesized from
compound 1c (Scheme 1) by Pandey and colleagues [7].
In this context, and in connection with a current project
in progress in our laboratory, we have investigated the
synthesis of 7-azabicyclo[2.2.1]heptane derivatives
starting from tropinone, and we report here our results.
Exo-2-substituted 7-azabicyclo[2.2.1]heptane deriva-
tives (1) are useful synthetic intermediates [1,2] for the
synthesis of a number of natural products, such as
epibatidine (2) (Scheme 1) [3]. One of the first and best
known synthetic approaches starts from commercially
Scheme 1
CO2Et
N
CO2R
N
H
N
Cl
N
CO2R'
N
1
O
O
2
4
a R= Et, R'= Me
b R, R'= Et
Tropinone (3)
c R, R'= Me
Scheme 2
available tropinone (3). Bai and co-workers reported a
synthesis of epibatidine [4] that used 1a as a key
intermediate (Scheme 1). The latter compound was
obtained in 56% yield from N-carbethoxy-7-azabicyclo-
[3.2.1]heptane (4) [5], after bromination (CuBr2,
AcOEt/CHCl3) followed by Favorskii rearrangement
(MeONa, DME). Daly and associates also prepared
intermediate 1b (Scheme 1), in their approach to
epiboxidine [5]. They obtained and isolated compound 1b
in an overall 12.5% yield from 4 after bromination (Br2,
HBr/AcOH) followed by Favorskii rearrangement
(EtONa, EtOH). In a more recent communication [6]
some epibatidine analogues have been synthesized from
1a (Scheme 1), this compound being prepared as reported
CO2Et
N
1. CuBr2
2. EtONa,
EtOH
CO2Et
4
37%
1b
Results and Discussion.
In our preliminary experiments tropinone (3) was
transformed into carbamate 4 which was submitted to the
bromination reaction [CuBr2 (2 equiv) added in 4 h 30
min] in a mixture of ethyl acetate/chloroform [4b],
followed by Favorskii rearrangement using sodium

1456
E. Gómez-Sánchez and J. Marco-Contelles
Vol 43
ethoxide in ethanol to give product 1b (Scheme 2). In our
hands this two-step protocol gave mixtures of the exo- and
endo-1b isomers in variable yields, ranging from 19-30%
and 7-13%, respectively. In the best experiment we
obtained exo-1b and endo-1b in 30% and 7% yield (37%
total yield), respectively, from compound 4. The
formation of the endo-1b is the result of a partial
epimerization process in the basic reaction medium.
Although our conditions are somewhat different with
respect to Bai’s procedure (DME, temperature), the
isolation of both epimers and thus, lack of complete
diastereoselectivity has already been reported in patent
literature while following Bai’s procedure (3:1, exo:endo)
[8d].
effect was observed when irradiating protons H2 and H4
1
in the H NMR spectrum. The elemental analysis and the
mass spectrum are in good agreement for a compound
with a C10H13Br2NO3 formula. These data strongly support
the non symmetrical, trans-2,4-dibromo structure 5 for
this compound.
The reaction of compound 5 with sodium ethoxide in
ethanol gave a new product in 52% yield, the structure
of which has been tentatively assigned to ketone 6
(Scheme 3). The same protocol (Br2, HBr/AcOH
followed by reaction with EtONa/EtOH) but without
isolation of the intermediate, gave the same ketone 6 in
a poorer yield (29%). Finally, when the bromination
was carried using CuBr2 (3 equiv.) added in small
portions over a period of 28 h (allowing for the green
color caused by each addition of CuBr2 to disappear),
followed by the usual Favorskii rearrangement
protocol, we obtained again ketone 6 in 22% yield from
carbamate 4. In these cases we observed very complex
reactions mixtures, detecting only traces of exo-1b
product. Regarding the structure assignment for
compound 6, the elemental analysis and the mass
spectrum (m/z 285 M+.) are in good agreement with a
C14H23NO5 formula. The IR spectrum of 6 showed a
strong absorption at 1735 cm-1, suggesting the
presence of a ketone substituted in the ꢁ-position with
an electronwithdrawing group, as one or two ethoxy
groups, and a band at 1705 cm-1, typical of a
carbamate. These functional moieties were confirmed
in the 13C NMR spectrum by a signal at 203.9 ppm
(ketone) and at 154.5 ppm (carbamate group); in
addition, we observed a quaternary carbon at 101.9
ppm, corresponding to the acetal moiety installed at
C2, three ethoxy groups (signals for the methylene and
the methyl groups at 61.2, 58.4, 57.0 ppm, and at 15.5,
15.1, 14.7 ppm, respectively). Accordingly, the 1H
NMR spectrum showed for protons H1 and H5
multiplets centered at 4.49 ppm, and two multiplets at
2.87 ppm (t, 14.9 Hz) and at 2.29 ppm (d, 14.9 Hz) for
H4. These protons couple in the HMQC experiment
with the secondary carbon at 46.8 ppm.
Major compound exo-1b has been previously reported
in patents [8] and by Daly [5], while minor endo-2 isomer
has been reported in patent literature [8]. The
spectroscopic data for compounds exo-1b and endo-1b are
in very good agreement with those recorded for 7-
carbethoxy-2-exo-(carbomethoxy)-7-azabicyclo[2.2.1]-
heptane [4b] and for 7-carbomethoxy-2-exo or (endo)-
(carbomethoxy)-7-azabicyclo[2.2.1]heptane [7].
We have also explored the bromination step using Br2
in HBr/AcOH [5]. Under these conditions we obtained the
Scheme 3
CO2Et
CO2Et
N
N
1
2
EtONa,
EtOH
OEt
OEt
Br
Br2, HBr/AcOH
99%
4
4
5
3
52%
Br
O
O
5
6
CO2Et
CO2Et
N
N
Ac2O, py
AcOH/H2O
O
O
OH
OAc
7
8
[5% (8%) from 6]
At this point, several considerations concerning the
bromination step have to be made. While for the previous
conditions (CuBr2, CHCl3/AcOEt) Bai and co-workers
only described the formation of two isomeric
monobromides whose spectroscopic data were not
provided, under the same experimental conditions, but
using AcOEt as a solvent, the patent literature also
described the formation of some dibromide (5%), as well
as the desired monobromides and unreacted starting
material [8d]. A mixture of dibromo derivatives (20%)
was also obtained by Daly et al. during their synthesis of
trans-2,4-dibromo derivative 5 in 99% yield (based on
Br2; Scheme 3). Other non-identified minor products
where also obtained, to account for the rest of the starting
material. The structure of this compound was deduced
from its NMR data. In the 1H NMR spectrum we analyzed
the multiplet for H1 and H5 centered at ꢀH= 4.86 ppm, as
well as two signals at ꢀ 5.37 (d, J= 3.6 Hz) and 4.34 (d, J=
2.0 Hz) that correlate (HMQC experiment) with tertiary
carbons at 54.2 and 52.9 ppm corresponding to C4 and
C2, respectively. Confirming our assignments no nOe

Nov-Dec 2006
Synthesis of 7-Azabicyclo[2.2.1]heptane Derivatives by Transformation of Tropinone
1457
informative was a band at 1770 cm-1 in the IR
spectrum, suggesting the presence of a vinyl acetate
moiety, confirmed by the signals at 168.3 (OCOCH3),
144.4 and 138.7 ppm (C=C-OCOCH3) in the 13C NMR
spectrum. In the 1H NMR spectrum we located the
typical signals for the carbamate moiety, indicating
that this group has resisted the acetal acid hydrolysis
conditions, as well as a vinylic proton (H4 at ꢂ 6.91, d,
J= 5.4 Hz) coupled with the triplet at 4.93 ppm (H5),
according to the 1H-1H COSY experiment. This
product is the result of the acetylation of the not
isolated, intermediate ꢃ-diketone (7), mostly present
in the stabilized ꢃ,ꢄ-unsaturated keto-enol tautomer
form (Scheme 3), obtained in the acid hydrolysis of
compound 6.
In summary, we have analyzed the synthesis of 7-
azabicyclo[2.2.1]heptane derivatives from tropinone, via
the usual two step protocol: bromination and Favorskii
rearrangement. We have found that the bromination
(CuBr2, AcOEt/CHCl3) plus Favorskii rearrangement
(EtONa, EtOH) of N-carbethoxytropinone (4), affords
mixtures of exo- and endo-isomers of 2,7-dicarbethoxy-7-
azabicyclo[2.2.1]heptane (1b) in variable and moderate
chemical yields (maximum 37%); that the bromination
(Br2, HBr/AcOH) of compound 4 gives ethyl trans-2,4-
dibromo-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate
(5) in 99% yield (Br2 as limiting reagent), a product
that on Favorskii rearrangement (EtONa/EtOH) affords
ethyl 2,2-diethoxy-3-oxo-8-azabicyclo[3.2.1]octane-8-
carboxylate (6) (52%).
intermediate 1b, just as described earlier for similar
conditions (Br2, AcOH) and compounds [9].
On the other hand, the diaxial dibromide 9 (whose data
was neither reported) was described by Bai as the only
product when treating 4 with Br2 in ether (66%).
However, when this product was submitted to several
different basic conditions (NaOMe/DME or toluene or
DCM; Et3N/MeOH or EtOH) no Favorskii product was
detected, obtaining product 10 (Scheme 4) instead [4d].
Scheme 4
CO2Et
N
CO2Et
N
Br
Br
Br
OR
O
O
R=Me, Et.
10
9
In scheme 5 we show a possible mechanism that accounts
for the appearance of product 6 in the Favorskii reaction of
compound 5. As it can be noted, this mechanism does not
rely on the typical cyclopropanone intermediate that would
lead to Favorskii products, but on a recent proposal made by
Föhlisch [10]. It is possible that in the early stages of the
mechanism the preferred pseudo-equatorial orientation of
the leaving bromide in compound 5 would account for the
observed result, explaining why in the case of Bai’s diaxial
dibromide no product 6 was detected.
Scheme 5
CO2Et
CO2Et
H
CO2Et
Br
N
N
N
NaBr
EtONa
EtONa
H
H
H
Br
Br
Br
Br
EtOH
EtO
OEt
O
O
O
Na
5
CO2Et
CO2Et
CO2Et
H
CO2Et
EtONa
NaBr
N
N
EtOH
N
N
O
H
EtO
EtO
EtO
EtO
EtO
Br
H
EtO
Br
EtONa
O
O
Na
O
Na
Na
6
Final confirmation of the structure proposed for 6
was obtained upon acid hydrolysis of ketone 6 in
AcOH/H2O followed by acetylation (Scheme 3) to give
compound 8 [ꢀmax(EtOH)= 225.0 nm, log ꢁ= 3.66]. The
structure of this molecule was easily established by its
analytical and spectroscopic data. Particularly
EXPERIMENTAL
Reactions were monitored by TLC using precoated silica gel
aluminium plates containing a fluorescent indicator (Merck,
5539). Anhydrous Na2SO4 was used to dry organic solutions
during work-ups and the removal of solvents was carried out

1458
E. Gómez-Sánchez and J. Marco-Contelles
Vol 43
under vacuum with
chromatography was performed using silica gel 60 (230-400
mesh, Merck). H spectra were recorded with a Varian VXR-
200S spectrometer and 13C NMR spectra were recorded with a
Bruker WP-200-SY. Values with (*) can be interchanged.
a
rotary evaporator. Flash column
(550 mg, 99%, taking into account bromine is the limiting
reagent): oil; IR (film) ꢀ 3446, 2981, 1734, 1705, 1422, 1327,
1
1
1107, 1030, 1015 cm-1; H NMR (CDCl3, 200 MHz) ꢁ 5.37 (d,
J= 3.6 Hz, 1 H, H4 exo), 4.86 (br s, 2 H, H1, H5), 4.34 (d, J=
2.0 Hz, 1 H, H2-endo), 4.28 (q, J= 7.1 Hz, 2 H, OCH2CH3),
2.32-2.20 (m, 1 H, H7-exo), 2.15-2.00 (m, 2 H, H6), 1.82-1.63
(m, 1 H, H7-endo), 1.36 (t, 3H, OCH2CH3); 13C NMR (CDCl3,
75 MHz): ꢁ 193.3 (CO, C3), 153.5 (OCON), 62.3 (OCH2CH3),
60.0 (C1)*, 58.6 (CH, C5)*, 54.1 (C4), 52.7 (C2), 29.8 (C7),
24.1 (C6), 14.7 (OCH2CH3); EM (CI): m/z 356.0 [M+1]+.
Anal. Calcd. for C10H13Br2NO3: C, 33.83; H, 3.69; N, 3.95.
Found: C, 34.06; H, 3.80; N, 3.84.
7-Carbethoxy-2-endo-(carbethoxy)-7-azabicyclo[2.2.1]heptane
(endo-1b) 7-carbethoxy-2-exo-(carbethoxy)-7-azabicyclo[2.2.1]-
heptane (exo-1b).
To a solution of N-carbethoxytropinone (4) [5] (730 mg, 3.70
mmol) in AcOEt (7.5 mL) and CHCl3 (7.5 mL), under argon and
stirring, at reflux, CuBr2 (1.653 g, 7.40 mmol) was added in
three portions, during 4 h 30 min. After 4 h, the reaction was
filtered, and the solvent was evaporated. The residue was
dissolved in AcOEt, washed with water, a 5% aqueous solution
of NaHCO3, and brine. The organic phase was dried (Na2SO4),
filtered and evaporated. The resulting crude was dissolved in
ethanol (20 mL) and treated with recently prepared EtONa (403
mg, 17.53 mmol) in ethanol (14.6 mL) at rt. After 3.5 h, water
was added and the mass was extracted with AcOEt. The organic
phase was washed with water, dried (Na2SO4), filtered, and the
solvent was evaporated to give a crude that was submitted to
chromatography (hexane: AcOEt, 15%) to give 7-carbethoxy-2-
endo-(carbethoxy)-7-azabicyclo[2.2.1]heptane (endo-1b) [8] (66
mg, 7% from 4) {[oil; IR (film) ꢀ 2927, 1712, 1375, 1299, 1191,
1164, 1102 cm-1; 1H NMR (CDCl3, 200 MHz) ꢁ 4.50 (t, J= 4.49
Hz, 1 H, H1), 4.30 (t, J= 4.40 Hz, 1 H, H4), 4.18 (q, J= 7.14 Hz,
2 H, OCH2CH3), 4.14 (q, J= 7.14 Hz, 2 H, OCH2CH3), 3.05 (m,
1 H, H2), 1.92-1.81 (m, 2 H, H3),1.70 (m, 2 H, H5, H6), 1.42
(m, 2 H, H5, H6), 1.29 (t, 3 H, OCH2CH3), 1.28 (t, 3 H,
Ethyl 2,2-diethoxy-3-oxo-8-azabicyclo[3.2.1]octane-8-carbox-
ylate (6).
(A) From Compound 5.
To a solution of compound 5 (300 mg, 0.87 mmol) in ethanol
(13 mL) a solution of EtONa (6.04 mmol) in ethanol (5 mL) was
added. After 3 h., the solvent was removed, water was added and
the crude was extracted with AcOEt. The organic phase was
washed with water, dried, and filtered. The residue was
submitted to chromatography (hexane: AcOEt, 15%) to give
compound 6 (129 mg, 52%).
(B1) From Product 4.
To a solution of N-carbethoxytropinone (4) (673 mg, 3.41
mmol) in CH2Cl2 (2.5 mL) a mixture of Br2 (0.2 mL, 3.89 mmol)
in 30% HBr/AcOH (2 mL) was added in 15 min at rt. After 3.5 h
the reaction was neutralized with an aqueous saturated solution
of NaHCO3, and extracted with AcOEt. The organic phase was
washed with water, dried, filtered and evaporated to give a
crude, that was dissolved in ethanol (15 mL). To this solution a
recently prepared solution of EtONa (379.6 mg, 16.51 mmol) in
ethanol (13.8 mL) was added dropwise. After 4.5 h the solvent
was removed, water was added, extracted with ethyl acetate,
washed with brine, dried (Na2SO4), and evaporated. The crude
was submitted to chromatography (hexane: AcOEt, 20%) to give
compound 6 (160 mg, 29%, taking into account bromine as the
limiting reagent).
OCH2CH3); 13C NMR (CDCl3, 75 MHz)
ꢁ 172.8
(CO2CH2CH3), 156.0 (OCON), 61.5 (OCH2CH3), 61.10
(OCH2CH3), 58.5 (C1), 57.4 (C4), 46.9 (C2), 32.8 (C3), 29.6
(C5)*, 25.8 (C6)*, 14.6 (OCH2CH3), 14.4 (OCH2CH3); MS (CI)
m/z 196.1 [M-OEt]+, 242.1 [M+1]+, 264 [M+Na]+. Anal. Calcd.
for C12H19NO4: C, 59.73; H, 7.94; N, 5.81. Found: C, 59.65; H,
7.81; N, 5.66} and 7-carbethoxy-2-exo-(carbethoxy)-7-aza-
bicyclo[2.2.1]heptane (exo-1b) [8] (262 mg, 30%) {oil; IR
(film) ꢀ 2980, 1735, 1707, 1376, 1315, 1184, 1159, 1101 cm-1;
1H NMR (CDCl3, 200 MHz) ꢁ 4.59 (d, J= 4.03 Hz, 1 H, H1),
4.40 (t, J= 4.03 Hz, 1 H, H4), 4.17 (q, J=7.14 Hz, 2 H,
OCH2CH3), 4.11 (q, J=7.14 Hz, 2 H, OCH2CH3), 2.58 (dd, J=
8.97, 4.94 Hz, 1 H, H2), 2.28 (m, 1 H, H3-exo), 1.83 (m, 2 H,
H5, H6), 1.68 (dd, J= 8.79, 12.36 Hz, 1H, H3-endo), 1.48 (m, 2
H, H5, H6), 1.30 (t, 3H, OCH2CH3), 1.26 ; 13C NMR (CDCl3, 75
MHz): ꢁ 173.7 (CO2CH2CH3), 155.7 (OCON), 61.4
(OCH2CH3), 61.2 (OCH2CH3), 59.6 (C1), 56.2 (C4), 47.9 (C2),
33.7 (C3), 29.8 (C5)*, 29.2 (C6)*, 14.9 (OCH2CH3), 14.5
(OCH2CH3); MS (CI): m/z 196.1 [M-OEt]+, 242.1 [M+1]+, 264.0
[M+Na]+, 505.2 [2M+Na]+. Anal. Calcd. for C12H19NO4: C,
59.73; H, 7.94; N, 5.81. Found: C, 59.81; H, 8.01; N, 5.92}.
(B2) From Product 4.
To a solution of N-carbethoxytropinone (4) (442.5 mg, 2.24
mmol) in CHCl3:AcOEt (10 mL, 1:1), under argon and at reflux
CuBr2 (1.5 g 6.73 mmoles, 3 equiv) was slowly added in 28 h,
allowing for the green color caused by each addition of CuBr2 to
disappear. After 4 h the reaction was cooled and filtered, and
washed with CHCl3. The solvent was removed and the crude
dissolved in ethyl ether, washed with water, 5% aqueous solution
of NaHCO3 and brine. The organic phase was dried (Na2SO4),
filtered, evaporated and the crude (590 mg) was dissolved in
ethanol (12 mL) and treated with a solution of sodium ethoxide
(273 mg, 11.88 mmol) in ethanol (9.9 mL). After 6 h the solvent
was evaporated, water was added and the resulting solution was
then extracted with ethyl acetate. The organic phase was washed
with water, dried (Na2SO4), filtered and the solvent evaporated to
give a crude that was submitted to chromatography (hexane:
AcOEt, 15%) to yield compound 6 (140 mg, 22%): oil; IR (film) ꢀ
Ethyl trans-2,4-dibromo-3-oxo-8-azabicyclo[3.2.1]octane-8-
carboxylate (5).
To a solution of N-carbethoxytropinone (4) (504 mg, 2.56
mmol) in CH2Cl2 (2 mL), Br2 (0.16 mL, 3.12 mmol) in 30%
HBr/AcOH (1.48 mL) was added. After 4 h, the mixture was
neutralized with aqueous saturated solution of NaHCO3,
extracted with ethyl acetate, washed with water, dried, and the
solvent evaporated. The residue was submitted to
chromatography (hexane: AcOEt, 15%) to give compound 5
1
3448, 2979, 1735, 1705, 1428, 1328, 1151, 1106, 1072 cm-1; H
NMR (CDCl3, 200 MHz) ꢁ 4.49 (m, 2 H, H1, H5), 4.15 (q, J= 7.1
Hz, 2 H, OCH2CH3), 3.9-3.1 (m, 4 H, 2 x OCH2CH3), 2.87 ppm (t,
J= 14.9 Hz, 1 H, H4), 2.29 ppm (d, 14.9 Hz), 3.00-2.83 (m, 1 H,

Nov-Dec 2006
Synthesis of 7-Azabicyclo[2.2.1]heptane Derivatives by Transformation of Tropinone
1459
REFERENCES
H4), 2.41-2.23 (d, J= 14.93 Hz, 1 H, H 4), 1.94-1.52 (m, 4 H, H6,
H7), 1.26 (t, J= 7.1 Hz, 3 H, OCH2CH3), 1.21 (t, J= 7.2 Hz, 3 H,
OCH2CH3), 1.09 (t, J= 7.2 Hz, 3 H, OCH2CH3); 13C NMR (CDCl3,
75 MHz) ꢀ 203.9 (CO, C3), 154.5 (OCON, C8), 101.9 (C2), 61.2
(OCH2CH3), 58.4 (OCH2CH3), 58.1 (C1)*, 57.0 (OCH2CH3), 53.6
(C5)*, 46.8 (C4), 27.8 (C6)**, 23.5 (C7)**, 15.5 (OCH2CH3),
15.1 (OCH2CH3), 14.7 (OCH2CH3); MS (CI): m/z 308.3 [M+23]+;
MS (EI): m/z 285 [M]+.
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Anal. Calcd. for C14H23NO5: C, 58.93; H, 8.12; N, 4.91.
Found: C, 58.76; H, 7.94; N, 4.86.
Acid Hydrolysis of Ethyl 2,2-diethoxy-3-oxo-8-azabicyclo-
[3.2.1]octane-8-carboxylate (6).
A solution of compound 6 (95 mg, 33 mmol) in THF (2 mL)
was treated with water (3.5 mL) and acetic acid (1.5 mL) at 80 ºC
for 23 h. The solvent was removed, and the crude was submitted
to chromatography (hexane/AcOEt, 30%) to give unreacted 6
(35.6 mg) and a new product (7), more polar (16 mg) that was
acetylated as usual (pyridine/Ac2O, 0.5 mL/0.5 mL) at rt for 22 h.
The solvents were evaporated and the crude chromatographied
(hexane/AcOEt, 20%) to give compound 8 [4 mg, 5% (8%) taking
into account the unreacted compound 6)] from 6): oil;
ꢁmax(EtOH)= 225.0 nm, log ꢂ=3.66; IR (film) ꢃ 2924, 1770, 1711,
1635, 1408, 1379, 1318, 1196, 1086 cm-1; 1H NMR (CDCl3, 200
MHz) ꢀ 6.91 (d, J= 5.4 Hz, 1 H, H4), 4.93 (t, J= 5.4 Hz, 1 H, H5),
4.73 (d, J= 7.0 Hz, 1 H, H1), 4.14 (q, J= 7.2 Hz, 2 H,
NCO2CH2CH3), 2.6-2.3 (m, 1 H, H7-exo), 2.23 (s, 3 H, OCOCH3),
2.3-2.1 (m, 1 H, H6-exo), 1.98-1.72 (m, 2 H, H6-endo, H7-endo),
1.25 (t, 3 H, NCO2CH2CH3); 13C NMR (CDCl3, 75 MHz) ꢀ 189.7
[C(2)=O], 168.3 (OCOCH3), 154.8 (NCO2CH2CH3), 144.4 (C3),
138.7 (C4), 63.3 (C1), 62.0 (NCO2CH2CH3), 54.0 (C5), 28.3 (C6),
24.5 (C7), 20.3 (OCOCH3), 14.5 (NCO2CH2CH3); MS (CI): m/z
254.1 [M+1]+ , 276.0 [M+23]+.
Anal. Calcd. for C12H15NO5: C, 56.91; H, 5.97; N, 5.53.
Found: C, 56.82; H, 5.65; N, 5.71.
Acknowledgments.
EGS is a I3P-CSIC fellow.