Thermal rearrangement of nitrone and nitrile oxide cycloadducts to bicyclopropylidene. Synthesis of 3-spirocyclopropane-4-pyridone and furo[2,3-c]pyridine derivatives

Article abstract of DOI:10.1021/jo951838l

Bicyclopropylidene smoothly undergoes 1,3-dipolar cycloadditions to nitrones or nitrile oxides under different reaction conditions. The strained bisspirocyclopropanated isoxazolidines obtained from nitrones easily rearrange upon heating with selective ope

Full text of DOI:10.1021/jo951838l

J . Org. Chem. 1996, 61, 1665-1672
1665
Th er m a l Rea r r a n gem en t of Nitr on e a n d Nitr ile Oxid e
Cycloa d d u cts to Bicyclop r op ylid en e.1 Syn th esis of
3-Sp ir ocyclop r op a n e-4-p yr id on e a n d F u r o[2,3-c]p yr id in e
Der iva tives†
Andrea Goti,*,‡ Beatrice Anichini,§ and Alberto Brandi*,§
Centro di Studio C.N.R. sui Composti Eterociclici, Dipartimento di Chimica Organica “U. Schiff”,
Universita` di Firenze, Via G. Capponi 9, I-50121 Firenze, Italy
Sergei Kozhushkov, Corinna Gratkowski, and Armin de Meijere*
Institut fu¨r Organische Chemie der Georg-August-Universita¨t Go¨ttingen, Tammannstrasse 2,
D-37077 Go¨ttingen, Germany
Received October 12, 1995X
Bicyclopropylidene smoothly undergoes 1,3-dipolar cycloadditions to nitrones or nitrile oxides under
different reaction conditions. The strained bisspirocyclopropanated isoxazolidines obtained from
nitrones easily rearrange upon heating with selective opening of one of the two spirofused
cyclopropane rings. This process produces 4-pyridone, 7-indolizinone, and 2-quinolizinone deriva-
tives containing a spirocyclopropane moiety in the R-position to the carbonyl group in good yields.
The same sequence of cycloaddition and rearrangement can be achieved in a “one-pot” operation
with considerable benefit for the reaction yield. Bisspirocyclopropaneisoxazolines obtained from
nitrile oxides are more stable than their saturated counterparts and rearrange only at higher
temperature less chemoselectively. Opening of both spiro-fused cyclopropyl rings followed by
aromatization produces interesting 2-substituted dihydrofuro[2,3-c]pyridine derivatives.
Sch em e 1
In tr od u ction
The synthetic methodology based on nitrone and nitrile
oxide cycloadditions to methylenecyclopropane followed
by thermal rearrangement of the resulting adducts to
give a functionalized pyridone (Scheme 1)2 has already
been demonstrated as a useful and versatile strategy to
obtain structurally differentiated azaheterocycles, includ-
ing alkaloids in racemic3 and nonracemic4 form.
The choice of bicyclopropylidene (BCP, 1) as a dipolaro-
phile in the same process appeared particularly interest-
ing, in order to expand the synthetic utility of this
methodology. BCP is a uniquely strained tetrasubsti-
tuted alkene,5 which has shown an unusually high
reactivity toward electron-deficient cycloaddends.6 This
is a consequence of the electronic properties of its
symmetrically substituted double bond, which is signifi-
cantly shorter than a regular C(sp2)dC(sp2) bond, and
can be considered to resemble the central bond in
butatriene to a certain extent.7 A recently developed new
synthesis of BCP8 has made this dipolarophile easily
available in large enough quantities for synthetic pur-
poses. Albeit BCP has been successfully used in [2 + 2]
and [2 + 4] cycloadditions,2d,6 no reaction with 1,3-dipoles
has been reported so far, apart from its oxidation with
ozone.6a
* Author to whom correspondence should be addressed.
† Dedicated to Professor Nikolai Zefirov on the occasion of his 60th
birthday.
‡ Centro di Studio C.N.R. sui Composti Eterociclici.
§ Dipartimento di Chimica Organica “U. Schiff”.
X Abstract published in Advance ACS Abstracts, February 1, 1996.
(1) Part 13 in the series Rearrangement of Isoxazoline 5-Spiro
Derivatives. Part 12: Brandi, A.; Cicchi, S.; Cordero, F. M.; Frignoli,
R.; Goti, A.; Picasso, S.; Vogel, P. J . Org. Chem. 1995, 60, 6806. This
paper is also to be considered as part 34 in the series Cyclopropyl
Building Blocks for Organic Synthesis. Part 33: Chaplinski, V.; de
Meijere, A. Angew. Chem., in press; Angew. Chem., Int. Ed. Engl., in
press.
(2) (a) Brandi, A.; Cordero, F. M.; De Sarlo, F.; Goti, A.; Guarna, A.
Synlett 1993, 1. (b) Brandi, A.; Du¨ru¨st, Y.; Cordero, F. M.; De Sarlo,
F. J . Org. Chem. 1992, 57, 5666. (c) Brandi, A.; Cordero, F. M.; De
Sarlo, F.; Gandolfi, R.; Rastelli, A.; Bagatti, M. Tetrahedron 1992, 48,
3323. (d) Goti, A.; Cordero, F. M.; Brandi, A. Top. Curr. Chem., in press.
(3) (a) Brandi, A.; Garro, S.; Guarna, A.; Goti, A.; Cordero, F.; De
Sarlo, F. J . Org. Chem. 1988, 53, 2430. (b) Cordero, F. M.; Brandi, A.;
Querci, C.; Goti, A.; De Sarlo, F.; Guarna, A. J . Org. Chem. 1990, 55,
1762. (c) Brandi, A.; Cordero, F. M.; Goti, A.; Guarna, A. Tetrahedron
Lett. 1992, 33, 6697. (d) Cordero, F. M.; Anichini, B.; Goti, A.; Brandi,
A. Tetrahedron 1993, 49, 9867.
(5) (a) Le Perchec, P.; Conia, J .-M. Tetrahedron Lett. 1970, 1587.
(b) Fitjer, L.; Conia, J .-M. Angew. Chem. 1973, 85, 347; Angew. Chem.,
Int. Ed. Engl. 1973, 12, 332. (c) Schmidt, A. H.; Schirmer, U.; Conia,
J .-M. Chem. Ber. 1976, 109, 2588.
(6) (a) de Meijere, A.; Erden, I.; Weber, W.; Kaufmann, D. J . Org.
Chem. 1988, 53, 152. (b) de Meijere, A.; Wenck, H.; Seyed-Mahdavi,
F.; Viehe, H. G.; Gallez, V.; Erden, I. Tetrahedron 1986, 42, 1291. (c)
Weber, W.; de Meijere, A. Synth. Commun. 1986, 16, 837.
(7) (a) Gleiter, R.; Haider, R.; Conia, J .-M.; Barnier, J .-P.; de Meijere,
A.; Weber, W. J . Chem. Soc., Chem. Commun. 1979, 130. (b) Traette-
berg, M.; Simon, A.; Peters, E. M.; de Meijere, A. J . Mol. Struct. 1984,
118, 333.
(4) (a) Cordero, F. M.; Cicchi, S.; Goti, A.; Brandi, A. Tetrahedron
Lett. 1994, 35, 949. (b) Cicchi, S.; Goti, A.; Brandi, A. J . Org. Chem.
1995, 60, 4743. (c) Reference 1 (part 12).
(8) de Meijere, A.; Kozhushkov, S. I.; Spaeth, T.; Zefirov, N. S. J .
Org. Chem. 1993, 58, 502.
0022-3263/96/1961-1665$12.00/0 © 1996 American Chemical Society

1666 J . Org. Chem., Vol. 61, No. 5, 1996
Ta ble 1. Cycloa d d ition s of Nitr on es 2a -f to 1 a n d Th er m a l Rea r r a n gem en ts of Isoxa zolid in es 3a -f
Goti et al.
The use of an olefin such as BCP (1), with its sym-
metrically substituted double bond, in our methodology
avoids any regiochemical problem in the cycloaddition
step (Scheme 1).2 Moreover, the presence of the added
cyclopropane ring, which is expected to survive the
rearrangement conditions, spiro-fused R to the carbonyl
group in the final azaheterocycles, might open new
pathways for further and useful synthetic elaborations
of the piperidone skeleton.
The structural assignments were unequivocally made
1
on the basis of their H and 13C NMR spectra. They show
signals of the eight protons on the cyclopropane ring (δ
0-1 ppm), the four respective carbons (δ 4-11 ppm), and
the proton bound to C3 on the isoxazolidine ring (singlet
at δ 3.85 for 3a , 3.48 for 3e, and 4.83 for 3f, multiplet
with typical values of vicinal coupling constants at δ 3.57,
3.56, and 3.46 for 3b, 3c, and 3d , respectively).
The thermal rearrangements of isoxazolidines 3a -f
(see Table 1) were achieved by heating 0.5-1 M solutions
in appropriate aromatic solvents at reflux temperatures.
As expected on the basis of the different thermal behavior
observed for the 5- and 4-spirocyclopropaneisox-
azolidines,2,3 the two spirocyclopropane rings on C4 and
C5 (isoxazolidine numbering) show different reactivity
upon heating and only the cyclopropane ring in the
5-position, adjacent to the labile N-O bond, is involved
in the thermal rearrangement. Thus, the totally chemo-
selective rearrangement afforded 3-spirocyclopropane-
pyridones 4a -f in good yields.
We report here on the cycloadditions of six nitrones
2a -f and four nitrile oxides 13a -d to 1 and the results
of the thermal rearrangement of the adducts.9
Resu lts a n d Discu ssion
The results of the cycloadditions of nitrones 2a -f to 1
are shown in Table 1. The cycloadditions to 1, despite
its being a tetrasubstituted alkene,10 were carried out
under relatively mild conditions (rt or 60 °C) using long
reaction times (from 7 to 30 days). Prolonged reaction
times instead of increased reaction temperatures proved
to be necessary because of the low thermal stability of
the cycloadducts (see below). The unexpectedly high
reactivity of 1 in nitrone cycloadditions has to be related
to its peculiar electronic properties, particularly to its
abnormally high lying HOMO.7a The yields of bisspiro-
cyclopropaneisoxazolidines 3a -f were good to moderate
and depended on the reactivity and the stability of the
nitrones involved.
The structural assignment was based on the observa-
tion of the characteristic signals for the piperidone
carbonyl group (13C NMR δ 208.7, 209.0, 210.1, 208.6,
206.1, and 208.3 for 4a -f, respectively; IR 1686-1690
cm-1) and for the cyclopropane moiety. The four protons
on the cyclopropane ring are differentiated by the ani-
sotropy of the carbonyl group, as two protons resonated
at δ 0.4-0.8 and the other two at δ 1-1.4 (with the
exception of 4e, because of the influence of the vicinal
ester group). The methyne protons R to the nitrogen gave
(9) Preliminary communication: Brandi, A.; Goti, A.; Kozhushkov,
S. I.; de Meijere, A. J . Chem. Soc., Chem. Commun. 1994, 2185.
(10) Ordinary tetraalkyl-substituted alkenes do not cycloadd ni-
trones. Cf. Gru¨nanger, P.; Vita-Finzi, P. Isoxazoles-Part One. In The
Chemistry of Heterocyclic Compounds; Taylor, E. C., Weissberger, A.,
Series Eds.; J ohn Wiley: New York, 1991.
1
singlets in the H NMR spectrum of 4a (δ 3.47), 4e (δ
3.01), and 4f (δ 4.24).
It is remarkable that, in every instance except entry
6, the thermal rearrangement selectively provided cyclic

3-Spirocyclopropane-4-pyridone and Furo[2,3-c]pyridine Derivatives
J . Org. Chem., Vol. 61, No. 5, 1996 1667
Sch em e 3
F igu r e 1.
Sch em e 4
Sch em e 2
+
-
radical 9 which then undergoes a facile 5-exo-trig cycliza-
tion (Scheme 3).
An attempt to purify 3c by distillation under reduced
pressure (10-2 Torr), at too low a temperature to give the
rearrangement (40 °C), led to the partial decomposition
to nitrone 2c by a retrocycloaddition process. Retro-
cycloadditions are well-known in the literature,13 par-
ticularly in the case of adducts derived from five-
membered cyclic nitrones. In the case of isoxazolidines
of type 3, the retrocycloaddition might also be favored
by the strain of the 2-fold spirocyclopropane annelation.
In order to avoid these retrocycloadditions and to simul-
taneously increase the yield of the final ketone, the two-
step procedure was turned into a more convenient “one-
pot” process. Toward that end, the mixture of the
starting materials was heated directly for the appropriate
time at the temperature required for the rearrangement
to occur. The results are shown in the last column of
Table 1. As expected, the yields in comparision with
those calculated for the two-step procedure, which are
reported in parentheses, were significantly improved in
every case. Only with nitrone 2b did the “one-pot”
process fail, probably due to the instability of the nitrone
upon prolonged heating at high temperature.
As the cycloaddition rearrangement process2,3 applied
to BCP (1) has proved to be of high efficiency in the
synthesis of new interesting heterocyclic R-spirocyclo-
propane annelated ketones, some of which have proved
to be DNA cleaving agents with promising potential,14 it
might favorably be extended by the use of substituted
bicyclopropylidenes, in order to obtain selectively sub-
stituted heterocycles. To test for this possibility, cyclo-
additions of the nitrone 2c to monosubstituted bicyclo-
propylidenes 10a and 10b15 were carried out (Scheme 4).
Unfortunately, in both cases complex mixtures of four
isomeric isoxazolidines 11 and 12 with very little selec-
tivity, albeit in high yield, were obtained. The mixtures
could neither be separated by chromatography nor sim-
plified by thermal rearrangement, no matter whether
reactions were carried out in two steps or in one pot.
These results indicate that only unsubstituted or, pos-
sibly, symmetrically disubstituted BCPs can be syntheti-
cally useful in this domino process.
products, without the formation of open-chain isomers,
which are usually obtained as side products from
5-spirocyclopropaneisoxazolidines.2a,3 This result might
be ascribed to the presence of the spiro-fused cyclopro-
pane ring that raises the rotational barriers in the
diradical intermediate increasing the proportion of reac-
tive rotamers, thus favoring the diradical coupling11 (path
a in Scheme 2). A similar effect brought about by a
cyclopropane ring, which increased the cyclization rate
by a factor of 10, has recently been reported.12
Only isoxazolidine 3f gave an open-chain compound of
type II (Scheme 2) in 24% yield besides cyclic ketone 4f
(50%). In this case, the 1,5-hydrogen shift is probably
facilitated by the mobility of the benzylic proton and by
the possible formation of a stable conjugated imine (5).
As a matter of fact, when the sample is heated for a
longer time, the aromatized isoquinoline derivative 6 can
also be obtained in low yield (8%) (Figure 1).
An isomeric side product was also observed in the
rearrangement of isoxazolidine 3e, in a ratio 1:4 along
with ketone 4e. It was difficult to separate this com-
pound from the major isomer; therefore its spectroscopic
data could only be obtained from those of enriched
fractions. The new compound did not show any analogy
with compounds of type II, and it was tentatively
assigned the structure 7a on the basis of its spectral data.
The 13C NMR spectrum of 7a showed diagnostic signals
for a cyclopentanone bearing a secondary amino sub-
stituent, i.e., a deshielded carbonyl group (δ 215.7 vs
206.1 for 4e), a quaternary carbon (δ 68.6), and a
nitrogen-bound methyl group resonating 13 ppm upfield
with respect to the same methyl in 4e (δ 30.7 vs 43.7).
1
In the H NMR spectrum no signal for an isolated C-H
was found, and the signals of the methylene groups,
relatively shielded, are not in accordance with protons
adjacent to nitrogen. Final confirmation of the structure
was proven by the direct derivatization of 7a to the
corresponding tosylate 7b in the crude reaction mixture.
Compound 7b was easily separable from 4e, and com-
plete characterization, including elemental analysis, was
carried out. The formation of cyclic isomer 7a can be
rationalized with the loss of a hydrogen adjacent to the
nitrogen in diradical intermediate 8 to afford imine
(13) Bianchi, G.; Gandolfi, R. In 1,3-Dipolar Cycloaddition Chem-
istry; Padwa, A., Ed.; J ohn Wiley: New York, 1984; Vol. 2, p 451.
(14) Goti, A.; Anichini, B.; Brandi, A.; de Meijere, A.; Citti, L.;
Nevischi, S. Tetrahedron Lett. 1995, 36, 5811.
(11) Bruice, T. C.; Pandit, U. K. J . Am. Chem. Soc. 1960, 82, 5858.
(12) J ung, M. E.; Gervay, J . J . Am. Chem. Soc. 1991, 113, 224.
(15) de Meijere, A.; Kozhushkov, S. I.; Zefirov, N. S. Synthesis 1993,
681.

1668 J . Org. Chem., Vol. 61, No. 5, 1996
Goti et al.
Ta ble 2. Cycloa d d ition s of Nitr ile Oxid es 13a -d to BCP
Sch em e 5
Sch em e 6
Nitrile oxides are more reactive than nitrones in 1,3-
dipolar cycloadditions toward unactivated alkenes, be-
cause of their low-lying LUMO. On the other hand, they
are also much less stable, mainly due to their facile
dimerization to furoxans. The dimerization of nitrile
oxides is largely preferred, when rather unreactive
dipolarophiles such as bicyclopropylidene (1) are present.
In such cases, however, stable nitrile oxides with bulky
substituents adjacent to the CNO group that hamper
dimerization can be used, but they usually need much
higher reaction temperatures before the cycloaddition will
occur. To study nitrile oxide cycloadditions onto 1, two
reactive nitrile oxides (13a ,b) and two sterically con-
gested nitrile oxides (13c,d ) were used (see Table 2).
The cycloaddition of benzonitrile oxide (13a ) at room
temperature gave a poor yield of the adduct 14a (less
than 10%), together with extensive formation of 3,4-
diphenylfuroxan. A somewhat better yield (40%, entry
1, Table 2) was obtained when 13a was slowly generated
by adding the corresponding benzohydroximoyl chloride
to a refluxing solution of 1 in THF in presence of
NaHCO3. The more reactive acetonitrile oxide (13b),
generated in situ from nitroethane according to Mu-
kaiyama’s method,16 gave, either at room temperature
or in refluxing ethereal solvents, very poor yields of 14b,
which could not be completely separated by flash chro-
matography from the mass of undesired dimethylfuroxan.
Mesitonitrile oxide (13c) needs much higher tempera-
tures to react, but in refluxing toluene gave a reasonably
high yield (67%) of isoxazoline 14c (entry 3, Table 2).
Under the same conditions, triphenylacetonitrile oxide
(13d ) (entry 4, Table 2) is too sluggish to react at an
acceptable rate.
reaction of 13a with 1, a solid product was isolated in
small quantity (5%) in addition to isoxazoline 14a . Its
formation depended on the reaction conditions, increasing
at higher temperatures and longer times. The structure
15 was assigned to the product (Scheme 5) on the basis
of the similarity of its NMR spectra with those of
rearrangement products 4 from the corresponding isox-
azolidines 3. Indeed, the 13C NMR spectrum showed the
carbonyl group (δ 206.7) and two methylene carbons of
the cyclopropane ring (δ 14.9 and 13.6). On the other
hand, the 1H NMR spectrum showed the methylenic
protons of the piperidone ring differentiated (δ 3.74, 3.51,
2.91 and 2.61) and four cyclopropyl protons at δ 1.45-
0.38.
Compound 15 was derived, according to elemental
analysis and mass spectral data, from the reaction of two
molecules of benzonitrile oxide (13a ) and one molecule
of BCP (1). Its formation may be accounted for along two
alternative routes (Scheme 6). Either primary mono-
adduct 14a first rearranges to 16 at the reaction tem-
perature (66 °C), and 16 subsequently cycloadds a second
molecule of 13a (route a in Scheme 6), or the second
molecule of 13a first cycloadds to isoxazoline 14a to give
isoxazolidine 17, which then undergoes a thermal re-
arrangement to 15 (route b).
Normally, spirocyclopropane-annelated isoxazolines
require for rearrangement higher temperatures than the
corresponding isoxazolidines, and also a higher temper-
ature than that involved in the reaction (66 °C). Indeed,
route a was ruled out after the demonstration that
prolonged heating of 14a in refluxing THF, under the
same conditions as applied for the cycloaddition, led to
quantitative recovery of the starting material. On the
contrary, the second hypothesis (route b) was confirmed
by generating 13a in a refluxing THF solution of pure
14a , which provided 15 as the only product, besides the
starting material and 3,4-diphenylfuroxan. Few ex-
amples of formation of side products by nitrile oxide
cycloaddition to the CdN double bond of isoxazolines at
room temperature have been reported in the literature,
just limited to benzonitrile oxide or its derivatives.17 In
one single example the bis-adduct was the major product
when the cycloaddition was carried out at higher tem-
The structural assignment to adducts 14a -d rests on
1
the observation of eight cyclopropane protons in the H
NMR spectrum (multiplets at δ 0.4-1.2 for 14a -c and
at δ -0.10-1.13 for 14d ) and of the corresponding
carbons (which give two signals for each compound at δ
7-10) and of the CdN group (δ 162-165) in the 13C NMR
spectrum.
Despite the poor results in most cases, except 14c, the
formation of cycloadducts is relevant, considering the
tetrasubstitution of the double bond in BCP (1).10 In the
(16) Mukaiyama, T.; Hoshino, T. J . Am. Chem. Soc. 1960, 82, 5339.

3-Spirocyclopropane-4-pyridone and Furo[2,3-c]pyridine Derivatives
J . Org. Chem., Vol. 61, No. 5, 1996 1669
Sch em e 7
Sch em e 8
nitrone (or nitrile oxide) cycloaddition-rearrangement
methodology2 to readily available bicyclopropylidene 1.8
Studies are underway in our laboratories in order to
outline useful synthetic elaborations of the rearranged
spirocyclopropane heterocycles, one example of which has
already been reported here in the ring expansion to
dihydrofuropyridines.
perature.18 In our case, the amount of side product 15
was sensibly increased by running the reaction in re-
fluxing benzene (14% vs 5%, Scheme 5).
As shown, 5-spirocyclopropaneisoxazolines undergo the
thermal rearrangement at higher temperatures than the
isoxazolidine counterparts.2 In fact, 14a and 14c were
stable below 140 °C in solution. At 170 °C in o-
dichlorobenzene, however, they both cleanly rearranged
to afford dihydrofuro[2,3-c]pyridines 18a and 18c (Scheme
7).
Exp er im en ta l Section
All the reactions were carried out under nitrogen or in
sealed tubes, and the solvents were appropriately dried before
use. Rf values refer to TLC on 0.25 mm silica gel plates (Merck
F254) obtained using the same eluent as in the column
chromatographies. Melting points were determined on a 510
Bu¨chi apparatus. NMR spectra were recorded on a Varian
Gemini (1H, 200 MHz), with CDCl3 as solvent; the NMR data
are reported in δ (ppm) from TMS. IR spectra were recorded
in CDCl3 solution on a Perkin-Elmer 881 spectrophotometer.
Mass spectra were recorded at 70 eV by GC inlet on a 5790A-
5970A Hewlett-Packard instrument or by direct inlet (for the
thermally labile cycloadducts) on a QMD 1000 Carlo Erba
1
In the H NMR spectra of 18 no signal of cyclopropane
protons could be observed, but signals for the dihydro-
furan ring (δ 4.65 and 4.63 for the methylene protons R
to the oxygen and δ 3.43 and 2.90 for the ones in â for
18a and 18c, respectively) and for the pyridine ring (δ
8.41 and 6.73 for 18a and δ 8.39 and 6.73 for 18c) were
detectable. This confirmed a complete aromatization of
the pyridine ring.
instrument. Elemental analyses were performed with
a
Perkin-Elmer 240 C analyzer. BCP derivatives used in this
work were prepared according to published procedures.8,15
Cycloa d d ition of Nitr on e 2a to Bicyclop r op ylid en e (1).
A solution of 1 (160 mg, 2 mmol) and 2a (203 mg, 1.5 mmol)
in benzene (0.5 mL) was heated in a sealed tube at 60 °C for
30 d. After cooling to room temperature, the solvent was
removed in vacuo and the crude product was purified by flash
chromatography on silica gel (eluent CH2Cl2-CH3OH 30:1) to
give the cycloadduct 3a (Rf 0.44, 300 mg, 1.4 mmol, 93%) as
an oil.
The mechanistic rationale for the formation of products
18 rests on the usual initial rearrangement of cyclo-
adducts 14 to tetrahydropyridones 16. These compounds
are probably very unstable under the harsh reaction
conditions used and undergo also the second cyclopropane
ring fission via a thermal acylcyclopropane-dihydrofuran
rearrangement to tetrahydrofuropyridines 19. Eventu-
ally aromatization of the dihydropyridine ring may easily
occur under the reaction conditions to give final products
18 (Scheme 7). This acylcyclopropane-tetrahydrofuran
rearrangement closely resembles the vinylcyclopropane-
cyclopentene rearrangement, but does not readily occur
under simple thermal activation.19 Finally, with stable
nitrile oxide 13d the cycloaddition and the rearrange-
ment can be achieved in one single operation at high
temperature to afford dihydrofuropyridine 18d in higher
overall yield (Scheme 8). However, dihydrofuropyridine
18c was obtained in poor yield (7%) in the corresponding
one-pot reaction of 1 with nitrile oxide 13c because of
its rearrangement to the corresponding isocyanate at 170
°C.
8-Met h yl-9-p h en yl-7-oxa -8-a za d isp ir o[2.0.2.3]n on a n e
(3a ): H NMR δ 7.33 (m, 5H), 3.85 (s, 1H), 2.77 (s, 3H), 0.97
1
(m, 2H), 0.65-0.30 (m, 4H), 0.20-0.03 (m, 2H); 13C NMR δ
137.8 (s), 128.8 (d, 2C), 128.3 (d, 2C), 127.9 (d), 79.7 (d), 66.7
(s), 44.7 (q), 33.6 (s), 9.9 (t), 8.4 (t), 6.9 (t), 6.5 (t); IR 3084,
3031, 3003, 2961, 1602, 1491, 1452, 1434 cm-1; MS m/ z 215
(M+, 8), 214 (4), 186 (14), 158 (69), 146 (31), 130 (36), 129 (100),
128 (39), 120 (31), 118 (96), 115 (80), 91 (42), 77 (54). Anal.
Calcd for C14H17NO: C, 78.10; H, 7.96; N, 6.51. Found: C,
77.91; H, 8.01; N, 6.32.
Cycloa d d ition of Nitr on e 2b to Bicyclop r op ylid en e (1).
A solution of 1 (110 mg, 1.4 mmol) and 2b (175 mg, 2.1 mmol)
in benzene (2 mL) was stirred at room temperature for 20 d.
The solvent was removed in vacuo, and the crude product was
purified by flash chromatography on silica gel (eluent ethyl
acetate) to give the cycloadduct 3b (Rf 0.25, 96 mg, 0.58 mmol,
42%) as an oil.
In conclusion, we have established a convenient access
to functionalized azaheterocycles by the extension of the
Dispir o[cyclopr opan e-1,2′-h exah ydr opyr r olo[1,2-b]isox-
1
a zole-3,1′′-cyclop r op a n e] (3b): H NMR δ 3.57 (t, J ) 6.0
Hz, 1H), 3.37-3.26 (m, 1H), 3.25-3.05 (m, 1H), 2.01-1.85 (m,
1H), 1.81-1.58 (m, 3H), 0.89-0.37 (m, 6H), 0.19-0.08 (m, 2H);
13C NMR δ 71.8 (d), 66.0 (s), 57.8 (t), 31.9 (s), 29.6 (t), 24.3 (t),
10.8 (t), 10.0 (t), 5.0 (t), 4.4 (t); IR 3079, 3004, 2971, 2875, 1444
cm-1; MS m/ z 165 (M+, 8), 164 (16), 150 (6), 136 (35), 109 (28),
108 (81), 81 (45), 80 (100), 79 (72), 68 (49), 67 (56). Anal. Calcd
for C10H15NO: C, 72.69; H, 9.15; N, 8.48. Found: C, 72.80;
H, 9.04; N, 8.04.
Cycloa d d ition of Nitr on e 2c to Bicyclop r op ylid en e (1).
A solution of 1 (264 mg, 3.3 mmol) and 2c (373 mg, 3.3 mmol)
in benzene (0.8 mL) was stirred at room temperature for 7 d.
The solvent was removed in vacuo, and the crude product was
(17) (a) Bettinetti, G. F.; Gamba, A. Gazz. Chim. Ital. 1970, 100,
1144. (b) Caramella, P.; Frattini, P.; Gru¨nanger, P. Tetrahedron Lett.
1971, 3817. (c) Bianchi, G.; De Micheli, C.; Gandolfi, R. J . Chem. Soc.,
Perkin Trans. 1 1972, 1711. (d) Gibert, J .-P.; J acquier, R.; Pe´trus, C.
Bull. Soc. Chim. Fr. 1979, 281. (e) Adembri, G.; Donati, D.; Fusi, S.;
Ponticelli, F. J . Chem. Soc., Perkin Trans. 1 1992, 2033. (f) Gandolfi,
R.; Tonoletti, G.; Rastelli, A.; Bagatti, M. J . Org. Chem. 1993, 58, 6038.
(18) Stverkova, S.; Zak, Z.; J onas, J . Liebigs Ann. Chem. 1993, 1169.
(19) (a) Hudlicky, T.; Reed, J . W. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York,
1990; Vol. 8, p 941 and references cited therein. (b) Hofmann, B.;
Reissig, H.-U. Chem. Ber. 1994, 127, 2327. (c) Lund, E. A.; Kennedy,
I. A.; Fallis, A. G. Tetrahedron Lett. 1993, 34, 6841. (d) Lee, P. H.;
Kim, J . S.; Kim, Y. C.; Kim, S. Tetrahedron Lett. 1993, 34, 7583.

1670 J . Org. Chem., Vol. 61, No. 5, 1996
Goti et al.
purified by flash chromatography on silica gel (eluent CH2Cl2-
CH3OH 24:1) to give the cycloadduct 3c (Rf 0.26, 509 mg, 2.6
mmol, 80%).
5-Meth yl-4-p h en yl-5-a za sp ir o[2.5]octa n -8-on e (4a ): oil,
Rf 0.29 (CH2Cl2-CH3OH 19:1), 63% yield; H NMR δ 7.35-
1
7.22 (m, 3H), 7.20-7.10 (m, 2H), 3.47 (s, 1H), 3.06 (m, 1H),
2.85-2.70 (m, 1H), 2.70-2.60 (m, 2H), 2.28 (s, 3H), 1.26 (m,
2H), 0.80-0.65 (m, 1H), 0.55-0.40 (m, 1H); 13C NMR δ 208.7
(s), 137.8 (s), 129.4 (d, 2C), 128.0 (d, 2C), 127.6 (d), 72.5 (d),
50.0 (t), 44.2 (q), 38.8 (t), 32.0 (s), 18.4 (t), 14.8 (t); IR: 3087,
3065, 3031, 3005, 2958, 2850, 1686, 1446, 1364 cm-1; MS m/ z
215 (M+, 15), 214 (3), 146 (12), 138 (100), 118 (33), 77 (19).
Anal. Calcd for C14H17NO: C, 78.10; H, 7.96; N, 6.51.
Found: C, 77.90; H, 8.02; N, 6.35.
Disp ir o[cyclop r op a n e -1,2′-6,6-d im e t h ylh e xa h yd r o-
p yr r olo[1,2-b]isoxa zole-3,1′′-cyclop r op a n e] (3c): colorless
liquid, bp 40 °C/0.1 Torr; 1H NMR δ 3.56 (dd, J ) 8.8, 4.3 Hz,
1H), 2.15-1.80 (m, 3H), 1.60 (m, 1H), 1.29 (s, 3H), 1.04 (s, 3H),
0.82-0.53 (m, 5H), 0.50-0.40 (m, 1H), 0.22-0.05 (m, 2H); 13
C
NMR δ 72.3 (d), 69.0 (s), 65.8 (s), 36.3 (t), 33.0 (s), 30.1 (t),
26.6 (q), 24.1 (q), 11.8 (t), 9.9 (t), 5.1 (t), 4.3 (t); IR 3079, 2999,
2972, 2943, 2871, 1450, 1365 cm-1; MS m/ z 193 (M+, 7), 192
(11), 178 (84), 136 (31), 122 (66), 108 (37), 96 (100), 94 (82), 82
(54), 81 (61), 79 (43). Anal. Calcd for C12H19NO: C, 74.57; H,
9.91; N, 7.25. Found: C, 74.63; H, 10.09; N, 7.69.
Spir o[cyclopr opan e-1,8′-octah ydr oin dolizin -7-on e] (4b):
oil, Rf 0.41 (CHCl3-CH3OH + 1% NH4OH 10:1), 60% yield;
1H NMR δ 3.34-3.24 (m, 1H), 3.23-3.10 (m, 1H), 2.77-2.40
(m, 4H), 2.27 (q, J ) 8.9 Hz, 1H), 2.01-1.69 (m, 2H), 1.64-
1.45 (m, 2H), 1.40-1.10 (m, 2H), 0.78-0.64 (m, 1H), 0.55-
0.44 (m, 1H); 13C NMR δ 209.0 (s), 65.4 (d), 54.6 (t), 50.0 (t),
38.9 (t), 32.2 (s), 25.8 (t), 22.0 (t), 15.2 (t), 10.6 (t); IR 3009,
2960, 2808, 2756, 1689, 1459, 1346 cm-1; MS m/ z 165 (M+,
16), 164 (100), 136 (22), 122 (21), 108 (22), 96 (100). Anal.
Calcd for C10H15NO: C, 72.69; H, 9.15; N, 8.48. Found: C,
72.58; H, 9.42; N, 8.09.
S p ir o [c y c lo p r o p a n e -1,8′-3,3-d im e t h y lo c t a h y d r o -
in d olizin -7-on e] (4c): oil, Rf 0.23 (CH2Cl2-CH3OH 24:1), 76%
yield; 1H NMR δ 3.23 (t, J ) 7.8 Hz, 1H), 3.07 (m, 1H), 2.72-
2.60 (m, 1H), 2.60-2.38 (m, 2H), 1.81-1.59 (m, 2H), 1.59-
1.40 (m, 2H), 1.35-1.05 (m, 2H), 1.19 (s, 3H), 0.95 (s, 3H), 0.73
(ddd, J ) 9.6, 7.2, 4.0 Hz, 1H), 0.46 (ddd, J ) 9.2, 7.2, 3.8 Hz,
1H); 13C NMR δ 210.1 (s), 62.0 (d), 60.3 (s), 42.3 (t), 40.0 (t),
38.5 (t), 33.0 (s), 27.6 (q), 23.0 (t), 19.5 (q), 16.0 (t), 10.5 (t); IR
3095, 3008, 2967, 2871, 2813, 2759, 2701, 1686, 1556, 1456,
1381 cm-1; MS m/ z 193 (M+, 4), 192 (5), 178 (100), 94 (20).
Anal. Calcd for C12H19NO: C, 74.57; H, 9.91; N, 7.25.
Found: C, 74.18; H, 9.97; N, 7.56.
Cycloa d d ition of Nitr on e 2d to Bicyclop r op ylid en e (1).
A solution of 1 (215 mg, 2.7 mmol) and 2d (392 mg, 4.0 mmol)
in benzene (3 mL) was heated in a sealed tube at 60 °C for 7
d. After cooling to room temperature, the solvent was removed
in vacuo and the crude product was purified by flash chroma-
tography on silica gel (eluent CH2Cl2-CH3OH 30:1) to give
the cycloadduct 3d (Rf 0.34, 180 mg, 1.0 mmol, 37%) as an oil.
Disp ir o[cyclop r op a n e-1,2′-h exa h yd r o[2H ]isoxa zolo-
1
[2,3-a ]p yr id in e-3,1′′-cyclop r op a n e] (3d ): H NMR: δ 3.46
(m, 1H), 2.71 (br d, J ) 10.0 Hz, 1H), 2.54 (dt, J ) 5.0, 9.5 Hz,
1H), 1.76 (m, 3H), 1.50-1.15 (m, 3H), 0.85 (m, 2H), 0.70 (dt,
J ) 9.4, 4.6 Hz, 1H), 0.50-0.10 (m, 5H); 13C NMR δ 71.74 (d),
66.2 (s), 55.8 (t), 28.8 (s), 26.01 (t), 24.8 (t), 23.2 (t), 9.6 (t), 7.0
(t), 5.8 (t), 4.5 (t); IR 3080, 3007, 2948, 2859, 1443 cm-1; MS
m/ z 179 (M+, 15), 178 (6), 150 (33), 136 (28), 122 (64), 108
(39), 100 (94), 94 (50), 55 (65), 41 (100). Anal. Calcd for C11H17
-
NO: C, 73.70; H, 9.56; N, 7.81. Found: C, 73.91; H, 9.41; N,
7.84.
Cycloa d d ition of Nitr on e 2e to Bicyclop r op ylid en e (1).
A solution of 1 (200 mg, 2.5 mmol) and 2e (327 mg, 2.5 mmol)
in THF (2 mL) was stirred at room temperature for 16 d. The
solvent was removed in vacuo, and the crude product was
purified by flash chromatography on silica gel (eluent petro-
leum ether-diethyl ether 1:4) to give the cycloadduct 3e (Rf
0.39, 418 mg, 1.98 mmol, 79%) as an oil.
Sp ir o[cyclop r op a n e-1,1′-oct a h yd r oq u in olizin -2-on e]
1
(4d ): oil, Rf 0.16 (CH2Cl2-CH3OH 20:1), 68% yield; H NMR
δ 3.15-2.98 (m, 2H), 2.85-2.35 (m, 4H), 2.15 (m, 1H), 1.85-
1.45 (m, 4H), 1.35-1.05 (m, 4H), 0.68 (m, 2H); 13C NMR δ 208.6
(s), 63.0 (d), 57.0 (t), 53.7 (t), 39.4 (t), 32.0 (s), 27.0 (t), 25.0 (t),
23.6 (t), 16.5 (t), 11.0 (t); IR 3019, 2946, 2862, 2814, 2771, 1690,
1657, 1350 cm-1; MS m/ z 179 (M+, 22), 178 (100), 150 (54),
122 (37), 110 (69). Anal. Calcd for C11H17NO: C, 73.70; H,
9.56; N, 7.81. Found: C, 73.59; H, 9.53; N, 7.57.
8-Meth yl-9-(eth oxycar bon yl)-7-oxa-8-azadispir o[2.0.2.3]-
1
n on a n e (3e): H NMR δ 4.20 (m, 2H), 3.48 (s, 1H), 2.87 (s,
3H), 1.26 (t, J ) 7.3 Hz, 3H), 0.89-0.60 (m, 5H), 0.45-0.16
(m, 3H); 13C NMR δ 169.8 (s), 75.6 (d), 66.1 (s), 61.0 (t), 46.2
(q), 30.3 (s), 14.2 (q), 10.4 (t), 9.1 (t), 6.1 (t), 5.2 (t); IR 3085,
2986, 2878, 1741, 1445, 1274 cm-1; MS m/ z 211 (M+, 5), 154
(4), 138 (25), 110 (80), 69 (100). Anal. Calcd for C11H17NO3:
C, 62.54; H, 8.11; N, 6.63. Found: C, 62.47; H, 8.50; N, 6.58.
Th er m a l Rea r r a n gem en t of th e Ad d u ct 3e. A solution
of 3e (146 mg, 0.69 mmol) in 1.5 mL of toluene was heated in
a sealed tube at 110 °C for 4 d. After cooling to room
temperature, the solution was concentrated in vacuo and the
crude product was chromatographed on a column of silica gel
(eluent CH2Cl2-CH3OH + 1% NH4OH 50:1) to give a mixture
of 4e and 7a (112 mg, 0.53 mmol, 76%) in a 4:1 ratio. Further
chromatographic separation with the same eluent gave 4e as
an analytically pure oil, and mixtures of 4e and 7a , enriched
in the latter component.
Cycloa d d ition of Nitr on e 2f to Bicyclop r op ylid en e (1).
A solution of 1 (200 mg, 2.5 mmol) and 2f (451 mg, 3.1 mmol)
in benzene (2.5 mL) was stirred at room temperature for 10
d. The solvent was removed in vacuo, and the crude product
was purified by flash chromatography on silica gel (eluent
petroleum ether-diethyl ether 1:4) to give the cycloadduct 3f
(Rf 0.51, 415 mg, 1.8 mmol, 73%) as a solid.
Disp ir o[cyclop r op a n e-1,1′-1,5,6,10b -t et r a h yd r o(2H )-
isoxa zolo[3,2-a ]isoqu in olin e-2,1′′-cyclop r op a n e] (3f): mp
55-56.5 °C; 1H NMR δ 7.19-7.02 (m, 3H), 6.84-6.78 (m, 1H),
4.83 (s, 1H), 3.60 (dt, J ) 4.3, 10.7 Hz, 1H), 3.25 (dt, J ) 10.3,
4.2 Hz, 1H), 3.06 (ddd, J ) 16.1, 11.0, 4.7 Hz, 1H), 2.85 (dt, J
) 16.1, 3.7 Hz, 1H), 0.88 (m, 2H), 0.67-0.53 (m, 1H), 0.48-
0.38 (m, 1H), 0.32-0.11 (m, 3H), 0.07-(-0.02) (m, 1H); 13C
NMR δ 134.4 (s), 132.5 (s), 128.3 (d), 127.1 (d), 125.9 (d, 2C),
67.1 (s), 66.9 (d), 49.8 (t), 30.3 (s), 28.7 (t), 8.2 (t), 8.1 (t), 7.8
(t), 3.2 (t); IR 3077, 3027, 3005, 2968, 2872, 1601, 1489, 1452,
1427 cm-1; MS m/ z 227 (M+, 12), 226 (12), 198 (88), 170 (72),
131 (42), 130 (100), 128 (52), 86 (40), 84 (62). Anal. Calcd for
C15H17NO: C, 79.26; H, 7.54; N, 6.16. Found: C, 79.52; H,
7.60; N, 5.84.
4-(E t h oxyca r b on yl)-5-m et h yl-5-a za sp ir o[2.5]oct a n -8-
on e (4e): oil, Rf 0.13; 1H NMR δ 4.18 (q, J ) 7.1 Hz, 2H), 3.24
(ddd, J ) 12.1, 9.9, 5.5 Hz, 1H), 3.04-2.92 (m, 1H), 3.01 (s,
1H), 2.74-2.43 (m, 2H), 2.51 (s, 3H), 1.67-1.56 (m, 1H), 1.26
(t, J ) 7.1 Hz, 3H), 1.06-0.93 (m, 2H), 0.65-0.55 (m, 1H); 13
C
NMR δ 206.1 (s), 170.1 (s), 70.9 (d), 60.6 (t), 48.7 (t), 43.7 (q),
38.1 (t), 29.5 (s), 21.3 (t), 14.4 (q), 10.1 (t); IR 2983, 2942, 2858,
1725 (covers the piperidone CdO absorbance), 1445, 1366
cm-1; MS m/ z 139 (26), 138 (M+ - COOEt, 100), 120 (29), 96
(28). Anal. Calcd for C11H17NO3: C, 62.54; H, 8.11; N, 6.63.
Found: C, 62.27; H, 7.80; N, 7.00.
7-(Eth oxyca r bon yl)-7-(m eth yla m in o)sp ir o[2.4]h ep ta n -
4-on e (7a ): Rf 0.11; 1H NMR δ 4.15 (q, J ) 7.1 Hz, 2H), 2.70-
2.20 (m, 5H), 2.28 (s, 3H), 1.25 (t, J ) 7.2 Hz, 3H), 1.20-1.00
(m, 3H), 0.80-0.70 (m, 1H); 13C NMR δ 215.7 (s), 173.0 (s),
68.6 (s), 61.0 (t), 38.6 (s), 35.4 (t), 30.7 (q), 26.0 (t), 16.6 (t),
14.3 (q), 11.5 (t); MS m/ z 138 (M+ - COOEt, 100), 81 (3), 68
(3), 42 (4).
In another run, 545 mg of a crude mixture of 4e and 7a
(4:1 ratio) obtained from 1 and 2e (3 mmol each) was directly
treated with p-toluenesulfonyl chloride (190 mg, 1 mmol) in
pyridine (5 mL) and stirred at rt for 15 h. After concentration
in vacuo, the residue was washed with saturated Na2CO3,
Gen er a l P r oced u r e for th e Th er m a l Rea r r a n gem en t
of Ad d u cts 3a -d . A solution of 1 mmol of 3a -d in 1 mL of
the appropriate solvent was heated in a sealed tube at the
temperature and time indicated in Table 1. After cooling to
room temperature, the solvent was removed in vacuo and the
crude mixture was chromatographed on silica gel to give the
rearranged piperidones 4a -d .

3-Spirocyclopropane-4-pyridone and Furo[2,3-c]pyridine Derivatives
J . Org. Chem., Vol. 61, No. 5, 1996 1671
extracted with Et2O (3 × 6 mL), and dried over Na2SO4. The
crude product was chromatographed on a column of silica gel
(eluent diethyl ether) to give 7b (117 mg, 0.32 mmol, 11%
based on 1) and 4e (220 mg, 1.04 mmol, 35% based on 1).
7-(E t h oxyca r b on yl)-7-((4-m e t h ylb e n ze n e su lfon yl)-
m eth yla m in o)sp ir o[2.4]h ep ta n -4-on e (7b): oil, Rf 0.60; 1H
NMR δ 7.79 (d, J ) 8.4 Hz, 2H), 7.29 (d, J ) 8.4 Hz, 2H), 4.24
(dq, J ) 2.0, 7.1 Hz, 2H), 2.98-2.90 (m, 2H), 2.81 (s, 3H), 2.48-
2.30 (m, 2H), 2.40 (s, 3H), 1.64-1.56 (m, 1H), 1.31 (t, J ) 7.1
Hz, 3H), 1.33-0.85 (m, 3H); 13C NMR δ 214.0 (s), 170.6 (s),
143.8 (s), 136.7 (s), 129.6 (d, 2C), 127.6 (d, 2C), 72.8 (s), 62.0
(t), 36.8 (s), 35.3 (t), 33.3 (q), 31.7 (s), 21.5 (q), 20.9 (t), 14.3
(t), 14.1 (q); MS m/ z 294 (6), 292 (M+ - COOEt, 100), 155
(30), 137 (15), 91 (43). Anal. Calcd for C18H23NO5S: C, 59.16;
H, 6.34; N, 3.83. Found: C, 59.43; H, 6.46; N, 3.47.
Th er m a l Rea r r a n gem en t of th e Ad d u ct 3f. A solution
of 3f (198 mg, 0.87 mmol) in 1.5 mL of xylenes was heated in
a sealed tube at 125 °C for 5 d. After cooling to room
temperature, the solvent was removed in vacuo and the crude
product was chromatographed on a column of silica gel (eluent
ethyl acetate) to give 4f (100 mg, 0.44 mmol, 50%) and a 3:1
mixture of 5 and 6 (64 mg, 32%). Spectral and analytical data
for 5 and 6 refer to highly enriched fractions in each compound
obtained after repeated purification.
1, 4f (Rf 0.13, 332 mg, 73%) and a fraction containing a 1:1.5
mixture of 5 and 6 (Rf 0.58, 35 mg, 8%).
Cycloa d d ition of Nitr on e 2c to Meth yl 1,1′-Bicyclo-
p r op ylid en e-2-ca r boxyla te (10a ). A solution of 10a (317
mg, 2.3 mmol) and 2c (339 mg, 3.0 mmol) in benzene (1.5 mL)
was stirred at rt for 18 d. After concentration under reduced
pressure, the residue was filtered through a short pad of silica
gel (eluent ethyl acetate) to give a complex mixture of the four
isomers 11a and 12a (533 mg, 2.1 mmol, 92%), in a 2.8:2.1:
1.2:1 ratio.
11a a n d 12a : oil, Rf 0.51; 1H NMR (values for the four
methoxycarbonyl groups) δ 3.64 (s, 3H); 3.62 (s, 3H); 3.61 (s,
3H); 3.59 (s, 3H); 13C NMR (values for the four CdO groups)
δ 170.9 (s, 2C overlapped); 170.8 (s); 170.7 (s); (values for the
four bridgehead carbons) δ 74.0 (d); 73.6 (d); 73.3 (d); 72.8 (d);
IR 2971, 2875, 1726, 1437, 1366, 1226 cm-1. Anal. Calcd for
C14H21NO3: C, 66.91; H, 8.42; N, 5.57. Found: C, 66.57; H,
8.47; N, 5.41.
Cycloa d d ition of Nitr on e 2c to 2-(P h en ylth io)-1,1′-
bicyclop r op ylid en e (10b ). A solution of 10b (94 mg, 0.5
mmol) and 2c (57 mg, 0.5 mmol) in CDCl3 (0.2 mL) was stirred
at rt for 10 d. The 1H NMR spectrum of the crude mixture
showed that the four isomeric adducts 11b and 12b were
formed in a 5.5:5:4:1 ratio.
11b a n d 12b: 1H NMR (values for the bridgehead protons)
δ 4.09-4.01 (m, 1H); 3.76-3.66 (m, 1H); 3.52 (m, 2H over-
lapped); 13C NMR (values for the four bridgehead carbons) δ
73.6 (d); 73.3 (d); 73.1 (d); 72.8 (d).
Cycloa d d ition of Nitr ile Oxid e 13a to Bicyclop r op yl-
id en e (1). A solution of benzohydroximoyl chloride20 (513 mg,
3.3 mmol) in THF (10 mL) was added dropwise over 6 h to a
stirred solution of 1 (240 mg, 3.0 mmol) containing NaHCO3
(277 mg, 3.3 mmol) in THF (3 mL), and the solution was heated
at reflux and stirred for an additional hour. The mixture was
cooled to room temperature, and the salts were filtered off over
Celite. Removal of the solvent in vacuo gave a crude mixture,
which was purified by flash chromatography on silica gel
(eluent petroleum ether-diethyl ether 4:1) to provide 14a (240
mg, 1.2 mmol, 40%) and 15 (44 mg, 0.14 mmol, 5%). An
analogous reaction carried out in refluxing benzene gave 20%
of 14a and 14% of 15.
Sp ir o[cyclop r op a n e-1,1′-2-oxo-1,2,3,4,5,6,7,11b-octa h y-
1
d r op yr id o[2,1-a ]isoqu in olin e] (4f): oil, Rf 0.16; H NMR δ
7.16-6.96 (m, 4H), 4.24 (s, 1H), 3.54-3.25 (m, 3H), 3.06-2.93
(m, 3H), 2.73-2.40 (m, 2H), 1.41-1.30 (m, 1H), 1.04-0.94 (m,
1H), 0.79-0.70 (m, 1H), 0.49-0.39 (m, 1H); 13C NMR δ 208.3
(s), 134.8 (s), 133.2 (s), 129.0 (d), 127.4 (d), 127.2 (d), 125.1
(d), 61.4 (d), 49.9 (t), 45.2 (t), 35.7 (t), 31.1 (s), 27.6 (t), 15.6 (t),
10.0 (t); IR 3080, 3025, 2927, 2852, 1689, 1597, 1542, 1438
cm-1; MS m/ z 227 (M+, 33), 226 (57), 158 (100), 143 (27), 131
(38), 130 (55). Anal. Calcd for C15H17NO: C, 79.26; H, 7.54;
N, 6.16. Found: C, 79.37; H, 7.44; N, 5.96.
1-(3,4-Dih yd r oisoq u in olin -1-yl)-1-p r op ion ylcyclop r o-
1
p a n e (5): oil, Rf 0.52; H NMR δ 7.75-7.18 (m, 4H), 3.71 (m,
2H), 2.74 (t, J ) 7.4 Hz, 2H), 2.33 (q, J ) 7.2 Hz, 2H), 1.56
(m, 2H), 1.31 (m, 2H), 0.88 (t, J ) 7.2 Hz, 3H); 13C NMR δ
209.3 (s), 165.3 (s), 137.6 (s), 130.9 (d), 128.9 (s), 127.7 (d),
127.1 (d), 125.4 (d), 47.3 (t), 34.0 (t), 29.6 (s), 25.6 (t), 17.1 (t,
2C), 7.9 (q); IR 3059, 2943, 2854, 1690, 1618, 1571, 1451 cm-1
;
9-P h en yl-7-oxa -8-a za d isp ir o[2.0.2.3]n on -8-en e (14a ):
MS m/ z 227 (M+, 25), 226 (81), 212 (18), 198 (24), 170 (100),
156 (31). Anal. Calcd for C15H17NO: C, 79.26; H, 7.54, N,
6.16. Found: C, 78.77; H, 7.56, N, 5.85.
1
white solid, mp 87-89 °C (hexane), Rf 0.34; H NMR δ 7.41
(m, 5H), 1.11 (m, 4H), 0.73 (m, 2H), 0.55 (m, 2H); 13C NMR δ
161.8 (s), 129.7 (d, 2C), 128.6 (s and d, 2 C overlapped), 127.4
(d, 2C), 70.1 (s), 32.4 (s), 8.8 (t, 2C), 8.2 (t, 2C); IR 3089, 3064,
3009, 2962, 2947, 2926, 1459, 1444, 1367 cm-1; MS m/ z 199
(M+, 40), 198 (100), 197 (26), 196 (65), 170 (53), 156 (39), 143
(42), 130 (33), 128 (37), 104 (46), 77 (61). Anal. Calcd for
C13H13NO: C, 78.36; H, 6.59; N, 7.03. Found: C, 78.73; H,
6.94; N, 6.63.
1-(Isoqu in olin -1-yl)-1-p r op ion ylcyclop r op a n e (6): oil, Rf
0.50; 1H NMR δ 8.50 (d, J ) 5.9 Hz, 1H), 8.13 (d, J ) 8.5 Hz,
1H), 7.85 (d, J ) 8.0 Hz, 1H), 7.72-7.64 (m, 3H), 2.16 (q, J )
7.2 Hz, 2H), 1.85 (m, 2H), 1.46 (m, 2H), 0.85 (t, J ) 7.2 Hz,
3H); 13C NMR δ 209.9 (s), 159.1 (s), 142.1 (d), 136.4 (s), 130.2
(d), 128.4 (s), 127.8 (d), 127.5 (d), 125.4 (d), 120.6 (d), 37.4 (s),
34.7 (t), 18.8 (t, 2C), 7.8 (q); IR 3120, 3058, 2981, 2875, 1691,
1619, 1561, 1498 cm-1; MS m/ z 225 (M+, 38), 224 (65), 210
(82), 196 (54), 168 (91), 167 (100), 154 (54). Anal. Calcd for
C15H15NO: C, 79.97; H, 6.71; N, 6.22. Found: C, 79.83; H,
6.78; N, 6.09.
On e-P ot Rea ction s of Nitr on es 2a ,c-f w ith Bicyclo-
p r op ylid en e (1) To Yield 4a ,c-f: Gen er a l P r oced u r e. A
solution of BCP and the nitrone in the solvent appropriate for
the rearrangement was heated in a sealed tube for the
appropriate time. The reaction mixture was purified by flash
chromatography on silica gel.
4a : 1 (204 mg, 2.5 mmol), 2a (265 mg, 2.0 mmol), toluene
(2 mL), 110 °C for 5 d, eluent CH2Cl2-CH3OH 19:1, 4a (257
mg, 61%).
4c: 1 (460 mg, 5.7 mmol), 2c (390 mg, 3.5 mmol), benzene
(2 mL), 80 °C for 7 d, eluent CH2Cl2-CH3OH 24:1, 4c (533
mg, 80%).
4d : 1 (144 mg, 1.8 mmol), 2d (255 mg, 2.6 mmol), xylenes
(2 mL), 125 °C for 6 d, eluent CH2Cl2-CH3OH 20:1), 4d (156
mg, 48%).
4e: 1 (168 mg, 2.1 mmol), 2e (294 mg, 2.2 mmol), toluene (4
mL), 110 °C for 4 d, eluent CH2Cl2-CH3OH + 1% NH4OH 50:
1, 4e and 7a (4:1, 296 mg, 67%).
Sp ir o[cyclop r op a n e-1,8′-3,8a -d ip h en yl-7-oxo-5,6,8,8a -
tetr a h yd r o-7H-1,2,4-oxa d ia zolo[4,5-a ]p yr id in e (15): pale
1
yellow solid, mp 84-86 °C, Rf 0.39; H NMR δ 8.01-7.96 (m,
2H), 7.29-7.22 (m, 5H), 7.18-7.11 (m, 3H), 3.74 (ddd, J ) 15.0,
11.8, 3.1 Hz, 1H), 3.51 (ddd, J ) 15.0, 5.1, 3.6 Hz, 1H), 2.91
(ddd, J ) 14.3, 11.8, 5.1 Hz, 1H), 2.61 (dt, J ) 14.3, 3.3 Hz,
1H), 1.45-1.34 (dt, J ) 4.4, 8.4 Hz, 1H), 0.96 (t, J ) 8.4 Hz,
2H), 0.38 (ddd, J ) 9.2, 7.7, 4.4 Hz, 1H); 13C NMR δ 206.7 (s),
164.1 (s), 139.1 (s), 132.5 (d), 129.3 (d, 2C), 129.0 (d, 2C), 128.2
(d), 127.9 (d, 2C), 126.9 (d, 2C), 124.5 (s), 119.5 (s), 51.9 (t),
42.3 (t), 41.3 (s), 14.9 (t), 13.6 (t); IR 3068, 3031, 2945, 1765,
1680, 1640, 1514, 1443, 1336 cm-1; MS m/ z 318 (M+, 5), 222
(12), 209 (6), 128 (27), 119 (23), 105 (100), 77 (44). Anal. Calcd
for C20H18N2O2: C, 75.45; H, 5.70; N, 8.80. Found: C, 75.16;
H, 5.75; N, 8.45.
Cycloa d d ition of Nitr ile Oxid e 13b to Bicyclop r op yl-
id en e (1). Triethylamine (70 µL, 0.5 mmol) and 1 (380 mg,
4.75 mmol) were added to a stirred solution of nitroethane (356
mg, 4.75 mmol) and p-chlorophenyl isocyanate (1.69 g, 11
mmol) in diethyl ether (10 mL). The reaction mixture was
stirred at rt for 7 d. Removal of the solvent in vacuo gave a
crude mixture of the adduct 14b and dimethylfuroxan in a 1:4
4f: 1 (160 mg, 2 mmol), 2f (382 mg, 2.6 mmol), xylenes (2.6
mL), 125 °C for 5 d, eluent CH2Cl2-CH3OH + 1% NH4OH 12:
(20) Corsico Coda, A.; Tacconi, G. Gazz. Chim. Ital. 1984, 114, 131.

1672 J . Org. Chem., Vol. 61, No. 5, 1996
Goti et al.
ratio. Compound 14b could not be completely separated from
dimethylfuroxan by flash chromatography on silica gel (eluent
CH2Cl2).
4-P h en yl-2,3-dih ydr ofu r o[3,2-c]pyr idin e (18a): yield 44%,
oil, Rf 0.33; 1H NMR δ 8.41 (d, J ) 5.5 Hz, 1H), 7.82-7.70 (m,
2H), 7.60-7.30 (m, 3H), 6.73 (d, J ) 5.5 Hz, 1H), 4.65 (t, J )
8.6 Hz, 2H), 3.43 (t, J ) 8.6 Hz, 2H); 13C NMR δ 167.7 (s),
154.5 (s), 149.8 (d), 139.3 (s), 128.5 (d), 128.4 (d, 2C), 127.8 (d,
2C), 120.9 (s), 104.5 (d), 71.9 (t), 29.1 (t); IR 3080, 2928, 1585,
1571, 1496, 1457, 1430 cm-1; MS m/ z 197 (M+, 85), 196 (100),
167 (29). Anal. Calcd for C13H11NO: C, 79.16; H, 5.62; N,
7.10. Found: C, 79.00; H, 5.86; N, 6.67.
9-Meth yl-7-oxa -8-a za d isp ir o[2.0.2.3]n on -8-en e (14b): Rf
1
0.41; H NMR δ 1.76 (s, 3H), 0.98 (m, 4H), 0.63 (m, 2H), 0.43
(m, 2H); 13C NMR δ 160.2 (s), 67.9 (s), 31.8 (s), 9.3 (q), 8.3 (t,
2C), 7.9 (t, 2C); MS m/ z 137 (M+, 8), 122 (9), 81 (12), 68 (30),
40 (100), 39 (56).
Cycloa d d ition of Nitr ile Oxid e 13c to Bicyclop r op yl-
id en e (1). A refluxing solution of 1 (103 mg, 1.3 mmol) and
13c21 (345 mg, 2.1 mmol) in toluene (3 mL) was stirred for 48
h. After cooling to room temperature, the reaction mixture
was concentrated in vacuo and the crude product was purified
by flash chromatography on silica gel (eluent petroleum ether-
diethyl ether 5:1), to give adduct 14c (211 mg, 0.87 mmol,
67%).
9-(2,4,6-Tr im eth ylp h en yl)-7-oxa -8-a za d isp ir o[2.0.2.3]-
n on -8-en e (14c): white solid, mp 110-111 °C, Rf 0.26; 1H
NMR δ 6.85 (s, 2H), 2.26 (s, 3H), 2.24 (s, 6H), 1.14-1.07 (m,
2H), 0.65-0.61 (m, 4H), 0.55-0.48 (m, 2H); 13C NMR δ 163.0
(s), 138.9 (s), 137.3 (s, 2C), 128.3 (d, 2C), 123.6 (s), 68.5 (s),
34.3 (s), 21.1 (q), 19.5 (q, 2C), 8.7 (t, 2C), 8.3 (t, 2C); IR 3033,
2958, 2927, 1609, 1449, 1350 cm-1; MS m/ z 241 (M+, 8), 240
(17), 226 (30), 212 (28), 198 (23), 184 (58), 170 (47), 145 (36),
144 (47), 130 (100), 119 (40), 115 (56), 103 (49), 91 (76). Anal.
Calcd for C16H19NO: C, 79.63; H, 7.94; N, 5.80. Found: C,
79.66; H, 8.14; N, 5.46.
4-(2,4,6-T r im e t h y lp h e n y l)-2,3-d ih y d r o fu r o [3,2-c]-
p yr id in e (18c): yield 44%, pale yellow solid, mp 81-83 °C,
1
Rf 0.40; H NMR δ 8.39 (d, J ) 5.5 Hz, 1H), 6.91 (br s, 2H),
6.73 (d, J ) 5.5 Hz, 1H), 4.63 (t, J ) 8.8 Hz, 2H), 2.90 (t, J )
8.8 Hz, 2H), 2.31 (s, 3H), 2.00 (s, 6H); 13C NMR δ 166.9 (s),
156.6 (s), 149.9 (d), 137.3 (s, 2C), 135.1 (s), 128.1 (d, 2C), 122.7
(s), 120.4 (s), 104.1 (d), 71.9 (t), 27.5 (t), 21.1 (q), 19.5 (q, 2C);
IR 2924, 2858, 1583, 1448, 1374 cm-1; MS m/ z 239 (M+, 31),
238 (52), 224 (100), 211 (40). Anal. Calcd for C16H17NO: C,
80.30; H, 7.16; N, 5.85. Found: C, 79.90; H, 7.18; N, 5.77.
On e-P ot Rea ction s of Nitr ile Oxid es 13c,d w ith Bicy-
clop r op ylid en e (1): Gen er a l P r oced u r e. A solution of an
excess of BCP (1) and nitrile oxide (2 mmol) in o-dichloroben-
zene (2.5 mL) was heated at 170 °C for 5 d. The reaction
mixture was purified by direct flash chromatography on silica
gel of the crude solution, eluting with petroleum ether to
eliminate o-dichlorobenzene and then with the appropriate
eluent.
Cycloa d d ition of Nitr ile Oxid e 13d to Bicyclop r op yl-
id en e (1). A solution of 1 (280 mg, 3.5 mmol) and 13d 22 (856
mg, 3.0 mmol) in toluene (6 mL) was heated in a sealed tube
at 110 °C for 7 d. The adduct 14d (189 mg, 0.52 mmol, 17%)
was collected by filtration of the precipitate formed by partial
concentration in vacuo of the reaction mixture.
4-(2,4,6-T r im e t h y lp h e n y l)-2,3-d ih y d r o fu r o [3,2-c]-
p yr id in e (18c): yield 7%.
4-(Tr ip h en ylm et h yl)-2,3-d ih yd r ofu r o[3,2-c]p yr id in e
(18d ): eluent petroleum ether-diethyl ether 2:1, Rf 0.44, pale
yellow solid, mp 152-154 °C, yield 21%; 1H NMR δ 8.32 (d, J
) 5.5 Hz, 1H), 7.38-7.10 (m, 15H), 6.70 (d, J ) 5.2 Hz, 1H),
4.29 (t, J ) 8.8 Hz, 2H), 2.15 (t, J ) 8.8 Hz, 2H); 13C NMR δ
167.2 (s), 160.8 (s), 148.0 (s), 144.7 (d), 131.1 (d, 6C), 127.3 (d,
6C), 126.0 (d, 3C), 124.4 (s, 3C), 104.5 (d), 71.4 (t), 66.2 (s),
29.6 (t); IR 3062, 3033, 2976, 2928, 1596, 1568, 1491, 1445
cm-1; MS m/ z 363 (M+, 16), 362 (11), 244 (29), 167 (23), 165
(38), 86 (66), 84 (100). Anal. Calcd for C26H21NO: C, 85.92;
H, 5.82; N, 3.85. Found: C, 85.79; H, 6.14; N, 3.44.
9-(Tr ip h en ylm eth yl)-7-oxa -8-a za d isp ir o[2.0.2.3]n on -8-
en e (14d ): white solid, mp 186-187 °C, Rf 0.17 (petroleum
ether-diethyl ether 9:1); 1H NMR δ 7.40-7.15 (m, 15H), 1.13
(m, 2H), 0.52 (m, 2H), 0.22 (m, 2H), -0.10 (m, 2H); 13C NMR
δ 164.9 (s), 142.1 (s, 3C), 130.5 (d, 6C), 127.7 (d, 6C), 126.7 (d,
3C), 70.8 (s), 60.0 (s), 32.0 (s), 10.1 (t, 2C), 7.6 (t, 2C); IR 3088,
3065, 3023, 1596, 1491, 1446 cm-1; MS m/ z 365 (M+, 0.6), 364
(1), 244 (13), 243 (91), 165 (100). Anal. Calcd for C26H23NO:
C, 85.45; H, 6.34; N, 3.83. Found: C, 85.80; H, 6.63; N, 3.68.
Th er m a l Rea r r a n gem en t of Ad d u cts 14a a n d 14c:
Gen er a l P r oced u r e. A solution of 14 (0.1 mmol) in o-
dichlorobenzene (1 mL) was heated in a sealed tube at 170 °C
for 5 d. The crude mixture was cooled to room temperature,
and the solvent was removed by elution with petroleum ether
through a short pad of silica gel. Compounds 18 were then
eluted with petroleum ether-diethyl ether 3:8.
Ack n ow led gm en t. This work was supported by the
MURST and CNR (Italy), the Fonds der Chemischen
Industrie, and BASF, Bayer, Degussa, Hoechst, and
Hu¨ls AG (chemicals). The authors are indebted to
CRUI-Italy (Conferenza dei Rettori delle Universita`
Italiane) and the German Academic Exchange Service
(DAAD) for additional financial support of this col-
laborative project within the Vigoni Program.
(21) Grundmann, C.; Dean, J . M. J . Org. Chem. 1965, 30, 2809.
(22) Beck, W.; Schuierer, E. Chem. Ber. 1964, 97, 3517.
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