Cycloadditions of nitrile oxides to α,β-unsaturated aldehydes. Frontier orbital interactions and secondary orbital interactions at work in determining regiochemistry

Article abstract of DOI:10.1016/S0040-4020(00)00356-2

The regiochemistry of the cycloadditions of nitrile oxides to crotonaldehyde and cinnamaldehyde has been determined and is dictated by frontier orbital interactions and secondary orbital interactions as well. In cycloadditions to α,β-unsaturated compounds the directive effect of the frontier orbital interactions can be diverted by steric drifts and secondary orbital interactions. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00356-2

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 4299±4309
Cycloadditions of Nitrile Oxides to a,b-Unsaturated Aldehydes.
Frontier Orbital Interactions and Secondary Orbital Interactions
at Work in Determining Regiochemistry
Lucio Toma,a Paolo Quadrelli,a Giancarlo Perrini,b Remo Gandol®,a Cristiana Di Valentin,a
Antonino Corsarob and Pierluigi Caramellaa,
*
a
Á
Dipartimento di Chimica Organica dell'Universita degli Studi di Pavia, Viale Taramelli 10, I-27100 Pavia, Italy
b
Á
Dipartimento di Scienze Chimiche dell'Universita di Catania, Viale A. Doria, 8, I-95125 Catania, Italy
Dedicated to Professor Rolf Huisgen on the occasion of his 80th birthday
Received 25 April 2000; accepted 2 May 2000
AbstractÐThe regiochemistry of the cycloadditions of nitrile oxides to crotonaldehyde and cinnamaldehyde has been determined and is
dictated by frontier orbital interactions and secondary orbital interactions as well. In cycloadditions to a,b-unsaturated compounds the
directive effect of the frontier orbital interactions can be diverted by steric drifts and secondary orbital interactions. q 2000 Elsevier Science
Ltd. All rights reserved.
Introduction
The regiochemistry of the 1,3-dipolar cycloadditions1 has
remained for a long time an unsolved problem (the `biggest
unsolved')2 until the frontier orbital (FO) theory3 provided
in 1973 a satisfactory rationalization of the main regio-
chemical trends involved in this area. In the same year,
Huisgen reported a thorough study on the cycloadditions
of nitrile oxides to a,b-unsaturated esters,4 which is the
obligatory reference and canon for any other regiochemical
result in nitrile oxide cycloadditions to a,b-unsaturated
compounds, and a FO analysis of the regiochemistry as
well. As a typical case benzonitrile oxide (BNO) adds to
crotonate and cinnamate esters yielding mixtures of 4- and
Scheme 1.
5-acyl-isoxazolines 1 and 2 (Scheme 1), where the 4-acyl
isomers are the major products (Table 1) in keeping with
the preferred binding of the nitrile oxide oxygen, which has
the highest HOMO coef®cient,3 to the b-carbon of the
a,b-unsaturated esters.
Table 1. Ratio of regioisomers 1/2 in the cycloadditions of BNO to croto-
noyl derivatives. The ratios related to the cinnamoyl derivatives are given in
parentheses
Over the years a few other regiochemical data on the
cycloadditions to a,b-unsaturated compounds became
available.5±7 Somewhat surprisingly the regioselectivity
of the cycloadditions to acyclic a,b-unsaturated
ketones was found to be slightly reduced (entry 4)8 rela-
tively to the esters, while the related cyclic dipolarophiles,
Entry
X
R1
R2
1/2
Ref.
1
2
3
4
5
6
7
8
OCH3
NH2
NHCH3
CH3
N(CH3)2
±OCH3±
±CH2CH2±
±NHCH2±
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
H
66:34 (70:30)
56:44 (72:28)
55:45 (66:34)
50:50 (59:41)
15:85 (24:76)
.9:1
4
12
12
8
12
9
Keywords: 1,3-dipolar cycloadditions; regiochemistry; isoxazoles; alde-
hydes; secondary orbital interactions.
* Corresponding author. Tel.: 139-382-507315; fax: 139-382-507323;
e-mail: quadrelli@chi®s.unipv.it
H
H
91:9
91:9
10
12
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00356-2

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L. Toma et al. / Tetrahedron 56 (2000) 4299±4309
a,b-unsaturated lactones (entry 6)9 or cyclic alkenones
(entry 7)10 afford mainly the 4-acyl cycloadducts 1 with
high regioselection.
because of the minor changes in the FOs of these cross-
conjugated systems14 and the drift of regioselection could
be satisfactorily related to the A values of substituents X, a
convenient and widely accessible steric parameter.15
A possible origin of the marked difference between the
cyclic and acyclic a,b-unsaturated carbonyl compounds as
well as the differences between the latter ones could reside
in the conformational equilibrium of the acyclic com-
pounds, which is determined by the steric interaction
between the acyl substituent X and the b-vinylic hydro-
gen.11 While the aldehydes adopt mainly the transoid
conformation 3, the esters and even more the ketones prefer
the cisoid conformation 4, which becomes almost exclusive
in the case of amides.
The following is a study of the regioselection in the cyclo-
addition of BNO and the stable mesitonitrile oxide (MNO)
to crotonaldehyde and cinnamaldehyde as well as to
acrolein. Since the a,b-unsaturated aldehydes de®nitely
adopt a transoid conformation in the ground state, regio-
selection should be high and approach that of the cyclic
derivatives, in the absence of other diverting effects.
Only a few papers dealt with the cycloadditions of nitrile
oxide to a,b-unsaturated aldehydes. By performing the
reaction with preformed BNO Stagno d'Alcontres16 isolated
the 3-phenyl-4,5-dihydro-isoxazole-5-carbaldehyde in the
cycloaddition to acrolein while De Sarlo17 obtained the
3,5-diphenyl-4,5-dihydro-isoxazole-4-carboxaldehyde and
bisadducts deriving from it in the case of cinnamaldehyde.
The in situ technique cannot be used here, since the presence
of a base causes fragmentation of the adducts.18,19 The in
situ technique applies well in cycloadditions to acetals,
which have been more frequently reported.16,17,19,20
Results
Crotonaldehyde
The tempting hypothesis is then that the changes in regio-
selectivity re¯ect the changes in the conformational
equilibria. While the transoid arrangement of the cyclic
dipolarophiles gives rise to highly regioselective cyclo-
additions, in keeping well with FO expectations, the cisoid
arrangement apparently is associated with a lower regio-
selection. In the latter case some unidenti®ed factors must
tip the balance away from cycloadduct 1 and/or toward
cycloadduct 2.
Cycloadditions of BNO to crotonaldehyde were performed
by adding the aldehyde to a neutral solution of preformed
BNO in diethyl ether at 0±58C. When using an excess of
crotonaldehyde (10 equiv.), evaporation of the solvent and
excess dipolarophile left a mixture containing mainly the
adduct 6a along with minor amounts of aromatic aldehyde
14a, the regioisomeric adduct 7a and the hydrated aldehyde
13a as well (Scheme 2). In the presence of a slight excess of
the aldehyde (1.5 equiv.) cycloadditions to the aldehyde
moieties of the adducts 6a and 7a compete and about a
half of them are converted in the diastereomeric couples
of bisadducts 8a, 9a and 10a, 11a respectively. These
further cycloadditions take place rather unselectively
affording comparable amounts of the diastereomeric
bisadducts 8a and 9a and resp. 10a and 11a.
Following this hypothesis, we have recently investigated the
cycloadditions to some crotonamides and cinnamamides,
which ®rmly adopt the cisoid conformation, and, for
comparison, to a few unsaturated lactams, which are
constrained in a transoid conformation.12 As usual for the
cyclic derivatives the unsaturated lactams display high
regioselection (entry 8) while the primary amides and
their N-methyl derivatives show ratios (entries 2,3) compar-
able to the esters and the ketones and are intermediate
between them. The N,N-dimethyl derivatives display
instead a neat reversal of regioselection (entry 5) and the
reversal becomes larger with increasing bulk of the N,N-
dialkyl substituents.
The adducts were separated by column chromatography.
From the reaction performed with excess crotonaldehyde,
the isoxazolinic aldehydes 6a (53%) and 7a (12%) were
obtained as thick and rather unstable oils. The aldehyde
6a undergoes oxidation to 14a upon standing in solvents
and the oxidation is faster in the presence of triethylamine.
The NMR spectrum of the oily 6a in CDCl3 shows the
presence of small peaks (3±5%) attributable to the enol
tautomer 12a, which disappears in a few hours with a
corresponding increase of the formyl and 5-methyl signals
of the aromatic aldehyde 14a. The relatively easy enoliza-
tion of 6a follows from its b-dicarbonyl structure, where the
4-isoxazolinic proton is a to the formyl and the CvN bond.
The enol 12a is well suited for autoxidation since the
detachment of the 5-isoxazolinic proton occurs with
aromatization. On the other hand the regioisomeric
aldehyde 7a hydrates easily because of the presence of the
Taking into account the larger steric sensitivity of the C end
of the 1,3-dipole,5,13 we attributed the changes in regio-
selection to the steric hindrance of the acyl substituents in
the approach 5, leading to the 4-acyl regioisomer 1. In the
case of the amides the N-substituents Rin, which are close to
the plane of attack of the nitrile oxide and are shown in the
shaded circle, have the largest steric effect. The steric model
works successfully in accounting for the changes in regio-
selection observed with the derivatives reported in Table 1

L. Toma et al. / Tetrahedron 56 (2000) 4299±4309
4301
Scheme 2.
a-electronegative substituent21 and was obtained from the
chromatographic separation essentially in the hydrated form
13a. The NMR spectra of the crude sample were rather
complex but showed however an almost complete equilibra-
tion towards the free aldehyde 7a after standing a few hours
in CDCl3. In the presence of bases 7a undergoes fragmenta-
tion to benzonitrile as shown in 15.18
Table 2. Ratios of the 4-acyl/ 5-acyl regioisomers 1/2 (reaction yields) in
the cycloadditions of BNO and MNO to a,b-unsaturated aldehydes as
determined by quantitative GC determinations of the corresponding
alcohols after NaBH4 reduction of the reaction mixtures. The ratios 1/2
reported for the related a,b-unsaturated esters are included for comparison
X
R
BNO
MNO
Stable derivatives of the aldehydes could be obtained with
p-nitrophenylhydrazine, which afforded the crystalline
p-nitrophenylhydrazones 16a and 17a, while NaBH4
reduction in methanol afforded the alcohols 18a and 19a,
identical with samples obtained by cycloaddition to crotyl
alcohol.
H
OCH3
H
OCH3
H
OCH3
CH3
CH3
C6H5
C6H5
H
81:19 (78%)
66:34a
85:15 (73%)
70:30a
6:94 (83%)
3.6:96.4a
89:11 (70%)
73:27a
57:43 (65%)
52:48b
11:89 (74%)
6.6:93.4a
H
a Ref. 4.
b Ref. 12.
In view of the dif®culties encountered in dealing with the
fragile aldehydes, for quantitative determinations we chose

4302
L. Toma et al. / Tetrahedron 56 (2000) 4299±4309
to reduce the reaction mixtures with NaBH4 and analyze the
mixture of the alcohols 18a and 19a by GC. Minor amounts
of the alcohol 20a, deriving from the reduction of the isoxa-
zole aldehyde 14a, were also observed and taken into
account in deriving the regiochemical ratio. The latter is
reported as the ratio of the 4-acyl/5-acyl regioisomers 1/2
in Table 2 along with the ratios of the esters for comparison.
separated out from the moist ether and spectroscopic data
support the structure 13e. Upon standing a few hours in
CDCl3 13e undergoes an almost complete equilibration
towards the free aldehyde 7e.
The spectra of the MNO cycloaddition mixtures are rather
complex, showing the presence of the aldehydes 6d,f and
7d,f as well as the enol 12d,f, the aromatic aldehyde 14d,f
and the hydrated form 13d,f in varying compositions
depending upon the runs and the story of the samples.
Cycloaddition of MNO to crotonaldehyde takes place
similarly with a few noteworthy differences. MNO cyclo-
additions display a higher propensity towards the formation
of bisadducts and the MNO cycloadduct 6b undergoes an
easier and almost complete tautomerization to the enol 12b.
The formation of the bisadducts can be reduced by using a
larger excess of the dipolarophile (20 equiv.) and their
enhanced formation can be ascribed to the more nucleo-
philic character of MNO. No sizeable amounts of the mono-
cycloadduct 21b to the aldehyde moiety of crotonaldehyde
could however be isolated or clearly detected in the NMR
spectra of the reaction mixtures.
For quantitative purposes the BNO and MNO cycloaddition
mixtures were again reduced with NaBH4 to yield the
alcohols 18c±f (120c±f) and 19c±f, which were quantita-
tively determined by GLC. Samples of the alcohols 18c±f
and 19c±f were independently obtained by cycloaddition to
cinnamyl and allyl alcohols.
Discussion
While the NMR spectra of the reaction mixtures show
prominent signals attributable to the main cycloadduct 6b,
crystallization afforded instead the rather insoluble crystal-
line enol 12b in fair yields (46%). In CDCl3 solution 12b
shows a minute tendency to equilibrate with 6b, while the
oxidation of 12b to the aromatic aldehyde 14b goes
smoothly to completion in a few days. The almost complete
tautomerization of 6b to 12b is presumably due to the relief
of the strain present in 6b owing to the hindrance between
the mesityl group at C-3, orthogonal to the plane of the
isoxazolinic ring, and the proximal formyl group present
on the sp3 C-4 carbon atom. Methylation of 12b with
NaH/CH3I in THF afforded the O- and N-methyl derivative
22b and 23b in a 3:1 ratio. The NMR spectrum of the
O-methyl derivative 22b shows an allylic coupling between
the vinylic proton (6.01 d, d, Jˆ3.0 Hz) and the 5-isoxazo-
linic proton (5.49 d, dq) and closely resembles the spectrum
of 12b. The N-methyl derivative shows instead the formyl
proton as a singlet at 8.74 d and the 5-isoxazolinic proton as
a quartet at 5.71 d.
Cycloadditions of nitrile oxide to a,b-unsaturated alde-
hydes afford fragile cycloadducts. The 4-formyl isoxazo-
lines 6 undergo enolization and subsequent oxidation
while the 5-formyl isoxazolines 7 are easily hydrated and
fragment in the presence of a base. In spite of these compli-
cations the ratios of Table 2 clearly show that nitrile oxide
cycloaddition to the a,b-unsaturated aldehydes are more
inclined to yield the 4-acyl cycloadducts 1 than the cyclo-
additions to the corresponding esters. On going from BNO
to the more nucleophilic MNO this preference increases in
the case of crotonaldehyde and acrolein, owing to their
highly polarized LUMOs, while it decreases in the case of
cinnamaldehyde, which has an almost unpolarized
LUMO.12
The regioselection in cycloadditions to crotonaldehyde
remains however well below the high standards observed
with the cyclic dipolarophiles of ®xed transoid conforma-
tion. Why does crotonaldehyde resist the combined
directive effect of the two FO interactions?
Chromatographic separation afforded the enol 12b and the
hydrated aldehyde 13b, which were converted to the stable
and crystalline p-nitrophenylhydrazones 16b and 17b and
by NaBH4 reduction to the alcohols 18b and 19b. Reduction
of the reaction mixtures with NaBH4 yielded the alcohols
18b (120b) and 19b, which were quantitatively determined
by GC.
We have performed a few model calculations on the
cycloaddition of HCNO to acrolein and crotonaldehyde.
The transition structures (TSs) have been located at the
HF 6-31Gp level, which gives satisfactory geometries for
pericyclic reactions,22 and single-point energies have been
evaluated at the B3LYP/6-31Gp level, to take into account
electron correlation.23 The acrolein TSs were also optimized
at the B3LYP/6-31Gp level but showed only minor energy
Cinnamaldehyde and acrolein
Table 3. Electronic activation energies calculated for the cycloadditions of
fulminic acid to crotonaldehyde and acrolein relative to reactants (in kcal/
mol)
In cycloadditions of BNO to cinnamaldehyde, the excess
cinnamaldehyde was distilled under vacuum up to
1208C/0.1 mmHg, and the NMR spectrum of the residue
showed the regioisomeric cycloadducts 6c17 and 7c and
the aromatic aldehyde 14c in a 7:1:1 ratio. On the other
hand in cycloadditions to acrolein the solvent and excess
acrolein were evaporated under vacuum without heating,
and the NMR spectrum of the residue showed a mixture
of 7e and its hydrated form 13e along with minor signals
of the regioisomeric adduct 6e and its oxidation product
14e. In the latter case colourless crystals mp 83±848C16
Cisoid aldehyde T4
T5
C4
C5
Crotonaldehyde
HF/6-31Gp
1.4
1.3
31.5 38.3 34.0 36.7
13.1 15.3 15.0 13.6
B3LYP/6-31Gp//HF/6-31Gp
Acrolein
HF/6-31Gp
1.7
1.6
1.7
30.9 33.8 33.4 32.8
11.7 11.3 13.7 10.0
11.6 10.9 13.4 10.1
B3LYP/6-31Gp//HF/6-31Gp
B3LYP/6-31Gp

L. Toma et al. / Tetrahedron 56 (2000) 4299±4309
4303
Figure 1. Transition structures for cycloadditions of fulminic acid to crotonaldehyde and acrolein at the B3LYP/HF(6-31Gp) level. The arrows point out the
energy changes which accompany the conformational switch of the a,b-unsaturated aldehyde.
and geometric changes. Inclusion of electron correlation is
essential to afford reliable TS energies of pericyclic reac-
tions22 and reproduce regioisomeric phenomena in HCNO
cycloadditions.24
C5 and T5 by 3.6 and 3.0 kcal/mol, respectively). The
observed changes nicely agree with the abundant experi-
mental evidence and discussions on the role and positional
dependence of steric effects in nitrile oxide cycloadditions,
which was provided by Huisgen in a thorough dissection of
rate and orientation data of a,b-unsaturated esters and other
dipolarophiles.25
The four possible TSs were labeled T4, T5, C4 and C5
where T and C refer to the transoid or cisoid conformation
of the a,b-unsaturated aldehydes and the numbers specify
the positions of the formyl group in the forming heterocyclic
ring. At all levels of calculation the more stable conforma-
tion of the a,b-unsaturated aldehydes in the ground state is
the transoid conformation. The energies of the cisoid
conformations and the energies of the TSs relative to the
reactants are given in Table 3. The four barriers for the
cycloadditions to crotonaldehyde are displayed in Fig. 1
by using the more reliable B3LYP energies along with the
four barriers of acrolein evaluated at the same level.
We attribute the remarkable stabilization of the TS C5 of
crotonaldehyde and acrolein to the very favorable secondary
orbital interactions between the nitrile oxide oxygen and the
aldehyde carbonyl. Indeed, as sketched in 24, the nucleo-
philic nitrile oxide oxygen is located in a position which
reminds the best BuÈrgi-Dunitz trajectory for the attack of
a nucleophile to a carbonyl carbon,26 with the oxygen px
lone pair pointing towards the pz orbital of the carbonyl
carbon. A more familiar way to illustrate the interaction is
sketched in 25 and 26, where the partial negative charge on
the nitrile oxide oxygen is spread towards the aldehyde
oxygen.
Fig. 1 clearly shows that the two TSs T4 and T5 for the
HCNO cycloaddition to the transoid crotonaldehyde are
well separated and maintain the ,2 kcal/mol difference
implied in the regiochemistry of cycloadditions to the
transoid cyclic derivatives. On going to the cisoid TS, C4
increases in energies by 1.9 kcal/mol with respect to T4, in
keeping with the similar albeit lower preference (1.3 kcal/
mol) of crotonaldehyde for the transoid conformation in the
ground state, while C5 drops instead by 1.7 kcal/mol
relatively to T5.
Therefore the two more favorable passes to the cycloadducts
1 and 2 are T4 and C5 and involve respectively the transoid
and the cisoid conformation of the a,b-unsaturated
aldehyde. The observed leak of regioselection can then be
attributed to the special factors which stabilize the TS C5,
allowing for avoidance of the high lying TS T5 in the forma-
tion of the 5-acyl cycloadduct 2. On going to the case of
acrolein all the four barriers decrease because of the reduced
steric hindrance between the reactants and the decrease is
larger for the less hindered TSs T5 and C5. The latter
eventually becomes the more easily viable pass for the
cycloadditions to acrolein and regioselection reverses.
The geometries of the reactants and the TSs are shown in
Fig. 2. The geometries of the TSs of acrolein and croton-
aldehyde are only slightly different. In the TSs T4 and T5
the aldehyde moiety is rotated with the aldehyde oxygen
moving downward relatively to the C1, C2, C3 plane of
the a,b-unsaturated aldehyde, to align the p,pp orbitals
with the adjacent forming bond. In TS C4 rotation occurs
upward for the same reason, while in TS C5 the rotation is
minute (2±38) and downwards. In the latter case the upward
rotation should occur with loss of overlap between the
nitrile oxide oxygen px lone pair and the pz orbital of the
Alternatively viewed, the introduction of a b-trans methyl
in acrolein reduces the rate of formation of the 4-acyl
cycloadduct 1 (raises T4 by 1.4 kcal/mol) but reduces
even more the formation of the 5-acyl cycloadduct 2 (raises

4304
L. Toma et al. / Tetrahedron 56 (2000) 4299±4309
Figure 2. Geometric features of the reactants and TSs in the cycloaddition of HCNO to crotonaldehyde. The related data of acrolein are shown in parentheses.
The curved arrows specify the rotation of the aldehyde oxygen out of the plane of the C1, C2, C3 aldehyde carbons in the directions shown.
carbonyl carbon as shown in 24 and is then avoided. In TS
C5 the distance between the nitrile oxide oxygen and the
acrolein in Diels±Alder cycloadditions has been often
reported22,25,27 in connection with studies on the Lewis
acid catalyzed Diels±Alder cycloadditions. Secondary
orbital interactions offer the most viable interpretation
and, the several possible secondary orbital interactions
involved in Diels±Alder stereoselectivities curiously seem
Ê
aldehyde carbon is 2.58 A, only slightly longer than the
Ê
adjacent forming O´´´C bond (2.25 A).
The involvement of the less stable cisoid conformation of

L. Toma et al. / Tetrahedron 56 (2000) 4299±4309
4305
to merge into the original Alder rule of `maximum accumu-
lation of unsaturations'.28 Other cases of conformational
switches in cycloadditions to enol ethers have been recently
reported by Rastelli24 and Houk.29
ratio. Crystallization from benzene afforded 19e (73%).
The mother liquors were evaporated and separated by
column chromatography giving 18e (0.8%) and further
19e (11%). Adduct 18e: mp 67±688C from ethanol/water;
(found C, 67.6; H, 6.3; N, 8.0. C10H11NO2 requires C, 67.78;
H, 6.26; N, 7.91); nOH 3350 cm21; dH: 2.02 (bs, 1H, OH);
3.6±4.0 (m, 3H, CH2 and H-4); 4.4±4.7 (m, 2H, H-5); 7.4±
7.5 (m, 3H, arom.); 7.7±7.8 (m, 2H, arom.). Cycloadditions
of MNO to the allylic alcohols (5 equiv.) in benzene have
been similarly performed. After keeping the solutions
1 month at r.t., the solvent and excess allylic alcohol was
evaporated under vacuum and column chromatography of
the residues afforded the couples of the regioisomeric
alcohols:
Conclusions
The nitrile oxide cycloadditions to crotonaldehyde take
place with moderate regioselection in spite of the combined
directive effects of both the FO interactions. Model calcula-
tions show that the leak of regioselection occurs because of
a competitive transition state involving the cisoid conformer
of the a,b-unsaturated aldehyde. A remarkably ef®cient
secondary orbital interaction between the nitrile oxide
oxygen and the aldehyde carbonyl more than compensate
the cost of the conformational change.
18b (35%) oil, bp 1908C (bath/0.1 mmHg); (found C, 72.1;
H, 8.2; N, 6.0. C14H19NO2 requires C, 72.07; H, 8.21; N,
6.00); nOH 3400 cm21; dH: 1.50 (d, 3H, CH3, Jˆ6.2 Hz);
2.26 (s, 6H, o,o0-CH3); 2.30 (s, 3H, p-CH3); 3.33 (m, 1H,
H-4); 3.67 (m, 2H, CH2); 1.80 (bs, 1H, OH); 4.72 (m, 1H,
H-5); 6.90 (s, 2H, Mes-H).
Secondary orbital interactions are presumably at work in
cycloadditions with a,b-unsaturated ketones, esters and
amides, thereby modifying the FO prescriptions. The effect
should be however attenuated in the series because of the
expected raising of the pp carbonyl.
19b (40%), mp 56±588C from ligroin; (found C, 72.0; H,
8.0; N, 5.9. C14H19NO2 requires C, 72.07; H, 8.21; N, 6.00);
n
OH 3500 cm21; dH: 1.16 (d, 3H, CH3, Jˆ7.2 Hz); 2.03 (bs,
1H, OH); 2.27 (s, 6H, o,o0-CH3); 2.31 (s, 3H, p-CH3); 3.57
(m, 1H, H-4); 3.75 and 3.96 (m, 2H, CH2); 4.40 (m, 1H,
H-5); 6.91 (s, 2H, Mes-H).
Experimental
All mps are uncorrected. Elemental analyses were done on a
C. Erba 1106 elemental analyzer. H NMR spectra were
1
recorded on a Bruker AC 300 spectrometer in CDCl3 solu-
tions, unless otherwise stated. Chemical shifts are expressed
in ppm from internal tetramethylsilane (d) and coupling
constants are in Hertz (Hz): b, broad; s, singlet; bs, broad
singlet; d, doublet; t, triplet; q, quartet; m, multiplet. IR
spectra (nujol mulls) were recordered on an FT-IR
Perkin±Elmer Paragon 1000 spectrophotometer and absorp-
tions (n) are in cm21. Column chromatography and tlc:
silica gel H60 and GF254 (Merck) respectively, eluent cyclo-
hexane/ethyl acetate 9:1 to ethyl acetate. GC analyses have
been carried out by means of an HP 5890 equipped with a
FID with an HP 5 column (30 m, 0.3 id) using nitrogen as
carrier, using the internal standard method for quantitative
determinations. The identi®cation of samples from different
experiments was secured by mixed mps and superimposable
IR spectra.
18d (22%), mp 89±908C from petroleum ether; (found C,
77.3; H, 7.1; N, 4.7. C19H21NO2 requires C, 77.26; H, 7.17;
N, 4.74); nOH 3380 cm21; dH: 1.55 (bs, 1H, OH); 2.21 (s,
6H, o,o0-CH3); 2.30 (s, 3H, p-CH3); 3.65±3.85 (m, 3H, H-4
and CH2); 5.68 (d, 1H, H-5, Jˆ7.0 Hz); 6.90 (s, 2H, Mes-H);
7.3±7.5 (m, 5H, arom.).
19d (47%), mp 140±1418C from benzene; (found C, 77.3;
H, 7.2; N, 4.8. C19H21NO2 requires C, 77.26; H, 7.17; N,
4.74); nOH 3330 cm21; dH: 2.11 (s, 6H, o,o0-CH3); 2.23 (s,
3H, p-CH3); 2.55 (bs, 1H, OH); 3.8±4.0 (m, 2H, CH2); 4.60
(d, 1H, H-4, Jˆ6.2 Hz); 5.02 (m, 1H, H-5); 6.78 (s, 2H,
Mes-H); 7.15±7.3 (m, 5H, arom.).
18f (1%) oil, bp 1908C (bath/0.1 mmHg); (found C, 71.2; H,
7.8; N, 6.4. C13H17NO2 requires C, 71.20; H, 7.82; N, 6.39);
nOH 3370 cm21; dH: 1.92 (bs, 1H, OH); 2.27 (s, 6H, o,o0-
CH3); 2.30 (s, 3H, p-CH3); 3.6±4.0 (m, 3H, H-4 and CH2);
4.50 (m, 1H, H-5); 6.93 (s, 2H, Mes-H).
Starting and reference materials
Benzhydroximoyl chloride was obtained by treatment of
benzaldoxime with sodium hypochlorite30 and mesitonitrile
oxide by oxidation of 2,4,6-trimethylbenzaldoxime with
bromine.31 Solutions of BNO in diethyl ether were prepared
with the procedure of Quilico and Speroni.32
19f (71%), mp 82±838C from ligroin; (found C, 71.1; H,
7.8; N, 6.4. C13H17NO2 requires C, 71.20; H, 7.82; N, 6.39);
nOH 3420 cm21; dH: 2.25 (s, 6H, o,o0-CH3); 2.29 (s, 3H,
p-CH3); 2.67 (bs, 1H, OH); 3.15 (m, 2H, H-4); 3.6±3.8
(m, 2H, CH2O); 4.85 (m, 1H, H-5); 6.90 (s, 2H, Mes-H).
The regioisomeric alcohols 18a, mp 79±808C (lit.33 oil)
from diisopropyl ether and 19a, mp 48±508C (lit.33 oil)
from petroleum ether, the regioisomeric alcohols 18c, mp
122±122.58C,33 and 19c, mp 93.5±95.58C,33 and alcohol
19e, mp 79±79.58C34 are known compounds and were
obtained by cycloaddition of BNO to crotyl,33 cinnamyl33
and allyl34 alcohols. In the BNO cycloaddition to allyl
alcohol (10 equiv.) in diethyl ether the main adduct 19e
and the regioisomeric adduct 18e are formed in a 99:1
The isoxazole aldehydes 14a, mp 55±568C35 and 14c, mp
113±1148C17 were obtained according to the literature and
the aldehydes 14e, mp 448C and 14f, mp 68±698C were
available from previous work.36 The aldehydes were
quantitatively reduced to the alcohols with NaBH4 in
methanol. After keeping 2 h at r.t. the mixtures were evapo-
rated, taken up in chloroform and washed with water.
Drying over Na2SO4 and evaporation afforded almost

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L. Toma et al. / Tetrahedron 56 (2000) 4299±4309
quantitatively the alcohols 20a,37 mp 80±28C from benzene,
20c, mp 138±1398C (lit.38 mp 137±1398C), 20e, oil; (found
C, 68.4; H, 5.3; N, 8.1. C10H9NO2 requires C, 68.56; H,
5.18; N, 8.00); nOH 3390 cm21; dH: 1.80 (bs, 1H, OH);
4.73 (s, 2H, CH2); 7.5±7.8 (m, 5H, arom.); 8.50 (s, 1H,
H-5), 20f, mp 90±918C from petroleum ether; (found C,
71.9; H, 7.1; N, 6.3. C13H15NO2 requires C, 71.86; H,
6.96; N, 6.45); nOH 3380 cm21; dH: 1.55 (bs, 1H, OH);
2.09 (s, 6H, o,o0-CH3); 2.35 (s, 3H, p-CH3); 4.38 (s, 1H,
CH2); 6.96 (s, 2H, Mes-H); 8.36 (s, 1H, H-5).
The NMR spectrum showed complex signals between 3±5.5
d, which simpli®ed upon standing. After a few hours the
aldehyde 7a was the major constituent: dH: 1.42 (d, 3H,
CH3, Jˆ7.0 Hz); 3.94 (dq, 1H, H-4, Jˆ3.8, 7.0 Hz); 4.64
(dd, 1H, H-5, Jˆ3.8, 1.0 Hz); 7.3±7.7 (m, 5H, arom.); 9.79
(d, 1H, CHO, Jˆ1.0 Hz). p-Nitrophenylhydrazone 17a:
yellow crystals, mp 185±1868C from ethanol; (found C,
62.8; H, 4.8; N, 17.1. C17H16N4O3 requires C, 62.95; H,
4.97; N, 17.28); dH (Acetone): 1.40 (d, 3H, CH3,
Jˆ7 Hz); 4.14 (m, 1H, H-4); 5.01 (t, 1H, H-5, Jˆ6 Hz);
7.0±8.2 (m, 10H, arom. and CHvN); 10.13 (bs, 1H, NH).
General procedure for the cycloadditions of BNO to the
a,b-unsaturated aldehydes
Reduction of the aldehydes 6a and 7a with NaBH4 in
methanol afforded the alcohols 18a (78%), mp 79±808C
from diisopropyl ether and respectively 19a (65%), mp
48±508C from petroleum ether, identical with the reference
compounds.
To a stirred solution of preformed BNO (10 mmol) in
diethyl ether at 08C the a,b-unsaturated aldehyde
(10 equiv.) was added. After keeping the reaction mixture
2 days at 0±58C the solvent and excess aldehyde was evapo-
rated under vacuum and in the case of cinnamaldehyde up to
1208C (bath)/0.1 mmHg. The residue was separated by
column chromatography or dissolved in methanol and
reduced by adding excess NaBH4 (2 equiv.) to the stirred
and ice-cooled solution. After keeping 2 h at r.t. the
mixtures were evaporated, taken up in chloroform and
washed with water. The organic layer, dried over Na2SO4
and evaporated, left a residue which was separated by
column chromatography and/or analyzed by GC. In a few
cases the cycloadditions and the subsequent reductions have
been performed under nitrogen. GC analyses showed the
same 18120/19 ratio and the expected change in the 18/
20 ratio. In the reactions performed under nitrogen the
isoxazole alcohols 20 are almost absent.
(B) When performing the cycloaddition with 2 equiv. of
crotonaldehyde, column chromatography afforded an
inseparable mixture of the four bisadducts 8a, 9a, 10a and
11a (26%) along with 14a (5%), 6a (24%) and 7a (8%). The
four bisadducts can be readily distinguished by NMR, which
shows well separated signals for the dioxazolinic protons at
dH 6.32 (d, Jˆ3.5 Hz), 6.21 (d, Jˆ5.8 Hz), 6.18 (d,
Jˆ3.0 Hz) and 6.04 (d, Jˆ5.8 Hz) in a 4:4:1:1 ratio. The
major bisadducts 8a and 9a were independently obtained by
exposure of aldehyde 6a to excess preformed BNO
(2 equiv.) and column chromatography, eluant benzene,
afforded the two bisadducts 8a and 9a in fair yields (72%)
and with a partial separation. The faster running oily dia-
stereoisomer displayed signals at dH 1.46 (d, 3H, CH3,
Jˆ6.5 Hz); 3.87 (dd, 1H, H-4, Jˆ3.5, 5.8 Hz); 5.07 (dq,
1H, H-5, Jˆ5.8, 6.5 Hz); 6.32 (d, 1H, dioxazolinic-H,
Jˆ3.5 Hz); 7.3±7.9 (m, 10H, arom.) while the slower
running oily diastereoisomer has signals at dH 1.43 (d,
3H, CH3, Jˆ6.5 Hz); 3.83 (dd, 1H, H-4, Jˆ4.0, 5.8 Hz);
5.03 (dq, 1H, H-5, Jˆ4.0, 6.5 Hz); 6.21 (d, 1H, dioxazoli-
nic-H, Jˆ5.8 Hz); 7.4±7.8 (m, 10H, arom.).
MNO cycloadditions have been similarly performed by
adding the aldehyde (10 equiv.) to a solution of MNO
(10 mmol) in anhydrous benzene (100 mL) ar r.t.. The reac-
tions went to completion in 3 days at r.t. (1 day for acrolein).
Cycloadditions of BNO to crotonaldehyde
The minor bisadducts 10a and 11a were similarly obtained
from 7a and partially separated by column chromatography,
eluant benzene. The faster running oily diastereoisomer
displayed signals at dH 1.42 (d, 3H, CH3, Jˆ7.2 Hz); 3.86
(dq, 1H, H-4, Jˆ4.0, 7.2 Hz); 4.55 (dq, 1H, H-5, Jˆ4.0,
5.8 Hz); 6.04 (d, 1H, dioxazolinic-H, Jˆ5.8 Hz); 7.4±7.9
(m, 10H, arom.) while the slower running diastereoisomer
could be puri®ed by crystallization: mp 168±1698C from
ethanol, (found C, 70.5; H, 5.3; N, 9.2; C18H16N2O3 requires
C, 70.11; H, 5.23; N, 9.09); dH 1.42 (d, 3H, CH3, Jˆ7.2 Hz);
3.85 (dq, 1H, H-4, Jˆ4.0, 7.2 Hz); 4.62 (dd, 1H, H-5, Jˆ3.0,
4.0 Hz); 6.18 (d, 1H, dioxazolinic-H, Jˆ3.0 Hz); 7.4±7.8
(m, 10H, arom.).
(A) Column chromatography afforded the aromatic alde-
hyde 14a (7%), mp 55±568C from petroleum ether and
identical with the reference compound, and the isoxazolinic
aldehydes 6a (53%) and 7a (12%) as thick oils.
6a: thick oil; nCvO 1721 cm21; dH: 1.48 (d, 3H, CH3,
Jˆ6.5 Hz); 4.12 (dd, 1H, H-4, Jˆ3.5, 5.8 Hz); 5.19 (m,
1H, H-5); 7.4±7.8 (m, 5H, arom.); 9.68 (d, 1H, CHO,
Jˆ3.5 Hz). The spectrum showed also a minor peak
attributable to the enol tautomer 12a [dH: 1.55 (d, 3H,
CH3, Jˆ6.3 Hz); 5.59 (dq, 1H, H-5, Jˆ2.8, 6.3 Hz); 7.05
(d, 1H, CHv, Jˆ2.8 Hz)] which disappeared after a few
hours with a corresponding increase of the signals of 14a
at dH: 2.80 (s, 3H, CH3) and 9.98 (s, 1H, CHO). p-Nitro-
phenylhydrazone 16a: yellow crystals, mp 163±1658C from
ethanol/water; (found C, 62.8; H, 5.0; N, 17.1. C17H16N4O3
requires C, 62.95; H, 4.97; N, 17.28); dH (Acetone): 1.44 (d,
3H, CH3, Jˆ6.5 Hz); 4.40 (t, 1H, H-4, Jˆ7 Hz); 4.95 (m,
1H, H-5); 7.1±8.1 (m, 10H, arom. and CHvN); 10.05 (bs,
1H, NH).
Cycloaddition of MNO to crotonaldehyde
Column chromatography afforded the aromatic aldehyde
14b (6%), the couple of diastereoisomeric bisadducts 8b
(8%) and 9b (9%), a mixture (2%) of the diastereomeric
bisadducts 10b and 11b, the enol 12b (47%) and the
hydrated aldehyde 13b (9%). In a duplicate experiment
the residue was taken up with diisopropyl ether and the
colorless crystals of 12b (43%) were ®ltered off.
7a: thick oil. The spectroscopic data indicated a mixture of
.
7a and the hydrated form 13a: nOH 3480, nCvO 1725 cm21

L. Toma et al. / Tetrahedron 56 (2000) 4299±4309
4307
14b: mp 40±418C from petroleum ether; (found C, 73.2; H,
6.5; N 6.1. C14H15NO2 requires C, 73.34; H, 6.59; N, 6.11);
n
CH3); 2.82 (s, 3H, CH3); 6.98 (s, 2H, Mes-H); 9.49 (s, 1H,
CHO).
alcohol 20b was obtained as colorless crystals, mp 121±
1228C from ligroin (found C, 72.5; H, 7.3; N, 6.2.
C14H17NO2 requires C, 72.70; H, 7.41; N, 6.06); nOH
3360 cm21; dH: 2.10 (s, 6H, o,o0-CH3); 2.17 (s, 3H,
p-CH3); 2.49 (d, 3H, CH3); 4.20 (bs, 1H, OH); 6.95 (s,
2H, Mes-H).
CvO 1682 cm21; dH: 2.11 (s, 3H, p-CH3); 2.36 (s, 6H, o,o0-
8b: mp 150±1518C from ethanol; (found C, 73.7; H, 7.2; N
7.2. C24H28N2O3 requires C, 73.44; H, 7.19; N, 7.14); dH:
1.53 (d, 3H, CH3, Jˆ6.5 Hz); 2.2±2.32 (m, 18H, CH3); 3.78
(d, 1H, H-4, Jˆ6.5, 3.0 Hz); 5.05 (m, 1H, H-5); 5.95 (d, 1H,
H-dioxazolinic, Jˆ3 Hz); 6.88 (s, 2H, Mes-H); 6.91 (s, 2H,
Mes-H).
Methylation of 12b was performed by adding NaH
(1.5 equiv.) to a stirred solution of 13b (0.3 mmol) and
MeI (5 equiv.) in anhydrous THF (30 mL) at r.t. After stand-
ing 2 h, 1 mL of methanol was added. After pouring in ice,
extraction with chloroform, drying over Na2SO4 and
evaporation of the solvent, column chromatography
afforded the O- and N-derivatives 22b and 23b in a 3:1
ratio. 22b (53%), mp 110±1118C from diisopropyl ether,
(found C, 73.3; H, 7.8; N, 5.7. C15H19NO2 requires C,
73.44; H, 7.81; N, 5.71); dH: 1.53 (d, 3H, CH3,
Jˆ6.2 Hz); 2.22 (s, 6H, o,o0-CH3); 2.32 (s, 3H, p-CH3);
3.65 (s, 3H, OCH3); 5.49 (dq, 1H, H-5, Jˆ3.0, 6.2 Hz);
6.01 (d, 1H, CHv, Jˆ3.0 Hz); 6.92 (s, 2H, Mes-H). The
Z con®guration of 22b is based on a NOESY experiment
which showed NOE correlation between the vinylic proton
and the o,o0-CH3. 23b, (20%), thick oil; (found C, 73.4; H,
7.8; N, 5.6. C15H19NO2 requires C, 73.44; H, 7.81; N, 5.71);
nCvO 1630 cm21; dH: 1.60 (d, 3H, CH3, Jˆ6.0 Hz); 2.24,
2.27, 2.34 (s, 3H, CH3); 2.98 (s, 3H, NCH3); 5.71 (q, 1H, H-
5, Jˆ6.0 Hz); 6.97 (s, 2H, Mes-H); 8.75 (s, 1H, CHO).
9b: mp 1468C from ligroin; (found C, 73.3; H, 7.2; N 7.2.
C24H28N2O3 requires C, 73.44; H, 7.19; N, 7.14); dH: 1.55
(d, 3H, CH3, Jˆ6.5 Hz); 2.1±2.3 (m, 18H, CH3); 3.75 (dd,
1H, H-4, Jˆ7.0, 4.6 Hz); 5.15 (m, 1H, H-5); 6.01 (d, 1H,
dioxazolinic-H, Jˆ4.6 Hz); 6.92 (s, 2H, Mes-H); 6.93 (s,
2H, Mes-H).
10111b: the oily mixture shows well separated doublets of
the dioxazolinic proton at dH 6.20 (d, Jˆ5.0 Hz) and 6.22
(d, Jˆ3.2 Hz). Upon standing it solidi®ed and crystalliza-
tion from ligroin afford a pure diastereoisomer, mp 130±
1338C (found C, 73.3; H, 7.2; N 7.2. C24H28N2O3 requires C,
73.44; H, 7.19; N, 7.14); dH: 1.23 (d, 3H, CH3, Jˆ6.5 Hz);
2.2±2.3 (m, 18H, CH3); 3.70 (m, 1H, H-4); 4.57 (dd, 1H,
H-5, Jˆ6.5, 5.0 Hz); 6.20 (d, 1H, dioxazolinic-H,
Jˆ5.0 Hz); 6.92 (s, 4H, Mes-H).
Cycloaddition of BNO to cinnamaldehyde
12b: mp 1638C from diisopropyl ether; (found C, 72.5; H,
7.5; N 6.3. C14H17NO2 requires C, 72.70; H, 7.41; N, 6.06);
dH: 1.52 (d, 3H, CH3, Jˆ6.5 Hz); 2.11, 2.13, 2.32 (s, 3H,
CH3); 5.51 (dq, 1H, H-5, Jˆ3.0, 6.5 Hz); 6.35 (d, 1H, CHv,
Jˆ3.0 Hz); 6.86 (s, 2H, Mes-H); 6.93 (bs, 1H, OH). After
standing a few hours the NMR displayed the signals of the
aromatic aldehyde 14b and minute signals attributable to
aldehyde 6b: 1.53 (d, 3H, CH3, Jˆ6.5 Hz); 2.25 (s, 6H,
o,o0-CH3); 2.32 (s, 3H, p- CH3); 4.02 (dd, 1H, H-4, Jˆ1.6,
8.0 Hz); 5.26 (dq, 1H, H-5, Jˆ8.0, 6.5 Hz); 6.94 (s, 2H,
Mes-H); 9.52 (d, 1H, CHO, Jˆ1.6 Hz). p-Nitrophenyl-
hydrazone 16b: yellow crystals, mp 176±1778C from
ethanol; (found C, 65.2; H, 15.2; N, 6.0. C20H22N4O3
requires C, 65.55; H, 6.05; N, 15.29); dH (Acetone): 1.49
(d, 3H, CH3, Jˆ6.5 Hz); 2.20 (s, 9H, CH3); 4.20 (dd, 1H,
H-4, Jˆ7.0, 5.0 Hz); 4.98 (m, 1H, H-5); 6.95 (s, 2H, Mes-
H); 7.02 (d, 2H, arom, Jˆ8.0 Hz.); 7.25 (d, 1H, CHvN,
Jˆ7.0 Hz); 8.10 (d, 2H, arom., Jˆ8.0 Hz); 10.5 (bs, 1H,
NH).
The NMR spectrum of the mixture showed the signals of the
aldehydes 6c, 7c and 14c in a 7:1:1 ratio. Column chromato-
graphy afforded 14c (8%), mp 113±1148C, and 6c (53%),
oil,17 along with the hydrated aldehyde 13c (11%) as a thick
oil. The NMR spectrum of 13c showed broad signals at 4.4±
5.5 d and, upon standing a few hours in CDCl3, 13c under-
went an almost complete equilibration to 7c: dH: 4.85 (dd,
1H, H-4, Jˆ3.5, 0.7 Hz); 4.98 (d, 1H, H-5, Jˆ3.5 Hz); 7.2±
7.7 (m, 10H, arom.); 9.86 (d, 1H, CHO, Jˆ0.7 Hz). NaBH4
reduction of 13c afforded the alcohol 19c (83%), mp 93.5±
95.58C, identical to the reference sample.
NaBH4 reduction of the cycloaddition mixture afforded the
alcohols 18c (120c) and 19c in a 85:15 ratio.
Cycloaddition of MNO to cinnamaldehyde
Column chromatography afforded a sample of the isoxazole
aldehyde 14d (11%), mp 888C from ethanol/water; (found
C, 78.0; H, 5.9; N, 4.8. C19H17NO2 requires C, 78.33; H,
5.88; N, 4.81); nCvO 1692 cm21; dH: 2.17 (s, 6H, o,o0-CH3);
2.38 (s, 3H, p-CH3); 7.11 (s, 2H, Mes-H); 7.6 (m, 3H,
arom.); 8.27 (m, 2H, arom.); 9.68 (s, 1H, CHO), which
was reduced to the alcohol 20d, mp 1398C from ethanol/
water; (found C, 77.8; H, 6.4; N, 4.8. C19H19NO2 requires C,
77.79; H, 6.53; N, 4.77); nOH 3320 cm21; dH: 1.70 (bs, 1H,
OH); 2.15 (s, 6H, o,o0-CH3); 2.36 (s, 3H, p-CH3); 4.46 (s,
2H, CH2); 6.99 (s, 2H, Mes-H); 7.5 (m, 3H, arom.); 7.97 (m,
2H, arom.). The cycloaddition mixture, when reduced with
NaBH4, afforded a comparable amounts of the alcohols 18d
and 19d, identical with the reference compounds, along with
minor amounts of the isoxazole alcohol 20d. GC analyses
gave a 57:43 ratio of 18d120d/19d.
13b, thick oil. It was converted into the p-nitrophenylhydra-
zone 17b: yellow crystals, mp 223±2248C from ethanol;
(found C, 65.3; H, 15.4; N, 5.9. C20H22N4O3 requires C,
65.55; H, 6.05; N, 15.29); dH (Acetone): 1.15 (d, 3H,
CH3, Jˆ7.0 Hz); 2.15 (s, 6H, CH3); 3.95 (m, 1H, H-4);
4.95 (dd, 1H, H-5, Jˆ5.1, 7.2 Hz); 6.85 (s, 2H, Mes-H);
7.15 (d, 2H, arom, Jˆ7.0 Hz); 7.50 (d, 1H, CHvN,
Jˆ5.1 Hz); 10.2 (bs, 1H, NH).
NaBH4 reduction of 12b, 13b and 14b afforded the stable
alcohols 18b, 19b, 20b. The alcohols 18b, thick oil, and
19b, mp 56±588C, are identical to the reference samples
obtained by MNO cycloaddition to crotyl alcohol. The

4308
L. Toma et al. / Tetrahedron 56 (2000) 4299±4309
Cycloaddition of BNO to acrolein
personal contacts and favourable interactions, which have
been maintained since a stay in Munich in 1967/1968.
Financial support by CNR and MURST is gratefully
acknowledged.
From the ethereal solution kept at 0±58C for 2 days, the
hydrated aldehyde 13e (16%) separated out: mp 83±848C
from water (lit.16 mp 84±858C); nOH 3300 cm21; dH
(DMSO): 3.3±3.4 (m, 2H, H-4); 4.48 (m, 1H, H-5); 4.80
(m, 1H, OCHO); 6.08 (m, 2H, OH); 7.4±7.7 (m, 5H, arom.).
dH (CDCl3): 2.95 (bs, 2H, OH); 3.3±3.5 (m, 2H, H-4); 4.80
(m, 1H, H-5); 5.10 (m, 1H, OCHO); 7.4±7.7 (m, 5H, arom.).
Upon standing a few hours in CDCl3 the sample underwent
a smooth conversion to the free aldehyde 7e, dH: 3.5±3.7
(m, 2H, H-4); 5.07 (ddd, 1H, H-5, Jˆ11.2, 6.0, 0.9 Hz);
7.4±7.7 (m, 5H, arom.); 9.83 (d, 1H, CHO, Jˆ0.9 Hz).
p-Nitrophenylhydrazone 17e: yellow crystals, mp 221±
2228C from ethanol; (lit.16 mp 199±2008C). dH (Acetone):
3.72 (d, 2H, H-4, Jˆ9.2 Hz); 5.42 (dt, 1H, H-5, Jˆ5.8,
9.2 Hz); 7.18 (d, 2H, arom., Jˆ9.0 Hz); 7.4±7.5 (m, 4H,
arom. and CHvN); 7.77 (m, 2H, arom.); 8.15 (d, 2H,
arom., Jˆ9.0 Hz); 10.24 (bs, 1H, NH). NaBH4 reduction
of a sample of 13e afforded quantitatively the alcohol 19e,
mp 79±808C, identical with the reference compound.
References
1. Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565, 633;
Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.,
Ed.; Wiley: New York, 1984; Vol. 1, p 1.
2. Huisgen, R. J. Org. Chem. 1968, 33, 2291.
3. Houk, K. N.; Sims, J.; Watts, C. R.; Luskus, L. J. J. Am. Chem.
Soc. 1973, 95, 7301; Houk, K. N.; Sims, J.; Duke, R. E.; Strozier,
R. W.; George, J. K. J. Am. Chem. Soc. 1973, 95, 7287.
4. Christl, M.; Huisgen, R. Chem. Ber. 1973, 106, 3345.
5. Caramella, P.; GruÈnanger, P. In 1,3-Dipolar Cycloaddition
Chemistry, Padwa, A., Ed.; Wiley: New York, 1984; Vol. 1, p 291.
6. Cossy, J.; Carrupt, P. A.; Vogel, P. In The Chemistry of Double
Bonded Functional Groups, Patai, S., Ed.; Wiley: New York,
1988; Vol. 2, p 1369.
7. Gandol®, R.; GruÈnanger, P. In Isoxazoles, Part 2; The
Chemistry of Heterocyclic Compounds, GruÈnanger, P., Vita
Finzi, P. Eds.; Wiley: New York, 1999; Vol. 49, p 467.
8. Bianchi, G.; Gandol®, R.; De Micheli, C. J. Chem. Res. 1981,
(S), 6; (M), 135.
The ethereal mother liquors were evaporated and the residue
was separated by column chromatography affording the
aldehyde 14e (3%), mp 448C, identical with the reference
compound and further 13e (54%).
9. Fisera, L.; Kozhina, N. D.; Stibranyi, L.; Badovskaja, L. A.
Chem. Papers 1986, 40, 685.
10. Bianchi, G.; De Micheli, C.; Gandol®, R.; GruÈnanger, P.; Vita
Finzi, P.; Vajna de Pava, O. Chem. Soc., Perkin Trans. I 1973,
1148.
On performing the cycloaddition under nitrogen, the NaBH4
reduction of the mixture afforded the alcohol 19e (70%),
along with 20e (1%), mp 508C and 18e (5%), mp 67±
688C, identical with the reference samples.
11. Shambayati, S.; Schreiber, S. L. In Comprehensive Organic
Synthesis, Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 1, p 283.
Cycloaddition of MNO to acrolein
12. Caramella, P.; Reami, D.; Falzoni, M.; Quadrelli, P.
Tetrahedron 1999, 55, 7027.
Column chromatography afforded the isoxazole aldehyde 14f
(5%), mp 68±698C from petroleum ether, identical with a
reference sample, and the hydrated aldehyde 13f (63%).
13. Sustmann, R.; Sicking, W. Chem. Ber. 1987, 120, 1471.
14. Phelan, N. F.; Orchin, M. J. Chem. Ed. 1968, 45, 633.
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13f: thick oil. The NMR showed broad signals at 3.2±3.3,
4.7±4.9 and 5.2 d attributable to 13e, which decreased upon
standing a few hours in CDCl3 because of the almost
complete conversion to the free aldehyde 7f: dH: 2.20 (s,
6H, o,o0-CH3); 2.32 (s, 3H, p-CH3); 3.5±3.5 (m, 2H, H-4);
5.06 (ddd, 1H, H-5, Jˆ10.8, 5.8, 0.9 Hz); 6.91 (s, 2H, Mes-
H); 9.89 (d, 1H, CHO, Jˆ0.9 Hz). p-Nitrophenylhydrazone
17f: yellow crystals, mp 232±2348C from ethanol; (found
C, 64.8; H, 5.9; N, 15.8. C19H20N4O3 requires C, 64.76; H,
5.72; N, 15.90); dH (Acetone): 2.25 (s, 6H, o,o0-CH3); 2.29
(s, 3H, p-CH3); 3.5±3.6 (m, 2H, H-4); 5.44 (m, 1H, H-5);
6.95 (s, 2H, Mes-H); 7.21 (d, 2H, arom., Jˆ9.0 Hz); 7.51 (d,
1H, CHv, Jˆ6.0 Hz); 8.16 (d, 2H, arom., Jˆ9.0 Hz); 10.21
(bs, 1H, NH). NaBH4 reduction of 13f afforded the alcohol
19f, mp 82±838C, identical to the reference sample.
17. De Sarlo, F.; Guarna, A.; Brandi, A. J. Heterocycl. Chem.
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1983, 39, 2231.
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24. Rastelli, A.; Gandol®, R.; Sarzi Amade, M. J. Org. Chem.
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NaBH4 reduction of the cycloaddition mixture gave the
alcohols 18f, 19f and 20f. GC analysis gave a 11:89 ratio
of 18f120f/19f.
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106, 3312.
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Acknowledgements
P. C. would like to express his appreciation and gratitude to
Prof. Rolf Huisgen for many fruitful discussions, warm

L. Toma et al. / Tetrahedron 56 (2000) 4299±4309
4309
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