Synthetic approach to imidazo[1,2-a]pyridine derivatives by the intramolecular nitrone cycloaddition methodology

Article abstract of DOI:10.1016/S0040-4020(02)00404-0

N-Benzyl and (R)-N-(α-phenylethyl) nitrones derived from 1-allyl-2-imidazolecarbaldehyde underwent intramolecular cycloaddition to give predominantly bridged-ring products, namely 5,6,8,9-tetrahydro-6,9-methanoimidazo[2,1-d][1,2,5]oxadiazepine derivatives. Catalytic hydrogenation of the latter furnished both racemic and enantiopure 6,8-functionalised 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridines.

Full text of DOI:10.1016/S0040-4020(02)00404-0

TETRAHEDRON
Pergamon
Tetrahedron 58 %2002) 4445±4450
Synthetic approach to imidazo[1,2-a]pyridine derivatives by the
intramolecular nitrone cycloaddition methodology
Diego Basso,a Gianluigi Broggini,a Daniele Passarella,b Tullio Pilati,c Alberto Terraneob
and Gaetano Zecchia,p
a
Á
Dipartimento di Scienze Chimiche, Fisiche e Matematiche dell'Universita dell'Insubria, via Lucini 3, 22100 Como, Italy
b
Á
Dipartimento di Chimica Organica e Industriale dell'Universita di Milano, via Golgi 19, 20133 Milano, Italy
cConsiglio Nazionale delle RicercheÐIstituto di Scienze e Tecnologie Molecolari, via Golgi 19, 20133 Milano, Italy
Received 16 January 2002;accepted 11 April 2002
AbstractÐN-Benzyl and %R)-N-%a-phenylethyl) nitrones derived from 1-allyl-2-imidazolecarbaldehyde underwent intramolecular cyclo-
addition to give predominantly bridged-ring products, namely 5,6,8,9-tetrahydro-6,9-methanoimidazo[2,1-d][1,2,5]oxadiazepine deriva-
tives. Catalytic hydrogenation of the latter furnished both racemic and enantiopure 6,8-functionalised 5,6,7,8-tetrahydro-imidazo[1,2-
a]pyridines. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
or an isoxazolidinic ring, the resultant structures contain
masked functionalities which can be brought to light
under reductive7 or oxidative8 conditions. Consequently,
this methodology has been successful for the preparation
of a variety of natural and unnatural compounds with
biological activities.6,7
Imidazo[1,2-a]pyridine derivatives are attracting interest
since some of them present pharmacological properties as
antiin¯ammatories,1 e.g. compounds of formula 1, or as
glycosidase inhibitors, which include the well-known
nagstatin 2 and its debranched analogue 3.2 A number of
molecules containing this bicyclic skeleton have been
described, both partially and fully saturated. However,
most of their syntheses seem rather occasional and suffer
from limited applicability.3 To our knowledge, the only
synthetic approaches of general value to imidazo[1,2-
a]pyridines are: %i) the cyclocondensation of ethylendia-
mines with 1,5-dicarbonyl compounds4 and %ii) the cycliza-
tion of 1-%imidazolyl)substituted aldoses.5
On continuing our research dealing with intramolecular
nitrone cycloaddition methodology as a route to alkaloid-
like molecules,9 we have investigated the accessibility of the
imidazo[1,2-a]pyridine system by way of nitrones derived
from 1-allyl-2-imidazolecarbaldehyde %5).
2. Results and discussion
First, we prepared the unknown aldehyde 5, starting from
the commercially available 1-allylimidazole through
hydroxymethylation followed by oxidation %Scheme 1).
To convert
5 into a nitrone species, we chose
benzylhydroxylamine due to: %i) its commercial availability,
%ii) the easy removal of the benzyl residue, and %iii) the
possibility of generating an optically active nitrone when
Intramolecular nitrone cycloadditions are known to consti-
tute an important tool in order to build complex hetero-
polycyclic systems with a high degree of regio- and
stereocontrol.6 Due to the formation of a dihydroisoxazole
Keywords: imidazo[1,2-a]pyridines;nitrones;intramolecular cyclo-
addition.
p
Corresponding author. Tel.: 139-031-326-219;fax: 139-031-326-230;
e-mail: mabuck@icil64.cilea.it
Scheme 1. Preparation of 1-allyl-2-imidazolecarbaldehyde.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020%02)00404-0

4446
D. Basso et al. / Tetrahedron 58 22002) 4445±4450
cycloadducts, we used %R)-a-phenylethylhydroxylamine
%9).11 As illustrated in Scheme 3, the reaction of aldehyde
5 with 9 in boiling toluene gave the same regioselectivity
that we observed with benzylhydroxylamine. The nitrone 10
was once again a transient intermediate and gave three
cycloadducts, which were isolated in pure state by column
chromatography. NMR data were consistent with two
diastereoisomeric bridged-ring structures and one fused-
ring structure, but did not allow the assignment of the
con®gurations of the new stereocentres. The X-ray crystal
structure analysis of the major product 11 %Fig. 1) revealed
an absolute con®guration aR,6S,9R and indirectly proved
that of its diasteroisomer 12. Unfortunately, compound 13
gave no crystals suitable for X-ray analysis and its absolute
con®guration remains undetermined.10
Scheme 2. Intramolecular cycloaddition of nitrone 6.
Scheme 3. Intramolecular cyloaddition of nitrone 10.
using %R)-a-phenylethylhydroxylamine. Treatment of alde-
hyde 5 with benzylhydroxylamine in re¯uxing toluene
formed the expected nitrone 6, which directly underwent
the intramolecular cycloaddition %Scheme 2). After 24 h,
working and chromatography gave two regioisomeric
cycloadducts in excellent overall yield. On the basis of the
NMR data, the major product was assigned as the bridged-
ring structure 7 and the minor one, the fused-ring structure
8.10 Both cycloadducts show a cis relationship of the two
new stereocentres as a consequence of the intramolecular
nature of the reaction, which suffers from a severe geometric
restraint between dipole and dipolarophile.
The regiochemical outcome of the above intramolecular
cycloadditions is characterized by the large predominance
of bridged-ring cycloadducts. This striking feature takes a
determinant role in the light of our planned target. A
possible explanation of the experimental ®nding relies
upon the greater proximity of the reactant groups in the
approach-type A, where the allyl pendant is bent towards
the inside, with respect to B where the allyl pendant is
disposed outside %Fig. 2). Consequently, the conformer A,
although less thermodynamically favoured due to its crowd-
ing, could be more reactive than B.
To support this view, which engages mainly conformational
factors and only marginally electronic effects, MM1 calcu-
lations were done on the substrate 6 by taking into account
different asyncronous pathways for each of the two possible
orientations. Table 1 summarizes the energy data obtained
on imposing various distances between the reaction centres.
Subsequently, with the aim of having in hand non-racemic
Figure 1. ORTEPIII plot of 11 determined by X-ray analysis. Thermal
ellipsoids at 50% probability level, hydrogen atoms not to scale.
Figure 2. Regioisomeric approaches for the intramolecular cycloaddition
of nitrones 6 and 10.

D. Basso et al. / Tetrahedron 58 22002) 4445±4450
Table 1. MM1 calculations for approach-types A and B
4447
Ê
Distance between atoms %A)
Energy %kcal/mol)
Approach-type A Approach-type B
C±Oˆ3.0;C±C ˆ2.7
C±Oˆ2.7;C±C ˆ3.0
C±Oˆ2.8;C±C ˆ2.6
C±Oˆ2.6;C±C ˆ2.8
C±Oˆ2.7;C±C ˆ2.5
C±Oˆ2.5;C±C ˆ2.7
26.1
23.2
27.6
25.3
30.0
27.4
24.8
23.1
27.2
25.4
30.3
28.0
Two important deductions follow from such data: %i) a
concerted mechanism, where the C±O bond formation is
more advanced than the C±C one, is favoured for all orien-
tations and distances;%ii) the competition between the two
approach-types A and B is dependent on the distances
considered, but the ®rst approach becomes the more stable
on shortening the distance between the reactant atoms, i.e.
on setting out for the transition state. Based on these, the
preferred formation of the bridged-ring cycloadduct may
®nd rationalization.
Scheme 5. Hydrogenation reactions of cycloadducts 11 and 12.
The second part of the present report is concerned with the
manipulation of the cycloadducts aimed to achieve
functionalised imidazo[1,2-a]pyridines. Among the
plethora of reductive conditions used to open the isoxa-
zolidine ring,7 we tested those illustrated in Scheme 4.
Lithium aluminium hydride treatment of 7 furnished the
N-benzylated aminoalcohol 14 in moderate yield. When
sodium in ethanol was used, we obtained the same product
accompanied by a sizeable amount of the fully aromatic
compound 16, plausibly due to the dehydration of 14
followed by spontaneous oxidation of the dihydropyridine
species 15. The best result was accomplished by catalytic
Scheme 6. Hydrogenation reactions of cycloadducts 8 and 13.
hydrogenation with Pd%OH)2/C in the presence of protic
catalysis. Under these conditions, the expected racemic
aminoalcohol 17 was isolated in excellent yield. At this
point, the catalytic hydrogenation of the diastereoisomeric
cycloadducts 11 and 12 provided both enantiomers of 17
%Scheme 5). Their enantiomeric purity was proven to be
total, within the experimental error limits, by means of the
1H NMR spectra of %^)-17, %1)-17 and %2)-17 taken at
300 MHz in the presence of %R)-O-acetylmandelic acid.
It remains to be said that the minor fused-ring cycloadducts
8 and 13 underwent catalytic hydrogenation to give,
respectively, the racemic pyrrolo[1,2-a]imidazole amino-
alcohol 18 and one enantiomer of it with undetermined
con®guration %Scheme 6).
3. Conclusion
6,8-Bifunctionalised
5,6,7,8-tetrahydro-imidazo[1,2-a]-
pyridines, both racemic and enantiopure, are accessible by
a synthetic sequence which involves as the key step the
intramolecular cycloaddition of nitrones derived from
1-allyl-2-imidazolecarbaldehyde.
The
regiochemical
outcome of the cycloaddition, i.e. the largely predominant
formation of bridged-ring cycloadducts, is the leading
feature for the construction of the target system and
therefore represents a stringent requisite for the general
applicability of the synthetic approach described in this
paper.
Scheme 4. Reduction reactions of cycloadduct 7.

4448
D. Basso et al. / Tetrahedron 58 22002) 4445±4450
4. Experimental
3.94±4.02 %2H, overlapping), 4.15±4.25 %4H, overlapping),
4.55 %1H, br s), 6.86 %1H, s), 7.17 %1H, s), 7.28±7.35 %3H,
m), 7.44 %2H, d, Jˆ7.1 Hz). 13C NMR %100 MHz, CDCl3):
dˆ49.5 %t), 49.8 %d), 58.8 %t), 64.9 %d), 72.4 %t), 114.8 %d),
127.2 %d), 128.4 %d), 128.7 %d), 134.7 %d), 137.5 %s), 150.8
4.1. General
Preparative column chromatography was carried out on
silica gel 60 %Merck) %mesh size 63±200 mm). Melting
points were measured on a BuÈchi B-540 heating unit and
are not corrected. NMR spectra were recorded on an
AVANCE 400 Bruker. Chemical shifts are reported in
ppm relative to CHCl3 %1Hˆ7.26) and CDCl3 %13Cˆ77.0)
as internal standard. Mass spectra were determined on a
WG-70EQ instrument. IR spectra were taken on a FT-IR
Perkin±Elmer 1725X spectrophotometer. Optical rotations
were measured on a Perkin±Elmer 241 polarimeter.
%s). MS: m/z 241 %M1). IR %nujol): n 1605, 1270, 750 cm21
.
C14H15N3O %241.3): calcd C 69.69, H 6.27, N 17.41;found
C 69.57, H 6.46, N 17.46. The second fraction contained
650 mg %61%) of %6Rp,9Sp)-8-benzyl-5,6,8,9-tetrahydro-
6,9-methanoimidazo[2,1-d][1,2,5]oxadiazepine %7) as
colourless crystals. Mp 150±1518C %from diisopropyl
1
ether). H NMR %300 MHz, CDCl3, 558C): dˆ2.21 %1H, d,
Jˆ11.5 Hz), 2.76 %1H, dt, Jˆ5.6, 11.1 Hz), 3.49 %1H, br s),
3.86±3.91 %2H, overlapping), 4.02 %1H, dd, Jˆ2.0,
12.5 Hz), 4.43 %1H, d, Jˆ4.4 Hz), 4.79 %1H, d, Jˆ6.2 Hz),
6.80 %1H, s), 6.99 %1H, s), 7.18±7.40 %5H, overlapping). 13C
NMR %100 MHz, CDCl3, room temperature): major con-
former: dˆ36.4 %t), 52.8 %t), 57.7 %d), 59.7 %t), 72.7 %d),
118.7 %d), 119.2 %d), 127.8 %d), 128.7 %d), 128.8 %d), 129.0
%d), 129.4 %d), 137.8 %s), 144.9 %s); minor conformer:
dˆ32.1 %t), 52.1 %t), 58.1 %d), 63.5 %t), 73.8 %d), 115.2 %d),
119.1 %d), 127.8 %d), 128.7 %d), 128.8 %d), 129.0 %d), 129.4
%d), 137.8 %s), 144.9 %s). MS: m/z 241 %M1). IR %nujol): n
1605, 1300, 740 cm21. C14H15N3O %241.3): calcd C 69.69, H
6.27, N 17.41;found C 69.73, H 6.18, N 17.24.
4.1.1. 1-Allyl-2-hydroxymethylimidazole /4). A solution
of 1-allylimidazole %5.0 mL, 46.3 mmol), trioxane %8.46 g,
94 mmol) and AcOH %0.5 mL) in DMSO %30 mL) was stir-
red at 1308C for 60 h. After cooling to room temperature and
addition of water %70 mL), the mixture was adjusted to pH 9
with 32% aqueous ammonia and extracted with AcOEt. The
organic layer was dried over Na2SO4, the solvent was
evaporated under reduced pressure and the residue was
chromatographed on a silica gel column with CHCl3/
1
MeOH 9:1 as eluent to give 2.55 g %40%) of 4. Oil. H
NMR %300 MHz, CDCl3): dˆ2.20 %1H, br s, missing after
deuteriation), 4.59 %2H, s), 4.61±4.65 %2H, m), 5.05 %1H, dd,
Jˆ1.1, 17.0 Hz), 5.20 %1H, dd, Jˆ1.1, 10.3 Hz), 5.93 %1H,
ddt, Jˆ5.5, 10.3, 17.0 Hz), 6.81 %1H, d, Jˆ1.1 Hz), 6.86
%1H, d, Jˆ1.1 Hz). 13C NMR %100 MHz, CDCl3): dˆ54.8
%t), 56.3 %t), 116.3 %t), 125.8 %d), 128.7 %d), 138.7 %d), 147.8
%s). MS: m/z 138 %M1). IR: n 3340 cm21. C7H10N2O %138.2):
calcd C 60.85, H 7.30, N 20.27;found C 61.02, H 7.44, N
20.14.
4.1.4. Reaction between 5and / R)-N-/a-phenylethyl)-
hydroxylamine. A suspension of %R)-N-%a-phenylethyl)-
hydroxylamine %1.19 g, 8.7 mmol), 5 %1.06 g, 7.8 mmol)
and MgSO4 %16.00 g) in toluene %120 mL) was heated
under stirring for 24 h. After cooling, ®ltration and evapora-
tion under reduced pressure left a residue which was
chromatographed on a silica gel column with AcOEt/light
petroleum/EtOH 7:2:1 as eluent. The ®rst fraction gave
99 mg %5%) of %1)-1-%a-phenylethyl)-1,3a,4,8b-tetra-
hydro-3H-imidazo[10,20:1,2]pyrrolo[3,4-c]isoxazole %13)
4.1.2. 1-Allyl-2-imidazolecarbaldehyde /5). A suspension
of 4 %2.50 g, 18.1 mmol) and MnO2 %22.62 g, 260 mmol) in
CHCl3 %90 mL) was stirred at 608C for 24 h. After ®ltration
through celite, the solvent was removed under reduced pres-
sure and the crude product was puri®ed by chromatographic
silica gel column with CHCl3/MeOH 9:1 as eluent to give
670 mg %37%) of 5. Oil. 1H NMR %300 MHz, CDCl3):
dˆ4.98±5.12 %2H, m), 5.11 %1H, dd, Jˆ1.1, 16.2 Hz),
5.25 %1H, dd, Jˆ1.1, 10.1 Hz), 5.77 %1H, ddt, Jˆ5.7, 10.1,
16.2 Hz), 7.16 %1H, s), 7.30 %1H, s), 9.81 %1H, s). 13C NMR
%100 MHz, CDCl3): dˆ50.1 %t), 119.1 %t), 126.4 %d), 132.1
%d), 132.8 %d), 143.6 %s), 182.4 %d). MS: m/z 136 %M1). IR: n
1690 cm21. C7H8N2O %136.2): calcd C 61.75, H 5.92, N
20.57;found C 61.72, H 6.09, N 20.38.
1
as a white solid. Mp 79±808C %from diisopropyl ether). H
NMR %300 MHz, CDCl3, 558C): dˆ1.61 %3H, d, Jˆ6.4 Hz),
3.85±4.24 %6H, overlapping), 4.71 %1H, d, Jˆ7.0 Hz), 6.83
%1H, s), 7.19 %1H, s), 7.27±7.48 %5H, overlapping). 13C
NMR %100 MHz, CDCl3): dˆ22.4 %q), 49.4 %d), 50.4 %t),
62.8 %d), 63.4 %d), 72.9 %t), 115.0 %d), 127.9 %d), 129.1 %d),
135.4 %d), 143.1 %s), 151.2 %s). MS: m/z 255 %M1). IR %nujol):
22
n 1605, 1285, 750 cm21. [a]D ˆ148.6 %cˆ0.091, CHCl3).
C15H17N3O %255.3): calcd C 70.56, H 6.71, N 16.46;found
C 70.69, H 6.54, N 16.64. The second fraction furnished
676 mg %34%) of %aR,6S,9R)-8-%a-phenylethyl)-5,6,8,9-
tetrahydro-6,9-methanoimidazo[2,1-d][1,2,5]oxadiazepine
%11) as colourless crystals. Mp 125±1268C %from diisopro-
1
pyl ether). H NMR %300 MHz, CDCl3): dˆ1.45 %3H, d,
Jˆ5.4 Hz), 2.19 %1H, d, Jˆ11.5 Hz), 2.84 %1H, br s), 3.23
%1H, br s), 3.92 %1H, br d, Jˆ12.3 Hz), 4.07 %1H, br d,
Jˆ12.3 Hz), 4.44 %1H, br s), 4.84 %1H, d, Jˆ6.3 Hz), 6.86
%1H, s), 7.05 %1H, s), 7.24±7.38 %5H, overlapping). 13C
NMR %100 MHz, CDCl3): dˆ22.6 %q), 35.3 %t), 52.6 %t),
56.1 %d), 64.9 %d), 72.6 %d), 118.7 %d), 127.8 %d), 128.2 %d),
128.7 %d), 128.9 %d), 143.1 %s), 145.2 %s). MS: m/z 255 %M1).
4.1.3. Reaction between 5and N-benzylhydroxylamine.
A suspension of N-benzylhydroxylamine hydrochloride
%0.83 g, 5.2 mmol), MgSO4 %9.00 g) and NaHCO3 %1.00 g,
12 mmol) in toluene %120 mL) was stirred for 10 min, then a
solution of 5 %0.60 g, 4.4 mmol) in toluene %10 mL) was
added. The mixture was heated under stirring for 24 h.
After cooling, ®ltration and evaporation under reduced pres-
sure left a residue which was chromatographed on a silica
gel column with AcOEt as eluent. The ®rst fraction gave
256 mg %24%) of %3aRp,8bRp)-1-benzyl-1,3a,4,8b-tetra-
hydro-3H-imidazo[10,20:1,2]pyrrolo[3,4-c]isoxazole %8) as
22
IR %nujol): n 1605, 1295, 740 cm21. [a]D ˆ168.3
%cˆ0.10, CHCl3). C15H17N3O %255.3): calcd C 70.56, H
6.71, N 16.46;found C 70.55, H 6.58, N 16.60. The third
fraction contained 258 mg %13%) of %aR,6R,9S)-8-%a-
phenylethyl)-5,6,8,9-tetrahydro-6,9-methanoimidazo[2,1-
d][1,2,5]oxadiazepine %12). Oil. 1H NMR %300 MHz,
1
a white solid. Mp 129±1308C %from diisopropyl ether). H
NMR %300 MHz, CDCl3): dˆ3.87 %1H, dd, Jˆ3.2, 8.9 Hz),

D. Basso et al. / Tetrahedron 58 22002) 4445±4450
4449
CDCl3, 558C): dˆ1.48 %3H, d, Jˆ6.5 Hz), 2.17 %1H, d,
Jˆ8.9 Hz), 2.73 %1H, br s), 3.28 %1H, br s), 3.85 %1H, dd,
Jˆ1.5, 12.5 Hz), 3.99 %1H, dd, Jˆ2.0, 12.5 Hz), 4.54 %1H, br
s), 4.78 %1H, d, Jˆ6.2 Hz), 6.83 %1H, s), 7.01 %1H, s), 7.20±
7.33 %5H, overlapping). 13C NMR %100 MHz, CDCl3, 558C):
dˆ22.2 %q), 34.1 %t), 52.5 %t), 56.0 %d), 66.2 %d), 72.6 %d),
118.8 %d), 127.4 %d), 127.7 %d), 128.2 %d), 128.7 %d), 128.9
%d), 144.0 %s), 145.6 %s). MS: m/z 255 %M1). IR %nujol): n
After ®ltration through celite, the solvent was removed
under reduced pressure. The residue was treated with
0.2 M aqueous KOH %5 mL) and extracted with CHCl3.
The organic layer was dried over Na2SO4 and evaporated
under reduced pressure. The crude product was chromato-
graphed on silica gel column as indicated below.
4.2.1. Hydrogenation of 7. Elution with CHCl3/MeOH
2:1 gave %6Rp,8Sp)-8-amino-6-hydroxy-5,6,7,8-tetrahydro-
imidazo[1,2-a]pyridine %17) as a white solid. Yield: 77%.
Mp 169±1708C %from diisopropyl ether). 1H NMR
%300 MHz, CDCl3): dˆ2.01 %1H, ddd, Jˆ2.2, 3.3,
14.3 Hz), 2.27 %1H, ddd, Jˆ2.2, 4.5, 14.3 Hz), 2.35 %3H,
br s, missing after deuteriation), 3.98 %1H, dd, Jˆ3.3,
12.9 Hz), 4.24 %1H, dd, Jˆ3.8, 12.9 Hz), 4.43±4.48 %1H,
m), 4.56 %1H, dd, Jˆ3.3, 4.5 Hz), 6.87 %1H, d, Jˆ1.1 Hz),
7.09 %1H, d, Jˆ1.1 Hz). 13C NMR %100 MHz, CDCl3):
dˆ33.4 %t), 44.3 %d), 52.6 %t), 65.0 %d), 119.0 %d), 128.8
%d), 148.1 %s). MS: m/z 153 %M1). IR %nujol): n 3315,
2920, 2860, 1615, 1280, 730 cm21. C7H11N3O %153.2):
calcd C 54.89, H 7.24, N 27.43;found C 55.03, H 7.18, N
27.51.
22
1605, 1300, 740 cm21. [a]D ˆ144.9 %cˆ0.13, CHCl3).
C15H17N3O %255.3): calcd C 70.56, H 6.71, N 16.46;
found C 70.73, H 6.58, N 16.29.
4.1.5. Reaction of 7 with LiAlH4. A solution of LiAlH4
%100 mg, 2.6 mmol) and 7 %100 mg, 0.41 mmol) in THF
%5 mL) was stirred under nitrogen at 608C for 24 h. The
mixture was treated with MeOH %20 mL), aqueous
AcONa 2.4 M %10 mL) and then extracted with CHCl3.
The organic layer was dried over Na2SO4 and the solvent
was removed under reduced pressure. The residue was chro-
matographed on silica gel column with CH2Cl2/MeOH 9:1
as eluent to give 37 mg %38%) of %6Rp,8Sp)-8-benzylamino-
6-hydroxy-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine %14)
as a white solid. Mp 116±1178C %from diisopropyl ether).
1H NMR %300 MHz, CDCl3): dˆ1.85 %1H, ddd, Jˆ2.1, 4.0,
14.6 Hz), 2.54 %1H, ddd, Jˆ2.0, 3.5, 14.6 Hz), 3.21 %2H, br
s, missing after deuteriation), 3.86, 4.01 %2H, AB,
Jˆ12.7 Hz), 3.97 %1H, dd, Jˆ3.2, 12.9 Hz), 4.18±4.27
%2H, overlapping), 4.41 %1H, br s), 6.82 %1H, s), 7.03 %1H,
s), 7.18±7.30 %5H, overlapping). 13C NMR %100 MHz,
CDCl3): dˆ29.4 %t), 50.8 %d), 51.7 %t), 53.1 %t), 65.4 %d),
119.8 %d), 127.8 %d), 128.6 %d), 128.8 %d), 129.1 %d), 138.8
%s), 144.5 %s). MS: m/z 243 %M1). IR %nujol): n 3320,
2905 cm21. C14H17N3O %243.3): calcd C 69.11, H 7.04, N
17.27;found C 69.09, H 6.88, N 17.31.
4.2.2. Hydrogenation of 11. Elution with CHCl3/MeOH 2:1
22
gave %1)-%6S,7R)-17. Yield: 41%. [a]D ˆ18.3 %cˆ0.08,
CHCl3).
4.2.3. Hydrogenation of 12. Elution with CHCl3/MeOH 2:1
22
gave %2)-%6R,7S)-17. Yield: 37%. [a]D ˆ211.4 %cˆ0.10,
CHCl3).
4.2.4. Hydrogenation of 8. Elution with CHCl3/MeOH/
NH3 20:1:1 gave %6Rp,7Sp)-7-amino-6,7-dihydro-6-hydroxy-
methyl-5H-pyrrolo[1,2-a]imidazolo %18). Yield: 73%. Oil.
1H NMR %300 MHz, CDCl3): dˆ2.1±3.0 %3H, br s, missing
after deuteriation), 3.07±3.19 %1H, m), 3.81 %1H, dd, Jˆ6.6,
11.7 Hz), 3.89±4.02 %3H, overlapping), 4.52 %1H, d,
Jˆ7.7 Hz), 6.84 %1H, d, Jˆ1.1 Hz), 7.06 %1H, d,
Jˆ1.1 Hz). 13C NMR %100 MHz, CDCl3): dˆ45.9 %t), 46.5
%d), 49.4 %d), 61.7 %t), 115.2 %d), 133.7 %d), 156.2 %s). MS: m/z
4.1.6. Reaction of 7 with Na in EtOH. To a solution of 7
%100 mg, 0.41 mmol) in absolute EtOH %5 mL), sodium
%150 mg, 6.5 mmol) was added portionwise under nitrogen.
After stirring at room temperature for 5 h, EtOH %20 mL)
was added and the mixture was evaporated under reduced
pressure. The residue was taken with water %15 mL) and
extracted with AcOEt. The organic layer was dried over
Na2SO4, evaporated under reduced pressure and the residue
was chromatographed on silica gel column with AcOEt/
MeOH 1:1 as eluent. The ®rst fraction gave 35 mg %38%)
of 8-benzylamino-imidazo[1,2-a]pyridine %16) as a white
153 %M1). IR: n 3365, 2960, 2920, 1600, 1260, 800 cm21
C7H11N3O %153.2): calcd C 54.89, H 7.24, N 27.43;found C
54.83, H 7.42, N 27.29.
.
4.2.5. Hydrogenation of 13. Elution with CHCl3/MeOH/
22
NH3 20:1:1 gave %1)-18. Yield: 52%. [a]D ˆ12.76
1
%cˆ0.16, CHCl3).
solid. Mp 102±1038C %from diisopropyl ether). H NMR
%300 MHz, CDCl3): dˆ4.50 %2H, d, Jˆ5.7 Hz), 5.80 %1H,
br s, missing after deuteriation), 6.06 %1H, d, Jˆ7.4 Hz),
6.61 %1H, t, Jˆ7.1 Hz), 7.28±7.54 %7H, overlapping). 13C
NMR %100 MHz, CDCl3): dˆ47.8 %t), 97.9 %d), 113.9 %d),
114.1 %d), 114.9 %d), 127.7 %d), 129.0 %d), 131.5 %d), 137.5
%s), 138.8 %s). MS: m/z 223 %M1). IR %nujol): n 3425, 1565,
1265, 740 cm21. C14H13N3 %223.3): calcd C 75.31, H 5.87, N
18.82;found C 75.23, H 6.05, N 18.81. The last fraction
contained 39 mg %37%) of 14.
4.3. X-Ray crystallographic analysis of 11
Single-crystal X-ray diffraction measurements were
performed on a Bruker APEX CCD diffractometer, graphite
Ê
monochromator, Mo Ka radiation %lˆ0.71073 A).
The crystal data are as follows: C15H17N3O, Mrˆ255.32,
orthorhombic, space group P212121, aˆ9.4024 %9),
Ê
Ê 3
bˆ11.0636 %10), cˆ12.5419 %12) A, Vˆ1304.7 %2) A ,
Zˆ4, Dcˆ 1.300 g cm23
,
m
%Mo Ka)ˆ0.084 mm21
;
4.2. General procedure for the hydrogenation reaction of
cycloadducts
13,728 collected data %2u,568), 1815 unique [982 with
Io.2s%Io)], Raveˆ0.0479. Structure was solved by direct
methods %SIR-92)12 and re®ned by full-matrix least-squares
%SHELX-97).13 The absolute con®guration at C1 and C4
was assigned upon the known stereochemistry at C12
%Fig. 1);geometrical parameters of the molecule are in the
A mixture of 10% Pd%OH)2/C %110 mg, 0.078 mmol) and
isoxazolidinic compound %0.41 mmol) in a 0.06N solution
of HCl in MeOH %15 mL) was stirred under H2 for 24 h.

4450
D. Basso et al. / Tetrahedron 58 22002) 4445±4450
Perkin Trans. 1 1990, 2160. %c) Katritzky, A. R.;Qiu, G.;He,
H.-Y.;Yang, B. J. Org. Chem. 2000, 65, 3683.
expected range;®nal disagreement factors for all
%observed) re¯ections: Rw%F2)ˆ0.0496%0.0466) and
Rˆ0.0540%0.0287). All crystallographic data %excluding
structure factors) were deposited to the Cambridge Crystal-
lographic Data Center as supplementary publication No.
CCDC 177068. Copies of the data can be obtained free of
charge on application to CCDC, 2 Union Road, Cambridge
CB2 1EZ, UK, e-mail deposit@ccdc.cam.ac.uk.
5. %a) Frankowski, A.;Seliga, C.;Bur, D.;Streith, J. Helv. Chim.
Acta 1991, 74, 934. %b) Tatsuta, K.;Miura, S.;Ohta, S.;Gunji,
H. Tetrahedron Lett. 1995, 36, 1085. %c) Tatsuta, K.;Miura, S.
Tetrahedron Lett. 1995, 36, 6721. %d) Tatsuta, K.;Miura, S.;
Gunji, H. Bull. Chem. Soc. Jpn 1997, 70, 427.
6. %a) Padwa, A. 1,3-Dipolar Cycloaddition Chemistry;Padwa,
A., Ed.;Wiley-Interscience: New York, 1984;Vol. II Chapter
12. %b) Confalone, P. N.;Huie, E. M. Org. React. 1988, 36, 1.
%c) Chiacchio, U.;Resci®na, A.;Romeo, G. Targets in Hetero-
cyclic Systems;Attanasi, O. A., Spinelli, D., Eds.;SCI: Rome,
1997;Vol. I, pp 225±276.
Acknowledgements
We are grateful to MURST and CNR for ®nancial support.
7. Torssell, K. B. G. Nitrile Oxides, Nitrones, and Nitronates in
Organic Synthesis;VCH: New York, 1988.
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broad and overlapping signals, while a better resolution was
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invertomers at the pyramidal nitrogen of the isoxazolidinic
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