The role of the carbonyl group in the intermolecular 1,3-cycloaddition of azido(2-heteroaryl)methanones with activated olefins

Article abstract of DOI:10.1039/b203577d

Treatment of the azido(2-heteroaryl)methanones 1-5 with methyl (E)-3-pyrrolidinoprop-2-enoate at room temperature yielded the methyl 1,2,3-triazolecarboxylate 6 and (2-heteroaryl) (pyrrolidino)methanones 1a-5a via an unusual 1,3-cycloaddition reaction. An

Full text of DOI:10.1039/b203577d

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The role of the carbonyl group in the intermolecular
1,3-cycloaddition of azido(2-heteroaryl)methanones
with activated olefins
1
Paolo Zanirato
Dipartimento di Chimica Organica ‘A. Mangini’, Università degli Studi di Bologna,
Viale Risorgimento 4, 40136 Bologna, Italy. E-mail: zanirato@ms.fci.unibo.it
Received (in Cambridge, UK) 12th April 2002, Accepted 29th April 2002
First published as an Advance Article on the web 15th May 2002
Treatment of the azido(2-heteroaryl)methanones 1–5 with methyl (E)-3-pyrrolidinoprop-2-enoate at room
temperature yielded the methyl 1,2,3-triazolecarboxylate 6 and (2-heteroaryl) (pyrrolidino)methanones
1a–5a via an unusual 1,3-cycloaddition reaction. Analogous reactions of the azidomethanones 1 and 2 with
the dipolarophiles methyl crotonate, methyl propiolate or methyl but-2-ynoate failed. In contrast, the strained
5-methylenebicyclo[2.2.1]hept-2-ene reacted smoothly with the carbonyl azides 1–5 to give triazoline adducts
which subsequently formed the (2-heteroaryl)(6-methylene-3-azatricyclo[3.2.1.02,4 ]octan-3-yl)methanones
1b–5b by loss of molecular nitrogen.
The 1,3-dipolar cycloaddition (1,3-DC) of organic azides to
dipolarophile olefins constitutes a powerful synthetic route
to 1,2,3-triazoline1 and 1,2,3-triazole2 substructures. Reactions
of this type enable the synthesis of azole-cyclic systems
containing a large range of functionalities, and give access
to compounds of preparative importance.3 Such azole-cyclic
systems have practical applications in fields such as agriculture
and medicine.4 The reaction is markedly favoured with activ-
ated ethylenes and acetylenes (i.e., strained olefins and those
carrying functional groups like OR, NR2, COOR)5 or when
high-pressure techniques are employed.6
Our interest in this topic is focused on the molecular orient-
ation in the 1,3-DC of aryl and heteroaryl azides with term-
inally substituted olefins.7 All such azides undergo 1,3-DC to
terminally silylated (or carboxylated) alkynes via a concerted
pathway and the additions are almost regiospecific.8 The
1,3-DC procedure was employed both as a method for trapping
thermally unstable heteroaryl azides and as a synthetic method
to obtain cyclic compounds. The chemistry of these reactions
was found to depend on the nature of the N-1 azido sub-
stituent.5,7 In addition to the chemistry of these reactions, we
are interested in the possible activity of 1,3-DC products
against Mycobacterium avium and M. tuberculosis.9 The large
number of cycloaddition reactions available allows the prep-
aration of many candidate compounds that can be tested for
biological activity.
oxylates and pyrrolidine. In the present study we examine the
chemistry of the 1,3-DC of a number of azido(2-heteroaryl)-
methanones by using MePA, 5-methylenebicyclo[2.2.1]hept-
2-ene (MBH), methyl crotonate [methyl (E)-2-methylbut-
2-enoate], (MeC) methyl propiolate (methyl propynoate)
(MeP) and methyl but-2-ynoate (MeB) as dipolarophiles. The
2-heteroaryls selected are furan- (1), thiophene- (2), 5-methyl-
thiophene- (3), selenophene- (4), and thieno[3,2-b]thiophene-
(5)-2-carbonyl azides. This work was undertaken to elucidate
the applicability of 1,3-DC to the synthesis of triazoles starting
from deactivated azides whose HOMO and LUMO energies are
1
presumably depressed. With this aim, H-NMR spectroscopy
was used to analyse the main products during the course of the
reactions.
Results and discussion
The reactions of the carbonyl azides 1–5 with MePA (exact
equimolar ratio; each 2 × 10Ϫ3 mol) in CDCl3 (1.0 cmϪ3
)
proceeded smoothly at room temperature, giving a solid pre-
cipitate within 20–25 days. The first ten days of reaction were
monitored by removing small aliquots from the reaction
1
mixture and analysing them by H-NMR spectroscopy. The
1
time evolution of the H-NMR spectra showed a monotonic
decrease in the peak intensities associated with the reactants
1
1–5 and MePA, and the concomitant appearance of H-NMR
Addition of azides to double or triple C–C bonds is
well characterized from both a theoretical10 and synthetic1–4
standpoint; however, the literature on 1,3-DC reactions in
which heteroaroyl azides are the dipole component is limited
to a few intramolecular reactions.11 Moreover, these azido-
cycloadditions were found to be in competition with the
Curtius rearrangement. To our knowledge, no report has
described the intermolecular 1,3-DC of heteroaroyl azides with
dipolarophiles as a route to azoles. Related examples would be
the known 1,3-DC involving azidoformates and benzoyl azide.12
High reactivity and regioselectivity have been observed in
the 1,3-DC of a number of aryl13a and heteroaryl azides13b and
methyl 3-pyrrolidinoacrylate (MePA). In addition, there is
experimental evidence that the triazoline adducts undergo
fragmentation to form N-substituted 1,2,3-triazole 4-carb-
proton signals that are firmly assignable to a mixture of
the triazole 6 and the (2-heteroaryl)(pyrrolidino)methanones
1a–5a. The spectra showed no evidence of other compounds.
After NMR analysis showed the disappearance of the starting
carbonyl azide, the suspensions were treated with a mixture of
hexane–chloroform (5 cm3; 4 : 1, v/v) and then stirred for 10 h.
The resulting suspensions were filtered and the solid products
characterized. In all cases the product was found to be the
triazole 6 (90%)14 Manipulation of the mother liquor yielded
the (2-heteroaryl)(pyrrolidino)methanones 1a–5a with com-
parable purities (85–88% yield). Structural assignments of
1
1a–5a and the triazole 6 were made on the basis of IR, H-,
13C-NMR, and exact mass spectra. The 1H-NMR spectrum of
compound 6 showed two singlets in a 1 : 3 ratio at δ 8.34 and
3.88 assignable to the CH and OCH3 moieties and the NH
1420
J. Chem. Soc., Perkin Trans. 1, 2002, 1420–1425
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b203577d

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signal is absent. Identical NMR, MS and physical data were
observed for a sample of 6 synthesized using the literature
procedure.14 The mass spectrum of 6 displayed a peak at m/z
127 corresponding in mass and isotopic abundance to the
molecular ion. However, no primary nitrogen loss (M Ϫ 28),
typical for the 1H-isomer, was observed. In contrast, the peak
at m/z 42 was twofold higher than the peak at m/z 41, typical for
2H-triazoles.15
Our findings indicate that the 1,3-DC of heteroaroyl azides
1–5 with MePA occurs smoothly to produce a single adduct
Ia (Scheme 1). This elusive adduct [i.e., methyl 5-pyrrolidino-
1-(2-heteroarylcarbonyl)-4,5-dihydro-1H-1,2,3-triazole-4-carb-
oxylate] undergoes displacement of the pyrrolidine from
the triazoline ring as previously observed in the cases of aryl
and heteroaryl azides.13 The basic pyrrolidine attacks the
carbonyl carbon, via nucleophilic addition at the trigonal
carbon, presumably to afford methyl 1-[hydroxy(pyrrolidino)(2-
heteroaryl)methyl]-1H-1,2,3-triazole-4-carboxylate (Ib), which
in turn releases the triazole 6 and the pyrrolidinomethanones
1a–5a in high yields. The observation of 6 as a product in all
of these reactions suggests, but does not require, the existence
of the tetrahedral intermediate Ib shown in Scheme 1.
1
The H- and 13C-NMR spectra of compounds 1a–5a before
manipulation indicated restricted rotation around the partial-
double carbonyl–pyrrolidine bond. A brief description of this
behaviour can be ascertained by the 1H-NMR spectra in
CDCl3, which display the four α-geminal protons as two
pseudotriplets centred at δ 3.5–3.8 (pyrrolidine α and αЈ, two
protons each) separated by 32.6, 18.3, 24.0, 15.8 and 22.7 Hz,
respectively. A similar but less extensive effect is observed for
the β-protons. The possibility of measuring by NMR spec-
troscopy the torsional barrier of the C–N bond in heteroaryl
carboxamides and their dependence upon the medium as been
reported.16 Compounds 1a–5a after work-up and samples of
1a and 2a, synthesized by displacement of the corresponding
heteroarene: carbonyl chloride with pyrrolidine,17 show
identical 1H-NMR spectra. In these instances the α-proton
signals were essentially broad singlets centered at the same
frequencies. These signals become separated upon addition
of trace amounts of pyrrolidine. The evidence suggests that
the presence of pyrrolidine modifies the C–N torsional barriers
through base-catalysed prototropic exchange.
The main purpose of the present work was to further char-
acterize the reactivity of azido(2-heteroaryl)methanones with
dipolarophile olefins. However, our attempts to obtain isolable
triazolines (or triazoles) by 1,3-DC reaction of the azides 1
and 2 in neat methyl crotonate, methyl propiolate or methyl
but-2-ynoate failed. Even after two months, the 1H-NMR
spectrum of the reaction mixture remained unchanged. In
contrast, 1,3-DC of the azides 1–5 with the strained 5-methyl-
enebicyclo[2.2.1]hept-2-ene (MBH) (exact equimolar ratio;
each 2 × 10Ϫ3 mol) in CDCl3 (1.0 cm3) proceeded smoothly,
affording (2-heteroaryl)(6-methylene-3-azatricyclo[3.2.1.02,4]-
octan-3-yl)methanones 1b–5b as the major product (Scheme 2).
Scheme 1
Scheme 2
J. Chem. Soc., Perkin Trans. 1, 2002, 1420–1425
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Table 1 Calculated HOMOs and LUMOs energies of azides 1–5 and
At room temperature the reactions were virtually complete
within 17–25 days. Release of molecular nitrogen was observed
in this period.
some dipolarophiles at HF/6-31G* level of theorya
Compound
EHOMO
ELUMO
As
a
representative example, the 1H-NMR spectrum
measured after nine days of reaction of the azide 1 showed the
formation of a novel 2-substituted heteroaryl AMX system
of 1b in the ratio 1 : 2.5. This indicates that the product 1b,
characterized by the three heteroaryl-proton signals (three
doublets of doublets) at δ 7.55, 7.13 and 6.51, is produced at the
expense of the starting compound 1, whose resonances are at
δ 7.66, 7.27 and 6.56.18 The relative shielding observed suggests
a reduction in the electron-withdrawing effect of the carbonyl
carbon. Of the compounds tested, the slowest reaction was
observed for the 5-methylthiophene 3, for which the ratio 3 : 3b
was 1 : 0.8 after nine days. The corresponding ratios for the
other compounds studied were 2 : 2b (1 : 1.5), 4 : 4b (1 : 2) and
5 : 5b (1 : 2).
1
Ϫ9.17
Ϫ9.35
Ϫ9.03
Ϫ9.12
Ϫ8.62
Ϫ8.18
Ϫ8.99
Ϫ10.22
Ϫ11.42
Ϫ10.80
2.27
1.95
2.03
1.77
1.63
4.09
4.63
3.38
3.30
3.59
2
3
4b
5
MePAc
MBHd
MeCe
MePf
MeBg
a In eV (1 eV = 23 kcal = 96.5 kJ). b Pseudopotential associated with
6-31G* basis set is used for heavy selenium atom. c Methyl (E)-
3-pyrrolidinoprop-2-enoate.
d 5-Methylenebicyclo[2.2.1]hept-2-ene.
e Methyl crotonate. f Methyl propiolate. g Methyl but-2-ynoate.
It is clear from Fig. 1 (traces b and c, c being that of the
spectrum of the separated product confirmed the main product
to be the aziridine 1b (77%, m/z 215). Analysis of the chrom-
atogram also indicated the presence of small amounts of four
isomers giving signals at m/z 215 (global 23%). These isomers
presumably arise from thermal rearrangement in the injector
and are not detected on the NMR time-scale.20 Similar
behaviour was observed for the azides 2–5. The structures
of the resulting compounds 1b–5b were assigned on the basis of
elemental analyses, IR, NMR and MS spectral data.
As expected, the 1,3-DC occurs almost exclusively at the
strained double bond C-2᎐C-3 of the bicycloheptene, leading
᎐
to formation of a labile triazoline adduct IIa which is then
converted to single aziridines by thermal release of molecular
nitrogen.12b (Scheme 2) The present study using deactivated
azides provides evidence for the applicability of 1,3-DC to
the synthesis of cyclic azoles with MePA or MBH as the
dipolarophile but not MeC, MeP or MeB. According to
Frontier Molecular Orbital (FMO) theory, the 1,3-DC
reactivity between an electron-poor azide and an electron-rich
dipolarophile involves interaction between the LUMO on the
1,3-dipole and the HOMO on the dipolarophile.21
To provide a quick method that might confirm this, we
performed time-inexpensive theoretical calculations focusing
on the HOMO and LUMO energies of the reactants. Calcu-
lations are carried out by using the set of programs in Spartan
Ј02 Windows.22 The RHF/6-31G* level of theory was used
to obtain structures and energies of the ground-state reactants
1–5, and MePA, MBH, MeC, MeP and MeB. A pseudopoten-
tial associated with the 6-31G* basis set is used to replace
the all-electron basis set for heavy selenium atom of compound
4. The calculated HOMO and LUMO energies presented in
Table 1 agree reasonably with those obtained by spectroscopic
techniques.21 It is clear from the data that the HOMO and
LUMO energy trends of the azides 1–5 are almost the same; the
small energy differences observed among the different azides
would be accounted for by the nature of the heteroaryl moiety.
Examining the sequence of the FMO energies we can argue that
the 1,3-DC reactions with the smallest energy gap are those
dominated by the interaction of the LUMOs of the azides 1–5
and the HOMOs of the dipolarophiles MePA and MBH. None
of the other combinations are likely to provide more favoured
1,3-DC interaction because of their larger energy gaps.
Fig. 1 1H NMR spectra in CDCl3 at 200 MHz in the region δ 2.6–6.4
Traces: a) neat 5-methylenebicycyclo[2.2.1]hept-2-ene; b) reaction
sample registered after nine days; c) final product 1b.
final product 1b) that significant reaction occurs to produce
mainly a single compound characterized by a novel H-2Ј and
H-3Ј AB-system at δ 2.96 and δ 2.87. (Primed loads are used
to denote the bicycloheptene numbering system) This system
is formed at the expense of the broad multiplet at δ 6.1 corre-
sponding to the ethylenic protons H-2Ј and H-3Ј of the bicyclic
olefin (trace a). It is noteworthy that the single peaks corre-
sponding to H-8Ј are almost unchanged during the reaction,
whereas the signals of other protons undergo various shifts.
H-7Ј (particularly the B-part of an AB-type quartet with
J 10.3 Hz), H-4Ј and H-1Ј are remarkably shielded, whereas
H-6Ј (particularly the B-part of an AB-type quartet with
J 15.8 Hz) appears to be deshielded. In the light of the present
1H-NMR data and those reported for related systems,19 an exo
ring-fused carbonyl aziridine structure is assigned to 1b.
Conclusions
The 1,3-DC reactions between five azido(2-heteroaryl)meth-
anones and various activated dipolarophiles were studied. The
reactivity towards different alkenes and alkynes of these carb-
onylazides varied considerably with respect to that of the aryl
and heteroaryl azides. It is noteworthy that only the dipolaro-
philes particularly activated or strained, like methyl (E)-3-
Comparison of the GC-MS mass spectrum of the final
mixture before chromatographic separation with the mass
1422
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pyrrolidinoprop-2-enoate and 5-methylenebicyclo[2.2.1]hept-2-
ene, were found to be suitable for the synthesis of cyclic azoles.
In these instances, the 1,3-adducts initially formed were
thermally labile or unstable, causing them to undergo further
reaction either by displacement of pyrrolidine or by loss
of molecular nitrogen. The carbonyl moiety of the azido-
(2-heteroaryl)methanones imposes practical limitations on the
choice of dipolarophile; however, the 1,3-DC of 1–5 with 5-
methylenebicyclo[2.2.1]hept-2-ene constitutes one of the most
important approaches for the synthesis of carbonyl aziridines.
Simple FMO calculations performed by self-consistent field
(SCF) method could be, at first hand, useful for predicting the
more favoured interactions of the carbonyl azides with different
dipolarophiles.
layers were washed with water and then dried over Na2SO4. The
solvent was eliminated under vacuum and the residue was
chromatographed on ‘Florisil’ (100–200 U.S. mesh, BDH)
column using petroleum ether (distillation range 30–60 ЊC) as
the eluent.
The resulting azido(thieno[3,2-b]thiophen-2-yl)methanone
5 was characterized by 1H-NMR, 13C-NMR, IR and high-
resolution mass spectroscopy. Compound 5 (87%), mp 98–99
ЊC; νmax/cmϪ1 2145 (N3), 1680 (CO); δH (200 MHz; CDCl3) 8.04
(1H, d, J 0.8, H-3), 7.66 (1H, d, J 5.3, H-5) and 7.30 (1H, q,
J 0.8 and 5.3, H-6); δC (50.3 MHz; CDCl3) 167.5, 146.1, 139.6,
136.2, 133.8 (d, J 187.0), 127.1 (d, J 176.2) and 120.3 (d,
J 175.2); m/z 209 (Mϩ, 100%), 181 (M Ϫ N2, 40.8), 167 (49.6),
153 (95.5), 139 (20.4), 126 (39.1), 109 (53.8), 95 (27.9), 69 (59.5)
and 45 (40.9); Found: Mϩ, 208.9717. C7H3N3OS2 requires M,
208.9717.
Experimental
Reactions of azido(2-heteroaryl)methanones 1–5 with methyl
(E )-3-pyrrolidinoprop-2-enoate at 25 ؇C. General procedure
Materials
2-Furoyl chloride, thiophene-2-carbonyl chloride, thionyl
dichloride, buthyl-lithium, ethyl chloroformate and sodium
azide were purchased from Aldrich Chimica Italiana and used
as received. Thieno[3,2-b]thiophene-2-carboxylic acid was
prepared from the corresponding 2-lithio-derivative and
carbon dioxide according to the literature procedure.23 Methyl
(E)-3-(pyrrolidinoprop-2-enoate was prepared following the
procedure described by Huisgen.24 The heteroaroyl azides 1–5
were prepared from the appropriate carboxylic acids via mixed
carboxylic-carbonic anhydride or carbonyl chloride and
sodium azide following the procedure described.18,25 Chrom-
atographic filtration was carried out on ‘Florisil’ BDH, 60–100
mesh.
A solution (2 × 10Ϫ3 : 2 × 10Ϫ3 mol; exact equimolar ratio in 1.0
cm3 of CDCl3) of a heteroaroyl azide (1, 0.274; 2, 0.306; 3,
0.334; 4, 0.400 5, 0.418 g) and MePA (0.310 g) was allowed to
react in a screw-cap tube for the appropriate time (20–25 days).
The time evolution of the reaction was monitored by analysing
small aliquots from the solutions using 1H NMR spectroscopy.
In all cases the intensities of peaks associated with the starting
azide 1–5 decreased and peaks appeared indicating the form-
ation of a mixture of methyl 1H-1,2,3-triazole-4-carboxylate
6 and the (2-heteroaryl)(pyrrolidino)methanones 1a–5a (see
text). After the disappearance of starting azide, the resulting
suspensions were treated with 5.0 cm3 of dry n-hexane–
chloroform (4 : 1, v/v) mixture and stirred for an additional 10 h.
The solid product was then filtered off under vacuum and the
residue was washed with cold hexane. The solid was character-
ized as almost pure methyl 1,2,3-triazole-4-carboxylate 6.
The mother liquor contained the corresponding (2-hetero-
aryl)(pyrrolidino)methanone 1a–5a, as confirmed by 1H-NMR
spectroscopy. This solution was concentrated by elimination of
the solvent under vacuum, and the oily residue was filtered
under nitrogen pressure on a ‘Florisil’ column using dry hexane
and then characterized by 1H-NMR, 13C-NMR, IR and
high-resolution mass spectroscopy.
Caution. Organic azides are potentially explosive! This
category of compounds has been subjected to risk evaluation.26
Explosions may occur when handling organic azides, although
we experienced no problems in handling basic solutions of
sodium azide or solid organic azides, which can be stored
indefinitely at Ϫ18 ЊC.
Instrumentation
Melting points were determined on a Kofler hot-stage appar-
atus and are uncorrected. IR spectra were recorded in film on
(2-Furyl)(pyrrolidino)methanone 1a. (88%), Mp 70–73 ЊC;
νmax/cmϪ1 2974, 2878, 1616 (CO), 1481, 1423 and 755; δH (300
MHz; CDCl3) 7.55 (1H, q, J 0.8 and 1.7, H-5), 7.16 (1H, q, J 0.8
and 3.5, H-3), 6.54 (1H, q, J 1.7 and 3.5, H-4), 3.72 (4H, bs,
H-α), and 1.99 (4H, bs, H-β); δC (75.4 MHz; CDCl3) 161.6,
149.1, 144.4 (d, J 203.7), 116.3 (d, J 177.7), 111.5 (d, J
177.2), 48.1 (t, J 142.8), 47.4 (t, J 142.8), 26.6 (t, J 132.3) and
23.7 (t, J 132.7); m/z 165 (Mϩ, 33.4 %), 137 (M Ϫ 28, 4.8), 110
(6.2), 95 (100), 70 (6.3) and 55 (4.7); Found: Mϩ, 165.0790.
C9H11NO2 requires M, 165.0790.
1
a Perkin-Elmer Spectrum 2000 FT–IR spectrometer. H- and
13C-NMR spectra were recorded on a Varian Gemini 200
(200 and 50.3 MHz, respectively) or 300 (300 and 75.4 MHz,
respectively) for solutions in CDCl3 using TMS and CHCl3 as
internal standards. Chemical shifts are in δ-units and J-values
are given in Hz. Mass spectra were recorded on VG7070E
instruments using electron impact ionization (70 eV). GS–MS
analyses were performed using a Hewlett-Packard G1800A
instrument. Calculations were performed using the program
Spartan ’02 Windows,22 running on an AMD K7 processor at
1333 MHz.
(2-Thienyl)(pyrrolidino)methanone 2a. (87%), Mp 66–68 ЊC;
νmax/cmϪ1 2974, 2878, 1616 (CO), 1430 and 725; δH (200 MHz;
CDCl3) 7.58 (1H, q, J 1.2 and 3.8, H-3), 7.50 (1H, q, J 1.2 and
5.05, H-5), 7.08 (1H, q, J 3.8 and 5.05, H-4), 3.53 (4H, bs, H-α)
and 2.00 (4H, bs, H-β); δC (50.3 MHz; CDCl3) 160.3, 139.3,
129.0 (d, J 185.9), 128.5 (d, J 168.8), 126.5 (d, J 168.2), 47.8 (t,
J 142.8), 46.4 (t, J 142.8), 25.6 (t, J 132.8) and 23.0 (t, J 132.8);
m/z 181 (Mϩ, 43.7%), 153 (M Ϫ 28, 7.7), 111 (100), 83 (6.7)
and 39 (19.0); Found: Mϩ, 181.0561. C9H11NOS requires M,
181.0561.
Synthetic procedure for the azido(thieno[3,2-b]thiophen-2-yl)-
methanone 5
To solutions containing 0.05 mol of the thieno[3,2-b]thiophene-
2-carboxylic acid (9.2 g) in 75 cm3 of anhydrous acetone at
0 ЊC was added 0.059 mol (5.95 g, 8.35 cm3) of triethylamine
in acetone (23 cm3) and 0.066 mol (7.2 g) of ethyl chloroformate
in acetone (23 cm3). The resulting mixtures were stirred at 0 ЊC
for 45 min and then a solution containing 0.085 mol (5.5 g) of
sodium azide in 19 cm3 of water was added dropwise over a
period of 1 h, after which the solution was warmed to room
temperature and stirred for another 30 min. The suspension
was poured into cold brine and the resulting aqueous mixture
was extracted twice with diethyl ether. The combined organic
(5-Methyl-2-thienyl)(pyrrolidino)methanone 3a. (85%), Mp
59–61 ЊC; νmax/cmϪ1 3098, 2970, 2876, 1590 (CO), 1457, 812,
and 739; δH (300 MHz; CDCl3) 7.37 (1H, d, J 3.7, H-3), 6.75
(1H, q, J 1.0 and 3.7, H-4), 3.74 (4H, bs, H-α), 2.50 (3H, d,
J. Chem. Soc., Perkin Trans. 1, 2002, 1420–1425
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J 1.0, Me) and 1.95 (4H, bs, H-β); δC (50.3 MHz; CDCl3) 161.4,
145.4, 139.1, 130.7 (d, J 167.0), 125.8 (d, J 166.5), 49.1 (t,
J 142.8), 47.7 (t, J 142.8), 26.7 (t, J 132.8), 24.1 (t, J 132.8) and
15.5 (q, J 129.6); m/z 195 (Mϩ, 17.8%), 125 (M Ϫ 70, 24.5), 97
(59.3), 96 (100), 68 (15.7), 40 (35.8) and 39 (12.0); Found: Mϩ,
195.0717. C10H13NOS requires M, 195.0718.
(2-Thienyl)(6-methylene-3-azatricyclo[3.2.1.02,4]octan-3-yl)-
methanones 2b. (80%), Oil; νmax/cmϪ1 3091, 2974, 1653 (CO),
1414, 1256, 839 and 720; δH (200 MHz; CDCl3) 7.73 (1H, q,
J 1.2 and 3.7, H-3), 7.52 (1H, q, J 1.2 and 5.0, H-5), 7.10 (1H, q,
J 3.7 and 5.0, H-4), 5.00 (1H, s), 4.79 (1H, s), 3.05 (1H, s), 2.97
(1H, d, J 5.3), 2.88 (1H, d, J 5.3), 2.71 (1H, s), 2.20 (1H, ‘d’,
J 15.8), 1.98 (1H, ‘d’, J 15.8), 1.61 (1H, ‘d’, J 10.2) and 1.07
(1H, ‘d’, J 10.2); δC (50.3 MHz; CDCl3) 170.5, 149.2, 138.3,
131.6 (‘d’, J 181.1), 131.4 (‘d’, J 169.0), 127.8 (‘d’, J 168.3),
106.5 (‘t’, J 156.6), 45.5 (‘d’, J 149.7), 39.9 (‘d’, J 177.6), 39.2
(‘d’, J 186.6), 36.7 (‘d’, J 148.5), 34.1 (‘t’, J 133.0) and 28.8 (‘t’,
J 135.7); m/z 231 (Mϩ, 7.9%), 202 (M Ϫ 29, 5.6), 153 (9.5), 111
(100), 104 (11.5), 91 (7.6), 83 (10.4), 77 (6.4), 70 (7.4), 53 (6.8),
45 (14.0) and 39 (47.5); Found: C, 67.5; H, 5.7; N, 6.1; S, 13.9.
C13H13NOS requires C, 67.5; H, 5.7; N, 6.1; S, 13.9%.
(Selenophen-2-yl)(pyrrolidino)methanone 4a. (85%), Mp 64–
66 ЊC; νmax/cmϪ1 2969, 2871, 1592 (CO), 1437 and 707; δH (200
MHz; CDCl3) 8.20 (1H, q, J 1.1 and 5.6, H-5), 7.73 (1H, q, J 1.1
and 4.0, H-3), 7.35 (1H, q, J 4.0 and 5.6, H-4), 3.74 (4H, bs,
H-α) and 1.99 (4H, bs, H-β); δC (50.3 MHz; CDCl3) 163.9,
139.4, 136.4 (d, J 186.5), 132.1 (d, J 166.1), 130.3 (d, J 167.5),
49.7 (t, J 143.4), 48.1 (t, J 143.4), 27.0 (t, J 133.3) and 24.5 (t,
J 133.3); m/z 229 (Mϩ, 45.0%), 159 (M Ϫ 70, 100), 131 (13.0),
70 (11.7), 56 (14.2) and 39 (46.6); Found: Mϩ, 229.0006.
C9H11NOSe requires M, 229.0006.
(5-Methyl-2-thienyl)(6-methylene-3-azatricyclo[3.2.1.02,4]-
octan-3-yl)methanones 3b. (75%), Oil; νmax/cmϪ1 2967, 2921,
1646 (CO), 1457, 1260, 884 and 702; δH (300 MHz; CDCl3) 7.55
(1H, d, J 3.7, H-3), 6.75 (1H, dq, J 1.0 and 3.7, H-4), 5.01 (1H,
s), 4.79 (1H, s), 3.03 (1H, s), 2.93 (1H, d, J 5.2), 2.84 (1H, d,
J 5.2), 2.69 (1H, bs), 2.51 (3H, s, J 1.0), 2.18 (1H, ‘d’, J 15.6),
1.97 (1H, ‘d’, J 15.6), 1.60 (1H, ‘d’, J 10.3) and 1.05 (1H, ‘d’,
J 10.3); δC (75.4 MHz; CDCl3) 170.7, 149.3, 147.2, 135.6, 135.1,
132.0 (J 168.0), 126.3 (J 156.8), 106.4 (‘t’, J 155.5), 45.5
(J 149.2), 39.7 (J 181.8), 39.1 (J 195.0), 36.7 (J 145.5), 34.1 (‘t’,
J 131.3), 28.8 (‘t’, J 139.2) and 15.8 (q, J 129.2); m/z 245 (Mϩ,
5.1%), 216 (M Ϫ 29, 9.4), 125 (100), 111 (7.9), 104 (9.0), 96
(5.9), 91 (2.9), 84 (3.4), 77 (13.6), 69 (6.2), 66 (7.4), 53 (28.4) and
39 (17.0); Found: C, 68.6; H, 6.1; S, 13.0. C14H15NOS requires
C, 68.5; H, 6.2; S, 13.1.
(Pyrrolidino)(thieno[3,2-b]thiophen-2-yl)methanone
5a.
(85%), Mp 114–16 ЊC; νmax/cmϪ1 3085, 2971, 2876, 1595 (CO),
1457, 1231 and 713; δH (200 MHz; CDCl3) 7.73 (1H, s, H-3),
7.51 (1H, d, J 5.4, H-5), 7.27 (1H, d, J 5.4, H-6), 3.78 (4H, bs,
H-α) and 1.99 (4H, bs, H-β); δC (50.3 MHz; CDCl3) 162.7,
142.5, 133.9, 132.6, 130.8 (d, J 186.5), 122.7 (d, J 172.0), 120.1
(d, J 174.0), 49.6 (t, J 143.5), 48.4 (t, J 143.5), 27.2 (t, J 134.0)
and 24.5 (t, J 134.0); m/z 237 (Mϩ, 58.1%), 167 (M Ϫ 70, 100),
139 (20.0), 95 (11.1) and 70 (4.8); Found: Mϩ, 237.0282.
C11H11NOS2 requires M, 237.0282.
Methyl 1H-1,2,3-triazole-4-carboxylate 6. (90%), Mp 143–45
ЊC (lit.,14 145 ЊC); νmax/cmϪ1 3137, 2941, 1732 (CO) and 778;
δH (200 MHz; acetone-D6) 8.34 (1H, s, H-5), 3.88 (3H, s, Me);
δC (50.3 MHz; acetone-D6) 162.2, 137.3, 133.5 (d, J 197.2) and
52.5 (q, J 147.4); m/z 127 (Mϩ, 10.9%), 96 (M Ϫ OMe, 100),
68 (13.9), 59 (10.2) and 40 (36.0); Found: Mϩ, 127.0382.
C4H5N3O2 requires M, 127.0382.
(Selenophen-2-yl)(6-methylene-3-azatricyclo[3.2.1.02,4]octan-
3-yl)methanones 4b. (73%), Oil; νmax/cmϪ1 3065, 2975, 1645
(CO), 1427, 1298, 886 and 700; δH (200 MHz; CDCl3) 8.24 (1H,
q, J 1.1 and 5.5, H-5), 7.94 (1H, q, J 1.1 and 3.9, H-3), 6.51 (1H,
q, J 3.9 and 5.5, H-4), 4.98 (1H, s), 4.78 (1H, s), 3.03 (1H, s),
2.96 (1H, d, J 5.3), 2.87 (1H, d, J 5.3), 2.69 (1H, s), 2.21 (1H,
‘d’, J 15.7), 1.96 (1H, ‘d’, J 15.7), 1.60 (1H, ‘d’, J 10.3) and 1.07
(1H, ‘d’, J 10.3); δC (50.3 MHz; CDCl3) 171.8, 148.9, 137.5 (‘d’,
J 186.7), 136.5, 133.6 (‘d’, J 166.8), 130.2 (‘d’, J 167.0), 106.4
(‘t’, J 157.3), 45.3 (‘d’, J 148.7), 39.9 (‘d’, J 181.1), 39.2 (‘d’,
J 185.2), 36.6 (‘d’, J 148.9), 33.9 (‘t’, J 131.3) and 28.6 (‘t’,
J 137.9); m/z 279 (Mϩ, 12.3%), 250 (M Ϫ 29, 3.6), 159 (100), 131
(10.8), 104 (32.8), 91 (15.0), 78 (12.4), 77 (28.0), 65 (14.1), 53
(19.5), 41 (18.1) and 39 (80.6); Found: Mϩ, 279.0162.
C13H13NOSe requires M, 279.0162.
Reactions of heteroaroyl azides 1–5 with 5-methylenebicyclo-
[2.2.1]hept-2-ene at 25 ؇C. General procedure
A solution (2 × 10Ϫ3 : 2 × 10Ϫ3 mol; exact molar ratio in 1.0 cm3
of CDCl3) of a heteroaroyl azide (1, 0.274; 2, 0.306; 3, 0.334; 4,
0.400; 5, 0.418 g) and 5-methylenebicyclo[2.2.1]hept-2-ene
(0.212 g) was allowed to react in a screw-cap tube for the
appropriate time (17–25 days). Over time, small aliquots of the
1
solutions were analysed by H-NMR spectroscopy, showing in
all cases the decrease of the starting azide and the formation of
a fundamental product. After the appropriate time the solution
was concentrated by elimination of the solvent under vacuum,
and the oily residue was purified, under medium nitrogen
pressure, on a ‘Florisil’ column using dry hexane with
increasing amounts of diethyl ether (up to 100%) as eluent. The
following (2-heteroaryl)(6-methylene-3-azatricyclo[3.2.1.02,4]-
octan-3-yl)methanones 1b–5b were characterized by 1H-NMR,
13C-NMR, IR and high-resolution mass spectroscopy.
(6-Methylene-3-azatricyclo[3.2.1.02,4]octan-3-yl)(thieno-
[3,2-b]thiophen-2-yl)methanone 5b. (85%), Resinous, dark
compound; νmax/cmϪ1 3083, 2978, 1647 (CO), 1501, 1363, 1333,
885 and 712; δH (200 MHz; CDCl3) 7.91 (1H, s, H-3), 7.56 (1H,
d, J 5.3, H-5), 6.51 (1H, d, J 5.3, H-6), 5.00 (1H, s), 4.79 (1H, s),
3.08 (1H, s), 3.01 (1H, d, J 5.5), 2.92 (1H, d, J 5.5), 2.73 (1H, s),
2.21 (1H, ‘d’, J 15.8), 1.98 (1H, ‘d’, J 15.8), 1.61 (1H, ‘d’, J 10.3)
and 1.09 (1H, ‘d’, J 10.3); δC (50.3 MHz; CDCl3) 171.0, 149.0,
140.0, 136.5, 134.3, 131.5 (‘d’, J 186.5), 123.7 (d, J 172.3), 119.7
(‘d’, J 174.2), 106.5 (‘t’, J 156.7), 45.4 (‘d’, J 146.9), 40.0 (‘d’,
J 180.4), 39.4 (‘d’, J 185.0), 36.7 (‘d’, J 150.8), 34.0 (‘t’, J 129.7)
and 28.7 (‘t’, J 137.7); m/z 287 (Mϩ, 11.3%), 258 (M Ϫ 29, 6.0),
167 (100), 139 (14.7), 104 (8.9), 95 (6.0), 93 (6.3), 79 (11.8), 77
(10.0), 69 (6.6), 53 (5.5) and 39 (7.8); Found: Mϩ, 287.0439.
C15H13NOS2 requires M, 287.0439.
(2-Furyl)(6-methylene-3-azatricyclo[3.2.1.02,4]octan-3-yl)-
methanones 1b. (75%), Oil; νmax/cmϪ1 3098, 2978, 1663 (CO),
1319, 1167, 884 and 762; δH (200 MHz; CDCl3) 7.55 (1H, q,
J 0.9 and 1.7, H-5), 7.13 (1H, q, J 0.9 and 3.5, H-3), 6.51 (1H, q,
J 1.7 and 3.5, H-4), 5.01 (1H, s), 4.79 (1H, s), 3.06 (1H, s), 2.96
(1H, d, J 5.3), 2.87 (1H, d, J 5.3), 2.72 (1H, s), 2.21 (1H, ‘d’,
J 15.8), 1.98 (1H, ‘d’, J 15.8), 1.58 (1H, ‘d’, J 10.3) and 1.07
(1H, ‘d’, J 10.3); δC (50.3 MHz; CDCl3) 167.0, 149.6, 148.6,
145.9 (‘d’, J 203.7), 116.7 (‘d’, J 179.2), 112.2 (‘d’, J 177.3),
106.9 (‘t’, J 157.5), 45.8 (‘d’, J 149.2), 39.7 (‘d’, J 182.2), 39.0
(‘d’, J 188.3), 37.2 (‘d’, J 150.5), 34.5 (‘t’, J 130.3) and 29.2 (‘t’,
J 135.8); m/z 215 (Mϩ, 13.9%), 186 (M Ϫ 29, 7.6), 104 (59.5), 95
(100), 91 (16.9), 84 (10.4), 77 (14.6), 65 (6.6), 53 (7.3) and 39
(42.7); Found: Mϩ, 215.0945. C13H13NO2 requires M, 215.0946.
Acknowledgements
We gratefully acknowledge the financial support of the
Ministero dell’Università e della Ricerca Scientifica e Tecno-
logica (MURST) and partial support from the ‘Progetto di
Finanziamento Triennale, Ateneo di Bologna.’
1424
J. Chem. Soc., Perkin Trans. 1, 2002, 1420–1425

View Article Online
11 G. Broggini, L. Garanti, G. Molteni and G. Zecchi, J. Chem. Res.
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9 Test carried out by the TAACF-NIAID/Southern Research
Institute, Colorado State University. E-mail: taacf1@sri.org.
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J. Chem. Soc., Perkin Trans. 1, 2002, 1420–1425
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