endolexo Facial selectivities in cycloaddition reactions of substituted 1,2,3-triazolium-1-methanides, unstabilised 1,3-dipoles, with some alkene dipolarophiles: Models for 1,2,3-triazolium-1-aminides: New tetracyclic pyrrolo[1,2-c][1,2,3]benzotriazole structures: Azolium 1,3-dipoles

Article abstract of DOI:10.1039/b103759p

endolexo Stereochemistry in the cycloaddition reactions of substituted 1,2,3-triazolium-1-aminide and 1,2,3-triazolium-1-methanide 1,3-dipoles has been explored for the dipolarophiles acrylonitrile and N-substituted maleimides. The cycloadditions with acrylonitrile displayed predominant endo-geometry but gave mixtures of endo- and exo-isomers. In contrast N-substituted maleimides gave almost exclusive exo-cycloadducts. The cycloaddition products are novel tri- and tetracyclic structures. Factors affecting endolexo selectivities are discussed for these systems. Generalisations are not reliable and each 1,3-dipole-dipolarophile pair needs to be carefully considered.

Full text of DOI:10.1039/b103759p

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endo/exo Facial selectivities in cycloaddition reactions of
substituted 1,2,3-triazolium-1-methanides, unstabilised 1,3-dipoles,
with some alkene dipolarophiles: models for 1,2,3-triazolium-
1-aminides: new tetracyclic pyrrolo[1,2-c][1,2,3]benzotriazole
structures: azolium 1,3-dipoles
1
R. N. Butler* and Leonie M. Wallace
Chemistry Department, National University of Ireland, Galway, Ireland
Received (in Cambridge, UK) 25th April 2001, Accepted 14th June 2001
First published as an Advance Article on the web 12th July 2001
endo/exo Stereochemistry in the cycloaddition reactions of substituted 1,2,3-triazolium-1-aminide and 1,2,3-
triazolium-1-methanide 1,3-dipoles has been explored for the dipolarophiles acrylonitrile and N-substituted
maleimides. The cycloadditions with acrylonitrile displayed predominant endo-geometry but gave mixtures
of endo- and exo-isomers. In contrast N-substituted maleimides gave almost exclusive exo-cycloadducts. The
cycloaddition products are novel tri- and tetracyclic structures. Factors affecting endo/exo selectivities are
discussed for these systems. Generalisations are not reliable and each 1,3-dipole–dipolarophile pair needs
to be carefully considered.
Introduction
The cycloaddition–rearrangement reactions of substituted
1,2,3-triazolium-1-aminide 1,3-dipoles 1 have wide synthetic
potential.1 They represent a part of the wider synthetic scope of
exocyclic azolium ylide 1,3-dipoles in general.1–4 Such reactions
are often characterized by rapid in situ rearrangements of the
immediately formed cycloadduct such that the steric features of
the initial cycloaddition may be lost in the subsequent steps.5
The general reaction as outlined in Scheme 1 illustrates the
difficulty where the rearrangement involves a 1,4-sigmatropic
shift (the 4 π-electrons being delocalised over 3 atoms as against
4 atoms for the more common 1,5-shift) and the facial selectiv-
ity of the dipolarophile substituents in the initial cycloadduct
is reversed in the final product (since endo-groups change to
exo- and vice versa during the sigmatropic rearrangement).
While many such reactions have been studied1 the endo/exo†
selectivity of the initial cycloaddition can only be inferred and
in many cases is not established. For example for the case
of compound 18 (Scheme 1) an X-ray crystal structure6,7 on
the final multiple fused ring system confirmed the CN in the
exo-position thereby indicating an initial endo-cycloaddition.
Recently we have found8 that the cycloadducts from the
unstabilized methanide dipole 4a (R = Ph) with reactive alkyne
dipolarophiles did not rearrange in situ. However cycloaddition
reactions could not be achieved with less reactive alkene
dipolarophiles with the dipole 4 (R = Ph) because the 1,3-
dipoles underwent ring-opening and ring-closure (RORC) to
products such as 6 and 20 (R = Ph) too rapidly. Hence the endo/
exo character of the initial cycloaddition could not be probed.
We have now found that the RORC process for the dipoles 4
and 5 with alkyl substituents on the triazole is slower and it is
possible to observe competitive cycloadditions but the RORC
process is however still dominant. Careful work-up and separ-
ation of the small quantities of cycloadducts have allowed
† The terms endo and exo refer to the 5,5-ring skeleton structures of
the fused pyrrolo[1,2-c][1,2,3]triazole (Scheme 2), and the pyrrolo-
[2,3-d][1,2,3]triazole and intermediate pyrazolo[2,3-c][1,2,3]triazole
(Scheme 1).
Scheme 1 Reagents: (i) N-substituted maleimides; (ii) acrylonitrile.
1
Some key H, 13C NMR shifts, ranges shown: 3; HA, 3.63–3.95 ppm;
HB, 4.67–5.19 ppm; 7-CH2, 2.20–2.40 ppm.
1778
J. Chem. Soc., Perkin Trans. 1, 2001, 1778–1784
DOI: 10.1039/b103759p
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Scheme 2 Reagents: (i) N-substituted maleimides; (ii) acrylonitrile.
us, for the first time, to determine the endo/exo selectivity of
the substituted 1-aminoimidazoles 6 and 7 with traces of the
the cycloadditions of the 1,2,3-triazolium-1-methanide 1,3-
dipoles 4 and 5 with the alkene dipolarophiles, N-substituted
maleimides and acrylonitrile. The results also provide a guide
for the reactions of 1,2,3-triazolium-1-aminide 1,3-dipoles 1
since these parallel the methanides. The results suggest that the
1,3-dipoles 1 should react with N-substituted maleimides to
give an initial unstable exo-cycloadduct 2B. The stable cyclo-
adducts 8–13 are models for this unstable cycloadduct 2B and
the exo geometry for the dicarboximido group in 2B infers an
endo-geometry for the rearranged series 3. This has now been
confirmed. The endo/exo selectivity in these systems needs to
be considered individually for each dipolarophile. We have
discussed the ring expansion (RORC) behaviour of azolium
methanides in depth previously9–11 and it is not considered
further here.
triazines 20 and 21. The compounds 8–13 are the first cyclo-
adducts from dipoles of type 4 and 5 with alkene dipolarophiles
and they are stable carbon analogues of the intermediates 2B
from the aminide dipoles 1 (Scheme 1). The structures and
stereochemistry of the products 3 and 8–13 were established
from microanalyses, proton and carbon-13 NMR spectra
which showed all of the expected signals and multiplicities.
Proton NMR assignments were confirmed by COSY and spin-
decoupled spectra and carbon-13 assignments were supported
by DEPT and off-resonance decoupled spectra. The endo-
stereochemistry of the series 3 was established by clear two-way
NOE enhancements from 6-HA to the bridging cyclohexane
7-CH2 methylene group (Scheme 1) (Fig. 1). The endo-geometry
of the N-substituted dicarboximido group in the series of struc-
tures 3a–3e means the initial cycloaddition to give 2B occurred
in the exo-manner. This cycloaddition–rearrangement reaction
also occurred with the parent N-unsubstituted maleimide
giving the product 3c (Table 1, entry 3). Separate methylation
of this gave compound 3d identical to that obtained from the
cycloaddition of 1 with N-methylmaleimide (Table 1, entry 4).
The exo-stereo orientation of the products 8–13 was also
established from NOE difference spectra. The four atoms
labeled HA, HB, Hexo and Hendo stood out in the spectra and were
readily assigned. For the series the Hexo atom appeared at 3.8–
4.1 δ but its geminal partner Hendo was not deshielded by the
dicarboxyimido group and appeared at 2.85–3.4 δ. This geminal
pair showed the expected J value of 11–13 Hz and intense NOE
enhancements. The shift ranges for HA, 3.0–3.6 δ, and HB 3.1–
Results and discussion
(i) N-Substituted maleimides
Somewhat unexpectedly the cycloadditions of maleimides with
the dipoles 1 in acetone and 4 and 5 in dichloromethane gave
cycloadducts with exo-stereochemistry. The cycloadducts 2B
(Scheme 1) were unstable and rearranged in situ to the products
3 where the N-substituted-dicarboxyimido group is now endo
to the fused 5,5-ring system. The cycloadducts from the 1,2,3-
triazolium-1-methanide dipoles 4 and 5 (Scheme 2) were the
stable exo-products 8–13. These were always accompanied by
J. Chem. Soc., Perkin Trans. 1, 2001, 1778–1784
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Table 1 Products
Entry
Compound
Mp/ЊC
Yield(%)
Compounde
Yield(%)
(i) From aminide 1,3-dipole 1
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
18
19
224–225a
255–257a
173–174b
193–194a
191–192c
173–174a
Gum
86d
90
78
—
—
—
—
—
—
—
—
—
—
—
—
—
—
90
66d
79
10
(ii) From methanide 1,3-dipoles 4, 5
8
9
8a
9a
153–154c
172–174c
177–179c
171–173c
Gum
19
20
17
29
17d
20
21d
22
11
30
8
6a
7a
7b
7c
6a
7a
6a
7a
7b
7c
7a
—
6a
—
75
57
76
55
58
69
65
73
65
65
70
—
80
—
10
11
12
13
14
15
16
17
18
9b
9c
10a
11a
12a
13a
13b
13c
16a
17a
14a
15a
133–136c
133–135c
132–133c
133–134c
Gum
127–129c
100–102c
Gum
5
10
5
19
Gum
a From ethanol. b From methanol.c From hexane : CH2Cl2. d Small quantities of intractable resins were encountered. e Ref. 9–11 and 22.
Dreiding molecular models gave distances from HA to the trans
C-atom bonded to C-3a of greater than 3.3 Å while the distance
from HA underneath the 5,5-ring to the C-atom bonded to the
planar C-3 was ca. 2.7 Å. For compounds 8, 10 and 12 NOE
effects from HA to the 3-C-Me group were readily observed in
both directions (Fig. 1). Similarly for compounds 9, 11 and 13
NOE effects in both directions were observed from HA to the
7-CH2 group in the cyclohexyl envelope.
These results show unequivocally that the cycloaddition has a
predominantly exo-orientation. Where both isomers were
encountered they were stable under the reaction conditions and
no interconversions occurred. The NOE effects from HA to the
substituents at C-3 and C-6a beneath the buckled fused 5,5-ring
also point to the reason for the exo-cycloaddition.
(ii) Acrylonitrile
We have previously reported6,7 the synthesis and X-ray crystal
structure of compound 18 (Scheme 1) from the reaction of the
dipole 1 with acrylonitrile. In this compound the CN group is in
the exo-position and there was no NOE from HA to the fused
benzo 7-CH2 group bonded at the C-6a bridgehead. In this
present work we have also isolated for the first time a small
quantity of the endo-isomer 19 in crude form and proton NMR
spectra of this compound showed an NOE from HA to the
bridgehead 7-CH2 as expected (Fig. 1). The agreement between
the NOE effects and the X-ray crystal structure of compound
18 is important. The fact that the isomer 18 is the major
product means that in the initial cycloaddition to the adduct 2A
(Scheme 1) the endo transition state is favoured in contrast to
the maleimide dipolarophiles. Hence it was expected, and
observed, that the endo-isomers 14 and 16 (Scheme 2) would be
the major products from the reactions of the dipoles 4 and
5 with acrylonitrile (Table 1, entries 18 and 19). Because of
competition from the RORC process via the intermediate 4A,
which we have discussed previously,9–11 only small quantities
of the compounds 14–17 were available. Nevertheless pure
samples of the major isomers were obtained by a work-up
which sacrificed the minor isomer and the NMR spectral
signals of the minor isomers were then obtained from spectra
of the mixtures. The more simple methyl derivatives 14 and
15 were again used as guides for the analysis of the NMR
spectra of the tricyclic substituted 2,3,7,8,9,10-hexahydro-
Fig. 1 Examples of key NOE effects (%) and some proton chemical
shifts.
3.65 δ were close and sometimes overlapped but they could
be readily assigned from COSY and single proton decoupled
spectra. The vicinal pair HA and HB showed expected J values
of 8–9 Hz and strong NOE enhancements. (Fig. 1). The com-
pounds 8, 10 and 12 were prepared as more simple analogues of
the tetracyclic structures 9, 11 and 13 and the strong signals of
the methyl groups at C-3 (2.15–2.20 δ) and C-3a (1.14–1.25 δ)
were particularly useful for NOE analyses. The results obtained
for the methyl derivatives 8, 10 and 12 were fully paralleled with
the more complicated spectra of the tetracyclic structures 9, 11,
13. For all of these compounds strong NOE effects were
observed, as expected between the geminal exo/endo proton
pairs at C-3 and C-6, between HB and 3- and 6-Hendo and
between the vicinal pair HA and HB (Fig. 1). There was no NOE
between HA and the trans CH3 or CH2 groups at the C-3a and
C-10a bridgeheads.
Computed structures using the NEMESIS programme and
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C-6a in the developing fused 5,5-ring system. Preliminary
results21 on a 1,3,4-thiadiazolium analogue of the dipole 4,
where the atom corresponding to C-3 in structures 8, 10 and 12
is a sulfur and the substituent is now moved one bond further
away from the bridgehead thereby removing the steric effect,
have shown endo-cycloadditions with N-substituted male-
imides. With acrylonitrile as dipolarophile the steric effect is
reduced and both stereoisomers are formed with a preference
for the endo-form possibly arising from the dipolar interaction
mentioned. The results show that generalizations of expected
endo- or exo-preferences with these systems would be unreliable
and each dipole–dipolarophile pair needs careful consideration.
Fig. 2 Proximity of substituents at C-1 and C-3a (6a) as planar
carbons change to tetrahedral in the transition state.
1H,5H-pyrrolo[1,2-c][1,2,3]benzotriazole derivatives 16 and 17.
The exclusive regiochemistry of these products is that
expected12 from a dipoleHOMO–dipolarophileLUMO interaction13
where the unsubstituted methanide terminus of the dipole
bonds to the unsubstituted terminus of the acrylonitrile. The
C-13 and proton NMR spectra confirmed this with the
expected multiplicities of the off-resonance decoupled carbon
signals for carbons 3, 3a and 4 (compounds 14, 15) and carbons
6a, 10a and 1 (compounds 16 and 17). In the proton spectra HA
was a doublet of doublets at 2.95 δ and gave NOE effects with
the adjacent cis Me group at C-3a for compound 14 and with
the 10-CH2 group for compound 16.
Experimental
Mps were measured on an Electrothermal apparatus. IR
spectra were measured with a Perkin-Elmer Spectrum 1000
FT-IR spectrometer. NMR spectra were measured on a JEOL
LAMBDA 400 MHz instrument with tetramethylsilane as an
internal reference and deuteriochloroform or hexadeuterio-
dimethyl sulfoxide or tetradeuteriomethanol as solvents.
J Values are given in Hz. The terms Jgem and Jvic refer to geminal
and vicinal proton pairs respectively. All carbon-13 NMR
assignments were supported by DEPT. Microanalyses were
measured on a Perkin-Elmer model 240 CHN analyser. The
substrate 1 was prepared as previously described1,6 and the
dipoles 4 and 5 were generated in situ from the corresponding
1-trimethylsilylmethyl-2,4,5-trisubstituted-1,2,3-triazolium tri-
fluoromethanesulfonate salts by methods previously
described8,22,23 using a literature24,25 process with CsF. The
required trisubstituted-1,2,3-triazoles were obtained by
deamination of the corresponding triazolium aminide
compounds 1, and/or the corresponding N-oxides, with PCl3 as
previously described.9,26 The following are a selection of typical
examples.
Conclusion
The results illustrate that minor kinetic effects have large influ-
ences on the stereochemical outcome of these cycloadditions.
The products once formed are stable and do not interconvert
or revert to starting materials. For acrylonitrile, which favours
the endo-isomer, the mixtures of both isomers encountered
indicates a difference in the energy between both transition
states14 of less than 1 kcalϪ1. It has been traditional to ascribe
preferred endo-cycloadditions to secondary orbital interactions
in the transition state.15,16 In the present cases, which involve
primary orbital interactions between the dipoleHOMO and
dipolarophileLUMO, favourable secondary orbital interactions
are indeed available for maleimides and acrylonitrile.13 Azo-
methine ylides derived from prototropy in α-amino acids, with
stabilised methanide termini, gave endo cycloadditions with
maleimides17 while those from N-(pyridin-2-yl)imines gave
almost equal mixtures of endo- and exo-isomers18 in reactions
where secondary orbital interactions favoured the endo-
transition state. The importance of normal polar effects in
the endo-phenomenon has recently been emphasized.14 In the
present reactions a polar interaction could arise through a
dipole moment alignment so that electron-withdrawing
substituents (δϪ) on the alkene would lie under the positive
terminus (the triazolium ring) of the 1,3-dipole and hence
favour an endo-transition state. Grigg19,20 highlighted the
importance of the subtle interplay of steric and electronic
effects in the endo-selectivity of cycloadditions with the
additional factor that 1,3-dipolar cycloadditions will involve
significant dipole moments of the substrates entering the
transition state20 and hence dipole alignments may occur to
reduce the dipole moment of the transition state. The exo-
cycloadditions observed here must be considered in the light
of all of these factors. A key structural feature of the 1,3-
dipoles herein is the substituent-bearing carbon (C-3 and C-6a,
Scheme 2) bonded to the α-carbon of the dipole. Models show
that this substituent at C-3 and C-6a provides a significant
steric effect with substituents on the incoming dipolarophile.
This is experimentally confirmed by the NOE effect from this
substituent to HA in the final exo-product (Fig. 1, structure
12a). If the endo isomer were to form from the N-substituted
maleimides the steric interaction from this C-3 and C-6a sub-
stituent to the larger –CO-N(R)-CO-unit should be sig-
nificantly greater (Fig. 2). Hence we believe that the almost
the exclusive exo-cycloadditions observed herein with the male-
imides are due to a steric effect from the substituents at C-3 and
N,2,4-Triphenyl-3a,6a-tetramethylene-3,3a,4,5,6,6a-hexahydro-
pyrrolo[2,3-d][1,2,3]triazole-endo-5,6-dicarboximide (or endo-
N,8,10-triphenyl-7,8,9,10-tetraazatricyclo[4.3.3.01,6]dodec-7-
ene-11,12-dicarboximide) (3a) (Table 1, entry 1)
A solution of compound 1 (0.29 g, 1 mmol) in dry acetone (10
cm3) was treated with N-phenylmaleimide (0.18 g, 1.04 mmol),
and stirred under reflux for 4 h and the solvent evaporated
under reduced pressure. The residue in CH2Cl2 (3 cm3) was
placed on a silica gel-60 column (230–400 mesh ASTM) and
eluted with a gradient mixture (1 : 0–0 : 1 v/v) of petroleum
spirit (bp 40–60 ЊC)–CH2Cl2 to give 3a (0.4 g, 86%), mp
224–225 ЊC (from EtOH or hexane–CH2Cl2) (Found: C, 72.5;
H, 5.5; N, 14.7. C28H25N5O2 requires C, 72.5; H, 5.4; N, 15.1%);
νmax(mull)/cmϪ1 1718, 1780 (C᎐O); δH (CDCl3) 1.26–1.54, 1.81–
᎐
1.92, 2.29–2.33, 2.54–2.59 (8H, m’s, (CH2)4), 3.86 (1H, d, J 8.8,
6-HA), 4.90 (1H, d, 5-HB), 6.9–6.93 (1H, m, aromatic), 7.24–
7.63 (12H, m, aromatic), 8.08 (2H, d, J 7.7, 2-Ph, 2Ј-H);
δC (CDCl3) 19.6, 21.0, 27.9, 30.0 (CH2)4, 52.2 (C-6), 61.0 (C-5),
79.3 (C-6a), 94.5 (C-3a), 118.6, 120.4, 122.8, 126.1, 128.7, 128.9,
131.7 (C, aromatic), 140.6, 143.5 (2-Ph, 4-Ph, both C-1Ј), 172.7,
174.4 (C᎐O). Intractable resins were also eluted.
᎐
N-(4Ј-Bromophenyl)-2,4-diphenyl-3a,6a-tetramethylene-3,3a,4,-
5,6,6a-hexahydropyrrolo[2,3-d][1,2,3]triazole-endo-5,6-dicarb-
oximide (3b) (Table 1, entry 2)
A solution of compound 1 (0.29 g, 1 mmol) in dry acetone (10
cm3) was treated with N-(4-bromophenyl)maleimide (0.25 g, 1
mmol), stirred under reflux for 3 h and cooled to give 3b (0.49 g,
90%), mp 255–257 ЊC (from EtOH) (Found: C, 62.2; H, 4.4;
N, 12.7. C28H24N5O2Br requires C, 62.0; H, 4.5; N, 12.9%);
νmax (mull)/cmϪ1 1725, 1785 (C᎐O); δ ([2H6]DMSO at 90 ЊC)
᎐
H
1.16–1.60, 2.24–2.28, 2.68–2.72 (8H, m’s, (CH2)4), 3.95 (1H, d,
J 8.6, 6-HA), 5.19 (1H, d, 5-HB), 6.75–6.79 (1H, m, aromatic),
J. Chem. Soc., Perkin Trans. 1, 2001, 1778–1784
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7.18–7.74 (11H, m, aromatic), 8.00 (2H, d, J 7.7, 2-Ph, 2Ј-H);
δC ([2H6]DMSO at 90 ЊC) 19.2, 19.3, 27.7, 29.0 (CH2)4, 51.7
(C-6), 60.1 (C-5), 79.0 (C-6a), 93.6 (C-3a), 116.9, 118.8, 122.3,
128.4, 128.6, 128.9, 129.3, 131.0, 132.2 (C, aromatic), 139.9,
exo-6-Cyano-2,4-diphenyl-3a,6a-tetramethylene-3,3a,4,5,6,6a-
hexahydropyrrolo[2,3-d][1,2,3]triazole (18) and its stereoisomer
(19) (Table 1, entry 6 and 7)
A solution of compound 1 (0.29 g, 1 mmol) in dry acetone
(10 cm3) was treated with acrylonitrile (0.7 cm3, 10 mmol),
stirred under reflux for 5 h and the solvent evaporated under
reduced pressure. The residue in CH2Cl2 (3 cm3) was placed
on a silica gel-60 column (230–400 mesh ASTM) and eluted
with a gradient mixture (1 : 0 to 0 : 1 v/v) of petroleum spirit
(bp 40–60 ЊC)–CH2Cl2. First eluted off the column was 18 (0.27
g, 79%) followed by 19 (0.034 g, 10%), a gum, which was
recolumned.
143.3 (2-Ph, 4-Ph, both C-1Ј), 172.7, 174.8 (C᎐O).
᎐
2,4-Diphenyl-3a,6a-tetramethylene-3,3a,4,5,6,6a-hexahydro-
pyrrolo[2,3-d][1,2,3]triazole-endo-5,6-dicarboximide (3c) (Table
1, entry 3)
A solution of compound 1 (0.29 g, 1 mmol) in dry acetone
(10 cm3) was treated with maleimide (0.1 g, 1.03 mmol), stirred
under reflux for 24 h and the solvent evaporated under reduced
pressure. The residue in CH2Cl2 (3 cm3) was placed on a silica
gel-60 column (230–400 mesh ASTM) and eluted with a grad-
ient mixture (1 : 0–0 : 1 v/v) of petroleum spirit (bp 40–60 ЊC)–
CH2Cl2 to give 3c (0.31 g, 78%), mp 173–174 ЊC (from MeOH)
(Found: C, 68.3; H, 5.4; N, 18.0. C22H21N5O2 requires C, 68.2;
18: mp 173–174 ЊC (from EtOH), lit.,6 mp 175 ЊC, spectra
previously reported;6 δH (CDCl3) 3.38–3.40 (1H, dd, J 8.0, <1,
6-HA, no NOE to 7-CH2).
19: (crude sample), gum: νmax (mull)/cmϪ1 2238 (C᎐N); δ
᎐
᎐
H
(CDCl3) 1.26–2.88 (8H, m, (CH2)4), 3.48–3.55 (2H, m, 5-Hendo
and 6-HA, NOE to 7-CH2, 1.3%), 3.74–3.79 (1H, dd, Jgem 11.7,
Jvic 8.0, 5-Hexo), 6.82–6.86 (1H, m, aromatic), 7.10–7.51 (7H, m,
aromatic), 8.10 (2H, d, J 7.7, 2-Ph, 2Ј-H); δC (CDCl3) 18.5, 19.8,
H, 5.5; N, 18.1%); νmax(mull)/cmϪ1 1718, 1774 (C᎐O), 3235
᎐
(N–H); δH (CD3OD) 1.24–1.74, 2.29–2.34, 2.53–2.57 (8H, m’s,
(CH2)4), 3.74 (1H, d, J 8.4, 6-HA), 4.88 (1H, d, 5-HB), 6.82–6.85
(1H, m, aromatic), 7.18–7.55 (7H, m, aromatic), 7.96 (2H, d,
J 8.0, 2-Ph, 2Ј-H); δC (CD3OD) 20.9, 21.1, 29.3, 30.9 (CH2)4,
54.4 (C-6), 63.2 (C-5), 80.0 (C-6a), 95.6 (C-3a), 119.9, 121.1,
123.8, 129.5, 130.2, 133.0 (C, aromatic), 142.0, 145.0 (2-Ph,
28.6, 29.9 (CH2)4, 36.6 (C-6), 49.5 (C-5), 79.3 (C-6a), 91.7
᎐
(C-3a), 117.9 (C᎐N), 119.0, 122.5, 122.9, 128.8, 131.6 (C,
᎐
aromatic), 141.0, 143.7 (2-Ph, 4-Ph, both C-1Ј).
4-Ph, both C-1Ј), 176.9, 178.9 (C᎐O).
N,1-Diphenyl-3,3a-dimethyl-3a,4,5,6-tetrahydro-1H-pyrrolo-
᎐
[1,2-c][1,2,3]triazole-exo-4,5-dicarboximide (8a) (Table 1, entry
8)
N-Methyl-2,4-diphenyl-3a,6a-tetramethylene-3,3a,4,5,6,6a-
hexahydropyrrolo[2,3-d][1,2,3]triazole-endo-5,6-dicarboximide
(3d) (Table 1, entry 4)
A solution of 4,5-dimethyl-2-phenyl-2H-1,2,3-triazole (0.43 g,
2.5 mmol) in trimethylsilylmethyl trifluoromethanesulfonate
(0.75 cm3, 3.75 mmol) and dry CH2Cl2(1 cm3) was stirred at
100 ЊC under a reflux condenser for 5 h, cooled to ambient
temperature and the solid was dissolved in dry CH2Cl2 (20 cm3).
N-Phenylmaleimide (2.15 g, 12.4 mmol) followed by CsF (0.57
g, 3.75 mmol) were added to the mixture, which was stirred for
18 h at ambient temperature, followed by 7 h at 60 ЊC after
which it was filtered to remove insoluble salts. The solvent
was removed under reduced pressure and the residue in CH2Cl2
(3 cm3) was placed on a silica gel-60 column (230–400 mesh
ASTM) and eluted with a gradient mixture (1 : 0–0 : 1 v/v) of
petroleum spirit (bp 40–60 ЊC)–CH2Cl2, followed by elution
with increasing portions of Et2O in the eluent. The first product
eluted off the column was 8a (0.18 g, 19%), mp 153–154 ЊC
(from hexane–CH2Cl2) (Found: C, 69.5; H, 5.65; N, 15.4.
C21H20N4O2 requires C, 70.0; H, 5.6; N, 15.5%); νmax (mull)/
cmϪ1 1716, 1774 (C᎐O); δ (CDCl3) 1.25 (3H, s, CH3-C-3a),
A solution of compound 1 (0.29 g, 1 mmol) in dry acetone (10
cm3) was treated with N-methylmaleimide (0.12 g, 1.08 mmol),
stirred under reflux for 1 h and the solvent evaporated under
reduced pressure. The residue was crystallised from ethanol to
give 3d (0.36 g, 90%), mp 193–194 ЊC (from EtOH) (Found: C,
68.4; H, 6.0; N, 17.5. C23H23N5O2 requires C, 68.8; H, 5.8;
N, 17.4%); νmax(mull)/cmϪ1 1701, 1771 (C᎐O); δ (CDCl3)
1.10–1.72, 2.07–2.10, 2.46–2.49 (8H, m’s, (CH2)4), 2.94 (3H, s,
CH3), 3.67 (1H, d, J 8.8, 6-HA), 4.69 (1H, d, 5-HB), 6.80–6.84
(1H, m, aromatic), 7.18–7.51 (7H, m, aromatic), 7.96 (2H, d,
J 7.3, 2-Ph, H-2Ј); δC (CDCl3) 19.7, 20.0, 28.1, 29.9 (CH2)4, 24.7
(N–Me), 52.1 (C-6), 60.8 (C-5), 78.8 (C-6a), 94.4 (C-3a), 118.3,
120.2, 122.7, 128.7, 128.9, 131.6 (C, aromatic), 140.7, 143.5
᎐
H
(2-Ph, 4-Ph, both C-1Ј), 173.9, 175.5 (C᎐O). (Compound 3d
᎐
(58%) was also obtained on methylation of 3c with MeI and
NaOH in 95% EtOH.)
᎐
H
2.20 (3H, s, CH3-C-3), 2.98–3.02 (1H, dd, Jgem 11.2, Jvic 8.0,
6-Hendo), 3.46–3.50 (1H, m, 5-HB), 3.53–3.56 (1H, m, 4-HA,
slight overlap with 5-HB), 3.90 (1H, dd, Jgem 11.2, Jvic <1,
6-Hexo), 6.94–6.97 (1H, m, aromatic), 7.26–7.52 (9H, m,
aromatic); δC (CDCl3) 11.4 (CH3-C-3a), 20.0 (CH3-C-3), 44.1
(C-4), 49.0 (C-5), 54.8 (C-6), 80.8 (C-3a), 115.7, 121.8, 126.3,
128.8, 129.0, 129.3, 131.5 (C, aromatic), 146.5 (1-Ph, C-1Ј),
N-tert-Butyl-2,4-diphenyl-3a,6a-tetramethylene-3,3a,4,5,6,6a-
hexahydropyrrolo[2,3-d][1,2,3]triazole-endo-5,6-dicarboximide
(3e) (Table 1, entry 5)
A solution of compound 1 (0.29 g, 1 mmol) in dry acetone (10
cm3) was treated with N-tert-butylmaleimide (0.145 cm3, 1.00
mmol), stirred under reflux for 18 h and the solvent evaporated
under reduced pressure. The residue in CH2Cl2 (3 cm3) was
placed on a silica gel-60 column (230–400 mesh ASTM) and
eluted with a gradient mixture (1 : 0–0 : 1 v/v) of petroleum
spirit (bp 40–60 ЊC)–CH2Cl2 to give 3e (0.29 g, 66%),
mp 191–192 ЊC (from hexane–CH2Cl2) (Found: C, 70.3; H, 6.6;
N, 15.8. C26H29N5O2 requires C, 70.4; H, 6.6; N, 15.8%);
νmax (mull)/cmϪ1 1711, 1774 (C᎐O); δ (CDCl3) 1.25–1.76,
152.7 (C-3), 174.3, 176.5 (C᎐O). Intractable resins were also
᎐
eluted and when the column was washed with acetone, 20a
(trace) and 6a (0.35 g, 75%) were eluted.
N,5-Diphenyl-2,3,7,8,9,10-hexahydro-1H,5H-pyrrolo[1,2-c]-
[1,2,3]benzotriazole-exo-1,2-dicarboximide (9a) (Table 1,
entry 9)
᎐
H
2.30–2.33, 2.71–2.74 (8H, m’s, (CH2)4), 1.58 (9H, s, C(Me)3),
3.62 (1H, d, J 8.8, 6-HA), 4.67 (1H, d, 5-HB), 6.81–6.85
(1H, m, aromatic), 7.22–7.52 (7H, m, aromatic), 8.00 (2H,
d, J 7.7, 2-Ph, 2-H); δC (CDCl3) 19.8, 19.9, 29.8, 29.9
(CH2)4, 28.2 (Me of C(Me)3), 51.4 (C-6), 58.9 (C of
C(Me)3), 60.0 (C-5), 79.5 (C-6a), 93.6 (C-3a), 117.2, 119.3,
122.7, 128.6, 128.8, 131.6 (C, aromatic), 140.6, 143.5 (2-Ph,
A solution of 2-phenyl-4,5,6,7-tetrahydro-2H-1,2,3-benzotri-
azole (0.5 g, 2.5 mmol) in trimethylsilylmethyl trifluorometh-
anesulfonate (0.75 cm3, 3.75 mmol) and dry CH2Cl2 (1 cm3) was
stirred at 80 ЊC under a reflux condenser for 5 h, cooled to
ambient temperature, and the solid was dissolved in dry CH2Cl2
(20 cm3) and treated with N-phenylmaleimide (2.08 g, 12 mmol)
followed by CsF (0.57 g, 3.75 mmol). The mixture was stirred at
ambient temperature for 18 h, filtered to remove insoluble salts
and the solvent was evaporated under reduced pressure. The
4-Ph, both C-1Ј), 174.4, 176.6 (C᎐O). Intractable resins were
᎐
also eluted.
1782
J. Chem. Soc., Perkin Trans. 1, 2001, 1778–1784

View Article Online
residue in CH2Cl2 (3 cm3) was placed on a silica gel-60 column
(230–400 mesh ASTM) and eluted with a gradient mixture
(1 : 0–0 : 1 v/v) of petroleum spirit (bp 40–60 ЊC)–Et2O. The
first product eluted off the column was the starting material,
2-phenyl-4,5,6,7-tetrahydro-2H-1,2,3-benzotriazole (0.03 g,
6%), followed by 9a (0.19 g, 20%), mp 172–174 ЊC (from
hexane–CH2Cl2) (Found: C, 71.9; H, 5.7; N, 14.6. C23H22N4O2
requires C, 71.5; H, 5.7; N, 14.5%); νmax (mull)/cmϪ1 1706, 1774
(N–Me), 48.1 (C-2), 54.1 (C-3), 56.5 (C-1), 81.0 (C-10a), 146.2,
122.1, 131.8, 117.9 (5-Ar, C-1Ј, C-2Ј, C-3Ј, C-4Ј), 155.8 (C-6a),
176.1, 178.0 (C᎐O). Also eluted off the column with acetone
᎐
were 21b (trace) and 7b (0.34 g, 65%).
endo-1-Cyano-5-phenyl-2,3,7,8,9,10-hexahydro-1H,5H-pyrrolo-
[1,2-c][1,2,3]benzotriazole (16a) and its stereoisomer (17a)
(Table 1, entry 18)
(C᎐O); δ (CDCl3) 1.53–2.06, 2.60–2.74 (8H, m’s, (CH2)4),
᎐
H
A solution of 2-phenyl-4,5,6,7-tetrahydro-2H-1,2,3-benzotri-
azole (0.5 g, 2.5 mmol) in trimethylsilylmethyl trifluorometh-
anesulfonate (0.75 cm3, 3.75 mmol) and dry CH2Cl2 (1 cm3) was
stirred at 80 ЊC under a reflux condenser for 5 h, cooled to
ambient temperature, and the solid was dissolved in dry CH2Cl2
(20 cm3) and treated with acrylonitrile (3.3 cm3, 49.5 mmol)
followed by CsF (0.57 g, 3.75 mmol). The mixture was stirred at
ambient temperature for 18 h, filtered to remove insoluble salts
and the solvent was evaporated under reduced pressure. The
residue in CH2Cl2 (3 cm3) was placed on a silica gel-60 column
(230–400 mesh ASTM) and eluted with a gradient mixture
(1 : 0–0 : 1 v/v) of petroleum spirit (bp 40–60 ЊC)–Et2O. The
first product eluted off the column was 17a (0.03 g, 5%)
followed by 16a (0.05 g, 8%).
3.34–3.39 (2H, m, 1-HA, 3-Hendo, overlap), 3.59–3.63 (1H, m,
2-HB), 4.08 (1H, dd, Jgem 14.1, Jvic <1, 3-Hexo), 7.12–7.48 (10H,
m, aromatic); δC (CDCl3) 21.3, 24.5, 26.5, 37.8 (CH2)4, 48.4 (C-
2), 54.8 (C-3), 56.4 (C-1), 81.3 (C-10a), 121.0, 125.5, 126.6,
128.6, 128.8, 129.3, 132.2 (C-aromatic), 147.1 (5-Ph, C-1Ј),
155.5 (C-6a), 175.4, 177.2 (C᎐O). Also eluted off the column
᎐
with acetone were 21a (trace) and 7a (0.29 g, 57%).
N-tert-Butyl-5-phenyl-2,3,7,8,9,10-hexahydro-1H,5H-pyrrolo-
[1,2-c][1,2,3]benzotriazole-exo-1,2-dicarboximide (11a) (Table
1, entry 13)
A solution of 2-phenyl-4,5,6,7-tetrahydro-2H-1,2,3-benzotri-
azole (0.5 g, 2.5 mmol) in trimethylsilylmethyl trifluorometh-
anesulfonate (0.75 cm3, 3.75 mmol) and dry CH2Cl2 (1 cm3) was
stirred at 80 ЊC under a reflux condenser for 5 h, cooled to
ambient temperature, and the solid was dissolved in dry CH2Cl2
(20 cm3) and treated with N-tert-butylmaleimide (1.73 cm3, 12
mmol) followed by CsF (0.57 g, 3.75 mmol). The mixture was
stirred at ambient temperature for 18 h, filtered to remove
insoluble salts and the solvent was evaporated under reduced
pressure. The residue in CH2Cl2 (3 cm3) was placed on a silica
gel-60 column (230–400 mesh ASTM) and eluted with a grad-
ient mixture (1 : 0–0 : 1 v/v) of petroleum spirit (bp 40–60 ЊC)–
Et2O. The first product eluted off the column was 11a (0.18 g,
20%), mp 133–136 ЊC (from hexane–CH2Cl2) (Found: C, 68.5;
H, 7.2; N, 15.5. C21H26N4O2 requires C, 68.8; H, 7.2; N, 15.3%);
17a: mp 100–102 ЊC (from hexane–CH2Cl2) (Found: C, 72.3;
H, 6.9; N, 21.0. C16H18N4 requires C, 72.1; H, 6.8; N, 21.0%);
νmax (mull)/cmϪ1 2238 (C᎐N); δ (CDCl3) 1.58–2.26, 2.78–2.81
᎐
᎐
H
(8H, m’s, (CH2)4), 2.02–2.10 (1H, m, 2-Hendo), 2.17–2.26 (1H, m,
2-Hexo), 3.29–3.43 (3H, m, 1-HA, 3-CH2), 6.98–7.01 (1H, m,
5-Ph, 4Ј-H), 7.26–7.31 (4H, m, 5-Ph, 2-HЈ, 3-HЈ); δC (CDCl3)
23.2, 25.8, 27.1, 38.0 (CH2)4, 30.2 (C-2), 37.3 (C-1), 57.0 (C-3),
᎐
80.9 (C-10a), 118.8 (C᎐N), 149.1, 116.1, 128.7, 122.2 (5-Ph, C-
᎐
1Ј, C-2Ј, C-3Ј, C-4Ј), 152.0 (C-6a).
16a: mp 127–129 ЊC (from hexane–CH2Cl2) (Found: C, 72.2;
H, 6.7; N, 21.1. C16H18N4 requires C, 72.1; H, 6.8; N, 21.0%);
νmax (mull)/cmϪ1 2235 (C᎐N); δ (CDCl3) 1.67–2.06, 2.80–2.85
᎐
H
(8H, m’s, (CH2)4), 2.28–2.35 (2H, m, 2-CH2), 3.01–3.05 (1H, dd,
J 7.4, 7.4, 1-HA), 3.32–3.35 (2H, m, 3-CH2), 6.99–7.01 (1H, m,
5-Ph, 4Ј-H), 7.26–7.31 (4H, m, 5-Ph, 2Ј-H, 3Ј-H); δC (CDCl3)
νmax (mull)/cmϪ1 1686, 1774 (C᎐O); δ (CDCl ) 1.44–1.99, 2.55–
᎐
H
3
2.62 (8H, m’s, (CH2)4), 1.49 (9H, s, C(Me)3), 2.99 (1H, d, J 7.0,
1-HA), 3.21–3.24 (2H, m, 2-HB, 3-Hendo, overlap), 3.89 (1H, dd,
Jgem 13.2, Jvic <1, 3-Hexo), 7.03–7.07 (1H, m, 5-Ph, 4Ј-H), 7.22–
7.28 (4H, m, 5-Ph, 2Ј-H, 3Ј-H); δC (CDCl3) 21.2, 24.7, 26.4, 38.4
(CH2)4, 27.9 (Me)3, 48.1 (C-2), 55.2 (C-3), 56.4 (C-1), 58.3 (C
of C(Me)3), 81.5 (C-10a), 147.4, 119.8, 128.7, 124.6 (5-Ph, C-1Ј,
23.2, 26.1, 26.7, 41.8 (CH2)4, 30.8 (C-2), 38.8 (C-1), 56.4 (C-3),
᎐
81.5 (C-10a), 119.7 (C᎐N), 148.9, 116.4, 128.7, 122.3 (5-Ph,
᎐
C-1Ј, C-2Ј, C-3Ј, C-4Ј), 151.9 (C-6a). Also eluted off the column
with acetone were 21a (trace) and 7a (0.37 g, 70%).
C-2Ј, C-3Ј, C-4Ј), 154.6 (C-6a), 177.3, 178.9 (C᎐O). Also eluted
᎐
off the column with acetone were 21a (trace) and 7a (0.37 g,
69%).
References
1 For a review see R. N. Butler and D. F. O’Shea, Heterocycles, 1994,
37, 571.
2 For a review see L. L. Rodina, A. Kolberg and B. Schulze,
Heterocycles, 1998, 49, 587.
3 Y. Tamura and M. Ikeda, Adv. Heterocycl. Chem., 1981, 29, 71.
4 R. Grashey, in 1,3-Dipolar Cycloaddition Chemistry, ed. A. Padwa,
J. Wiley & Sons Inc., New York, 1984, Vol. 1, p. 733.
5 R. N. Butler, D. Cunningham, E. G. Marren and P. McArdle,
Tetrahedron Lett., 1988, 29, 3331; R. N. Butler, D. Cunningham,
E. G. Marren, P. McArdle and D. F. O’Shea, J. Chem. Res. (S),
1992, 256.
6 R. N. Butler, A. M. Evans, A. M. Gillan, J. P. James, E. McNeela,
D. Cunningham and P. McArdle, J. Chem. Soc., Perkin Trans. 1,
1990, 2537.
7 R. N. Butler, A. M. Evans, E. McNeela, G. A. O’Halloran, P. D.
O’Shea, D. Cunningham and P. McArdle, J. Chem. Soc., Perkin
Trans. 1, 1990, 2527.
8 R. N. Butler, P. D. McDonald, P. McArdle and D. Cunningham,
J. Chem. Soc., Perkin Trans. 1, 1996, 1617.
9 R. N. Butler, J. P. Duffy, D. Cunningham, P. McArdle and L. A.
Burke, J. Chem. Soc., Perkin Trans. 1, 1992, 147.
10 R. N. Butler, K. M. Daly, J. M. McMahon and L. A. Burke, J. Chem.
Soc., Perkin Trans. 1, 1995, 1083; R. N. Butler, E. C. McKenna, J. M.
McMahon, K. M. Daly, D. Cunningham and P. McArdle, J. Chem.
Soc., Perkin Trans. 1, 1997, 2919.
N-Methyl-5-(4Ј-bromophenyl)-2,3,7,8,9,10-hexahydro-1H,5H-
pyrrolo[1,2-c][1,2,3]benzotriazole-exo-1,2-dicarboximide (13b)
(Table 1, entry 16)
A solution of 2-(4Ј-bromophenyl)-4,5,6,7-tetrahydro-2H-1,2,3-
benzotriazole (0.5 g, 1.8 mmol) in trimethylsilylmethyl trifluoro-
methanesulfonate (0.54 cm3, 2.7 mmol) and dry CH2Cl2 (1 cm3)
was stirred at 80 ЊC under a reflux condenser for 5 h, cooled to
ambient temperature, and the solid was dissolved in dry CH2Cl2
(20 cm3) and treated with N-methylmaleimide (1.0 g, 9 mmol)
followed by CsF (0.41 g, 2.7 mmol). The mixture was stirred at
ambient temperature for 18 h, filtered to remove insoluble salts
and the solvent was evaporated under reduced pressure. The
residue in CH2Cl2 (3 cm3) was placed on a silica gel-60 column
(230–400 mesh ASTM) and eluted with a gradient mixture
(1 : 0–0 : 1 v/v) of petroleum spirit (bp 40–60 ЊC)–Et2O. The
first product eluted off the column was 13b (0.08 g, 11%), mp
133–134 ЊC (from hexane–CH2Cl2) (Found: C, 53.3; H, 4.8; N,
13.5. C18H19N4O2Br requires C, 53.6; H, 4.8; N, 13.9%); νmax
(mull)/cmϪ1 1701, 1773 (C᎐O); δ (CDCl ) 1.53–2.06, 2.56–2.71
᎐
H
3
(8H, m’s, (CH2)4), 2.91 (3H, s, N–Me), 3.24–3.32 (2H, m, 1-HA,
3-Hendo, overlap), 3.42–3.44 (2H, m, 2-HB), 3.91 (1H, dd, Jgem
13.9, Jvic <1, 3-Hexo), 7.13 (2H, d, J 8.8, 5-Ar, 3Ј-H), 7.41 (2H, d,
5-Ar, 2Ј-H); δC (CDCl3) 21.3, 24.6, 26.5, 37.9 (CH2)4, 25.2
11 R. N. Butler, M. O. Cloonan, J. M. McMahon and L. A. Burke,
J. Chem. Soc., Perkin Trans. 1, 1999, 1709.
12 For
a
review see R. Huisgen, 1,3-Dipolar Cycloaddition
Chemistry, ed. A. Padwa, J. Wiley & Sons Inc., New York, 1984,
J. Chem. Soc., Perkin Trans. 1, 2001, 1778–1784
1783

View Article Online
Vol. 1, p. 128; J. W. Lown, in 1,3-Dipolar Cycloaddition Chemistry,
ed. A. Padwa, J. Wiley & Sons Inc., New York, 1984, Vol. 1,
p. 653.
19 R. Grigg, S. Surrendrakumar, S. Thianpatanagul and D. Vipond,
J. Chem. Soc., Perkin Trans. 1, 1988, 2693.
20 R. Grigg and V. Sridharan, Adv. Cycloaddit., 1993, 3, 161.
21 R. N. Butler, and G. M. Smyth, unpublished results.
22 R. N. Butler and D. C. Grogan, J. Chem. Res. (S), 1997, 428.
23 R. N. Butler, P. D. McDonald, P. McArdle and D. Cunningham,
J. Chem. Soc., Perkin Trans. 1, 1994, 1653.
13 R. N. Butler, F. A. Lysaght and L. A. Burke, J. Chem. Soc. Perkin
Trans. 2, 1992, 1103.
14 J. I. Garcia, J. A. Mayoral and L. Salvatella, Acc. Chem. Res., 2000,
33, 658.
15 R. B. Woodward and R. Hoffmann, The Conservation of Orbital
Symmetry, Academic Press, New York, 1970.
16 J. A. Berson, Tetrahedron, 1992, 48, 1.
24 E. Vedejs, S. Larsen and F. G. West, J. Org. Chem., 1985, 50, 2170.
25 R. C. F. Jones, J. R. Nichols and M. T. Cox, Tetrahedron Lett., 1990,
31, 233.
17 K. Amornraksa, R. Grigg, H. Q. N. Gunaratne, J. Kemp and
V. Sridharam, J. Chem. Soc., Perkin Trans. 1, 1987, 2285.
18 R. Grigg, H. Q. N. Gunaratne, V. Sridharan and S. Thianpatanagul,
Tetrahedron Lett., 1983, 24, 4363.
26 R. N. Butler, F. A. Lysaght, P. D. McDonald, C. S. Pyne, P. McArdle
and D. Cunningham, J. Chem. Soc., Perkin Trans. 1, 1996, 1623;
R. N. Butler, A. M. Gillan, S. Collier and J. P. James, J. Chem. Res.
(S), 1987, 332.
1784
J. Chem. Soc., Perkin Trans. 1, 2001, 1778–1784