Photochemical and thermal intramolecular 1,3-dipolar cycloaddition reactions of new o-stilbenemethylene-3-sydnones and their synthesis

Article abstract of DOI:10.3762/bjoc.7.196

New trans-and cis-o-stilbene-methylene-sydnones 3a,b were synthesized by transforming the trans-and cis-o-aminomethylstilbene derivative, obtained by reduction of corresponding o-cyano derivatives, into glycine ester derivatives (43 and 31% yield) followed by hydrolysis (90 and 96% yield), nitrosation and ring closure with acetic acid anhydride (30 and 40% yield). The products were submitted to photochemical and thermal intramolecular [3 + 2] cycloadditions to afford diverse heteropolycyclic compounds. Photochemical reactions afforded cis-3-(4-methylphenyl)-3a,8-dihydro-3H-pyrazolo[5,1-a]isoindole (11, 12.5% yield) and trans-3-(4-methylphenyl)-3a,8-dihydro-3H-pyrazolo[5,1-a]isoindole (12, 5% yield). Thermal reactions afforded 3-(4-methylphenyl)-3,3a,8,8a- tetrahydroindeno[2,1-c]pyrazole (14, 50% yield) and 11-(4-methylphenyl)-9,10- diazatricyclo[7.2.1.02,7]dodeca-2,4,6,10-tetraene (15, 22% yield).

Full text of DOI:10.3762/bjoc.7.196

Photochemical and thermal intramolecular
1,3-dipolar cycloaddition reactions of new o-stilbene-
methylene-3-sydnones and their synthesis
Kristina Butković1,2, Željko Marinić3, Krešimir Molčanov4,
Biserka Kojić-Prodić4 and Marija Šindler-Kulyk*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1663–1670.
1Department of Organic Chemistry, Faculty of Chemical Engineering
and Technology, University of Zagreb, Marulićev trg 19, 10 000
Zagreb, Croatia, 2present address: Galapagos istraživački centar,
Prilaz baruna Filipovića 29, 10 000 Zagreb, Croatia, 3Center for NMR,
Rudjer Bošković Institute, Bijenička cesta 54, 10 000 Zagreb, Croatia
and 4Laboratory for Chemical and Biological Crystallography,
Department of Physical Chemistry, Rudjer Bošković Institute,
Bijenička cesta 54, 10 000 Zagreb, Croatia
doi:10.3762/bjoc.7.196
Received: 10 October 2011
Accepted: 11 November 2011
Published: 13 December 2011
Associate Editor: C. Stephenson
© 2011 Butković et al; licensee Beilstein-Institut.
Email:
License and terms: see end of document.
Marija Šindler-Kulyk* - marija.sindler@fkit.hr
* Corresponding author
Keywords:
[3 + 2] cycloaddition; isoindoles; nitrile imines; pyrazoles; sydnones
Abstract
New trans- and cis-o-stilbene-methylene-sydnones 3a,b were synthesized by transforming the trans- and cis-o-aminomethyl-
stilbene derivative, obtained by reduction of corresponding o-cyano derivatives, into glycine ester derivatives (43 and 31% yield)
followed by hydrolysis (90 and 96% yield), nitrosation and ring closure with acetic acid anhydride (30 and 40% yield). The prod-
ucts were submitted to photochemical and thermal intramolecular [3 + 2] cycloadditions to afford diverse heteropolycyclic com-
pounds. Photochemical reactions afforded cis-3-(4-methylphenyl)-3a,8-dihydro-3H-pyrazolo[5,1-a]isoindole (11, 12.5% yield) and
trans-3-(4-methylphenyl)-3a,8-dihydro-3H-pyrazolo[5,1-a]isoindole (12, 5% yield). Thermal reactions afforded 3-(4-methyl-
phenyl)-3,3a,8,8a-tetrahydroindeno[2,1-c]pyrazole (14, 50% yield) and 11-(4-methylphenyl)-9,10-diazatricyclo[7.2.1.02,7]dodeca-
2,4,6,10-tetraene (15, 22% yield).
Introduction
Sydnones belong to the group of five-membered heterocyclic One of the most characteristic reactions of sydnones is the inter-
compounds referred to as being "mesoionic" and have been molecular 1,3-dipolar cycloaddition. In the presence of
widely studied since their discovery [1-5]. They can be repre- acetylenic or ethylenic dipolarophiles, sydnones undergo cyclo-
sented as hybrids of a number of mesomeric ionic structures addition reactions, which can be induced thermally [4,6,7] or
(Figure 1).
photochemically [8-17], giving different pyrazole and/or pyra-
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Figure 1: Resonance structures of the sydnone ring.
Figure 2: Illustration of intramolecular [3 + 2] cycloadditions.
zoline derivatives, depending on the applied dipolarophile of a heterostilbene [17] (1, Figure 3) or is directly attached at
(Scheme 1). Namely, sydnones are masked 1,3-dipoles that by the ortho position to the stilbene 2 [21-23]. Upon photolysis of
photolysis give nitrile imine intermediates, or in thermal reac- compound 1, where the sydnone moiety is part of a heterostil-
tions react as cyclic azomethine imines.
bene system, cis–trans isomerization was the main process, and
no intramolecular cycloadducts were found owing to the
unfavourable conformation of the formed intermediate in the
trans configuration. The existence of the nitrile imine inter-
mediate as a result of competitive photolysis of the sydnone
moiety was confirmed on irradiation of 1 in the presence of
acrolein and isolation of the pyrazoline derivative (F, Figure 3)
[17]. In the case of stilbenylsydnones 2, where the sydnone
moiety is directly connected to the ortho position of the stil-
bene, the cyclization of the formed nitrile imine intermediate
leading to benzodiazepine ring closure (G, Figure 3) was the
Scheme 1: Thermal and photochemical intermolecular [3 + 2] cycload-
ditions.
Intramolecular 1,3-dipolar cycloadditions of sydnone deriva-
tives have not been as thoroughly investigated, and so far only a
few examples are known [18-20]. Photochemically induced
intramolecular 1,3-dipolar cycloadditions have been studied on
3,4-disubstituted sydnone derivatives [18,19] (Figure 2, A and
B), wherein indolopyrazole and pyrazolobenzoxazine struc-
tures are formed (Figure 2, C and D).
Heimgartner and coworkers also carried out the thermally
induced reaction of 3-(o-allylphenyl)-4-phenylsydnone (A) and
obtained the cycloadduct E (Figure 2) with the oxycarbonyl
group remaining in the structure [18].
Figure 3: Styryl-sydnone 1 and stilbenyl sydnone 2 and their photo-
products F and G, respectively; target molecules 3 in this work.
We have been studying photochemical reactions of conjugated
heterostilbene derivatives in which the sydnone moiety is part
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main intramolecular process [22]. In a continuation of our The isomers were separated by column chromatography and
interest in the synthesis of heteropolycyclic compounds we further treated separately to achieve the final products in cis and
extended our research to new stilbene-sydnone derivatives 3 trans configurations. Reduction of 6a (trans) or 6b (cis) with
(Figure 3). In such a system, where two chromophores, stilbene LiAlH4 in anhydrous ether afforded amino derivative 7a (trans,
and sydnone, are divided by a methylene bridge, an intramo- 94%) or 7b (cis, 93%). In the 1H NMR spectra new signals
lecular 1,3-dipolar cycloaddition and the formation of diverse from the methylene protons appeared at 3.88 ppm (7a) and
polycyclic compounds could be expected. Herein we describe, 3.62 ppm (7b) confirming the reduction. By further nucleo-
for the first time, the synthesis of cis- and trans-3-(stilbenyl- philic substitution, from 7a (trans) or 7b (cis) and ethyl
methyl)sydnones and their photochemical and thermal intramo- bromoacetate, the ester 8a (trans) or 8b (cis) was prepared. On
lecular transformations to heteropolycyclic structures.
purification by column chromatography, the byproducts,
obtained by disubstitution reaction of the amino compound,
were separated, and the pure 8a (43%) or 8b (31%) was
Results and Discussion
In the investigation of 3-{2-[2-(4-tolyl)ethenyl]phenyl}methyl- isolated. The obtained esters showed the presence of the carbon-
sydnones, 3a (trans) and 3b (cis), were prepared by a sequence yl group at ~1740 cm−1 in the IR spectra and the carbonyl
of reactions (Scheme 2) starting from o-cyanotoluene (see carbon at ~172 ppm in the 13C NMR spectra. The esters 8a or
Supporting Information File 1 for full experimental data). Bro- 8b were hydrolysed to the amino acid 9a (trans, 90%) or 9b
mination of o-cyanotoluene afforded 2-(bromomethyl)benzoni- (cis, 96%). The obtained amino acids were transformed to
trile (4) [24], which was transformed to triphenylphosphonium N-nitroso glycine 10a or 10b and, without isolation or further
salt 5 [25] followed by Wittig reaction with 4-methylbenzalde- purification, were submitted to dehydration with acetic acid
hyde to 2-(4-methylstyryl)benzonitrile (6a,b) [26]. The product anhydride to give sydnone 3a (trans) or 3b (cis). After column
was obtained as a mixture of 6a (trans isomer, 40%) and 6b (cis chromatography the pure 3a (30%) or 3b (42%) was isolated.
isomer, 60%).
The best indication that the sydnone structures were formed was
Scheme 2: Synthesis of the target molecules 3a and 3b.
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given by the singlet at ~6 ppm in the 1H NMR spectrum, char- The structure of the minor photoproduct 12, different from the
acteristic for the proton H-4 in the sydnone ring, as well as structure 11 only in trans orientation of the protons B and C,
those in the 13C NMR spectrum, namely the CH and CO was also evident from NMR spectra by using 2D NMR tech-
sydnone carbons at ~94 and ~169 ppm, respectively.
niques. The doublets at 4.90 ppm and 4.37 ppm with a coupling
constant of 15.6 Hz are assigned to geminal protons G. The
The irradiation experiments with the trans isomer (3a) or cis singlet at 6.57 ppm is assigned to proton A. The chemical shift
isomer (3b) were performed in ~10−3 M benzene solution in a of proton A is the same as in structure 11. The other two signals
Rayonet reactor at 300 nm under anaerobic conditions (purged at 3.97 ppm and 4.70 ppm appear as singlets, and they are
with argon). The absorption maximum of trans isomer (3a) is at assigned to protons C and B, respectively, based on weak inter-
300 nm (ε 37453) and of cis isomer (3b) at 291 nm (ε 16228), actions in the COSY and NOESY spectra. Nevertheless, the
thus upon irradiation both isomers were excited. The irradiation proton H-5 of the fused benzene ring in structure 12 is in the
of the isomers was performed until full conversion. The irradi- multiplet together with other aromatic protons, which is in
ation of either the trans or cis isomer, or of the mixture of accordance with the proposed structure.
isomers, resulted in the formation of two products in the same
mutual ratio, along with large amounts of unidentified high- The structure of the photoproducts was confirmed by an ad-
molecular-weight products. Separation by column chromatog- ditional experiment on the crude reaction mixture with DDQ
raphy in combination with thin layer chromatography gave di- (Scheme 4) in which, as expected for the predicted structures,
hydropyrazolo-isoindoles, 11 (12.5%) and 12 (5%) (Scheme 3). the aromatization reaction took place forming the pyrazolo-
isoindole 13. Compound 13 arose also on silica gel during the
The structure of the photoproducts was determined by spectro- purification of either 11 or 12.
scopic methods. The molecular ions of 11 and 12, m/z 248 in
the mass spectra, indicate that the structures have lost CO2 rela-
tive to the starting compound. In the 1H and 13C NMR spectra,
the signals are found in an area which is characteristic for satu-
rated cyclic compounds. The major product is assigned to com-
pound 11 based on the following data: In 1H NMR spectrum the
signals at 4.98 ppm and 4.43 ppm are doublets with coupling
constants of 15.6 Hz and are assigned to geminal protons G-1
and G-2. The other two signals at 4.92 and 4.24 ppm are also
doublets but with coupling constants of 10.8 Hz. Based on the
interaction of the proton at 5.88 with the proton at 4.92 ppm in
the NOESY spectrum, the doublet at 5.88 is assigned to proton
H-5, the doublet at 4.92 ppm to proton B and the doublet at 4.24
to proton C. Interaction of proton H-5 with proton B is also
visible in HMBC spectrum. The signal at 6.53 ppm was
assigned to proton A based on COSY interaction with proton C.
The rather large high-field shift of the aromatic proton H-5 can
be explained by an anisotropic effect of the tolyl group and thus
Scheme 4: Aromatization with DDQ.
confirms the cis orientation of protons B and C.
Scheme 3: Photolysis of cis- or trans-3.
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The irradiation of 3a or 3b until full conversion, as previously as a masked azomethine dipole, and the double bond of the stil-
mentioned, produced a mixture of 11 and 12 along with decom- bene moiety could proceed in different ways. The orientation of
position and high-molecular-weight products. On shorter irradi- the sydnone ring toward the π bond of the stilbene in combina-
ation time (10 min, in benzene or acetonitrile) 3a (trans isomer) tion with the double bond configuration can give various formal
afforded, according to 1H NMR, the photomixture of predomi- [3 + 2] intramolecular cycloadducts.
nantly 3b (cis isomer) with only traces of starting 3a and
tricyclic photoproducts 11 and 12. Under the same irradiation On heating of 3a (trans) in toluene until full conversion (4 h)
conditions, 3b (cis isomer) as starting compound gave a one product in 50% yield was isolated from the reaction mix-
photomixture of cis isomer and the newly formed product 11 in ture after column chromatography. From the molecular ion
1:1 ratio with only traces of 3a (trans isomer), along with some (m/z 248) of the product and its 13C NMR spectrum it was
unidentified side products. The experimental results show that obvious that in the cycloaddition CO2 elimination took place.
the trans-(3a) and cis-(3b) isomerize and react with different Fragmentation of the product and the presence of an ion at m/z
efficiency, and that the isomerization, as in the case of stilbene 220 suggests a structure in which the expulsion of nitrogen is
itself [27], is shifted toward the cis isomer. It follows that the possible. The structure 14 (Scheme 6) was determined by ad-
reaction is stereospecific and that photoproduct 11 is formed ditional NMR techniques, NOE and HMBC interactions, and by
from the cis configuration of the stilbene moiety and the photo- single crystal X-ray structure analysis (Figure 4) of the crystal
product 12 from the trans configuration, although the forma- formed in an NMR tube by slow evaporation of the solvent.
tion of 12 via epimerization of 11 could not be eliminated. It is
also evident that there are several competitive processes, which
are summarized in Scheme 5.
On irradiation of 3a (trans) or 3b (cis) parallel competitive
processes are in operation, namely, trans–cis and cis–trans
isomerization of the stilbene moiety, and photolysis of the
sydnone ring resulting in the formation of the nitrile imine inter-
mediate. The nitrile imine species is, in intramolecular dipolar
Scheme 6: Thermal reaction of trans-3.
[3 + 2] cycloaddition, trapped by the cis- or trans-double bond
of the stilbene, giving cycloadducts 11 or 12, respectively.
Also, when compound 3b (cis) was refluxed in xylene (9 h) or
We also performed the thermal intramolecular reactions with toluene (19 h) only one cycloadduct 15 was isolated
the starting compounds 3a and 3b. Theoretically the intramo- (Scheme 7), besides decomposition products, in 22% yield. The
lecular 1,3-dipolar cycloaddition of the sydnone moiety, acting structure of 15 was determined by spectroscopic methods.
Scheme 5: Possible mechanism for the formation of the photoproducts.
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Figure 5: Proposed stereochemical pathway of sydnone ring (CH–N)
and trans- and cis-stilbene (α–β).
Figure 4: ORTEP of compound 14.
Scheme 7: Thermal reaction of cis-3.
Figure 6: Proposed stereochemical pathway of sydnone ring (N–CH)
and trans- and cis-stilbene (α–β).
In the 1H NMR spectrum two pairs of geminal protons were
found at 4.51 and 4.21 ppm (A, B) and at 3.71 and 3.35 ppm (E,
D). The doublet at 3.95 ppm, coupled with one geminal proton trans double bond, leading to the products, is the pathway
(D), was assigned to proton C. In the 13C NMR spectrum, one presented in Figure 5. The regiospecific and stereospecific for-
of the five quaternary carbons is shifted to 176 ppm, which mation of the products 14 and 15 could be explained by this ap-
corresponds to an sp2-carbon in the vicinity of nitrogen. In the proach of the sydnone ring (Scheme 8). The cycloadducts, cA
NOESY spectrum the interaction of protons A and B with an from trans isomer and cB from cis isomer, lose CO2 under the
aromatic proton (H-2) at 7.00 ppm is seen, as well as the inter- reaction conditions to afford intermediates 14A and 14 B, res-
action of proton C with protons E and D. Since the NOE inter- pectively. Owing to the favourable conformation in the case of
action is seen between protons A and E we concluded that biradical 15A, the 1,3-H abstraction and formation of the C–N
protons A and E must lie on the same side of the six-membered double bond in product 15 is possible. In the biradical 14A the
ring. In addition, the interaction of proton C with tolyl (H-10) intramolecular hydrogen abstraction is not favourable, but 1,2-
and H-5 protons was seen.
alkyl shift takes place followed by formation of the N–N double
bond in product 14.
In order to explain the diverse structures (14 and 15) and their
formation mechanism, we analysed the possible ways of intra- Monitoring the reaction by thin layer chromatography revealed
molecular [3 + 2] cycloaddition relating to the arrangement of that the [3 + 2] cycloaddition is much faster in the case of the
the sydnone ring towards the cis and trans double bond trans isomer (3a). After the 4 h reflux of the toluene solution of
(Figure 5 and Figure 6).
the trans isomer, the 1H NMR spectrum of the crude reaction
mixture showed complete conversion, while the cis isomer (3b)
As presented in Figure 5, the sydnone ring could be oriented to under the same conditions showed complete conversion only
the double bond in such a way that the bonds are formed at the after 19 h. This evidence led us to believe that the formation of
C(Sy)–α(St) and N(Sy)–β(St) positions, or, as presented in the "C–α/Ν–β" adduct cA proceeds via an energetically
Figure 6, at the N(Sy)–α(St) and C(Sy)–β(St) positions. The favoured transition state due to a possible secondary π–π inter-
favoured arrangement of the sydnone ring toward the cis and action of the tolyl and carbonyl groups.
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isomer 3b gives polycyclic compound 15. Stilbene-methylene-
sydnones are useful substrates for photochemical and thermal
intramolecular [3 + 2] cycloaddition reactions to heteropoly-
cyclic compounds.
Supporting Information
Supporting Information File 1
Experimental details and characterization data for all
compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-196-S1.pdf]
Supporting Information File 2
1H NMR and APT spectra of 3a, 3b, 11–15, NOESY
spectra of 11, 12, 14 and 15 and X-ray data for 14.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-196-S2.pdf]
Acknowledgements
This work was supported by grants from the Ministry of
Science, Education and Sports of the Republic of Croatia (grant
nos. 125-0982933-2926, 098-0982929-2917, 098-1191344-
2943).
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