Synthesis and photochemistry of 3-(o-stilbeneyl)-4-H/Me/Ph-sydnones; Intramolecular cyclization to 1,2-benzodiazepines and/or quinolines

Article abstract of DOI:10.1016/j.tet.2010.10.013

Stilbeneylsydnone derivatives were synthesized by a sequence of reactions in good yields. Irradiation of 3-stilbeneyl-4-methylsydnone 4 gives 1H-1,2-benzodiazepine derivative 7 as the main product along with 2-methylquinoline derivative 20. Irradiation of 3-stilbeneyl-4-phenylsydnone 5 afforded only 1H-1,2-benzodiazepine derivative 8 whereas on irradiation of 4-unsubstituted 3-stilbeneylsydnone 3 no benzodiazepine derivative was detected. An efficient novel photochemical approach to 1H-1,2-benzodiazepines has been found from the new 3-(o-stilbeneyl)-4-substituted-sydnones via intramolecular 1,7-electrocyclization reaction of the photogenerated nitrile imines.

Full text of DOI:10.1016/j.tet.2010.10.013

Tetrahedron 66 (2010) 9356e9362
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and photochemistry of 3-(o-stilbeneyl)-4-H/Me/Ph-sydnones;
intramolecular cyclization to 1,2-benzodiazepines and/or quinolines
a
a,
ꢀ a
ꢀ b
ꢀ a
ꢁ
ꢁ
*
Kristina Butkovic , Dragana Vuk , Zeljko Marinic , Josip Penic , Marija Sindler-Kulyk
a
ꢀ
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulicev trg 19, 10000 Zagreb, Croatia
Center for NMR, Rudjer Boskovic Institute, Bijenicka cesta 54, 10000 Zagreb, Croatia
b
ꢁ
ꢀ
ꢁ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 June 2010
Received in revised form 14 September 2010
Accepted 4 October 2010
Available online 19 October 2010
Stilbeneylsydnone derivatives were synthesized by a sequence of reactions in good yields. Irradiation of
3-stilbeneyl-4-methylsydnone 4 gives 1H-1,2-benzodiazepine derivative 7 as the main product along
with 2-methylquinoline derivative 20. Irradiation of 3-stilbeneyl-4-phenylsydnone 5 afforded only 1H-
1,2-benzodiazepine derivative 8 whereas on irradiation of 4-unsubstituted 3-stilbeneylsydnone 3 no
benzodiazepine derivative was detected. An efficient novel photochemical approach to 1H-1,2-benzo-
diazepines has been found from the new 3-(o-stilbeneyl)-4-substituted-sydnones via intramolecular
1,7-electrocyclization reaction of the photogenerated nitrile imines.
Keywords:
Cyclization
Benzodiazepines
Nitrile imines
Stilbenes
Ó 2010 Elsevier Ltd. All rights reserved.
Sydnones
Quinolines
1. Introduction
dipolar compounds known as ‘mesoionic’ and can be represented
as hybrids of a number of mesomeric/ionic forms. Since their early
In continuation of our work on photochemical intramolecular
reactions of o-substituted stilbenes with pyrrole ring (1)1,2 we ex-
tended our research to new heteroaromatic derivatives, sydnone
derivatives 2,3 and 34 (Fig. 1) as substrates for photochemical
transformations to heteropolycyclic structures. Our basic idea was
to introduce the general synthetic method to 1H-1,2-benzodiaze-
pine derivatives (6e8) by intramolecular trapping of photochemi-
cally generated nitrile imines starting from 4-unsubstituted (3),
4-alkyl- (4), and 4-aryl-3-stilbeneylsydnone (5) (Fig. 1).
Benzodiazepines are a class of compounds belonging to psy-
choactive drugs with versatile sedative, hypnotic, anxiolytic, anti-
convulsant, muscle relaxant, and amnesic properties.5 They are
seven-membered anelated hetarenes with two nitrogens in the
seven-membered ring, which could be in [1,2], [1,3], [1,4], and [1,5]
mutual position and they are synthesized on diverse methods.6 So
far the only photochemical pathway to 1H-1,2-benzodiazepine
derivatives6a,7 was photoinduced ring expansion reaction of
N-iminoquinolinium ylide dimers. To the best of our knowledge
there are no examples of their synthesis from sydnones. Sydnones8
are the five-membered heterocycles. They belong to a class of
discovery by Earl and Mackney in 1935, sydnones have been widely
studied,9 not only because of their structure, physical properties,
and reactivity, but also because of various biological properties.
CH3
R
R
C
N
N
CO
HN
O
2
1
R
R'
CR'
N
C
N
N
N
CO
H
O
6 R' = H
3 R' = H
7 R' = alkyl
8 R' = aryl
4 R' = alkyl
5 R' = aryl
* Corresponding author. Tel.: þ3851 4597242; e-mail address: marija.sindler@
ꢁ
fkit.hr (M. Sindler-Kulyk).
Fig. 1.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.013

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K. Butkovic et al. / Tetrahedron 66 (2010) 9356e9362
9357
Numerous sydnones have been synthesized and their photo-
chemical behavior studied.10 All investigators have essentially
substantiated the salient features of the mechanistic suggestions
advanced by Krauch et al.11 for the transformations of sydnones
(Scheme 1).
The irradiation experiments on 3e5 were performed in 10ꢀ3 M
solutions of benzene and/or acetonitrile in a Rayonet reactor at
300 nm (3, 4) and 350 nm (5) until the full conversion (based on 1H
NMR 60 min for 3 and 4, 20 min for 5) under anaerobic conditions.
The photomixture of 3-substituted sydnones 3a/3b contained
a complex mixture of many products in small quantities. On sepa-
ration by column chromatography it was possible to isolate only
quinolines 19a/19b and trans-o-aminostilbenes 9a/9b (Scheme 3).
No 1,2-benzodiazepine structure 6, unsubstituted at the 3-position,
was detected. Contrary to these results, the irradiation of 4-phenyl
substituted 3-stilbeneylsydnone 5 gave only benzodiazepine de-
rivative 8 in good yield whereas the irradiation of 4-methyl-3-stil-
beneylsydnone 4 afforded a mixture of benzodiazepine 7 and
quinoline 20 in 4:1 ratio, and moderate yield. The obtained new
photoproducts are identified by MS and NMR using 2D techniques.
The structure of quinoline 20 was obvious from its MS spectrum,
where the m/z 233 indicated on loss of CO and NO, in addition to its
1H and 13C NMR spectra. Finally, its structure is irrevocably con-
firmed by its independent synthesis using the described method for
some other derivatives.13 The structures of known compounds 19a,b
were confirmed by comparison of their spectroscopic data in liter-
ature.14 The compounds 7 and 8 showed in MS spectrum m/z 248
and m/z 310, respectively, which indicated on loss of CO2 and ben-
zodiazepine structure. Combining the data from IR, 1H, and 13C NMR
using the additional COSY and NOESY techniques the benzodiaze-
pines 7 and 8 are completely analyzed.
R
R
R'
R'
R
R'
-CO2
N
N
N
N
N
hν
R'
N N C R
CO
CO
N
O
O
diaziridine
diazirine
sydnone
nitrile imine
Scheme 1.
In this work we describe for the first time the photochemical
behavior of stilbeneylsydnones 3e5, a system in which the sydnone
ring at the position 3 is directly coupled to the ortho-position of the
stilbene moiety. If the excitations of 3e5 would give the nitrile
imine intermediates they should undergo intramolecular 1,7-elec-
trocyclization to the target benzodiazepine derivatives 6e8 (Fig. 1).
Namely, nitrile imines, generated thermally from o-alkenyl
substituted arylhydrazonoyl halogenides,12 gave benzodiazepine
derivatives by 1,7-electrocyclization process.
On irradiation of 4-phenyl derivative 5 possible formation of the
side product, 2-phenylquinoline derivative was ruled out by com-
parison the NMR spectra of photomixture with the 1H NMR spec-
trum of, for this purpose, prepared 2,3-diphenylquinoline (21,
Experimental section).
It is obvious from the experiments that in our fully conjugated
system several competitive processes are operating. The main
pathway of the reaction depends on the substituent in the position
4 of the starting sydnone. The desired benzodiazepine derivatives 7
and 8 (Scheme 3) are formed in good yields from 3,4-disubstituted
sydnones by 1,7-electrocyclization of nitrile imines 23, formed by
initial CO2 elimination, followed by 1,5-H shift and formation of
fully unsaturated seven-membered ring. As depicted in Scheme 3
the plausible formation mechanism of the quinolines 19 and 20
might be best explained via imine radical 22, formed by NO and/or
2. Results and discussion
Investigating compounds, 3-{2-[2-(phenyl/4-tolyl)ethenyl]phe-
nyl}sydnones (3a,b) and 4-methyl/phenyl-3-{2-[2-(4-tolyl)ethenyl]
phenyl}sydnones (4,5) were prepared by a sequence of reactions
starting from o-aminostilbene 9a/9b (Scheme 2). By substitution
reaction with the esters of
a-bromoacetic acid, a-bromopropionic
acid or -bromophenyl acetic acid, respectively, the esters of amino
a
acids 10a,be12 were obtained and hydrolyzed to amino acid de-
rivatives 13a,be15. The obtained acids were transformed to
N-nitroso glycines 16a,be18 and without isolation, and further
purification submitted to ring closure by dehydratation with acetic
anhydride to sydnones 3e5. All new compounds are spectroscop-
ically characterized and identified.
R
R
R
R'
1. NaOH, H2O
2. HCl
BrCHCOOR''
R'
R'
NHCHCOOH
NaOAc, EtOH
NH2
NHCHCOOR''
10a R=H, R'= H, R''= Et
9a R=H
13a R=H, R'= H
9b R= CH3
10b R= CH3, R'= H, R''= Et
11 R= CH3, R'= CH3, R''= Et
13b R= CH3, R'= H
14 R= CH3, R'= CH3
15 R= CH3, R'= C6H5
12 R= CH3, R'= C6H5, R''= Me
R
R
R'
C
NaNO2, HCl, H2O
(CH3CO)2O
R'
N
N
CO
NCHCOOH
NO
O
3a R=H, R'= H
16a R=H, R'= H
3b R= CH3, R'= H
4 R= CH3, R'= CH3
5 R= CH3, R'= C6H5
16b R= CH3, R'= H
17 R= CH3, R'= CH3
18 R= CH3, R'= C6H5
Scheme 2.

ꢀ
9358
K. Butkovic et al. / Tetrahedron 66 (2010) 9356e9362
R
R
R
R
R'
hν
R'
R'
C
N
N
C
N
N
N
-CO2
N
N CR'
23
CO
CO
N
O
O
3a R = H, R' = H
-NO
-CO
3b R = CH3 R' = H
R
4 R = CH3, R' = CH3
5 R = CH3, R'= C6H5
R
R'
N
N
N
N
C R'
22
1,5-H
R
R
R
R'
N
R'
N
H
NH2
19a R = H, R' = H (12%)
9a R = H, R'= H (8%)
19b R = CH3, R' = H (14%)
20 R = CH3, R' = CH3(10%)
7 R = CH3, R' = CH3 (39%)
8 R = CH3, R'= C6H5 (67%)
9b R = CH3, R'= H (8%)
Scheme 3.
CO extrusion, followed by an addition to the stilbene double bond.
This is in accordance with the literature data for the photolysis of 3-
phenylsydnone where the imine radical intermediate, in contrast to
3,4-diphenylsydnone, has been detected by electron spin reso-
nance spectroscopy.15 However, bearing in mind the experimental
conditions and impossibility to give an exact number of radicals
generated in the photochemical process, the authors did not rule
out also the possibility of nitrile imine intermediates formation.
Aminostilbenes 9 are probably by-products formed by hydrolysis of
some intermediates.
3. Conclusion
We have found a new synthetic route to 3-substituted 1H-1,2-
benzodiazepines by photolysis of 3-stilbeneyl-4-substituted syd-
nones and 1,7-electrocyclization of the formed nitrile imines.
Although in case of only 3-substituted sydnone derivative 3 expected
benzodiazepine structure 6 was not isolated the formation of nitrile
imine intermediate 23 could not be completely excluded. If the
benzodiazepine derivative 6 had been formed, but in small quanti-
ties, it could have been disintegrated during working up procedures.
It should be mentioned that whereas the phenyl derivative 8 is
a stable compound the methyl derivative 7 decomposes during the
purification in favor of formation of one other compound, indazole
derivative E-24 (Scheme 4). The compound was isolated and
identified by spectroscopic methods. The E-configuration was
based on NOESY experiments. The interaction was seen between
the methyl protons of the acetyl group at 2.31 ppm and aromatic
doublet at 7.15 ppm. A plausible mechanism of its formation is
depicted in Scheme 4. It could be assumed that the compound 7
undergoes hydrolysis and ring opening followed by five-membered
ring closure and subsequent dehydrogenation.
4. Experimental
4.1. General
The 1H and 13C NMR spectra were recorded on a Bruker AV-600
Spectrometer at 300 and 600 MHz. All NMR spectra were measured
in CDCl3 or DMSO using tetramethylsilane as reference. UV spectra
were measured on a Varian Cary 50 UV/VIS Spectrophotometer. IR
spectra were recorded on FTIR-ATR Vertex 70 Bruker or Per-
kineElmer M-297 spectrophotometer. Mass spectra were obtained
on Extrel FT MS 2001 DD, Auto Spec Q (VG Analytical Manchester,
GB), on Platform LCZ (Micromass, UK) and/or on a Varian Saturn
2200 equipped with Factor Four Capillary Column VF-5ms. Irradi-
ations were performed in a quartz or Pyrex vessel in a Rayonet
reactor equipped with RPR 3000 and/or 3500 Aꢁ lamps. All irradi-
ation experiments were carried out in deaerated solutions by
bubbling a stream of argon for 15 min prior to irradiation. Melting
points were obtained using an Original Kofler Mikroheitztisch ap-
paratus (Reichert, Wien) and are uncorrected. Elemental analyses
were carried out on PerkineElmer, Series II, CHNS Analyzer 2400 at
CH3
CH3
H2O
CH3
CH3
O
N
N
H
HN NH2
7
ꢁ
ꢀ
Rudjer Boskovic Institute. Silica gel (Merck 0.063e0.2 mm) was
used for chromatographic purifications. Thin layer chromatography
(TLC) was performed on Merck precoated silica gel 60 F254 plates.
Solvents were purified by distillation.
H3C
O
CH3
OH
H3C
CH3
Compounds 3a and 3b were prepared according to literature
procedure for 3b3 however no physical and spectral data were given
for the intermediates: 10b and 13b. All reported yields in this work
are isolated yields. Aminostilbenes 9a,b are prepared according to
literature.3,16
N
NH
N
24
E-
N
H
Scheme 4.

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K. Butkovic et al. / Tetrahedron 66 (2010) 9356e9362
9359
4.2. Synthesis of stilbeneylsidnones 3e5
4.2.1. Preparation of esters 10e12.
on silica gel using dichloromethane/petroleum ether (7/3) mixture
as eluent. In first fractions was isolated ester 12 and then unreacted
amine.
4.2.1.2.1. trans-Methyl-N-{2-[2-(4-methylphenyl)ethenyl]phenyl}
4.2.1.1. General procedure for 10a/10b and 11. A solution of
corresponding amine 10a/10b (0.0174 mol), anhydrous sodium
acetate (2.14 g, 0.0261 mol, 1.5 equiv), and ethyl ester of corre-
amino-(a-phenyl)acetate, 12. Yield 634 mg (74.0%), yellow solid,
mp 147 ꢁC. TLC Rf¼0.62 (6/4 CH2Cl2/petroleum ether). UV (EtOH)
lmax/nm (3
/dm3 molꢀ1 cmꢀ1): 249 (8953), 289 (9725), 343 (6433).
sponding acid [
a
-bromoacetic acid (0.0174 mol) for 10a/10b or
a
-
IR (KBr) nmax/cmꢀ1: 3434 (NH), 2948 (CH), 1737 (CO). 1H NMR
(300 MHz, CDCl3)
bromopropionic acid (0.0174 mol) for 11] was heated at reflux for
18 h. Then cold water (70 mL) was added with stirring and cooling
in ice bath. The reaction mixture was neutralized with NaHCO3 and
then extracted with dichloromethane (3ꢂ25 mL). The dichloro-
methane extracts were dried over anhydrous Na2SO4 and concen-
trated. The crude product was purified by column chromatography
on silica gel using dichloromethane/petroleum ether (6/4) mixture
as eluent. In first fractions ester was isolated and then unreacted
amine.
d
ppm: 7.51 (d, 1H, J¼7.6 Hz), 7.44 (d, 2H,
J¼7.9 Hz), 7.41e7.31 (m, 5H), 7.24 (d, 1H, J¼16.0 Hz, H-7/8), 7.18 (d,
2H, J¼7.9 Hz), 7.03 (t, 1H, J¼7.6 Hz), 6.99 (d, 1H, J¼16.0 Hz, H-7/8),
6.75 (t, 1H, J¼7.6 Hz), 6.41 (d, 1H, J¼7.6 Hz), 5.13 (s, 1H, CH), 3.74 (s,
3H, CH3), 2.37 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3)
d ppm: 172.6
(s, CO), 143.4 (s), 137.8 (s), 137.7 (s), 135.0 (s), 131.4 (d), 129.6 (d),
129.1 (d), 128.8 (d), 128.5 (d), 127.6 (d), 127.4 (d), 126.7 (d), 124.8
(s), 123.1 (d), 118.6 (d), 112.3 (d), 61.1 (q, CH3-est), 53.1 (d, CH), 21.5
(q, CH3). MS m/z: 357 (Mþ, 100%). Elemental analysis calcd
C24H23NO2 (Mr¼357): C 80.64, H 6.49, N 3.92%; C 80.36, H 6.69, N
4.02%.
4.2.1.1.1. trans-Ethyl-N-{2-[2-phenylethenyl]phenyl}amino-
acetate, 10a. Yield 2.05 g (42.0%), yellow solid, mp 52 ꢁC, metha-
nol; TLC Rf¼0.42 (6/4 CH2Cl2/petroleum ether). UV (EtOH) lmax
nm (
/dm3 molꢀ1 cmꢀ1): 247 (17,705), 287 (16,882), 346 (10,620).
IR (KBr)nmax/cmꢀ1: 3417 (NH), 3059, 3025, 2982, 2930 (CH), 1741
(C]O). 1H NMR (300 MHz, CDCl3)
/
3
4.2.2. Preparation of acids 13e15.
d
ppm: 7.56 (d, 2H, J¼7.5 Hz),
4.2.2.1. General procedure for 13a/13b and 14. Suspension of
corresponding ester (0.0115 mol) and NaOH (0.552 g, 0.0138 mol)
dissolved in water (30 mL) was heated for 3 h at reflux after which
time the reaction mixture was homogeneous. After cooling the
reaction mixture was extracted with dichloromethane (3ꢂ5 mL).
The aqueous layer was acidified to pH 4 with concentrated
hydrochloric acid. A white solid precipitated from the solution and
collected by filtration.
7.46e7.20 (m, 6H), 7.03 (d, 1H, J¼16.2 Hz), 6.85 (t, 1H, J¼7.5 Hz),
6.59 (d, 1H, J¼7.5 Hz), 4.29 (q, 2H, J¼7.2 Hz), 3.98 (s, 2H), 1.33 (t,
3H, J¼7.2 Hz). 13C NMR (75 MHz, CDCl3)
d ppm: 170.9 (s, C]O),
144.2 (s), 137.3 (s), 130.9 (d), 128.7 (d), 128.5 (d), 127.4 (d), 127.3
(d), 126.3 (d), 124.2 (s), 123.8 (d), 118.2 (d), 111.0 (d), 61.2 (t), 45.8
(t), 14.0 (q). MS m/z: 281 (Mþ, 56.9%). Elemental analysis calcd (%)
C18H19NO2 (Mr¼281.35): C 76.84, H 6.81, N 4.98%; found C 77.10, H
6.81, N 5.08%.
4.2.2.1.1. trans-N-{2-[2-Phenylethenyl]phenyl}aminoacetic acid,
13a. Yield 2.25 g (77.2%); white solid, mp 138e139 ꢁC. IR (KBr)
nmax/cmꢀ1: 3424 (NH), 1725 (C]O). 1H NMR (300 MHz, CDCl3)
4.2.1.1.2. trans-Ethyl-N-{2-[2-(4-methylphenyl)ethenyl]phenyl}
aminoacetate, 10b. Yield 2.84 g (55.4%), yellow oil; TLC Rf¼0.42 (6/4
CH2Cl2/petroleum ether). UV (EtOH) lmax/nm (
3
/dm3 molꢀ1 cmꢀ1):
d
ppm: 7.53 (d, 2H, J¼7.5 Hz), 7.44e7.18 (m, 7H), 7.00 (d, 1H,
J¼16.2 Hz), 6.85 (t, 1H, J¼7.5 Hz), 6.58 (d, 1H, J¼7.5 Hz), 4.25 (br s,
1H, NH), 4.00 (s, 2H). 13C NMR (75 MHz, CDCl3)
ppm: 175.7 (s, C]
201 (21,128), 278 (18,270), 294 (18,770). IR (neat) nmax/cmꢀ1: 3415
(NH), 3022, 2981, 2921 (CH),1740 (C]O). 1H NMR (300 MHz, CDCl3)
d
d
ppm: 7.48e7.44 (m, 3H), 7.28e7.20 (m, 4H), 7.01 (d, 1H,
O), 143.4 (s), 136.9 (s), 130.9 (d), 128.4 (d), 128.2 (d), 127.2 (d), 127.1
(d), 126.0 (d), 124.1 (s), 123.3 (d), 118.4 (d), 110.8 (d), 45.3 (t). MS m/
z: 253 (Mþ, 42.5%). Elemental analysis calcd C16H15NO2
(Mr¼253.30): C 75.87, H 5.97, N 5.53%; found C 76.25, H 5.79, N
5.83%.
J¼16.2 Hz), 6.86 (t, 1H, J¼7.8 Hz), 6.59 (d, 1H, J¼7.8 Hz), 4.30 (q, 2H,
J¼6.9 Hz), 3.98 (s, 2H), 2.41 (s, 3H), 1.34 (t, 3H, J¼6.9 Hz). 13C NMR
(75 MHz, CDCl3) d ppm: 170.9 (s, C]O), 144.1 (s), 137.3 (s), 134.6 (s),
130.9 (d), 129.2 (d), 128.5 (d), 127.2 (d), 126.3 (d), 124.5 (s), 122.7 (d),
118.3 (d), 111.0 (d), 61.2 (t), 45.9 (t), 21.1 (q), 14.0 (q). MS m/z: 295
(Mþ, 82.3%).
4.2.2.1.2. trans-N-{2-[2-(4-Methylphenyl)ethenyl]phenyl}amino-
acetic acid, 13b. Yield 2.30 g (75.0%), white solid, mp 117e118 ꢁC. UV
4.2.1.1.3. trans-Ethyl-N-{2-[2-(4-methylphenyl)ethenyl]phenyl}
(EtOH) lmax/nm (3
/dm3 molꢀ1 cmꢀ1): 203 (13,736), 216 (13,425),
amino-(
a-methyl)acetate, 11. Yield 2.76 g (51.3%), yellow solid, mp
250 (11,987), 289 (12,522). IR (KBr) nmax/cmꢀ1:e3300e2500 (asos.
46e47 ꢁC; TLC Rf¼0.43 (6/4 CH2Cl2/petroleum ether). UV (EtOH)
COOH), 3428 (NH), 3023, 2918, 2754 (CH), 1727 (C]O). 1H NMR
lmax/nm (
3
/dm3 molꢀ1 cmꢀ1): 205 (19,953), 216 (19,952), 247
(600 MHz, DMSO)
d
ppm: 7.52 (d, 2H, J¼7.8 Hz), 7.44 (d, 1H,
(15,849), 289 (18,621), 349 (11,749). IR(KBr) nmax/cmꢀ1: 3371 (NH),
J¼7.8 Hz), 7.34 (d, 1H, J¼16.2 Hz), 7.17 (d, 2H, J¼7.8 Hz), 7.05 (t, 1H,
J¼7.8 Hz), 6.97 (d, 1H, J¼16.2 Hz), 6.61 (t, 1H, J¼7.8 Hz), 6.40 (d, 1H,
J¼7.8 Hz), 3.85 (s, 2H), 2.30 (s, 3H). 13C NMR (150 MHz, DMSO)
3011, 2982, 2937, 2871 (CH-ar), 1732 (CO). 1H NMR (600 MHz,
CDCl3)
d
ppm: 7.42 (d, 2H, J¼8.0 Hz), 7.39 (d,1H, J¼7.4 Hz), 7.14e7.18
(m, 4H), 6.95 (d, 1H, J¼16.0 Hz), 6.80 (t, 1H, J¼7.4 Hz), 6.61 (d, 1H,
J¼7.4 Hz), 4.19 (q, 2H, J¼7.2 Hz), 4.16 (q, 1H, J¼6.9 Hz), 2.37 (s, 3H),
1.51 (d, 3H, J¼6.9 Hz), 1.25 (t, 3H, J¼7.2 Hz). 13C NMR (150 MHz,
d ppm: 172. 8 (s, CO),145.3 (s),136.6 (s),135.0 (s),129.2 (d),128.6 (d),
128.3 (d), 126.5 (d), 125.8 (d), 123.2 (d), 122.5 (s), 116.6 (d), 110.5 (d),
44.8 (t), 20.9 (q). MS m/z: 267 (Mþ, 49.7%). Elemental analysis calcd
C17H17NO2 (Mr¼267.32): C 76.38, H 6.41, N 5.24%; found C 76.22, H
6.29, N 5.19%.
CDCl3)
d ppm: 174.6 (s, CO), 144.0 (s), 137.5 (s), 134.9 (s), 131.1 (d),
129.4 (d), 128.7 (d), 127.6 (d), 126.5 (d), 125.0 (s), 123.2 (d), 118.6 (d),
111.8 (d), 61.2 (t), 52.4 (d), 21.3 (q), 19.1 (q), 14.2 (q). MS m/z: 309
(Mþ, 100%). Elemental analysis calcd C20H23NO2 (Mr¼309): C 77.64,
H 7.49, N 4.53%; found C 77.80, H 7.58, N 4.56%.
4.2.2.1.3. trans-N-{2-[2-(4-Methylphenyl)ethenyl]phenyl}amino-
(a
-methyl)acetic acid, 14. Yield 3.07 g (95.0%), white solid, mp
115e118 ꢁC. UV (EtOH) lmax/nm ( /dm3 molꢀ1 cmꢀ1): 203 (20,417),
3
215 (19,055), 253 (16,218), 289 (17,378), 349 (10,000). IR (KBr) nmax
/
4.2.1.2. Preparation of trans-methyl-N-{2-[2-(4-methylphenyl)
cmꢀ1: e3300e2500 (asoc. COOH), 3407 (NH), 3020, 2978, 2922,
ethenyl]phenyl}amino-(
9b (500 mg, 2.4 mmol), anhydrous sodium acetate (300 mg,
3.6 mmol), and methyl ester of -bromophenyl acetic acid (950 mg,
a
-phenyl)acetate, 12. A solution of amine
2875 (CH-ar), 1710 (CO). 1H NMR (600 MHz, DMSO)
d ppm: 7.55 (d,
2H, J¼8.0 Hz), 7.47 (d, 1H, J¼7.8 Hz), 7.44 (d, 1H, J¼16.0 Hz), 7.18 (d,
2H, J¼8.0 Hz), 7.08 (t, 1H, J¼7.5 Hz), 6.98 (d, 1H, J¼16.0 Hz), 6.65 (t,
1H, J¼7.5 Hz), 6.47 (d, 1H, J¼7.8 Hz), 4.02 (q, 1H, J¼7.3 Hz), 2.31 (s,
a
6.0 mmol) was heated at reflux for 7 h. After cooling, light yellow
crystals were precipitated from the solution and collected by fil-
tration. The crude product was purified by column chromatography
3H), 1.48 (d, 3H, J¼7.4 Hz). 13C NMR (150 MHz, DMSO)
d ppm: 176.5
(s, CO), 145.3 (s), 137.0 (s), 135.4 (s), 129.6 (d), 129.0 (d), 128.7 (d),

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K. Butkovic et al. / Tetrahedron 66 (2010) 9356e9362
9360
127.1 (d), 126.3 (d), 123.7 (d), 123.3 (s), 117.4 (d), 111.5 (d), 51.8 (d),
was added with stirring and cooling in ice bath. After neutralization
with Na2CO3$H2O, dichloromethane (15 mL) was added. The organic
layer was separated and combined with additional dichloromethane
extracts (3ꢂ10 mL), dried, and concentrated. Sydnone 3b was iso-
lated from the crude mixture by column chromatography using
dichloromethane as eluent. Spectroscopic data of isolated 3b are
identical with literature data:3 1.04 g (91.4%), yellow solid, mp
21.3 (q), 18.6 (q). MS m/z: 281 (Mþ, 100%).
4.2.2.2. Preparation of trans-N-{2-[2-(4-methylphenyl)ethenyl]
phenyl}amino-(a-phenyl)acetic acid, 15. In a suspension of 12
(0.25 g, 0.7 mmol) and NaOH (0.04 g, 1.1 mmol) dissolved in water
(20 mL), ethanol (15 mL) was added and reaction mixture was
heated for 24 h at reflux, after which time the reaction mixture was
homogeneous. Volume was reduced by evaporation toe1/3 V, then
the reaction mixture was extracted with dichloromethane
(3ꢂ5 mL). The aqueous layer was acidified to pH 4 with concen-
trated hydrochloric acid. A white solid precipitated from the solu-
tion and was collected by filtration. Yield on 15 is 183 mg (76.0%);
white solid, mp 191e193 ꢁC. IR (KBr) nmax/cmꢀ1:e3300e2500 (asoc.
COOH), 3436 (NH), 3028, 2914 (CH), 1707 (CO). 1H NMR (300 MHz,
162e164 ꢁC. 1H NMR (600 MHz, CDCl3)
d
ppm: 7.89 (d,1H, J¼8.1 Hz),
7.64 (m, 1H, J¼7.95 Hz), 7.48e7.46 (d, 2H), 7.33 (d, 2H, J¼8.2 Hz), 7.17
(d, 2H, J¼8.2 Hz), 7.17 (d, 1H, J¼16.2 Hz), 6.80 (d, 1H, J¼16.2 Hz), 6.55
(s, 1H, CH-syd), 2.36 (s, 3H, CH3).
4.2.3.3. General procedure for the preparation of sydnones 4 and
5. We have found that the compounds 4 and 5 could be prepared
from corresponding esters, 11 and 12, respectively, without iso-
lation and purification of their acids (14, 15), and nitroso derivatives
(17, 18). After hydrolysis of esters (1 mmol, the procedure is de-
scribed in 4.2.2.) and extraction with dichloromethane, to the
aqueous layer NaNO2 (3 equiv calculated on amount of starting
ester) was added. After stirring for 30 min the reaction mixture was
put in an ice bath and acidified to pH 4 by dropwise addition of
concentrated hydrochloric acid. A light brown solid precipitated
from the solution. The mixture was stirred with cooling for addi-
tional 3 h and then dichloromethane was added. The organic layer
was separated and combined with additional dichloromethane
extracts, dried, and concentrated. Acetic anhydride was added in
residue and reaction mixture was put on dark place for 7 days. Then
water (50 mL) was added with stirring and cooling on the ice bath.
After neutralization with Na2CO3$H2O, dichloromethane (20 mL)
was added. The organic layer was separated and combined with
additional dichloromethane extracts (3ꢂ15 mL), dried, and con-
centrated. Sydnones were isolated from crude mixture by column
chromatography using dichloromethane.
DMSO)
d ppm: 7.56e7.52 (m, 4H), 7.44e7.29 (m, 5H), 7.20 (d, 2H,
J¼7.9 Hz), 7.01 (d, 1H, J¼15.6 Hz), 6.99 (t, 1H, J¼7.9 Hz), 6.55 (t, 1H,
J¼7.9 Hz), 6.46 (d, 1H, J¼7.9 Hz), 5.17 (s, 1H), 2.32 (s, 3H). 13C NMR
(75 MHz, DMSO)
d ppm: 172.8 (s, CO), 143.5 (s), 138.4 (s), 136.7 (s),
134.6 (s), 129.4 (d), 129.2 (d), 128.4 (d), 128.3 (d), 127.7 (d), 127.4 (d),
126.5 (d), 126.4 (d), 123.6 (s), 123.1 (d), 117.4 (d), 112.0 (d), 59.7 (d,
CH), 20.8 (q, CH3). MS m/z: 344 (Mþþ1, 100%).
4.2.3. Preparation of sydnones 3e5.
4.2.3.1. Preparation of trans-3-{2-[2-phenylethenyl]phenyl}syd-
none, 3a. A suspension of 13a (400 mg, 1.6 mmol) and sodium ni-
trite (165 mg, 2.4 mmol) in water (1 mL) was cooled down and
stirred at 0 ꢁC for 1 h. Then the reaction mixture was acidified to pH
4 by the dropwise addition of concentrated hydrochloric acid. A
light brown solid precipitated from the solution. The mixture was
stirred for additional 3 h with cooling at 0 ꢁC and then dichloro-
methane (5 mL) was added. The organic layer was separated and
combined with additional dichloromethane extracts (3ꢂ5 mL),
dried, and concentrated. Acetic anhydride (2 mL) was added to the
residue and reaction mixture was put on dark place for seven days.
Then water (50 mL) was added with stirring and cooling on the ice
bath. After neutralization with Na2CO3$H2O, dichloromethane
(10 mL) was added. The organic layer was separated and combined
with additional dichloromethane extraction (3ꢂ5 mL), dried, and
concentrated. Sydnone was isolated from crude mixture by column
chromatography using dichloromethane as eluent. Compound 3a:
392 mg (92.7%), white solid, mp 125e127 ꢁC; TLC Rf¼0.24 (CH2Cl2).
4.2.3.3.1. trans-4-Methyl-3-{2-[2-(4-methylphenyl)ethenyl]phe-
nyl}sydnone, 4. Yield 172 mg (58.8%); white solid, mp 146e147 ꢁC;
TLC Rf¼0.18 (CH2Cl2). UV (EtOH) lmax/nm (
3
/dm3 molꢀ1 cmꢀ1): 203
(22,909), 231 (14,125), 312 (28,184). IR (KBr) nmax/cmꢀ1: 3060, 3033,
2995, 2945, 2912 (CH), 1733 (CO-syd). 1H NMR (600 MHz, CDCl3)
d
ppm: 7.92 (d, 1H, J¼7.9 Hz), 7.67 (t, 1H, J¼7.7 Hz), 7.49 (t, 1H,
J¼7.7 Hz), 7.37 (d, 1H, J¼7.9 Hz), 7.31 (d, 2H, J¼8.0 Hz), 7.17e7.20 (m,
3H), 6.58 (d, 1H, J¼16.1 Hz), 2.37 (s, 3H), 1.96 (s, 3H). 13C NMR
(150 MHz, CDCl3) d ppm: 168.7 (s, CO-syd), 139.4 (s), 134.2 (d), 133.5
(s), 132.5 (s), 131.8 (d), 130.6 (s), 129.2 (d), 127.9 (d), 126.5 (d), 126.3
(d),125.9 (d),118.0 (d),106.4 (s, C-syd), 20.8 (q), 6.9 (q). MS m/z: 292
(Mþ, 100%), 248 (11), 207 (60). Elemental analysis calcd C18H16N2O2
(Mr¼292): C 73.95, H 5.52, N 9.58%; found C 73.79, H 5.60, N 9.64%.
4.2.3.3.2. trans-4-Phenyl-3-{2-[2-(4-methylphenyl)ethenyl]phe-
nyl}sydnone, 5. Yield 64 mg (18.0%), white solid, mp 132e133 ꢁC;
UV (EtOH) lmax/nm (
IR (KBr) nmax/cmꢀ1
(300 MHz, CDCl3)
3
/dm3 molꢀ1 cmꢀ1): 223 (17,326), 298 (30,724).
:
3145 (CH-syd), 1752 (CO-syd). 1H NMR
d
ppm: 7.90 (d, 1H, J¼7.98 Hz), 7.67 (m, 1H,
J¼7.98 Hz), 7.50e7.27 (m, 7H), 7.21 (d, 1H, J¼16.2 Hz), 6.86 (d, 1H,
J¼16.1 Hz), 6.57 (s, 1H, H-Syd). 13C NMR (75 MHz, CDCl3)
d ppm:
168.3 (s, CO-syd), 135.4 (s), 134.2 (d), 132.6 (s), 132.0 (d), 131.9 (s),
128.6 (d), 128.5 (d), 128.6 (d), 126.8 (d),126.6 (d), 125.1 (d), 119.5 (d),
97.8 (d, C-syd). MS m/z: 264 (Mþ, 35.6%), 234 (87.3%), 206 (100%),178
(45.8%). Elemental analysis calcd C16H12N2O2 (Mr¼264.28): C 72.72,
H 4.58, N 10.60%; found C 72.73, H 4.46, N 10.57%.
Rf¼0.46 (CH2Cl2). UV (EtOH) lmax/nm (
(15,169), 315 (22,959). IR (KBr) nmax/cmꢀ1: 2925 (CH), 1737 (CO). 1H
NMR (600 MHz, CDCl3)
3
/dm3 molꢀ1 cmꢀ1): 233
d
ppm: 7.86 (d, 1H, J¼7.8 Hz), 7.66 (t, 1H,
J¼7.8 Hz), 7.45 (t, 1H, J¼7.8 Hz), 7.42 (d, 1H, J¼7.8 Hz), 7.28e7.27 (m,
2H), 7.21e7.19 (m, 5H), 7.13 (d, 2H, J¼7.8 Hz), 7.02 (d, 1H, J¼16.0 Hz),
6.62 (d, 1H, J¼16.0 Hz), 2.34 (s, 3H). 13C NMR (150 MHz, CDCl3)
4.2.3.2. Preparation of trans-3-{2-[2-(4-methylphenyl)ethenyl]
phenyl}sydnone, 3b from 13b. A suspension of 13b (1.08 g, 4.1 mmol)
inwater (25 mL) andhydrochloric acid (1.5 mL) was cooleddown and
stirred at 0 ꢁC for 2 h. Then a suspension of sodium nitrite (423 mg,
6.2 mmol) in water (3 mL) was added dropwise. Reaction mixture
was stirred with cooling for 1 h and then additional amount of so-
dium nitrite (141 mg in 3 mL of water) was added and cooling with
stirring was continued for an hour. Then dichloromethane (15 mL)
was added and the organic layer was separated and combined with
additional dichloromethane extracts (3ꢂ10 mL), dried, and concen-
trated. Acetic anhydride (5 mL) was added in residue, and reaction
mixture was put on dark place for seven days. Then water (100 mL)
d ppm: 167.1 (s, CO-syd), 139.3 (s), 134.8 (d), 134.5 (s), 133.3 (s),
132.5 (d), 132.4 (s), 129.7 (d), 128.9 (d), 128.9 (d), 128.7 (d), 127.2 (d),
127.1 (d), 126.9 (d), 126.6 (d), 124.7 (s), 119.0 (d), 109.5 (s, C-syd),
21.52 (q). MS m/z: 355 (Mþþ1, 32%). Elemental analysis calcd
C23H18N2O2 (Mr¼354): C 77.95, H 5.12, N 7.90%; found C 77.62, H
5.32, N 8.01%.
4.3. Irradiation experiments
4.3.1. Irradiation of 3a and 3b. A solution of 3a or 3b in benzene or
acetonitrile (3a: 5.0ꢂ10ꢀ3 M; 3b: 4.7ꢂ10ꢀ3 M) was purged with
argon for 15 min and irradiated at 300 nm in a Rayonet reactor in

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K. Butkovic et al. / Tetrahedron 66 (2010) 9356e9362
9361
a quartz tube for 60 min. Solvent was removed in vacuum and the
oily residue subjected to chromatography on silica gel column and
thin layer chromatography using dichloromethane and/or dichlo-
romethane/diethyl ether (9.8/0.2) mixture as eluent affording
quinoline 19a14 and 19b,14 respectively, and aminostilbenes 9a/9b.
70 ꢁC under an atmosphere of nitrogen for 4 h. The reaction was
then cooled to room temperature and rendered basic (pH 8) with
10% aq sodium bicarbonate (50 mL). The mixture was extracted
with ethyl acetate (3ꢂ20 mL). The organics were combined and
washed thoroughly with saturated NaCl (aq), dried over MgSO4,
and filtered. Following reduction of the solvent in vacuo, the ma-
terial remaining was subjected to chromatography on silica gel
using dichloromethane as eluent.
4.3.2. Irradiation of trans-4. A solution of trans-4 (50 mg, 0.17 mmol)
in benzene (38 mL) was purged with argon for 15 min and irradiated
at 300 nm in a Rayonet reactor in a quartz tube for 40 min. The solvent
was removed in vacuo and the oily residue subjected to chromatog-
raphy on silica gel column using dichloromethane and/or dichloro-
methane/diethyl ether (9.8/0.2) mixture as eluent. Quinoline 20 and
benzodiazepine 7 were isolated.
2-Methyl-3-phenylquinoline, 20: 220 mg (28.6%) (physical and
spectroscopic data given in 4.3.2.).
2,3-Diphenylquinoline, 21: 300 mg (23.9%), colorless solid, mp
81e82 ꢁC. UV (EtOH) lmax/nm ( /dm3 molꢀ1 cmꢀ1): 208 (40,956),
3
235 (39,406), 258 (34,686), 329 (6017). IR (neat) nmax/cmꢀ1: 3057,
3034, 2922 (CH). 1H NMR (300 MHz, CDCl3)
ppm: 8.21 (d, 1H,
d
4.3.2.1. 2-Methyl-3-(4-methyphenyl)quinoline, 20. Yield 4 mg
(10.0%); yellow oil, TLC Rf¼0.19 (9.8/0.2 CH2Cl2/Et2O). UV (EtOH)
J¼8.4 Hz), 8.16 (s, 1H), 7.85 (d, 1H, J¼8.1 Hz), 7.73 (t, 1H, J¼7.9 Hz),
7.56 (t,1H, J¼7.4 Hz), 7.47e7.43 (m, 2H), 7.30e7.22 (m, 8H). 13C NMR
lmax/nm (
3
/dm3 molꢀ1 cmꢀ1): 214 (37,802), 232 (38,984), 320
(75 MHz, CDCl3) d ppm: 158.6 (s), 147.5 (s), 140.6 (s), 140.2 (s), 137.7
(4616). IR (neat) nmax/cmꢀ1: 3053, 2920 (CH). 1H NMR (600 MHz,
CDCl3)
(d), 134.7 (s), 130.2 (d), 129.9 (d), 129.8 (d), 129.6 (d), 128.4 (d), 128.2
(d), 128.1 (d), 127.7 (d), 127.4 (d), 127.4 (s), 126.9 (d). MS m/z: 382
(Mþþ1, 100%), 251 (8%). Elemental analysis, calcd for C21H15N2
(Mr¼381): C 89.65, H 5.37, N 4.98%; found C 89.63, H 5.48, N 5.06%.
d
ppm: 8.06 (d, 1H, J¼8.0 Hz), 7.95 (s, 1H), 7.78 (d, 1H,
J¼8.0 Hz), 7.69 (t, 1H, J¼8.0 Hz), 7.50 (t, 1H, J¼8.0 Hz), 7.30 (d, 2H,
J¼8.3 Hz), 7.29 (d, 2H, J¼8.3 Hz), 2.67 (s, 3H, CH3) 2.45 (s, 3H, CH3).
13C NMR (150 MHz, CDCl3)
d ppm: 157.6 (s), 147.0 (s), 137.4 (s), 137.0
(s), 136.0 (d), 135.8 (s), 129.2 (d), 129.1 (d), 129.1 (d), 128.5 (d), 127.4
(d), 127.0 (s), 126.0 (d), 24.6 (q, CH3), 21.2 (q, CH3). MS m/z: 233 (Mþ,
100%). Elemental analysis, calcd for C17H15N (Mr¼233.12): C 87.52,
H 6.48, N 6.00%; found C 87.31, H 6.02, N 6.13%.
4.5. Decomposition of benzodiazepine 7
During the purification and isolation of 7 on silica gel column
and thin layer chromatography the amount of 7 was rapidly de-
creasing in favor of E-24 formation: (E)-1-(3H-indazol-3-ylidene)-1-
(p-tolyl)propan-2-one, 24: 1H NMR (600 MHz, CDCl3)
d ppm: 7.47 (d,
4.3.2.2. 3-Methyl-4-(4-methylphenyl)-1H-1,2-benzodiazepine,
7. Yield 16 mg (39.0%); oily matter; TLC Rf¼0.10 (9.8/0.2 CH2Cl2/
Et2O). IR (KBr) nmax/cmꢀ1: 3324 (NH), 3023, 2921, 2852 (CH). 1H
1H, J¼7.0 Hz, H-2), 7.41 (t, d,1H, J¼7.0 Hz, H-4), 7.32 (d, 2H, J¼8.1 Hz,
H-10), 7.27e7.24 (m, 3H, H-11, and H-3), 7.15 (d, 1H, J¼7.0 Hz, H-5),
2.39 (s, 3H, CH3), 2.31 (s, 3H, COCH3). 13C NMR (150 MHz, CDCl3)
NMR (600 MHz, CDCl3)
J¼7.8 Hz), 7.04 (s, 1H), 6.85 (d, J¼7.8 Hz), 6.50 (br s, NH), 2.38 (s, 3H,
CH3) 1.88 (s, 3H, CH3). 13C NMR (150 MHz, CDCl3)
ppm: 162.3 (s),
d ppm: 7.24e7.19 (m, 6H), 7.09 (t, 1H,
d
ppm: 196.1 (s, CO), 153.5 (s, C-8), 145.6 (s, C-7), 137.1 (s, C-12),
d
133.1 (d, C-4), 132.9 (s), 130.0 (s), 128.9 (d, C-10), 128.5 (d, C-11),
128.2 (d, C-3), 121.6 (d, C-2), 118.8 (d, C-5), 20.8 (q, CH3), 12.1 (q,
COCH3). MS m/z: 263 (MþþH, 100%).
156.3 (s), 148.1 (s), 143.5 (s), 137.8 (s), 135.3 (d), 131.2 (s), 129.7 (d),
129.5 (d), 129.3 (d), 127.7 (d), 124.7 (d), 120.2 (d), 21.4 (q, CH3), 21.2
(q, CH3). MS m/z: 248 (Mþ, 100%).
Acknowledgements
4.3.3. Irradiation of trans-5. A solution of 5 (50 mg, 0.14 mmol) in
benzene (41 mL) was purged with argon for 15 min and irradiated at
350 nm in a Rayonet reactor in a Pyrex tube for 20 min. The solvent
was removed in vacuo and the oily residue subjected to chroma-
tography on silica gel column using dichloromethane and/or
dichloromethane/diethyl ether (9.8/0.2) mixture as eluent affording
4-(4-Methylphenyl)-3-phenyl-1H-1,2-benzodiazepine, 8: 43 mg
(67.0%), yellow solid, mp 147e148 ꢁC; Rf¼0.18 (CH2Cl2). UV (EtOH)
This work was supported by grants from the Ministry of
Science, Education and Sports of the Republic of Croatia (grant no.
125-0982933-2926, 098-0982929-2917).
Supplementary data
1H and 13C NMR spectra of compounds 4, 5, 7, 8, 20, and NOE of
8, HMBC of 24. Supplementary data associated with this article can
be found in online version at doi:10.1016/j.tet.2010.10.013. These
data include MOL files and InChIKeys of the most important com-
pounds described in this article.
lmax/nm (
nmax/cmꢀ1: 3318 (NH), 3055, 3016, 2912, 2852 (CH). 1H NMR
(600 MHz, CDCl3)
3
/dm3 molꢀ1 cmꢀ1): 245 (20,585), 290 (15,994). IR (KBr)
d
ppm: 7.47 (s, 1H), 7.38 (d, 2H, J¼7.6 Hz), 7.27 (d,
1H, J¼7.6 Hz), 7.21 (t, 1H, J¼7.6), 7.16e7.10 (m, 6H), 7.01 (d, 2H,
J¼7.6 Hz), 6.88 (d,1H, J¼7.6 Hz), 6.81 (br s,1H, NH), 2.25 (s, 3H, CH3).
13C NMR (150 MHz, CDCl3)
d ppm: 163.5 (s), 149.2 (s), 141.7 (s), 137.6
References and notes
(s), 137.5 (s), 137.5 (d), 136.7 (s), 131.5 (s), 129.8 (d), 129.8 (d), 129.3
(d), 128.8 (d), 128.8 (d), 128.1 (d), 127.4 (d), 125.2 (d), 120.6 (d), 21.3
(q, CH3). MS m/z: 311 (Mþþ1, 100%). Elemental analysis, calcd for
C22H18N2 (Mr¼310): C 85.13, H 5.85, N 9.03%; found C 84.91, H 5.53,
N 9.04%.
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