1,3-Dipolar cycloaddition between acetylenic dipolarophiles and sydnone-N-ylides as bis(1,3-dipoles)

Article abstract of DOI:10.1016/j.tet.2015.10.021

1,3-Dipolar cycloaddition reaction of sydnone-N-ylides, as model bis(1,3-dipoles), with acetylenic dipolarophiles in 1,2-epoxybutane under reflux gave exclusively pyrroloazines containing a sydnone moiety that resulted by preferred reaction of the N-ylide

Full text of DOI:10.1016/j.tet.2015.10.021

Accepted Manuscript
1,3-Dipolar cycloaddition between acetylenic dipolarophiles and sydnone-N-ylides as
bis(1,3-dipoles)
Florin Albota, Drăghici Constantin, Mino R. Caira, Florea Dumitrascu
PII:
S0040-4020(15)30121-6
10.1016/j.tet.2015.10.021
TET 27193
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 June 2015
Revised Date: 24 September 2015
Accepted Date: 6 October 2015
Please cite this article as: Albota F, Constantin D, Caira MR, Dumitrascu F, 1,3-Dipolar cycloaddition
between acetylenic dipolarophiles and sydnone-N-ylides as bis(1,3-dipoles), Tetrahedron (2015), doi:
10.1016/j.tet.2015.10.021.
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ACCEPTED MANUSCRIPT
1,3-Dipolar cycloaddition between acetylenic
Leave this area blank for abstract info.
dipolarophiles and sydnone-N-ylides as
bis(1,3-dipoles)
Florin Albotaa, Drăghici Constantina, Mino R. Cairab,*, Florea Dumitrascua,*
a Centre of Organic Chemistry ‘‘C. D. Nenitzescu’’, Roumanian Academy, Spl Independent¸ei 202B, 060023
Bucharest, Romania
b Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
1
E
2
O
O
X
N
E
X
Br-
O
N
O
N
N
+
CH2CO
CO
N+
Ph
8 examples, 43-56%
Reflux 10 h
Et
N+
Ph
E 1
E 2
X = CH or N
O
E1 = E2 = CO2R or E1 = CO2R, E2 = H

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
1,3-Dipolar cycloaddition between acetylenic dipolarophiles and sydnone-N-
ylides as bis(1,3-dipoles)
Florin Albotaa, Drăghici Constantina, Mino R. Cairab,*, Florea Dumitrascua,*
a Centre of Organic Chemistry ‘‘C. D. Nenitzescu’’, Roumanian Academy, Spl Independenței 202B, 060023 Bucharest, Romania
b Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
1,3-Dipolar cycloaddition reaction of sydnone-N-ylides, as model bis(1,3-dipoles), with
acetylenic dipolarophiles in 1,2-epoxybutane under reflux gave exclusively pyrroloazines
containing a sydnone moiety that resulted by preferred reaction of the N-ylide 1,3-dipole with
the acetylenic dipolarophiles. The assembled sydnone-ylide hybrid structures were generated in
situ from N-heteroaromatic bromides. The structure of the new compounds was assigned by IR
and NMR spectroscopy and confirmed by X-ray analysis for a representative compound.
Available online
Keywords:
Sydnone-N-ylides
2009 Elsevier Ltd. All rights reserved
.
bis(1,3-dipoles)
1,3-dipolar cycloaddition
pyrrolo[2,1-a]phthalazine
pyrrolo[2,1-a]isoquinoline
1. Introduction
2
3
Sydnones are mesoionic heterocyclic compounds with a 1,2,3-
oxadiazole skeleton. They were discovered in 1935 by Earl and
Mackney1 and their mesoionic structure was assigned in 1949 by
Baker and Ollis.2 Sydnones present an array of biological
properties such as antibacterial,3,5 antifungal,3,5 antimicrobial,4-6
anticancer,5,7 antiproliferative,8 anti-HIV,8 anti-inflammatory and
analgesic activities.9
N
R1
N+
N
1
N
N
O
2
R
5
O
4
1
2
3
Sydnones (Figure 1) undergo two main chemical reactions,
namely 1,3-dipolar cycloaddition to form pyrazoles and
electrophilic substitution at C-4.10 The hydrogen atom at position
4 of the sydnone ring can be substituted with a wide variety of
electrophiles via e.g. chlorination,11 bromination,11 iodination,11-13
and acylation.14 The most important chemical reaction of
sydnones is 1,3-dipolar cycloaddition with alkynes to give
pyrazoles that have numerous applications as pharmaceuticals
and agrochemicals.15-21
Fig. 1. The structure of sydnone 1, pyrrolo[2,1-a]isoquinoline
2 and pyrrolo[2,1-a]phthalazine 3.
As a result of their interesting chemistry, biological and
physicochemical properties, sydnones have already been the
subject of various reviews.10,23,24
On the other hand, the pyrroloazines, pyrrolo[2,1-
a]phthalazines and pyrrolo[2,1-a]isoquinolines have attracted
more attention due to their biological25-30 and optical31,32
properties. Furthermore, pyrrolo[2,1-a]isoquinoline serves as the
scaffold of important classes of alkaloids such as lamellarins,
crispine, salsoline, erythrina and annosqualine.33 The most
versatile method of synthesis of pyrroloazines is the 1,3-dipolar
cycloaddition reaction between heteroaromatic N-ylides and
acetylenic dipolarophiles.34-52
Also, the sydnones served as a key intermediate in the
synthesis of the alkaloid withasomnine22 and as starting material
for obtaining other heterocyclic compounds.19
___________
Herein we report the generation of sydnone-N-ylides as
bis(1,3-dipoles) and their reactivity in the 1,3-dipolar
cycloaddition reaction with acetylenic dipolarophiles.
a e-mail: fdumitra@yahoo.com
b Tel.: +27-21-650-3071; fax: +27-21-650-5195; e-mail:
Mino.Caira@uct.ac.za

2
Tetrahedron
ACCEPTED MANUSCRIPT
2. Results and discussion
The structure of the azinium bromides 7a,b was assigned by
ATR-IR, 1H-NMR and 13C-NMR spectroscopy. The ATR-IR
spectral features are the presence of vibrational bands of the C=O
groups at 1681 and 1678 cm-1 respectively for CO-CH2, whereas
the bands for the carbonyl groups of the sydnone ring appear at
1776 and 1782 cm-1 respectively. In the 1H-NMR spectra of 7a,b
the methylene groups appear as deshielded singlets with δ of 6.46
ppm and 6.48 respectively due to their direct bonding to the
quaternary nitrogen and C=O group. The 13C-NMR spectrum for
the azinium bromides presents all the expected signals. The
characteristic shifts for the carbonylic atoms are at ~ 167 ppm for
the endocyclic C=O of the sydnone ring and at ~176 ppm for the
exocyclic C=O. The carbon atoms of the methylene groups
appear at ~ 66 and 69 ppm, respectively. The C-1 carbons are
strongly deshielded at ~ 150 ppm due to their proximity to the
nitrogen atom.
Based on the capacity of a sydnone and a heteroaromatic N-
ylide to act as 1,3-dipoles in 3+2 cycloaddition reaction, our
intention was to assemble the sydnone and N-ylide 1,3-dipoles
within the same molecule (Figure 2) and to investigate the
reactivity of the resulting bis(1,3-dipole) towards acetylenic
dipolarophiles.
R1
N+
N
O
het
N
CH CO
_
O
+
4
sydnone 1,3-dipole
N-ylide 1,3-dipole
het = heteroaromatic N-heterocycle
2.2. Reactions of bromides 7a,b with alkynes
Fig. 2. The structure of sydnone-N-ylides 4.
The reaction of the sydnone-N-ylides (Scheme 3) was carried
out by refluxing the bromides 7 with acetylenic dipolarophiles 12
in 1,2-epoxybutane. The latter solvent was employed both as
reaction medium and for its ability to act as a base to generate the
N-ylide from quaternary bromide 7. One of the advantages of
using 1,2-epoxybutane rather than other solvents and bases is the
atom economy owing to the fact that the products of the reaction
are only aromatized cycloadducts 13. With other solvents and
bases, the compounds 13 were obtained together with their
corresponding dihydroderivatives 17.34-36,47,50,54,55
2.1. Synthesis of azinium salts 7
The starting materials for the generation of sydnone-N-ylides
4 were the bromides 7a,b which were synthesized in good yields
by the quaternization reaction of isoquinoline and phthalazine
5a,b with 4-bromoacetyl-3-phenylsydnone 6 (Scheme 1). The
azinium bromides 7a,b were subsequently used in the generation
of sydnone-N-ylides 4.
7
6
6a
E1
5
8
E 2
X
N
O
5
4
3
6
9
O
acetone
10a
10b
CO
O
X
X
N
10
N
3
BrCH2CO
Br
N
+
N+
Ph
reflux
E
O
N
1
N
1
N
+
2
2
CH2CO
Ph
E
7
N+
Ph
4
2
8
1
O
X
Br
5a,b
a X = CH
b X = N
Et
6
7a,b
a X = CH
b X = N
O
N
N
+
CH2CO
N+
Ph
O
7a,b
a X = C
b X = N
Reflux 10h
+
7
6
Scheme 1. Synthesis of bromides 7a,b.
6a
5
1
2
8
O
X
N
E
E
O
N
The 4-bromoacetyl-3-phenylsydnone 6 was synthesized using
9
10a
10b
CO
10
N+
Ph
4
12a-d
3
a
method described in the literature53 starting from the
a E1 = CO2Me, E2 = CO2Me
b E1 = CO2Et, E2 = CO2Et
c E1 = CO2Me, E2 = H
d E1 = CO2Et, E2 = H
1
1
2
E
2
E
commercial product N-phenylglycine 8 (Scheme 2). In the
process of synthesizing compound 6 we developed an improved
method for the preparation of 4-acetyl-3-phenylsydnone 11 by
performing in only one step the cyclization of the N-nitroso-N-
phenylglycine 9 to 3-phenylsydnone 10 followed by its
acetylation.
13a-h
a X = C, E1 = CO2Me, E2 = CO2Me
b X = C, E1 = CO2Et, E2 = CO2Et
c X = C, E1 = CO2Me, E2 = H
d X = C, E1 = CO2Et, E2 = H
e X = N, E1 = CO2Me, E2 = CO2Me
f
X = N, E1 = CO2Et, E2 = CO2Et
g X = N, E1 = CO2Me, E2 = H
h X = N, E1 = CO2Et, E2 = H
Classical Method
Scheme 3. Synthesis of hybrid structures 13a-h.
In order to investigate the reactivity of sydnone-N-ylides
towards acetylenic dipolarophiles the cycloaddition reactions
were performed with large excess of acetylenic dipolarophiles
and prolonged reaction time (e.g. under reflux in 1,2-
epoxybutane for 48 h). Careful investigation by NMR
spectroscopy of the crude reaction product indicated that in all
cases, no compound resulted from 1,3-dipolar cycloaddition of
the sydnone moiety and the acetylenic dipolarophiles. Instead,
the formation of compounds 13 was a result of 1,3-dipolar
cycloaddition of the N-ylide 1,3-dipole and the acetylenic
dipolarophiles, demonstrating that under the reaction conditions
reported, the sydnone 1,3-dipole is not sufficiently reactive.
Ph
N
Ph
N
Ph
N+
HONO
H
N
Ac2O
-H2O
H
H
-
H
N
O
H
H
O
HO
HO
O
O
O
10
8
9
Ac2O
New
"one pot"
method
Ac2O
HClO4
Ph
N+
Ph
N+
-
Br2, CH3COOH
-
COCH2Br
COCH3
N
N
O
O
O
O
11
6
Scheme 2. Synthesis of 4-bromoacetyl-3-phenylsydnone 6
.

3
2.3. Structural characterization of compounds 13
ACCEPTED MANUSCRIPT
The structures of the N-hybrid heterocycles 13a-h were
confirmed by elemental analysis, as well as IR and NMR
spectroscopy, and for one representative case (13c) by X-ray
analysis (see below). The NMR data confirm the proposed
structures for the cycloadducts 13a-h. Additional evidence was
obtained using heteronuclear correlation spectroscopy
(HETCOR) and 1H-1H COSY.
The proton H-2 is present as a strongly deshielded singlet in
the range 8.16-8.50 ppm. This is present only when the
acetylenic dipolarophile 12 is a terminal alkyne. The H-10 proton
is strongly deshielded with a shift in the range 8.52-9.85 ppm and
this is good evidence that the ester group is attached to C-1 of the
pyrrole ring, thus highlighting the regioselectivity of the
cycloaddition reaction.
The chemical shifts of C-1 from the pyrroloazine moiety and
C-4 from the sydnone ring are shielded and appear in the range
107.6–111.7 ppm. The ester groups are deshielded in the range
164.1–165.0 ppm. The chemical shift of the carbonyl group of
the sydnone ring was found to be 164.8–166.1 ppm and was
deduced by comparison with those from the starting material 6
and literature data.53 The carbonyl group between the
pyrroloazine and sydnone heterocycles is strongly deshielded,
appearing at 168.8–170.9 ppm.
Fig. 3. The X-ray structure of 13c. Thermal ellipsoids are
drawn at the 50% probability level and intramolecular C-
H···O hydrogen bonds are indicated as dotted lines. Bond
lengths in the sydnone moiety are C20-C21 1.420(2), C21-
O23 1.424(1), O23-N24 1.370(1), N24-N25 1.301(1), N25-
C20 1.360(1), C21-O22 1.207(1) Å.
2.4. X-Ray structural confirmation
The X-ray structure of 13c, as a representative member of the
new hybrid heterocyclic series resulting from the cycloaddition
of the sydnone-N-ylide, is shown in Figure 3 and a summary of
the crystal and refinement data is provided in section 4.5. Full
details appear in the CIF file (Supplementary material). Bond
lengths associated with the 1,2,3-oxadiazole ring in 13c are
typical of those reported in the crystallographic literature for the
sydnone moiety.56 In particular, those in the molecule of 13c
(listed in the caption to Figure 3) are in close agreement with the
corresponding lengths recently reported for 4-bromoacetyl-3-
phenylsydnone.57 Regarding the planarity of the 1,2,3-oxadiazole
ring in 13c, the maximum deviation of any of the five atoms from
the least-squares plane is 0.006(1) Å. The 13-membered
pyrroloisoquinoline system is very slightly bowed, with a
maximum atomic deviation of 0.075(1) Å and this moiety is
inclined at an angle of 32.8(1)° to the 1,2,3-oxadiazole ring. The
orientations of the remaining residues (phenyl ring C26-C31 and
the -CO-OCH3 substituent) are evident from the torsion angles
C20-N25-C26-C27 [70.6(2)°], C4-C3-C14-O16 [-23.2(2)°] and
2.5. Mechanistic considerations
The reaction mechanism for obtaining hybrid heterocycles 13
(Scheme 4) implies, in the first step, the opening of the 1,2-
epoxybutane ring by the reaction with the bromide ion to form
the alkoxide 14, which abstracts the methylene proton, generating
the N-ylide 4 in situ. In the next step, the N-ylide reacts with the
acetylenic dipolarophiles 12a-d to form the primary cycloadduct
17, which undergoes aromatization to yield the final
cycloadducts 13a-h.
O
OH
O
N+
N+
het
het
+
+
-
CHCOSyd
H
CH-COSyd
Br
Br-
Br
4A
15
14
16
E1
E2
in situ
het
het
het
+
N
COSyd
E2
N
COSyd
H
N
-
CH-COSyd
12a-d
H
E1
13a-h
1
E
E2
4B
17
C3-C14-O16-C17
[177.4(1)°].
The
overall
molecular
conformation of 13c is largely determined by the intramolecular
C-H···O hydrogen bonds shown in Figure 3. For these, the C···O
and H···O distance pairs are as follows: C6-H···O19 [2.835(1),
2.22 Å], C11-H···O15 [2.980(2), 2.18 Å] and C4-H···O22
[3.047(1), 2.40 Å]. The reported values are all significantly less
than the corresponding sums of the van der Waals radii (C···O
3.22, H···O 2.72 Å,).58
Ph
N+
O
Syd :
N
O
Scheme 4. Reaction mechanism of 1,3-dipolar cycloaddition.
Molecules of 13c associate as centrosymmetric dimers via
intermolecular C-H···O hydrogen bonding and further crystal
cohesion is effected by π-stacking of inversion-related
pyrroloisoquinoline units with closest approach 3.528(1) Å.
3. Conclusions
In conclusion, the bis-1,3-dipolar structures 4, incorporating
both sydnone and N-heteroaromatic N-ylides (isoquinolinium and
phthalazinium N-ylides) in the same molecule, reacted by reflux
in 1,2-epoxybutane with acetylenic dipolarophiles to form
pyrroloazines with a sydnone moiety 13. The compounds 13
resulted from 1,3-dipolar cycloaddition of the acetylenes with the
N-ylide 1,3-dipole preferentially, owing to the lack of reactivity

4
Tetrahedron
of the sydnone 1,3-dipole under the reported experimental
4.3 General procedure for the synthesis of pyrrolo[2,1-a]azines
ACCEPTED MANUSCRIPT
conditions. The synthesis of the new compounds represents an
easy access to 4-hetaroyl-sydnones (Het-CO-Sydnones),
compounds that to our knowledge are not reported in the
literature. The aroylation of sydnones at the 4 position is
otherwise difficult to achieve. The structure of the new hybrid
heterocycles 13 was assigned by elemental analysis, ATR-IR,
NMR spectroscopy and for one case was confirmed by X-ray
analysis. In addition, a one-step method for the synthesis of 4-
acetyl-3-phenylsydnone 11 was developed starting from N-
nitroso-N-phenylglycine 9 and acetic anhydride. The new method
circumvents isolation of 3-phenylsydnone and its subsequent
acetylation.
13a-h
To a suspension of 7 (3 mmol) in 10 mL of 1,2-epoxybutane
was added 12 (4 mmol). The reaction mixture was heated at
reflux with stirring for 10 h when a solution was obtained. The
solvent was evaporated in vacuum and the residue was treated
with methanol or ethanol. The yellow precipitate was filtered by
suction and washed with methanol or ethanol. The product was
purified by crystallization from an appropriate solvent.
4.3.1.
Dimethyl
3-[(3-phenylsydnon-4-yl)-oxomethyl]-
(13a): The
pyrrolo[2,1-a]isoquinoline-1,2-dicarboxylate
compound was purified by crystallization from acetonitrile-
ethanol (1:1), yield 48%, mp 171-173 ºC. Found: C, 63.77; H,
3.91; N, 9.15. C25H17N3O7 requires C, 63.70; H, 3.63; N, 8.91. IR
(ATR): 1760 cm-1 (νC=O endocyclic); 1711 cm-1 (νC=O exocyclic).
1H NMR (300 MHz, CDCl3) δ (ppm): 3.90, 3.99 (2s, 6H, 2Me),
7.03 (d, 1H, J = 7.4 Hz, H-6), 7.52-7.75 (m, 8H, H-7, H-8, H-9,
H-2’, H-3’, H-4’, H-5’, H-6’), 8.52-8.55 (m, 1H, H-10), 8.65 (d,
1H, J = 7.4 Hz, H-5). 13C NMR (75 MHz, CDCl3) δ (ppm): 52.8,
53.0 (2Me), 109.0, 111.4 (C-1, C-4syd), 116.2 (C-6), 122.2,
124.0, 126.5, 129.5, 132.3 (C-2, C-3, C-6a, C-10a, C-10b), 123.4
(C-5), 124.3 (C-2’, C-6’), 125.0 (C-10), 127.2, 128.5, 129.2 (C-7,
C-8, C-9), 129.8 (C-3’, C-5’), 132.4 (C-4’), 135.0 (C-1’), 164.8,
164.9 (2COO), 166.1 (CO-endocyclic), 170.6 (CO-exocyclic).
4. Experimental
4.1. General
Melting points were determined on a Boëtius hot plate
microscope. The IR spectra were recorded on a FT-IR Bruker
Vertex 70. The NMR spectra were recorded on a Varian Gemini
1
300 BB instrument, operating at 300 MHz for H-NMR and 75
MHz for 13C-NMR. Supplementary evidence was given by
HETCOR and COSY experiments. Structural elucidation was
achieved by X-ray diffraction analysis of a representative
compound.
4.3.2. Diethyl 3-[(3-phenylsydnon-4-yl)-oxomethyl]-pyrrolo[2,1-
a]isoquinoline-1,2-dicarboxylate (13b): The compound was
purified by crystallization from acetonitrile-ethanol (1:1), yield
53%, mp 139-141 ºC. Found: C, 64.71; H, 4.51; N, 8.69.
C27H21N3O7 requires C, 64.93; H, 4.24; N, 8.41. IR (ATR): 1763
cm-1 (νC=O endocyclic); 1716 cm-1 (νC=O exocyclic). 1H NMR (300
MHz, CDCl3) δ (ppm): 1.38, 1.43 (2t, 6H, J = 7.4 Hz, 2Me),
4.34, 4.48 (2q, 4H, J = 7.4 Hz, 2CH2), 7.06 (d, 1H, J = 7.7 Hz, H-
6), 7.56-7.76 (m, 8H, H-7, H-8, H-9, H-2’, H-3’, H-4’, H-5’, H-
6’), 8.55-8.58 (m, 1H, H-10), 8.70 (d, 1H, J = 7.7 Hz, H-5). 13C
NMR (75 MHz, CDCl3) δ (ppm): 14.1, 14.2 (2Me), 61.9, 62.1
(2CH2), 109.2. 112.1 (C-1, C-4syd), 116.2 (C-6), 122.3, 124.3
126.9, 129.7 132.5 (C-2, C-3, C-6a, C-10a, C-10b), 123.6 (C-5),
124.4 (C-2’, C-6’), 125.2 (C-10), 127.3, 128.6, 129.2 (C-7, C-8,
C-9), 129.9 (C-3’, C-5’), 132.4 (C-4’), 135.1 (C-1’), 164.5, 165.0
(2COO), 165.9 (CO-endocyclic), 170.9 (CO-exocyclic).
4.2. General procedure for synthesis of azine bromides 7a,b
To a solution of 6 (1.98 g, 7 mmol) (4-bromoacetyl-3-
phenylsydnone) in 25 mL of acetone was added 5a,b (7 mmol).
The solution was heated at reflux with stirring for 4 h and after
cooling the precipitate was filtered and washed with acetone. The
crude product was used without further purification.
4.2.1.
2-[2-(3-Phenylsydnon-4-yl)-2-oxoethyl]isoquinolinium
bromide (7a): The compound was purified by crystallization
from ethanol, yield 87%, mp 245-246 ºC. Found C, 55.67; H,
3.67; N, 10.47. C19H14BrN3O3 requires C, 55.36; H, 3.42; N,
10.19. IR, (ATR): 1776 cm-1 (νC=O endocyclic); 1681 cm-1 (νC=O
exocyclic). 1H NMR (300 MHz, CDCl3 + TFA) δ (ppm): 6.46 (s,
2H, CH2), 7.52-7.57, 7.60-7.67 (2m, 5H, Ph), 7.96-8.02, 8.12-
8.22, 8.41-8.44 (3m, 4H, H-5,H-6, H-7, H-8), 8.28 (d, 1H, J = 6.9
Hz, H-4), 8.46 (d, 1H, J = 6.9 Hz, H-3), 9.76 (s, 1H, H-1). 13
C
4.3.3. Methyl 3-[(3-phenylsydnon-4-yl)-oxomethyl]-pyrrolo[2,1-
a]isoquinoline-1-carboxylate (13c): The compound was purified
by crystallization from acetonitrile, yield 43%, mp 227-228 ºC.
Found: C, 67.11; H, 3.87; N, 10.44. C23H15N3O5 requires C,
66.83; H, 3.66; N, 10.16. IR (ATR): 1758 cm-1 (νC=O endocyclic);
1700 cm-1 (νC=O exocyclic). 1H NMR (300 MHz, CDCl3) δ (ppm):
3.88 (s, 3H, Me), 7.06 (d, 1H, J = 7.4 Hz, H-6), 7.48-7.62 (m,
8H, H-7, H-8, H-9, H-2’, H-3’, H-4’, H-5’, H-6’), 8.41 (s, 1H, H-
2), 9.22 (d, 1H, J = 7.4 Hz, H-5), 9.73-9.76 (m, 1H, H-10). 13C
NMR (75 MHz, CDCl3) δ (ppm): 52.1 (Me), 107.6, 111.1 (C-1,
C-4syd), 116.0 (C-6), 122.3, 124.5, 130.9, 138.0 (C-3, C-6a, C-
10a, C-10b), 124.2 (C-2’, C-6’), 124.7 (C-5), 126.7, 128.1, 129.8
(C-7, C-8, C-9), 128.4 (C-10), 129.9 (C-3’, C-5’), 130.5 (C-2),
NMR (75 MHz, CDCl3 + TFA) δ (ppm): 66.6 (CH2), 105.3 (C-
4,Syd), 125.0 (2C, o-Ph), 126.2, 127.3, 131.1, 133.3, 135.8,
138.3 (C-3, C-4, C-5, C-6, C-7, C-8), 127.7, 138.2 (C-4a, C-8a),
129.8 (2C, m-Ph), 131.9 (p-Ph), 134.0 (C-1, Ph), 151.3 (C-1),
167.4 (CO-endocyclic), 176.3 (CO-exocyclic).
4.2.2.
2-[2-(3-Phenylsydnon-4-yl)-2-oxoethyl]phthalazinium
bromide (7b): The compound was purified by crystallization
from a mixture of ethanol and acetonitrile (3:1), yield 85%, mp
231-234 ºC Found: C, 52.69; H, 3.36; N, 13.82. C18H13BrN4O3
requires C, 52.32; H, 3.17; N, 13.56. IR (ATR): 1782 cm-1 (νC=O
1
endocyclic); 1678 cm-1 (νC=O exocyclic). H NMR (300 MHz,
CDCl3 + TFA) δ (ppm): 6.48 (s, 2H, CH2), 7.49-7.63 (m, 5H,
Ph), 8.28-8.34 (m, 2H, H-6, H-7), 8.40-8.45, 8.69-8.71 (2m, 2H,
H-5, H-8), 9.56 (s, 1H, H-4); 10.64 (s, 1H, H1). 13C NMR (75
MHz, CDCl3 + TFA) δ (ppm): 69.3 (CH2), 105.3 (C4-Syd),
124.9 (2C, o-Ph), 127.8, 128.0 (C-4a, C-8a), 127.9, 133.3, (C-5,
C-8), 129.8 (2C, m-Ph), 131.9 (C, p-Ph), 133.9 (C-1, Ph), 136.9,
140.6 (C-6, C-7), 153.9, 154.2 (C-1, C-4), 167.1 (CO-
endocyclic), 175.6 (CO-exocyclic).
132.4 (C-4’), 135.4 (C-1’), 164.8 (COO),
endocyclic), 169.0 (CO-exocyclic).
165.6 (CO-
4.3.4. Ethyl 3-[(3-phenylsydnon-4-yl)-oxomethyl]-pyrrolo[2,1-
a]isoquinoline-1-carboxylate (13d): The compound was purified
by crystallization from acetonitrile, yield 47%, mp 199-201 ºC.
Found: C, 67.74; H, 4.29; N, 10.12. C24H17N3O5 requires C,
67.44; H, 4.01; N, 9.83. IR (ATR): 1755 cm-1 (νC=O endocyclic);
1701 cm-1 (νC=O exocyclic). 1H NMR (300 MHz, CDCl3) δ (ppm):
1.48 (t, 3H, J = 7.1 Hz, Me), 4.46 (q, 2H, J = 7.1 Hz, CH2), 7.17
(d, 1H, J = 7.4 Hz, H-6), 7.59-7.78 (m, 8H, H-7, H-8, H-9, H-2’,

5
H-3’, H-4’, H-5’, H-6’), 8.50 (s, 1H, H-6), 9.34 (d, 1H, J = 7.4
Hz, H-5), 9.84-9.87 (m, 1H, H-10). 13C NMR (75 MHz, CDCl3) δ
(ppm): 14.6 (Me), 61.0 (CH2), 107.7, 111.7 (C-1, C-4 syd), 116.0
(C-6), 122.3, 124.6, 131.0, 138.1 (C-3, C-6a, C-10a, C-10b),
124.3 (C-2’, C-6’), 124.9 (C-5), 126.8, 128.2, 129.8 (C-7, C-8, C-
9), 128.6 (C-10), 129.9 (C-3’, C-5’), 130.5 (C-2), 132.4 (C-4’),
135.4 (C-1’), 164.5 (COO), 165.6 (CO-endocyclic), 169.1 (CO-
exocyclic).
3, C-6a, C-10a, C-10b), 124.6 (C-2’, C-6’), 124.8 (C-2), 127.7,
ACCEPTED MANUSCRIPT
127.9, 130.1 (C-7, C-8, C-10), 129.8 (C-3’, C-5’), 132.3 (C-4’),
133.2 (C-9), 135.3 (C-1’), 146.5 (C-6), 164.1 (COO), 165.2
(CO-endocyclic), 168.9 (CO-exocyclic).
4.4. Procedure for the synthesis of 4-acetyl-3-phenylsydnone (11)
A solution of 9 (10 g, 55 mmol) in 30 mL of acetic anhydride
was stirred until dissolution occurred and then was kept at room
temperature for 24 h. The solution was then cooled on an ice bath
and perchloric acid 60% (1.5 mL) was added dropwise. The
reaction was stirred for 12 h and the reaction mixture was poured
into cold water and then neutralized with (ca. 10 g) sodium
carbonate. The precipitate was filtered and washed with water on
the filter and the compound 11 was dried at room temperature.
4.3.5.
Dimethyl
3-[(3-phenylsydnon-4-yl)-oxomethyl]-
(13e): The
pyrrolo[2,1-a]phthalazine-1,2-dicarboxylate
compound was purified by crystallization from acetonitrile and
ethanol (1:1), yield 54%, mp 214-215 ºC. Found: C, 61.31; H,
3.65; N, 11.88. C24H16N4O7 (472) requires C, 61.02; H, 3.41; N,
11.68. IR (ATR): 1726 cm-1 (νC=O endocyclic), 1709 cm-1 (νC=O
1
exocyclic). H NMR (300 MHz, CDCl3) δ (ppm): 3.87 (s, 3H,
4.5. Crystal and refinement data for 13c
Me), 3.95 (s, 3H, Me), 7.54-7.69 (m, 6H, H-8, H-2’, H-3’, H-4’,
H-5’, H-6’), 7.80-7.85 (m, 2H, H-7, H-9), 8.54 (s, 1H, H-6),
8.96-8.99 (m, 1H, H-10). 13C NMR (75 MHz, CDCl3) δ (ppm):
52.6 (Me), 52.8 (Me), 108.0, 108.2 (C-1, C-4syd), 121.6, 122.5,
125.9, 126.7, 126.8 (C-2, C-3, C-6a, C-10a, C-10b), 124.6 (C-2’,
C-6’), 125.6 (C-10), 128.3 (C-7), 129.6 (C-8), 129.7 (C-3’, C-5’),
132.5 (C-4’), 133.6 (C-9), 134.8 (C-1’), 147.1 (C-6), 164.6,
164.7 (2COO), 165.1 (CO-endocyclic), 170.2 (CO-exocyclic).
The X-ray structure of 13c was determined by direct methods and
refined by full-matrix least-squares, as detailed in the CIF file
(Supplementary Material). A summary of the salient data is as
follows: C23H15N3O5, M = 413.38, 0.32 × 0.18 × 0.17 mm3,
monoclinic, space group P21/n (No. 14), a = 11.2661(2), b =
8.1641(2), c = 20.8189(4) Å, β = 94.320(1)°, V = 1909.43(7) Å3,
Z = 4, Dc = 1.438 g/cm3, F000 = 856, MoKα radiation, λ =
0.71073 Å, T = 173(2)K, 2θmax = 56.6º, 9111 reflections
collected, 4724 unique (Rint = 0.0223). Final GooF = 1.032, R1 =
0.0370, wR2 = 0.0954, R indices based on 3650 reflections with I
>2σ(I) (refinement on F2), 282 parameters, 0 restraints, CCDC
no. 1404872.
4.3.6. Diethyl 3-[(3-phenylsydnon-4-yl)-oxomethyl]-pyrrolo[2,1-
a]phthalazine-1,2-dicarboxylate (13f): The compound was
purified by crystallization from ethyl acetate, yield 56%, mp 134-
136 ºC. Found: C, 62.64; H, 4.31; N, 11.42. C26H20N4O7 requires
C, 62.40; H, 4.03; N, 11.19. IR (ATR): 1763 cm-1 (νC=O
1
endocyclic); 1706 cm-1 (νC=O exocyclic). H NMR (300 MHz,
CDCl3) δ (ppm): 1.26, 1.33 (2t, 6H, J = 7.1 Hz, 2Me), 4.28, 4.36
(2q, 4H, J = 7.1 Hz, 2CH2), 7.46-7.63 (m, 6H, H-8, H-2’, H-3’,
H-4’, H-5’, H-6’), 7.73-7.79 (m, 2H, H-7, H-9), 8.46 (s, 1H, H-
6), 8.88-8.91 (m, 1H, H-10). 13C NMR (75 MHz, CDCl3) δ
(ppm): 14.1, 14.2 (2Me), 61.7, 61.8 (2CH2), 108.4, 108.5 (C-1,
C-4syd), 121.7, 122.7, 125.7, 126.7, 126.8 (C-2, C-3, C-6a, C-
10a, C-10b), 124.6 (C-2’, C-6’), 125.6 (C-10), 128.3 (C-7), 129.5
(C-8), 129.7 (C-3’, C-5’), 132.5 (C-4’), 133.5 (C-9), 134.9 (C-
1’), 147.0 (C-6), 164.1 (COO), 164.8 (COO, CO-endocyclic),
170.3 (CO-exocyclic).
Acknowledgements
M.R.C. thanks the University of Cape Town and the NRF
(Pretoria) for research support. Any opinion, findings and
conclusions or recommendations expressed in this material are
those of the author and therefore the NRF does not accept any
liability in that regard.
References and notes
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1704 cm-1 (νC=O exocyclic). 1H NMR (300 MHz, CDCl3) δ (ppm):
1.45 (t, 3H, J = 7.1 Hz, Me), 4.43 (q, 2H, J = 7.1 Hz, CH2), 7.55-
7.65 (m, 6H, H-8, H-2’, H-3’, H-4’, H-5’, H-6’), 7.84-7.93 (m,
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(CH2), 108.0, 109.6 (C-1, C-4syd), 122.3, 126.3, 126.8, 130.8 (C-
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Supplementary Material
Supplementary data associated with this article:
Crystallographic Information File (CIF) for compound 13c,
listing crystal data, experimental and refinement details, and
molecular parameters (bond lengths, bond angles and torsion
angles).