Radical cyclization and 1,5-hydrogen transfer in selected aromatic diazonium salts

Article abstract of DOI:10.3987/COM-13-12863

2-(Methyl-(3-methyl-1-phenyl-1H-pyrazol-5-yl)carbamoyl)thiophene- 3-diazonium hydrogen sulfate 20, 2-(methyl-(3-methylisoxazol-5-yl)carbamoyl)- benzenediazonium hydrogen sulfate 21 and 2-(methyl(phenyl)carbamoyl)- benzenediazonium hydrogen sulphate 22 were synthesized and reacted with a CuSO₄/NaCl/ascorbic acid combination to give complex mixtures. The structures of the reaction products were elucidated, depending upon the pathways followed. Compound 20 almost exclusively afforded an Ar-5 cyclization product and trace amounts of the product derived from a competing Ar-6 Pschorr closure. In the case of compound 21, the Ar-6 cyclization was not observed, while the Ar-5 cyclization and 1,5-hydrogen radical transfer processes equally occurred. Finally, the Ar-6 cyclization was observed as the main process for compound 22, accompanied by the Ar-5 cyclization and, in a much lesser extent, by an 1,5-hydrogen radical transfer process.

Full text of DOI:10.3987/COM-13-12863

HETEROCYCLES, Vol. 89, No. 1, 2014
83
HETEROCYCLES, Vol. 89, No. 1, 2014, pp. 83 - 101. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 14th October, 2013, Accepted, 31st October, 2013, Published online, 14th November, 2013
DOI: 10.3987/COM-13-12863
RADICAL CYCLIZATION AND 1,5-HYDROGEN TRANSFER IN
SELECTED AROMATIC DIAZONIUM SALTS
Benedetta Maggio,a Gianfranco Fontana,b Demetrio Raffa,a Francesco
Ferrante,c and Giuseppe Daidonea,*
aDepartment of Biological, Chemical and Pharmaceutical Sciences and
_
Technologies (STEBICEF) Pharmaceutical Chemistry Section, Università degli
Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy
bDepartment of Biological, Chemical and Pharmaceutical Sciences and
Technologies (STEBICEF), Chemistry Section, Università degli Studi di Palermo,
Viale delle Scienze, ed. 17, 90128 Palermo, Italy
cDepartment of Physics and Chemistry, Università degli Studi di Palermo, Viale
delle Scienze, ed. 17, 90128 Palermo, Italy
*E-mail: giuseppe.daidone@unipa.it
Abstract – 2-(Methyl-(3-methyl-1-phenyl-1H-pyrazol-5-yl)carbamoyl)thiophene-
3-diazonium hydrogen sulfate 20, 2-(methyl-(3-methylisoxazol-5-yl)carbamoyl)-
benzenediazonium hydrogen sulfate 21 and 2-(methyl(phenyl)carbamoyl)-
benzenediazonium hydrogen sulphate 22 were synthesized and reacted with a
CuSO4/NaCl/ascorbic acid combination to give complex mixtures. The structures
of the reaction products were elucidated, depending upon the pathways followed.
Compound 20 almost exclusively afforded an Ar-5 cyclization product and trace
amounts of the product derived from a competing Ar-6 Pschorr closure. In the
case of compound 21, the Ar-6 cyclization was not observed, while the Ar-5
cyclization and 1,5-hydrogen radical transfer processes equally occurred. Finally,
the Ar-6 cyclization was observed as the main process for compound 22,
accompanied by the Ar-5 cyclization and, in a much lesser extent, by an
1,5-hydrogen radical transfer process.
INTRODUCTION
Hanson and co-workers described the use of a combination of CuSO4 and NaCl in the presence of
ascorbic acid to perform the Sandmeyer reaction of 4-chlorobenzenediazonium chloride in a

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HETEROCYCLES, Vol. 89, No. 1, 2014
homogeneous aqueous phase, leading to 1,4-dichlorobenzene.1 Ascorbic acid serves to reduce Cu(II) to
Cu(I) which, in turn, reduces the diazonium ion to a diazenyl radical. The latter decomposes to dinitrogen
and a 4-chlorophenyl radical. Complexes of Cu(II) ions with chloride ions then transfer a chlorine atom to
the 4-chlorophenyl radical to afford the final product.
We found in previous studies that, under the foregoing conditions, diazonium salt 2 (Scheme 1) affords
neither the product of the classical Sandmeyer reaction, chloro-derivative 3, nor the expected product of a
competing Pschorr ring closure, tricyclic derivative 4. On the contrary, a mixture of epimeric products 7,
presumably via radical intermediates 5 and 6, were obtained as the major reaction products.2 We also
isolated the derivative 9, due to a 1,5-hydrogen atom transfer process, and trace amounts of the hydroxy
spiro epimers 8.3
O
NH2
O
N2HSO4
O
Cl
N
N
N
N
N
N
N
N
N
Ph
Ph
Ph
1
2
3
CuSO4/ascorbic acid/NaCl
O
N
N
O
N
N
N
N
N
N
N
Ph
Ph
O
Ph
4
5
6
X
O
N
N
N
H
N
N
N
Ph
Ph
O
7
9
X = Cl:
trans/cis mixture
8
X = OH:
Scheme 1
When we transformed, under the above conditions, the diazonium salt 10 (Scheme 2) derived from
4-amino-N-1,3-trimethyl-N-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-1H-pyrazole-5-carboxamide,4
a
different reaction pattern was observed. In fact, in this case we isolated the chlorinated spiro derivatives
14 and the product of the Pschorr ring closure 12 together with its structural isomer 16.

HETEROCYCLES, Vol. 89, No. 1, 2014
85
N
N
N2HSO4
O
O
N
N
N
N
N
N
O
N
N
N N
N N
Ph
N
Ph
Ph
10
11
12
Cl
N
O
N
N
(CuCln)2-n
N
N
N
N
N
N
N
N
N
N
N
N
Ph
Ph
Ph
O
O
15
13
14 trans/cis mixture
O
N
N
N
N
N
Ph
16
Scheme 2
In continuing research on this type of reaction,2-5 and in order to establish the role of the aromatic
moieties, linked by the amide bridge on the reaction pathway we became interested in investigating the
transformation of diazonium salts 20–22 derived from the corresponding amines 17–19 (Figure 1).
NH2
O
O
NH2
O
NH2
N
N
N
N
N
O
N
S
Ph
17
18
19
N2HSO4
O
O
N2HSO4
O
N2HSO4
N
N
N
N
N
O
N
S
Ph
20
21
22
Figure 1
RESULTS AND DISCUSSION
The amino-derivatives 17–19 were synthesized accordingly to Scheme 3.

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HETEROCYCLES, Vol. 89, No. 1, 2014
NO2
O
O
NX2
NO2
MeI/KOH
+
N
N
N
N
N
N
N
COCl
S
N
NH2
H
S
Ph
S
Ph
Ph
24
Fe/5%
AcOH
23
25
X = O: 26
X = H: 17
S
NaNO2/H2SO4
Cl
S
CuSO4/NaCl/ascorbic acid
0-5 °C to rt, 1h
O
N
N2HSO4
N
+
O
N
N
N
N
N
N
O
S
N
Ph
Ph
Ph
28
20
27 1.1:1 trans/cis mixture
H2N
O2N
NO2
1. MeI/KOH
2. SnCl2
+
N
N
N
N
O
NH2
O
N
H
O
O
COCl
O
29
30
31
18
NaNO2/H2SO4
O
N
O
O
N
O4SHN2
CuSO4/NaCl/ascorbic acid
0-5 °C to rt, 1 h
+
+
N
N
N
N
N
O
O
H
N
O
O
O
O
N
O
32
33
34
21
CuSO4/NaCl
ascorbic acid
N
NaNO2/H2SO4
N
+
HO
0-5 °C to rt, 1 h
N
O
NX2
N
O
N2HSO4
O
O
22
36
37 trans/cis 1:2
35
X = O:
Fe / 5% AcOH
+
X = H: 19
H
N
O
O
N
O
38
39
Scheme 3

HETEROCYCLES, Vol. 89, No. 1, 2014
87
Table 1. Results of the radical mediated transformations of compounds 2, 10, 20–22
Entry
Compound
Path a Products
(%)
Path b Products Path c Products
(%)
(%)
1
2
3
4
5
2
77 (37)
0
9 (< 1)
0
10
20
21
22
147 + 16 (15)
277 (28)
12 (7)
28 (2)
0
0
33 (6), 34 (14)
377(9), 38 (3)
32 (13)
39 (3)
36 (25)
Compound 17 was obtained by reduction of nitro-derivative 26 with Fe/5% AcOH; compound 26 is the
product of the methylation of 25, which in turn arises from the coupling reaction between amine 24 and
the acyl chloride 23.
A slightly modified procedure in which the final reduction step was performed with SnCl2, was employed
for the synthesis of the amine 18. Finally, the known amine 19 was prepared from the nitro-derivative 35
accordingly to a reported procedure.6
The diazonium compounds 20–22 were prepared from the corresponding amines and subsequently
subjected in situ to the reaction conditions suitable for the generation of the aryl radical (CuSO4, NaCl,
ascorbic acid).1,2 After stirring 1 hour at rt, the products reported in Scheme 3 and Table 1 were isolated.
Together with some data already reported by some of us,2,4 the following discussion also includes new
computational data concerning compounds 2 and 10 for an useful comparison.
From the analysis of the structures of reaction products it is possible to gain information on the chemical
behavior of the radical intermediates involved in the reaction pathways.
The initially originated 2-aryl radicals 40–42, subsequently follow the transformations depicted in
Scheme 4. The intramolecular cyclization, to give second generation tricyclic radicals, can follow two
possible paths: a 5-exo-trig closure (path a) giving rise to the spiro systems 6, 43–45 (in the following
discussion collectively referred to as I) and a 6-endo-trig closure (path b) giving rise to the tri-cyclic
systems 46–48 (II). Another possibility is the occurrence of a 1,5-hydrogen shift (path c) from the
N-methyl group to the aryl center to give the methylene radicals 49–51 (III).

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HETEROCYCLES, Vol. 89, No. 1, 2014
R
Y
R
Y
R
Y
R
Y
X
X
X
a
b
main
N
products
O
O
N
N
X
slow
N
fast
N
N
N
N
N
N
O
N
N
O
Ph
Ph
Ph
Ph
12:
46a:
40a:
43a:
X = NMe, Y = N, R = Me
X = NMe, Y = N, R = Me
X = NMe, Y = N, R = Me
X = NMe, Y = N, R = Me
28: X = S, Y = CH, R = H
46b: X = S, Y = CH, R = H
40b: X = S, Y = CH, R = H
43b: X = S, Y = CH, R = H
c
R
side products not
observed
Y
N
N
X
N
O
CH2
Ph
49a: X = NMe, Y = N, R = Me
49b:
X = S, Y = CH, R = H
a
b
side
main
products
products
not
O
N
slow
N
fast
N
X
N
N
X
O
N
observed
X
O
41a: X = NPh
41b: X = O
6: X = NPh
44: X = O
47a: X = NPh
47b: X = O
c
side products observed
N
N
X
CH2O
50a:
X = NPh
50b: X = O
c
b
O
N
O
N
slow
N
N
a
CH2O
O
42
36
48
51
main product
fast
side products
observed
side products observed
O
N
N
O
N
O
53
52
45
Scheme 4

HETEROCYCLES, Vol. 89, No. 1, 2014
89
It was found that all of the diazonium salts 2, 10, 20–22 follow the path a whereas the path b is only
followed by 10, 20 and 22 (Schemes 1–4). Moreover, path a is the dominant one for all of the cases but
the compound 22, that mostly follows the way b giving compound 36 as major product, through the
radical 48. This result appears to be in accordance with the Baldwin's rules8 relying with the closure mode
of simple aliphatic radicals, i.e. 5-exo-trig closure is dominant with respect to the 6-endo-trig, mainly on
the ground of sterical reasons. When the cyclization process involves the radical's addition to an aromatic
moiety, a competition between the two pathways does occur.9,10 In these cases, despite the 5-exo-trig – or
“Ar-5” – cyclization is still the one kinetically preferred, 6-member rings containing final products of the
type 6-endo-trig – or “Ar-6” – are obtained. This is likely due to the occurrence of alternative reaction
pathways such as the oxidation of the radical to a cation, followed by a rearrangment of the latter. It is not
surprising that in the case of the hetero-aromatic systems reported in this work the products derived from
the spiro radicals are mainly obtained. This is due to the quite less aromatic character (and as a
consequence the more localized nature of the  electron density in the C-4, C-5 formal double bond11) of
the hetero-aromatic ring acceptor. On the other hand, the Cu/promoted Pschorr radical 6-endo-trig
cyclisation to give both phenanthrene9 and phenanthridone12 systems are well documented.
It is worthy of further comment that we did not find products derived from a 6-exo (or “Ar-6”) mode of
closure in the case of compound 22 (Scheme 1), as instead is the case for the cited compound 22 and for
compounds 10 and 20 (Schemes 2 and 3) that gave the “Ar-6” products 12 and 28 in trace amounts,
through the radicals 46. This is probably explainable with the oxidation by Cu2+ of the radical 45 to the
corresponding spiro cation (Scheme 6), which can account for the formation of compound 36. The higher
reactivity of the electron-rich pyrazolinyl radicals 43a,b and 6 makes the subsequent reaction with
(CuCln)2-n complexes (see discussion below) faster than the oxidation.
In order to gain a better understanding of the radical's transformation processes described above, we
evaluated the thermodinamic of the reaction courses depicted in the Scheme 4 by means of computational
methods based on Density Functional theory. In particular the free energy variations (G°) were
evaluated by taking into consideration the conformations of the aryl radicals 40–42 with the higher degree
of similarity between reactant and product (Scheme 5): C1 is the conformation related to both the radical
closures, while C2 is the one related to the hydrogen shift process.

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HETEROCYCLES, Vol. 89, No. 1, 2014
R
X
Y
N
O
Me
O
O
N
Ar
R
O
I
R
R
Ar
H
Ar
CH2
X
N
X
N
H2C
X
Y
Y
Y
Me
R
C1
C2
III
O
X
N
Y
X Y
R
Me
II
N NPh
C S
Me
H
N O
Me
HC C CH
H
H
Scheme 5
Table 2 reports the estimation of the G° values referred to the conformations C1 and C2; the former is
the one largely dominant in every case but for the radical 41b; in this case both the conformations can be
considered equally populated, within the accuracy limit of the computational method employed. From the
data reported in Table 2, it is evident as the conclusion that can be inferred from a thermodinamical
control of the investigated reactions are in line with those deduced from the kinetic behaviour.
Table 2. G°s in KJ mol-1 for the conversions C1 → C2, C1 → I, C1 → II and C2 → III of the aryl
radicals 40 - 42
41a
40a
40b
41b
42
G°(C1 → C2)
G°(C1 → I)
15.7
-123.7
-61.5
-72.3
11.1
-109.9
-84.9
-99
13.7
-107.3
-71.9
-80.6
2.7
17.4
-88.1
-102
-75.5
-128.4
-81.4
-65.5
G° (C1 → II)
G°(C2 → III)
The evolution of the cyclized radical is related to the relative trend to give one of the four possible radical
quenching processes: i) The ligand transfer reaction with (CuCln)2-n complexes to give chloro-substituted
derivatives. ii) The direct cyclization to give an aromatic system (Pschorr reaction). iii) The radical

HETEROCYCLES, Vol. 89, No. 1, 2014
91
coupling to give a dimer. iv). The oxidation by Cu2+, without Cl transfer, to give a cation. A
“non-classical”2 Sandmayer reaction (i) is given by the radicals I arising from all of the compounds but
21 (Scheme 6). Further, while the compounds 2, 10 and 20 give predominantly the chloro
spiro-derivatives 7, 14 and 27, compound 22 give the 6-Ar cyclization compound 36 as the main product
together with the epimeric alcohols trans- and cis-37 and trace amount of the ketone 38 (Schemes 3 and
4).
This result reflects the relative electronic character, and as a consequence the nucleophilicity, of the
radicals I. The fact that an alcohol is isolated in the case of 22, without any trace of chloro compounds,
can be rationalised by the intervention of a fast oxidation step. The formation of the product 36 is easily
explained by the known tendency of the five member cyclic cation to quickly rearrange to the six member
one.9 Further, the reaction pathway proposed in Scheme 6 for the intermediate 45 is supported by the
reported evidence of a higher Cl/H2O+ transfer ratio by any [Cu(II)Cln(H2O)m](2-n) species.13 In the case
of compound 21, it can be argued that the reaction of the radical 44 (Schemes 4 and 3) with any Cu
species is much slower than the dimerization, giving the product 33. The formation of compound 34 is
easily explained by the sequence reported in Scheme 6.
The reaction pathway c – 1,5-hydrogen atom shift – is mainly followed by the radical 41b arising from
the precursors 21 and, in a much lower extent, by the radical 42 formed from 22 (Schemes 4 and 3). Both
the radicals 50b and 51 given by 41b and 42 bring to the N-demethylated products 32 and 39 through one
or both the mechanisms depicted in Scheme 7.
The ionic mechanism should be favored by the intrinsic stability of the immonium ion14 originated by the
Cu(II) oxidation of the radicals 50b and 51. In the case of 21, this process completely outclasses the
oxidation/rearrangement steps, that are instead dominant in the case of 22. This significant difference can
be explained on the ground of the above cited conformational freedom of the radicals arising from 21
with respect to 22 (Schemes 3 and 4). The calculated data reported in tab. 2: G° (C1 → C2) 2.7 KJ mol-1
for 41b vs. 17.4 KJ mol-1 for 42, support this statement.

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HETEROCYCLES, Vol. 89, No. 1, 2014
Type I radicals
R
Cl
Y
R
Y
X
X
N2HSO4
O
N
R
Y
N
N
N
N
N
N
O
N
N
O
X
Ph
Ph
14:
X = NMe, Y = N, R = Me
Ph
10:
43a:
X = NMe, Y = N, R = Me
X = NMe, Y = N, R = Me
(CuCln)2-n
20: X = S, Y = CH, R = H
43b: X = S, Y = CH, R = H
27: X = S, Y = CH, R = H
Cl
O
N2HSO4
N
N
N
N
N
O
N
N
N
O
N
Ph
Ph
Ph
2
7
6
O
N
O
N
O
N2HSO4
N
N
O
N
O
N
O
N
O
N
O
21
44
33
+
O
N
N
N
O
O
N
O
34
Cu(II)
fast
N
N
O
O
N2HSO4
N
O
45
22
H2O
Cu(II)
O
HO
N
O
N
O
38
37
Scheme 6

HETEROCYCLES, Vol. 89, No. 1, 2014
93
Ar1
Ar2
N
CuCl3
Ox.
CH2O
Cl
Ar1
HO
Ar2
Ar1
Ar2
Ar1
Ar2
N
N
H
H2O
N
O
- CH2O
O
CH2
CH2O
50b, 51
32, 39
Ar1
Ar2
N
O
CH2
Scheme 7
CONCLUSIONS
The products distribution of the radicals mediated transformation of a set of aromatic diazonium
compounds is fairly complex but explainable on the ground of the several reaction pathways accessible
by the intermediates involved.
The initial aryl radical gives rise mainly to a 5-exo-trig (or Ar-5) cyclisation when the radical attacks a
hetero-aromatic system (compounds 2, 10, 20, 21). On the other hand, when the attack involves a
benzenic ring (compound 22), the intervention of a more complex oxidative pathway makes the Ar-6
cyclization mode the one dominant, yielding the phenanthridone-like compound 36 as the main reaction
product. An 1,5-hydrogen shift side reaction occurs in some cases and is quite relevant in the case of
compound 21. Both kinetic and thermodinamic based arguments can account for the experimental
evidences collected. The final products structure depends also on the particular reaction course followed
by the radical intermediates.
Despite its complexity, the reaction pattern described in the present study is on the whole internally
coherent, rightly integrated within the body of literature evidences concerning the diazonium compound's
radical chemistry and give a further insight into the class of the hetero-aromatic systems. A contribution to
the general radical cyclisation rules can be added, i.e. radicals of the general pattern showed below follow
the “Ar-5” closure path rather than the “Ar-6” one (Figure 2).
Ar-6
O
O
N
N
N
N
X
X
X = O, N-R (Ar)
Ar-5
N
X
N
O
Figure 2

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HETEROCYCLES, Vol. 89, No. 1, 2014
Finally, all of the spiro derivatives reported in the present study can be considered as potentially active
biological agents because many compounds that possess a spirooxyindole moiety were shown to exhibit
significant biological activity.15
EXPERIMENTAL
Generals
Reaction progress was monitored by TLC on silica gel plates (Merck 60, F254, 0.2 mm). Organic solutions
were dried over Na2SO4. Evaporation refers to the removal of solvent on a rotary evaporator under
reduced pressure. All melting points were determined on a Büchi 530 capillary melting point apparatus
and are uncorrected. IR spectra were recorded with a Perkin Elmer Spectrum RXI FT-IR System
1
13
spectrophotometer as solid in KBr disc or nujol. H NMR and C NMR spectra of all compounds but
27-cis/trans were obtained in CDCl3 or DMSO-d6 solutions on a Bruker AC 250 F or Bruker AC series
300 spectrometers. 1H NMR and 13C NMR spectra of compounds 27-cis/trans were obtained on a Bruker
Avance II 400 spectrometer. In all cases tetramethylsilane was used as an internal standard; chemical
shifts are expressed in  values (ppm). Mass spectra at 70 eV were obtained using an 3400-CX Varian gas
chromatograph fitted with a Saturn 3 mass spectrometer. For compound 33 the mass spectra was obtained
by a Shimadzu LCMS2010 apparatus. Merck silica gel (Kiesegel 60/230-400 mesh) was used for flash
chromatography (FC) columns. Yields refer to products after one crystallization. The name of the
compounds were obtained using the ChemDraw Ultra 12.0 software.
Computational Details
All calculations have been performed in the framework of density functional theory by using the
Gaussian 09 software.16 The Becke 3-parameters hybrid functional B3LYP,17 consisting of Becke
exchange functional plus the Lee, Yang and Parr correlation functional has been used joined with the
Dunning's correlation consistent polarized valence double zeta (cc-pVDZ). The geometry optimizations
have been followed by the calculation of the harmonic frequencies, in order to verify the nature of
minimum in the potential energy surface of the structure obtained and to calculate the zero-point
vibrational contribution to the energy. The molecular Gibbs free energies of formation have been
calculated by adding the estimated zero-point, thermal and entropic contributions (T = 298 K, p = 1 bar)
to the SCF energy.
N-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-3-nitrothiophene-2-carboxyamide (25)
To a solution of commercially available 3-methyl-1-phenyl-1H-pyrazol-5-amine (17.3 g, 0.1 mol) in dry
CHCl3 (450 mL), 3-nitrothiophene-2-carbonyl chloride (19.2 g, 0.1 mol) was added; the resulting solution

HETEROCYCLES, Vol. 89, No. 1, 2014
95
was refluxed for 5 h. After the first hour, triethylamine (14 mL) was added in four portions (7, 3.5, 2 x
1.75 mL respectively, with intervals of 1 h between additions). Then the reaction was quenched with ice
cold water. The organic phase was dried onto Na2SO4 and solvent was evaporated. The residue was
crystallized from EtOH to give compound 25 (50%); a yellow orange solid; mp 140–143 °C (EtOH); R
1
(Nujol) cm-1 3193 (NH), 1678 (CO); H NMR (250 MHz, CDCl3)  2.36 (3H, s, Me), 6.72 (1H, s,
pyrazole H-4), 7.46-7.66 (7H, m, phenyl and thienyl protons), 10.75 (1H, br s, exchangable with D2O);
13C NMR (75 MHz, CDCl3) 13.49, 98.42, 124.95 (2C), 126.43, 128.31, 129.13, 129.29 (2C), 134.97,
136.93, 139.41, 142.85, 149.21, 154.09; MS m/z 328 (M+). Anal. Calcd for C15H12N4O3S: C, 54.87; H,
3.68; N, 17.06). Found: C, 55.01; H, 3.81; N, 17.26.
3-Amino-N-methyl-N-(3-methyl-1-phenyl-1H-pyrazol-5-yl)thiophene-2-carboxyamide (17)
In a three neck round bottomed flask, compound 25 (32.8 g, 0.1 mol) was solubilized in hot acetone (360
mL), then KOH (21.87 g, 0.39 mol) was added in one portion and a solution of methyl iodide (9.27 mL)
in acetone (50 mL) was added dropwise. The reaction mixture was refluxed for 1 h. The resulting
suspension was filtered off and the obtained solution evaporated. Finally, the solid residue was
crystallized from EtOAc to give N-methyl-N-(1-phenyl-3-methyl-1H-pyrazol-5-yl)-3-nitrothiophene-
2-carboxyamide (26) (23%) as a yellow solid (mp 90–93 °C) and directly employed in the subsequent
step after partial characterization by proton NMR. 1H NMR (250 MHz, CDCl3) 2.21 (3H, s, Me), 3.46
(3H, s, Me), 6.08 (1H, s, pyrazole H-4), 7.30-7.44 (7H, m, phenyl and thienyl protons).
Powdered Fe (80 g, 1.4 mol) was added to 100 mL of a 5% (v/v) aqueous acetic acid solution and stirred
at 100 °C for 15 min. Then N-methyl-N-(1-phenyl-3-methyl-1H-pyrazol-5-yl)-3-nitrothiophene-2-
carboxyamide (26) (44.5 g, 0.13 mol) was added within 1 h. The reaction mixture was stirred for 1 h more
and then the pH was raised to 8 by adding aq. NaHCO3(sat.). The mixture was filtered, the solid material
washed with water until neutrality, dried by standing overnight at rt and extracted with boiling CHCl3 (3 x
150 mL). The solution was dried onto sodium sulphate and evaporated. The solid residue was crystallized
from EtOH to give compound 17 (80%); a pale yellow solid; mp 120–122 °C; R (nujol) cm-1 3488 and
3371 (NH2), 1618 (CO); 1H NMR (250 MHz, CDCl3) 2.37 (3H, s, Me), 3.17 (3H, s, Me), 4.16 (2H, s br.
exchangeable with D2O, NH2); 6.20 (1H, s, pyrazole H-4), 6.43-7.44 (7H, m, phenyl and thienyl protons);
13C NMR (75MHz, CDCl3)  14.22, 37.36, 100.95, 106.31, 119.12, 122.88 (2C), 127.38, 129.11, 131.01
(2C), 138.40, 141.16, 149.29, 155.96, 165.92; MSm/z 312 (M+). Anal. Calcd for C16H16N4OS: C, 61.52;
H, 5.16; N, 17.93. Found: C, 61.72; H, 5.32; N, 18.17.
2-Amino-N-methyl-N-(3-methylisoxazol-5-yl)benzamide (18)

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N-Methyl-(3-methylisoxazol-5-yl)-2-nitrobenzamide (6.70 g, 0.026 mol), previously prepared following
the literature procedure,18 were added to a continuously stirred suspension of SnCl2 (14.60 g, 0.077 mol)
in HClconc. (30 mL) while keeping the reaction temperature below 10 °C with an ice bath. The final
suspension was further stirred for 24 h. Then the reaction was quenched with iced water (300 mL) and
basified by adding 125 mL of a 40% (w/v) NaOH solution. Then the reaction mixture was extracted with
EtOAc (3 x 250 mL), and the organic phase was washed with water, dried with Na2SO4 and evaporated.
The solid residue was crystallized from EtOH to give compound 18 (65%), a colourless solid; mp
1
70–73 °C; IR (KBr) cm-1 3481 and 3369 (NH2), 1648 (CO); H NMR (250 MHz, CDCl3) 2.19 (s, 3H,
Me), 3.45 (s, 3H, Me), 4.78 (br s, 2H, exchangeable with D2O, NH2), 5.77 (s, 1H, isoxazole 4-H),
6.65-7.27 (m, 4H, C6H4); 13C NMR (75 MHz, CDCl3)  11.91, 35.54, 93.89, 116.94, 117.07, 117.11,
128.88, 132.21, 147.10, 163.34, 164.73, 170.00; MS m/z 231 (M+). Anal. Calcd for C12H13N3O2: C, 62.33;
H, 5.67; N, 18.17. Found: C, 62.51; H, 5.90; N, 18.40.
Preparation and transformation of 2-(methyl-(3-methyl-1-phenyl-1H-pyrazol-5-yl)carbamoyl)-
thiophene-3-diazonium hydrogen sulfate (20)
The solution of compounds 20 was prepared from the corresponding amines 17 (2 g, 6.41 mmol) by
treating with 2.5 M H2SO4 (12.8 mL) and 2.5 M NaNO2 (2.65 mL) while keeping temperature at 0–5 °C.
The transformation reaction was carried out following the procedure of Hanson1 which has been modified
by us.2 After 15 min the resulting solution of 20 was diluted with 305 mL of a cold (0–5 °C) solution of
CuSO4·5H2O (0.3 M) and sodium chloride (0.75 M). Ascorbic acid was then added (0.28 g, 1.59 mmol)
and stirring was continued for 1 h at room temperature. The suspension was filtered off and the solid
residue was dried between porous plates and subsequently chromatographed following the FC
procedure:19 external diameter column 5 cm, EtOAc/light petroleum (bp 40–70 °C) (3:7 v/v) as eluent,
silica gel (170 g), fractions each 50 mL. Fractions 16-38 were evaporated, and the residue was
crystallized to give compounds 27 (trans/cis 1.2:1 mixture).
The partial separation of the epimers was obtained operating a very fast FC with a Biotage® apparatus,
using Et2O/light petroleum (bp 40–70 °C) as eluent. Compound cis-27 was obtained pure, whereas
trans-27 was contaminated with about 15% of cis isomer, as judged by 1H NMR.
cis-4-Chloro-5,5’-dimethyl-2-phenyl-2,4-dihydrospiro[pyrazole-3,4-thieno[2,3-c]pyrrol]-6(5’H)-one
(cis-27):20 16%; a pale yellow solid; mp 178–180 °C (EtOH); IR (KBr) cm-1 1697 (CO); 1H NMR (400
MHz, CDCl3) 2.25 (s, 3H, Me), 2.67 (s, 3H, Me), 5.25 (s, 1H, pyrazoline H-4), 6.79 (d, J = 7.0 Hz, 2H),
6.90 (t, J = 5.9 Hz, 1H), 7.09-7.15 (m, 3H), 7.76 (d, J = 4.5 Hz, 1H); 13C NMR (100 MHz,
CDCl3)13.39, 27.27, 67.35, 86.58, 115.68 (2C), 119.52, 122.28, 129.05 (2C), 136.44, 136.73, 143.06,

HETEROCYCLES, Vol. 89, No. 1, 2014
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146.97, 153.95, 162.57. Anal. Calcd for C16H14ClN3OS: C, 57.91; H, 4.25; N, 12.66. Found: C, 57.75; H,
4.50; N, 12.50.
trans-4-Chloro-5,5’-dimethyl-2-phenyl-2,4-dihydrospiro[pyrazole-3,4-thieno[2,3-c]pyrrol]-6(5’H)-
1
one (trans-27):20,21 IR (Nujol) cm-1 1702 (CO); H NMR (400 MHz, CDCl3) 2.26 (s, 3H, Me), 2.80 (s,
3H, Me), 4.94 (s, 1H, pyrazoline H-4), 6.72 (d, J = 7.1 Hz, 2H), 6.89 (t, J = 6.0 Hz, 1H), 7.07-7.17 (m,
13
3H), 7.66 (d, J = 4.3 Hz, 1H); C NMR (100 MHz, CDCl3) 13.43, 25.69, 66.76, 87.86, 116.24 (2C),
122.29, 122.46, 128.95 (2C), 134.57, 136.44, 142.39, 146.85, 151.17, 162.30. Anal. Calcd for
C16H14ClN3OS: C, 57.91; H, 4.25; N, 12.66. Found: C, 57.85; H, 4.54; N, 12.52.
Fractions 66-94 of the first cromatographic procedure afforded a residue which was crystallized from
EtOH to give 1,4-dimethyl-3-phenyl-3H-pyrazolo[3,4-b]thieno[3,2-d]pyridine-5(4H)-one (28)
1
(2.1%); a colourless solid, mp 195–196 °C; IR(KBr) cm-1 1636 (CO); H NMR (250 MHz, (CDCl3)
2.63 (3H, s, Me), 3.29 (3H, s, Me), 7.44-7.84 (7H, m, C6H5 and thiophene protons); 13C NMR (75MHz,
CDCl3) 13.74, 31.76, 102.74, 121.52, 125.14, 127.54 (2C), 129.28 (2C), 129.47, 134.89, 138.33, 139.67,
142.16, 143.19, 158.55;S m/z 295 (M+). Anal. Calcd for C16H13N3OS: C, 65.06; H, 4.44; N, 14.23.
Found: C, 65.16; H, 4.62; N, 14.37.
Preparation and trasformation of 2-(methyl-(3-methyl-isoxazol-5yl)carbamoyl)benzenediazonium
hydrogen sulfate (21)
The solution of compounds 21 was prepared from the corresponding amine 18 (3 g, 12.98 mmol) by
treating with 2.5 M H2SO4 (26 mL) and 2.5 M NaNO2 (5.37 mL) while keeping temperature at 0–5 °C.
The transformation reaction was carried out following the procedure of Hanson1 which has been modified
by us.2 After 15 min the resulting solution of 21 was diluted with 620 mL of a cold (0–5 °C) solution of
CuSO4·5H2O (0.3 M) and sodium chloride (0.75 M). Ascorbic acid was then added (0.57 g, 3.24 mmol)
and stirring was continued for 1 h at room temperature. The mixture was extract with EtOAc (3 x 250
mL) and the organic phase was washed with water, dried with Na2SO4 and evaporated. The residue was
washed with EtOAc (2.5 mL) and the suspension filtered off affording a quasi-pure solid product which
was crystallized from EtOH to give 4’-(2,3’-dimethyl-3-oxo-4’H-spiro[isoindoline-1,5’-isoxazol]-
4’-yl)-2,3’-dimethyl-4’H-spiro[isoindoline-1,5’-isoxazol]-3-one (33) (6.4%); a colourless solid; mp >
1
270 °C; IR (KBr) cm-1 1724, 1711; H NMR (250 MHz, CDCl3) 2.34 (s, 6H, 2x Me), 2.81 (s, 6H,
13
2xMe), 3.83 (s, 2H, isoxazolines 4-H), 7.37-7.52 (m, 8H, 2xC6H4); C NMR (75MHz, CDCl3)4.54,
24.37, 52.75, 101.11, 123.47, 124.53, 130.98, 131.93, 132.25, 138.04, 155.88, 164.86; MS m/z 431
( M+1). Anal. Calcd for C24H22N4O4: C, 66.97; H, 5.15; N, 13.02. Found: C, 66.75; H, 5.20; N, 13.29.

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The mother liquors of the above suspension were evaporated and the residue chromatographed following
the FC procedure:19 external diameter column 5 cm, EtOAc/light petroleum (bp 40–70 °C) ( 3:7 v/v) as
eluent, silica gel (192 g), fractions each 50 mL. Fractions 15-23 were evaporated, and the residue was
crystallized from EtOAc/light petroleum to give a compound which was identical in all respects (MS,
1H-NMR, mixed mp, TLC) with an authentic specimen of N-methylphthalimide (34) (14.4%). Fractions
31-36 left a residue which was crystallized from EtOH to give N-(3-methyl-isoxazol-5-yl)benzamide
1
(32)22 (13.3%); mp 144–146 °C; IR (KBr) cm-1 3344 (NH), 1677 (CO); H NMR (250 MHz, CDCl3)
2.28 (s, 3H, CH3), 6.39 (s, 1H, pyrazole H-4), 7.47-7.92 (m, 5H, C6H5), 9.08 (br s, 1H, exchangeable
with D2O, NH); MS m/z 203 (M+1).
Preparation and trasformation of 2-(methyl(phenyl)carbamoyl)benzenediazonium hydrogen
sulphate (22)
The solution of compounds 22 was prepared from the corresponding amine 19 (3.39 g, 15 mmol) by
treating with 2.5 M H2SO4 (30 mL) and 2.5 M NaNO2 (6.21 mL) while keeping temperature at 0–5 °C.
The transformation reaction was carried out following the procedure of Hanson1 which has been modified
by us.2 After 15 min the resulting solution of 22 was diluted with 714 mL of a cold (0–5 °C) solution of
CuSO4·5H2O (0.3 M) and sodium chloride (0.75 M). Ascorbic acid was then added (0.66 g, 3.75 mmol)
and stirring was continued for 1 h at room temperature. The mixture was extract with EtOAc (3 x 250
mL) and the organic phase was washed with water, dried with Na2SO4 and evaporated. The residue was
chromatographed following the FC procedure18: external diameter column 5 cm, EtOAc/light petroleum
(bp 40–70 °C) (4:6 v/v) (3 L) and 6:4 v/v (3 L) as eluents, silica gel (230 g), fractions each 50 mL.
Fractions 15-23 were evaporated, and the residue was crystallized from cyclohexane to give
5-methylphenanthridine-6(5H)-one (36)6 (25%); mp 104–105 °C (benzene/light petroleum (bp
1
40–70 °C)); H NMR (250 MHz, DMSO-d6) 3.72 (s, 3H, Me), 7.32-8.52 (m, 8H, 2 x C6H4); MS m/z

209 (M+).
Fractions 24–33 left a residue which was crystallized from EtOAc to give N-phenylbenzamide (39)
(3.4%); mp 156–58 °C (lit.,24 160–161 °C from EtOH); 1H NMR (300 MHz, DMSO-d6) 7.07-7.97
(m, 10H, 2 x C6H5), 10.23 (s, 1H, exchangeable with D2O, NH); MS m/z 197 (M+).
Further eluition gave fractions 46–58 from which a residue was obtained. Crystallization of the residue
gave 2-methylspiro[cycloexa[2,5]diene-1,1’-isoindoline]-3’,4-dione (38) (3%); a colouless solid, mp
213–215 °C (EtOAc/light petroleum bp 40–70 °C); IR (KBr) cm-1 1708, 1664 (CO). 1H NMR (300 MHz,
CDCl3) 2.88 (s, 3H, Me), 6.51 (d, J = 8.1 Hz, 2H, cycloexadiene protons), 6.75 (d, J = 8.2 Hz, 2H,
cycloexadiene protons), 7.38 (d, J = 5.7 Hz, 1H, phenyl proton), 7.63 (m, 2H, phenyl protons), 7.82 (d, J

HETEROCYCLES, Vol. 89, No. 1, 2014
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13
= 7.8, 1H, phenyl proton); C NMR (300 MHz, CDCl3) 25.69, 64.29, 122.87, 123.57, 129.63, 131.16
(2C), 131.80, 132.50, 141.37, 147.64 (2C), 166.91, 184.17. Anal. Calcd for C14H11NO2: C, 74.65; H,
4.92; N, 6.22). Found: C, 74.42; H, 5.06; N, 6.30.
Continuing eluition, fractions 70-81 and 82-114 were collected. Evaporation left residues wich were
crystallized from EtOAc to give epimers trans-37 and cis-37 respectively.
trans-4-Hydroxy-2’-methylspiro[cycloexa[2,5]diene-1,1’-isoindolin]-3’-one (trans-37):20 (3%);
a
1
colourless solid, mp 120–122 °C (EtOAc); IR (KBr) cm-1 1665 (CO); H NMR (300 MHz, DMSO-d6)
2.74 (s, 3H, Me), 4.55 (m, 1H, cycloexadiene proton), 5.35 (m, 3H, one exchangeable with D2O, OH
and cycloexadiene protons), 6.28 (dd, J = 8.5, 1.9 Hz, 2H, cycloexadiene protons), 7.42-7.71 (ABCD m,
13
4H, C6H4); C NMR (75 MHz, DMSO-d6) 24.67, 59.78, 62.69, 122.58, 123.27, 126.93 (2C), 128.63,
131.06, 131.83, 134.81 (2C), 147.42, 166.44. Anal. Calcd for C14H13NO2: C, 73.99; H, 5.77; N, 6.16.
Found: C, 74.12; H, 5.96; N, 6.30.
cis-4-Hydroxy-2’-methylspiro[cycloexa[2,5]diene-1,1’-isoindolin]-3’-one (cis-37):21 (6%); a colourless
solid, mp 189–191 °C (EtOAc); IR (KBr) cm-11682 (CO); 1H NMR (300 MHz, DMSO-d6) 2.82 (s, 3H,
Me), 4.69 (br s, 1H, cycloexadiene proton), 5.38 (d, J = 9.9 Hz, 2H, cycloexadiene protons), 5.42 (d, J =
6.6 Hz, 1H, exchangeable with D2O, OH), 6.23 (d, J = 9.9 Hz, 2H, cycloexadiene protons), 7.26 (d, X
part of an ABCX pattern, J = 9.0 Hz, 1H, phenyl proton), 7.53-7.75 (ABC part m, 3H, phenyl protons);
13C NMR (75 MHz, DMSO-d6) 24.71, 59.68, 62.41, 122.29, 122.65, 125.85 (2C), 128.30, 130.69,
131.58, 133.74 (2C), 147.43, 166.18. Anal. Calcd. for C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found: C,
74.01; H, 5.86; N, 6.35.
ACKNOWLEDGEMENTS
Financial support from “Fondo di Finanziamento della Ricerca di Ateneo (ex 60%)” and PON
1
a3_00053-PLASS are gratefully acknowledged. H (400 MHz) and 13C (100 MHz) NMR data were
provided by Centro Grandi Apparecchiature – UNINetLab – Università di Palermo funded by P.O.R.
Sicilia 2000-2006, Misura 3.15 Quota Regionale.
REFERENCES (AND NOTES)
1.
2.
P. Hanson, J. R. Jones, B. C. Gilbert, and A. W. Timms, J. Chem. Soc., Perkin Trans. 2, 1991, 1009.
G. Daidone, B. Maggio, D. Raffa, S. Plescia, F. Benetollo, and G. Bombieri, J. Chem. Soc., Perkin
Trans. 1, 1998, 2891.
3.
4.
B. Maggio, D. Raffa, M. V. Raimondi, and G. Daidone, Molecules, submitted.
B. Maggio, G. Daidone, D. Raffa, S. Plescia, G. Bombieri, and F. Meneghetti, Helv. Chim. Acta,
2005, 88, 2272.

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HETEROCYCLES, Vol. 89, No. 1, 2014
5.
B. Maggio, D. Raffa, M. V. Raimondi, S. Cascioferro, S. Plescia, M. A. Sabatino, G. Bombieri, F.
Meneghetti, and G. Daidone, ARKIVOC, 2008, xvi, 130.
R. A. Heacock and D. H. Hey, J. Chem. Soc., 1952, 1508.
Formed as mixtures of epimers.
6.
7.
8.
9.
J. E. Baldwin, J. Chem. Soc. Chem. Comm., 1976, 734.
P. Hanson, P. W. Lövenich, S. C. Rowell, P. H. Walton, and A. W. Timms, J. Chem. Soc., Perkin
Trans. 2, 1999, 49.
10. J. C. Chottard and M. Julia, Tetrahedron, 1972, 28, 5615.
11. A. R. Katritzky and J. M. Lagowski, ‘Comprehensive Heterocyclic Chemistry’, vol. 5, ed. by K. T.
Potts, Pergamon Press, 1984, part 4A, pp. 1–38.
12. D. H. Hey and T. M. Moynehan, J. Chem. Soc., 1959, 1563.
13. P. Hanson, R. C. Hammond, B. C. Gilbert, and A. W. Timms, J. Chem. Soc., Perkin Trans. 2, 1995,
2195.
14. A. H. Lewin, A. H. Dinwoodie, and T. Cohen, Tetrahedron, 1966, 22, 1527.
15. D. Chunhui, L. Bio, and R. J. S. Corey, Beilstein J. Org. Chem., 2012, 8, 986 and references cited
therein.
16. Gaussian 09, Revision C.01, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A.
Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M.
Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada,
M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H.
Nakai, T. Vreven, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E.
Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell,
J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B.
Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin,
R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth,
P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, Ö. Farkas, J. B. Foresman, J. V. Ortiz, J.
Cioslowski, and D. J. Fox, Gaussian, Inc., Wallingford CT, 2009.
17. (a) A. D. Becke, J. Chem. Phys., 1993, 98, 1372; (b) C. Lee, W. Yang, and R. G. Parr, Phys. Rev. B,
1988, 37, 785; (c) P. J. Stephens, J. F. Devlin, C. F. Chabalowsky, and M. J. Frisch, J. Phys. Chem.,
1994, 98, 11623.
18. M. L. Baajardi, G. Daidone, D. Raffa, and S. Plescia, Heterocycles, 1986, 24, 1367.
19. W. C. Still, M. Kahn, and A. Mitra, J. Org. Chem., 1978, 43, 2923.
20. The relative stereochemistry was deduced on the ground of the supposed deshielding effect due to
the magnetic anisotropy of the aromatic ring on the CHOH and CHCl protons of cis-37 and cis-27

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respectively, compared with the trans isomers. This hypothesis was supported by the values of 1H
shielding tensor computed for the four compounds at the optimized geometry (available in the
supporting material) by using the B3LYP/aug-cc-pvdz level: observed vs calculated proton : 0.12
vs. 0.13 ppm for 37 and 0.50 vs. 0.31 for 27.
21. NMR values were obtained by extrapolation of the mixture spectra.
22. S. I. Sviridov, A. A. Vasil’ev, and S. V. Shorshnev, Tetrahedron, 2007, 63, 12195.
23. C. N. Webb, Org. Synth., 1941, 1, 82.