A novel chemoselective synthesis of 3H-spiro[isobenzofuran-1,3'-pyrazole] derivatives by oxidative cleavage of their corresponding dihydroindeno[1,2-c]pyrazoles

Article abstract of DOI:10.1007/s13738-014-0578-4

Abstract This paper reports a new and simple procedure for the synthesis of 3H-spiro[isobenzofuran-1,3'-pyrazole] derivatives by reacting 1-benzylidene-2-phenylhydrazine derivatives with ninhydrin in acetic acid medium at room temperature followed by oxidative cleavage of their corresponding dihydroindeno[1,2-c]pyrazoles. 1-Benzylidene-2-phenylhydrazine derivatives were prepared via the reaction between phenylhydrazine and benzaldehyde derivatives. Easy procedure, mild reaction conditions, high yields in short reaction times, availability of starting materials, and no formation of by-product are the advantages of this approach.

Full text of DOI:10.1007/s13738-014-0578-4

J IRAN CHEM SOC
DOI 10.1007/s13738-014-0578-4
ORIGINAL PAPER
A novel chemoselective synthesis of 3H‑spiro[isobenzofuran‑1,3′‑
pyrazole] derivatives by oxidative cleavage of their corresponding
dihydroindeno[1,2‑c]pyrazoles
Mohammad Reza Mohammadizadeh · Fatemeh Basti
Received: 13 August 2014 / Accepted: 17 December 2014
©
Iranian Chemical Society 2014
Abstract This paper reports a new and simple procedure
for the synthesis of 3H-spiro[isobenzofuran-1,3′-pyrazole]
derivatives by reacting 1-benzylidene-2-phenylhydra-
zine derivatives with ninhydrin in acetic acid medium at
room temperature followed by oxidative cleavage of their
corresponding dihydroindeno[1,2-c]pyrazoles. 1-Ben-
zylidene-2-phenylhydrazine derivatives were prepared via
the reaction between phenylhydrazine and benzaldehyde
derivatives. Easy procedure, mild reaction conditions, high
yields in short reaction times, availability of starting mate-
rials, and no formation of by-product are the advantages of
this approach.
molecules as they possess antiepileptic, antibiotic and anti-
depressant activities as well as their presence in biologi-
cally active molecules [4–7]. On the other hand, pyrazole
and its derivatives have also been focus of considerable
attention due to their broad variety of properties. There is
large variety of compounds having the pyrazole core struc-
ture that are of importance in agrochemical and pharma-
ceutical activities [8].
While isobenzofuranone and pyrazole derivatives have
attracted significant attention, the preparation of spiro-
heterocyclic compounds incorporating isobenzofuranone
and pyrazole motifs has not been the subject of much
research.
Keywords 3H-spiro[isobenzofuran-1,3′-pyrazole] ·
Ninhydrin · 1-Benzylidene-2-phenylhydrazine ·
Dihydroindeno[1,2-c]pyrazole
We have been synthesizing numerous novel spiro-type
molecules that have isobenzofuranone moiety through an
oxidative cleavage strategy [9–11]. Herein, we apply this
strategy to the synthesis of new spirocyclic compounds
containing isobenzofuranone and pyrazole skeleton named
3H-spiro[isobenzofuran-1,3′-pyrazole].
Introduction
Synthesis of compounds with specific chemical structures
and biological properties may be important and has always
been considered by chemists. Many efforts have been
made to provide the efficient ways to produce a wide range
of derivatives in each series. One of these compounds
which has always been the focus of attention for various
research groups is phthalide[1(3H)-isobenzofuranone]
frameworks, a bunch of natural products possessing bio-
logical activity as well as synthetic goals [1–3]. 3-Substi-
tuted spiro-type phthalides are especially very important
Experimental
General
Melting points were measured on an Electrothermal 9100
apparatus. IR spectra were recorded on A Jasco IR-460
Plus spectrometer. Mass spectra were recorded on an Agi-
lent 8430 mass spectrometer operating at an ionization
potential of 70 eV. H and C-NMR spectra were recorded
at 500.1, 400.2 and 125.7, 100.6 MHz, respectively, on a
BRUKER DRX 500 and 400-AVANCE FT-NMR instru-
ment with CDCl and DMSO as solvent. The reagents
and solvents used in this work were obtained from Fluka,
Merck and Aldrich companies and used without further
1
13
M. R. Mohammadizadeh (*) · F. Basti
Department of Chemistry, Faculty of Sciences, Persian Gulf
University, Bushehr 75169, Iran
3
e-mail: mrmohamadizadeh@pgu.ac.ir
1
3

J IRAN CHEM SOC
purification. The reaction monitoring was accomplished by
TLC on silica gel PolyGram SILG/UV254 plates.
CDCl ), 7.12–7.17 (m, 3H, CH of Ar), 7.25–7.29 (m, 2H,
CH of Ar), 7.30–7.31 (m, 1H, CH of Ar), 7.68–7.76 (m,
3
2
H, CH of Ar), 8.12–8.14 (m, 1H, CH of Ar), 8.35–8.41
1
3
General procedure for the preparation
(m, 4H, CH of Ar); C-NMR (100 MHz, CDCl ), δ 90.8,
3
of 1-benzylidene-2-phenylhydrazine derivatives (3a‑j)
117.6, 121.9, 124.2, 125.6, 126.4, 126.9, 127.1, 129.6,
1
31.9, 134.3, 135.7, 138.1, 139.5, 141.6, 148.1, 166.8,
To a mixture of phenylhydrazine (1 mmol) in ethanol
191.0. Anal. Calcd. for C H N O (399.36): C 66.17, H
2
2
13
3
5
(
5 mL) aldehyde was added followed by some drops of
3.28, N 10.52; Found: C 66.13, H 3.25, N 10.49. MS m/z
(%): 400 ([M ] , 1), 399 ([M] , 3), 383 (20), 223 (43),
179 (base peak), 104 (39), 91 (40), 77 (86), 76 (66).
+1 +
+
acetic acid. The resulting mixture was disrupted under
reflux conditions for 15 min using a magnetic stirrer. The
reaction progress was looked for by TLC using a mixture
of ethyl acetate/n-hexane (1:10). After completion of the
reaction and cooling to room temperature, water (5 mL)
was added. Pure product was obtained after filtration and
washing with n-hexane (3 × 5 mL). All compounds were
known and identified by comparison of their melting points
with previously reported values [12–14].
5′‑(4‑Fluorophenyl)‑2′‑phenyl‑3H‑spiro[isobenzofuran‑1,3′‑
pyrazole]‑3,4′(2′H)‑dione (5c)
Red powder; mp: 200–203 °C; IR (KBr), (ῡmax, cm−1):
1
1,794, 1,739, 1,597, 1,531, 1,496; H-NMR (400 MHz,
CDCl ): δ 7.10–7.15 (m, 3H, CH of Ar), 7.23–7.30 (m,
3
3
H, CH of Ar), 7.67–7.75 (m, 2H, CH of Ar), 7.78 (d,
3
3
General procedure for the preparation of 3H-spiro[isobenz
ofuran-1,3′-pyrazole] derivatives in AcOH medium
J = 8.8 Hz, 2H, CH of Ar), 8.12 (d, J = 6.4 Hz, 1H, CH
of Ar), 8.33 (d, J = 8.4 Hz, 2H, CH of Ar); C-NMR
100 MHz, CDCl ), 90.7, 112.9, 117.5, 118.6, 121.9,
3
13
(
3
A mixture of 1-benzylidene-2-phenylhydrazine 3 (1 mmol),
and ninhydrin 4 (1 mmol) in acetic acid (3 mL), was stirred
at room temperature for 3 h. Then, a solution of Pb(OAc)4
125.5, 126.2, 126.9, 127.0, 129.6, 131.9, 132.5, 132.7,
135.6, 138.4, 139.5, 141.7, 166.8, 191.1. Anal. Calcd. for
C H FN O (372.35): C 70.96, H 3.52, N 7.52; Found C
22
13
2
3
+1 +
(1 mmol) in acetic acid (2 mL) was added and the resulting
70.93, H 3.48, N 7.47. MS: m/z(%): 373 ([M ] , 22), 372
+
mixture was allowed to rotate for additional 40 min at room
temperature. After completion, confirmed by TLC, water
([M] , 98), 356 (16), 179 (99), 104 (73), 91 (37), 77 (88),
76 (base peak).
(5 mL) was added to the reaction mixture and pure product
was obtained after filtration and washing with a mixture of
EtOAc/n-hexane (1:10, 3 × 5 mL).
5′‑(4‑Bromophenyl)‑2′‑phenyl‑3H‑spiro[isobenzofuran‑1,3′‑
pyrazole]‑3,4′(2′H)‑dione (5d)
5
3
′‑(4‑Chlorophenyl)‑2′‑phenyl‑3H‑ spiro[isobenzofuran‑1,
′‑pyrazole]‑3,4′(2′H)‑dione (5a)
Red powder; mp: 158–161 °C; IR (KBr), (ῡmax, cm−1):
1,788, 1,737, 1,596, 1,514, 1,497; H-NMR (400 MHz,
1
CDCl ), δ 7.08–7.11 (m, 3H, CH of Ar), 7.22–7.26 (m, 3H,
3
Red powder; mp: 161–164 °C; IR (KBr), (ῡmax, cm−1):
CH of Ar), 7.65 (d, J = 8.6 Hz, 2H, CH of Ar), 7.68–7.73
3
1
13
1
,789, 1,737, 1,597, 1,516, 1,497; H-NMR (400 MHz,
(m, 2H, CH of Ar), 8.08–8.12 (m, 3H, CH of Ar); C-
CDCl ), δ 7.07–7.11 (m, 3H, CH of Ar), 7.22–7.25 (m, 3H,
NMR (100 MHz, CDCl ), δ 90.6, 117.2, 122.0, 124.4,
3
3
3
CH of Ar), 7.49 (d, J = 8.6 Hz, 2H, CH of Ar), 7.65–7.23
124.8, 126.9, 127.0, 127.1, 127.5, 129.4, 131.7, 132.2,
135.5, 139.6, 139.9, 141.9, 167.0, 191.6. Anal. Calcd. for
C H BrN O (433.25): C 60.99, H 3.02, N 6.47; Found:
3
3
(
1
m, 2H, CH of Ar), 8.06 (dd, J = 6.2 Hz, J = 1.9 Hz,
1
2
3
13
H, CH of Ar), 8.16 (d, J = 8.7 Hz, 2H, CH of Ar); C-
2
2
13
2
3
+2 +
NMR (100 MHz, CDCl ), δ 90.6, 117.2, 122.0, 124.8,
C 60.95, H 2.99, N 6.45. MS, m/z (%): 435 ([M ] , 4),
434 ([M ] , 20), 433 ([M] , 4), 416 (6), 223 (base peak),
179 (98), 104 (56), 91 (27), 77 (54), 76 (78).
3
+
1 +
+
1
1
26.6, 126.9, 127.1, 127.3, 129.2, 129.4, 131.7, 135.5,
36.0, 139.5, 139.9, 141.9, 167.0, 191.7. Anal. Calcd. for
C H ClN O (388.80): C 67.96, H 3.37, N 7.21; Found:
2
2
13
2
3
+
2 +
C 67.93, H 3.33, N 7.16. MS, m/z (%): 390 ([M ] , 20),
89 ([M ] , 15), 388 ([M] , 66), 372 (14), 223 (98), 209
4‑(3,4′‑Dioxo‑2′‑phenyl‑2′,4′‑dihydro‑3H‑ spiro[isobenzof
uran‑1,3′‑pyrazole]‑5′‑yl)benzonitrile (5e)
+
1 +
+
3
(
96), 179 (base peak), 105 (99), 91 (43), 77 (61), 76 (29).
Red powder; mp: 159–162 °C; IR (KBr), (ῡmax, cm−1):
2,222, 1,786, 1,746, 1,597, 1,526, 1,497; H-NMR
1
5
′‑(4‑Nitrophenyl)‑2′‑phenyl‑3H‑ spiro[isobenzofuran‑1,3′
‑pyrazole]‑3,4′(2′H)‑dione (5b)
(400 MHz, CDCl ), δ 7.00–7.09 (m, 3H, CH of Ar), 7.16–
3
7
.29 (m, 5H, CH of Ar), 7.55–7.72 (m, 2H, CH of Ar),
Red powder; mp: 214–217 °C; IR (KBr), (ῡmax, cm−1):
8.10–8.12 (m, 1H, CH of Ar), 8.19–8.23 (m, 2H, CH of
Ar); C-NMR (100 MHz, CDCl ), δ 90.6, 117.2, 122.0,
1
13
1
,790, 1,732, 1,596, 1,523, 1,497; H-NMR (400 MHz,
3
1
3

J IRAN CHEM SOC
+
1 +
1
1
24.3, 124.4, 124.6, 126.9, 127.1, 128.1, 128.2, 129.4,
31.6, 135.5, 139.7, 140.0, 142.0, 162.6, 167.1, 191.9.
74.52, H 3.94, N 7.87. MS: m/z (%): 355 ([M ] , 4), 354
+
([M] , 19), 338 (7), 223 (88), 179 (base peak), 104 (27), 91
Anal. Calcd. for C H N O (379.37): C 72.82, H 3.45, N
(17), 77 (40), 76 (50).
2
3
13
3
3
1
1.08; Found: C 72.79, H 3.43, N 11.06. MS m/z (%): 380
+1 +
+
([M ] , 3), 379 ([M] , 11), 363 (26), 223 (61), 179 (base
2′‑(4‑Bromophenyl)‑5′‑(4‑methoxyphenyl)‑3H‑spiro[isobe
nzofuran‑1,3′‑pyrazole]‑3,4′(2′H)‑dione (5i)
peak), 104 (24), 91 (11), 77 (54), 76 (45).
5
3
′‑(4‑Methoxyphenyl)‑2′‑phenyl‑3H‑spiro[isobenzofuran‑1,
′‑pyrazole]‑3,4′(2′H)‑dione (5f)
Red powder; mp: 167–169 °C; IR (KBr), (ῡmax, cm−1):
1,783, 1,746, 1,606, 1,536, 1,487; H-NMR (400 MHz,
1
3
3
CDCl ), δ 3.91 (s, 3H, CH ), 6.93 (dd, J = J = 2.6 Hz,
3
3
1
2
Red powder; mp: 148–151 °C; IR (KBr), (ῡmax, cm−1):
1
CDCl ), δ 3.91 (s, 3H, CH ), 7.03–7.09 (m, 5H, CH of Ar),
7
1H, CH of Ar), 6.95 (dd, J = J = 2.6 Hz, 1H, CH of
3
3
1
2
1
3
3
,784, 1,745, 1,608, 1,578, 1,497; H-NMR (400 MHz,
Ar), 7.02 (dd, J = J = 2.4 Hz, 1H, CH of Ar), 7.05
1
2
3 3
1
(dd, J = J = 2.4 Hz, 1H, CH of Ar), 7.19–7.22 (m,
3
3
2
3 3
1
.21–7.29 (m, 3H, CH of Ar), 7.64–7.71 (m, 2H, CH of
1H, CH of Ar), 7.33 (dd, J = J = 2.6 Hz, 1H, CH of
2
3
3
3 3
1
Ar), 8.09 (dd, J = 6.2 Hz, J = 1.6 Hz, 1H, CH of Ar),
Ar), 7.35 (dd, J = J = 2.6 Hz, 1H, CH of Ar), 7.66–
1
2
2
3
13
8
.16 (d, J = 9.2 Hz, 2H, CH of Ar); C-NMR (100 MHz,
7.73 (m, 2H, CH of Ar), 8.09–8.12 (m, 1H, CH of Ar),
3
3
CDCl ), δ 55.4, 90.5, 114.4, 116.9, 120.6, 122.0, 124.0,
8.13 (dd, J = J = 2.4 Hz, 1H, CH of Ar); 8.16 (dd,
3
1
2
3
3
13
1
1
26.8, 127.2, 127.8, 129.3, 131.5, 135.4, 140.3, 140.6,
42.3, 161.2, 167.3, 192.3. Anal. Calcd. for C H N O
J = J = 2.4 Hz, 1H, CH of Ar); C-NMR (100 MHz,
1
2
CDCl ), δ 55.5, 90.3, 114.5, 117.0, 118.3, 120.3, 122.0,
2
3
16
2
4
3
(
384.38): C 71.87, H 4.20, N 7.29; Found: C 71.84, H 4.17,
126.9, 127.1, 127.9, 131.7, 132.3, 135.5, 139.4, 140.9,
141.9, 161.4, 166.9, 192.1. Anal. Calcd. for C H BrN O
4
+
1 +
+
N 7.26. MS: m/z (%): 385 ([M ] , 4), 384 ([M] , 16), 368
2
3
15
2
(
(
16), 301 (29), 223 (33), 179 (62), 104 (63), 90 (50), 77
55), 76 (base peak).
(463.28): C 59.63, H 3.26, N 6.05; Found: C 59.60, H 3.24,
+2 +
+1 +
N 6.02. MS, m/z (%): 465 ([M ] , 8), 464 ([M ] , 35),
+
4
63 ([M] , 8), 446 (20), 301 (97), 257 (49), 178 (46), 104
2
′‑Phenyl‑5′‑(p‑tolyl)‑3H‑spiro[isobenzofuran‑1,3′‑pyrazo
(68), 90 (56), 76 (base peak).
le]‑3,4′(2′H)‑dione (5g)
2
′‑(4‑Bromophenyl)‑5′‑(p‑tolyl)‑3H‑spiro[isobenzofuran‑1,
Red powder; mp: 158–161 °C; IR (KBr), (ῡmax, cm−1):
3′‑pyrazole]‑3,4′(2′H)‑dione (5j)
1
1
,787, 1,748, 1,596, 1,541,1,497; H-NMR (400 MHz,
CDCl ), δ 2.5 (s, 3H, CH ), 7.04–7.10 (m, 3H, CH of Ar),
Red powder; mp: 189–192 °C; IR (KBr), (ῡmax, cm−1):
1,799, 1,747, 1,588, 1,535, 1,487; H-NMR (400 MHz,
3
3
1
7
.21–7.28 (m, 3H, CH of Ar), 7.31–7.34 (m, 2H, CH of
Ar), 7.64-7.71 (m, 2H, CH of Ar), 8.08–8.13 (m, 3H, CH
CDCl ), δ 2.43 (s, 3H, CH ), 6.92–6.94 (m, 2H, CH of Ar),
3
3
1
3
of Ar), C-NMR (100 MHz, CDCl ), δ 21.6, 90.6, 117.1,
6.96–7.18 (m, 2H, CH of Ar), 7.26–7.31 (m, 3H, CH of
Ar), 7.67–7.78 (m, 2H, CH of Ar), 8.05–8.07 (m, 3H, CH
3
1
1
22.0, 124.4, 125.3, 126.1, 126.8, 127.2, 129.4, 129.7,
31.5, 135.4, 140.2, 140.4, 140.7, 142.2, 167.2, 192.1.
1
3
of Ar); C-NMR (100 MHz, CDCl ), δ 22.7, 90.4, 114.6,
3
Anal. Calcd. for C H N O (368.38): C 74.99, H 4.38, N
118.3, 119.5, 123.1, 125.1, 126.0, 127.3, 128.0, 130.8,
132.8, 133.4, 135.1, 136.6, 140.1, 141.9, 164.9, 192.1.
Anal. Calcd. for C H BrN O (447.28): C 61.76, H 3.38,
2
3
16
2
3
7
.60; Found: C 74.95, H 4.36, N 7.58. MS: m/z(%): 369
+1 + +
[M ] , 18), 368 ([M] , 79), 352 (17), 223 (base peak),
(
2
3
15
2
3
1
79 (99), 104 (55), 91 (36), 77 (67), 76 (81).
N 6.26; Found: C 61.73, H 3.34, N 6.22. MS, m/z (%): 449
(
+2 + +1 + +
[M ] , 5), 448 ([M ] , 19), 447 ([M] , 5), 432 (14),
2
′,5′‑Diphenyl‑3H‑spiro[isobenzofuran‑1,3′‑pyrazole]‑3,4′
301 (58), 257 (36), 178 (49), 104 (66), 90 (36), 76 (base
peak).
(2′H)‑dione (5 h)
Red powder; mp: 150–153 °C; IR (KBr), (ῡmax, cm−1):
1
1
,786, 1,730, 1,599, 1,526,1,494; H-NMR (400 MHz,
Results and discussion
CDCl ), δ 7.06–7.11 (m, 3H, CH of Ar), 7.22–7.27 (m,
3
3
H, CH of Ar), 7.47-7.55 (m, 3H, CH of Ar), 7.65–7.72
The synthesis of 3H-spiro[isobenzofuran-1,3′-pyrazole]
derivatives from the reaction between 1-benzylidene-
2-phenylhydrazine derivatives and ninhydrin followed by
oxidative cleavage of their corresponding product was stud-
ied (Scheme 1).
(
(
m, 2H, CH of Ar), 8.09–8.12 (m, 1H, CH of Ar), 8.21
dd, J = 7.8 Hz, J = 1.6 Hz, 2H, CH of Ar); C-
3
3
13
1
2
NMR (100 MHz, CDCl ), δ 90.6, 117.1, 122.0, 124.6,
3
1
1
26.0, 126.8, 127.1, 128.1, 128.9, 129.4, 130.1, 131.6,
35.4, 140.1, 140.5, 142.2, 167.2, 191.9. Anal. Calcd. for
As can be seen in Scheme 1, initially according to
the previously reported procedure, the derivatives of
C H N O (354.36): C 74.57, H 3.98, N 7.91; Found: C
2
2
14
2
3
1
3

J IRAN CHEM SOC
Scheme 1 Total path-
way for the synthesis of
O
NH NH2
H
O
3
H-spiro[isobenzofuran-1,3′-
EtOH
H
OH
+
R2
1 +
R
NH N C
pyrazole] derivatives
OH
R2
1
R1
2
O
3
a-j
4
1
2
) AcOH, r.t., 3 h
) Pb(OAc) , 40 min
4
O
R1
O
N
N
O
R2
5
a-j
Table 1 Synthesis of new derivatives of 3H-spiro[isobenzofuran-
followed by oxidative cleavage of their corresponding prod-
1
,3′-pyrazole] 5a‑j
uct by Pb(OAc) was resulted in 3H-spiro[isobenzofuran-
4
1
,3′-pyrazole] (Table 1). The results show that the desired
products were obtained in excellent yields and substituted
groups on aromatic rings did not have any profound influ-
ence on the reactivity. Yet, oxidative cleavage step was very
fast and clean and the pure products were precipitated at
the end and extra action was not required for purification.
Note that when periodic acid was used as oxidizing agent
in the oxidative cleavage of vicinal diol 6a, the product 5a
was obtained in only 55 % yield.
The molecular structures of all products 5a‑j were iden-
1
tified from their mass spectrometric analyses, IR, H-NMR,
C-NMR spectra and elemental analyses. Spectral data of
5
R1
R2
Yield (%)a
13
compound 5a, for instance, are as follows: The mass spec-
trum of 5a displayed the molecular ion peak at m/z 372,
which is in agreement with the proposed structure. The IR
spectrum of this compound showed absorption bands due
to the carbonyl groups of the lactone and ketone at 1,794,
a
b
c
d
e
f
Cl
H
H
H
H
H
H
H
H
Br
Br
94
97
95
93
94
91
91
92
89
89
NO2
F
Br
CN
OCH3
CH3
H
−1
−1
1
,739 cm , respectively, and at 1,597, 1,531, 1,496 cm
1
for C=N, C=C and C–N bonds. The H-NMR spectrum of
this compound shows 12 protons in the aromatic region that
correspond well with the structure of this compound. The
g
h
i
OCH3
CH3
1
13
H-decoupled C-NMR spectrum of 5a showed 19 distinct
j
resonances in agreement with the suggested structure.
For more information about the mechanism, in the syn-
thesis of compound 5a, the reaction was stopped before
a
Refers to isolated pure products
adding the Pb(OAc) and the product was isolated and
4
1
13
1
-benzylidene-2-phenylhydrazine were prepared by the
identified on the basis of their IR, H-NMR, C-NMR data
and elemental analyses. Spectral data confirmed a vicinal
cyclic diol structure in this step (Scheme 2).
The H-NMR spectrum of 6a in CDCl3 exhibited
two single sharp signals at 3.58 and 4.19 ppm due to the
hydroxyl protons, together with aromatic protons which
condensation reaction between phenylhydrazine and benza-
ldehyde derivatives (3a‑j). These known compounds were
identified by comparing their melting points with previ-
ously reported values. The reaction of these compounds
with ninhydrin in acetic acid medium at room temperature
1
1
3

J IRAN CHEM SOC
Scheme 2 Synthesis of vicinal
diol 6a by reaction of com-
pound 3a with ninhydrin
Cl
O
O
O
OH
N
H
AcOH
r.t. 3h
OH
OH
+
Cl
NH N C
OH
N
3a
4
6a
Scheme 3 Proposed mecha-
nism for the formation of
compounds 5a‑j
O
O
NH NH2
H
H
OH
EtOH
R2
R1
+
NH
N
C
+
OH
-
H O
2
O
4
R2
1
3a-j
R1
2
O
O
OH
R1
OH
R1
AcOH
N
NH
H
N
N
O
O
-
H O
2
B
B = H O
2
or
R2
C
H CO2
R2
3
7
8
R2
OAc
OAc
O
R1
Pb
OH
O
O
-
2 Pb(OAc)2
N
Pb(OAc)4, AOcH
N
OH N
N
O
R2
9
R1
6a-j
O
R1
OH
O
δ
O
O
O
R2
R1
O
N
HO
H O
2
N
O
N
N
- H O
2
N
δ
N
O
1
0
11
5a-j
R2
R1
R2
were resonated as multiplets in the region at δ = 7.13–
.98 ppm. The H decoupled C-NMR spectrum of 6a
showed distinct signals in agreement with the proposed
structure. (see Supplementary data).
3, due to the presence of nitrogen containing free electron
pair conjugated with carbon–nitrogen double bond. This
carbon is bearing some negative charge and nucleophilic
attacks are firstly made through the carbon [16, 17]. There-
fore, 1-benzylidene-2-phenylhydrazines 3 attack the nin-
hydrin and after passing the intermediate 8 followed by
intramolecular attack of nitrogen to other carbonyl group of
ninhydrin, dihydroindeno[1,2-c]pyrazole compounds 6a–j
are synthesized. Then, the oxidative cleavage of these cyclic
1
13
7
A
plausible mechanism for the synthesis of
3H-spiro[isobenzofuran-1,3′-pyrazole] derivatives is
depicted in Scheme 3. At first, from the condensation reac-
tion between phenylhydrazine and benzaldehyde derivatives,
the corresponding 1-benzylidene-2-phenylhydrazines are
obtained [15]. The 1-benzylidene-2-phenylhydrazine deriva-
tives (phenylhydrazones) 3 act as enamines. In compound
diols by Pb(OAc) produces the orthogonal intermediate 10
4
through intermediate 9. Because of the strong intramolecular
1
3

J IRAN CHEM SOC
2. J.J. Beck, S.C. Chou, J. Nat. Prod. 70, 891 (2007)
interactions between the nitrogen and the carbonyl group
next to it in such rings [18], a large positive charge assem-
bled on the nitrogen in the intermediate 10. Hydrolysis of
this intermediate produces the compound 11 which forms
the final product by intramolecular sterification reaction.
3
4
. R. Fittig, G. Ebert, Ann. Chem. 126, 162 (1883)
. F.J. Urban, B.G. Anderson, M.A. Stewart, G.R. Young, Org. Pro-
cess Res. Dev. 3, 460 (1999)
5. V.J. Bauer, B.J. Duffy, D. Hoffman, S.S. Klioze, R.W. Kosley,
A.R. McFadden, L.L. Martin, H.H. Ong, H.M. Geyer, J. Med.
Chem. 19, 1315 (1976)
6
. F. Konno, T. Ishikawa, M. Kawahata, K. Yamaguchi, J. Org.
Chem. 71, 9818 (2006)
7. M. Chitambar, Z. Wang, Y. Liu, A. Rockett, S. Maldonado, J. Am.
Conclusion
Chem. Soc. 134, 10670 (2012)
8
. J. Elguero, P. Goya, N. Jagerovic, A.M.S. Silva, Pyrazoles as
Drugs: Facts and Fantasies, in Targets in Heterocyclic Systems,
ed. by O.A. Attanasi, D. Spinelli (Royal Society of Chemistry,
Cambridge, 2002), pp. 52–98
In conclusion, this work described a novel method for
the preparation of a wide variety of new spirocyclic com-
pounds containing isobenzofuranone and pyrazole moi-
eties, named 3H-spiro[isobenzofuran-1,3′-pyrazole] by
oxidative cleavage of dihydroindeno[1,2-c]pyrazoles. This
one-pot and simple procedure can be a convenient and
effective method for the synthesis of a wide range of novel
drug-like spiroindolines.
9. M.R. Mohammadizadeh, M. Bahramzadeh, S.Z. Taghavi, Tetra-
hedron Lett. 51, 5807 (2010)
1
0. M.R. Mohammadizadeh, N. Firoozi, R. Aradeh, Helv. Chim.
Acta 94, 410 (2011)
11. G.H. Mahdavinia, M.R. Mohammadizadeh, N. Ariapour, M.
Alborz, Tetrahedron Lett. 55, 1967 (2014)
1
2. G. Nagalakshmi, T.K. Maity, B.C. Maiti, Pharmacologyonline 1,
228 (2011)
1
Acknowledgments The authors would like to acknowledge finan-
cial support provided by Persian Gulf University for carrying out this
research.
1
1
1
3. E.A. Dikusar, V.I. Potkin, Russ. J. Gen. Chem. 79, 953 (2009)
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