Lewis Acid Catalyzed Regio- and Diastereoselective Synthesis of Spiroisoxazolines via One-Pot Sequential Knoevenagel Condensation/1,3-Dipolar Cycloaddition Reaction

Article abstract of DOI:10.1055/s-0037-1610676

A ZnCl ₂ -catalyzed regio- and diastereoselective one-pot sequential Knoevenagel condensation/1,3-dipolar cycloaddition reaction of CH acids (oxindole, 1,3-indandione, and 3 H -pyrazol-3-one), aldehydes, and dibromoformaldoxime has been established. The method allows the synthesis of diversely functionalized spiroisoxazolines in good isolated yields under mild reaction conditions. Moreover, the preparation of spiroindene-isoxazole-1,3-diones containing benzoimidazole or benzothiazole moieties as new ligands for the metal-catalyzed coupling reactions and C-H activation is demonstrated.

Full text of DOI:10.1055/s-0037-1610676

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–K
paper
A
en
H. Yazdani, A. Bazgir
Paper
Synthesis
Lewis Acid Catalyzed Regio- and Diastereoselective Synthesis
of Spiroisoxazolines via One-Pot Sequential Knoevenagel
Condensation/1,3-Dipolar Cycloaddition Reaction
Hossein Yazdani
NH
Ayoob Bazgir*
- One-pot synthesis
- Gram scale
- Broad synthetic application
- Broad substrate scope
- Mild reaction conditions
- Cheap Lewis acid
O
Ar
O
O
ArCH2O
+
Department of Chemistry, Shahid
Beheshti University G.C., Tehran
1983963113, Iran
N
H
N
10 examples (64–84%)
high diastereo- and
regioselectivity
Br
a_bazgir@sbu.ac.ir
O
O
O
OH
N
O
N
+
ArCH2O
Br
Br
Br
O
Ar
5 examples (74–83%)
high regioselectivity
Y
N
O
XH
+
O
O
N
N
O
Y
X = S, NH
Y = S, NH
X
Ar
O
Ar
6 examples (76–85%)
new ligands for C–C coupling
Received: 31.10.2018
Accepted after revision: 08.11.2018
Published online: 09.01.2019
cause of their outstanding biological activities.5 Natural and
non-natural spiroisoxazolines have become evident as aus-
picious drug candidates resulting in a general antiprolifera-
tive effect on various cancer cell lines.6 The 11-deoxyfistu-
larin-3, a natural product containing spiroisoxazoline moi-
ety is cytotoxic toward estrogen dependent MCF-7 breast
cancer cells.5e Similarly, homoaerothionin5f and psammap-
lysin A5g with spiroisoxazoline framework have physiologi-
cal activities. The calculation methods have indicated that
isoxazoline ring could coordinate to metals7 and several
isoxazoline and spiroisoxazoline skeletons have been syn-
thesized by multi-step methods and reported as promising
ligands for transition-metal-catalyzed reactions.7,8
DOI: 10.1055/s-0037-1610676; Art ID: ss-2018-n0326-op
Abstract A ZnCl2-catalyzed regio- and diastereoselective one-pot se-
quential Knoevenagel condensation/1,3-dipolar cycloaddition reaction
of CH acids (oxindole, 1,3-indandione, and 3H-pyrazol-3-one), alde-
hydes, and dibromoformaldoxime has been established. The method al-
lows the synthesis of diversely functionalized spiroisoxazolines in good
isolated yields under mild reaction conditions. Moreover, the prepara-
tion of spiroindene-isoxazole-1,3-diones containing benzoimidazole or
benzothiazole moieties as new ligands for the metal-catalyzed coupling
reactions and C–H activation is demonstrated.
Keywords 1,3-dipolar cycloaddition reaction, isoxazolines, nitrile ox-
ides, spirooxindoles, spiroindandiones, coupling reaction
The two-component 1,3-dipolar cycloaddition reaction
of nitrile oxide and exocyclic methylenes is the most devel-
oped synthetic method for the spiroisoxazoline synthesis.9
Recently, 4-bromospiroisoxazolines were synthesized by a
two-step method (1,3-dipolar cycloaddition/intramolecular
cyclization).6 It is notable that only a few publications ad-
dress the synthesis of spiroisoxazolines by the 1,3-dipolar
cycloaddition sequential reaction.4f,10 Therefore, a simple,
efficient, and applicable sequential method for the synthe-
sis of spiroisoxazolines is still in high demand. According to
the above reports and as a continuation of our interest in
the synthesis of spiroheterocycles,11 herein, we report a Zn-
Cl2-catalyzed regio- and diastereoselective one-pot sequen-
tial Knoevenagel condensation/1,3-dipolar cycloaddition
method for the synthesis of diversely functionalized
spiroisoxazolines and spiroisoxazolines containing benzo-
imidazole or benzothiazole moieties.
The Lewis acid catalyzed one-pot sequential reactions,
which consist of several simultaneous bond-forming reac-
tions in a one-pot manner,1 are an attractive and powerful
synthetic method for the synthesis of diverse complex mol-
ecules from simple precursors.2 Due to savings in time,
chemicals, and effort, sequential reactions can increase
synthetic efficiency and provide a positive environmental
impact by reducing chemical use.3 Among sequential reac-
tions, the 1,3-dipolar cycloaddition-based sequential reac-
tions for isoxazole derivatives synthesis is one of the best
examples.4
The development of simple and effective methods for
the synthesis of spiroisoxazoline framework as a one of the
most important isoxazole derivatives has attracted atten-
tion in the area of synthetic and medicinal chemistry be-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

B
H. Yazdani, A. Bazgir
Paper
Synthesis
Initial investigation was started by the reaction of oxin-
dole (1), 4-bromobenzaldehyde (2a), and bromonitrile ox-
ide precursor 3 as a model reaction. When the model reac-
tion was performed in the presence of Na2CO3 as base in
THF at 45 °C for 10 hours, the spiro[indoline-3,5′-isoxazol]-
2-one 4a was obtained in 37% isolated yield (Table 1, entry
1). Then, different bases such as Et3N, CaCO3, K2CO3, and
NaHCO3 were screened in the model reaction (entries 2–5).
It was found that NaHCO3 is the optimal base for the reac-
tion (entry 5). When we tested the reaction under base-free
conditions, the yield of the product was trace (entry 6).
Subsequently, different solvents were tested in the model
reaction in the presence of NaHCO3 (entries 6–9). Low
yields were obtained in EtOAc and CH2Cl2 (entries 9 and 10)
and the reaction did not proceed in EtOH and MeOH as
protic solvents (entries 7 and 8). Therefore, THF was select-
ed as the best medium for the reaction (entry 5). In addi-
tion, some experiments were performed at different tem-
peratures; 45 °C was determined to be the optimum reac-
tion temperature (entries 1, 11, and 12). Since, Lewis acids
could increase the yields in 1,3-dipolar reactions,12 we in-
vestigated several Lewis acids as promoters in the model re-
action. As can be seen from Table 1, most of the Lewis acids
gave the product in much better yields (entries 13–18). To
our delight, ZnCl2 was found to be a superior catalyst pro-
viding the desired product 4a in 75% isolated yield. Addi-
Table 1 Optimization of the Reaction Conditionsa
CHO
NH
OH
N
NH
conditions
O
O
Br
O
*
+
*
O
N
Br
Br
N
*
*
H
Br
Br
N
O
Br
Br
1
2a
3
4a
5
major Isomer
minor isomer
Entry
Solvent
Base
Lewis acid (mol%)
Temp (°C)
Time (h)
Yield (%)b
rr (%)c 4a:5
drd
≥95:5
1
2
THF
THF
THF
THF
THF
THF
EtOH
MeOH
EtOAc
CH2Cl2
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Na2CO3
Et3N
–
45
45
45
45
45
45
45
45
45
reflux
25
60
45
45
45
45
45
45
45
45
45
45
45
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
3
41
93:7
≥95:5
94:6
–
43
≥95:5
≥95:5
≥95:5
≥95:5
–
3
CaCO3
–
39
4
K2CO3
–
38
94:6
5
NaHCO3
–
–
48
≥95:5
–
6
–
trace
trace
trace
39
7
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
–
–
–
8
–
–
–
9
–
≥95:5
≥95:5
≥95:5
≥95:5
≥95:5
72:28
70:30
64:36
74:26
70:30
≥95:5
≥95:5
≥95:5
≥95:5
≥95:5
≥95:5
≥95:5
≥95:5
≥95:5
≥95:5
≥95:5
≥95:5
≥95:5
≥95:5
≥95:5
≥95:5
≥95:5
≥95:5
≥95:5
≥95:5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
–
40
–
42
–
46
ZnO (10)
SnCl2 (10)
HAuCl4 (10)
ZrCl4 (10)
CAN (10)
FeCl3 (10)
ZnCl2 (10)
ZnCl2 (10)
ZnCl2 (10)
ZnCl2 (5)
ZnCl2 (20)
66
45
68
60
43
58
75
81
2
74
3
57
3
82
a Oxindole (1; 1 mmol), 4-bromobenzaldehyde (2a; 1 mmol), dibromoformaldoxime (3; 1 mmol), base (1.5 mmol), and solvent (4 mL).
b Isolated yield.
c Regioisomer ratios (determined by 1H NMR analysis of the crude reaction mixture).
d Diastereomeric ratios for 4a (determined by 1H NMR analysis of the crude reaction mixture).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

C
H. Yazdani, A. Bazgir
Paper
Synthesis
tionally, we tested a lower reaction time (entries 21 and
22). To our surprise, the reaction in the presence of ZnCl2
(10 mol %) in THF at 45 °C afforded the product in 81% iso-
lated yield after 3 hours. Thus, we chose NaHCO3 as base,
THF as solvent in the presence of ZnCl2 as catalyst at 45 °C
as the optimum reaction conditions for further studies.
After optimization of the reaction conditions, the scope
of the sequential Knoevenagel condensation/1,3-dipolar cy-
cloaddition method was examined using substituted alde-
hydes 2a–j. As illustrated in Table 2, the reaction was suc-
cessfully extended to various aldehydes containing elec-
tron-withdrawing as well as electron-donating groups and
the spiro[indoline-3,5′-isoxazol]-2-ones 4a–j were ob-
tained in good isolated yields. Reasonable yields were also
obtained using sterically demanding benzaldehydes 2f,g as
well as 2-naphthaldehyde (2h).
Figure 1 X-ray crystal structure of 4g
H
N
O
NaHCO3
CHO
Br
ZnCl2 (10 mol%)
CuI (10 mol%)
O
N
OH
Br
N
O
+
THF, 45 °C
3 h
N
Br
O
H
O
6
3
1
O
N
7 72%
Table 2 Synthesis of Spiroindoline-isoxazol-2-ones 4a
Br
H
N
Scheme 1 Synthesis of bromoisoxazol-5-ylspiro[indoline-3,5′-isoxaz-
ol]-2-one 7
OH
Br
O
NaHCO3, ZnCl2 (10 mol%)
N
O
+
ArCHO
+
O
N
N
Ar
THF, 3 h
45 °C
Br
H
3
1
2
4
Br
merous products. To our delight, when the reaction was
carried out under same reaction conditions in the presence
of 10 mol% CuI, the product 3′-bromo-4′-{4[(3-bromoisox-
azol-5-yl)methoxy]phenyl}-4′H-spiro[indoline-3,5′-isoxaz-
ol]-2-one (7) was obtained in 72% isolated yield after 3
hours.
To indicate the feasibility of the present approach, the
reaction was scaled up to a gram-scale. Under the opti-
mized reaction conditions, 4-bromobenzaldehyde (10
mmol) and oxindole (10 mmol) were reacted with dibro-
moformaldoxime (10 mmol) in the presence of ZnCl2 (10
mol%) and the corresponding product 4a was achieved in
80% yield without any loss of regio- and diastereoselectivi-
ty.
>
dr: 95:5
Product 4
Ar
Yield (%)b
rr (%)c
a
b
c
d
e
f
4-BrC6H4
Ph
81
75
71
75
72
65
84
69
75
64
≥95:5
≥95:5
92:8
4-MeC6H4
4-MeOC6H4
4-EtOC6H4
2-FC6H4
93:7
≥95:5
94:6
g
h
i
2-BrC6H4
90:10
91:9
2-naphthyl
4-ClC6H4
≥95:5
93:7
To further explore the potential of this protocol for new
spiroisoxazole synthesis, the reaction involving 1,3-indan-
dione (8) was carried out to afford the 2′H-spiro[indene-
2,5′-isoxazole]-1,3-diones 9 in good isolated yields (Table
3).
j
3-HOC6H4
a dr: ≥95 (determined by 1H NMR analysis of the crude product).
b Isolated yield.
c Determined by 1H NMR analysis of the crude reaction mixture.
It is notable that two pairs of regioisomers may be
formed in the reaction. The 1H NMR spectra of the crude re-
action mixture without any purification reveals the isomer
4 as the major isomer and other isomers were produced in
trace amounts. High regio- and diastereoselectivity were
obtained in all cases. The single-crystal X-ray analysis of the
product 4g revealed the regio- and stereochemistry of the
products (Figure 1).
As expected, the reaction of 5-methyl-2-phenyl-2,4-di-
hydro-3H-pyrazol-3-one (10), 2-naphthaldehyde, and di-
bromoformaldoxime
afforded
the
1-oxa-2,7,8-tri-
azaspiro[4.4]nona-2,8-dien-6-one 11 in 60% yield under the
same reaction conditions (Scheme 2).
The structures all of the products were deduced from
1
their IR, H, and 13C NMR spectra and elemental analysis.
The stereochemistry of product 9b was confirmed by sin-
gle-crystal X-ray analysis (Figure 2).
To demonstrate the utility of the synthesized bromo-
spiroisoxazoles, nucleophilic substitution with some amino
or mercapto heterocycles were also performed. The sequen-
tial 1,3-dipolar cycloaddition/nucleophilic substitution of
When the reaction of oxindole (1), 4-[(prop-2-yn-1-
yl)oxy]benzaldehyde (6), and dibromoformaldoxime (3)
was performed under the same reaction conditions
1
(Scheme 1), TLC and H NMR spectra of the reaction mix-
ture showed a combination of starting materials and nu-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

D
H. Yazdani, A. Bazgir
Paper
Synthesis
Table 3 Synthesis of Spiro[indene-2,5′-isoxazole]-1,3-diones 9
arylideneindandione 12, dibromoformaldoxime (3), and
amino or mercapto heterocycles 13 afforded spiro[indene-
2,5′-isoxazole]-1,3-dione containing benzoimidazole or
benzothiazole moieties 14 in good isolated yields (Scheme
3).
Metal-catalyzed coupling reactions have a wide applica-
tion in modern organic and medicinal chemistry.13 A re-
markable factor in the efficiency of coupling reaction is the
nature of the ligand and an increasing tendency to apply al-
ternative ligands instead of expensive air-sensitive phos-
phine ligands is evident.14 The synthesized novel spiroinde-
neisoxazoles containing benzoimidazole or benzothiazole
14 seems to have promising potential as ligands for transi-
tion metal coupling reactions. Therefore, some metal-cata-
lyzed coupling reactions were chosen to evaluate the effi-
ciency of the synthesized ligands (Scheme 4). First, the
Suzuki (Scheme 4, eq. 1) and Suzuki-like (Scheme 4, eq. 2)
O
OH
NaHCO3, ZnCl2 (10mol%)
N
O
O
Ar
+
ArCHO
+
O
THF, 3 h
45 °C
Br
Br
N
3
2
8
O
Br
9
Product 9
Ar
Yield (%)a
rr (%)b
a
b
c
4-MeC6H4
78
83
74
79
80
≥95:5
≥95:5
≥95:5
≥95:5
≥95:5
4-MeOC6H4
2-naphthyl
4-ClC6H4
d
e
4-BrC6H4
a Isolated yield.
b Determined by 1H NMR analysis of the crude reaction mixture.
Ph
N
NaHCO3
N
OH
O
ZnCl2 (10 mol%)
N
CHO
+
O
N
O
+
THF, 45 °C
3 h
Br
Br
N
N
Ph
Br
11
10
yield: 60%
rr: >95:5
dr: >95:5
Scheme 2 Synthesis of 1-oxa-2,7,8-triazaspiro[4.4]nona-2,8-dien-6-
one 11
Figure 2 X-ray crystal structure of 9b
O
O
O
N
N
OH
Ar
Y
N
NaHCO3, ZnCl2 (10 mol%)
N
Y
XH
+
+
X
THF, 45 °C
3 h
O
Br
Br
Ar
X = S, NH
Y = S, NH
O
12
3
13
14
O
O
H
O
H
O
H
N
N
O
N
N
O
N
N
N
N
N
S
H
N
N
O
O
H
O
Br
Cl
MeO
14a 78%
14b 80%
14c 76%
O
H
O
H
O
N
N
O
O
N
H
N
O
N
N
S
N
S
H
N
H
O
N
S
O
O
MeO
MeO
MeO
14d 85%
14e 82%
14f 81%
Scheme 3 Synthesis of spiroindene-isoxazoles containing benzoimidazole or benzothiazole
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

E
H. Yazdani, A. Bazgir
Paper
Synthesis
reactions of phenylbronic acid (15a) were performed in the
presence of selected ligands 14b, 14d, and 14e. As can be
seen from Scheme 4, all tested ligands showed good effi-
ciency and led to the biphenyl (16a) and benzophenone
(17) as desired products in good isolated yields in short re-
action times. It was found that the ligand 14b resulted the
higher isolated yield and in the absence of any ligands prod-
ucts 16a and 17 were obtained in 68% and 33% isolated
yield, respectively (Scheme 4).15 The ligand 14b was tested
in copper-catalyzed homocoupling of 4-methoxyphenyl-
bronic acid (15b) and the desired 4,4′-dimethoxy-1,1′-bi-
phenyl (16b) was obtained in 90% isolated yield. It is nota-
ble that in the absence of ligand 14b, the product 16b was
obtained in <14% isolated yield (Scheme 4).16
tion that was tested in this study. Recently, the effect of
bidentate ligands in Ni-catalyzed C–H arylation of benzo-
thiazoles has been investigated and confirms the use of
bidentate ligands leading to a higher yield.18 Thus, the Ni-
catalyzed reaction of aryl bromides 18 and benzothiazole
(19) in the presence of ligand 14b and t-BuOLi as base in
THF afforded the 2-arylbenzothiazoles 20 in good isolated
yield after 24 hours (Table 4). When the reaction was car-
ried out in the absence of ligand, the products 20b, 20c, and
20g were obtained in low yields (Table 4).
Table 4 Synthesis of 2-Arylbenzothiazoles
N
S
Ni(OAc)2 (10 mol%), 14b
N
S
+
ArBr
Ar
t-BuOLi, THF (reflux)
Due to wide application of metal-catalyzed C–H activa-
tion in organic and medicinal chemistry,17 the Ni-catalyzed
C–H arylation of benzothiazoles was the final probe reac-
24 h
19
18
20
Product 20
Ar
Ph
Yield (%)
a
b
c
64
Ph–Br
4-MeC6H4
71 (10)a
57 (trace)a
70
Ph–Ph
(eq. 1)
Pd(OAc)2 (0.5 mol%), L
K2CO3, EtOH/H2O
60 °C, 20 min
B(OH)2
16a
4-ClC6H4
d
e
f
4-MeOC6H4
4-EtOC6H4
4-PhOCH2C6H4
4-biphenyl
O
66
15a
O
Ph
Cl
(eq. 2)
59
Ph
Ph
Pd(OAc)2 (0.5 mol%), L
K2CO3, toluene
80 °C, 2 h
17
g
61 (<10)a
a Yield in the absence of ligand.
L = 14b or 14d or 14e
O
Table 5 compares the efficiency of the Ni(OAc)2/14b cat-
alytic system with the efficiency of some other reported
nickel catalysts in the C–H arylation of benzothiazole with
4-bromotoluene (18b). Table 5 shows that although all the
methods have good efficiency, some of these methods suf-
fer from one or more of the drawbacks, such as using ex-
pensive organic solvents, high temperatures, and require
longer reaction times to achieve reasonable yields. The
present catalytic system offers high activity and good yield
in reasonable reaction time under mild conditions.
O
O
N
N
O
N
N
N
H
S
N
H
N
O
H
O
MeO
O
O
MeO
14b
14d
N
N
S
N
H
O
These results imply that the synthesized ligands have a
good efficiency to catalyze the various coupling reactions
with good yields of the products. The research on ligand ef-
ficiency of newly synthesized ligands in metal-catalyzed
organic transformations is under progress in our lab and re-
sults will be reported shortly.
In summary, novel sequential Knoevenagel condensa-
tion/1,3-dipolar cycloaddition reactions were developed,
which led to the formation of substituted spiroisoxazolines
with good regio- and stereoselectivity under mild condi-
tions in the presence of ZnCl2 as catalyst. This methodology
can be used to generate a large number of therapeutically
relevant spiroisoxazoline scaffolds in good yields. The utili-
ty of the present method was demonstrated by synthesiz-
ing privileged spiroindeneisoxazoles containing benzoimid-
azole and benzothiazole as new ligands for metal-catalyzed
coupling reactions.
MeO
14e
Ligand
14b
14d
14e No ligand
Yield (%)
of 14a
97
89
92
80
88
78
68
33
Yield (%)
of 15
OMe
Cu(OH)2 (1 mol%), 14b
B(OH)2
H2O/EtOH, 25 °C air,
50 min
MeO
MeO
15b
16b
Ligand
16b
No ligand
<14
Yield (%)
90
Scheme 4 Probe coupling reactions to evaluate the synthesized ligand
efficiency
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

F
H. Yazdani, A. Bazgir
Paper
Synthesis
Table 5 Comparison of Efficiency of Various Catalytic Systems for C–H Arylation of Benzothiazole
Entry
Catalytic system
Solvent
Time (h)
Temp (°C)
Yield (%)
Ref.
1
2
3
4
5
Ni(OAc)2/2,2′-bipyridyl
NiBr2/1,10-phenanthroline
Pd (TMHD)2
1,4-dioxane
diglyme
NMP
36
4
85
150
125
100
70
48
67
65
95
71
18
19
36
18
24
20
PXPd/Cu(Xantphos)I
Ni(OAc)2/14b
toluene
THF
21
this work
3′-Bromo-5′-(p-tolyl)-5′H-spiro[indoline-3,4′-isoxazol]-2-one (4c)
Melting points were determined on a melting point apparatus and are
uncorrected. IR spectra were taken with a Bomem FT-IR MB spec-
trometer. The NMR spectra were recorded on a Bruker DRX-300
Avance spectrometer. Mass spectra were recorded on an Agilent
5975C VL MSD spectrometer with Tripe-Axis Detector operating at an
ionization potential of 70 eV. Elemental analyses were performed us-
ing a Heraeus CHN-O-Rapid analyzer. The X-ray diffraction measure-
ments were made with a STOE IPDS-II diffractometer with graphite-
monochromated MoKα radiation. All chemicals were purchased from
Merck or Aldrich and were used without further purification.
Colorless solid; yield: 253 mg (71%); mp 181–183 °C.
IR (KBr): 3423, 3164, 1725, 1613 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 2.27 (3 H, s, CH3), 5.03 (1 H, s, CH),
6.29 (1 H, d, 3JHH = 7.5 Hz, ArH), 6.62 (1 H, t, 3JHH = 6.2 Hz, ArH), 6.78 (1
H, d, 3JHH = 7.5 Hz, ArH), 7.03–7.31 (5 H, m, ArH), 10.70 (1 H, s, NH).
13C NMR (75 MHz, DMSO-d6): δ = 24.4, 63.1, 88.5, 110.6, 122.1, 122.3,
127, 129, 129.5, 129.9, 131.5, 138.5, 142.5, 143.8, 175.5.
MS (EI): m/z = 356 (M+).
Anal. Calcd for C17H13BrN2O2: C, 57.16; H, 3.67; N, 7.84. Found: C,
57.07; H, 3.61; N, 7.75.
One-Pot Sequential Synthesis of Spiroisoxazolines 4, 9, and 11;
General Procedure
A mixture of aldehyde 2 (1 mmol), C–H acid (oxindole, 1,3-indandi-
one or 3H-pyrazol-3-one) (1 mmol), ZnCl2 (13.63 mg, 10 mol%), and
NaHCO3 (126 mg, 1.5 mmol) in THF (4 mL) was stirred for 30 min at
45 °C. Then, dibromoformaldoxime (3; 203 mg, 1 mmol) was added
and stirred for 2.5 h. After completion of the reaction, the solvent was
removed under vacuum and the crude mixture was washed with H2O
(10 mL). The solid residue was crystallized from CH2Cl2/n-hexane
(1:2) to afford the desired pure product.
3′-Bromo-4′-(4-methoxyphenyl)-4′H-spiro[indoline-3,5′-isoxaz-
ol]-2-one (4d)
Pale yellow powder; yield: 280 mg (75%); mp 205–207 °C.
IR (KBr): 3343, 2952, 1725, 1606 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 3.72 (3 H, s, OCH3), 5.0 (1 H, s, CH),
6.28 (1 H, d, 3JHH = 7.5 Hz, ArH), 6.63 (1 H, t, 3JHH = 6.2 Hz, ArH), 6.77 (1
H, d, 3JHH = 7.5 Hz, ArH), 6.90 (2 H, d, 3JHH = 7.8 Hz, ArH), 7.05 (2 H, d,
3JHH = 7.8 Hz, ArH), 7.15 (1 H, t, 3JHH = 6.8 Hz, ArH), 10.66 (1 H, s, NH).
13C NMR (75 MHz, DMSO-d6): δ = 55.5, 62.8, 88.4, 110.6, 114.6, 117.4,
122.0, 122.3, 123.7, 127.1, 130.8, 131.5, 142.7, 143.8, 159.7, 175.6.
3′-Bromo-4′-(4-bromophenyl)-4′H-spiro[indoline-3,5′-isoxazol]-
2-one (4a)
Colorless solid; yield: 342 mg (81%); mp 220–222 °C.
MS (EI): m/z = 372 (M+).
IR (KBr): 3297, 1712, 1606, 1480 cm–1
.
Anal. Calcd for C17H13BrN2O3: C, 54.71; H, 3.51; N, 7.51. Found: C,
54.78; H, 3.45; N, 7.59.
1H NMR (300 MHz, DMSO-d6): δ = 5.17 (1 H, s, CH), 6.30 (1 H, d, 3JHH
=
9 Hz, ArH), 6.67 (1 H, t, 3JHH = 6 Hz, ArH), 6.80 (1 H, d, 3JHH = 9 Hz, ArH),
7.13 (2 H, d, 3JHH = 9 Hz, ArH), 7.20 (1 H, d, 3JHH = 9 Hz, ArH), 7.58 (2 H,
d, 3JHH = 9 Hz, ArH), 10.73 (1 H, s, NH).
3′-Bromo-5′-(4-ethoxyphenyl)-5′H-spiro[indoline-3,4′-isoxazol]-
2-one (4e)
13C NMR (75 MHz, DMSO-d6): δ = 62.7, 88.6, 110.8, 122.0, 122.1,
Colorless solid; yield: 279 mg (72%), mp 173–175 °C.
126.9, 129.4, 131.1, 131.5, 131.7, 133.9, 141.9, 143.8, 175.3.
MS (EI): m/z = 422 (M+).
IR (KBr): 3330, 2979, 1725, 1617 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 1.30 (3 H, t, 3JHH = 6.6 Hz, CH3), 3.98
(2 H, q, 3JHH = 6.6 Hz, OCH2), 5.01 (1 H, s, CH), 6.29 (1 H, d, 3JHH = 7.5 Hz,
ArH), 6.64 (1 H, t, 3JHH = 6.7 Hz, ArH), 6.78 (1 H, d, 3JHH = 7.5 Hz, ArH),
6.90 (2 H, d, 3JHH = 8.4 Hz, ArH), 7.05 (2 H, d, 3JHH = 8.4 Hz, ArH), 7.16 (1
H, t, 3JHH = 5.9 Hz, ArH), 10.68 (1 H, s, NH).
Anal. Calcd for C16H10Br2N2O2: C, 45.53; H, 2.39; N, 6.64. Found: C,
45.67 ; H, 2.31; N, 6.54.
3′-Bromo-4′-phenyl-4′H-spiro[indoline-3,5′-isoxazol]-2-one (4b)
Pale yellow powder; yield: 258 mg (75%); mp 112–113 °C.
13C NMR (75 MHz, DMSO-d6): δ = 15, 62.8, 63.5, 88.4, 110.6, 115.1,
122.1, 122.3, 123.6, 127.1, 130.8, 131.5, 142.7, 143.8, 159, 175.6.
MS: m/z = 306 (M+ – Br).
IR (KBr): 3244, 2959, 1725, 1619, 1474 cm–1
1H NMR (300 MHz, DMSO-d6): δ = 5.10 (1 H, s, CH), 6.21–6.81 (3 H, m,
.
ArH), 7.15–7.35 (6 H, m, ArH), 10.72 (1 H, s, NH).
13C NMR (75 MHz, DMSO-d6): δ = 63.4, 88.6, 110.7, 122.0, 122.2,
Anal. Calcd for C18H15BrN2O3: C, 55.83; H, 3.90; N, 7.23. Found: C,
55.78; H, 3.94; N, 7.15.
126.9, 129.1, 129.3, 129.5, 131.5, 132.0, 142.2, 143.8, 175.5.
MS (EI): m/z = 342 (M+).
3′-Bromo-4′-(2-fluorophenyl)-4′H-spiro[indoline-3,5′-isoxazol]-2-
one (4f)
Anal. Calcd for C16H11BrN2O2: C, 56.00; H, 3.23; N, 8.16. Found: C,
55.86 ; H, 3.31; N, 8.11.
Pale yellow powder; yield: 234 mg (65%); mp 174–176 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

G
H. Yazdani, A. Bazgir
Paper
Synthesis
IR (KBr): 3197, 1725, 1619, 1467 cm–1
.
IR (KBr): 3290, 2952, 1719, 1619, 1460 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 5.17 (1 H, s, CH), 6.43 (1 H, t, 3JHH
=
1H NMR (300 MHz, DMSO-d6): δ = 5.17 (1 H, s, CH), 6.31 (1 H, m, ArH),
6.67–6.83 (2 H, m, ArH), 7.12–7.18 (3 H, m, ArH), 7.57–7.60 (2 H, m,
ArH), 10.74 (1 H, s, NH).
13C NMR (75 MHz, DMSO-d6): δ = 62.7, 88.5, 110.8, 122.0, 122.1,
122.5, 126.9, 131.6, 131.7, 131.8, 132.3, 141.8, 143.8, 175.3.
6 Hz, ArH), 6.65 (1 H, t, 3JHH = 6 Hz, ArH), 6.79 (1 H, d, 3JHH = 9 Hz, ArH),
7.14 (2 H, m, ArH), 7.27 (2 H, m, ArH), 7.39 (1 H, m, ArH), 10.79 (1 H,
br s, NH).
13C NMR (75 MHz, DMSO-d6): δ = 58.3, 88.5, 110.9, 116.1, 116.3,
122.3, 122.6, 125.3, 126.5, 130.8, 131.8, 139.7, 143.5, 158.9, 162.2,
175.4.
MS (EI): m/z = 298 (M+ – Br).
Anal. Calcd for C16H10BrClN2O2: C, 50.89; H, 2.67; N, 7.42. Found: C,
50.79; H, 2.59; N, 7.50.
MS (EI): m/z = 360 (M+).
Anal. Calcd for C16H10BrFN2O2: C, 53.21; H, 2.79; N, 7.76. Found: C,
53.38; H, 2.67; N, 7.89.
3′-Bromo-4′-(3-hydroxyphenyl)-4′H-spiro[indoline-3,5′-isoxazol]-
2-one (4j)
3′-Bromo-4′-(2-bromophenyl)-4′H-spiro[indoline-3,5′-isoxazol]-
2-one (4g)
Colorless solid; yield: 231 mg (64%); mp 88–90 °C.
IR (KBr): 3330, 1715, 1608, 1468 cm–1
.
Colorless solid; yield: 354 mg (84%), mp 236–238 °C.
1H NMR (300 MHz, DMSO-d6): δ = 4.97 (1 H, s, CH), 6.29 (1 H, m, ArH),
6.56–6.82 (5 H, m, ArH), 7.17 (2 H, m, ArH), 9.64 (1 H, br s, OH), 10.71
(1 H, s, NH).
13C NMR (75 MHz, DMSO-d6): δ = 63.3, 88.5, 110.6, 116.1, 120.1,
122.1, 122.2, 126.9, 127.4, 130.3, 131.5, 131.9, 132.2, 133.17, 142.3,
143.7, 175.5.
IR (KBr): 3197, 1732, 1619, 1460 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 5.16 (1 H, s, CH), 6.15 (1 H, d, 3JHH
=
7.1 Hz, ArH), 6.61 (1 H, t, 3JHH = 6.3 Hz, ArH), 6.82 (1 H, d, 3JHH = 7.4 Hz,
ArH), 7.17–7.58 (5 H, m, ArH), 10.90 (1 H, s, NH).
13C NMR (75 MHz, DMSO-d6): δ = 63.6, 88.2, 110.9, 122.2, 125.5,
126.6, 128.8, 130.5, 131.3, 131.5, 131.9, 133.6, 139.9, 144.1, 175.3.
MS (EI): m/z = 421 (M+).
MS (EI): m/z = 358 (M+).
Anal. Calcd for C16H11BrN2O3: C, 53.50; H, 3.09; N, 7.80. Found: C,
53.43; H, 3.13; N, 7.68.
Anal. Calcd for C16H10Br2N2O2: C, 45.53; H, 2.39; N, 6.64. Found: C,
45.47; H, 2.35; N, 6.70.
3′-Bromo-4′-{4[(3-bromoisoxazol-5-yl)methoxy]phenyl}-4′H-
spiro[indoline-3,5′-isoxazol]-2-one (7)
X-ray Crystal Data19
C16H10Br2N2O2: M = 422.06 g/mol, monoclinic system, space group
P21/n, a = 8.9032(12) Å, b = 22.989(3) Å, c = 15.1818(19) Å, β =
96.677(11)°, V = 3086.3(7) Å3, Z = 8, Dc = 1.817 Mg.m–3, crystal di-
mension of 0.45 × 0.40 × 0.20 mm. The structure was solved by using
SHELXS. The structure refinement and data reduction was carried out
with SHELXL of the X-Step32 suite of programs. The non-hydrogen at-
oms were refined anisotropically by full matrix least-squares on F2
values to final R1 = 0.0954, wR2 = 0.2005 and S = 0.833 with 397 pa-
rameters using 6743 independent reflection (θ range = 2.23–27.00°).
Hydrogen atoms were located from expected geometry and were not
refined.
Colorless solid; yield: 372 mg (72%); mp 178–179 °C.
1H NMR (300 MHz, DMSO-d6): δ = 5.06 (1 H, s, CH), 5.33 (2 H, s,
OCH2), 6.26 (1 H, s, HC=C), 6.60–6.63 (1 H, m, ArH), 6.66–6.81 (2 H, m,
ArH), 6.94–7.20 (5 H, m, ArH), 9.90 (1 H, s, NH).
13C NMR was not recorded due to the low solubility of 7.
MS (EI): m/z = 439 (M+ – Br).
Anal. Calcd for C20H13Br2N3O4: C, 46.27; H, 2.52; N, 8.09. Found: C,
46.11; H, 2.65; N, 8.21.
3′-Bromo-4′-(p-tolyl)-4′H-spiro[indene-2,5′-isoxazole]-1,3-dione
(9a)
3′-Bromo-4′-(naphthalen-2-yl)-4′H-spiro[indoline-3,5′-isoxazol]-
Colorless solid; yield: 290 mg (78%); mp 177–178 °C.
2-one (4h)
IR (KBr): 2950, 1755, 1714 cm–1
.
Colorless solid; yield: 273 mg (69%); mp 210–212 °C.
IR (KBr): 3177, 3051, 1739, 1619 cm–1
1H NMR (300 MHz, CDCl3): δ = 2.31 (3 H, s, CH3), 4.99 (1 H, s, CH), 6.92
(2 H, d, 3JHH = 8.8 Hz, ArH), 7.10 (2 H, d, 3JHH = 8.8 Hz, ArH), 7.73–8.10
(4 H, m, ArH).
13C NMR (75 MHz, CDCl3): δ = 21.2, 66.2, 88.1, 124, 124.2, 126.2,
129.6, 136.7, 137.2, 139.2, 139.4, 140.3, 141.5, 150.2, 191.9.
.
1H NMR (300 MHz, DMSO-d6): δ = 5.28 (1 H, s, CH), 6.29 (1 H, d, 3JHH
=
7.2 Hz, ArH), 6.47 (1 H, m, ArH), 6.78 (1 H, d, 3JHH = 7.2 Hz, ArH), 6.08
(1 H, m, ArH), 7.28 (1 H, d, 3JHH = 8.1 Hz, ArH), 7.53–7.58 (2 H, m, ArH),
7.76 (1 H, s, ArH), 7.90–7.92 (3 H, m, ArH), 10.77 (1 H, s, NH).
MS (EI): m/z = 369 (M+).
13C NMR (75 MHz, DMSO-d6): δ = 63.6, 88.6, 110.7, 122, 122.2, 126.9,
127, 127.1, 128.1, 128.3, 128.4, 128.9, 129, 129.7, 131.6, 133, 133.1,
142.3, 143.8, 175.6.
Anal. Calcd for C18H12BrNO3: C, 58.40; H, 3.27; N, 3.78. Found: C,
58.38; H, 3.24 ; N, 3.74.
MS (EI): m/z = 392 (M+).
3′-Bromo-4′-(4-methoxyphenyl)-4′H-spiro[indene-2,5′-isoxazole]-
1,3-dione (9b)
Anal. Calcd for C20H13BrN2O2: C, 61.09; H, 3.33; N, 7.12. Found: C,
61.01; H, 3.26; N, 7.02.
Colorless solid; yield: 322 mg (83%); mp 197–198 °C.
IR (KBr): 2959, 1759, 1712, 1600 cm–1
.
3′-Bromo-4′-(4-chlorophenyl)-4′H-spiro[indoline-3,5′-isoxazol]-2-
one (4i)
1H NMR (300 MHz, CDCl3): δ = 3.78 (3 H, s, OCH3), 4.98 (1 H, s, CH),
6.80 (1 H, d, 3JHH = 8.9 Hz, ArH), 6.97 (2 H, d, 3JHH = 8.9 Hz, ArH), 7.74–
8.10 (4 H, m, ArH).
Colorless solid; yield: 284 mg (75%), mp 212–213 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

H
H. Yazdani, A. Bazgir
Paper
Synthesis
13C NMR (75 MHz, CDCl3): δ = 55.2, 66, 88.2, 114.2, 121, 124, 124.2,
131.1, 136.7, 137.2, 139.6, 140.3, 141.5, 160.1, 192.1, 194.7.
3-Bromo-9-methyl-4-(naphthalen-2-yl)-7-phenyl-1-oxa-2,7,8-tri-
azaspiro[4.4]nona-2,8-dien-6-one (11)
MS (EI): m/z = 385 (M+).
Gray powder; yield: 262 mg (60%); mp 212–214 °C.
IR (KBr): 3058, 2945, 1717, 1500 cm–1
1H NMR (300 MHz, DMSO-d6): δ = 2.39 (3 H, s, CH3), 5.95 (1 H, s, CH),
.
Anal. Calcd for C18H12BrNO4: C, 55.98; H, 3.13; N, 3.63. Found: C,
55.91; H, 3.18; N, 3.55.
7.09–7.28 (5 H, m, ArH), 7.55–7.94 (7 H, m, ArH).
X-ray Crystal Data20
13C NMR (75 MHz, DMSO-d6): δ = 13.2, 63.6, 90.1, 118.6, 125.9, 126.8,
127.1, 127.4, 128.0, 128.5, 129.4, 129.8, 132.8, 133.1, 136.9, 142.4,
158.8, 166.8.
C18H12BrNO4 (CCDC 1827669): M = 386.19 g/mol, triclinic system,
space group P-1 bar, a = 7.830(3) Å, b = 8.561(3) Å, c = 13.585(4) Å, β =
102.92(3)°, V = 79093(4) Å3, Z = 2, Dc = 1.622 Mg.m–3, crystal dimen-
sion of 0.50 × 0.40 × 0.35 mm. The structure was solved by using
SHELXS. The structure refinement and data reduction was carried out
with SHELXL of the X-Step32 suite of programs. The non-hydrogen at-
oms were refined anisotropically by full matrix least-squares on F2
values to final R1 = 0.0711, wR2 = 0.1404 and S = 0.874 with 217 pa-
rameters using 3408 independent reflection (θ range = 2.67–27.00°).
Hydrogen atoms were located from expected geometry and were not
refined.
MS (EI): m/z = 433 (M+).
Anal. Calcd for C22H16BrN3O2: C, 60.84; H, 3.71; N, 9.68. Found: C,
60.70; H, 3.62; N, 9.61.
Spiroindene-Isoxazoles Containing Benzimidazole or Benzothi-
azole 14; General Procedure
A mixture of arylidene compound 12 (1 mmol), dibromoformaldox-
ime (3; 203 mg, 1 mmol), ZnCl2 (13.63 mg, 10 mol%), and Na2CO3 (212
mg, 2 mmol) in THF (5 mL) was stirred at 45 °C for 3 h. Then, amino or
mercapto heterocycle 13 (1 mmol) was added and stirred for 24 h. Af-
ter completion of the reaction, the solvent was removed under vacu-
um and the crude mixture was washed with hot H2O (10 mL). Then,
the solid residue was crystallized from CH2Cl2/n-hexane (1:2) to af-
ford the respective pure product.
3′-Bromo-4′-(naphthalen-2-yl)-4′H-spiro[indene-2,5′-isoxazole]-
1,3-dione (9c)
Colorless solid; yield: 300 mg (74%); mp 200–202 °C.
IR (KBr): 2950, 1751, 1713, 1565 cm–1
1H NMR (300 MHz, DMSO-d6): δ = 5.64 (1 H, s, CH), 7.11–7.14 (1 H, m,
.
ArH), 7.53–7.61 (4 H, m, ArH), 7.88–8.13 (6 H, m, ArH).
3′-[(1H-Benzo[d]imidazol-2-yl)amino]-4′-(4-bromophenyl)-4′H-
spiro[indene-2,5′-isoxazole]-1,3-dione (14a)
13C NMR (75 MHz, DMSO-d6): δ = 65.4, 88.9, 123.8, 126.8, 127.1,
128.2, 128.4, 129.5, 132.8, 133.1, 137.9, 140.1, 140.8, 141.3, 191.8,
194.1.
Pale yellow powder; yield: 381 mg (78%); mp 128–130 °C.
IR (KBr): 3368, 2965, 1710, 1554, 1443 cm–1
.
MS (EI): m/z = 405 (M+).
1H NMR (300 MHz, DMSO-d6): δ = 5.35 (1 H, s, CH), 7.04–8.04 (12 H,
m, ArH), 8.80 (1 H, br s, NH), 12.47 (1 H, s, NH).
13C NMR (125 MHz, DMSO-d6): δ = 64.3, 88.4, 106.9, 123.9, 124.8,
128.6, 129.1, 129.2, 129.8, 130.6, 131.7, 134.1, 137.90, 137.99, 140.1,
140.4, 141.3, 141.9, 166.6, 176.3, 191.8, 193.8.
Anal. Calcd for C21H12BrNO3: C, 62.09; H, 2.98; N, 3.45. Found: C,
61.99; H, 2.95; N, 3.38.
3′-Bromo-4′-(4-chlorophenyl)-4′H-spiro[indene-2,5′-isoxazole]-
1,3-dione (9d)
MS (EI): m/z = 486 (M+).
Pale yellow powder; yield: 307 mg (79%); mp 184–186 °C.
Anal. Calcd for C24H15BrN4O3: C, 59.15; H, 3.10; N, 11.50. Found: C,
59.04; H, 3.03; N, 11.41.
IR (KBr): 2945, 1712, 1580, 1487 cm–1
1H NMR (300 MHz, CDCl3): δ = 4.99 (1 H, s, CH), 7.00 (2 H, d, 3JHH = 9
.
3
3
Hz, ArH), 7.27 (2 H, d, JHH = 9 Hz, ArH), 7.77 (1 H, JHH = 9 Hz, ArH),
3'-((1H-Benzo[d]imidazol-2-yl)amino)-4'-(4-methoxyphenyl)-4'H-
spiro[indene-2,5'-isoxazole]-1,3-dione (14b)
7.90 (2 H, m, ArH), 8.08 (1 H, 3JHH = 9 Hz, ArH).
13C NMR (75 MHz, DMSO-d6): δ = 64.4, 88.4, 122.9, 123.9, 124.9,
130.3, 132.07, 132.1, 137.9, 138.0, 140.1, 140.4, 141.3, 191.8, 193.9.
MS (EI): m/z = 389 (M+).
Pale yellow powder; yield: 350 mg (80%); mp 193–195 °C.
IR (KBr): 3384, 2968, 1715, 1545, 1431 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 3.71 (3 H, s, OCH3), 5.42 (1 H, s,
CH), 6.87–8.08 (12 H, m, ArH), 8.60 (1 H, br s, NH), 12.47 (1 H, s, NH).
13C NMR (75 MHz, DMSO-d6): δ = 55.5, 65.1, 89, 109.9, 114.5, 122.4,
122.7, 123.8, 124.7, 126.9, 131.3, 132.7, 137.8, 137.9, 140.1, 141.07,
141.3, 159.9, 168.5, 192, 194.2.
Anal. Calcd for C17H9BrClNO3: C, 52.27; H, 2.32; N, 3.59. Found: C,
52.40; H, 2.23; N, 3.70.
3′-Bromo-4′-(4-bromophenyl)-4′H-spiro[indene-2,5′-isoxazole]-
1,3-dione (9e)
MS (EI): m/z = 438 (M+).
Colorless solid; yield: 349 mg (80%); mp 171–173 °C.
Anal. Calcd for C25H18N4O4: C, 68.49; H, 4.14; N, 12.78. Found: C,
68.63; H, 4.12; N, 12.85.
IR (KBr): 3078, 2952, 1709, 1586 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 5.54 (1 H, s, CH), 7.07 (2 H, d, 3JHH
=
8.6 Hz, ArH), 7.40 (2 H, d, 3JHH = 8.6 Hz, ArH), 7.74–8.13 (4 H, m, ArH).
3′-[(1H-Benzo[d]imidazol-2-yl)thio]-4′-(4-chlorophenyl)-4′H-
spiro[indene-2,5'-isoxazole]-1,3-dione (14c)
13C NMR (75 MHz, DMSO-d6): δ = 64.3, 88.5, 123.9, 124.9, 129.1,
129.8, 131.7, 134.2, 137.9, 138.0, 140.1, 140.5, 141.3, 191.8, 193.9.
MS (EI): m/z = 434 (M+).
Pale yellow powder; yield: 348 mg (76%); mp 180–182 °C.
IR (KBr): 3347, 2970, 1717, 1534 cm–1
.
Anal. Calcd for C17H9Br2NO3: C, 46.93; H, 2.09; N, 3.22. Found: C,
46.85; H, 2.03; N, 3.12.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

I
H. Yazdani, A. Bazgir
Paper
Synthesis
1H NMR (300 MHz, DMSO-d6): δ = 7.59 (3 H, m, ArH), 7.81 (2 H, d,
3JHH = 9 Hz, ArH), 7.96 (5 H, m, ArH), 8.50 (2 H, m, ArH), 12.52 (1 H, s,
NH).
separated and the filtrate was extracted with EtOAc (2 × 5 mL). The
organic solvents were removed under vacuum and the product 16
was purified by recrystalization.
13C NMR (125 MHz, DMSO-d6): δ = 90.9, 109.9, 122.7, 123.5, 123.6,
124.3, 129.2, 129.7, 130.1, 131.5, 132.0, 132.6, 135.8, 136.3, 136.4,
138.3, 139.9, 142.3, 144.1, 168.5, 188.9, 189.5.
Biphenyl (16a)
Colorless solid; yield: 150 mg (97%); mp 68–69 °C (Lit.22 mp 67–69 °C).
MS (EI): m/z = 459 (M+).
IR (KBr): 2936, 1582, 1556, 1046 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.41 (2 H, m, ArH), 7.51 (4 H, m, ArH),
7.65 (4 H, m, ArH).
Anal. Calcd for C24H14ClN3O3S: C, 62.68; H, 3.07; N, 9.14; Found: C,
62.60; H, 3.02; N, 9.03.
3′-[(1H-Benzo[d]imidazol-2-yl)thio]-4′-(4-methoxyphenyl)-4′H-
spiro[indene-2,5′-isoxazole]-1,3-dione (14d)
4,4′-Dimethoxybiphenyl (16b)
Colorless solid; yield: 193 mg (90%); mp 176–178 °C (Lit.22 mp 173–
Pale yellow powder; yield: 388 mg (85%); mp 167–169 °C.
174 °C).
IR (KBr): 3352, 2963,1710, 1549 cm–1
.
IR (KBr): 2924, 1588, 1560, 1042 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 3.72 (3 H, s, OCH3), 5.39 (1 H, s,
CH), 6.73–7.15 (8 H, m, ArH), 7.58–8.08 (4 H, m, ArH), 10.10 (1 H, br s,
NH).
1H NMR (300 MHz, CDCl3): δ = 6.99 (4 H, d, 3JHH = 6.67 Hz, ArH), 7.5 (4
H, d, 3JHH = 6.67 Hz, ArH).
13C NMR (75 MHz, DMSO-d6): δ = 56.5, 66.1, 89.0, 109.9, 114.4, 122.3,
122.7, 123.6, 124.7, 126.9, 131.3, 132.7, 137.7, 137.8, 140.16, 140.18,
141.0, 141.3, 159.9, 168.5, 192.0, 194.2.
2-Arylbenzothiazoles 20; General Procedure
A 10 mL round-bottomed flask was charged with benzothiazole (19;
135 mg, 1 mmol), arylbenzene 18 (1 mmol), 14b (52.56 mg, 12 mol%),
Ni(OAc)2 (17.68 mg, 10 mol%), t-BuOLi (160 mg, 2 mmol) and anhyd
THF (5 mL). The mixture was stirred at reflux conditions for 24 h
(TLC). The mixture was cooled to r.t. and the solvent was evaporated
under reduced pressure. The mixture was diluted with EtOAc (10 mL)
and successively washed with H2O and brine. The organic layer was
dried (MgSO4) and concentrated under reduced pressure. The residue
was purified by preparative TLC eluting with EtOAc/hexane (20:80,
v/v) to afford the corresponding product 20.
MS (EI): m/z = 455 (M+).
Anal. Calcd for C25H17N3O4S: C, 65.92; H, 3.76; N, 9.23. Found: C,
65.76; H, 3.66; N, 9.11.
3′-(Benzo[d]thiazol-2-ylamino)-4′-(4-methoxyphenyl)-2′H-
spiro[indene-2,5′-isoxazole]-1,3-dione (14e)
Pale yellow powder; yield: 374 mg (82%); mp 276–278 °C.
IR (KBr): 3327, 2973, 1721, 1560, 1459 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 3.78 (3 H, s, OCH3), 7.02 (2 H, br s,
ArH), 7.38–8.08 (11 H, m, ArH and NH), 8.64 (1 H, br s, NH).
2-Phenylbenzo[d]thiazole (20a)
Colorless solid; yield: 135 mg (64%); mp 114–115 °C (Lit.23 mp 114 °C).
13C NMR (75 MHz, DMSO-d6): δ = 55.9, 92.6, 95.5, 114.3, 121.6, 122.4,
122.8, 123.7, 124.8, 126.9, 129.3, 131.7, 132.2, 136.0, 142.0, 144.9,
148.4, 148.7, 154.0, 157.8, 176.6, 184.2.
IR (KBr): 3053, 1628, 1582, 1460 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.41 (1 H, t, 3JHH = 7.5 Hz, ArH), 7.52 (4
H, s, ArH), 7.93 (1 H, d, 3JHH = 7.8 Hz, 1 H), 8.12 (3 H, m, ArH).
MS (EI): m/z = 455 (M+).
2-p-Tolylbenzo[d]thiazole (20b)
Colorless solid; yield: 160 mg (71%); mp 84–85 °C (Lit.24 mp 86 °C).
Anal. Calcd for C25H17N3O4S: C, 65.92; H, 3.76; N, 9.23. Found: C,
65.88; H, 3.81; N, 9.17.
IR (KBr): 3058, 1630, 1580, 1426 cm–1
1H NMR (300 MHz, CDCl3): δ = 2.44 (3 H, s, CH3), 7.32 (2 H, d, 3JHH = 6.0
Hz, ArH), 7.39 (1 H, t, JHH = 9.0 Hz, ArH), 7.51 (1 H, t, JHH = 9.0 Hz,
ArH), 7.91 (1 H, d, 3JHH = 9.0 Hz, ArH), 8.01 (2 H, d, 3JHH = 6.0 Hz, ArH),
8.99 (1 H, d, 3JHH = 9.0 Hz, ArH).
.
4′-(4-Methoxyphenyl)-3′-(thiazol-2-ylamino)-4′H-spiro[indene-
2,5′-isoxazole]-1,3-dione (14f)
3
3
Pale yellow powder; yield: 329 mg (81%); mp 237–239 °C.
IR (KBr): 3342, 2991, 1718, 1557 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 3.77 (3 H, s, OCH3), 6.95 (2 H, s,
ArH), 7.44–8.00 (8 H, m, ArH, =CH), 8.47 (2 H, br s, NH).
2-(4-Chlorophenyl)benzo[d]thiazole (20c)
Colorless solid; yield: 140 mg (57%); mp 117–118 °C (Lit.25 mp 117–
119 °C).
IR (KBr): 3016, 1618, 1455, 1254 cm-1.
13C NMR (125 MHz, DMSO-d6): δ = 55.5, 92.4, 95.3, 114.2, 115.4,
122.5, 123.5, 124.6, 128.9, 132.0, 135.6, 138.6, 141.8, 154.5, 157.6,
166.4, 176.3, 184.4.
MS (EI): m/z = 405 (M+).
1H NMR (300 MHz, DMSO-d6): δ = 7.49 (1 H, t, 3JHH = 9.0 Hz, ArH), 7.57
(1 H, t, 3JHH = 9.0 Hz, ArH), 7.65 (2 H, d, 3JHH = 9.0 Hz, ArH), 8.14 (4 H,
m, ArH).
Anal. Calcd for C21H15N3O4S: C, 62.21; H, 3.73; N, 10.36. Found: C,
62.29; H, 3.65; N, 10.42.
2-(4-Methoxyphenyl)benzo[d]thiazole (20d)
Yellow solid; yield: 169 mg (70%); mp 118–119 °C (Lit.26 mp 119–120 °C).
Suzuki Reaction; General Procedure
A mixture of phenylbronic acid (15a; 146 mg, 1.2 mmol), bromoben-
zene (157 mg, 1.0 mmol), Pd(OAc)2 (12.22 mg, 0.5 mol %), ligand (1
mol%) and K2CO3 (2 mmol) in H2O/EtOH (3 mL, 1:1) was stirred at
60 °C for 20 min. After completion of the reaction, the catalyst was
IR (KBr): 3020, 1612, 1426, 1265 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

J
H. Yazdani, A. Bazgir
Paper
Synthesis
1H NMR (300 MHz, CDCl3): δ = 3.92 (3 H, s, OCH3), 7.02 (2 H, d, 3JHH
9.0 Hz, ArH), 7.37 (1 H, m, ArH), 7.49 (1 H, m, ArH), 7.90 (1 H, d, 3JHH
9.0 Hz, ArH), 8.06 (3 H, m, ArH).
=
=
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2-(4-Ethoxyphenyl)benzo[d]thiazole (20e)
Light yellow solid; yield: 168 mg (66%); mp 124–125 °C (Lit.27 mp
126–128 °C).
IR (KBr): 3028, 1624, 1442, 1220 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 1.35 (3 H, t, 3JHH = 6.6 Hz, CH3), 4.12 (2
H, q, 3JHH = 6.6 Hz, OCH2), 7.09 (2 H, m, ArH), 7.41 (1 H, m, ArH), 7.51
(1 H, m, ArH), 8.02 (3 H, m, ArH), 8.09 (1 H, d, 3JHH = 9.0 Hz, ArH).
2-[4-(Benzyloxy)phenyl]benzo[d]thiazole (20f)
Light yellow solid; yield: 187 mg (59%); mp 165–166 °C (Lit.28 mp
166.1–167.2 °C).
IR (KBr): 3043, 1632, 1434, 1266 cm–1
.
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Raucher, D.; Walker, L. R.; Hamme, A. T. II. Tetrahedron Lett.
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1H NMR (300 MHz, CDCl3): δ = 5.22 (2 H, s, OCH2), 7.21 (3 H, m, ArH),
7.43 (4 H, m, ArH), 7.50 (3 H, m, ArH), 8.06 (4 H, m, ArH).
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Tsujihara, T.; Arai, M. A.; Bajracharya, G. B.; Suzuki, T.; Onitsuka,
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(d) Takenaka, K.; Mohanta, S. C.; Patil, M. L.; Rao, C. L.; Takizawa,
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B.; Koranne, P. S.; Tsujihara, T.; Takizawa, S.; Onitsuka, K.; Sasai,
H. Synlett 2009, 310. (f) Guo, J.-Y.; Minko, Y.; Santiago, C. B.;
Sigman, M. S. ACS Catal. 2017, 7, 4144. (g) Zhu, R.; Buchwald, S.
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2-([1,1′-Biphenyl]-4-yl)benzo[d]thiazole (20g)
Yellow solid; yield: 175 mg (61%); mp 138–139 °C (Lit.29 mp 140–141 °C).
IR (KBr): 3010, 1623, 1570, 1460 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 6.61 (2 H, m, ArH), 7.00 (2 H, m, ArH),
7.49 (5 H, m, ArH), 7.67 (3 H, m, ArH), 8.16 (1 H, m, ArH).
Funding Information
We gratefully acknowledge the financial support from the Research
Council of Shahid Beheshti University and the Iran National Science
Foundation (INSF) (Project Number 96011205).
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(9) (a) Said, A. M.; Savage, G. P. J. Org. Chem. 2011, 76, 6946.
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1635.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610676.
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(10) Adamo, M. F. A.; Donati, D.; Duffy, E. F.; Sarti-Fantoni, P. J. Org.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K