Unified Approach to Pyrazole-Fused Heterocyclic and Carbocyclic Motifs through One-Pot Condensation and Intramolecular Dipolar Cycloaddition Reaction

Article abstract of DOI:10.1055/s-0035-1562533

A one-pot synthesis of highly substituted pyrazoles that are fused to dihydrochromenes, dihydroquinolines and cyclopentane motifs, from readily available precursors is reported. The reaction involves conversion of alkyne-tethered aldehydes into the corresponding tosylhydrazones, base-mediated generation of diazo compounds, and subsequent intramolecular dipolar cycloaddition reaction. A range of internal and terminal alkynes as well as bromoalkyne compounds can be employed as the tethered dipolarophile to afford the corresponding cycloadducts.

Full text of DOI:10.1055/s-0035-1562533

SYNTHESIS
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1
4
3
7
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2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–F
paper
A
K. V. Divya et al.
Paper
Synthesis
Unified Approach to Pyrazole-Fused Heterocyclic and Carbocyclic
Motifs through One-Pot Condensation and Intramolecular Dipolar
Cycloaddition Reaction
R3
K. Vijay L. Divya
A. Meena
Thachapully D. Suja*1
N
HN
O
TsNHNH2
R3
EtOH, 25 °C
R1
R1
then 5 N NaOH
50 °C, 8 h
X
R2
X
R2
Medicinal Chemistry and Pharmacology Division, CSIR-Indian
Institute of Chemical Technology, Hyderabad 500 007, India
tdsuja@gmail.com
43–97%
R1 = Cl, Br, NO2, OMe, etc.
2 = H, alkyl; R3 = H, Et, Ph, Br; X = O, NTs
17 examples
R
suja@cuh.ac.in
Received: 30.05.2016
Accepted after revision: 15.07.2016
Published online: 01.09.2016
very high for this intermolecular process; however, a five-
fold excess of the dipolarophile is required. Additionally,
the use of internal alkynes to generate trisubstituted pyra-
zoles was not explored.
DOI: 10.1055/s-0035-1562533; Art ID: ss-2016-t0392-op
Abstract A one-pot synthesis of highly substituted pyrazoles that are
fused to dihydrochromenes, dihydroquinolines and cyclopentane mo-
tifs, from readily available precursors is reported. The reaction involves
conversion of alkyne-tethered aldehydes into the corresponding tosyl-
hydrazones, base-mediated generation of diazo compounds, and sub-
sequent intramolecular dipolar cycloaddition reaction. A range of inter-
nal and terminal alkynes as well as bromoalkyne compounds can be
employed as the tethered dipolarophile to afford the corresponding cy-
cloadducts.
Intramolecular dipolar cycloaddition (IDC) reactions
constitute a powerful and versatile synthetic strategy for
the construction of fused and spiro-polycyclic systems from
readily available precursors.8 The inherent regio- and ste-
reochemical preferences of dipolar cycloaddition reactions
are often amplified in IDC reactions because of the geomet-
rical demands imposed by the tethering of dipole and dipo-
larophile. Therefore, IDC reactions have featured signifi-
cantly as key bond-forming events in numerous natural
product syntheses.9 The intramolecular variant of dipolar
cycloaddition reactions of alkynes and diazo compounds
generated from tosyl hydrazones are, however, less investi-
gated.10 A report by Chandrasekhar describes the use of pre-
formed tosylhydrazones that incorporate a bromoalkene di-
polarophile (Scheme 1, b).10b The initially formed cycload-
duct undergoes aromatization through dehydrobromina-
tion to afford pyrazoles. The bromovinyl group acts as a
synthetic equivalent of a terminal alkyne and this method
affords 3-unsubstituted pyrazoles.
We surmised that the experimentally simple approach
of the IDC reaction of terminal and internal alkynes and di-
azo compounds would lead to the generation of fused pyra-
zole derivatives. A detailed investigation on the feasibility
of this approach for the construction of oxygen and nitro-
gen heterocycles as well as carbocycles fused to pyrazoles
was undertaken. In addition to the generation of such poly-
cyclic systems, we also aimed to study the effects of addi-
tional substituents R2 and R3 on the alkynyl moiety on the
outcome of the IDC reaction. Our efforts in this direction
culminated in the development of a unified, convenient,
one-pot approach to the synthesis of highly substituted
Key words intramolecular dipolar cycloaddition, pyrazoles, tosyl hy-
drazones, diazo compounds, alkynes
The pyrazole nucleus is widespread in a number of
pharmaceutical agents and agrochemicals,2 and the synthe-
sis of pyrazoles and their annulated derivatives has become
increasingly important. Cyclocondensation of hydrazine de-
rivatives and 1,3-dicarbonyl compounds (Knorr pyrazole
synthesis) is one of the most widely used methods for pyra-
zole construction.3 Although the simplicity and efficiency
of this approach is remarkable, the control of regiochemis-
try is challenging in the reaction of unsymmetrical sub-
strates.4 The reaction between alkynes and diazo com-
pounds through 1,3-dipolar cycloaddition is another useful
method for the generation of pyrazole derivatives.5 Howev-
er, the hazardous nature of diazo compounds is a serious
limitation of this method. The availability of new methods
for the generation of diazo compounds from stable tosylhy-
drazones has addressed this issue to a large extent.6 In
2003, Aggarwal reported that 3-substituted pyrazoles can
be conveniently prepared through intermolecular 1,3-dipo-
lar cycloaddition of terminal alkynes and aryldiazometh-
anes generated in situ (Scheme 1, a).7 The regioselectivity is
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

B
K. V. Divya et al.
Paper
Synthesis
by TLC analysis) in acetonitrile, tetrahydrofuran (THF), and
ethanol. Exposure of the tosylhydrazone to various bases
was then attempted to generate the diazo compound. The
use of 5 N NaOH and acetonitrile as solvent resulted in the
formation of the expected cycloadduct 2a in 47% yield at
room temperature (entry 1). The yield of the product rose
to 87% when the reaction temperature was increased to
50 °C (entry 2). A slightly diminished yield of 2a (75%) was
obtained when the strength of base was reduced to 2 N (en-
try 3). Other bases such as potassium carbonate, 1,8-diaza-
bicyclo[5.4.0]undec-7-ene (DBU), sodium hydride, and po-
tassium tert-butoxide mediated the formation of the diazo
compound and IDC reaction, albeit in significantly lower
yields (entries 4–7). Reaction in THF at 50 °C using 5 N
NaOH furnished 2a in 83% yield. The best yield of 2a (96%)
was obtained when the reaction was carried out in ethanol
using 5 N NaOH at 50 °C (entry 9).
a) Intermolecular (Aggarwal, ref. 7)
NHTs
5 equiv
R
N
N
H
O
TsNHNH2
N
N
N
R
MeCN
3 h
Ph
5M NaOH
Ph
Ph
Ph
b) Intramolecular (Chandrasekhar, ref. 10b)
NHTs
N
HN
O
N
N
N
R
R
R
NaH
Br
Br
– HBr
tautomerism
THF
O
O
c) General, one-pot, intramolecular approach (this work)
R3
O
N
HN
X
TsNHNH2
R3
EtOH, 25 °C
R1
R1
then 5 N NaOH
50 °C, 12 h
R2
R2
X
The generality and scope of this one-pot protocol for ac-
cessing dihydrochromenopyrazoles such as 2a was then in-
vestigated. Variously substituted O-propargyl salicylalde-
hydes 1b–p were subjected to the optimized reaction con-
ditions and the corresponding cycloadducts 2b–p were
obtained. The results are listed in Scheme 2.
X = O, NTs
Scheme 1 Pyrazole construction through 1,3-dipolar cycloaddition re-
actions of alkynes and diazo compounds
fused pyrazole derivatives (Scheme 1, c). Our findings are
described in detail in the following sections.
R3
The investigations began by subjecting O-propargyl sa-
licylaldehyde (1a) to reaction conditions for hydrazone syn-
thesis, generation of the corresponding diazo compound
and subsequent IDC reaction in one-pot. The method de-
scribed by Aggarwal was deemed as a suitable starting
point for this purpose.7 The reaction conditions that were
tested are listed in Table 1. The formation of tosyl hydra-
zone from 1a proceeded to near completion (as indicated
O
N
HN
TsNHNH2, EtOH
25 °C, 3 h
R3
R1
R1
then 5 N NaOH
50 °C, 12 h
R2
N
O
1b–p
O
2b–p
R2
N
HN
HN
N
HN
O
X
X
O
O
2b, X = Cl, 91%
2c, X = Br, 71%
2d, X = NO2, 86%
2e, X = OMe, 55%
Y
Table 1 Optimization of Reaction Conditionsa
2f, X = H, Y = OEt, 97%
2g, X = Y = Cl, 91%
2h, X = Y = t-Bu, 96%
2i, 97%
N
O
HN
TsNHNH2
25 °C, 3 h
N
HN
N
HN
O
X
R
Ph
then base, 12 h
O
O
1a
2a
O
Me
2j, X = H, R = Ph, 77%
2n, 97%
Entry
Base
Temp (°C)
Solvent
Yield (%)b
2k, X = Cl, R = Ph, 43%
2l, X = H, R = Et, 70%
2m, X = Cl, R = Et, 60%
1
2
3
4
5
6
7
8
9
5 N NaOH
5 N NaOH
2 N NaOH
K2CO3
25
50
50
50
50
50
0
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
47
87
75
56
46
55
47
83
96
N
HN
O
N
HN
Br
Ph
O
Me
2p, 95%
DBU
2o, 95%
NaH
Scheme 2 Scope of the dihydrochromenopyrazole synthesis (isolated
yields given)
t-BuOK
5 N NaOH
5 N NaOH
50
50
As evident from the results presented in Scheme 2, sub-
stitutions at various positions on the dihydrochromenopyr-
azole may be achieved by using this one-pot approach. Al-
kyl and aryl groups are well-tolerated on the propargylic
EtOH
a Reaction conditions: 1a (0.5 mmol), TsNHNH2 (0.5 mmol), solvent (3 mL),
3 h; then base, 8 h.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

C
K. V. Divya et al.
Paper
Synthesis
and terminal alkynyl carbons (2n–o). Additionally, salicyl-
aldehydes bearing halo and nitro functionalities afforded
the corresponding products 2b–d, 2g, and 2m in high
yields. Importantly, bromopyrazole derivative 2p was ob-
tained in 95% yield from the corresponding bromoalkyne. It
may be noted that 3-bromopyrazoles are valuable medici-
nal agents and very few methods are available for their syn-
thesis.11 The formation of 2p also demonstrates the com-
patibility of a bromoalkyne in the IDC reaction. In short,
this one-pot method allows convenient access to valuable
functionalized dihydrochromenopyrazole derivatives from
readily available starting materials.
using chromium trioxide (Scheme 5).15 It may be noted that
structural scaffolds generated by the fusion of coumarin to
various heterocyclic rings are valuable targets in medicinal
chemistry.16
N
N
HN
HN
CrO3
pyrdine, CH2Cl2
O
O
O
2a
7, 71%
Scheme 5 Oxidative conversion of dihydrochromenopyrazole 2a into
pyrazolocoumarin 7
This synthetic approach was also successfully applied
for the generation of analogous nitrogen heterocycles.
Alkynyl aldehydes 3a and 3b,12 derived from 2-aminobenz-
aldehyde, underwent the condensation–IDC reaction se-
quence efficiently to afford dihydropyrazoloquinolines 4a
and 4b in excellent yields (Scheme 3).
In summary, a convenient one-pot protocol for access-
ing pyrazole-fused polycyclic scaffolds was developed. The
method relies of the base-mediated generation of diazo
compounds in situ from N-tosyl hydrazones of aldehydes
tethered to alkynes. Formation of the tosyl hydrazones and
subsequent diazo compound-alkyne intramolecular dipolar
cycloaddition reactions were conveniently carried out in
one pot under environmentally benign reaction conditions
(ethanol and aqueous NaOH). The protocol allows the syn-
thesis of pyrazolo-dihydrochromenes endowed with vari-
ous substituents at defined positions. The method is also
applicable for the synthesis of pyrazolo-dihydroquinoline
derivatives as well as cyclopentane-fused pyrazoles, and a
R2
R2
N
HN
O
O
TsNHNH2, EtOH
25 °C, 3 h
Br
R1
R2
then 5 N NaOH
50 °C, 12 h
R1
K2CO3
MeCN
N
R1
NHTs
N
Ts
Ts
3a, R1= R2 = H
4a, R1= R2 = H, 95%
4b, R1= Me, R2 = Ph, 97%
3b, R1= Me, R2 = Ph
representative
pyrazolo-coumarin
was
synthesized
through oxidation of a cycloadduct. This method delivers
valuable products from readily available starting materials
and nonhazardous reagents in a simple one-pot operation.
Scheme 3 One-pot synthesis of dihydropyrazoloquinoline derivatives
4a and 4b
The versatility of the IDC reaction is further illustrated
in the synthesis of cyclopentane-fused pyrazoles 5a and 5b.
The methylene-tethered alkynyl aldehydes 6a and 6b13
were smoothly converted into the cycloadducts 5a and 5b
under slightly modified conditions of the one-pot IDC reac-
tion (Scheme 4). Here, acetonitrile was found to be a better
solvent than ethanol as the use of the former gave cleaner
products in slightly improved yields.
All the reactions were carried out in flame-dried glassware. All re-
agents were purchased and used without prior purification. Technical
grade EtOAc and hexanes were used for column chromatography and
distilled prior to use. Analytical thin-layer chromatography was per-
formed using aluminum backed UVF254 precoated silica gel plates.
Visualization of the spots was achieved by exposure to UV light
and/or iodine vapor. Column chromatography was carried out with
silica gel (60–120 mesh and 100–200 mesh). Melting points were re-
corded with an electrothermal apparatus and are uncorrected. IR
spectra were obtained with a Perkin Elmer 881 or FTIR 820/PC instru-
ment and values are expressed in cm–1. All 1H NMR and 13C NMR spec-
tra were recorded in CDCl3 and DMSO-d6 as solvents with a Varian
Bruker 300 MHz, a Varian Unity 400 MHz, or an Avance 500 MHz
spectrometer at ambient temperature; chemical shifts (δ) are given in
ppm on a scale downfield from TMS, and coupling constants (J) are in
Hz. The signal patterns are indicated as: s, singlet; d, doublet; t, trip-
let; dd, doublet of doublet; m, multiplet. Mass spectra were obtained
with a Finnegan Mat1020B, a micromass VG 70–70H or an Agilent
technologies LC/MSD treapSL spectrometer operating at 70 eV by us-
ing the direct inlet system. High-resolution mass spectra (HRMS)
were recorded with a QSTAR XL Hybrid MS/MS mass spectrometer.
Propargyl ethers 1a–p and sulfonamides 3a and 3b were prepared ac-
cording to reported procedures.17 Oxidative conversion of 2a into cou-
marin derivative 7 was carried out as described for a similar system.15
R
R
TsNHNH2, 25 °C
MeCN, 3 h
NH
then 5 N NaOH
50 °C, 12 h
O
N
6a, R = H
6b, R = NO2
5a, R = H, 61%
5b, R = NO2, 30%
Scheme 4 Synthesis of cyclopentane-fused pyrazoles through the
one-pot IDC reaction
The synthetic utility of the cycloadducts generated in
the present study is illustrated by the conversion of dihy-
drochromenopyrazole 2a into pyrazolocoumarin 7.14 This
oxidation was carried out in a straightforward manner by
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

D
K. V. Divya et al.
Paper
Synthesis
Synthesis of Dihydrochromenopyrazoles; Typical Procedure
IR (KBr): 3421, 3140, 2922, 1626, 1588, 1461, 1276, 1155, 1118, 1018,
784 cm–1
.
To a solution of 1a (0.5 mmol) in EtOH (3 mL), TsNHNH2 (0.5 mmol)
was added and the solution was stirred for 3 h at r.t. under nitrogen
atmosphere. NaOH (5 N, 100 μL, 0.5 mmol) was added and the solu-
tion was stirred at r.t. for 20 min. The temperature was then increased
to 50 °C and stirring was continued until complete consumption of
hydrazone was observed by TLC. The solvent was evaporated and the
residue was diluted with distilled water (5 mL) and extracted with di-
chloromethane (3 × 5 mL). The combined organic extract was washed
with brine and dried over anhydrous sodium sulfate. Solvent was re-
moved under reduced pressure and the product was purified by col-
umn chromatography (hexane–EtOAc, 70:30) to furnish fused pyra-
zoles as the pure product.
1H NMR (400 MHz, CDCl3): δ = 7.61 (d, J = 8.8 Hz, 1 H), 7.36 (s, 1 H),
6.59 (dd, J = 2.4, 8.4 Hz, 1 H), 6.55 (d, J = 2.1 Hz, 1 H), 5.31 (d, J =
0.8 Hz, 2 H), 3.81 (s, 3 H).
13C NMR (75 MHz, CDCl3 + DMSO-d6): δ = 159.8, 154.3, 122.3, 110.5,
109.0, 107.0, 101.9, 63.6, 54.6.
HRMS: m/z [M + H] calcd for C11H11N2O2: 203.0821; found: 203.0815.
6-Ethoxy-1,4-dihydrochromeno[4,3-c]pyrazole (2f)
Yield: 105 mg (97%); white solid; mp 178–180 °C.
IR (KBr): 3334, 3115, 2920, 1566, 1470, 1445, 1264, 1111, 1040, 997,
728 cm–1
.
1,4-Dihydrochromeno[4,3-c]pyrazole (2a)
1H NMR (500 MHz, CDCl3): δ = 7.39 (s, 1 H), 7.33 (dd, J = 1.5, 7.5 Hz,
1 H), 6.95 (t, J = 8 Hz, 1 H), 6.87 (dd, J = 1.5, 8.5 Hz, 1 H), 5.39 (d, J =
0.5 Hz, 2 H), 4.14 (q, J = 7 Hz, 2 H), 1.47 (t, J = 7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 147.6, 142.9, 140.7, 125.5, 121.0, 118.5,
114.2, 113.0, 110.7, 64.2, 63.9, 14.5.
Yield: 83 mg (96%); white solid; mp 173–175 °C.
IR (KBr): 3113, 2909, 1612, 1590, 1464, 1346, 1214, 1027, 815,
741 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.71 (dd, J = 2, 7.5 Hz, 1 H), 7.39 (s,
1 H), 7.24–7.20 (m, 1 H), 7.01 (td, J = 1, 7.5 Hz, 1 H), 6.97 (dd, J = 1,
8 Hz, 1 H), 5.32 (s, 2 H).
HRMS: m/z [M + H] calcd for C12H13N2O2: 217.0977; found: 217.0970.
13C NMR (125 MHz, CDCl3): δ = 154.0, 142.0, 129.5, 125.5, 122.1,
121.8, 117.7, 117.2, 116.6, 63.7.
6,8-Dichloro-1,4-dihydrochromeno[4,3-c]pyrazole (2g)
Yield: 109 mg (91%); white solid; mp 164–166 °C.
HRMS: m/z [M + H] calcd forC10H9N2O: 173.0715; found: 173.0708.
IR (KBr): 3326, 2925, 1611, 1443, 1378, 1257, 1161, 1102, 978, 757,
674 cm–1
.
8-Chloro-2,4-dihydrochromeno[4,3-c]pyrazole (2b)
1H NMR (500 MHz, CDCl3): δ = 7.74 (d, J = 2.5 Hz, 1 H), 7.71 (s, 1 H),
7.34 (d, J = 2.5 Hz, 1 H), 4.52 (s, 2 H).
13C NMR (75 MHz, CDCl3 + DMSO-d6): δ = 147.4, 127.7, 125.3, 121.8,
Yield: 94 mg (91%); white solid; mp 160–162 °C.
IR (KBr): 3425, 2928, 1655, 1471, 1027, 1001, 822, 766 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 2.4 Hz, 1 H), 7.39 (s, 1 H),
7.15 (dd, J = 2.4, 8.8 Hz, 1 H), 6.90 (d, J = 8.8 Hz, 1 H), 5.31 (s, 2 H).
13C NMR (75 MHz, CDCl3+DMSO-d6): δ = 151.7, 127.9, 125.8, 125.0,
119.7, 110.1, 64.2.
HRMS: m/z [M
+ H] calcd for C10H7Cl2N2O: 240.9935; found:
240.9929.
121.4, 117.8, 113.9, 110.5, 63.6.
6,8-Di-tert-butyl-1,4-dihydrochromeno[4,3-c]pyrazole (2h)
Yield: 136 mg (96%); white solid; mp 188–190 °C.
HRMS: m/z [M + H] calcd for C10H8ClN2O: 207.0325; found: 207.0321.
IR (KBr): 3136, 2957, 2862, 1632, 1466, 1440, 1208, 1081, 1000 cm–1
.
8-Bromo-1,4-dihydrochromeno[4,3-c]pyrazole (2c)
Yield: 89 mg (71%); white solid; mp 146–148 °C.
IR (KBr): 3162, 2923, 1581, 1467, 1384, 1216, 1057, 761 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.61 (d, J = 2.0 Hz, 1 H), 7.39 (s, 1 H),
7.29 (d, J = 2.0 Hz, 1 H), 5.23 (s, 2 H), 1.41 (s, 9 H), 1.32 (s, 9 H).
.
1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 2.4 Hz, 1 H), 7.39 (s, 1 H),
7.30 (dd, J = 2.4, 8.8 Hz, 1 H), 6.85 (d, J = 8.4 Hz, 1 H), 5.32 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 150.2, 143.8, 138.2, 125.3, 125.2,
124.1, 117.9, 117.0, 112.0, 62.6, 35.0, 34.5, 31.5, 29.9.
13C NMR (75 MHz, CDCl3): δ = 152.2, 139.4, 130.7, 125.0, 124.2, 119.6,
HRMS: m/z [M + H] calcd for C18H25N2O: 285.1967; found: 285.1969.
118.2, 113.1, 110.4, 63.6.
1,4-Dihydrobenzo[5,6]chromeno[4,3-c]pyrazole (2i)
Yield: 108 mg (97%); white solid; mp 158–160.
HRMS: m/z [M + H] calcd for C10H8BrN2O: 250.982; found: 250.9818.
1,4-Dihydro-8-nitrochromeno[4,3-c]pyrazole (2d)
IR (KBr): 3346, 3106, 2917, 2856, 1620, 1517, 1462, 1371, 1213, 1009,
Yield: 93 mg (86%); pale-yellow solid; mp 152–154 °C.
812, 741 cm–1
.
IR (KBr): 3369, 2973, 2870, 1589, 1331, 1286, 1096, 788 cm–1
1H NMR (500 MHz, CDCl3): δ = 8.85 (d, J = 3.0 Hz, 1 H), 8.16 (dd, J = 2.5,
9.0 Hz, 1 H), 7.73 (s, 1 H), 7.09 (d, J = 8.5 Hz, 1 H), 4.59 (s, 2 H).
13C NMR (75 MHz, CDCl3+DMSO-d6): δ = 161.5, 139.8, 130.3, 130.2,
124.1, 124.0, 116.9, 116.5, 114.9, 65.5.
.
1H NMR (400 MHz, CDCl3): δ = 9.21 (d, J = 8.4 Hz, 1 H), 7.79 (d, J =
8 Hz, 1 H), 7.73 (d, J = 8.8 Hz, 1 H), 7.60–7.57 (m, 1 H), 7.45 (s, 1 H),
7.43–7.38 (m, 1 H), 7.20 (d, J = 8.8 Hz, 1 H), 5.37 (d, J = 0.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 153.2, 144.3, 129.9, 129.8, 128.2,
127.3, 125.8, 124.1, 122.9, 118.6, 112.5, 111.7, 63.4.
HRMS: m/z [M + H] calcd for C14H11N2O: 223.0871; found: 223.0868.
HRMS: m/z [M + H] calcd for C10H8N3O3: 218.0566; found: 218.0559.
1,4-Dihydro-3-phenylchromeno[4,3-c]pyrazole (2j)
1,4-Dihydro-7-methoxychromeno[4,3-c]pyrazole (2e)
Yield: 96 mg (77%); white solid; mp 268–230 °C.
IR (KBr): 3421, 3121, 2922, 2853, 1613, 1469, 1216, 748, 687 cm–1
Yield: 55 mg (55%); white solid; mp 170–172 °C.
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

E
K. V. Divya et al.
Paper
Synthesis
1H NMR (300 MHz, CDCl3): δ = 7.71 (dd, J = 0.9, 4.5 Hz, 1 H), 7.50–7.40
(m, 5 H), 7.23 (d, J = 0.9, 4.5 Hz, 1 H), 7.04–6.98 (m, 2 H), 5.49 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 127.2, 126.1, 124.4, 120.2, 119.7,
1H NMR (500 MHz, CDCl3): δ = 9.25 (d, J = 8.5 Hz, 1 H), 7.80 (d, J =
8.0 Hz, 1 H), 7.75 (d, J = 8.5 Hz, 1 H), 7.61–7.58 (m, 1 H), 7.52–7.51 (m,
4 H), 7.50–7.39 (m, 2 H), 7.21 (d, J = 8.5 Hz, 1 H), 5.84 (q, J = 6.5 Hz,
1 H), 1.57 (d, J = 6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 150.3, 129.2, 129.1, 129.0, 128.8,
128.4, 127.6, 127.5, 126.3, 126.1, 125.7, 123.2, 118.7, 113.7, 110.9,
70.0, 21.3.
115.0, 106.4, 62.4.
HRMS: m/z [M + H] calcd for C16H13N2O: 249.1028; found: 249.1024.
8-Chloro-1,4-dihydro-3-phenylchromeno[4,3-c]pyrazole (2k)
HRMS: m/z [M + H] calcd for C21H17N2O: 313.1341; found: 313.1339.
Yield: 61 mg (43%); white solid; mp 294–296 °C.
IR (KBr): 3423, 2923, 2854, 1628, 1466, 1218, 1110, 799 cm–1
.
3-Bromo-1,4-dihydrochromeno[4,3-c]pyrazole (2p)
Yield: 119 mg (95%); white solid; mp 214–216 °C.
1H NMR (300 MHz, CDCl3+DMSO-d6): δ = 7.74 (d, J = 2.4 Hz, 1 H),
7.50–7.44 (m, 4 H), 7.38 (d, J = 6.9 Hz, 1 H), 7.12 (dd, J = 2.4, 8.7 Hz,
1 H), 6.90 (d, J = 8.7 Hz, 1 H), 5.51 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 127.2, 126.8, 126.3, 124.4, 124.0,
119.6, 116.7, 106.5, 63.9.
IR (KBr): 3149, 2925, 2854, 1728, 1626, 1453, 1348, 1206, 993, 917,
819, 754 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.41–7.39 (m, 1 H), 7.23–7.21 (m, 1 H),
7.02–6.98 (m, 2 H), 5.24 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 152.8, 129.5, 121.6, 121.2, 116.6,
114.6, 110.1, 63.3.
HRMS: m/z [M
+ H] calcd for C16H12ClN2O: 283.0638; found:
280.0636.
HRMS: m/z [M + H] calcd for C10H8BrN2O: 250.982; found: 250.9816.
3-Ethyl-1,4-dihydrochromeno[4,3-c]pyrazole (2l)
Yield: 70 mg (70%); white solid; mp 255–256 °C.
IR (KBr): 3062, 2924, 2853, 1605, 1511, 1470, 1213, 1085, 746 cm–1
1H NMR (500 MHz, CDCl3): δ = 7.66 (dd, J = 1.5, 7.5 Hz, 1 H), 7.21–7.17
(m, 1 H), 6.99–6.95 (m, 2 H), 5.26 (s, 2 H), 2.66 (q, J = 7.5 Hz, 2 H), 1.26
(t, J = 7.5 Hz, 3 H).
4,5-Dihydro-5-tosyl-1H-pyrazolo[4,3-c]quinolone (4a)
.
Yield: 156 mg (96%); white solid; mp 154–156 °C.
IR (KBr): 3139, 2923, 1595, 1464, 1344, 1164, 1040, 673, 570 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.82 (dd, J = 1.2, 8.0 Hz, 1 H), 7.60 (dd,
J = 1.6, 7.6 Hz, 1 H), 7.41–7.37 (m, 1 H), 7.34–7.30 (m, 1 H), 7.21 (s,
1 H), 7.08 (d, J = 8.0 Hz, 2 H), 6.86 (d, J = 8.0 Hz, 2 H), 4.93 (s, 2 H), 2.19
(s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 153.8, 141.9, 141.5, 129.2, 122.1,
121.6, 117.8, 117.0, 108.4, 63.6, 18.5, 12.9.
HRMS: m/z [M + H] calcd for C12H13N2O: 201.1028; found: 201.1030.
13C NMR (125 MHz, CDCl3): δ = 142.3, 134.2, 133.9, 127.9, 127.4,
126.8, 126.5, 126.2, 125.1, 121.7, 110.9, 42.7, 20.6.
8-Chloro-3-ethyl-1,4-dihydrochromeno[4,3-c]pyrazole (2m)
HRMS: m/z [M
+ H] calcd for C17H16N3O2S: 326.0963; found:
Yield: 69 mg (59%); white solid; mp 138–140 °C.
326.0961.
IR (KBr): 3358, 3125, 2924, 1602, 1510, 1462, 1216, 807 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.67 (d, J = 2.5 Hz, 1 H), 7.13 (dd, J = 2.5,
8.5 Hz, 1 H), 6.88 (d, J = 8.5 Hz, 1 H), 5.25 (s, 2 H), 2.68 (q, J = 7.5 Hz,
2 H), 1.28 (t, J = 7.5 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 152.4, 142.3, 140.6, 128.9, 121.9,
119.6, 118.4, 108.6, 63.7, 18.4, 12.9.
4,5-Dihydro-4-methyl-3-phenyl-5-tosyl-1H-pyrazolo[4,3-c]quino-
lone (4b)
Yield: 199 mg (96%); white solid; mp 238–240 °C.
IR (KBr): 3143, 2924, 2854, 1735, 1466, 1220, 806 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.84 (dd, J = 1.2, 8.4 Hz, 1 H), 7.65 (dd,
J = 1.6, 7.6 Hz, 1 H), 7.55–7.53 (m, 2 H), 7.53–7.38 (m, 5 H), 7.36 (d, J =
6 Hz, 2 H), 7.35 (d, J = 6.4 Hz, 2 H), 5.73 (q, J = 6.8 Hz, 1 H), 2.20 (s,
3 H), 1.39 (d, J = 6.8 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 141.8, 133.4, 131.1, 128.3, 127.9,
127.4, 126.9, 126.6, 126.2, 125.5, 124.9, 121.0, 113.3, 48.8, 21.0, 20.2.
HRMS: m/z [M
+ H] calcd for C12H12ClN2O: 235.0638; found:
235.0636.
1,4-Dihydro-4-methyl-3-phenylchromeno[4,3-c]pyrazole (2n)
Yield: 126 mg (96%); white solid; mp 290–291 °C.
IR (KBr): 3061, 2922, 1614, 1464, 1214, 746 cm–1
.
HRMS: m/z [M
+ H] calcd for C24H22N3O2S: 416.1433; found:
1H NMR (400 MHz, CDCl3): δ = 7.71 (dd, J = 1.6, 7.6 Hz, 1 H), 7.50–7.46
(m, 4 H), 7.43–7.41 (m, 1 H), 7.24–7.22 (m, 1 H), 7.03–6.98 (m, 2 H),
5.83 (q, J = 6.8 Hz, 1 H), 1.51 (d, J = 6.8 Hz, 3 H).
416.1427.
3-Phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole (5a)
Yield: 43 mg (47%); viscous oil.
13C NMR (125 MHz, CDCl3): δ = 152.2, 141.4, 140.0, 130.1, 129.5,
128.9, 128.3, 126.6, 122.0, 121.4, 117.6, 116.8, 113.7, 71.1, 22.0.
IR (KBr): 3419, 2924, 2855, 1633, 1462, 1023, 801, 693 cm–1
.
HRMS: m/z [M + H] calcd for C17H15N2O: 263.1184; found: 263.1182.
1H NMR (500 MHz, CDCl3): δ = 7.61–7.59 (m, 2 H), 7.41 (t, J = 7.0 Hz,
2 H), 7.32–7.28 (m, 1 H), 2.85 (t, J = 7.5 Hz, 2 H), 2.76 (t, J = 7.5 Hz,
2 H), 2.54 (quin, J = 7.5 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 146.8, 143.7, 139.4, 138.2, 125.8,
124.3, 123.5, 30.8, 24.3, 24.0.
4-Methyl-3-phenyl-1,4-dihydrobenzo[5,6]chromeno[4,3-c]pyra-
zole (2o)
Yield: 148 mg (95%); white solid; mp 153–155 °C.
IR (KBr): 3250, 2923, 2854, 1616, 1457, 1379, 1212, 813, 744 cm–1
.
HRMS: m/z [M + H] calcd for C12H13N2: 185.1079; found: 185.1077.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

F
K. V. Divya et al.
Paper
Synthesis
3-(4-Nitrophenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole (5b)
Yield: 33 mg (30%); pale-yellow solid; mp 190–192 °C.
(5) (a) Wu, L.-L.; Ge, Y.-C.; He, T.; Zhang, L.; Fu, X.-L.; Fu, H.-Y.; Chen,
H.; Li, R.-X. Synthesis 2012, 44, 1577. (b) Kong, Y.; Tang, M.;
Wang, Y. Org. Lett. 2014, 16, 576. (c) Hari, Y.; Tsuchida, S.; Sone,
R.; Aoyama, T. Synthesis 2007, 3371. (d) Li, P.; Zhao, J.; Wu, C.;
Larock, R. C.; Shi, F. Org. Lett. 2011, 13, 3340. (e) Tufariello, J. J. In
1,3-Dipolar Cycloaddition Chemistry; Vol. 2; Padwa, A., Ed.; John
Wiley & Sons: New York, 1984, 83.
(6) (a) Aggarwal, V. K.; Alonso, E.; Hynd, G.; Lydon, K. M.; Palmer,
M. J.; Porcelloni, M.; Studley, J. R. Angew. Chem. Int. Ed. 2001, 40,
1430. (b) Aggarwal, V. K.; de Vicente, J.; Bonnert, R. V. Org. Lett.
2001, 3, 2785.
IR (KBr): 3337, 3134, 2924, 2853, 1598, 1515, 1343, 1159, 1106, 853,
693 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.27 (d, J = 8.5 Hz, 2 H), 7.83 (d, J =
8.5 Hz, 2 H), 2.92–2.90 (m, 2 H), 2.80 (br s, 2 H), 2.65 (t, J = 6.0 Hz,
2 H).
13C NMR (125 MHz, CDCl3): δ = 146.7, 144.1, 138.5, 129.6, 125.8,
125.3, 124.3, 30.9, 24.4, 24.0.
HRMS: m/z [M + H] calcd for C12H12N3O2: 230.0930; found: 230.0926.
(7) Aggarwal, V. K.; de Vicente, J.; Bonnert, R. V. J. Org. Chem. 2003,
68, 5381.
(8) Menon, R. S.; Nair, V. Intramolecular 1,3-Dipolar Cycloadditions
of Alkenes, Alkynes, and Allenes, In Comprehensive Organic Syn-
thesis, 2nd ed., Vol. 4; Molander, G. A.; Knochel, P., Eds.; Oxford:
Elsevier, 2014, 1281–1341.
(9) Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247.
(10) (a) Wang, W.-L.; Feng, Y.-L.; Gao, W.-Q.; Luo, X.; Deng, W.-P. RSC
Adv. 2013, 3, 1687. (b) Chandrasekhar, S.; Rajaiah, G.; Srihari, P.
Tetrahedron Lett. 2001, 42, 6599. (c) Yang, T.; Zhang, T.; Yang, S.;
Chen, S.; Li, X. Org. Biomol. Chem. 2014, 12, 4290.
Acknowledgment
T.D.S. thanks the Science and Engineering Research Board (SERB), De-
partment of Science and Technology (DST), India, for the award of a
Young Scientist Start-up Research Grant (CS-179/2013). Funding in
part from the Council of Scientific Industrial Research (CSIR), India, in
the form of the 12th five-year plan project ‘Affordable Cancer Thera-
peutics (CSC-0301)’ is also acknowledged.
(11) Janin, Y. L. Chem. Rev. 2012, 112, 3924.
(12) (a) Sze, E. M. L.; Koh, M. J.; Tjia, Y. M.; Rao, W.; Chan, P. W. H.
Tetrahedron 2013, 69, 5558. (b) Jalal, S.; Bera, K.; Sarkar, S.; Paul,
K.; Jana, U. Org. Biomol. Chem. 2014, 12, 1759.
Supporting Information
Supporting information for this article is available online at
(13) Compounds 6a and 6b were prepared from 5-hexyn-1-ol
through Sonogashira coupling and oxidation, see: (a) Moodie, L.
W. K.; Larsen, D. S. Eur. J. Org. Chem. 2014, 1684. (b) Lu, H.; Li, C.;
Jiang, H.; Lizardi, C. L.; Zhang, X. P. Angew. Chem. Int. Ed. 2014,
53, 7028.
http://dx.doi.org/10.1055/s-0035-1562533.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F