Synthesis of novel spiro[cyclopropane-indazole] derivatives via magnesium-mediated conjugate addition of bromoform

Article abstract of DOI:10.3184/174751914X14102462623785

A novel series of 2,2-dibromo-3-aryl-1′-phenyl-6′,7′-dihydrospiro[cyclopropane-1,5′-indazol]-4′(1′H)-ones derivatives were prepared in moderate to good yields by conjugate addition of bromoform to (E )-5-arylmethylene-1-phenyl-6,7-dihydro-1H-indazol- 4(5H

Full text of DOI:10.3184/174751914X14102462623785

558 RESEARCH PAPER
VOL. 38 SEPTEMBER, 558–561
JOURNAL OF CHEMICAL RESEARCH 2014
Synthesis of novel spiro[cyclopropane-indazole] derivatives via
magnesium-mediated conjugate addition of bromoform
Jinlong Yana*, Zhihong Dengb and Guoqiang Kuangb
aDepartment of Biology and Chemical Engineering, Jiaozuo Teachers College, Jiaozuo, Henan 454001, P.R. China
bKey Laboratory of Theoretical Chemistry and Molecular Simulation of Ministry of Education, Hunan Province College Key Laboratory of QSAR/
QSPR, School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan, Hunan 411201, P.R. China
A novel series of 2,2-dibromo-3-aryl-1′-phenyl-6′,7′-dihydrospiro[cyclopropane-1,5′-indazol]-4′(1′H)-ones derivatives were
prepared in moderate to good yields by conjugate addition of bromoform to (E)-5-arylmethylene-1-phenyl-6,7-dihydro-1H-
indazol-4(5H)-ones in the presence of magnesium under N2. The structures of all the products were characterised by 1H NMR,
13C NMR, IR spectroscopy, elemental analysis and mass spectrometry.
Keywords: cyclopropane, indazole, spiroheterocyclic
Cyclopropane rings are a significant feature in a wide variety
of natural products and in drug molecules such as erispatene,
indolizomycin, halicholactone and related compounds.1–4 In
the past years, many valuable compounds which contain a
cyclopropane ring have been synthesised and isolated, such as
the insecticide (+)‑trans‑chrysanthemic acid, the plant hormone
precursor 1‑aminocyclopropane‑1‑carboxylic acid (ACC), the
renal dehydropeptidase inhibitor cilastatin and the anticancer
agent (+)‑ptaquiloside.5,6 Spirocyclopropanes represent an
important area of cyclopropane research and many useful
products have been synthesised and investigated (Fig. 1).7,8
During these studies many ways to synthesise cyclopropanes
have been developed and the main methods include additions
of dihalocarbenes, diazoalkanes, or sulfonium ylides to alkenes
or activated alkenes.9–11 However, all these methods are not
well suited for the preparation of spirocyclopropanes from
enones. In particular, the Mg‑mediated addition of bromoform
to enones is a convenient and efficient way to synthesise
spirocyclopropanes.12
anti‑inflammatory, antibacterial, and anticancer activities.13–15
Despite the proven importance of indazolone derivatives in
biomedical research, a convenient and efficient synthesis
of such compounds remains a challenge. We now describe
efforts to design and synthesise novel indazolone derivatives
with potential biological activity, and the introduction of
cyclopropane rings into indazolone molecules. We herein report
a convenient and efficient way to synthesise a series of new
spiro‑indazolone compounds containing a cyclopropane ring
framework by Mg‑mediated conjugate addition of bromoform
(Scheme 1). In this procedure, the reaction actually proceeds
via conjugate addition of Br3CMgBr to the enone rather than by
cycloaddition of dibromocarbene.12
Results and discussion
The condensation reaction of 1‑phenyl‑6,7‑dihydro‑1H‑
indazol‑4(5H)‑one 1 with the appropriate aromatic aldehyde
gave (E)‑5‑arylmethylene‑1‑phenyl‑6,7‑dihydro‑1H‑indazol‑
4(5H)‑ones 2 in moderate yields in a simple operation.
Subsequent conjugate addition of bromoform (20 equiv.) in the
presence of Mg (10 equiv.) to the indazolones 2 resulted in the
formation of the dibromo‑cyclopropanes 3 in moderate to high
During research on small‑molecule modulators, indazole
and indazolone derivatives have attracted increasing interest
because of their various biological properties such as
O
O
Cl
O
R
N
H
O
O
spiro[cyclopropane-indolin]-one
spirooctanone
spiro[chromene-cyclopropan]-one
Fig. 1 Some important compounds bearing a spirocyclopropane moiety.
Br
O
O
Br
O
H
CHBr3, Mg
40% aqueous KOH
Ar
N
N
Ar
N
THF, 0°C-RT
EtOH, 3 h, 80 ¡ãC
N
N
N
Ph
Ph
Ph
3a-3i
1
2a-2i
Ar: a,
b,
c,
d
e
C6H5; 4-ClC6H4; 4-FC6H4; , 4-CH3C6H4; , 4-(CH3)3CC6H4;
f
g
h
i
, 4-CH3SC6H4; , 4-CH3OC6H4; ,3,5-(CH3O)2C6H3; , 3,4,5-(CH3O)3C6H2;
Scheme 1
* Correspondent. E‑mail: jinlongyan1234@163.com
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JOURNAL OF CHEMICAL RESEARCH 2014 559
Table 1 Synthesis of spiro[cyclopropane-indazol] derivatives
to the tolyl methyl protons, the CH (HC‑3) in the cyclopropane
ring and the pyrazole ring CH (HC‑3′) proton, respectively.
The 13C NMR spectrum of the product 3d exhibited the
presence of a carbonyl carbon at δ 185.2 (C‑4′). The signals at δ
21.3 and 30.5 were assigned to the carbons from the CH2 units
of H2C‑7′ and H2C‑6′ respectively (based on HSQC). The signal
at δ 37.8 is in agreement with the carbon of the CH (HC‑3),
from the cyclopropane ring (based on HSQC). The signal at δ
42.0 is in accord with the spiro carbon of C‑1.
Entry
Ar
Product
Time/h
Yield/%
1
2
3
4
5
6
7
8
9
C6H5
4Cl–C6H4
4-FC6H4
4-CH3C6H4
4-(CH3)3CC6H4
4-CH3SC6H4
4-CH3OC6H4
3,5-(OCH3)2C6H3
3,4,5-(OCH3)3C6H2
3a
3b
3c
3d
3e
3f
3g
3h
3i
2.0
2.5
3.0
1.5
2.0
1.5
2.5
1.0
1.5
52
86
68
62
71
56
75
82
88
1
In the H–13C HMBC map of 3d (Fig. 2), protons from the
H2C‑6′ and H2C‑7′ units from the indazolone ring and HC‑3
in the cyclopropane ring correlate with the spiro carbon C‑1
(42.0 ppm), whilst the protons from H2C‑6′ correlate with the
C‑3 carbon (37.8 ppm). The correlation of H2C‑6′ and HC‑3 with
C‑4′ indicates the carbonyl carbon (C‑4′) at 185.2 ppm. The
stereochemistry of the products was determined by NOESY. It
is straightforward to differentiate 3 from its isomer (in which
Ar and H have been interchanged) since the latter would, of
course, be expected to show a NOESY correlation. There is no
correlation between the HC‑3 proton and the H2C‑6′ protons
in the NOESY spectrum of 3d, which indicates that the HC‑3
proton and those from the H2C‑6′ moiety are on different sides
of the cyclopropane ring. This stereochemistry of the products
3a–i is similar to the result reported previously.12
yields (Table 1). The progress of this reaction was monitored
by TLC and the target products were purified by flash column
chromatography on silica gel. In order to expand the range
of substrates for this reaction, different arylidene groups
containing either electron donating or electron withdrawing
substituents (in 2) were tested in the reaction. As shown in
Table 1, the conjugate addition‑cyclopropanation reaction
sequence was complete in less than 3 h, and the products were
isolated in moderate to high yield (52–88%). The substituents
on the benzylidene moiety in 2 have little effect on the yield or
the reaction time.
A plausible mechanism for the conversion of 2 to 3 is outlined
in Scheme 2. Firstly, magnesium reacts with excess bromoform
to form initially tribromomethylmagnesium‑bromide which
undergoes conjugate addition to the enone moiety of the
indazolone 2. The resulting enolate intermediate cyclises to
give the spiro‑cyclopropane ketone, 2,2‑dibromo‑3‑aryl‑1′‑
phenyl‑6′,7′‑dihydrospiro[cyclopropane‑1,5′‑indazol]‑4′(1′H)‑
one 3. Evidence for the participation of a tribromomethyl
enolate in related reactions has been reported recently.12
The structures of all compounds 2a–i and 3a–i were
established by a variety of spectroscopic techniques (NMR,
IR, MS and elemental analysis). The elemental analysis and
MS (ESI) of 3d were consistent with the formula C22H18Br2N2O,
which indicated addition of the bromoform to the (E)‑5‑
(4‑methylbenzylidene)‑1‑phenyl‑6,7‑dihydro‑1H‑indazol‑
4(5H)‑one 2d. The IR spectrum of 3d revealed the presence
1
of a carbonyl stretching band at 1680 cm–1. The H NMR
spectrum of 3d revealed the presence of two double doublets
of doublets at δ 2.01 (ddd, J1 =14.0 Hz, J2 =4.5 Hz, J3 =2.0 Hz,
1H) and at 2.58 (ddd, J1 =14.0 Hz, J2 =12.5 Hz, J3 =4.5 Hz,
1H) corresponding to the protons of the C‑6′ methylene group.
Another double doublet of doublets at δ 3.46 (ddd, J1 =17.0 Hz,
J2 =12.5 Hz, J3 =4.5 Hz, 1H) together with a multiplet in the
range 2.89–2.92 ppm corresponded to the C‑7′ methylene
protons. Three singlets at δ 2.33, 3.91 and 8.16 corresponded
Conclusion
A facile and novel synthesis of 2,2‑dibromo‑3‑aryl‑1′‑phenyl‑
6′,7′‑dihydrospiro[cyclopropane‑1,5′‑indazol]‑4′(1′H)‑ones by
the conjugate addition of bromoform to (E)‑5‑arylmethylene‑1‑
phenyl‑6,7‑dihydro‑1H‑indazol‑4(5H)‑ones in the presence of
Mg in THF has been developed. This work provides a simple
method to synthesise spiro(dibromocyclopropanated) products
incorporating the important indazolone and cyclopropane
rings.
Br
2
O
4'
Br
3
Experimental
1
H
Compound 2 was prepared according to the reported procedure.16
All NMR spectra were recorded on a Bruker AV‑II 500 MHz NMR
spectrometer, operating at 500 MHz for 1H, and 125 MHz for 13C. TMS
N
N
Ph
6
'
7'
1
was used as an internal reference for both H and 13C chemical shifts
and CDCl3 was used as solvent. MS was obtained with a Finnigan
LCQ Advantage MAX mass spectrometer. IR spectra were recorded
Fig. 2 Partial HMBC diagram of 3d.
CHBr3(excess)
THF
CHBr3
Mg
CHBr2MgBr
CHBr2
O
Ar
Br
N
O
O
Br
CBr3
Ar
N
H
2
Ph
cyclisation
CBr3MgBr
N
N
Ar
N
-
Br
N
Ph
Ph
3
Scheme 2 A plausible mechanism for the conversion of 2 to 3.
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560 JOURNAL OF CHEMICAL RESEARCH 2014
on a PE‑2000 spectrometer in KBr pellets and are reported in cm–1.
Melting points were measured with a Yanaco MP500 melting point
apparatus and are uncorrected. Elemental analysis was measured
by Elementar analyser (vario EL II). Mg turnings were activated by
washing with 1% dilute HCl, water, and acetone followed by drying
in an oven overnight. The solvents were all distilled prior to use. THF
was distilled from sodium. Other commercially available materials
were purchased from Aladdin‑Reagent, and were used without further
purification.
3.16 (t, J=6.5 Hz, 2H), 7.26 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz,
2H), 7.41–7.45 (m, 1H), 7.49–7.54 (m, 4H), 7.75 (s, 1H), 8.20 (s, 1H);
13C NMR (CDCl3, 125 MHz) δ 15.3, 22.7, 26.5, 121.1, 123.6, 125.8,
128.3, 129.5, 130.2, 132.3, 134.2, 135.7, 138.5, 139.6, 139.7, 147.8,
183.4; IR (KBr) νmax/cm–1 1650; MS (ESI) m/z 347 [M+H]+. Anal.
calcd for C21H18N2OS: C, 72.80; H, 5.24; N, 8.09; found: C, 72.68; H,
5.21; N, 8.13%.
(E)-5-(4-Methoxybenzylidene)-1-phenyl-6,7-dihydro-1H-indazol-
1
4(5H)-one (2g): White solid, yield 56%; m.p. 192–193 °C; H NMR
(CDCl3, 500 MHz): δ 3.03 (t, J=6.5 Hz, 2H), 3.17 (t, J=6.5 Hz, 2H),
3.84 (s, 3H), 6.94 (d, J=8.5 Hz, 2H), 7.37 (d, J=8.5 Hz, 2H), 7.41–7.44
(m, 1H), 7.49–7.53 (m, 4H), 7.77 (s, 1H), 8.19 (s, 1H); 13C NMR (CDCl3,
125 MHz) δ 22.7, 26.4, 55.4, 114.0, 121.2, 123.6, 128.2, 128.4, 129.5,
131.5, 132.9, 136.0, 138.6, 139.5, 147.7, 159.8, 183.5; IR (KBr) νmax/cm–1
1655; MS (ESI) m/z 331 [M+H]+. Anal. calcd for C21H18N2O2: C, 76.34;
H, 5.49; N, 8.48; found: C, 76.45; H, 5.54; N, 8.42%.
(E)-5-(3,5-Dimethoxybenzylidene)-1-phenyl-6,7-dihydro-1H-
indazol-4(5H)-one (2h): White solid, yield 58%; m.p. 188–189 °C;
1H NMR (CDCl3, 500 MHz): δ 3.01 (t, J=6.5 Hz, 2H), 3.15 (t,
J=6.5 Hz, 2H), 3.81 (s, 6H), 7.41–7.44 (m, 1H), 7.49–7.53 (m, 4H), 7.72
(s, 1H), 8.19 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 22.8, 26.5, 55.4,
100.3, 107.6, 121.2, 123.6, 128.3, 129.5, 135.3, 136.0, 137.8, 138.5,
139.5, 148.0, 160.7, 183.3; IR (KBr) νmax/cm–1 1663; MS (ESI) m/z 361
[M + H]+. Anal. calcd for C22H20N2O3: C, 73.32; H, 5.59; N, 7.77; found:
C, 73.28; H, 5.68, N7.71%.
Synthesis of (E)-5-arylmethylene-1-phenyl-6,7-dihydro-1H-indazol-
4(5H)-one (2a-i); general procedure
A
solution of 1‑phenyl‑6,7‑dihydro‑1H‑indazol‑4(5H)‑one
1
(10 mmol) and the appropriate aromatic aldehyde (10 mmol) in EtOH
(10 mL) was stirred at 80 °C for 3 h in the presence of 40% aqueous
NaOH (2 mL). Then the crude product was isolated by filtration
through a Buchner funnel. The residue thus obtained was washed
with water and purified by crystallisation from ethanol to give pure
product 2.
(E)-5-Benzylidene-1-phenyl-6,7-dihydro-1H-indazol-4(5H)-one
(2a): White solid, yield 65%; m.p. 188–189 °C, (lit.17 162–163 °C);
1H NMR (CDCl3, 500 MHz): δ 3.05 (t, J=6.5 Hz, 2H), 3.16–3.19
(m, 2H), 7.36–7.38 (m, 1H), 7.40–7.46 (m, 5H), 7.51–7.54 (m, 4H),
7.82 (s, 1H), 8.21 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 22.8, 26.4,
121.2, 123.6, 128.3, 128.4, 128.5, 129.5, 129.6, 134.9, 135.9, 136.1,
138.6, 139.5, 147.9, 183.5; IR (KBr) νmax/cm–1 1655; MS (ESI) m/z 301
[M + H]+. Anal. calcd for C20H16N2O: C, 79.98; H, 5.37; N, 9.33; found:
C, 79.85; H, 5.46; N, 9.21%.
(E)-1-Phenyl-5-(3,4,5-trimethoxybenzylidene)-6,7-dihydro-1H-
indazol-4(5H)-one (2i): White solid, yield 52%; m.p. 191–192 °C;
1H NMR (CDCl3, 500 MHz): δ 3.05 (t, J=6.5 Hz, 2H), 3.19 (t,
J=6.5 Hz, 2H), 3.88 (s, 6H), 3.89 (s, 3H), 6.62 (s, 2H), 7.42–7.45 (m,
1H), 7.50–7.54 (m, 4H), 7.74 (s, 1H), 8.19 (s, 1H); 13C NMR (CDCl3,
125 MHz) δ 22.7, 26.5, 56.2, 61.0, 107.0, 121.1, 123.6, 128.3, 129.5,
131.4, 134.3, 136.3, 138.4, 138.5, 139.5, 147.8, 153.1, 183.2; IR (KBr)
(E)-5-(4-Chlorobenzylidene)-1-phenyl-6,7-dihydro-1H-indazol-
1
4(5H)-one (2b): White solid, yield 58%; m.p. 208–209 °C; H NMR
(CDCl3, 500 MHz): δ 3.05 (t, J=6.5 Hz, 2H), 3.12–3.14 (m, 2H),
7.33 (d, J=8.5 Hz, 2H), 7.40 (d, J=8.5 Hz, 2H), 7.43–7.46 (m,
1H), 7.51–7.55 (m, 4H), 7.75 (s, 1H), 8.21 (s, 1H); 13C NMR (CDCl3,
125 MHz) δ 22.7, 26.4, 121.1, 123.6, 128.4, 128.8, 129.5, 130.9, 134.3,
134.4, 134.8, 135.4, 138.5, 139.6, 147.8, 183.1; IR (KBr) νmax/cm–1 1655;
MS (ESI) m/z 335 [M+H]+. Anal. calcd for C20H15ClN2O: C, 71.75; H,
4.52; N, 8.37; found: C, 71.57; H, 4.58; N, 8.42%.
ν
max/cm–1 1654; MS (ESI) m/z 391 [M+H]+. Anal. calcd for C23H22N2O4:
C, 70.75; H, 5.68; N, 7.17; found: C, 70.61; H, 5.64; N, 7.22%.
Synthesis of 2,2-dibromo-3-aryl-1′-phenyl-6′,7′-dihydrospiro-[cyclo-
propane-1,5′-indazol]-4′(1′H)-ones (3a–i); general procedure
Bromoform (5.4 g, 2 mL, 22 mmol) was dropwise added into a
stirred mixture of magnesium (192 mg, 8 mmol) and the appropriate
(E)‑5‑arylmethylene‑1‑phenyl‑6,7‑dihydro‑1H‑indazol‑4(5H)‑one
2 (1 mmol) in dry THF (20 mL) over a period of 10 min at 0 °C under a
protective N2 atmosphere. After that, the reaction mixture was brought
to room temperature. The reaction was conducted until TLC analysis
showed that none of the reactant remained. Then the reaction mixture
was quenched with saturated aqueous NH4Cl (10 mL). The organic
layer was separated and concentrated in vacuo to give the crude
product. The latter was subjected to column chromatography using
petroleum‑ethyl acetate (6:1) as eluent to afford the corresponding
spiro‑cycle 3.
(E)-5-(4-Fluorobenzylidene)-1-phenyl-6,7-dihydro-1H-indazol-
1
4(5H)-one (2c): White solid, yield 69%; m.p. 190–191 °C; H NMR
(CDCl3, 500 MHz): δ 3.04 (t, J=6.5 Hz, 2H), 3.13 (t, J=6.5 Hz, 2H),
7.11 (d, J=8.5 Hz, 2H), 7.36–7.39 (m, 2H), 7.42–7.46 (m, 1H), 7.51–7.54
(m, 4H), 7.75 (s, 1H), 8.20 (s, 1H); 13C NMR (CDCl3, 125 MHz)
δ 22.7, 26.3, 115.5, 115.7, 121.1, 123.5, 128.3, 129.5, 131.5, 131.6,
131.89, 131.91, 134.7, 135.0, 138.5, 139.6, 147.8, 161.5, 163.5, 183.3;
IR (KBr) νmax/cm–1 1656; MS (ESI) m/z 319 [M+H]+. Anal. calcd for
C20H15FN2O: C, 75.46; H, 4.75; N, 8.80; found: C, 75.31; H, 4.69; N,
8.71%.
(E)-5-(4-Methylbenzylidene)-1-phenyl-6,7-dihydro-1H-indazol-
1
4(5H)-one (2d): White solid, yield 59%; m.p. 211–212 °C; H NMR
(CDCl3, 500 MHz): δ 3.02 (t, J=6.5 Hz, 2H), 3.16 (t, J=6.5 Hz,
2H), 7.22 (d, J=8.0 Hz, 2H), 7.30 (d, J=8.0 Hz, 2H), 7.41–7.44 (m,
1H), 7.49–7.51 (m, 4H), 7.78 (s, 1H), 8.19 (s, 1H); 13C NMR (CDCl3,
125 MHz) δ 21.4, 22.8, 26.4, 121.2, 123.6, 128.3, 129.2, 129.5, 129.7,
2,2-Dibromo-1′,3-diphenyl-6′,7′-dihydrospiro[cyclopropane-1,5′-
indazol]-4′(1′H)-one (3a): White solid, yield 52%; m.p. 199–201 °C;
1H NMR (CDCl3, 500 MHz): δ 2.01 (ddd, J1 =14.0 Hz, J2 =4.5 Hz,
J3 =2.0 Hz, 1H), 2.59 (ddd, J1 =14.0 Hz, J2 =12.5 Hz, J3 =4.5 Hz,
1H), 2.91 (ddd, J1 =17.0 Hz, J2 =4.5 Hz, J3 =2.0 Hz, 1H), 3.46 (ddd,
J1 =17.0 Hz, J2 =12.5 Hz, J3 =4.5 Hz, 1H), 3.97 (s, 1H, HC‑3), 7.27 (d,
J=8.0 Hz, 2H), 7.31–7.37 (m, 3H), 7.43 (d, J=7.5 Hz, 1H), 7.51 (d,
J=8.5 Hz, 1H), 7.56 (t, J=8.5 Hz, 3H), 8.17 (s, 1H, HC‑3); 13C NMR
(CDCl3, 125 MHz) δ 21.3, 30.5, 35.2, 38.0, 42.1, 119.8, 123.6, 127.7,
128.48, 128.51, 129.5, 129.9, 133.1, 138.4, 139.3, 148.9, 185.1; IR
(KBr) νmax/cm–1 1686; MS (ESI) m/z 391 [M–Br]+. Anal. calcd for
C21H16Br2N2O: C, 53.42; H, 3.42; N, 5.93; found: C, 53.35; H, 3.52; N,
5.86%.
2,2-Dibromo-3-(4-chlorophenyl)-1′-phenyl-6′,7′-dihydrospiro-
[cyclopropane-1,5′-indazol]-4′(1′H)-one (3b): White solid, yield
86%; m.p. 202–204 °C; 1H NMR (CDCl3, 500 MHz): δ 1.98 (ddd,
J1 =14.0 Hz, J2 =4.5 Hz, J3 =2.0 Hz, 1H), 2.58 (ddd, J1 =14.0 Hz,
J2 =12.5 Hz, J3 =4.5 Hz, 1H), 2.94 (ddd, J1 =17.0 Hz, J2 =4.5 Hz,
J3 =2.0 Hz, 1H), 3.47 (ddd, J1 =17.0 Hz, J2 =12.5 Hz, J3 =4.5 Hz, 1H),
133.0, 134.1, 136.2, 138.58, 138.64, 139.5, 147.8, 183.5; IR (KBr) νmax
/
cm–1 1660; MS (ESI) m/z 315 [M+H]+. Anal. calcd for C21H18N2O: C,
80.23; H, 5.77; N, 8.91; found: C, 80.12; H, 5.83; N, 8.86%.
(E)-5-[4-(tert-Butyl)benzylidene]-1-phenyl-6,7-dihydro-1H-
indazol-4(5H)-one (2e):White solid, yield 72%; m.p. 184–185 °C;
1H NMR (CDCl3, 500 MHz): δ 1.35(s, 9H), 3.03 (t, J=6.5 Hz, 2H),
3.19 (d, J=6.5 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.5 Hz,
2H), 7.51–7.52 (m, 3H), 7.79 (s, 1H), 8.20 (s, 1H); 13C NMR (CDCl3,
125 MHz) δ 22.8, 26.4, 31.2, 34.8, 121.2, 123.6, 125.5, 128.2, 129.6,
133.0, 134.1, 138.6, 139.5, 147.8, 151.8, 183.5; IR (KBr) νmax/cm–1 1671;
MS (ESI) m/z 357 [M+H]+. Anal. calcd for C24H24N2O: C, 80.87; H,
6.79; N, 7.86; found: C, 80.69; H, 6.65; N, 7.83%.
(E)-5-[4-(Methylthio)benzylidene]-1-phenyl-6,7-dihydro-1H-
indazol-4(5H)-one (2f): White solid, yield 46%; m.p. 195–196 °C;
1H NMR (CDCl3, 500 MHz): δ 2.52 (s, 3H), 3.04 (t, J=6.5 Hz, 2H),
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3.91 (s, 1H, HC‑3), 7.21 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H),
7.45 (t, J=7.5 Hz, 1H), 7.51–7.58 (m, 4H), 8.17 (s, 1H, HC‑3); 13C NMR
(CDCl3, 125 MHz) δ 21.3, 30.4, 34.7, 37.3, 42.1, 119.7, 123.5, 128.5,
128.8, 129.6, 131.3, 131.5, 133.8, 139.3, 148.8, 184.7; IR (KBr) νmax/cm–1
1677; MS (ESI) m/z 425 [M–Br]+. Anal. calcd for C21H15Br2ClN2O: C,
49.79; H, 2.98; N, 5.53; found: C, 49.83; H, 3.05; N, 5.51%.
2,2-Dibromo-3-(4-fluorophenyl)-1′-phenyl-6′,7′-dihydrospiro-
[cyclopropane-1,5′-indazol]-4′(1′H)-one (3c): White solid, yield
68%; m.p. 190–192 °C; 1H NMR (CDCl3, 500 MHz): δ 2.00 (ddd,
J1 =14.0 Hz, J2 =4.5 Hz, J3 =2.0 Hz, 1H), 2.58 (ddd, J1 =14.0 Hz,
J2 =12.5 Hz, J3 =4.5 Hz, 1H), 2.94 (ddd, J1 =17.0 Hz, J2 =4.5 Hz,
J3 =2.0 Hz, 1H), 3.48 (ddd, J1 =17.0 Hz, J2 =12.5 Hz, J3 =4.5 Hz,
1H), 3.92 (s, 1H, HC‑3), 7.07 (d, J=8.5 Hz, 2H), 7.24–7.28 (m, 2H),
7.44–7.47 (m, 1H), 7.53–7.59 (m, 4H), 8.18 (s, 1H, HC‑3); 13C NMR
(CDCl3, 125 MHz) δ 21.3, 30.4, 35.0, 37.3, 42.1, 115.5, 115.7, 119.8,
123.6, 128.5, 128.78, 128.81, 129.5, 131.56, 131.62, 138.4, 139.3, 148.8,
161.2, 163.2, 184.9; IR (KBr) νmax/cm–1 1683; MS (ESI) m/z 409 [M–
Br]+. Anal. calcd for C21H15Br2FN2O: C, 51.46; H, 3.08; N, 5.72; found:
C, 51.48; H, 3.18; N, 5.78%.
2,2-Dibromo-1′-phenyl-3-(p-tolyl)- 6′,7′-dihydrospiro-
[cyclopropane-1,5′-indazol]-4′(1′H)-one (3d): White solid, yield
62%; m.p. 196–198 °C; 1H NMR (CDCl3, 500 MHz): δ 2.01 (ddd,
J1 =14.0 Hz, J2 =4.5 Hz, J3 =2.0 Hz, 1H), 2.33 (s, 3H, –CH3), 2.58
(ddd, J1 =14.0 Hz, J2 =12.5 Hz, J3 =4.5 Hz, 1H), 2.92 (ddd, J1 =17.0 Hz,
J2 =4.5 Hz, J3 =2.0 Hz, 1H), 3.46 (ddd, J1 =17.0 Hz, J2 =12.5 Hz,
J3 =4.5 Hz, 1H), 3.91 (s, 1H, HC‑3), 7.16–7.18 (m, 4H), 7.43 (t,
J=7.5 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 8.16
(s, 1H, HC‑3); 13C NMR (CDCl3, 125 MHz) δ 21.2, 21.3, 30.5, 35.6,
37.6, 42.0, 119.9, 123.6, 128.5, 129.2, 129.5, 129.8, 130.0, 137.4, 138.4,
139.3, 148.9, 185.2; IR (KBr) νmax/cm–1 1680; MS (ESI) m/z 405 [M–
Br]+. Anal. calcd for C22H18Br2N2O: C, 54.35; H, 3.73; N, 5.76; found:
C54.44; H, 3.62; N, 5.71%.
(s, 1H, HC‑3); 13C NMR (CDCl3, 125 MHz) δ 21.3, 30.5, 35.8, 37.4,
42.0, 55.3, 114.0, 120.0, 123.6, 125.0, 128.5, 129.5, 131.0, 138.4, 139.3,
148.9, 159.0, 185.2; IR (KBr) νmax/cm–1 1672; MS (ESI) m/z 421 [M–
Br]+. Anal. calcd for C22H18Br2N2O2: C, 52.62; H, 3.61; N, 5.58; found:
C, 52.51; H, 3.69; N, 5.54%.
2,2-Dibromo-3-(3,5-dimethoxyphenyl)-1′-phenyl-6′,7′-
dihydrospiro-[cyclopropane-1,5′-indazol]-4′(1′H)-one (3h): White
solid, yield 82%; m.p. 178–180 °C; 1H NMR (CDCl3, 500 MHz): δ 2.09
(ddd, J1 =14.0 Hz, J2 =4.5 Hz, J3 =2.0 Hz, 1H), 2.59 (ddd, J1 =14.0 Hz,
J2 =12.5 Hz, J3 =4.5 Hz, 1H), 2.94 (ddd, J1 =17.0 Hz, J2 =4.5 Hz,
J3 =2.0 Hz, 1H), 3.48 (ddd, J1 =17.0 Hz, J2 =12.5 Hz, J3 =4.5 Hz,
1H), 3.78 (s, 6H, –OCH3), 3.93 (s, 1H, HC‑3), 6.42 (s, 3H), 7.43–7.46
(m, 1H), 7.52–7.58 (m, 4H), 8.17 (s, 1H, HC‑3); 13C NMR (CDCl3,
125 MHz) δ 21.4, 30.7, 35.0, 38.2, 42.1, 55.4, 99.6, 107.8, 119.8, 123.6,
128.5, 129.5, 135.0, 138.4, 139.3, 148.9, 160.8, 185.0; IR (KBr) νmax/cm–1
1678; MS (ESI) m/z 451 [M–Br]+. Anal. calcd for C23H20Br2N2O3: C,
51.90; H, 3.79; N, 5.26; found: C, 51.74; H, 3.68; N, 5.29%.
2,2-Dibromo-1′-phenyl-3-(3,4,5-trimethoxyphenyl)-6′,7′-
dihydrospiro[cyclopropane-1,5′-indazol]-4′(1′H)-one (3i): White
solid, yield 88%; m.p. 184–186 °C; 1H NMR (CDCl3, 500 MHz): δ 2.06
(ddd, J1 =14.0 Hz, J2 =4.5 Hz, J3 =2.0 Hz, 1H), 2.59 (ddd, J1 =14.0 Hz,
J2 =12.5 Hz, J3 =4.5 Hz, 1H), 2.96 (ddd, J1 =17.0 Hz, J2 =4.5 Hz,
J3 =2.0 Hz, 1H), 3.48 (ddd, J1 =17.0 Hz, J2 =12.5 Hz, J3 =4.5 Hz, 1H),
3.84 (s, 3H, –OCH3), 3.84 (s, 6H, –OCH3), 3.92 (s, 1H, HC‑3), 6.47
(s, 2H), 7.43–7.46 (m, 1H), 7.51–7.58 (m, 4H), 8.17 (s, 1H, HC‑3);
13C NMR (CDCl3, 125 MHz) δ 21.4, 30.8, 35.2, 38.2, 42.1, 56.2, 60.9,
106.9, 119.8, 123.6, 128.3, 128.5, 129.5, 137.5, 138.3, 139.2, 148.9,
153.2, 185.1; IR (KBr) νmax/cm–1 1677; MS (ESI) m/z 481 [M–Br]+.
Anal. calcd for C24H22Br2N2O4: C, 51.27; H, 3.94; N, 4.98; found: C,
51.24; H, 3.78; N, 5.12%.
This research was supported by National Natural Science
Foundation of China (Nos. 21172065).
2,2-Dibromo-3-[4-(tert-butyl)phenyl]-1′-phenyl-6′,7′-dihydrospiro-
[cyclopropane-1,5′-indazol]-4′(1′H)-one (3e): White solid, yield
1
71%; m.p. 175–177 °C; H NMR (CDCl3, 500 MHz): δ 1.32 (s, 9H,
Received 20 May 2014; accepted 10 August 2014
Paper 1402667 doi: 10.3184/174751914X14102462623785
Published online: 25 September 2014
–C(CH3)3), 2.07 (ddd, J1 =14.0 Hz, J2 =4.5 Hz, J3 =2.0 Hz, 1H), 2.59
(ddd, J1 =14.0 Hz, J2 =12.5 Hz, J3 =4.5 Hz, 1H), 2.92 (ddd, J1 =17.0 Hz,
J2 =4.5 Hz, J3 =2.0 Hz, 1H), 3.47 (ddd, J1 =17.0 Hz, J2 =12.5 Hz,
J3 =4.5 Hz, 1H), 3.92 (s, 1H, HC‑3), 7.20 (d, J=8.0 Hz, 2H), 7.37 (d,
J=8.5 Hz, 2H), 7.43–7.46 (m, 1H), 7.52–7.58 (m, 4H), 8.18 (s, 1H,
HC‑3′); 13C NMR (CDCl3, 125 MHz) δ 21.3, 30.5, 31.3, 34.6, 35.6, 37.8,
42.0, 119.9, 123.6, 125.4, 128.4, 129.51, 129.52, 130.0, 138.4, 139.3,
148.9, 150.6, 185.2; IR (KBr) νmax/cm–1 1676; MS (ESI) m/z 447 [M–
Br]+. Anal. calcd for C25H24Br2N2O: C, 56.84; H, 4.58; N, 5.30; found:
C, 56.90; H, 4.39; N, 5.14%.
2,2-Dibromo-3-[4-(methylthio)phenyl]-1′-phenyl-6′,7′-dihydrospiro-
[cyclopropane-1,5′-indazol]-4′(1′H)-one (3f): White solid, yield
56%; m.p. 167–169 °C; 1H NMR (CDCl3, 500 MHz): 1.99 (ddd,
J1 =14.0 Hz, J2 =4.5 Hz, J3 =2.0 Hz, 1H), 2.47 (s, 1H, –SCH3), 2.56
(ddd, J1 =14.0 Hz, J2 =12.5 Hz, J3 =4.5 Hz, 1H), 2.90 (ddd, J1 =17.0 Hz,
J2 =4.5 Hz, J3 =2.0 Hz, 1H), 3.45 (ddd, J1 =17.0 Hz, J2 =12.5 Hz,
J3 =4.5 Hz, 1H), 3.89 (s, 1H, HC‑3), 7.17 (d, J=8.5 Hz, 2H), 7.21–7.25
(m, 2H), 7.41–7.45 (m, 1H), 7.50–7.57 (m, 4H), 8.16 (s, 1H, HC‑3′);
13C NMR (CDCl3, 125 MHz) δ 15.5, 21.3, 30.5, 35.3, 37.5, 42.1, 119.8,
123.6, 128.5, 129.5, 129.6, 130.3, 138.2, 138.4, 139.3, 148.8, 185.0;
IR (KBr) νmax/cm–1 1672; MS (ESI) m/z 437 [M–Br]+. Anal. calcd for
C22H18Br2N2OS: C, 50.98; H, 3.50; N, 5.41; found: C, 50.78; H, 3.63; N,
5.31%.
References
1
2
3
4
D.Y.K. Chen, R.H. Pouwer and J.A. Richard, Chem. Soc. Rev., 2012, 41,
4631.
L.N. Wang, J.Z. Zhang, X. Li, X.N. Wang, C.F. Xie, J.C. Zhou and H.X.
Lou, Org. Lett., 2012, 14, 1102.
S. Gomi, D. Ikeda, H. Nakamura, H. Naganawa, F. Yamashita, K. Hotta, S.
Kondo, Y. Okami, H. Umezawa and Y. Iitaka, J. Antibiot., 1984, 37, 1491.
H. Niwa, K. Wakamatsu and K. Yamada, Tetrahedron Lett., 1989, 30,
4543.
5
6
7
J. Pietruszka, Chem. Rev., 2003, 103, 1051.
G. Kumaraswamy and M. Padmaja, J. Org. Chem., 2008, 73, 5198.
V.A. D’yakonov, O.A. Trapeznikova, A. Meijere and U.M. Dzhemilev,
Chem. Rev., 2014, doi:10.1021/cr400291c.
8
9
C.M.R. Volla, I. Atodiresei and M. Rueping, Chem. Rev., 2014, 114, 2390.
J.S. Alford and H.M.L. Davies, Org. Lett., 2012, 14, 6020.
10 C.J. Thibodeaux, W.C. Chang and H.W. Liu, Chem. Rev., 2012, 112, 1681.
11 H. Lebel, J.F. Marcoux, C. Molinaro and A.B. Charette, Chem. Rev., 2003,
103, 977.
12 E. Gopi and I.N.N. Namboothiri, J. Org. Chem., 2013, 78, 910.
13 J.C. Lien, F.Y. Lee, L.J. Huang, S.L. Pan, J.H. Guh, C.M. Teng and S.C.
Kuo, J. Med. Chem., 2002, 45, 4947.
2,2-Dibromo-3-(4-methoxyphenyl)-1′-phenyl-6′,7′-dihydrospiro-
[cyclopropane-1,5′-indazol]-4′(1′H)-one (3g): White solid, yield
75%; m.p. 158–160 °C; 1H NMR (CDCl3, 500 MHz): δ 2.00 (ddd,
J1 =14.0 Hz, J2 =4.5 Hz, J3 =2.0 Hz, 1H), 2.56 (ddd, J1 =14.0 Hz,
J2 =12.5 Hz, J3 =4.5 Hz, 1H), 2.90 (ddd, J1 =17.0 Hz, J2 =4.5 Hz,
J3 =2.0 Hz, 1H), 3.45 (ddd, J1 =17.0 Hz, J2 =12.5 Hz, J3 =4.5 Hz, 1H),
3.79 (s, 3H, –OCH3), 3.79 (s, 1H, HC‑3), 6.88 (d, J=9.0 Hz, 2H), 7.18
(d, J=8.0 Hz, 2H), 7.43 (t, J=7.5 Hz, 1H), 7.50–7.57 (m, 4H), 8.16
14 M. Boehringer, H.J. Boehm, D. Bur, H. Gmuender, W. Huber, W. Klaus,
D. Kostrewa, H. Kuehne, T. Luebbers, N. Meunier‑Keller and Mueller, F.
J. Med. Chem., 2000, 43, 2664.
15 H. Cerecetto, A. Gerpe, M. Gonzalez, V.J. Aran and C.O. de Ocariz, Mini-
Rev. Med. Chem., 2005, 5, 869.
16 P. Schenone, L. Mosti and G. Menozzi. J. Heterocyclic Chem., 1982, 19,
1355.
17 L. Mosti, L. Sansebastiano, P. Fossa, P. Schenone and F. Mattioli, Farmaco,
1992, 47, 357.
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