Silver-catalyzed [3+2]-cycloaddition of benzynes with diazocarbonyl species via a postulated (1H-indazol-1-yl)silver intermediate

Article abstract of DOI:10.1039/c2ob26760h

We reported a new synthesis of 2-aryl-2H-indazoles via a silver-catalyzed [3+2]-cycloaddition of benzynes with diazocarbonyl reagents. We postulate that this transformation involves the generation of (1H-indazol-1-yl)silver to activate a subsequent arylation with the second benzyne.

Full text of DOI:10.1039/c2ob26760h

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COMMUNICATION
Silver-catalyzed [3+2]-cycloaddition of benzynes with diazocarbonyl species
via a postulated (1H-indazol-1-yl)silver intermediate†
Chiou-Dong Wang and Rai-Shung Liu*
Received 7th September 2012, Accepted 4th October 2012
DOI: 10.1039/c2ob26760h
We reported a new synthesis of 2-aryl-2H-indazoles via a
silver-catalyzed [3+2]-cycloaddition of benzynes with diazo-
carbonyl reagents. We postulate that this transformation
involves the generation of (1H-indazol-1-yl)silver to activate
a subsequent arylation with the second benzyne.
Introduction
The synthesis of indazole derivatives has attracted considerable
Scheme 2 Reaction protocols in the presence or absence of Ag+.
attention because many naturally occurring compounds possess
such a motif1 including nigellicine,1b,c nigeglanine,1d and nigel-
lidine,1e as shown in Scheme 1. More importantly, indazole
derivatives have found widespread applications in pharmaceuti-
cals because of their potent bioactivities2 such as anti-cancer,3,5
HIV protease inhibition4 and anti-platelet activities.6
III.10,11 In this work, we assess the presence of Ag(I) ions to
affect intermediate B, giving distinct 2-phenylindazole species
IV. We postulate that the change of reaction chemoselectivity is
attributed to the formation of (1H-indazol-1yl)silver C via an
interception of initial intermediate B.
Among the reported syntheses of indazole derivatives,7–11
[3+2]-cycloadditions of benzynes with diazocarbonyl
reagents9–11 appear to be appealing and efficient because of their
convenient operations under mild conditions; general reaction
protocols are provided in Scheme 2. For α-substituted diazocar-
bonyl esters, their reactions with benzynes afforded 2-acylinda-
zole products I via a 1,2-acyl shift of intermediates A.9f For
unsubstituted diazo species, their resulting intermediates B
underwent a 1,3-hydrogen shift to give indazole species II that
further reacted with benzyne to give 1-phenylindazole products
Results and discussion
Shown in Table 1 is the effect of metal ions on the [3+2]-
cycloadditions of diazocarbonyl species 1a with benzyne precur-
sor 2a.12 Our initial goal is to study the feasibility of gold–
benzyne species toward a nucleophilic attack of a diazo species
1a. As shown in entry 1, the treatment of diazo species 1a with
benzyne precursor 2a (2.2 equiv.), tetrabutylammonium fluoride
(TBAF, 3 equiv.) and PPh3AuOTf (5 mol%) in dichloromethane
(DCM, 25 °C, 10 h) gave 2-phenylindazole 3a in 40% yield,
together with unreacted diazo 1a in 25% yield. Under the same
conditions, the use of AgSbF6 and AgOTf, each at 5 mol%, gave
2-phenylindazole 3a in increased yields of 55% and 72%
respectively (entries 2 and 3). For AgOTf, an increasing pro-
portion of species 2a (3 equiv.) and TBAF (4 equiv.) enabled a
complete conversion of starting diazo species 1a into 2-phenyl-
indazole 3a with the yield of up to 80%. With these reagent pro-
portions, both CuBr and Cu(OTf)2 showed poor
chemoselectivities (entries 5 and 6), giving 1- and 2-phenylinda-
zoles 5a (50–60%) and 3a (5–10%) in addition to unsubstituted
indazole 4a13 (30%). For other solvents (entries 7–10), the reac-
tions with an AgOTf catalyst proceeded also efficiently in
Scheme 1 Selected naturally occurring compounds.
Department of Chemistry, National Tsing-Hua University, Hsinchu,
Taiwan, ROC. E-mail: rsliu@mx.nthu.edu.tw; Fax: +88635711082;
Tel: +88635721424
†Electronic supplementary information (ESI) available. CCDC 900208.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c2ob26760h
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Table 1 Effects of metal on reaction chemoselectivity
Table 2 Reactions over various α-carbonyldiazo speciesa,b
Time Compoundsc
Entry
1
n
m
Catalystb
Solvent (h)
(yield, %)
2.2
3
AuClPPh3/ DCM
AgOTf
10
1a (25), 3a (40)
2
3
4
5
6
7
8
9
2.2
2.2
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
AgSbF6
AgOTf
AgOTf
CuBr
DCM
DCM
DCM
DCM
10
10
4
4
4
10
4
4
1a (17), 3a (55)
1a (15), 3a (72)
3a (80)
3a (5), 4a (30), 5a (60)
3a (10), 4a (30), 5a (50)
1a (15), 3a (42)
3a (65), 5a (12)
3a (74)
Cu(OTf)2 DCM
AgOTf
AgOTf
AgOTf
—
DCE
THF
CH3CN
THF
10
4
4a (32), 5a (45%)
a [1a] = 0.1 M. b 5 mole%. c Product yields are reported after separation
from a silica column. d TBAF = 1.0 M solution in THF.
a [1] = 0.1 M. b Product yields are reported after separation from a silica
column.
Table 3 Reactions with various benzyne precursorsa,b
Fig. 1 ORTEP drawing of compound 3a.
Entry
Benzyne
Compounds (yields, %)
1
2
3
4
5
R = Me (2b)
R, R = –(CH2)3– (2c)
R = F (2d)
R = Cl (2e)
R = OMe (2f)
6b (76%)
6c (72%)
6d (70%)
6e (82%)
CH3CN (74% 3a), but less satisfactorily in dichloroethane (42%
3a) and THF (65% 3a). In the absence of a catalyst, we only
obtained 3-carbonylindazole 4a (32%) and 1-phenyl-3-carbonyl-
indazole species 5a (45%), consistent with Yamamoto’s obser-
Complicated mixture
vation.11
The
molecular
structure
of
2-phenyl-3-
a [1] = 0.1 M, 2 (3 equiv.). b Product yields are reported after separation
from a silica column.
carbonylindazole 3a was confirmed by an X-ray diffraction
study;14 its ORTEP drawing is shown in Fig. 1. Compound 3a
showed 1H NMR resonances within 7.0–8.0 ppm whereas its
regioisomer 5a exhibited two doublets in downfield regions
(8.3–8.6 ppm).
2-phenyl-3-carbonylindazoles 3h–3k in 49–62% yields (entries
7–10). We also tested the reaction on 2-indolylketone diazo
species 1l (entry 11) that gave desired 2-phenyl-3-carbonylinda-
zole 3l in 46% yield. This reaction also worked for an alkeny-
lketone diazo derivative, producing 2-phenylindazole 3m in 44%
yield (entry 12).
Table 3 shows the results for the silver-catalyzed reactions of
diazo species 1c with various o-(trimethylsilyl)aryl triflates 2b–
2f under the same conditions. For precursors 2b and 2c, their
corresponding 2-phenyl-3-carbonylindazoles 6b and 6c were
obtained in 76% and 72% yields respectively (entries 1 and 2).
The reactions worked well for precursors bearing difluoro- and
We prepared various diazocarbonyl species 1b–1m to test the
scopes of diazo reagents; the results are depicted in Table 2.
Herein, resulting products 3b–3m showed 1H NMR patterns
resembling those of parent analogue 3a. Entries 1–6 show the
applicability of this silver-catalyzed reaction to diazo substrates
1b–1g bearing either an electron-rich or -deficient phenyl substi-
tuient (R = tert-butyl, methoxy, fluoro, chloro, bromo and
thifluoromethyl), giving expected 2-phenyl-3-carbonylindazoles
3b–3g in 72–95% yields. We also prepared heteroaryl ketone
diazo species 1h–1k including 1- or 2-furanyl and -thienyl sub-
stituents; their silver catalytic reactions with benzynes afforded
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Conclusions
In summary, we have developed a new approach toward the syn-
thesis of 2-aryl-2H-3-carbonylindazole with the use of AgOTf.
This reaction shows distinct chemoselectivity from those
reported earlier by Yamamoto et al.11 We postulate that the role
of the Ag(+) ion is to intercept the initially formed 3-acyl-3H-
indazole intermediate under the action of fluoride; this process is
postulated to give (1H-indazol-1-yl)silver C. Further application
of this work toward the synthesis of bioactive molecules is under
current investigation.
Experimental
Scheme 3 Effects of fluorides and AgOTf.
General methods
Unless otherwise noted, all reactions were carried out under a
nitrogen atmosphere in oven-dried glassware using a standard
syringe, a cannula and a septa apparatus. Tetrahydrofuran and
hexane were dried with sodium benzophenone and distilled
before use. Dichloromethane, 1,2-dichloroethane and acetonitrile
were dried over CaH2 and distilled before use. 1H NMR and 13
C
NMR spectra were recorded on varian 400 MHz and Bruker
400 MHz spectrometers using CDCl3 as the internal standard.
Synthesis of phenyl(2-phenyl-2H-indazol-3-yl)methanone
(3a). To a dichloromethane solution (1.4 mL) of AgOTf
(4.39 mg, 5 mol%) was added a DCM solution (1 mL) of
2-diazo-1-phenylethanone (1a, 50 mg, 0.34 mmol) and 2-(tri-
methylsilyl)-phenyltrifluoromethanesulfonate (2a, 306 mg,
1.02 mmol); the mixture was stirred briefly for 5 min before it
was added to a dichloromethane solution (1 mL) of TBAF
(1.37 mL, 1 M in THF) via a syringe pump over a period of 4 h.
The mixture was stirred for an additional 0.5 h before it was con-
centrated and eluted through a silica column (hexane–EA =
30 : 1) to afford compound 3a (81 mg, 80%) as a white solid;
Scheme 4 A plausible reaction route.
dichloro groups, giving desired 2-phenyl-3-carbonylindazoles 6d
and 6e in satisfactory yields. In contrast, the reaction was not
compatible with electron-rich benzyne like species 2f, leading to
products with complicated mixtures.
Shown in Scheme 3 are our efforts to improve the chemoselec-
tivity of diazo ester species 1n; this process may enable us to
understand the reaction mechanism. Treatment of starting 1n
with benzyne precursor 2a (3 equiv.), TBAF (4 equiv.) and
AgOTf (5 mol%) in DCM (25 °C, 4 h) gave a mixture of 2- and
1-phenyl-3carbonylindazoles 3n and 5n (83%, 3n : 5n = 4 : 1).
The use of a high AgOTf loading (10 mol%) increased the
3n : 5n ratio to 5 : 1 (entry 2), compatible with our expectation.
On the other hand, an increased amount of TBAF (5 equiv.,
entry 3) assisted also the production of desired 2-phenyl-3-car-
1
mp: 163–165 °C; IR (neat, cm−1): 3172, 1660, 1593, 765; H
NMR (400 MHz, CDCl3): δ 7.88–7.84 (m, 3 H), 7.61–7.56 (m,
1 H), 7.53–7.51 (m, 2 H), 7.46–7.34 (m, 7 H), 7.18–7.14 (m,
1 H); 13C NMR (100 MHz, CDCl3): δ 185.8, 148.4, 140.4,
137.7, 133.4, 132.1, 129.8, 128.9, 128.8, 128.5, 126.9, 125.4,
124.9, 123.9, 120.5, 118.4; HRMS calcd for C20H14N2O:
298.1106, found: 298.1104.
bonylindazole 3n with 3n : 5n
=
4.3 : 1. Accordingly,
increasing loadings of TBAF and AgOTf are helpful to produce
desired 3a.
Spectral data for (4-tert-butylphenyl)(2-phenyl-2H-indazol-3-
yl)methanone (3b). White solid; mp: 124–125.7 °C; IR (neat,
1
cm−1): 3170, 1658, 1587, 834; H NMR (400 MHz, CDCl3): δ
Scheme 4 shows a plausible mechanism to account for the
effect of Ag+ and fluoride on the reaction chemoselectivity. The
initial [3+2]-cycloaddition reaction between diazo species 1a
and benzyne presumably produced 3-acyl-3H-indazole B. In the
absence of Ag(I), this species will undergo a slow 1,3-hydrogen
shift to give 3-carbonyl-indazole 4a that further reacts with
benzyne to give 1-phenyl-3-carbonylindazole 5a. We postulate
that species B is quite acidic and readily deprotonated by
fluoride to give a carbonyl-stabilized anion D that can be trapped
by Ag(I) to give (1H-indazol-1-yl)silver C. Its reaction with
benzyne is expected to form distinct arylation product 3a.
Accordingly, formation of compound 3a is highly dependent on
the concentration of both fluoride and Ag(I) ions, consistent with
our observation in Scheme 3.
7.86 (d, J = 8.8 Hz, 1 H), 7.83–7.80 (m, 2 H), 7.52–7.50 (m,
2 H), 7.47–7.44 (m, 2 H), 7.42–7.34 (m, 5 H), 7.19–7.15 (m,
1 H), 1.34 (s, 9 H); 13C NMR (100 MHz, CDCl3): δ 185.5,
157.5, 148.4, 140.4, 134.9, 132.4, 129.9, 128.9, 128.6, 126.8,
125.5, 125.3, 124.6, 123.7, 120.5, 118.3, 35.1, 30.9; HRMS
calcd for C24H22N2O: 354.1732, found: 354.1730.
Spectral data for (4-methoxyphenyl)(2-phenyl-2H-indazol-3-
yl)methanone (3c). Yellow solid; mp: 126.6–128.2 °C; IR (neat,
1
cm−1): 3152, 1643, 1552, 841; H NMR (400 MHz, CDCl3):
δ 7.88 (d, J = 8.8 Hz, 2 H), 7.85 (d, J = 8.8 Hz, 1 H), 7.54–7.51
(m, 2 H), 7.43–7.34 (m, 5 H), 7.15 (dd, J = 6.8, 7.6 Hz, 1 H),
6.93 (d, J = 8.8 Hz, 2 H), 3.87 (s, 3 H); 13C NMR (100 MHz,
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CDCl3): δ 184.5, 164.0, 148.3, 140.3, 132.4, 132.3, 130.3,
128.9, 128.6, 126.8, 125.2, 124.4, 123.6, 120.4, 118.2, 113.8,
55.4; HRMS calcd for C21H16N2O2: 328.1212, found: 328.1211.
δ 178.6, 149.7, 148.5, 144.3, 140.2, 132.7, 129.0, 128.9, 127.8,
127.0, 125.3, 124.8, 123.2, 120.1, 118.4, 109.4; HRMS calcd
for C18H12N2O2: 288.0899, found: 288.0893.
Spectral data for (4-fluorophenyl)(2-phenyl-2H-indazol-3-yl)-
methanone (3d). White solid; mp: 198–202 °C; IR (neat, cm−1):
3144, 1650, 1493, 1222, 830; 1H NMR (400 MHz, CDCl3):
δ 7.89–7.86 (m, 3 H), 7.52–7.49 (m, 2 H), 7.44–7.36 (m, 5 H),
7.21–7.17 (m, 1 H), 7.13–7.09, (m, 2 H); 13C NMR (100 MHz,
CDCl3): δ 184.3, 165.9 (d, J = 255 Hz), 148.5, 140.3, 134.0 (d,
J = 3 Hz), 132.5 (d, J = 10 Hz), 131.9, 129.0, 128.9, 127.0,
125.4, 125.1, 123.9, 120.3, 118.5, 115.8 (d, J = 22 Hz); HRMS
calcd for C20H13FN2O2: 316.1012, found: 316.1014.
Spectral data for (2-phenyl-2H-indazol-3-yl)(thiophen-2-yl)-
methanone (3j). Yellow solid; mp: 175.3–176 °C; IR (neat,
1
cm−1): 1658, 1573, 1524, 748; H NMR (400 MHz, CDCl3):
δ 7.86 (d, J = 8.8 Hz, 1 H), 7.76–7.74 (m, 1 H), 7.65–7.63 (m,
2 H), 7.61–7.54 (m, 2 H), 7.45–7.36 (m, 4 H), 7.23–7.19 (m,
1 H), 7.12–7.10 (m, 1 H); 13C NMR (100 MHz, CDCl3):
δ 177.8, 148.5, 144.1, 140.2, 135.5, 135.4, 132.0, 129.1, 128.9,
128.2, 127.0, 125.3, 124.8, 123.4, 120.3, 118.4; HRMS calcd
for C18H12N2OS: 304.0670, found: 304.0673.
Spectral data for (4-chlorophenyl)(2-phenyl-2H-indazol-3-yl)-
methanone (3e). Yellow solid; mp: 181.5–185.3 °C; IR (neat,
cm−1): 3180, 1673, 1590, 1094, 862; 1H NMR (400 MHz,
CDCl3): δ 7.87 (dd, J = 0.8, 8.8 Hz, 1 H), 7.80–7.77 (m, 2 H),
7.51–7.49 (m, 2 H), 7.43–7.35 (m, 5 H), 7.38–7.35 (m, 2 H),
7.21–7.17 (m, 1 H); 13C NMR (100 MHz, CDCl3): δ 184.5,
148.5, 140.2, 139.9, 136.0, 131.7, 131.1, 129.0, 128.9, 128.9,
127.0, 125.4, 125.2, 123.9, 120.2, 118.5; HRMS calcd for
C20H13ClN2O: 332.0716, found: 332.0118.
Spectral data for (2-phenyl-2H-indazol-3-yl)(thiophen-3-yl)-
methanone (3k). Yellow solid; mp: 155.7–157.4 °C; IR (neat,
1
cm−1): 1660, 1569, 1520, 752; H NMR (400 MHz, CDCl3):
δ 7.99 (dd, J = 1.2, 2.8 Hz, 1 H), 7.86 (d, J = 8.8 Hz, 1 H),
7.55–7.52 (m, 4 H), 7.44–31 (m, 5 H), 7.21–7.17 (m, 1 H); 13C
NMR (100 MHz, CDCl3): δ 179.1, 148.4, 142.0, 140.3, 135.0,
132.7, 129.0, 128.8, 127.7, 126.9, 126.6, 125.3, 124.8, 123.5,
120.3, 118.4; HRMS calcd for C18H12N2OS: 304.0670, found:
304.0671.
Spectral data for (4-bromophenyl)(2-phenyl-2H-indazol-3-yl)-
methanone (3f). Yellow solid; mp: 155–160.8 °C; IR (neat,
cm−1): 3164, 1669, 1573, 1067, 870; 1H NMR (400 MHz,
CDCl3): δ 7.87 (d, J = 8.8 Hz, 1 H), 7.73–7.70 (m, 2 H),
7.60–7.57 (m, 2 H), 7.51–7.48 (m, 1 H), 7.44–7.35 (m, 5 H),
7.21–7.17 (m, 1 H); 13C NMR (100 MHz, CDCl3): δ 184.6,
148.4, 140.2, 136.4, 131.9, 131.6, 131.2, 129.0, 128.9, 128.7,
127.0, 125.4, 125.2, 123.9, 120.2, 118.5; HRMS calcd for
C20H13BrN2O: 376.0211, found: 376.0210.
Spectral data for (1-methyl-1H-indol-2-yl)(2-phenyl-2H-
indazol-3-yl)methanone (3l). Yellow solid; mp: 175–178.7 °C;
IR (neat, cm−1): 3161, 1655, 1622, 1585, 763; 1H NMR
(400 MHz, CDCl3): δ 7.86 (d, J = 8.8 Hz, 1 H), 7.67–7.58 (m, 4
H), 7.47–7.36 (m, 6 H), 7.25 (s, 1 H), 7.20–7.14 (m, 2 H), 4.09
(s, 3 H); 13C NMR (100 MHz, CDCl3): δ 177.2, 148.4, 140.9,
140.5, 135.6, 133.2, 129.1, 128.8, 126.9, 126.7, 125.8, 125.2,
124.5, 123.6, 123.3, 121.0, 120.8, 118.2, 116.0, 110.4, 31.9;
HRMS calcd for C23H17N3O: 351.1372, found: 351.1366.
Spectral data for (2-phenyl-2H-indazol-3-yl)(4-(trifluoro-
Spectral data for (E)-3-phenyl-1-(2-phenyl-2H-indazol-3-yl)
prop-2-en-1-one (3m). Yellow oil; IR (neat, cm−1): 3174, 3062,
1680, 1554, 752; H NMR (400 MHz, CDCl3): δ 8.05 (dd, J =
0.8, 8.8 Hz, 1 H), 7.87 (dd, J = 0.8, 8.8 Hz, 1 H), 7.72 (d, J =
16 Hz, 1 H), 7.60–7.50 (m, 5 H), 7.44–7.32 (m, 7 H), 6.99 (d,
J = 16 Hz, 1 H); 13C NMR (100 MHz, CDCl3): δ 181.4, 148.6,
144.5, 140.8, 134.3, 133.8, 130.8, 129.4, 129.2, 128.9, 128.4,
127.2, 126.1, 125.6, 124.8, 123.8, 120.9, 118.6; HRMS calcd
for C22H16N2O: 324.1263, found: 324.1268.
methyl)phenyl)methanone
(3g). White
solid;
mp:
154.3–156.6 °C; IR (neat, cm−1): 3189, 1694, 1592, 1325, 854;
1H NMR (400 MHz, CDCl3): δ 7.91 (t, J = 8 Hz, 3 H), 7.68 (d,
J = 8.4 Hz, 2 H), 7.05–7.48 (m, 2 H), 7.42–34 (m, 5 H),
7.23–7.20 (m, 1 H); 13C NMR (100 MHz, CDCl3): δ 184.5,
148.6, 140.7, 140.3, 134.5 (d, J = 33 Hz), 131.5, 130.0, 129.1,
129.1, 127.2, 125.6, 125.6, 125.5, 124.2, 123.4 (d, J = 271 Hz),
120.2, 118.7; HRMS calcd for C21H13F3N2O: 366.0980, found:
366.0985.
1
Spectral data for (2-(3,4-dimethylphenyl)-5,6-dimethyl-2H-
indazol-3-yl)(4-methoxyphenyl)methanone (6b). White solid;
Spectral data for furan-2-yl(2-phenyl-2H-indazol-3-yl)metha-
none (3h). Yellow solid; mp: 138–140.5 °C; IR (neat, cm−1):
1
mp: 135–136.7 °C; IR (neat, cm−1): 3159, 1658, 1579, 852; H
1
1650, 1592, 764; H NMR (400 MHz, CDCl3): δ 7.86 (d, J =
NMR (400 MHz, CDCl3): δ 7.87 (d, J = 8.8 Hz, 2 H), 7.58 (s,
1 H), 7.33 (d, J = 2.4 Hz, 1 H), 7.15–7.08 (m, 3 H), 6.92 (d, J =
8.8 Hz, 2 H), 3.87 (s, 3 H), 2.37 (s, 3 H), 2.25 (s, 3 H), 2.24 (s,
6 H); 13C NMR (100 MHz, CDCl3): δ 184.8, 163.9, 148.1,
138.3, 137.5, 137.1, 137.1, 134.7, 132.4, 131.3, 130.7, 129.9,
126.1, 122.8, 122.5, 118.9, 116.9, 113.8, 55.5, 20.8, 20.6, 19.7,
19.4; HRMS calcd for C25H24N2O2: 384.1838, found: 384.1840.
8.4 Hz, 1 H), 7.69 (d, J = 8.4 Hz, 1 H), 7.55 (s, 1 H), 7.54 (d,
J = 8 Hz, 2 H), 7.43–7.35 (m, 4 H), 7.25–7.19 (m, 2 H), 6.51
(dd, J = 1.6, 3.6 Hz, 1 H); 13C NMR (100 MHz, CDCl3):
δ 172.5, 152.1, 148.5, 147.5, 140.4, 131.5, 129.0, 128.7, 127.0,
125.1, 124.9, 123.7, 120.9, 120.3, 118.3, 112.6; HRMS calcd
for C18H12N2O2: 288.0899, found: 288.0892.
Spectral data for furan-3-yl(2-phenyl-2H-indazol-3-yl)metha-
none (3i). Yellow solid; mp: 170–173 °C; IR (neat, cm−1): 1662,
1587, 772; H NMR (400 MHz, CDCl3): δ 7.90 (d, J = 0.8 Hz,
1 H), 7.84 (d, J = 8.8 Hz, 1 H), 7.66 (d, J = 8.8 Hz, 1 H),
7.54–7.51 (m, 2 H), 7.45–7.34 (m, 5 H), 7.23–7.19 (m, 1 H),
6.81 (d, J = 0.8 Hz, 1 H); 13C NMR (100 MHz, CDCl3):
Spectral data for (2-(2,3-dihydro-1H-inden-5-yl)-2,5,6,7-tetra-
hydrocyclopenta[f]indazol-3-yl)(4-methoxyphenyl)methanone
(6c). White solid; mp: 164.2–166 °C; IR (neat, cm−1): 3168,
1651, 1568, 849; H NMR (400 MHz, CDCl3): δ 7.88 (d, J =
8.8 Hz, 2 H), 7.60 (s, 1 H), 7.37 (s, 1 H), 7.18 (s, 2 H), 7.12 (s,
1
1
1 H), 6.93 (d, J = 8.8 Hz, 2 H), 2.97 (dt, J = 0.8, 7.2 Hz, 2 H),
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2.90–2.84 (m, 6 H), 2.10–2.03 (m, 4 H); 13C NMR (100 MHz,
CDCl3): δ 184.9, 163.8, 148.7, 145.2, 145.1, 144.7, 142.7,
138.9, 132.4, 131.5, 130.8, 124.4, 123.5, 123.2, 121.2, 113.8,
113.8, 112.0, 55.5, 32.7, 32.6, 32.5, 32.4, 26.4, 25.5; HRMS
calcd for C27H24N2O2: 408.1838, found: 408.1840.
128.4, 127.9, 127.5, 126.3, 124.4, 123.8, 123.7, 122.4, 110.8,
66.7; HRMS calcd for C21H16N2O2: 328.1212, found: 328.1215.
Acknowledgements
Spectral data for (2-(3,4-difluorophenyl)-5,6-difluoro-2H-
indazol-3-yl)(4-methoxyphenyl)methanone (6d). White solid;
mp: 110–112.3 °C; IR (neat, cm−1): 3147, 1666, 1579, 1231,
We thank National Science Council and Education of Ministry,
Taiwan, for financial support of this work.
1
855; H NMR (400 MHz, CDCl3): δ 7.82 (d, J = 8.8 Hz, 2 H),
7.52 (dd, J = 6.4, 9.6 Hz, 1 H), 7.44–7.39 (m, 1 H), 7.21–7.17
(m, 2 H), 7.07 (dd, J = 8.0, 10 Hz, 1 H), 6.96 (d, J = 8.8 Hz, 2
H), 3.89 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ 183.6, 164.6,
153.4–148.7 (m, 4C), 144.5 (d, J = 11 Hz), 136.2 (dd, J = 3,
8 Hz), 133.3 (d, J = 6 Hz), 132.3, 129.6, 121.4 (dd, J = 4, 6 Hz),
119.3(d, J = 20 Hz), 117.5 (d, J = 18 Hz), 115.0 (d, 20 Hz),
114.3, 105.7 (dd, J = 1, 22 Hz), 104.1 (dd, J = 1, 22 Hz), 55.6;
HRMS calcd for C21H12F4N2O2: 400.0835, found: 400.0837.
Notes and references
1 (a) A. Schmidt, Adv. Heterocycl. Chem., 2003, 85, 67; (b) Atta-ur-
Rahman, S. Malik, H. Cun-heng and J. Clardy, Tetrahedron Lett., 1985,
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J. Clardy, Tetrahedron Lett., 1995, 36, 1993.
2 S. Brase, C. Gil and K. Knepper, Bioorg. Med. Chem., 2002, 10, 2415.
3 M. De Lena, V. Lorusso, A. Latorre, G. Fanizza, G. Gargano,
L. Caporusso, M. Guida, A. Catino, E. Crucitta, D. Sambiasi and
A. Mazzei, Eur. J. Cancer, 2001, 37, 364.
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J. Org. Chem., 1997, 62, 5627; (b) J. D. Rodgers, B. L. Johnson,
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5 B. K. Keppler and M. Hartmann, Met.-Based Drugs, 1994, 1, 145.
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7 Earlier examples: (a) J. Elguero, in Comprehensive Heterocyclic Chem-
istry, ed. A. R. Katritzky and C. W. Rees, Pergamon, New York, 1984,
vol. 5, p. 167; (b) E. G. Kovach and D. E. Barnes, J. Am. Chem. Soc.,
1954, 76, 1176.
Spectral data for (5,6-dichloro-2-(3,4-dichlorophenyl)-2H-
indazol-3-yl)(4-methoxyphenyl)methanone (6e). White solid;
mp: 153–156.2 °C; IR (neat, cm−1): 3168, 1672, 1598, 1089,
1
858; H NMR (400 MHz, CDCl3): δ 7.96 (s, 1 H), 7.83 (d, J =
8.0 Hz, 2 H), 7.69 (dd, J = 0.8, 2.4 Hz, 1 H), 7.50 (s, 1 H), 7.47
(dd, J = 0.8, 8.8 Hz, 1 H), 7.32–7.29 (m, 1 H), 6.98 (d, J = 8.0
Hz, 2 H), 3.91 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ 183.4,
164.8, 147.0, 139.0, 133.6, 133.4, 132.5, 132.5, 132.4, 130.7,
129.9, 129.6, 127.1, 124.3, 122.4, 121.2, 119.4, 114.4, 55.7;
HRMS calcd for C21H12Cl4N2O2: 463.9643, found: 463.9645.
Spectral data for (1H-indazol-3-yl)(phenyl)methanone
(4a). White solid; mp: 188.3–191 °C; IR (neat, cm−1): 3182,
1628, 1492, 740; H NMR (400 MHz, CDCl3): δ 8.45 (d, J =
8.0 Hz, 1 H), 8.27 (dd, J = 0.8, 8.0 Hz, 2 H), 7.61–7.34 (m,
6 H); 13C NMR (100 MHz, CDCl3): δ 189.1, 140.7, 137.8,
132.5, 130.3, 128.1, 128.0, 127.6, 123.7, 123.4, 122.9, 109.8;
HRMS calcd for C14H10N2O: 222.0793, found: 222.0795.
8 Select recently examples: (a) P. Li, C. Wu, J. Zhao, D. C. Rogness and
F. Shi, J. Org. Chem., 2012, 77, 3149; (b) Y. Fang, C. Wu, R. C. Larock
and F. Shi, J. Org. Chem., 2011, 76, 8840; (c) M. R. Kumar, A. Park,
N. Park and S. Lee, Org. Lett., 2011, 13, 3542; (d) P. Li, J. Zhao, C. Wu,
R. C. Larock and F. Shi, Org. Lett., 2011, 13, 3340; (e) C. Li, T. Zhang,
Z. Zeng, X. Liu, Y. Zhao, B. Zhang and Y. Feng, Org. Lett., 2012, 14, 47;
(f) C. Wu, Y. Fang, R. C. Larock and F. Shi, Org. Lett., 2010, 12, 2234.
9 (a) R. Huisgen and R. Knorr, Naturwissenschaften, 1961, 48, 716;
(b) W. Reid and M. Schőn, Ann. Chem., 1965, 869, 141; (c) G. Baum,
R. Bernard and H. Shechter, J. Am. Chem. Soc., 1967, 89, 5307;
(d) G. Baum and H. Shechter, J. Org. Chem., 1976, 41, 2120;
(e) T. Yamazaki and H. Shechter, Tetrahedron Lett., 1972, 13, 4533;
(f) T. Yamazaki, G. Baum and H. Shechter, Tetrahedron Lett., 1974, 15,
4421.
10 Z. Liu, F. Shi, P. D. G. Martinez, C. Raminelli and R. C. Larock, J. Org.
Chem., 2008, 73, 219.
11 (a) T. Jin and Y. Yamamoto, Angew. Chem., Int. Ed., 2007, 46, 3323;
(b) T. Jin, F. Yang and Y. Yamamoto, Collect. Czech. Chem. Commun.,
2009, 74, 957.
12 See selected examples: (a) Y. Hemishima, T. Sonoda and H. Kobayashi,
Chem. Lett., 1983, 1211; (b) C. Raminelli, Z. Liu and R. C. Larock,
J. Org. Chem., 2006, 71, 4689; (c) Z. Liu, X. Zhang and R. C. Larock,
J. Am. Chem. Soc., 2005, 127, 15716; (d) Z. Liu and R. C. Larock,
J. Am. Chem. Soc., 2005, 127, 13112; (e) J. Zhao and R. C. Larock, Org.
Lett., 2005, 7, 4273; (f) Z. Liu and R. C. Larock, J. Org. Chem., 2006,
71, 3198; (g) D. C. Rogness, N. A. Markina, J. P. Waldo and
R. C. Larock, J. Org. Chem., 2012, 77, 2743; (h) C. Lu,
A. V. Dubrovskiy and R. C. Larock, J. Org. Chem., 2012, 77, 2279;
(i) G. Chai, Y. Qiu, C. Fu and S. Ma, Org. Lett., 2011, 13, 5196.
13 C. Francois, S. Silvia, L. Remi, C. Valerie and R. Sylvain, Tetrahedron,
2007, 63, 419.
1
Spectral data for phenyl(1-phenyl-1H-indazol-3-yl)methanone
(5a). White solid; mp: 142.5–145.1 °C; IR (neat, cm−1): 3179,
1
1642, 1580, 735; H NMR (400 MHz, CDCl3): δ 8.56 (d, J =
8.4 Hz, 1 H), 8.42 (d, J = 8.4 Hz, 2 H), 7.78–7.76 (m, 3 H),
7.61–7.40 (m, 8 H); 13C NMR (100 MHz, CDCl3): δ 188.5,
143.4, 139.8, 139.4, 137.7, 132.5, 130.6, 129.5, 128.1, 127.8,
127.7, 125.4, 124.1, 123.4, 123.4, 110.6; HRMS calcd for
C20H14N2O: 298.1106, found: 298.1104.
Spectral data for benzyl 2-phenyl-2H-indazole-3-carboxylate
(3n) and benzyl 1-phenyl-1H-indazole-3-carboxylate (5n). White
solid; mp: 127.5–130.6 °C; IR (neat, cm−1): 3125, 1665, 1586,
1
763; H NMR (400 MHz, CDCl3): (3n) select peaks: δ 8.08 (d,
J = 8.4 Hz, 1 H), 7.84 (d, J = 8.8 Hz, 1 H), 5.33 (s, 2 H); (5n)
select peaks: δ 8.27 (d, J = 8.4 Hz, 1 H), 7.85–7.69 (m, 3 H),
5.53 (s, 2 H), other peaks are overlapped; 13C NMR (100 MHz,
CDCl3): (3n) δ 159.1, 148.3, 140.9, 135.2, 129.3, 128.6, 128.5,
128.3, 128.2, 127.0, 126.3, 125.6, 124.7, 124.1, 121.4, 118.5,
66.7; (5n) δ 162.4, 140.2, 139.2, 136.7, 135.9, 129.4, 128.5,
14 X-ray crystallographic data of compound 3a was deposited at Cambridge
Crystallographic Deposit Center (CCDC-900208).
8952 | Org. Biomol. Chem., 2012, 10, 8948–8952
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