Facile two-step synthesis of 3-substituted indazoles using diazo(trimethylsilyl)methylmagnesium bromide

Article abstract of DOI:10.1039/b907796k

Diazo(trimethylsilyl)methylmagnesium bromide readily reacted with various ketones and aldehydes to give the corresponding 2-diazo-(2-trimethylsilyl) ethanols. These were efficiently converted to indazoles bearing hydroxymethyl units at the 3-position by intermolecular [3 + 2] cycloaddition with benzynes. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b907796k

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Facile two-step synthesis of 3-substituted indazoles using
diazo(trimethylsilyl)methylmagnesium bromide†
Yoshiyuki Hari,*a Ryosuke Soneb and Toyohiko Aoyama*b
Received 17th April 2009, Accepted 17th April 2009
First published as an Advance Article on the web 22nd May 2009
DOI: 10.1039/b907796k
Diazo(trimethylsilyl)methylmagnesium bromide readily reacted with various ketones and aldehydes to
give the corresponding 2-diazo-(2-trimethylsilyl)ethanols. These were efficiently converted to indazoles
bearing hydroxymethyl units at the 3-position by intermolecular [3 + 2] cycloaddition with benzynes.
paper, we wish to describe the details of our results on this new
methodology in indazole synthesis.
Introduction
Indazole, an aza analog of indole, is a very attractive phar-
macophore for drug discovery and a number of its derivatives
are known to possess potent pharmacological activity including
anti-inflammatory, anti-tumor or anti-HIV activity.1,2 However,
efficient methods for the preparation of indazole derivatives are
still lacking. For instance, the introduction of electrophiles at the
3-position of indazoles is very difficult and can only be achieved
by quite limited approaches.3,4 Thus, the development of more
efficient and convenient methodologies is in great demand.
Intermolecular [3 + 2] cycloaddition between diazomethane
derivatives and benzynes would be a powerful methodology
towards facilitating the synthesis of indazoles bearing various sub-
stituents at the 3-position (eqn (1)).5 However, the diazomethane
derivatives used would mainly be limited to diazoketones, dia-
zoacetates, or phenyl- and trimethylsilyl-diazomethanes due to
problems with the safety of handling and with the inherent stability
of diazomethanes.
Results and discussion
Initially, as shown in Scheme 1, the reaction of the 2-diazo-
(2-trimethylsilyl)ethanol 2a, prepared from 4-phenylbutan-2-one
1a and Me3SiC(MgBr)N2, with (2-trimethylsilyl)phenyl triflate 310
in the presence of KF and [18]crown-6 in THF was examined
using three different reaction times (1 h, 6 h, and 24 h). When
the reaction was carried out for 1 h, 3 disappeared by TLC
and the desired indazole 4a bearing a hydroxymethyl unit at the
3-position and its O-trimethylsilyl derivative 5a were obtained in
44% and 54% yields from 1a, respectively. Increasing the reaction
time led to a significant increase in the yield of 4a along with a
reduction in that of 5a, indicating that the trimethylsilyl group of
5a was gradually removed by KF. The reaction for 24 h gave only
4a in 93% yield. When, in the absence of 3, 2a was treated with
KF in THF-d8 for 1 h, 1H NMR analysis of the reaction mixture
showed that 2a and epoxide 6a existed as a 2:3 mixture and no
desilylated diazoalcohol 7a was detected (Scheme 2). This result
suggests that the resulting 7a immediately decomposed to 6a due
to its lability. Therefore, the [3 + 2] cycloaddition reaction giving
indazoles would be expected to occur between 2a, not 7a, and
benzyne generated from 3 (Scheme 3).
(1)
We have engaged in the development of new synthetic methods
using trimethylsilyldiazomethane (Me3SiCHN2)6 and recently
found that its magnesium bromide salt [Me3SiC(MgBr)N2]7
smoothly reacted with simple carbonyl compounds to
efficiently and readily afford the corresponding 2-diazo-(2-
trimethylsilyl)ethanols,8 which were converted to multi-substituted
pyrazoles by intermolecular [3 + 2] cycloaddition reactions
with propiolates.9 Thus, we applied this method using Me3SiC-
(MgBr)N2 to a greater variety of carbonyl compounds as elec-
trophiles and investigated the [3 + 2] cycloaddition reaction of the
resulting 2-diazo-(2-trimethylsilyl)ethanols with benzynes towards
the convenient synthesis of various 3-substituted indazoles. In this
aGraduate School of Pharmaceutical Sciences, Osaka University, 1-6
Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail: hari@phs.osaka-u.
ac.jp; Fax: +81 6 6879 8201; Tel: +81 6 6879 8201
bGraduate School of Pharmaceutical Sciences, Nagoya City University,
3-1 Tanabe-dori, Mizuho, Nagoya 467-8603, Japan. E-mail: aoyama@phar.
nagoya-cu.ac.jp; Fax: +81 52 836 3439; Tel: +81 52 836 3439
† Electronic supplementary information (ESI) available: Characterization
data for 2-diazo-(2-trimethylsilyl)ethanols, and 1H and 13C spectra for all
new compounds. See DOI: 10.1039/b907796k
Scheme 1 Examination of the reaction time.
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treatment with 10% HCl aq. after the reaction afforded 4j in
79% yield with complete desilylation of 5j (entry 9). Aromatic
and aliphatic aldehydes 1k and 1l also gave the corresponding
indazoles 4k and 4l, though the yields were somewhat low (43–
46%) compared with those from ketones (entries 10 and 11).
Under the same reaction conditions, other benzyne precursors
8–10 also underwent the cycloaddition reaction with 2a (Fig. 1).
Thus, the use of naphthyl derivative 8 as a benzyne precursor gave
the corresponding benzoindazole 11a in 81% yield. Reaction with
m-methoxybenzyne generated from 9 afforded a 1:1.2 separable
mixture of 12a and 12a¢ in 67% yield.12 Similarly, the benzyne
precursor 10 furnished a mixture of 13a and 13a¢ in 74% yield
(13a:13a¢ = 1:2).12
Scheme 2 1H NMR experiment.
Scheme 3 Plausible reaction mechanism.
Next, the synthesis of 3-substituted indazoles using other car-
bonyl compounds was surveyed and the results were summarized
in Table 1. When 4-methoxybenzophenone 1b was used, the
corresponding 3-substituted indazole 4b was obtained in 74% yield
in two steps (entry 1). Other ketones 1c–f bearing aromatics as
well as heteroaromatics, like pyridine and thiophene, also afforded
desired indazoles 4c–f in good to high yields (66–82%)(entries 2–5).
Moreover, the dimethyl acetal moiety in 1g was tolerated under the
reaction conditions to give 4g in 74% yield (entry 6). Interestingly,
this reaction system was applicable to even b-ketoester 1h with an
active methylene moiety and an ester group and the desired 4h was
obtained in 59% yield (entry 7).11 Reaction of Me3SiC(MgBr)N2
with an a,b-unsaturated ketone exclusively proceeded through
1,2-addition to give the corresponding diazoalcohol which was
converted to 4i in 68% yield from 1i (entry 8). In the case of
bulky ketone 1j, silylated indazole 5j was isolated in 58% yield as
a major product together with 4j (18% yield). However, successive
Fig. 1 Structures of benzyne precursors used and indazoles synthesized.
In addition, we also found that hydrogenolysis of the
(3-hydroxymethyl)indazoles 4a and 4c using palladium hydroxide
readily gave the corresponding 3-alkyl congeners 14a and 14c
(Scheme 4).
Table 1 Synthesis of 3-substituted indazoles from carbonyl compoundsa
Entry
Substrate
R1
R2
Yieldb (%)
1
2
3
4
5
6
7
8
9
1b
1c
1d
1e
1f
1g
1h
1i
4-MeOPh
Ph
4-CF3Ph
2-Pyridyl
2-Thienyl
(MeO)2CHCH2
MeOCOCH2
Ph
Me
Me
Me
Me
Me
Me
Me
Et
4b, 74
4c, 77
4d, 69
4e, 66
Scheme 4 Hydrogenolysis of 4a and 4c.
4f, 82
4g, 74
4h, 59
=
(E)-PhCH CH
4i, 68
1j
i-Pr
i-Pr
4-MeOPh
4j, 18; 5j, 58 (4j, 79c)
4k, 43
Conclusions
10
11
1k
1l
H
H
4l, 46
We have achieved the facile and two-step synthesis of 3-substituted
indazoles from carbonyl compounds. To our knowledge, this is the
first example of indazole synthesis using 2-diazoethanols and the
present method would be very valuable for the preparation of
indazoles possessing 3-hydroxymethyl units.
a In all reactions, Me3SiC(MgBr)N2 (1.1–1.2 eq.), 3 (1.0 eq.), KF (3.0 eq.)
and [18]crown-6 (3.5 eq.) were used. See ESI† for details. b Isolated yield
from 1. c Treatment with 10% hydrochloric acid for 10 min before work-up
of the reaction mixture was performed.
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1-(1H-Indazol-3-yl)-1-phenylethanol (4c).3
Experimental
1-[4-(trifluoromethyl)phenyl]-1-(1H-indazol-3-yl)ethanol (4d).
General
◦
1
White powder; m.p. 151–153 C. H-NMR (acetone-d6) d: 2.12
(s, 3H), 5.27 (br s, 1H), 6.95 (dd, 1H, J = 7.0, 8.0 Hz), 7.26 (dd,
1H, J = 7.0, 8.5 Hz), 7.49 (d, 1H, J = 8.5 Hz), 7.61–7.69 (m, 3H),
7.79 (d, 2H, J = 8.0 Hz), 12.10 (br s, 1H). 13C-NMR (acetone-d6)
All melting points were measured on a Yanagimoto micro melting
points apparatus and are uncorrected. IR spectra were recorded
on a Shimadzu FTIR-8400S spectrophotometer. 1H and 13C NMR
spectra were recorded on a JEOL JNM-EX-270 spectrometer (1H,
270 MHz; 13C, 67.8 MHz). MS spectra (bp = base peak) were
recorded on a JEOL JMS-SX-102A spectrometer. A solution of
MgBr2 in Et2O–toluene (1:1) was prepared from MgBr2 etherate
(Aldrich) dried well under reduced pressure at 100 ◦C, anhydrous
Et2O and anhydrous toluene. Carbonyl compounds 1a–l were
distilled prior to use.
d: 31.22, 74.63, 110.50, 120.48, 121.25, 122.79, 125.24 (q, 1JC-F
=
=
3
2
270 Hz), 125.34 (q, JC-F = 4 Hz), 126.60, 128.61 (q, JC-F
4
32 Hz), 142.62, 151.32, 153.47 (q, JC-F = 1 Hz). IR (neat) n:
3283 cm-1. MS (EI): m/z = 306 (M+, 20.3), 291 (bp). HRMS (EI):
calcd for C16H13F3N2O (M+), 306.0980, found, 306.0979.
1-(Pyridin-2-yl)-1-(1H-indazol-3-yl)ethanol
(4e). Colorless
crystals; m.p. 150–151 ◦C. 1H-NMR (acetone-d6) d: 2.05 (s, 3H),
6.07 (br s, 1H), 6.94 (dd, 1H, J = 7.5, 8.0 Hz), 7.21–7.26 (m,
2H), 7.45–7.54 (m, 2H), 7.64–7.75 (m, 2H), 8.55 (d, 1H, J =
4.5 Hz), 12.07 (br s, 1H). 13C-NMR (acetone-d6) d: 29.88, 74.85,
110.43, 120.32, 121.11, 121.40, 122.71, 122.81, 126.41, 137.61,
142.51, 147.80, 150.87, 165.05. IR (nujol) n: 3250 cm-1. MS (EI):
m/z = 239 (M+, 44.3), 224 (M+ - CH3, bp). HRMS (EI): calcd
for C14H13N3O (M+), 239.1059, found, 239.1054.
Representative procedure of 3-substituted indazoles
Under an argon atmosphere, n-BuLi (1.66 M in hexane solution,
0.72 mL, 1.2 mmol) was added to a solution of TMSCHN2 (1.77 M
in hexane solution, 0.68 mL, 1.2 mmol) in anhydrous THF (5 mL)
at -78 ◦C and the mixture was stirred at -78 ◦C for 20 min. After
the addition of MgBr2 [1.00 M in toluene–Et2O (1:1) solution,
1.20 mL, 1.2 mmol], the mixture was further stirred at -78 ◦C for
20 min. 4-Phenyl-2-butanone 1a (150 mL, 1.0 mmol) was added
to the above mixture at -78 ◦C and the mixture was further
stirred at -78 ◦C for 1.5 h. After the addition of H2O (1 mL)
at -78 ◦C, the mixture was extracted with EtOAc (30 mL ¥ 3).
The organic extracts were washed with H2O (10 mL) and brine
(10 mL), dried over Na2SO4, and concentrated in vacuo to give
unpurified 2a8 (261 mg), which was dissolved in THF (5 mL)
and 2-(trimethylsilyl)phenyl trifluoromethanesulfonate 3 (243 mL,
1.0 mmol), KF (183 mg, 3.0 mmol) and [18]crown-6 (925 mg,
3.5 mmol) were added. After being stirred at room temperature
1-(1H-Indazol-3-yl)-1-(thiophen-2-yl)ethanol
(4f). Yellow
syrup. 1H-NMR (CDCl3) d: 2.14 (s, 3H), 4.99 (br s, 1H), 6.79–6.86
(m, 2H), 6.95 (dd, 1H, J = 7.0, 8.0 Hz), 7.13 (d, 1H, J = 5.0 Hz),
7.18–7.24 (m, 2H), 7.48 (d, 1H, J = 8.0 Hz), 11.58 (br s, 1H).
13C-NMR (CDCl3) d: 30.93, 72.72, 110.22, 119.48, 120.47, 121.41,
124.05, 124.65, 126.33, 126.48, 141.51, 150.28, 151.21. IR (neat) n:
3259 cm-1. MS (EI): m/z = 244 (M+, 33.7), 229 (M+ - Me, 78.1),
145 (bp). HRMS (EI): calcd for C13H12N2OS (M+), 244.0670,
found, 244.0670.
2-(1H-Indazol-3-yl)-4,4-dimethoxybutan-2-ol
(4g). Yellow
R
for 24 h, the mixture was filtered through a short pad of Celiteꢀ and
1
syrup. H-NMR (CDCl3) d: 1.73 (s, 3H), 2.33 (dd, 1H, J = 7.5,
14.5 Hz), 2.54 (dd, 1H, J = 4.0, 14.5 Hz), 3.21 (s, 3H), 3.26 (s,
3H), 4.51 (dd, 1H, J = 4.0, 7.5 Hz), 4.74 (br s, 1H), 7.11 (dd,
1H, J = 7.0, 8.0 Hz), 7.32 (dd, 1H, J = 7.0, 8.5 Hz), 7.44 (d,
1H, J = 8.5 Hz), 8.00 (d, 1H, J = 8.0 Hz), 11.27 (br s, 1H).
13C-NMR (CDCl3) d: 30.00, 43.85, 52.47, 53.59, 72.03, 102.74,
109.94, 120.03, 120.20, 121.91, 126.31, 141.49, 150.88. IR (neat)
n: 3271 cm-1. MS (EI): m/z = 250 (M+, 7.8), 161 (bp). HRMS
(EI): calcd for C13H18N2O3 (M+), 250.1318, found, 250.1317.
the filtrate was concentrated in vacuo. The residue was diluted with
EtOAc, then the EtOAc solution was washed with 1M KHCO3
(10 mL ¥ 3), and concentrated in vacuo. The residue was purified
by silica gel column chromatography (hexane–EtOAc, 2:1) to give
4a (249 mg, 93% from 1a).
2-(1H-Indazol-3-yl)-4-phenylbutan-2-ol (4a). Yellow syrup.
1H-NMR (CDCl3) d:1.78 (s, 3H), 2.31–2.45 (m, 3H), 2.63–2.76
(m, 1H), 4.15 (br s, 1H), 6.98 (d, 2H, J = 6.5 Hz), 7.05–7.16 (m,
4H), 7.27 (dd, 1H, J = 7.5, 8.0 Hz), 7.38 (d, 1H, J = 8.0 Hz), 7.84
(d, 1H, J = 8.0 Hz), 11.05 (br s, 1H). 13C-NMR (CDCl3) d: 29.31,
30.47, 44.72, 73.41, 110.15, 119.29, 120.51, 121.26, 125.45, 126.65,
128.09, 128.14, 141.93, 142.02, 151.11. IR (neat) n: 3256 cm-1.
MS (EI): m/z = 266 (M+, 2.2), 161 (bp). HRMS (EI): calcd for
C17H18N2O (M+), 266.1419, found, 266.1420.
Methyl 3-hydroxy-3-(1H-indazol-3-yl)butanoate (4h). Yellow
syrup. 1H-NMR (CDCl3) d: 1.73 (s, 3H), 2.92, 3.43 (AB, 2H, J =
16.0 Hz), 3.63 (s, 3H), 4.86 (br s, 1H), 7.14 (dd, 1H, J = 7.0, 8.0 Hz),
7.34 (dd, 1H, J = 7.0, 8.5 Hz), 7.41 (d, 1H, J = 8.5 Hz), 8.09 (d,
1H, J = 8.0 Hz), 10.74 (br s, 1H). 13C-NMR (CDCl3) d: 29.25,
44.69, 51.81, 71.66, 109.75, 120.17, 120.42, 122.14, 126.60, 141.47,
150.47, 173.54. IR (neat) n: 3277, 1715 cm-1. MS (EI): m/z = 234
(M+, 18.5), 161 (bp). HRMS (EI): calcd for C12H14N2O3 (M+),
234.1005, found, 234.0999.
(1H-Indazol-3-yl)(4-methoxyphenyl)(phenyl)methanol (4b).
1
Yellow syrup. H-NMR (CDCl3) d:3.69 (s, 3H), 4.80 (br s, 1H),
6.73 (d, 2H, J = 9.0 Hz), 6.87 (dd, 1H, J = 6.5, 8.0 Hz), 6.96 (d,
1H, J = 8.0 Hz), 7.09 (d, 1H, J = 8.5 Hz), 7.14–7.23 (m, 6H),
7.32–7.36 (m, 2H), 11.17 (br s, 1H). 13C-NMR (CDCl3) d: 55.13,
78.89, 110.08, 113.08, 120.61, 120.94, 121.75, 126.29, 127.25,
127.58, 127.75, 128.99, 137.61, 141.33, 145.47, 150.74, 158.53.
IR (neat) n: 3259 cm-1. MS (EI): m/z = 330 (M+, 29.3), 312
(bp). HRMS (EI): calcd for C21H18N2O2 (M+), 330.1368, found,
330.1365.
(E)-2-(1H-Indazol-3-yl)-4-phenylbut-3-en-2-ol
(4i). Yellow
syrup. 1H-NMR (CDCl3) d: 1.91 (s, 3H), 4.20 (br s, 1H), 6.66 (d,
1H, J = 16.0 Hz), 6.69 (d, 1H, J = 16.0 Hz), 7.01 (dd, 1H, J =
7.5, 8.0 Hz, Ar), 7.12–7.30 (m, 7H), 7.83 (d, 1H, J = 8.0 Hz),
11.56 (br s, 1H). 13C-NMR (CDCl3) d: 28.74, 73.11, 110.17,
119.65, 120.42, 121.57, 126.40, 126.50, 127.32, 127.93, 128.24,
134.50, 136.35, 141.60, 149.86. IR (neat) n: 3254 cm-1. MS (EI):
2806 | Org. Biomol. Chem., 2009, 7, 2804–2808
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m/z = 264 (M+, 1.2), 245 (bp). HRMS (EI): calcd for C17H16N2O
128.05, 128.37, 129.01, 132.46, 140.56, 141.78, 151.16. IR (neat)
n: 3283 cm-1. MS (EI): m/z = 316 (M+, 31.8), 298 (bp). HRMS
(EI): calcd for C21H20N2O (M+), 316.1576, found, 316.1572.
(M+), 264.1263, found, 264.1284.
3-(1H-Indazol-3-yl)-2-methylpentan-3-ol (4j). Yellow syrup.
1H-NMR (CDCl3) d: 0.69 (t, 3H, J = 7.5 Hz), 0.73 (d, 3H, J =
7.0 Hz), 1.08 (d, 3H, J = 7.0 Hz), 2.11 (dq, 2H, J = 7.5, 7.5 Hz),
2.29 (sep, 1H, J = 7.0 Hz), 3.51 (br s, 1H), 7.13 (dd, 1H, J = 7.0,
8.0 Hz), 7.37 (dd, 1H, J = 7.0, 8.5 Hz), 7.46 (d, 1H, J = 8.5 Hz),
7.81 (d, 1H, J = 8.0 Hz), 10.21 (br s, 1H). 13C-NMR (CDCl3)
d: 8.28, 16.59, 17.75, 31.16, 37.34, 78.42, 109.92, 119.74, 120.37,
121.57, 126.60, 141.99, 150.25. IR (neat) n: 3258 cm-1. MS (EI):
m/z = 218 (M+, 4.7), 175 (bp). HRMS (EI): calcd for C13H18N2O
(M+), 218.1419, found, 218.1418.
2-(5-Methoxy-1H-indazol-3-yl)-4-phenylbutan-2-ol
(12a).
1
Yellow syrup. H-NMR (CDCl3) d: 1.77 (s, 3H), 2.31–2.50 (m,
3H), 2.67–2.78 (m, 1H), 3.83 (s, 3H), 7.02–7.12 (m, 4H), 7.16–7.23
(m, 3H), 7.31 (d, 1H, J = 9.0 Hz). 13C-NMR (CDCl3) d: 29.12,
30.56, 44.56, 55.85, 73.43, 101.16, 110.95, 118.82, 119.79, 125.51,
128.14, 128.18, 137.86, 142.15, 150.56, 154.22. IR (neat) n:
3263 cm-1. MS (EI): m/z = 296 (M+, 7.0), 236 (bp). HRMS (EI):
calcd for C18H20N2O2 (M+), 296.1525, found, 296.1519.
2-(6-Methoxy-1H-indazol-3-yl)-4-phenylbutan-2-ol
(12a¢).
1-(1H-Indazol-3-yl)-2-methylpropan-1-ol (4k). White powder;
m.p. 133–134 ◦C. 1H-NMR (DMSO-d6) d: 0.83 (d, 3H, J = 7.0 Hz),
1.12 (d, 3H, J = 7.0 Hz), 2.21–2.33 (m, 1H), 4.68 (dd, 1H, J = 4.5,
7.5 Hz), 5.40 (d, 1H, J = 4.5 Hz), 7.15 (dd, 1H, J = 7.5, 8.0 Hz),
7.41 (dd, 1H, J = 7.5, 8.0 Hz), 7.57 (d, 1H, J = 8.0 Hz), 7.98
(d, 1H, J = 8.0 Hz), 12.80 (br s, 1H). 13C-NMR (DMSO-d6) d:
19.11, 19.20, 34.00, 73.78, 109.82, 119.23, 120.70, 121.41, 125.53,
140.88, 147.75. IR (nujol) n: 3144 cm-1. MS (EI): m/z = 190 (M+,
10.9), 147 (bp). HRMS (EI): calcd for C11H14N2O (M+), 190.1106,
found, 190.1108.
1
Yellow syrup. H-NMR (CDCl3) d: 1.75 (s, 3H), 2.27–2.45 (m,
3H), 2.68–2.79 (m, 1H), 3.86 (s, 3H), 6.79–6.83 (m, 2H), 7.06–7.14
(m, 3H), 7.17–7.23 (m, 2H), 7.71 (d, 1H, J = 9.5 Hz). 13C-NMR
(CDCl3) d: 29.43, 30.56, 44.85, 55.52, 73.19, 91.00, 112.74, 114.27,
122.17, 125.53, 128.17, 128.23, 142.20, 143.42, 159.61. IR (neat)
n: 3296 cm-1. MS (EI): m/z = 296 (M+, 4.9), 192 (bp). HRMS
(EI): calcd for C18H20N2O2 (M+), 296.1525, found, 296.1522.
2-(4-Methyl-1H-indazol-3-yl)-4-phenylbutan-2-ol (13a). Yel-
low syrup. 1H-NMR (CDCl3) d: 1.82 (s, 3H), 2.33–2.50 (m, 2H),
2.61–2.67 (m, 2H), 2.83 (s, 3H), 3.22 (br s, 1H), 6.96 (d, 1H, J =
4.0 Hz), 7.09–7.13 (m, 3H), 7.18–7.25 (m, 4H), 9.98 (br s, 1H).
13C-NMR (CDCl3) d: 23.33, 29.40, 30.68, 44.73, 73.08, 107.43,
119.82, 123.03, 125.51, 126.72, 128.18, 128.20, 132.03, 142.27,
142.91, 151.32. IR (neat) n: 3271 cm-1. MS (EI): m/z = 280 (M+,
7.4), 175 (bp). HRMS (EI): calcd for C18H20N2O (M+), 280.1576,
found, 280.1573.
(1H-Indazol-3-yl)(4-methoxyphenyl)methanol (4l). Colorless
◦
1
crystals; mp 140–143 C. H-NMR (acetone-d6) d: 3.71 (s, 3H),
5.08 (br s, 1H), 6.23 (s, 1H), 6.85 (d, 2H, J = 8.5 Hz), 7.00 (dd,
1H, J = 7.0, 8.0 Hz), 7.27 (dd, 1H, J = 7.0, 7.5 Hz), 7.44–7.49 (m,
3H), 7.74 (d, 1H, J = 8.0 Hz), 12.08 (br s, 1H). 13C-NMR (acetone-
d6) d: 55.33, 71.46, 110.60, 113.99, 120.46, 121.23, 122.13, 126.65,
128.15, 136.62, 142.48, 149.45, 159.40. IR (nujol) n: 3192 cm-1.
MS (EI): m/z = 254 (M+, 67.3), 236 (bp). HRMS (EI): calcd for
C15H14N2O2 (M+), 254.1055, found, 254.1055.
2-(7-Methyl-1H-indazol-3-yl)-4-phenylbutan-2-ol (13a¢). Yel-
low syrup. 1H-NMR (CDCl3) d: 1.77 (s, 3H), 2.31–2.40 (m, 3H),
2.50 (s, 3H), 2.71–2.77 (m, 1H), 3.69 (br s, 1H), 7.03–7.21 (m,
7H), 7.70 (d, 1H, J = 8.0 Hz), 10.25 (br s, 1H). 13C-NMR
(CDCl3) d: 16.78, 29.34, 30.52, 44.70, 73.28, 118.83, 119.04, 119.84,
120.96, 125.45, 126.65, 128.09, 128.18, 142.15, 151.78. IR (neat) n:
3416 cm-1. MS (EI): m/z = 280 (M+, 1.8), 262 (bp). HRMS (EI):
calcd for C18H20N2O (M+), 280.1576, found, 280.1562.
2-(1H-Indazol-3-yl)-4-phenyl-2-(trimethylsilyloxy)butane (5a).
1
Yellow oil. H-NMR (CDCl3) d: 0.03 (s, 9H), 1.91 (s, 3H), 2.27–
2.41 (m, 2H), 2.54–2.67 (m, 2H), 7.06–7.21 (m, 6H), 7.28–7.37 (m,
2H, Ar), 8.05 (d, 1H, J = 8.0 Hz), 10.52 (br s, 1H). 13C-NMR
(CDCl3) d: 2.18, 27.78, 30.91, 46.50, 76.43, 109.58, 120.16, 121.10,
122.86, 125.41, 126.37, 128.09, 128.18, 141.50, 142.35, 151.14. IR
(neat) n: 3213 cm-1. MS (EI): m/z = 338 (M+, 1.1), 323 (M+
-
Representative procedure for hydrogenation of 4a
Me, 31.9), 233 (bp). HRMS (EI): calcd for C20H26N2OSi (M+),
338.1815, found, 338.1813.
20% Pd(OH)2-C (70 mg, 0.1 mmol) and cyclohexene (1 mL,
10 mmol) were added to a solution of 4a (53 mg, 0.2 mmol) in
THF (5 mL). After being refluxed for 5 h, the mixture was filtered
through filter paper and the filtrate was concentrated in vacuo.
The residue was purified by silica gel column chromatography
(hexane–EtOAc, 5:1) to give 14a (36 mg, 72%).
3-(1H-Indazol-3-yl)-2-methyl-3-(trimethylsilyloxy)pentane (5j).
1
Yellow syrup. H-NMR (CDCl3) d: 0.20 (s, 9H), 0.86–0.92 (m,
9H), 2.02–2.15 (m, 1H), 2.17–2.27 (m, 1H), 2.30–2.43 (m, 1H),
7.08 (dd, 1H, J = 7.0, 8.0 Hz), 7.29 (dd, 1H, J = 7.0, 8.5 Hz),
7.36 (d, 1H, J = 8.5 Hz), 8.06 (d, 1H, J = 8.0 Hz), 10.11 (br s,
1H). 13C-NMR (CDCl3) d: 2.73, 9.00, 17.99, 18.34, 31.99, 39.31,
84.37, 109.52, 119.86, 122.91, 123.86, 125.93, 141.26, 149.30. IR
(neat) n: 3175 cm-1. MS (EI): m/z = 275 (M+ - Me, 39.5), 247
(bp). HRMS (EI): calcd for C15H23N2OSi (M+ - Me), 275.1580,
found, 275.1582.
3-(1-Methyl-3-phenylpropyl)-1H-indazole (14a)
1
Pale yellow oil. H-NMR (CDCl3) d: 1.49 (d, 3H, J = 7.0 Hz),
2.00–2.13 (m, 1H), 2.23–2.37 (m, 1H), 2.53–2.70 (m, 2H), 3.34
(sext, 1H, J = 7.0 Hz), 7.08–7.16 (m, 4H), 7.20–7.26 (m, 2H),
7.31–7.42 (m, 2H), 7.71 (d, 1H, J = 8.0 Hz), 10.15 (br s, 1H).
13C-NMR (CDCl3) d: 20.52, 32.70, 33.97, 38.35, 109.83, 119.95,
120.44, 121.27, 125.54, 126.50, 128.14, 128.30, 141.27, 142.20,
151.07. IR (neat) n: 3178 cm-1. MS (EI): m/z = 250 (M+, 8.7),
146 (bp). HRMS (EI): calcd for C17H18N2 (M+), 250.1470, found,
250.1474.
2-(1H-benzo[f ]indazol-3-yl)-4-phenylbutan-2-ol (11a). Orange
syrup. 1H-NMR (CDCl3) d: 1.89 (s, 3H), 2.43–2.54 (m, 3H), 2.66–
2.78 (m, 1H), 4.21 (br s, 1H), 6.94–7.07 (m, 5H), 7.21–7.33 (m,
2H), 7.63–7.66 (m, 2H), 7.83 (d, 1H, J = 8.0 Hz), 8.42 (s, 1H),
11.31 (br s, 1H). 13C-NMR (CDCl3) d: 28.93, 30.50, 44.57, 73.71,
104.96, 120.16, 120.88, 123.13, 125.40, 125.77, 127.21, 128.02,
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3-(1-Phenylethyl)-1H-indazole (14c)
Ochoa, L. Boiani, P. Buccino, H. Cerecetto, A. Gerpe, M. Gonza´lez,
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Synthones in Organic Chemistry, ed. A. Dondoni, JAI, London, 1993,
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7 Y. Hari, S. Tsuchida and T. Aoyama, Tetrahedron Lett., 2006, 47, 1977.
8 For example, the 2-diazo-(2-trimethylsilyl)ethanols prepared from
ketones with Me3SiC(Li)N2 in place of Me3SiC(MgBr)N2 have been
reported to be labile and to produce trimethylsilylated epoxides by
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9 Y. Hari, S. Tsuchida, R. Sone and T. Aoyama, Synthesis, 2007, 3371.
10 We selected 3 as a benzyne precursor because benzyne can be
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◦
1
White powder, m.p. 115–118 C. H-NMR (CDCl3) d: 1.84 (d,
3H, J = 7.0 Hz), 4.58 (q, 1H, J = 7.0 Hz), 7.01 (dd, 1H, J = 7.0,
8.0 Hz), 7.16–7.35 (m, 6H), 7.40 (d, 2H, J = 8.5 Hz), 9.97 (br s,
1H). 13C-NMR (CDCl3) d: 21.02, 38.94, 109.55, 120.18, 120.72,
121.54, 126.25, 126.52, 127.47, 128.37, 141.32, 144.76, 150.09. IR
(nujol) n: 3182 cm-1. MS (EI): m/z = 222 (M+, 63.0), 207 (bp).
HRMS (EI): calcd for C15H14N2 (M+), 222.1157, found, 222.1144.
Acknowledgements
This work was financially supported by a Grant-in-Aid for
Scientific Research (KAKENHI), the Osaka University Life
Science Young Independent Researcher Support Program (Japan
Science and Technology Agency), a Grant-in-Aid for Research
in Nagoya City University and a Grant-in-Aid from Asahi Kasei
Pharma Co. Award in Synthetic Organic Chemistry, Japan.
Notes and references
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11 The ethyl derivative, ethyl acetoacetate, has a pKa value of 10.68: R.
Brouillard and J. E. Dubois, J. Org. Chem., 1974, 39, 1137.
12 The structures were determined by NOESY measurements.
2808 | Org. Biomol. Chem., 2009, 7, 2804–2808
This journal is
The Royal Society of Chemistry 2009
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