Design and synthesis of a new indazole library: direct conversion of?N-methoxy-N-methylamides (Weinreb amides) to 3-keto and 3-formylindazoles

Article abstract of DOI:10.1016/j.tet.2006.10.063

Nucleophilic addition of Grignard or lithiated reagents on the new Weinreb amides 3 and 4 afforded efficiently the corresponding ketones and allowed the design and synthesis of a new indazole library. These 3-ketoindazoles were obtained by a direct and or

Full text of DOI:10.1016/j.tet.2006.10.063

Tetrahedron 63 (2007) 419–428
Design and synthesis of a new indazole library: direct conversion
of N-methoxy-N-methylamides (Weinreb amides) to 3-keto and
3-formylindazoles
*
Franc¸ois Crestey, Silvia Stiebing, Remi Legay, Valerie Collot and Sylvain Rault
ꢀ
ꢀ
´
Department of Chemistry, Centre d’Etudes et de Recherche sur le Medicament de Normandie (CERMN), UPRES EA-3915,
U.F.R. des Sciences Pharmaceutiques, Universite de Caen Basse-Normandie 5, rue Vaubenard, 14032 CAEN Cedex, France
´
´
Received 15 August 2006; revised 19 October 2006; accepted 23 October 2006
Available online 15 November 2006
Abstract—Nucleophilic addition of Grignard or lithiated reagents on the new Weinreb amides 3 and 4 afforded efficiently the corresponding
ketones and allowed the design and synthesis of a new indazole library. These 3-ketoindazoles were obtained by a direct and original con-
version of N-methoxy-N-methylamides with good yields. Furthermore, the reduction of 3 with LiAlH4 furnished the corresponding aldehydes
as a versatile and efficient pathway to 3-formylindazoles.
Ó 2006 Elsevier Ltd. All rights reserved.
O
1. Introduction
OH
O
O
MeO
MeO
Weinreb et al. have discovered that N-methoxy-N-methyl-
amides (commonly named Weinreb amides) could be
combined with both Grignard and lithiated reagents, and
were important valuable carbonyl equivalents.1 The stable
metal-chelated tetrahedral intermediates which were formed
resisted further nucleophilic attack, and did not produce ter-
tiary alcohols even with a large excess of organometallic
compound.2 Use of these Weinreb amides became one of
the most straightforward methods for the preparation of
ketones and aldehydes.3
i
N
O
N
N
H
2b
H
O
1
O
N
OH
R
iii
R
ii
N
N
N
R'
N
H
2a-b
3a-b R'=H
4a-b R'=Boc
R=H, OMe
Scheme 1. Reagents: (i) (1) NaOH aq (1.03 equiv), 50 ꢀC; (2) NaNO2 aq
(1 equiv), H2SO4 concd, 0 ꢀC; (3) SnCl2$2H2O (2.4 equiv), HCl concd,
98%; (ii) NH(OMe)Me$HCl (1.1 equiv), pyridine (2.2 equiv), then EDC
(2 equiv), pyridine (2 equiv), THF, rt, 68–84%; (iii) (Boc)2O (2 equiv),
TEA (1.1 equiv), DMAP (cat.), CH2Cl2, rt, 58–98%.
Thus in a study devoted to develop mild and flexible strate-
gies to design new indazole libraries and synthesize hetero-
cyclic scaffolds to prepare new valuable building blocks in
medicinal chemistry,4 we devised an efficient method for
the synthesis of various 1-(1H-indazol-3-yl)ketones. An in-
depth survey of the literature did not show such a study.5 For
example, 3-acylindazoles were obtained from the halogen–
metal exchange starting from 3-bromoindazole with very
poor yields,5c from the easeless Knochel’s methodology
with cuprates starting from 3-iodoindazoles,5f or recently
using hazardous diazo substances.5i
O
O
O
N
R''
R
R
R''Li or R''MgX
N
N
THF or Et2O
-84 °C to rt
N
N
H
R'
3a-b, 4a-b
5a-k
R=H, OMe
R'=H, Boc
With this in mind, we decided to synthesize original Weinreb
amides 3a,b and 4a,b (Scheme 1), which were then treated
with lithium and magnesium nucleophiles (Scheme 2).
Scheme 2.
Herein we would like to report the convergent synthetic ap-
proach to new indazoles by direct conversion of Weinreb
amides to ketones.
* Corresponding author. Tel.: +33 231934169; fax: +33 231931188; e-mail:
valerie.collot@unicaen.fr
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.10.063

420
F. Crestey et al. / Tetrahedron 63 (2007) 419–428
Table 2. Synthesis of 3-ketoindazoles 5a–k
2. Results and discussion
Reactant R00Li/R00MgX
Equiv
5
R00
Ph
Product (%)
Weinreb amides 3a,b and 4a,b were obtained starting from
the 3-carboxylic indazoles 2a,b. Carboxylic acid 2a was
commercially available, and compound 2b was obtained
by treatment of 5-methoxyisatine 1 with aqueous sodium hy-
droxide, then aqueous sodium nitrite in sulfuric acid.6,7
Finally the intermediate diazonium salt was reduced with a
cooled solution of tin(II) chloride dihydrate in hydrochloric
acid to give the corresponding carboxylic acid 2b in 98%
yield (Scheme 1 and Table 1). N-Methoxy-N-methylamides
are usually prepared from commercially available N,O-di-
methyl-hydroxylamine hydrochloride and an acid chloride
or another activated derivative. Our preliminary attempts to
transform the acids 2a,b to the corresponding Weinreb
amides were performed using dicyclohexylcarbodiimide
(DCC), the most important of coupling agents.8 The desired
products were obtained after purification by column chroma-
tography but the yields were lower than 55%. In order to
improve these yields, we decided to use 1-(3-dimethylamino-
propyl)-3-ethylcarbodiimide hydrochloride (EDC). The
basic advantage of EDC is the water-solubility of the result-
ing-urea avoiding further purifications.9 Thus, the coupling
reaction with N,O-dimethyl-hydroxylamine hydrochloride,
EDC and pyridine as base in THF at room temperature fur-
nished the Weinreb amides 3a and 3b in 84 and 68% yields,
respectively. This method was already easily scaled up for the
synthesis of multigram amounts (>10 g) of compound 3a,
whose structure has been confirmed by X-ray analysis.10
1
2
3
4
5
4a
3a
3a
3b
4b
PhMgBr
PhMgBr
PhLi
5a (70)
5
5
5
5
5a (92)
5a (85)
5b (40)
5b (46)
Ph
Ph
Ph
Ph
PhMgBr
PhMgBr
6
3a
2-MeO–PhMgBr
5
5c (57)
MeO
7
8
9
3a
3b
3a
i-PrMgCl
i-PrMgCl
MeMgBr
n-BuLi
5
5
5
5
6
5
5d (81)
5e (30)
5f (82)
5g (37)
5h (62)
5i (8)
10 3a
11 3a
12 3a
Ph
Li
Ph
MgBr
O
N
13 3a
14 3a
6
7
5j (37)
5k (23)
MgBr
Table 1. Synthesis of the protected Weinreb amides 4
2 (%)
3 (%)
4 (%)
Me3Si
Li
H
R¼H (a)
Com.
98
84
68
98
58
R¼OMe (b)
Com.: commercially available.
deprotected compound 5a was isolated in 70% yield (Table
2, entry 1). Finally the Boc protected group did not seem to
be necessary since the reaction loaded with unprotected
amide 3a gave the compound 5a in 92% yield (Table 2, entry
2). The same reaction was carried out with 5-methoxy deriv-
atives 3b and 4b to afford compound 5b in 40 and 46%
yields, respectively (Table 2, entries 4 and 5). These poor
results were due to the fact that the amide 3b was slightly
soluble in THF or Et2O, and the Boc protecting group didn’t
really improve the solubility of the compound 4b.
Subsequent protection of the indazole nucleus with tert-
butyloxycarbonyl (Boc), in the presence of triethylamine
(TEA) and a catalytic amount of dimethylaminopyridine
(DMAP) in dichloromethane,11 afforded the protected com-
pounds 4a and 4b in 98 and 58% yields, respectively
1
(Scheme 1 and Table 1). For the latter, H NMR and 13C
NMR experiments were specially interesting. The protons
of the N-methyl at d 3.39 ppm, and the carbons of the
N-methyl and the N-methoxy of protected amide 4a at
d 33.1 and d 61.6 ppm, respectively, appeared as a broad
singlet. For the compound 4b, the H4 on indazole nucleus
at d 7.54 ppm, and the carbon of the N-methoxy at
d 61.2 ppm also appeared as a broad singlet. These results
seemed to be the outcome of a slow conformational process
often seen with amide structures and were confirmed by the
use of a high temperature NMR technique. Indeed the broad
singlet became a narrow peak.
We decided to perform the reactions at ꢁ84 ꢀC in THF or
Et2O with 5 equiv of the Grignard or lithiated reagents for
an important reason: an excess of organometallic reagent
must be necessary because of the acidity of the indazolyl
NH proton, which is inevitably the first to be removed. To
compare the reactivity of the amide 3a with lithiated species,
compound 5a was obtained after reaction with phenyl-
lithium in 85% yield (Table 2, entry 3). 2-Methoxyphenyl-
magnesium bromide gave the indazole 5c in 57% yield
(Table 2, entry 6). With iso-propylmagnesium chloride,
amides 3a and 3b provided compounds 5d and 5e in 81
and 30% yields, respectively (Table 2, entries 7 and 8).
Methylmagnesium bromide and n-butyllithium afforded
the corresponding indazoles 5f and 5g in 82 and 37% yields,
respectively (Table 2, entries 9 and 10). Lithium phenylace-
tylide was generated in situ at low temperature in THF with
To examine the usefulness of these Weinreb amides 3a,b and
4a,b, various organometallic reagents were used to give the
ketones 5a–k (Scheme 2 and Table 2).
The first attempt was realized with bromobenzene and
magnesium turnings in ether to generate in situ phenylmag-
nesium bromide, and protected amide 4a. In fact only

F. Crestey et al. / Tetrahedron 63 (2007) 419–428
421
6 equiv of phenylacetylene and 6 equiv of n-butyllithium.
The Weinreb amide 3a was then added to give the desired
compound 5h in 62% yield (Table 2, entry 11). But with
1-propynylmagnesium bromide, amide 3a provided com-
pound 5i in only 8% yield (Table 2, entry 12). The reaction
of Weinreb amide 3a with vinylmagnesium bromide
(6 equiv) and lithium (trimethylsilyl)acetylide (7 equiv) did
not afford the expected products (Table 2, entries 13 and 14).
In the first case, it is well known that the addition of vinyl
Grignard reagent to Weinreb amide generally led to the vinyl
ketone in poor yields. The reason is that the synthesized
product mainly reacts in a Michael addition with the released
N,O-dimethyl-hydroxylamine.12 After the quenching proce-
dure, the vinyl ketone was not detected and the b-amino-
ketone 5j was obtained in 37% yield. In the second case,
surprisingly no desired product was detected even before
the quenching procedure, only the desilylated compound
5k was obtained in 23% yield. It was a direct pathway to
access terminal alkynes.
The [2-(trimethyl-silanyl)-ethoxymethyl] group (SEM) was
supposed to be more stable in the presence of lithium spe-
cies.15 Thus protection in a biphasic mixture CH2Cl2/KOH
(50% solution in water) in the presence of SEM-Cl
(1.1 equiv) and a catalytic amount of TBABr4g,16 provided
Weinreb amide 8 in a very good yield (Scheme 4).
F
F
O
N
OMe
OMe
O
O
O
ii
F
F
N
+
N
N
SEM
N
N
N
R'
3a R'=H
R'=SEM
9a SEM
9b
3:1
i
8
Scheme 4. Reagents: (i) SEM-Cl (1.1 equiv), CH2Cl2/KOH aq 50%, TBABr
(0.01 equiv), rt, 91%; (ii) 3,5-difluoroanisole (1.2 equiv), n-BuLi
(1.2 equiv), THF, ꢁ84 ꢀC to rt, 72%.
Next our efforts for the obtention of the ketoindazoles fo-
cused on the introduction of the 2,6-difluoroanisole moiety
on the amides 3a or 4a. This kind of fluoro compound could
be very interesting with a lot of pharmacological targets. Fur-
thermore there were few examples of ortho lithiation of
difluoro-alkoxyaryl compounds described in literature13 be-
cause of the difficult regioselectivity control. First of all 4-
bromo-3,5-difluoroanisole (5 equiv) reacted with i-PrMgCl
(5.5 equiv) to generate in situ the aryl Grignard using
Knochel’s procedure.14a After 1 h at ꢁ84 ꢀC, the indazole
3a was added, but the quenching procedure and the usual
work-up gave the starting material and the debrominated
product 3,5-difluoroanisole. In view of this result 3,5-
difluoroanisole was chosen to introduce our desired moiety
but after 1 h at ꢁ84 ꢀC when the amide 3a and 3,5-difluoro-
anisole (5 equiv) were added to a cooled stirred solution of
the Schlosser’s ‘super base’14b (n-BuLi, 5 equiv, t-BuOK,
5 equiv), only starting materials were recovered. With this
in mind the base was changed and the coupled compound
6a and the deprotected coupled product 6b were obtained re-
spectively in 7 and 25% yields using the protected Weinreb
amide 4a, n-BuLi (1.5 equiv) and 3,5-difluoroanisole
(1.5 equiv). Nevertheless these conditions provided a lot of
by-products: a compound resulting from self-condensation
of the 3,5-difluoroanisole 7 in 13% yield, indazole 3a in
5% yield and starting material 4a in 22% yield (Scheme 3).
The lithium reagent was generated in situ with 3,5-difluoro-
anisole (2 equiv) and n-butyllithium (2 equiv). Indazole 8
was added to give mainly, after the quenching procedure,
the aromatic trifluoro-compound 7, whose structure was
confirmed according to the 1D and 2D NMR experiments.
In order to decrease the rate of formation of this by-product,
only 1.2 equiv of 3,5-difluoroanisole and n-butyllithium
were used, according to the procedure used to obtain 2,6-di-
fluoro-4-methoxyaniline.17 These conditions provided a
mixture of (N-1 and N-2)-SEM-indazole in 72% yield with
1
a 9a/9b ratio of 3:1, determined by H NMR. Indeed the
chemical shift of the NCH2O group is always more un-
shielded in the case of (N-2)-SEM than (N-1)-SEM com-
pound. Starting material 8 was also obtained in 25% yield
but it could be easily separated by simple column chromato-
graphy (Scheme 4).
Moreover we wanted to know if aldehydes could be obtained
with Dibal-H as described in literature.1a,18 To this end, the
reduction of the amide 3a was realized in THF at ꢁ84 ꢀC
with 3 equiv of Dibal-H. The reaction was monitored by
TLC and after 2 h the starting material was not completely
consumed. Two additional equivalents of Dibal-H were
then added to achieve full conversion and after purification
aldehyde 10a was obtained in 31% yield along with the
N-methoxy-N-methylamine 11 in 69% yield (Scheme 5).
This result was surprising because the reduction of Weinreb
amides into the corresponding amines was usually per-
formed with 9-BBN.19
F
O
N
F
O
OMe
O
OMe
O
i
N
F
+
N
O
N
O
N
F
N
O
N
O
N
H
7%
N
25%
4a
Boc
H
Boc
6a
6b
OMe
F
Dibal-H
THF
-84 °C to rt
N
+
N
N
N
N
H
N
31%
69%
+
5%
+
3a
4a
+
MeO
H
H
3a
10a
11
22%
F
7
F
13%
Scheme 5.
Scheme 3. Reagents: (i) 3,5-difluoroanisole (1.5 equiv), n-BuLi (1.5 equiv),
THF, ꢁ84 ꢀC to rt.
1
Compound 11 also possessed a particularity in H NMR
because the CH2 appeared as a broad singlet at d 4.28 ppm.
Crystallization of this amine allowed us to record X-ray data
and to confirm its structure.20
Finally after this encouraging result the protecting group was
changed to decrease the rate of formation of the by-products.

422
F. Crestey et al. / Tetrahedron 63 (2007) 419–428
However, by performing the reaction with LiAlH4
(1.5 equiv) in THF at ꢁ15 ꢀC, we could obtain the aldehydes
10a and 10b in 76 and 64% yields, respectively, without any
detectable amount of by-products (Scheme 6).21 Finally
a new synthesis22 of 3-formylindazoles was developed in
two steps starting from carboxylic acids.
(16 mL) heated at 50 ꢀC. The solution was cooled to 0 ꢀC
and a cooled solution of sodium nitrite (1.73 g in 8 mL of
water, 25 mmol, 1 equiv) was added followed by a cooled
solution of H2SO4 (95%) (2.6 mL in 40 mL of water,
48.8 mmol, 1.95 equiv). The rate of addition was rapid
such that the temperature never rose above 4 ꢀC. After the
end of the addition, the cooled solution was stirred for 1 h.
Then a cooled solution of HCl (37%) with SnCl2$2H2O
(13.5 g in 20 mL of HCl, 60 mmol, 2.4 equiv) was added
and the mixture was stirred for 16 h and then filtrated. The
resulting solid was washed with water to give 5-methoxy-
1H-indazole-3-carboxylic acid 2b as a yellow solid
(4.71 g, 98%); dec 250 ꢀC. IR (KBr): 3140, 2925, 1700,
O
O
O
N
H
R
R
LiAlH4 (1.5 equiv)
THF, -15 °C to rt
N
N
N
H
N
H
10a-b
64-76%
3a-b
1
1489, 1240, 1170, 1057, 802 cmꢁ1. H NMR (DMSO-d6)
R=H, OMe
d: 3.80 (s, 3H), 7.06 (dd, J¼8.9 Hz and J¼2.2 Hz, 1H),
7.40 (d, J¼2.2 Hz, 1H), 7.54 (d, J¼8.8 Hz, 1H), 13.68 (br
s, 1H). MS (EI): m/z (%)¼192 (M+, 100), 177 (35), 133
(23), 105 (14). HRMS/ESI calcd for C9H8N2O3 [M]+
192.0535; found 192.0535.
Scheme 6.
In conclusion, with the aim of developing flexible strategies
for the design of new indazole libraries, we have studied
a new and efficient methodology for the synthesis of 1H-in-
dazole-3-Weinreb amides by the use of EDC and the corre-
sponding carboxylic acids. We have developed a strategy to
prepare in good yields 3-formylindazoles from carboxylic
acids. Comparing with the rare previous syntheses in the
3-acylindazole series, the present one excels by its simplicity
and becomes a versatile pathway to access scaffolds to get
a broader diversity via a vast range of further reactions.
Moreover, a lot of various ketones have been synthesized
by direct conversion of N-methoxy-N-methylamides with
organometallic compounds. These original heterocycles
can provide valuable building blocks in medicinal chemistry
for a wide range of applications, particularly in development
of serotonine receptor ligands (5HT).
3.3. General procedure for the synthesis of the Weinreb
amides 3
To a solution of the chosen carboxylic acid 2 in THF (350–
400 mL) was added at room temperature the N,O-dimethyl-
hydroxylamine hydrochloride (1.1 equiv). The temperature
of the mixture was decreased to 0 ꢀC and distilled pyridine
(2.2 equiv) was added. The solution was stirred for 1.5 h at
0 ꢀC and then at room temperature for 1 h. Distilled pyridine
(2 equiv) and EDC (2 equiv) were successively added and
the reaction mixture was stirred overnight, then concentrated
in vacuo. Water (400 mL) was added and the resulting solid
was filtered and washed with water to obtain the desired
Weinreb amide 3a or 3b.
3. Experimental section
3.1. General
3.3.1. N-Methoxy-N-methyl-1H-indazole-3-carboxamide
(3a).5d Starting from 1H-indazole-3-carboxylic acid 2a (6 g,
37 mmol) and following the general procedure, N-methoxy-
N-methyl-1H-indazole-3-carboxamide 3a was obtained as
a light yellow solid (6.39 g, 84%); mp 106–108 ꢀC. TLC
Rf ¼0.4 (EtOAc/cyclohexane, 2:1). IR (KBr): 3176, 1607,
1494, 1334, 1251, 1098, 981, 911, 779, 756 cmꢁ1. 1H NMR
(CDCl3) d: 3.57 (s, 3H), 3.84 (s, 3H), 7.28 (t, J¼8.3 Hz,
1H), 7.42 (t, J¼8.3 Hz, 1H), 7.54 (d, J¼8.3 Hz, 1H), 8.22
(d, J¼8.3 Hz, 1H), 10.90 (br s, 1H). 13C NMR (CDCl3) d:
33.9, 61.6, 110.0, 122.4, 122.6, 123.4, 127.1, 138.4, 140.6,
163.4. MS (EI): m/z (%)¼205 (M+, 30), 175 (14), 146 (91),
145 (100), 118 (20), 117 (25), 90 (63). Anal. Calcd for
C10H11N3O2: C, 58.53; H, 5.40; N, 20.48. Found: C, 58.76;
H, 5.59; N, 20.67.
All commercially available reagents were used as received
without further purification. Reaction mixtures were stirred
magnetically and monitored by TLC using 0.2 mm
Macherey–Nagel Polygram SIL G/UV254 precoated plates.
Column chromatography was performed using CarloErba-
SDS 60A 70–200 mm silica gel. Melting points (uncorrected)
€
were determined on a Kofler melting point apparatus. IR
spectra were taken with a Perkin–Elmer spectrum X FT-IR
spectrometer. 1H NMR (400 MHz) and 13C NMR
(100 MHz) spectra were recorded on a JEOL Lambda 400
Spectrometer. 19F NMR (376 MHz) spectra were recorded
on a Brucker Avance DRX 400 instrument using CFCl3 as
internal reference. Chemical shifts (d) are expressed in parts
per million downfield from tetramethylsilane as an internal
standard and the coupling constants are in hertz. Mass spectra
were recorded on a JEOL JMS GCMate with ionizing poten-
tial of 70 eV and with pfk as internal standard for high-
resolution. Elemental analyses were performed at the‘Institut
de Recherche en Chimie Organique Fine’ (Rouen, France).
3.3.2. N,5-Dimethoxy-N-methyl-1H-indazole-3-carbox-
amide (3b). Starting from 5-methoxy-1H-indazole-3-car-
boxylic acid 2b (3.5 g, 18.2 mmol) and following the
general procedure, N,5-dimethoxy-N-methyl-1H-indazole-
3-carboxamide 3b was obtained as a brown solid (2.93 g,
68%); dec 180 ꢀC. TLC Rf ¼0.15 (EtOAc/cyclohexane,
1:1). IR (KBr): 3468, 3139, 1617, 1581, 1462, 1366, 1298,
1281, 1217, 1123, 1046, 993, 945, 844, 814, 725,
1
3.2. 5-Methoxy-1H-indazole-3-carboxylic acid 2b
697 cmꢁ1. H NMR (CDCl3) d: 3.57 (s, 3H), 3.86 (s, 3H),
3.87 (s, 3H), 7.09 (dd, J¼9.0 Hz and J¼2.4 Hz, 1H), 7.44
(d, J¼9.0 Hz, 1H), 7.62 (d, J¼2.4 Hz, 1H), 10.69 (br s,
1H). MS (EI): m/z (%)¼235 (M+, 16), 176 (12), 175 (100),
5-Methoxyisatine 1 (4.43 g, 25 mmol) was added in a mix-
ture of NaOH (1.03 g, 25.8 mmol, 1.03 equiv) and water

F. Crestey et al. / Tetrahedron 63 (2007) 419–428
423
147 (8), 120 (15). Anal. Calcd for C11H13N3O3: C, 56.16; H,
5.57; N, 17.86. Found: C, 56.45; H, 5.42; N, 17.12.
solution was heated under reflux conditions for 10 min and
then kept for 1 h at room temperature and quenched with
saturated aqueous NH4Cl solution. The organic layer was
washed with brine, dried over MgSO4, filtered and evapo-
rated in vacuo. The crude material was purified by column
chromatography on silica gel (EtOAc/cyclohexane, 1:3) to
give the desired indazole 5a or 5b.
3.4. General procedure for the synthesis of the protected
Weinreb amides 4
A catalytic amount of DMAP, TEA (1.1 equiv) and (Boc)2O
(2 equiv) were successively added at 0 ꢀC to a cooled solu-
tion of the chosen indazole 3 in CH2Cl2. After the end of
the addition, the mixture was stirred at 0 ꢀC for 1 h and
then for 2 h at room temperature. The organic layer was
washed successively with an aqueous HCl (0.5 N) solution,
water and brine, dried over MgSO4, filtered and evaporated
in vacuo. The crude material was purified by flash column
chromatography on silica gel (EtOAc/cyclohexane, 1:2) to
give, after trituration with petroleum ether, the desired pro-
tected Weinreb amide 4a or 4b.
3.5.1. 1H-Indazol-3-yl(phenyl)methanone (5a).5c Starting
from N-methoxy-N-methyl-1H-indazole-3-carboxamide 3a
(410 mg, 2 mmol) and following the general procedure,
1H-indazol-3-yl(phenyl)methanone 5a was obtained as a
white solid (410 mg, 92%); mp 190–192 ꢀC. TLC Rf ¼0.4
(EtOAc/cyclohexane, 1:3). IR (KBr): 3186, 1626, 1451,
1358, 1226, 1174, 1086, 929, 884, 745, 698 cmꢁ1 1H
.
NMR (CDCl3) d: 7.22–7.64 (m, 6H), 8.31 (d, J¼7.1 Hz,
2H), 8.49 (d, J¼8.3 Hz, 1H), 10.45 (br s, 1H). 13C NMR
(CDCl3) d: 109.8, 123.0, 123.4, 123.8, 127.7, 127.8, 128.0,
128.2, 130.4, 132.6, 137.9, 140.8, 189.2. MS (EI): m/z
(%)¼222 (M+, 100), 221 (28), 194 (48), 193 (13), 145
(38), 105 (71), 90 (14), 77 (75). Anal. Calcd for
C14H10N2O: C, 75.66; H, 4.54; N, 12.60. Found: C, 75.32;
H, 4.34; N, 11.81.
3.4.1. tert-Butyl 3-{[methoxy(methyl)amino]carbonyl}-
1H-indazole-1-carboxylate (4a). Starting from N-meth-
oxy-N-methyl-1H-indazole-3-carboxamide 3a (600 mg,
2.9 mmol) and following the general procedure, tert-butyl
3-{[methoxy(methyl)amino]carbonyl}-1H-indazole-1-car-
boxylate 4a was obtained as a white solid (875 mg, 98%);
mp 75–77 ꢀC. TLC Rf ¼0.7 (EtOAc/cyclohexane, 1:1). IR
(KBr): 3448, 3184, 3064, 2925, 1626, 1449, 1225, 1085,
3.5.2. (5-Methoxy-1H-indazol-3-yl)(phenyl)methanone
(5b). Starting from tert-butyl 5-methoxy-3-{[methoxy-
(methyl)amino]carbonyl}-1H-indazole-1-carboxylate 4b
(360 mg, 1 mmol) and following the general procedure,
(5-methoxy-1H-indazol-3-yl)(phenyl)methanone 5b was
obtained as a yellow solid (120 mg, 46%); mp 64 ꢀC. TLC
Rf ¼0.25 (EtOAc/cyclohexane, 1:3). IR (KBr): 3162, 2921,
1618, 1452, 1408, 1366, 1327, 1264, 1206, 1179, 1077,
1
884, 745, 697, 638 cmꢁ1. H NMR (CDCl3) d: 1.60 (s,
9H), 3.39 (br s, 3H), 3.80 (s, 3H), 7.24 (t, J¼7.8 Hz, 1H),
7.41 (t, J¼8.0 Hz, 1H), 8.00–8.06 (m, 2H). 13C NMR
(CDCl3) d: 27.7, 33.1 (br s), 61.6 (br s), 84.9, 113.9,
122.0, 124.1, 124.9, 128.7, 139.7, 142.1, 148.5, 170.5. MS
(EI): m/z (%)¼305 (M+, 7), 245 (6), 205 (5), 146 (11), 145
(100). Anal. Calcd for C15H19N3O4: C, 59.01; H, 6.27; N,
13.76. Found: C, 58.87; H, 6.41; N, 13.49.
1
1023, 806, 716, 689 cmꢁ1. H NMR (CDCl3) d: 3.94 (s,
3H), 7.15 (dd, J¼9.0 Hz and J¼2.4 Hz, 1H), 7.29–7.63
(m, 4H), 7.86 (d, J¼2.4 Hz, 2H), 8.30 (d, J¼7.6 Hz, 1H),
10.50 (br s, 1H). MS (EI): m/z (%)¼252 (M+, 79), 175
(11), 105 (100), 78 (71). Anal. Calcd for C15H12N2O2: C,
71.42; H, 4.79; N, 11.10. Found: C, 71.52; H, 4.54; N, 11.00.
3.4.2. tert-Butyl 5-methoxy-3-{[methoxy(methyl)amino]-
carbonyl}-1H-indazole-1-carboxylate (4b). Starting
from N,5-methoxy-N-methyl-1H-indazole-3-carboxamide
3b (600 mg, 2.6 mmol) and following the general procedure,
tert-butyl 5-methoxy-3-{[methoxy(methyl)amino]carbonyl}-
1H-indazole-1-carboxylate 4b was obtained as a yellow oil
(494 mg, 58%). TLC Rf¼0.5 (EtOAc/cyclohexane, 2:3). IR
(KBr): 3622, 3512, 3467, 3104, 2979, 2930, 2852, 1763,
1742, 1652, 1619, 1504, 1456, 1426, 1395, 1371, 1344,
1315, 1281, 1254, 1159, 1099, 1067, 1040, 1010, 976,
3.6. General procedure for the addition of the Grignard
reagents or lithiated reagents to 3
To a stirred solution under argon of the chosen indazole 3 in
freshly distilled THF (18 mL) at ꢁ84 ꢀC was added the
Grignard reagent (5–6 equiv) or the lithiated reagent (5–
7 equiv). The reaction mixture was allowed to react at this
temperature over 2 h, then allowed to warm to room temper-
ature and left to react for an additional hour. The solution
was quenched with saturated aqueous NH4Cl solution,
then extracted with EtOAc. The organic layer was washed
with brine, dried over MgSO4, filtered and evaporated
in vacuo. The crude material was purified by column chro-
matography on silica gel to give the desired indazole 5c,
5d, 5e, 5f, 5g, 5i, 5j or 5k.
1
913, 853, 819, 762 cmꢁ1. H NMR (CDCl3) d: 1.72 (s,
9H), 3.53 (br s, 3H), 3.88 (s, 3H), 3.94 (s, 3H), 7.17 (dd,
J¼9.2 Hz and J¼2.4 Hz, 1H), 7.54 (br s, 1H), 8.02 (d,
J¼9.0 Hz, 1H). 13C NMR (CDCl3) d: 28.1, 30.2, 55.7,
61.2 (br s), 85.3, 101.8, 115.1, 120.7, 126.4, 135.4, 141.5,
148.8, 157.0, 164.5. MS (EI): m/z (%)¼335 (M+, 23), 235
(42), 176 (14), 175 (100). HRMS/ESI calcd for
C16H21N3O5 [M]+ 335.1481; found 335.1476.
3.5. General procedure for the addition of PhMgBr to 3
or 4
3.6.1. 1H-Indazol-3-yl(2-methoxyphenyl)methanone
(5c). Starting from N-methoxy-N-methyl-1H-indazole-3-
carboxamide 3a (575 mg, 2.8 mmol) and following the
general procedure, 1H-indazol-3-yl(2-methoxyphenyl)-
methanone 5c was obtained, after purification by column
chromatography using a gradual eluent (EtOAc/cyclo-
hexane, 1:3–1:1), as a white solid (400 mg, 57%); dec
To magnesium turnings (5 equiv) was added slowly bromo-
benzene (5 equiv) in anhydrous Et2O (5–16 mL) under
argon for 10 min by keeping a mild reflux to start the reac-
tion. The mixture was heated under reflux conditions for
1 h and then cooled to 0 ꢀC. The chosen indazole 3 or 4 in
anhydrous Et2O (10–16 mL) was added slowly and the
1
132 ꢀC. TLC Rf ¼0.4 (EtOAc/cyclohexane, 2:3). H NMR

424
F. Crestey et al. / Tetrahedron 63 (2007) 419–428
(CDCl3) d: 3.78 (s, 3H), 7.06–7.10 (m, 2H), 7.39 (t, J¼
7.1 Hz, 1H), 7.45–7.58 (m, 4H), 8.42 (d, J¼8.3 Hz, 1H),
10.70 (br s, 1H). 13C NMR (CDCl3) d: 56.3, 110.7, 112.2,
120.7, 123.1, 123.2, 124.3, 128.0, 129.7, 130.4, 132.5, 141.1,
144.2, 158.1, 190.8. MS (EI): m/z (%)¼252 (M+, 100), 235
(32), 234 (24), 223 (19), 221 (22), 145 (33), 135 (58), 132
(61), 131 (41), 121 (35), 92 (21), 90 (15). HRMS/EI calcd
for C15H12N2O2 [M]+ 268.0899; found 268.0907.
1-(1H-indazol-3-yl)pentan-1-one 5g was obtained, after pu-
rification by column chromatography (EtOAc/cyclohexane,
1:2), as a white solid (210 mg, 37%); mp 134 ꢀC. TLC
Rf ¼0.7 (EtOAc/cyclohexane, 2:3). IR (KBr): 3223, 2954,
2361, 1655, 1621, 1586, 1501, 1458, 1354, 1245, 1134,
1
1047, 960, 904, 778, 739 cmꢁ1. H NMR (CDCl3) d: 0.97
(t, J¼7.3 Hz, 3H), 1.45 (st, J¼7.6 Hz, 2H), 1.80 (qt,
J¼7.6 Hz, 2H), 3.20 (t, J¼7.8 Hz, 2H), 7.34 (dt, J¼8.0 Hz
and J¼1.0 Hz, 1H), 7.45 (dt, J¼8.3 Hz and J¼1.2 Hz,
1H), 7.55 (d, J¼8.5 Hz, 1H), 8.41 (d, J¼7.8 Hz, 1H),
10.50 (br s, 1H). 13C NMR (CDCl3) d: 14.6, 23.2, 27.2,
39.4, 110.4, 122.4, 123.5, 124.3, 128.1, 141.1, 144.0,
198.6. MS (EI): m/z (%)¼202 (M+, 55), 173 (11), 161
(13), 160 (100), 146 (18), 145 (100), 132 (28), 118 (20),
90 (29). Anal. Calcd for C12H14N2O: C, 71.26; H, 6.98; N,
13.85. Found: C, 71.34; H, 6.71; N, 13.52.
3.6.2. 1-(1H-Indazol-3-yl)-2-methylpropan-1-one (5d).
Starting from N-methoxy-N-methyl-1H-indazole-3-carbox-
amide 3a (505 mg, 2.5 mmol) and following the general pro-
cedure, 1-(1H-indazol-3-yl)-2-methylpropan-1-one 5d was
obtained, after purification by column chromatography
(EtOAc/cyclohexane, 1:3), as a white solid (375 mg, 81%);
mp 130–132 ꢀC. TLC Rf ¼0.65 (EtOAc/cyclohexane, 2:3).
IR (KBr): 3293, 2967, 1652, 1447, 1373, 1325, 1250,
1136, 1100, 965, 907, 857, 735 cmꢁ1. 1H NMR (CDCl3) d:
1.31 (d, J¼6.8 Hz, 6H), 3.95 (sept, J¼6.8 Hz, 1H), 7.34 (t,
J¼7.3 Hz, 1H), 7.45 (t, J¼8.6 Hz, 1H), 7.55 (d, J¼8.3 Hz,
1H), 8.41 (d, J¼8.0 Hz, 1H), 10.80 (br s, 1H). 13C NMR
(CDCl3) d: 19.0, 36.5, 109.9, 122.2, 122.9, 123.7, 127.4,
141.2, 142.8, 201.9. MS (EI): m/z (%)¼188 (M+, 100),
145 (100), 118 (21), 117 (25), 91 (13), 90 (55). Anal. Calcd
for C11H12N2O: C, 70.19; H, 6.43; N, 14.88. Found: C,
70.55; H, 6.66; N, 14.50.
3.6.6. 1-(1H-Indazol-3-yl)but-2-yn-1-one (5i). Starting
from N-methoxy-N-methyl-1H-indazole-3-carboxamide 3a
(575 mg, 2.8 mmol) and following the general procedure,
1-(1H-indazol-3-yl)but-2-yn-1-one 5i was obtained, after
purification by column chromatography using a gradual elu-
ent (EtOAc/cyclohexane, 1:3–1:2), as a pink solid (42 mg,
8%); dec 159–161 ꢀC. TLC Rf ¼0.3 (EtOAc/cyclohexane,
2:3). IR (KBr): 3246, 2212, 1610, 1584, 1449, 1358, 1257,
1
1218, 1159, 1065, 1003, 917, 868, 740 cmꢁ1. H NMR
(CDCl3) d: 2.19 (s, 3H), 7.38 (t, J¼8.1 Hz, 1H), 7.49 (t,
J¼8.0 Hz, 1H), 7.58 (d, J¼8.3 Hz, 1H), 8.38 (d, J¼8.0 Hz,
1H), 10.68 (br s, 1H). MS (EI): m/z (%)¼184 (M+, 100),
156 (60), 155 (41), 145 (11), 127 (11), 118 (13), 90 (14).
Anal. Calcd for C11H8N2O: C, 71.73; H, 4.38; N, 15.21.
Found: C, 71.70; H, 4.24; N, 14.84.
3.6.3. 1-(5-Methoxy-1H-indazol-3-yl)-2-methylpropan-1-
one (5e). Starting from N,5-dimethoxy-N-methyl-1H-inda-
zole-3-carboxamide 3b (475 mg, 2 mmol) and following
the general procedure, 1-(5-methoxy-1H-indazol-3-yl)-2-
methylpropan-1-one 5e was obtained, after purification by
column chromatography (CH2Cl2/MeOH, 98:2), as a yellow
solid (130 mg, 30%); mp 175 ꢀC. TLC Rf ¼0.6 (CH2Cl2/
MeOH, 98:2). IR (KBr): 3170, 2970, 1650, 1469, 1450,
1342, 1325, 1256, 1220, 1123, 1098, 1028, 965, 945, 835,
3.6.7. 1-(1H-Indazol-3-yl)-3-[methoxy(methyl)amino]-
propan-1-one (5j). Starting from N-methoxy-N-methyl-
1H-indazole-3-carboxamide 3a (575 mg, 2.8 mmol) and
following the general procedure, 1-(1H-indazol-3-yl)-3-
[methoxy(methyl)amino]propan-1-one 5j was obtained, af-
ter purification by column chromatography using a gradual
eluent (EtOAc/cyclohexane, 1:2–1:1), as a yellow solid
(242 mg, 37%); mp 97 ꢀC. TLC Rf ¼0.3 (EtOAc/cyclohex-
ane, 2:3). IR (KBr): 3227, 2937, 1644, 1585, 1457, 1404,
1348, 1247, 1134, 1106, 1040, 1006, 963, 905, 775,
1
792, 773 cmꢁ1. H NMR (CDCl3) d: 1.30 (d, J¼6.8 Hz,
6H), 3.80–3.95 (m, 4H), 7.10 (dd, J¼9.0 Hz and J¼2.4 Hz,
1H), 7.43 (d, J¼9.0 Hz, 1H), 7.78 (d, J¼2.4 Hz, 1H), 10.48
(br s, 1H). 13C NMR (CDCl3) d: 19.0, 36.3, 55.7, 101.4,
110.9, 120.1, 123.2, 136.9, 142.3, 157.0, 202.0. MS (EI):
m/z (%)¼218 (M+, 32), 175 (100), 147 (6), 120 (9). HRMS/
EI calcd for C12H14N2O2 [M]+ 218.1055; found 218.1058.
753 cmꢁ1 1H NMR (CDCl3) d: 2.19 (s, 3H), 3.21 (t,
.
3.6.4. 1-(1H-Indazol-3-yl)ethanone (5f).5c Starting from N-
methoxy-N-methyl-1H-indazole-3-carboxamide 3a (575 mg,
2.8 mmol) and following the general procedure, 1-(1H-
indazol-3-yl)ethanone 5f was obtained, after purification
by column chromatography (EtOAc/cyclohexane, 1:1), as a
white solid (370 mg, 82%); mp 184–186 ꢀC. TLC Rf ¼0.5
(EtOAc/cyclohexane, 2:3). IR (KBr): 3194, 1655, 1584,
1450, 1342, 1251, 1210, 1156, 1045, 1002, 953, 906, 778,
J¼6.8 Hz, 2H), 3.46–3.53 (m, 5H), 7.32 (t, J¼8.1 Hz, 1H),
7.49 (t, J¼8.1 Hz, 1H), 7.55 (d, J¼8.5 Hz, 1H), 8.38 (d,
J¼7.8 Hz, 1H), 11.19 (br s, 1H). 13C NMR (CDCl3) d:
37.0, 45.3, 55.8, 60.1, 110.1, 122.0, 122.9, 123.8, 127.5,
141.3, 143.9, 196.5. MS (EI): m/z (%)¼233 (M+, 1), 202
(55), 173 (11), 161 (15), 160 (31), 146 (13), 145 (100), 90
(23). Anal. Calcd for C12H15N3O2: C, 61.79; H, 6.48; N,
18.01. Found: C, 61.85; H, 6.67; N, 17.59.
1
753, 610 cmꢁ1. H NMR (CDCl3) d: 2.76 (s, 3H), 7.34 (t,
J¼7.7 Hz, 1H), 7.46 (t, J¼8.3 Hz, 1H), 7.55 (d, J¼8.3 Hz,
1H), 8.40 (d, J¼8.3 Hz, 1H), 10.54 (br s, 1H). 13C NMR
(CDCl3) d: 26.8, 109.8, 121.6, 122.8, 123.8, 127.5, 141.1,
144.2, 195.2. MS (EI): m/z (%)¼160 (M+, 54), 145 (100),
90 (55). Anal. Calcd for C9H8N2O: C, 67.49; H, 5.03; N,
17.49. Found: C, 67.29; H, 4.98; N, 17.20.
3.6.8. 1-(1H-Indazol-3-yl)prop-2-yn-1-one (5k). Starting
from N-methoxy-N-methyl-1H-indazole-3-carboxamide 3a
(575 mg, 2.8 mmol) and following the general procedure,
1-(1H-indazol-3-yl)prop-2-yn-1-one 5k was obtained, after
purification by column chromatography (EtOAc/cyclo-
hexane, 1:2), as a yellow solid (110 mg, 23%); dec 158 ꢀC.
TLC Rf ¼0.4 (EtOAc/cyclohexane, 2:3). IR (KBr): 3312,
3212, 2095, 1635, 1453, 1423, 1368, 1252, 1204, 1141,
3.6.5. 1-(1H-Indazol-3-yl)pentan-1-one (5g). Starting
from N-methoxy-N-methyl-1H-indazole-3-carboxamide 3a
(575 mg, 2.8 mmol) and following the general procedure,
1
1109, 1006, 981, 731 cmꢁ1. H NMR (CDCl3) d: 3.47 (s,
1H), 7.40 (t, J¼7.8 Hz, 1H), 7.51 (t, J¼7.8 Hz, 1H), 7.60

F. Crestey et al. / Tetrahedron 63 (2007) 419–428
425
(d, J¼8.5 Hz, 1H), 8.37 (d, J¼8.0 Hz, 1H), 10.75 (br s, 1H).
13C NMR (CDCl3) d: 79.6, 80.8, 110.2, 121.7, 122.4, 124.6,
128.1, 141.2, 144.5, 172.0. MS (EI): m/z (%)¼170 (M+,
100), 142 (68), 118 (19), 115 (33), 114 (14), 91 (12). Anal.
Calcd for C10H6N2O: C, 70.58; H, 3.55; N, 16.46. Found:
C, 70.35; H, 3.85; N, 16.10.
3-carboxamide 3a (30 mg, 5%) and starting material 4a
(200 mg, 22%).
1
Compound 6a: TLC Rf¼0.5 (EtOAc/cyclohexane, 1:3). H
NMR (CDCl3) d: 1.71 (s, 9H), 3.82 (s, 3H), 6.50–6.55 (m,
2H), 7.46 (t, J¼8.1 Hz, 1H), 7.58 (t, J¼8.6 Hz, 1H), 8.13
(d, J¼8.5 Hz, 1H), 8.41 (d, J¼8.0 Hz, 1H). 13C NMR
3.7. 1-(1H-Indazol-3-yl)-3-phenylprop-2-yn-1-one (5h)
(CDCl3) d: 28.0, 56.0, 86.1, 98.3 (m), 109.9 (t, JC–F
¼
19.9 Hz), 114.4, 122.7, 124.0, 125.4, 129.3, 140.8, 146.5,
148.4, 161.7 (dd, JC–F¼252.0 Hz and JC–F¼10.7 Hz),
163.2 (t, JC–F¼14.0 Hz), 184.0. HRMS/EI calcd for
C20H18F2N2O4 [M]+ 388.1234; found 388.1242.
To a stirred solution under argon of phenylacetylene
(1.85 mL, 16.8 mmol, 6 equiv) in freshly distilled THF
(20 mL) at ꢁ84 ꢀC was added n-butyllithium (6.8 mL,
2.5 M in hexane, 17.08 mmol, 6.1 equiv). After 1 h at
ꢁ84 ꢀC, a solution of N-methoxy-N-methyl-1H-indazole-
3-carboxamide 3a (575 mg, 2.8 mmol) in distilled THF
(12 mL) was added dropwise. The reaction mixture was
allowed to react at this temperature over 30 min, then
allowed to warm to room temperature and left to react for an
additional hour. The solution was quenched with saturated
aqueous NH4Cl solution, then extracted with EtOAc. The
organic layer was washed with brine, dried over MgSO4,
filtered and evaporated in vacuo. The crude material was
purified by column chromatography on silica gel (EtOAc/
cyclohexane, 1:2) to give 1-(1H-indazol-3-yl)-3-phenyl-
prop-2-yn-1-one 5h as a yellow solid (430 mg, 62%); dec
190 ꢀC. TLC Rf ¼0.5 (EtOAc/cyclohexane, 2:3). IR (KBr):
3152, 2194, 1636, 1489, 1449, 1406, 1370, 1350, 1272,
1245, 1152, 1136, 1107, 978, 794, 763, 752, 690 cmꢁ1. 1H
NMR (CDCl3) d: 7.37–7.51 (m, 5H), 7.60 (d, J¼8.6 Hz,
1H), 7.71 (d, J¼6.8 Hz, 2H), 8.43 (d, J¼7.6 Hz, 1H),
11.06 (br s, 1H). 13C NMR (CDCl3) d: 88.1, 92.7, 110.9,
120.5, 122.2, 122.5, 124.5, 128.1, 128.8, 130.9, 133.4,
141.7, 144.8, 172.9. MS (EI): m/z (%)¼246 (M+, 100),
219 (15), 218 (81), 189 (19), 129 (83), 109 (17), 101 (14).
Anal. Calcd for C16H10N2O: C, 78.04; H, 4.09; N, 11.38.
Found: C, 77.52; H, 4.17; N, 10.82.
Compound 6b: mp 210 ꢀC. TLC Rf¼0.25 (EtOAc/cyclohex-
1
ane, 1:3). H NMR (CDCl3) d: 3.65 (s, 3H), 6.36–6.45 (m,
2H), 7.30 (t, J¼8.0 Hz, 1H), 7.38–7.43 (m, 2H), 8.30 (d,
J¼8.0 Hz, 1H), 11.20 (br s, 1H). 13C NMR (CDCl3) d:
55.8, 98.1 (m), 110.0, 110.4 (t, JC–F¼21.5 Hz), 121.8,
122.2, 124.2, 127.7, 140.9, 144.1, 148.4, 160.9 (dd, JC–F
¼
246.7 Hz and JC–F¼10.7 Hz), 162.5 (t, JC–F¼13.3 Hz),
183.5. HRMS/EI calcd for C15H10F2N2O2 [M]+ 288.0710;
found 288.0704.
Compound 7: mp 64–66 ꢀC. TLC Rf¼0.65 (EtOAc/cyclo-
hexane, 1:3). IR (KBr): 3094, 2957, 2853, 1619, 1581,
1512, 1474, 1451, 1422, 1332, 1290, 1248, 1199, 1144,
1
1079, 1061, 1022, 833, 730, 692 cmꢁ1. H NMR (CDCl3)
d: 3.80 (s, 3H), 3.81 (s, 3H), 6.51–6.57 (m, 2H), 6.63 (dt,
J¼10.8 Hz and J¼2.2 Hz, 1H), 6.78 (dddt, J¼10.6 Hz,
J¼2.4 Hz, J¼1.3 Hz and J¼1.3 Hz, 1H), 6.78 (m, 1H).
13C NMR (CDCl3) d: 55.4, 55.7, 98.2 (m), 101.0 (d, JC–F
¼
24.8 Hz), 109.6 (dt, JC–F¼22.3 Hz and JC–F¼2.5 Hz),
109.8 (td, JC–F¼19.0 Hz and JC–F¼2.5 Hz), 112.0 (m),
131.5 (d, JC–F¼10.7 Hz), 160.38 (t, JC–F¼14.9 Hz), 160.48
(dd, JC–F¼247.8 Hz and JC–F¼9.9 Hz), 160.54 (d, JC–F
¼
12.3 Hz), 163.2 (d, JC–F¼242.9 Hz). 19F NMR (CDCl3) d:
ꢁ112.7 (m, 1F), ꢁ113.5 (dt, J¼9.9 Hz and J¼1.3 Hz, 2F).
MS (EI): m/z (%)¼268 (M+, 100), 253 (11), 225 (22).
HRMS/EI calcd for C14H11F3O2 [M]+ 268.0711; found
268.0711. Anal. Calcd for C14H11F3O2: C, 62.69; H, 4.13.
Found: C, 62.34; H, 4.22.
3.8. (2,6-Difluoro-4-methoxyphenyl)(1H-indazol-3-yl)-
methanone (6a), tert-butyl 3-(2,6-difluoro-4-methoxy-
benzoyl)-1H-indazole-1-carboxylate (6b) and
2,30,6-trifluoro-4,50-dimethoxybiphenyl (7)
To a stirred solution under argon of 3,5-difluoroanisole
(520 mL, 4.4 mmol, 1.5 equiv) in freshly distilled THF
(40 mL) at ꢁ84 ꢀC was added n-butyllithium (1.8 mL,
2.5 M in hexane, 4.4 mmol, 1.5 equiv). After 1 h at ꢁ84 ꢀC,
a solution of tert-butyl 3-{[methoxy(methyl)amino]car-
bonyl}-1H-indazole-1-carboxylate 4a (900 mg, 3 mmol) in
distilled THF (15 mL) was added dropwise. The reaction
mixture was allowed to react at this temperature over 2 h,
then allowed to warm to room temperature and left to react
for an additional hour. The solution was quenched with sat-
urated aqueous NH4Cl solution, then concentrated in vacuo
and taken up in EtOAc. The organic layer was washed with
an aqueous solution of HCl (0.5 M), then brine, dried over
MgSO4, filtered and evaporated in vacuo. The crude material
was purified by column chromatography on silica gel
(EtOAc/cyclohexane, 1:3) to give tert-butyl 3-(2,6-difluoro-
4-methoxybenzoyl)-1H-indazole-1-carboxylate 6a (80 mg,
7%) as a yellow oil, (2,6-difluoro-4-methoxyphenyl)(1H-
indazol-3-yl)methanone 6b (210 mg, 25%) as a white
solid, 2,30,6-trifluoro-4,50-dimethoxybiphenyl 7 (100 mg,
13%) as a white solid, N-methoxy-N-methyl-1H-indazole-
3.9. 1-[2-(Trimethyl-silanyl)-ethoxymethyl]-N-methoxy-
N-methyl-1H-indazole-3-carboxamide (8)
To a cooled solution of N-methoxy-N-methyl-1H-indazole-
3-carboxamide 3a (3 g, 14.6 mmol), TBABr (47 mg,
0.15 mmol, 0.01 equiv), KOH (50% solution in water,
15 mL) in CH2Cl2 (20 mL) was added at 0 ꢀC dropwise
SEM-Cl (2.73 mL, 16.1 mmol, 1.1 equiv). After the end of
the addition, the mixture was stirred rapidly at 0 ꢀC for 1 h
and then for 2 h at room temperature. CH2Cl2 (50 mL) and
water (70 mL) were added, and the organic layer was
washed with brine, dried over MgSO4, filtered and evapo-
rated in vacuo. The crude material was purified by flash
column chromatography on silica gel (EtOAc/cyclohexane,
1:6) to give 1-[2-(trimethyl-silanyl)-ethoxymethyl]-N-
methoxy-N-methyl-1H-indazole-3-carboxamide 8 as a light
yellow oil (4.47 g, 91%). TLC Rf¼0.7 (EtOAc/cyclohexane,
1:1). IR (KBr): 3446, 2953, 1652, 1619, 1487, 1436, 1305,
1249, 1143, 1084, 1026, 973, 860, 786, 751, 694 cmꢁ1. 1H
NMR (CDCl3) d: ꢁ0.08 (s, 9H), 0.88 (t, J¼8.5 Hz, 2H),
3.51 (s, 3H), 3.57 (t, J¼8.5 Hz, 2H), 3.87 (s, 3H), 5.73 (s,

426
F. Crestey et al. / Tetrahedron 63 (2007) 419–428
2H), 7.26 (t, J¼8.0 Hz, 1H), 7.37 (t, J¼8.3 Hz, 1H), 7.55 (d,
J¼8.4 Hz, 1H), 8.21 (d, J¼8.0 Hz, 1H). 13C NMR (CDCl3) d:
ꢁ1.4, 17.7, 35.0, 61.7, 66.7, 78.3, 109.7, 122.6, 124.9, 127.2,
137.7, 140.1, 163.4. MS (EI): m/z (%)¼335 (M+, 3), 275 (26),
218 (19), 217 (34), 101 (10), 74 (100). HRMS/ESI calcd for
C16H25N3O3Si [M]+ 335.1665; found 335.1679.
(1.5 equiv). The mixture was stirred at ꢁ15 ꢀC for 1 h and
then at room temperature for 12 h. The solution was placed
at 0 ꢀC and quenched with an aqueous HCl solution (2 N)
and extracted with EtOAc. The organic layer was washed
with brine, dried over MgSO4, filtered and evaporated
in vacuo. The crude material was purified by column chro-
matography on silica gel (EtOAc/cyclohexane, 1:2) to obtain
the desired 3-formylindazole 10a or 10b.
3.10. (2,6-Difluoro-4-methoxyphenyl){1-[2-(trimethyl-
silanyl)-ethoxymethyl]-1H-indazol-3-yl}methanone (9a)
and (2,6-difluoro-4-methoxyphenyl){2-[2-(trimethyl-si-
lanyl)-ethoxymethyl]-2H-indazol-3-yl}methanone (9b)
3.11.1. 1H-Indazole-3-carbaldehyde (10a).22b Starting
from N-methoxy-N-methyl-1H-indazole-3-carboxamide 3a
(1.63 g, 7.9 mmol) and following the general procedure,
1H-indazole-3-carbaldehyde 10a was obtained as a white
solid (880 mg, 76%); mp 140 ꢀC. TLC Rf ¼0.7 (EtOAc/
cyclohexane, 2:1). IR (KBr): 3435, 3188, 2926, 1698,
To a stirred solution under argon of 3,5-difluoroanisole
(700 mL, 6 mmol, 1.2 equiv) in freshly distilled THF
(40 mL) at ꢁ84 ꢀC was added n-butyllithium (2.4 mL,
2.5 M in hexane, 6 mmol, 1.2 equiv). After 1 h at ꢁ84 ꢀC,
1
1670, 1466, 1339, 1257, 1088, 801, 739 cmꢁ1. H NMR
a
solution of 1-[2-(trimethyl-silanyl)-ethoxymethyl]-N-
(CDCl3) d: 7.38 (t, J¼8.0 Hz, 1H), 7.50 (t, J¼8.5 Hz, 1H),
7.58 (d, J¼8.3 Hz, 1H), 8.34 (d, J¼8.0 Hz, 1H), 10.31 (s,
1H), 10.98 (br s, 1H). 13C NMR (CDCl3) d: 110.0, 121.0,
122.1, 124.2, 128.0, 141.2, 144.9, 187.4. MS (EI): m/z
(%)¼146 (M+, 100), 145 (59), 118 (39), 91 (31), 90 (19),
86 (46), 84 (71). Anal. Calcd for C8H6N2O: C, 65.75; H,
4.14; N, 19.17. Found: C, 65.46; H, 4.12; N, 19.09.
methoxy-N-methyl-1H-indazole-3-carboxamide 8 (1.68 g,
5 mmol) in distilled THF (15 mL) was added dropwise. The
reaction mixture was allowed to react at this temperature
over 2 h, then allowed to warm to room temperature and
left to react for an additional hour. The solution was quenched
with saturated aqueous NH4Cl solution, then concentrated in
vacuo and taken up in EtOAc. The organic layer was washed
with an aqueous solution of HCl (0.5 M), then brine, dried
over MgSO4, filtered and evaporated in vacuo. The crude
material was purified by column chromatography on silica
gel (EtOAc/cyclohexane, 1:4) to give a mixture of (2,6-di-
fluoro-4-methoxyphenyl){1-[2-(trimethyl-silanyl)-ethoxy-
methyl]-1H-indazol-3-yl}methanone 9a and (2,6-difluoro-4-
methoxyphenyl){2-[2-(trimethyl-silanyl)-ethoxymethyl]-
2H-indazol-3-yl}methanone 9b as a light yellow oil (1.52 g,
72%) and starting material 8 (426 mg, 25%). TLC Rf ¼0.9
(EtOAc/cyclohexane, 2:3). IR (KBr): 2953, 1633, 1581,
1471, 1443, 1413, 1347, 1304, 1249, 1201, 1149, 1086,
1042, 882, 836, 786, 753 cmꢁ1. MS (EI): m/z (%)¼418
(M+, 3), 346 (16), 345 (71), 302 (58), 301 (29), 171 (54),
157 (12), 131 (19), 103 (12), 81 (18), 74 (100). HRMS/ESI
calcd for C21H24F2N2O3Si [M]+ 418.1524; found 418.1513.
3.11.2. 5-Methoxy-1H-indazole-3-carbaldehyde (10b).22d
Starting from N,5-dimethoxy-N-methyl-1H-indazole-3-car-
boxamide 3b (1.6 g, 6.8 mmol) and following the general
procedure, 5-methoxy-1H-indazole-3-carbaldehyde 10b
was obtained as a brown solid (840 mg, 64%); mp 214–
216 ꢀC. TLC Rf ¼0.5 (EtOAc/cyclohexane, 1:1). IR (KBr):
3204, 1664, 1482, 1452, 1323, 1259, 1217, 1077, 1021,
1
838, 796, 719 cmꢁ1. H NMR (CDCl3) d: 3.91 (s, 3H),
7.15 (dd, J¼9.0 Hz and J¼2.4 Hz, 1H), 7.46 (d, J¼9.0 Hz,
1H), 7.67 (d, J¼2.2 Hz, 1H), 10.27 (s, 1H), 10.49 (br s,
1H). MS (EI): m/z (%)¼176 (M+, 100), 161 (24), 133 (32),
105 (19). Anal. Calcd for C9H8N2O2: C, 61.36; H, 4.58; N,
15.90. Found: C, 61.76; H, 4.52; N, 15.53.
3.12. 1-(1H-Indazol-3-yl)-N-methoxy-N-methylmethan-
amine (11)
Compound 9a: 1H NMR (CDCl3) d: ꢁ0.07 (s, 9H), 0.87 (t,
J¼8.3 Hz, 2H), 3.54 (t, J¼8.3 Hz, 2H), 3.84 (s, 3H), 5.76
(s, 2H), 6.51–6.53 (m, 2H), 7.40 (t, J¼8.1 Hz, 1H), 7.50 (t,
J¼8.5 Hz, 1H), 7.64 (d, J¼8.3 Hz, 1H), 8.42 (d, J¼8.0 Hz,
1H). 13C NMR (CDCl3) d: ꢁ1.2, 18.0, 56.4, 67.2, 78.9,
98.6 (m), 110.6, 111.2 (t, JC–F¼20.7 Hz), 123.1, 124.1,
124.8, 127.9, 141.3, 143.5, 161.8 (dd, JC–F¼251.0 Hz and
JC–F¼10.6 Hz), 163.0 (t, JC–F¼13.9 Hz), 184.0.
Compound 9b: 1H NMR (CDCl3) d: ꢁ0.06 (s, 9H), 0.94 (t,
J¼8.3 Hz, 2H), 3.66 (t, J¼8.3 Hz, 2H), 3.89 (s, 3H), 6.24 (s,
2H), 6.57–6.59 (m, 2H), 6.92 (d, J¼8.6 Hz, 1H), 7.16 (t,
J¼8.2 Hz, 1H), 7.33 (t, J¼8.3 Hz, 1H), 7.86 (d, J¼8.8 Hz,
1H). 13C NMR (CDCl3) d: ꢁ1.1, 18.2, 56.6, 67.6, 82.0,
99.1 (m), 111.2 (t, JC–F¼18.2 Hz), 119.7, 119.8, 124.5,
126.7, 127.1, 132.2, 148.2, 161.5 (dd, JC–F¼251.5 Hz and
JC–F¼10.1 Hz), 163.7 (t, JC–F¼13.6 Hz), 176.9.
To a stirred solution under argon of N-methoxy-N-methyl-
1H-indazole-3-carboxamide 3a (575 mg, 2.8 mmol) in
freshly distilled THF (16 mL) at ꢁ84 ꢀC was added Dibal-
H (8.4 mL, 1 M in THF, 8.4 mmol, 3 equiv). The reaction
mixture was stirred at ꢁ84 ꢀC for 1 h, warmed slowly at
room temperature for 1 h, then stirred at room temperature
for 1 h. The reaction was monitored by TLC. The solution
was placed at 0 ꢀC and Dibal-H (5.6 mL, 5.6 mmol, 2 equiv)
was added. The reaction mixture was allowed to react at this
temperature over 1 h, then allowed to warm to room temper-
ature and left to react for an additional hour. The solution
was quenched with water, filtered on Celite, then extracted
with EtOAc. The organic layer was washed with brine, dried
over MgSO4, filtered and evaporated in vacuo. The crude
material was purified by column chromatography on silica
gel (EtOAc/cyclohexane, 1:4) to give 1H-indazole-3-carbal-
dehyde 10a (125 mg, 31%) and 1-(1H-indazol-3-yl)-N-
methoxy-N-methylmethanamine 11, after trituration in
petroleum ether, as a white solid (370 mg, 69%); mp
69 ꢀC. TLC Rf ¼0.4 (EtOAc/cyclohexane, 2:1). IR (KBr):
3224, 2954, 2878, 1620, 1501, 1438, 1354, 1244, 1132,
3.11. General procedure for the synthesis of 3-formyl-
indazoles 10
To a cooled solution of the chosen indazole 3 in freshly
distilled THF (40 mL) was added at ꢁ15 ꢀC LiAlH4
1
1122, 1072, 1046, 972, 959, 753 cmꢁ1. H NMR (CDCl3)

F. Crestey et al. / Tetrahedron 63 (2007) 419–428
427
Crestey, F.; Collot, V.; Stiebing, S.; Rault, S. Tetrahedron
2006, 62, 7772–7775; (g) Crestey, F.; Collot, V.; Stiebing, S.;
Rault, S. Synthesis 2006, 3506–3514.
d: 2.68 (s, 3H), 3.42 (s, 3H), 4.28 (br s, 2H), 7.14 (t,
J¼7.8 Hz, 1H), 7.35 (t, J¼8.3 Hz, 1H), 7.49 (d, J¼8.3 Hz,
1H), 7.89 (d, J¼7.8 Hz, 1H), 11.50 (br s, 1H). 13C NMR
(CDCl3) d: 45.0, 56.7, 59.9, 110.1, 120.6, 121.0, 122.5,
126.7, 141.2, 142.6. MS (EI): m/z (%)¼191 (M+, 10), 161
(9), 160 (78), 132 (27), 131 (100). Anal. Calcd for
C10H13N3O: C, 62.81; H, 6.85; N, 21.97. Found: C, 62.84;
H, 6.46; N, 21.77.
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L. G.; Zolnikova, N. A. Tetrahedron Lett. 2003, 44, 5453–
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Acknowledgements
We thank Dr. Christophe Philippo for helpful suggestions,
and Jean-Franc¸ois Lohier for X-ray diffraction analysis.
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2006.10.063.
6. Buu-Hoi, N. P.; Hoeffinger, J. P.; Jacquignon, P. J. Heterocycl.
Chem. 1964, 1, 239–241.
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