Synthesis of 3-(Tosylalkyl)indazoles and their desulfonylation reactions a new entry to 3-substituted indazoles by an unprecedented friedel-crafts process

Article abstract of DOI:10.1002/ejoc.200900222

Reaction of indazoles with aldehydes in the presence of ptoluenesulfinic acid affords the corresponding sulfonyl indazoles in satisfactory yields. The reported Friedel-Crafts process is rather unusual on indazoles because of the reduced electronic density

Full text of DOI:10.1002/ejoc.200900222

FULL PAPER
DOI: 10.1002/ejoc.200900222
Synthesis of 3-(Tosylalkyl)indazoles and their Desulfonylation Reactions –
A New Entry to 3-Substituted Indazoles by an Unprecedented Friedel–Crafts
Process
Silvia Campetella,[a] Alessandro Palmieri,[a] and Marino Petrini*[a]
Keywords: Alkylation / Arenes / Electrophilic substitution / Nitrogen heterocycles / Fused-ring systems
Reaction of indazoles with aldehydes in the presence of p-
toluenesulfinic acid affords the corresponding sulfonyl ind-
azoles in satisfactory yields. The reported Friedel–Crafts pro-
cess is rather unusual on indazoles because of the reduced
electronic density of the heterocycle. The obtained sulfonyl
indazoles can be desulfonylated under reductive conditions,
finally leading to 3-alkylated indazoles.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
with nucleophilic reagents.[11] In this paper, we demonstrate
that indazoles 1 undergo a similar process in which a pre-
liminary Friedel–Crafts reaction with an aldehyde leads to
corresponding alcohol 2 (Scheme 1). Upon dehydration,
under acidic conditions, indazolium salt 3 is formed, and
this highly electrophilic species readily reacts with arenesul-
finic acid to give sulfonyl indazole 4. To the best of our
knowledge, this process represents the first example of an
intermolecular Friedel–Crafts reaction on these heterocyclic
systems.[12]
Introduction
Products of natural origin based on the indazole nucleus
are rather uncommon and have been isolated from extracts
of a limited number of plant species.[1] Conversely, a large
amount of synthetically prepared compounds recognize a
key structural feature in the indazole ring that is responsible
for their enhanced biological activity.[2] Indazole-containing
derivatives are known for their anti-aggregatory and vaso-
relaxant properties,[3] antimicrobial,[4] anti-inflammatory
activities,[5] and anticancer effects.[6] From a synthetic
standpoint, the indazole ring may be assembled by ex-
ploiting an intramolecular coupling of arenediazo groups
with vicinal o-methyl groups or by reaction of hydrazines
with functionalized arenecarbonyl derivatives.[7] Introduc-
tion of carbon frameworks into the indazole system can be
carried out at the nitrogen atom as well as at 3-position in
the pyrazole ring.
The latter process could be in principle correlated to the
very popular Friedel–Crafts reaction, currently used to
functionalize indoles at the same position.[8] However, the
reduced electronic density of the pyrazole ring in indazoles
sorely prevents the 3-position from attack by carbon elec-
trophiles. As a matter of fact, because halogenation of ind-
azoles occurs regioselectively at 3-C, the corresponding halo-
indazoles can be profitably involved in a Suzuki or Heck
cross-coupling by using aryl or alkenyl reagents.[9] Recently,
we reported that indoles react with aldehydes in the pres-
ence of arenesulfinic acids, leading to 3-(1-arylsulfonylalk-
Scheme 1. Synthesis of sulfonyl indazoles via indazolium salt inter-
mediate.
Results and Discussion
A three-component coupling of indazoles 1 with alde-
yl)indoles.[10] These compounds behave similarly to gramine hydes 5 and p-toluenesulfinic acid in dichloromethane at
derivatives, as under basic conditions they eliminate arenes- reflux affords the corresponding sulfonyl indazoles 6 in sat-
ulfinic acid to give an alkylideneindolenine that may react isfactory yields (Table 1). p-Toluenesulfinic acid, besides be-
ing a reagent, is also able to provide a certain degree of
[a] Dipartimento di Scienze Chimiche, Università di Camerino,
acidity in the reaction medium. However, the acidity level
brought by p-toluenesulfinic acid is not adequate to prop-
erly shift the equilibrium toward complete formation of sul-
Via S. Agostino 1, 62032 Camerino, Italy
Fax: +39-0737-402297
E-mail: marino.petrini@unicam.it
3184
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3184–3188

Synthesis of 3-(Tosylalkyl)indazoles and their Desulfonylation Reactions
fonyl indazoles. Therefore, p-toluenesulfonic acid is added
Other nucleophiles (halides, nitro, etc.) could in principle
to the reaction mixture to provide the necessary acidity. The be used to trap the intermediate vinylogous iminium ion,
success of this procedure is closely related to the thermo- but none of them seem to be able to impart the necessary
dynamic stability of compounds 6, which provide the neces- stability to the final product. The poor reactivity of the in-
sary driving force for their efficient formation.
dazole system in Friedel–Crafts reactions obviously poses
some limitations on the nature of aldehydes usable for this
procedure. Straight-chain aldehydes react properly with in-
dazole even when functional groups are present, provided
that their position is far from the carbonyl group (Table 1,
Entries 5–7). Ketones and aldehydes bearing substituents in
close proximity to the carbonyl group react sluggishly with
indazole under typical reaction conditions. Preliminary
attempts to force the process by using high-boiling solvents
(1,2-dichloroethane, toluene, dioxane) or by increasing the
acidity of the mixture did not give any appreciable results.
Arylaldehydes also give disappointing results, even though
they contain electron-withdrawing groups such as in 4-ni-
trobenzaldehyde. Substitution of the aromatic ring in ind-
azoles 1 is also troublesome. The presence of substituents
at the 4-position prevents the formation of any product 6,
regardless of the electronic aptitude of the corresponding
group. Concerning the 5- and 6-positions, iodo, chloro, and
Table 1. Synthesis of sulfonyl indazoles 6 by reaction of indazoles
1 with aldehydes 5 and p-toluenesulfinic acid.
Table 2. Desulfonylation of sulfonyl indazoles 6 by Na(Hg) amal-
gam.
[a] Indazole (1.05 mmol), aldehyde (1 mmol), p-toluenesulfinic acid
(1.2 mmol), p-toluenesulfonic acid (0.5 mmol) in dichloromethane
(3 mL) at 40 °C for 4 h. [b] Yield of pure, isolated products. [c] Re-
action carried out in 1,2-dichloroethane at reflux. [d] Reaction car-
ried out in 1,4-dioxane at reflux.
[a] Sulfonyl indazole (0.5 mmol), 5% Na(Hg) amalgam (0.9 g),
Na2HPO4 (2 mmol) in dry ethanol (5 mL) at room temperature for
2 h. [b] Yield of pure, isolated products.
Eur. J. Org. Chem. 2009, 3184–3188
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3185

S. Campetella, A. Palmieri, M. Petrini
FULL PAPER
for 4 h and, after cooling, was then diluted with CH2Cl2 (12 mL).
The organic solution was extracted with saturated NaHCO3
(3ϫ2 mL) and then dried with Na2SO4. Crude product 6 obtained
after removal of the solvent at reduced pressure was purified by
flash chromatography (hexanes/ethyl acetate, 9:1).
nitro groups make the corresponding indazoles 1 totally un-
reactive, whereas fluoro and methoxy groups react with al-
dehydes, although a consistently lower yield of obtained
products 6 is observed (Table 1, Entries 8 and 9). These fin-
dings support the involvement of electronic and steric fac-
tors in our process, although the lack of reactivity of
branched aldehydes clearly indicates a prevalence of steric
effects. The importance of the sulfonyl group in synthesis
mostly stems from its activating properties as a leaving
group and its ability to stabilize carbanions.[13] Because the
sulfonyl moiety is seldom present in final targets, different
procedures directed to its removal are available.[14]
Substitution of the sulfonyl groups with hydrogen atoms
can be readily performed by following a classical procedure
that employs Na(Hg) amalgam in protic solvents
(Table 2).[15] The desulfonylation reaction is operationally
simple and occurs with an interesting degree of chemoselec-
tivity, as evidenced in the retention of the chlorine atom in
compound 7e (Table 2, Entry 5). The whole two-step syn-
thetic operation leading to compounds 7 from indazole is
equivalent to an alkylation reaction that cannot be ac-
complished directly by using organometallic reagents or by
sp3-carbon electrophiles on indazole.
3-{1-[(4-Methylphenyl)sulfonyl]propyl}-1H-indazole (6a): Yield:
0.258 g, (82%). White solid. M.p. 83–85 °C. IR (nujol): ν = 739,
˜
1
1147, 1595, 1614 cm–1. H NMR (400 MHz, CDCl3): δ = 0.87 (t,
J = 7.3 Hz, 3 H), 2.32 (s, 3 H), 2.54–2.72 (m, 2 H), 5.43 (dd, J =
4.7, 10.3 Hz, 1 H), 7.09 (d, J = 8.5 Hz, 2 H), 7.15 (t, J = 8.1 Hz, 1
H), 7.29–7.41 (m, 4 H), 7.66 (d, J = 8.1 Hz, 1 H), 7.95 (br. s, 1 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 10.5, 20.7, 21.9, 80.6,
109.9, 121.2, 121.9, 124.6, 127.3, 129.5, 129.8, 132.8, 135.8, 141.0,
145.5 ppm. MS (EI): m/z (%) = 159 (100), 131 (12), 117 (8), 91 (10),
77 (7). C17H18N2O2S (314.40): calcd. C 64.94, H 5.77, N 8.91;
found C 6.78, H 5.89, N 9.09.
3-{1-[(4-Methylphenyl)sulfonyl]hexyl}-1H-indazole
(6b): Yield:
0.253 g (71%). White solid. M.p. 95–98 °C. IR (nujol): ν = 1145,
˜
1594, 1614 cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.77 (t, J =
7.3 Hz, 3 H), 1.09–1.33 (m, 6 H), 2.31 (s, 3 H), 2.45–2.57 (m, 1 H),
2.58–2.72 (m, 1 H), 5.51 (dd, J = 3.0, 11.5 Hz, 1 H), 7.08 (d, J =
8.5 Hz, 2 H), 7.14 (t, J = 8.1 Hz, 1 H), 7.28–7.36 (m, 4 H), 7.65 (d,
J = 8.1 Hz, 1 H), 7.94 (br. s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 14.1, 21.9, 22.5, 25.4, 26.7, 31.2, 79.2, 109.9, 121.2,
121.9, 124.6, 127.3, 129.5, 129.7, 132.8, 135.7, 140.8, 145.5 ppm.
MS (EI): m/z (%) = 201 (6), 157 (10), 131 (12), 91 (7), 77 (6), 126
(100), 32 (18). C20H24N2O2S (356.48): calcd. C 67.38, H 6.79, N
7.86; found C 67.50, H 6.95, N 7.99.
Conclusions
3-{1-[(4-Methylphenyl)sulfonyl]-3-phenylpropyl}-1H-indazole (6c):
In summary, a three-component coupling of indazoles
with aldehydes and p-toluenesulfinic acid leading to sulfo-
nyl indazoles was described. The reduced electronic density
of the indazole ring usually prevents its reaction with car-
bon electrophiles, making the corresponding Friedel–Crafts
process hardly achievable. As for the parent indole deriva-
tives, the mechanism involves electrophilic attack of the al-
dehyde to the indazole followed by loss of a water molecule.
The resulting indazolium salt is intercepted by the p-tolu-
enesulfinate anion, leading to the final product. Although
limited to straight-chain aldehydes, to the best of our
knowledge, this reaction represents the first successful sub-
stitution brought about by carbon electrophiles on the ind-
azole ring. The obtained sulfonyl indazoles can undergo re-
ductive desulfonylation to afford 3-alkylindazoles in good
yields.
Yield: 0.285 g (73%). White solid. M.p. 124–126 °C. IR (nujol): ν
˜
1
= 742, 749, 1134, 1597, 1616 cm–1. H NMR (400 MHz, CDCl3):
δ = 2.32 (s, 3 H), 2.33–2.43 (m, 1 H), 2.66–2.75 (m, 1 H), 2.79–2.90
(m, 1 H), 2.96–3.08 (m, 1 H), 5.40 (d, J = 10.7 Hz, 1 H), 6.92–6.97
(m, 2 H), 7.08 (d, J = 8.5 Hz, 2 H), 7.13–7.37 (m, 8 H), 7.70 (d, J =
8.1 Hz, 1 H), 8.01 (br. s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 21.8, 28.5, 31.5, 77.5, 109.9, 121.2, 122.0, 124.6, 126.7, 127.3,
128.8, 129.5, 129.7, 132.7, 136.0, 139.3, 145.5 ppm. MS (EI): m/z
(%) = 233 (100), 218 (26), 206 (10), 157 (16), 131 (75), 115 (46),
104 (60), 91 (20), 77 (24). C23H22N2O2S (390.50): calcd. C 70.74,
H 5.68, N 7.17; found C 70.88, H 5.51, N 7.31.
3-{1-[(4-Methylphenyl)sulfonyl]nonyl}-1H-indazole (6d): Yield:
0.279 g (70%). White solid. M.p. 83–85 °C. IR (nujol): ν = 663, 751,
˜
1
907, 1153, 1597, 1615, 3057 cm–1. H NMR (400 MHz, CDCl3): δ
= 0.82 (t, J = 7.3 Hz, 3 H), 1.07–1.35 (m, 12 H), 2.32 (s, 3 H),
2.47–2.58 (m, 1 H), 2.59–2.73 (m, 1 H), 5.51 (dd, J = 3.4, 11.5 Hz,
1 H), 7.10 (d, J = 8.1 Hz, 2 H), 7.16 (t, J = 7.7 Hz, 1 H), 7.29–7.42
(m, 4 H), 7.66 (dd, J = 0.9, 8.1 Hz, 1 H), 7.94 (br. s, 1 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 14.2, 21.8, 22.8, 25.8, 26.8, 29.0,
29.2, 29.3, 31.9, 79.6, 110.0, 121.2, 121.9, 125.8, 127.3, 129.5, 129.7,
133.2, 135.7, 141.0, 145.4 ppm. MS (EI): m/z (%) = 242 (24), 171
(19), 157 (88), 131 (100), 118 (44), 105 (23), 91 (7), 77 (19), 32 (22).
C23H30N2O2S (398.56): calcd. C 69.31, H 7.59, N 7.03; found C
69.09, H 7.72, N 6.88.
Experimental Section
General Remarks: 1H NMR spectra were recorded at 400 MHz
with a Varian Mercury Plus 400. 13C NMR spectra were recorded
at 100 MHz. Mass spectra were carried out by using the EI tech-
nique (70 eV) with a GC–MS Agilent Technologies 6850 SerieII/
5973 Inert instrument. Microanalyses were performed with a
CHNS-O analyzer Model EA 1108 from Fisons Instruments. IR
spectra were recorded with a Perkin–Elmer Paragon 500 FTIR. All
chemicals used were commercial.
3-{6-Chloro-1-[(4-methylphenyl)sulfonyl]hexyl}-1H-indazole
(6e):
Yield: 0.266 g (68%). Yellow oil. IR (neat): ν = 750, 814, 907, 1146,
˜
1596, 1615, 3064 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.10–1.32
(m, 2 H), 1.35–1.52 (m, 2 H), 1.59–1.68 (m, 2 H), 2.31 (s, 3 H),
2.47–2.58 (m, 1 H), 2.61–2.73 (m, 1 H), 3.40 (dt, J = 1.7, 6.4 Hz,
2 H), 5.50 (dd, J = 3.4, 11.5 Hz, 1 H), 7.08 (d, J = 8.1 Hz, 2 H),
7.11–7.18 (m, 1 H), 7.25–7.36 (m, 4 H), 7.65 (dd, J = 0.9, 8.1 Hz,
1 H), 7.94 (br. s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
21.8, 25.1, 26.3, 26.6, 32.2, 44.9, 78.9, 109.8, 121.3, 121.9, 124.6,
General Procedure for the Synthesis of Sulfonylindazoles 6: To a
stirred solution of indazole 1 (1.05 mmol), p-toluenesulfinic acid
(1.2 mmol), and p-toluenesulfonic acid monohydrate (0.5 mmol) in
CH2Cl2 (3 mL) was added carbonyl compound 5 (1 mmol) at room
temperature. The resulting reaction mixture was stirred at reflux
3186
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3184–3188

Synthesis of 3-(Tosylalkyl)indazoles and their Desulfonylation Reactions
127.4, 129.5, 129.8, 132.7, 135.8, 140.9, 145.6 ppm. MS (EI): m/z
3-Propyl-1H-indazole (7a): Yield: 62 mg (77 %). Yellow oil. IR
(%) = 236 (10), 234 (32), 199 (10), 157 (97), 131 (100), 105 (31), 77 (neat): ν = 740, 765, 911, 1466, 1499, 1616, 3060 cm–1. 1H NMR
˜
(25). C20H23ClN2O2S (390.93): calcd. C 61.45, H 5.93, N 7.17;
found C 61.57, H 5.76, N 7.25.
(400 MHz, CDCl3): δ = 0.93 (t, J = 7.3 Hz, 3 H), 1.90–2.01 (m, 2
H), 4.34 (t, J = 7.3 Hz, 2 H) 7.10–7.15 (m, 1 H), 7.32–7.44 (m, 2
H), 7.72 (dt, J = 0.9, 8.1 Hz, 1 H), 7.99 (s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 11.7, 23.5, 50.7, 109.3, 120.5, 121.3, 124.2,
126.3, 132.9, 139.7 ppm. MS (EI): m/z (%) = 160 (28) [M]+, 131
(100), 118 (23), 103 (20), 91 (9), 77 (36), 63 (10), 51 (12), 39 (8).
C10H12N2 (160.22): calcd. C 74.97, H 7.55, N 17.48; found C 75.24,
H 7.31, N 17.59.
3-{1-[(4-Methylphenyl)sulfonyl]dec-9-enyl}-1H-indazole (6f): Yield:
0.258 g (63%). White solid. M.p. 70–73 °C. IR (nujol): ν = 752, 908,
˜
1152, 1596, 1614, 1640, 3062 cm–1. 1H NMR (400 MHz, CDCl3): δ
= 1.10–1.35 (m, 10 H), 1.96 (q, J = 7.7 Hz, 2 H), 2.33 (s, 3 H),
2.47–2.59 (m, 1 H), 2.60–2.73 (m, 1 H), 4.87–4.98 (m, 2 H), 5.51
(dd, J = 3.0, 11.1 Hz, 1 H), 5.69–5.81 (m, 1 H), 7.10 (d, J = 8.1 Hz,
2 H), 7.16 (t, J = 7.7 Hz, 1 H), 7.29–7.42 (m, 4 H), 7.67 (d, J =
8.1 Hz, 1 H), 7.94 (br. s, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 21.8, 25.7, 26.7, 28.8, 28.9, 29.0, 29.2, 33.9, 77.4, 110.0, 114.4,
121.2, 121.9, 124.6, 127.3, 129.5, 129.7, 132.8, 135.6, 135.7, 139.3,
145.5 ppm. MS (EI): m/z (%) = 254 (17), 211 (8), 171 (17), 157 (98),
131 (100), 118 (49), 105 (29), 91 (7), 77 (26), 32 (27). C24H30N2O2S
(410.57): calcd. C 70.21, H 7.36, N 6.82; found C 70.34, H 7.22, N
6.58.
3-Hexyl-1H-indazole (7b): Yield: 89 mg (88 %). Yellow oil. IR
(neat): ν = 739, 764, 909, 1465, 1499, 1616, 3061 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 0.86 (t, J = 7.3 Hz, 3 H), 1.21–1.40 (m, 6
H), 1.87–2.00 (m, 2 H), 4.38 (t, J = 7.3 Hz, 2 H), 7.15 (dt, J = 1.3,
8.1 Hz, 1 H), 7.34–7.45 (m, 2 H), 7.74 (d, J = 8.1 Hz, 1 H), 8.00
(s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.2, 22.7, 26.7,
30.0, 31.6, 49.1, 109.2, 120.5, 121.3, 124.1, 126.3, 132.8, 139.5 ppm.
MS (EI): m/z (%) = 202 (16) [M]+, 173 (14), 131 (100), 118 (33),
103 (9), 91 (5), 77 (17). C13H18N2 (202.30): calcd. C 77.18, H 8.97,
N 13.85; found C 77.37, H 9.12, N 13.09.
3-{6-Benzyloxy-1-[(4-methylphenyl)sulfonyl]hexyl}-1H-indazole (6g):
Yield: 0.277 g (60%). White solid. M.p. 85–87 °C. IR (nujol): ν =
˜
662, 750, 907, 1085, 1117, 1150, 1596, 1614 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 1.10–1.30 (m, 2 H), 1.31–1.57 (m, 4 H),
2.31 (s, 3 H), 2.46–2.58 (m, 1 H), 2.60–2.73 (m, 1 H), 3.35 (t, J =
6.4 Hz, 2 H), 4.40 (s, 2 H), 5.50 (dd, J = 3.9, 11.5 Hz, 1 H), 7.08
(d, J = 8.1 Hz, 2 H), 7.14 (t, J = 7.7 Hz, 1 H), 7.23–7.36 (m, 9 H),
7.65 (d, J = 8.1 Hz, 1 H), 7.93 (br. s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 21.8, 25.6, 25.7, 26.7, 29.5, 70.2, 73.0, 79.1,
109.9, 121.2, 121.9, 124.6, 127.3, 127.7, 127.8, 128.6, 129.5, 129.7,
132.9, 135.7, 138.7, 140.9, 145.5 ppm. MS (EI): m/z (%) = 306 (8),
215 (41), 157 (36), 131 (83), 118 (75), 91 (100), 77 (27), 65 (15).
C27H30N2O3S (462.60): calcd. C 70.10, H 6.54, N 6.06; found C
70.33, H 6.64, N 6.27.
3-(3-Phenylpropyl)-1H-indazole (7c): Yield: 94 mg (80 %). White
waxy solid. IR (neat): ν = 740, 761, 909, 1008, 1460, 1498, 1602,
˜
1
3059 cm–1. H NMR (400 MHz, CDCl3): δ = 2.25–2.36 (m, 2 H),
2.66 (t, J = 7.7 Hz, 2 H), 4.41 (t, J = 6.8 Hz, 2 H), 7.14–7.22 (m,
4 H), 7.27–7.38 (m, 4 H), 7.75 (d, J = 8.1 Hz, 1 H), 8.03 (s, 1 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 31.4, 33.1, 48.3, 109.2,
120.7, 121.4, 124.2, 126.3, 126.4, 128.7, 133.1, 139.7, 141.3 ppm.
MS (EI): m/z (%) = 236 (26) [M]+, 131 (100), 118 (15), 104 (9), 91
(11), 77 (13). C16H16N2 (236.31): calcd. C 81.32, H 6.82, N 11.85;
found C 81.02, H 6.59, N 11.61.
3-Nonyl-1H-indazole (7d): Yield: 112 mg (92%). Yellow oil. IR
1
(neat): ν = 739, 908, 1007, 1425, 1465, 1500, 1616, 3062 cm–1. H
˜
6-Fluoro-3-{1-[(4-methylphenyl)sulfonyl]-3-phenylpropyl}-1H-ind-
NMR (400 MHz, CDCl3): δ = 0.87 (t, J = 7.3 Hz, 3 H), 1.18–1.39
(m, 12 H), 1.86–1.99 (m, 2 H), 4.38 (t, J = 7.3 Hz, 2 H), 7.14 (t, J
= 7.7 Hz, 1 H), 7.32–7.44 (m, 2 H), 7.73 (d, J = 8.1 Hz, 1 H), 8.00
(s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.3, 22.8, 27.1,
29.4, 29.5, 29.6, 30.1, 32.0, 49.1, 109.2, 120.5, 121.3, 124.2, 126.2,
132.8, 139.6 ppm. MS (EI): m/z (%) = 244 (10) [M]+, 187 (6), 173
(14), 131 (100), 118 (32), 103 (6), 77 (9). C16H24N2 (244.38): calcd.
C 78.64, H 9.90, N 11.46; found C 78.90, H 9.81, N 11.63.
azole (6h): Yield: 0.122 g (30%). Brown viscous oil. IR (neat): ν =
˜
736, 908, 1149, 1377, 1455, 1597, 1626, 3027 cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 2.22–2.53 (m, 1 H), 2.34 (s, 3 H), 2.68–
2.91 (m, 2 H), 2.94–3.06 (m, 1 H) 5.29 (d, J = 10.7 Hz, 1 H), 6.92–
6.96 (m, 2 H), 7.10 (d, J = 8.1 Hz, 2 H), 7.13–7.37 (m, 7 H), 7.63
(dd, J = 5.1, 8.9 Hz, 1 H), 7.99 (br. s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 21.8, 28.2, 31.4, 77.5, 96.2, 111.7, 112.0,
122.5, 122.6, 126.8, 129.5, 129.8, 130.6, 131.7, 132.7, 136.1, 139.2,
145.7, 161.4 ppm. C23H21FN2O2S (408.49): calcd. C 67.63, H 5.18,
N 6.86; found C 67.81, H 5.33, N 6.99.
3-(6-Chlorohexyl)-1H-indazole (7e): Yield: 110 mg (93%). Yellow
1
oil. IR (neat): ν = 741, 908, 1425, 1465, 1499, 1616, 3061 cm–1. H
˜
NMR (400 MHz, CDCl3): δ = 1.25–1.38 (m, 2 H), 1.40–1.51 (m, 2
H), 1.68–1.77 (m, 2 H), 1.87–1.98 (m, 2 H), 3.48 (t, J = 6.8 Hz, 2
H), 4.38 (t, J = 6.8 Hz, 2 H), 7.10–7.15 (m, 1 H), 7.33–7.42 (m, 2
H), 7.72 (dt, J = 0.9, 8.1 Hz, 1 H), 7.98 (s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 26.3, 26.6, 29.8, 32.5, 45.1, 48.8, 109.1,
120.5, 121.3, 124.1, 126.3, 132.9, 139.5 ppm. MS (EI): m/z (%) =
238 (10) [M + 2]+, 236 (30) [M]+, 201 (22), 187 (12), 173 (20), 131
(100), 118 (75), 103 (26), 91 (10), 77 (42), 41 (19). C13H17ClN2
(236.74): calcd. C 65.95, H 7.24, N 11.83; found C 65.77, H 7.11,
N 11.58.
5-Methoxy-3-{1-[(4-methylphenyl)sulfonyl]tridecyl}-1H-indazole
(6i): Yield: 0.155 g (32%). Brown viscous oil. IR (neat): ν = 734,
˜
912, 1152, 1374, 1460, 1601, 1629, 3033 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 0.87 (t, J = 7.3 Hz, 3 H), 1.10–1.38 (m, 20 H), 2.34 (s,
3 H), 2.47–2.68 (m, 2 H), 3.84 (s, 3 H), 5.47 (d, J = 9.0 Hz, 1 H),
6.97–7.08 (m, 2 H), 7.13 (d, J = 8.1 Hz, 2 H), 7.24–7.39 (m, 3 H),
7.82 (br. s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.3, 21.8,
22.9, 25.7, 26.6, 29.0, 29.3, 29.5, 29.6, 29.7, 29.8, 29.9, 32.1, 55.9,
79.6, 100.5, 111.0, 119.2, 129.4, 129.7, 130.6, 131.7, 132.9, 134.9,
145.4, 155.3 ppm. C28H40N2O3S (484.69): calcd. C 69.38, H 8.32,
N 5.78; found C 69.12, H 8.15, N 5.91.
3-Dec-9-enyl-1H-indazole (7f): Yield: 120 mg (94%). Yellow oil. IR
General Procedure for the Synthesis of 3-Alkylindazoles 7: 5 %
Na(Hg) amalgam (0.9 g) and Na2HPO4 (2 mmol) were added at
room temperature to a stirred solution of sulfonyl indazole 6
(0.5 mmol) in dry EtOH (5 mL). After stirring for 2 h at room tem-
perature, the mixture was filtered through a short pad of florisil,
which was subsequently washed with CH2Cl2 (3ϫ3 mL). Crude
product 7 obtained after removal of the solvent was purified by
column chromatography (hexanes/ethyl acetate, 95:5).
(neat): ν = 740, 909, 1005, 1426, 1465, 1499, 1616, 1640, 3063 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 1.20–1.39 (m, 10 H), 1.86–1.97
(m, 2 H), 2.01 (q, J = 7.3 Hz, 2 H), 4.37 (t, J = 7.3 Hz, 2 H), 4.89–
5.01 (m, 2 H), 5.73–5.85 (m, 1 H), 7.10–7.16 (m, 1 H), 7.33–7.43
(m, 2 H), 7.72 (d, J = 8.1 Hz, 1 H), 7.99 (s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 27.0, 29.0, 29.2, 29.3, 29.5, 30.0, 33.9, 49.1,
109.2, 114.3, 120.5, 121.3, 124.1, 126.2, 132.8, 139.3, 139.5 ppm.
MS (EI): m/z (%) = 256 (7) [M]+, 173 (9), 131 (100), 118 (56), 103
Eur. J. Org. Chem. 2009, 3184–3188
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3187

S. Campetella, A. Palmieri, M. Petrini
FULL PAPER
[7] Review: a) A. Schmidt, A. Beutler, B. Snovydovych, Eur. J.
Org. Chem. 2008, 4073–4095. For some recent papers, see: b)
C. M. Counceller, C. C. Eichman, B. C. Wray, J. P. Stambuli,
Org. Lett. 2008, 10, 1021–1023; c) Z. Liu, F. Shi, P. D. G. Mart-
inez, C. Raminelli, R. C. Larock, J. Org. Chem. 2008, 73, 219–
226; d) P. D. Lokhande, A. Raheem, S. T. Sabale, A. R.
Chabukswar, S. C. Jagdale, Tetrahedron Lett. 2007, 48, 6890–
6892.
(9), 77 (18), 55 (10), 41 (15). C17H24N2 (256.39): calcd. C 79.64, H
9.44, N 10.93; found C 79.86, H 9.31, N 10.78.
3-[6-(Benzyloxy)hexyl]-1H-indazole (7g): Yield: 137 mg (89%). Yel-
low oil. IR (neat): ν = 739, 908, 1006, 1101, 1427, 1455, 1464, 1498,
˜
1
1615, 3062 cm–1. H NMR (400 MHz, CDCl3): δ = 1.27–1.47 (m,
4 H), 1.54–1.66 (m, 2 H), 1.88–1.99 (m, 2 H), 3.43 (t, J = 6.8 Hz,
2 H), 4.37 (t, J = 7.3 Hz, 2 H), 4.47 (s, 2 H), 7.11–7.16 (m, 1 H),
7.24–7.43 (m, 7 H), 7.73 (dd, J = 0.9, 8.1 Hz, 1 H), 7.99 (s, 1 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 25.9, 26.7, 29.6, 29.8, 48.9,
70.2, 72.9, 109.1, 120.4, 121.1, 124.0, 126.1, 127.5, 127.7, 128.4,
132.7, 138.7, 139.4 ppm. MS (EI): m/z (%) = 308 (4) [M]+, 217 (20),
131 (100), 118 (53), 103 (5), 91 (28), 77 (11). C20H24N2O (308.42):
calcd. C 77.89, H 7.84, N 9.08; found C 78.07, H 8.02, 9.27.
[8] M. Bandini, A. Melloni, S. Tommasi, A. Umani-Ronchi, Syn-
lett 2005, 1199–1222.
[9] a) F. Crestey, V. Collot, S. Stiebing, S. Rault, Synthesis 2006,
3506–3514; b) S. Kazzouli, L. Bouissane, M. Khouili, G. Guil-
laumet, Tetrahedron Lett. 2005, 46, 6163–6167; c) L. Bouissane,
S. Kazzouli, S. Leonce, B. Pfeiffer, E. M. Rakib, M. Khouili,
G. Guillaumet, Bioorg. Med. Chem. 2006, 14, 1078–1088; d)
B.-M. Swahn, F. Huerta, E. Kallin, J. Malmstroem, T. Weigelt,
J. Viklund, P. Womack, Y. Xue, L. Oehberg, Bioorg. Med.
Chem. Lett. 2005, 15, 5095–5099.
Acknowledgments
[10] A. Palmieri, M. Petrini, J. Org. Chem. 2007, 72, 1863–1866.
[11] a) R. R. Shaikh, A. Mazzanti, M. Petrini, G. Bartoli, P. Mel-
chiorre, Angew. Chem. Int. Ed. 2008, 47, 8707–8710; b) M. Pe-
trini, R. R. Shaikh, Tetrahedron Lett. 2008, 49, 5645–5648; c)
A. Palmieri, M. Petrini, R. R. Shaikh, Synlett 2008, 1845–1851;
d) R. Ballini, A. Palmieri, M. Petrini, R. R. Shaikh, Adv.
Synth. Catal. 2008, 350, 129–134.
[12] An intramolecular reaction between an aldehyde and an ind-
azole occurs under basic conditions leading to indolo[1,2-b]-
indazoles, albeit in poor yield: Y. Zhu, K. Kaneko, O. Kato, Y.
Kiryu, N. Takatsu, K. Shiono, H. Katayama, Heterocycles
2003, 61, 147–162.
[13] a) N. S. Simpkins, Sulphones in Organic Synthesis; Pergamon
Press, Oxford, 1993; b) C. Nájera, J. M. Sansano, Recent Res.
Devel. Org. Chem. 1998, 2, 637–683.
[14] C. Nájera, M. Yus, Tetrahedron 1999, 55, 10547–10658.
[15] E. J. Corey, M. Chaykovsky, J. Am. Chem. Soc. 1965, 87, 1345–
1353.
Financial support from the University of Camerino (National Pro-
ject “Sintesi organiche ecosostenibili mediate da nuovi sistemi cata-
litici”) is gratefully acknowledged.
[1] A. Schmidt, Adv. Heterocycl. Chem. 2003, 85, 67–171.
[2] H. Cerecetto, A. Gerpe, M. González, V. J. Arán, C. A. de Ocá-
riz, Mini-Rev. Med. Chem. 2005, 5, 869–878.
[3] C. S. Raman, H. Li, P. Martásek, G. Southam, B. S. S. Masters,
T. L. Poulos, Biochemistry 2001, 40, 13448–13455.
[4] X. Li, S. Chu, V. A. Feher, M. Khalili, Z. Nie, S. Margosiak,
V. Nikulin, J. Levin, K. G. Sprankle, M. E. Tedder, R. Almassy,
K. Appelt, K. M. Yager, J. Med. Chem. 2003, 46, 5663–5673.
[5] X. Lin, J. Busch-Petersen, J. Deng, C. Edwards, Z. Zhang, J. K.
Kerns, Synlett 2008, 3216–3220.
[6] G.-D. Zhu, J. Gong, V. B. Gandhi, K. Woods, Y. Luo, X. Liu,
R. Guan, V. Klinghofer, E. F. Johnson, V. S. Stoll, M. Mamo,
Q. Li, S. H. Rosenberg, V. L. Giranda, Bioorg. Med. Chem.
2007, 15, 2441–2452.
Received: March 3, 2009
Published Online: May 11, 2009
3188
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3184–3188