A 'click' approach to the synthesis of 3-[2-(1-alkyltriazol-4-yl)ethyl] indoles

Article abstract of DOI:10.1055/s-0029-1216901

Copper-catalyzed cycloaddition of N-(tert-butoxycarbonyl)-3-(1-tosyl-3- butynyl)-1H-indole with various azides readily provides the corresponding (triazolylethyl)indoles. These derivatives can be regarded as indole-3-propionic acid mimics because of the e

Full text of DOI:10.1055/s-0029-1216901

PAPER
3143
A ‘Click’ Approach to the Synthesis of 3-[2-(1-Alkyltriazol-4-yl)ethyl]indoles
S
ynthesis of 3-[2-(1-A
a
r
-yl)ethy
i
l]indol
n
e
s
o Petrini,* Rafik R. Shaikh
Dipartimento di Scienze Chimiche, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy
Fax +39(0737)402297; E-mail: marino.petrini@unicam.it
Received 30 April 2009; revised 5 May 2009
a landmark review article by Sharpless and co-workers
Abstract: Copper-catalyzed cycloaddition of N-(tert-butoxycarbo-
nyl)-3-(1-tosyl-3-butynyl)-1H-indole with various azides readily
provides the corresponding (triazolylethyl)indoles. These deriva-
tives can be regarded as indole-3-propionic acid mimics because of
the electronic features of the triazole ring that are closely related to
the amido group. The obtained (indolylethyl)triazoles can be further
functionalized exploiting an elimination–addition reaction involv-
ing the tosyl group.
several years ago.11
A practical entry to functionalized 3-[2-(1-alkyltriazol-4-
yl)ethyl]indoles 3 exploiting a ‘click reaction’ would in-
volve a cycloaddition between an azide and 3-(3-buty-
nyl)indoles 4 according to Scheme 1. Azido derivatives
are easily obtained by simple nucleophilic displacement
by alkaline metal azides; conversely, 3-(3-butynyl)in-
doles are less readily available substrates for this purpose.
The latter derivatives are usually prepared by dibromoalk-
enylation–elimination of 3-(indol-3-yl)propanals follow-
ing the Corey–Fuchs method.12
Key words: alkynes, cycloadditions, heterocycles, indoles, nucleo-
philic additions
The triazole group is present in a large number of biolog-
ically active compounds such as antibiotics and antiviral
agents.1 The high aromatic stabilization pertaining to the
triazole ring, coupled with its strong dipole moment, sug-
gests a potential utilization of this heterocycle as a bio-
isostere, mimicking some common polar functional
groups.2 Indeed, the triazole nucleus has some structural
features referable to the amide bond and the involvement
of the triazole unit in the field of peptidomimetics has
been fully demonstrated.3 In this context, amido deriva-
tives 1 and 2 of indole-3-propionic acid (IPA) are known
to possess interesting biological properties as antioxidant
agents4 and acetylcholinesterase (AChE) inhibitors target-
ed to alleviate cognitive deficits in Alzheimer’s disease.5
Furthermore, these compounds find other useful applica-
tions as mimetics of the active core of melanocortins6 and
in the treatment of inflammatory diseases.7 Substitution of
the amido group with a triazole ring could be of some in-
terest in providing a practical entry to a new class of de-
rivatives 3 joining the pharmacophoric properties of the
indole nucleus with those of the triazole ring (Figure 1).
O
O
NH
NH
N
N
H
N
HN
N
Cl
1 anti-inflammatory activity
Cl
2 AChE inhibitor
N
R
N
N
R1
N
H
3 triazole analogue
Figure 1 Biologically active compounds featuring the indole-3-
propionic acid unit
R
N
R
N
The assembling of 1,2,3-triazole systems is profitably car-
ried out exploiting 1,3-dipolar cycloadditions between
terminal alkynes and azides under thermal conditions
(Huisgen reaction).8 This procedure suffers from poor re-
gioselectivity since a mixture of 1,4- and 1,5-disubstituted
triazoles is usually obtained.9 Nowadays, the insertion of
the triazole moiety in different structural entities is made
easy by the copper-catalyzed azide–alkyne cycloaddition
that provides, with outstanding regioselectivity, 1,4-di-
substituted triazoles.3a,10 This process represents the most
important issue in ‘click chemistry reactions’ as defined in
R1N3
N
R1
click reaction
N
H
N
H
3
4
Scheme 1 ‘Click reaction’ of 3-(3-butynyl)indoles 4
Ts
Ts
Cl
NaH, DMF, 0 °C
N
N
72%
Boc
Boc
5
6
SYNTHESIS 2009, No. 18, pp 3143–3149
Advanced online publication: 14.07.2009
DOI: 10.1055/s-0029-1216901; Art ID: Z08509SS
x
x.
x
x
.
2
0
0
9
Scheme 2 Synthesis of N-(tert-butoxycarbonyl)-3-(1-tosyl-3-buty-
nyl)-1H-indole (6)
© Georg Thieme Verlag Stuttgart · New York

3144
M. Petrini, R. R. Shaikh
PAPER
Recently, we have introduced N-(tert-butoxycarbonyl)-3- Initial studies of the reaction of alkynylindole 6 with
(tosylmethyl)-1H-indole (5) whose a-sulfonyl anion is azides 7 were carried out following the standard proce-
able to react with various electrophilic reagents leading to dure set by Sharpless and co-workers who used 1 mol%
various 3-substituted indoles.13 Among different electro- copper(II) sulfate pentahydrate and 5 mol% sodium ascor-
philes used for this purpose, propargyl chloride is effec- bate in a 1:1 mixture of tert-butyl alcohol and water.14
tive in giving the corresponding alkylated product 6 that Modest results were obtained using the original proce-
represents an ideal reagent for the ‘click cycloaddition re- dure, but the chemical yield of the cycloadducts 8 can be
action’ (Scheme 2). In this paper we report the unprece- substantially improved by moving to a different solvent
dented
synthesis
of
3-[2-(1-alkyltriazol-4-yl)-1- couple combination (THF–H2O, 1:1) and increasing the
tosylethyl]indoles 8 and their further functionalization at amount of the catalyst up to 13 mol% (Table 1).
the carbon atom bearing the tosyl group.
Table 1 Synthesis of (Indolylethyl)triazoles 8 by Copper-Catalyzed Cycloaddition of Alkynylindole 6 with Functionalized Azides 7
Ts
N
Ts
N
R1N3
7
NR1
sodium ascorbate (40 mol%)
CuSO4⋅5H2O (13 mol%)
THF–H2O (1:1), r.t., 12 h
N
Boc
N
Boc
6
8
Entry
Azide 7
Producta 8
Yieldb (%)
1
2
7a BnN3
8a (R1 = Bn)
81
78
77
78
80
75
75
77
76
80
76
7b 4-FC6H4CH2N3
7c 3-ClC6H4CH2N3
7d CH2=CH(CH2)3N3
7e (E)-PhCH=CHCH2N3
7f THPO(CH2)2N3
7g EtO2C(CH2)3N3
7h NCCH2N3
8b (R1 = CH2C6H4-4-F)
8c (R1 = CH2C6H4-3-Cl)
8d [R1 = (CH2)3CH=CH2]
8e [R1 = (E)-CH2CH=CHPh]
8f [R1 = (CH2)2OTHP]
8g [R1 = (CH2)3CO2Et]
8h (R1 = CH2CN)
3
4
5
6
7
8
9
7i Me(CH2)4CH(Me)N3
7j cyclopentyl azide
7k cyclohexyl azide
8i [R1 = CH(Me)(CH2)4Me]
8j (R1 = cyclopentyl)
8k (R1 = cyclohexyl)
10
11
.
N3
.
N
Ts
N
O
OMe
O
N
OMe
12
81
O
O
N
O
O
Boc
8l
7l
Ts
N
N
N
N
Boc
N3
N3
13
70
N
Ts
7m
N
N
N
Boc
8m
a All products were identified on the basis of their IR and NMR spectra.
b Yield of pure product isolated by column chromatography.
Synthesis 2009, No. 18, 3143–3149 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-[2-(1-Alkyltriazol-4-yl)ethyl]indoles
3145
A number of simple and functionalized azides 7 can be and the crude sulfonylindole is then made to react with
used for this purpose taking into account that azides show two representative methylene-active compounds leading
a particular affinity for alkynes; thus, many chemoselec- to the functionalized products 12 (Table 2). Potassium
tivity troubles usually associated with common synthetic fluoride on basic alumina is usually the basic promoter of
processes are avoided. Since the mechanism of the choice for most of the processes involving the reaction of
copper-catalyzed cycloaddition is not a truly pericyclic re- (sulfonylmethyl)indoles 9 with easily enolizable re-
action and entails the formation of a copper acetylide in- agents;20 however, for this transformation, sodium hy-
termediate in a stepwise process, simple unsaturations in dride in tetrahydrofuran was found to provide better yields
the azide are easily tolerated (Table 1, entries 4 and 5). In- of the substituted indolyl derivatives 12.
clusion of other functional entities such as acetal, ester
Table 2 N-Boc Deprotection of (Indolylethyl)triazoles 8 and Reac-
tion with Methylene-Active Compounds in the Presence of Sodium
Hydride in Tetrahydrofuran
and cyano groups are likewise possible in the final cy-
cloadducts (Table 1, entries 6–8). Secondary azides, when
used for this reaction, retain a satisfactory level of reactiv-
N
Ts
N
1. TFA,
CH2Cl2,
r.t., 3 h
ity allowing the introduction of a cyclic framework in
product 8 (Table 1, entries 9–11). Carbohydrate systems
bearing azido groups are commonly involved in copper-
catalyzed cycloadditions aimed at the synthesis of glyco-
sides, oligosaccharide mimetics and other carbohydrate
arrays.15 Azide 7l, obtained from L-ribose,16 efficiently re-
acts with alkynylindole 6 leading to derivative 8l as an
equimolar diastereomeric mixture. Finally, 1,4-diazido-
butane (7m) was tested in the copper-catalyzed cycload-
dition with the aim of verifying the preference evidenced
by linear a,w-diazidoalkanes towards formation of mono-
triazolyl derivatives (Table 1, entry 13).17 Rather surpris-
ingly, reaction of an equimolar amount of compound 7m
with alkynylindole 6 leads to a 3:2 mixture of the monoad-
duct and bisadduct 8m. The monoadduct is almost exclu-
sively obtained only when a 0.5 equivalent of alkyne 6 is
used. Conversely, 3.5 equivalents of alkyne 6 are required
in order to obtain bisadduct 8m as the sole product.18
W
W
NR1
N
N
NR1
2.
W
W
N
Boc
NaH, THF,
r.t., 2 h
N
H
8
12
Entry Starting Material 8 Nucleophile Producta 12
Yieldb
(%)
1
2
3
4
8a (R1 = Bn)
8a (R1 = Bn)
CH2(CO2Et)2 12a (W = CO2Et) 75
CH2(CN)2 12b (W = CN) 76
8j (R1 = cyclopentyl) CH2(CO2Et)2 12c (W = CO2Et) 73
8j (R1 = cyclopentyl) CH2(CN)2
12d (W = CN) 75
a All products were identified on the basis of their IR and NMR spec-
tra.
b Yield of pure product isolated by column chromatography.
The synthetic interest in (indolylethyl)triazoles of type 8
also stems from the opportunity offered by these com-
pounds of a further functionalization at the carbon bearing
the tosyl group. As previously demonstrated, a base-
induced elimination of arenesulfinic acid from derivatives
9 is able to produce the 3-alkylideneindole intermediates
10 which may react with nucleophiles leading to the final
products 11 (Scheme 3).19
In summary, we have demonstrated that by a copper-cat-
alyzed cycloaddition of N-(tert-butoxycarbonyl)-3-(1-to-
syl-3-butynyl)-1H-indole (6) with various azides it is
possible to efficiently prepare a hitherto unknown class of
compounds in which the triazole ring mimics the amido
group in indole-3-propionic acid derivatives. A base-pro-
moted elimination of the tosyl group from deprotected (in-
dolylethyl)triazoles allows the formation of a vinylogous
imino intermediate that can add carbanionic reagents. The
latter process represents a further option to introduce
functionalized frameworks into the (indolylethyl)triazole
system.
R1
SO2Ar
R1
base
Nu
– ArSO2H
N
H
R
N
R
1H NMR spectra were recorded at 400 MHz on a Varian Mercury
Plus 400 instrument in CDCl3 as solvent. 13C NMR spectra were re-
corded at 100 MHz or 50 MHz (on a Varian Gemini 200) in CDCl3
as solvent. Microanalyses were performed with a CHNS-O analyzer
Model EA 1108 from Fisons Instruments. IR spectra were recorded
with a Perkin-Elmer Paragon 500 FT-IR instrument. THF was re-
fluxed over sodium wire and then distilled.
9
10
Nu
R1
N
H
R
11
tert-Butyl 3-{2-(1-Benzyl-1H-1,2,3-triazol-4-yl)-1-[(4-methyl-
phenyl)sulfonyl]ethyl}-1H-indole-1-carboxylate (8a); Typical
Procedure
Scheme 3 General strategy for the further functionalization of (aryl-
sulfonylmethyl)indoles
Alkynylindole 6 (0.21 g, 0.5 mmol) was dissolved in a mixture of
THF (6 mL) and H2O (6 mL), and then azide 7a (0.066 g, 0.5
mmol), sodium ascorbate (0.041 g, 0.2 mmol) and CuSO4·5H2O
(0.016 g, 0.065 mmol) were sequentially added at r.t. The mixture
was stirred for 12 h at r.t., then was diluted with H2O (10 mL) and
Removal of the N-tert-butoxycarbonyl (N-Boc) protecting
group from products 8 is easily accomplished under acidic
conditions (TFA, CH2Cl2) in nearly quantitative yield,
Synthesis 2009, No. 18, 3143–3149 © Thieme Stuttgart · New York

3146
M. Petrini, R. R. Shaikh
PAPER
extracted with CH2Cl2 (3 × 15 mL). The combined organic extracts
were washed with brine (2 × 5 mL) and then dried (MgSO4). Re-
moval of the solvent under reduced pressure gave crude 8a which
was purified by column chromatography on silica gel (CHCl3–
MeOH, 95:5).
13C NMR (100 MHz, CDCl3): d = 21.7, 26.6, 28.3, 29.2, 29.9, 30.2,
49.4, 63.1, 84.5, 112.0, 115.3, 116.4, 119.6, 122.2, 123.0, 124.9,
126.8, 129.3, 129.4, 129.6, 129.7, 134.3, 136.6, 143.1, 145.0, 149.4.
Anal. Calcd for C29H34N4O4S (534.67): C, 65.15; H, 6.41; N, 10.41.
Found: C, 65.34; H, 6.33; N, 10.50.
Yield: 0.23 g (81%); yellowish solid; mp 82–84 °C.
IR (KBr): 1727, 1376, 1264, 1142 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.64 (s, 9 H), 2.35 (s, 3 H), 3.52
(dd, J = 11.1, 14.5 Hz, 1 H), 3.80 (dd, J = 4.3, 14.9 Hz, 1 H), 4.87
(dd, J = 4.4, 11.1 Hz, 1 H), 5.30 (s, 2 H), 6.91–6.94 (m, 3 H), 7.07–
7.11 (m, 2 H), 7.17 (d, J = 8.1 Hz, 2 H), 7.21–7.34 (m, 4 H), 7.49 (s,
1 H), 7.59 (d, J = 8.1 Hz, 2 H), 8.06 (d, J = 8.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.8, 25.7, 28.3, 54.1, 62.9, 84.5,
111.9, 115.2, 119.5, 122.3, 123.0, 124.8, 126.8, 127.7, 129.2, 129.3,
129.5, 129.7, 134.3, 134.6, 143.5, 145.0, 149.4.
tert-Butyl 3-(1-[(4-Methylphenyl)sulfonyl]-2-{1-[(E)-3-phenyl-
2-propenyl]-1H-1,2,3-triazol-4-yl}ethyl)-1H-indole-1-carboxy-
late (8e)
Yield: 80%; yellow solid; mp 120–123 °C.
IR (KBr): 1734, 1601, 1372, 1159 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.62 (s, 9 H), 2.35 (s, 3 H), 3.54
(dd, J = 11.1, 14.5 Hz, 1 H), 3.82 (dd, J = 4.3, 14.5 Hz, 1 H), 4.86
(dd, J = 4.3, 11.4 Hz, 1 H), 4.92 (d, J = 6.4 Hz, 2 H), 6.21 (dt,
J = 6.4, 15.8 Hz, 1 H), 6.94 (d, J = 15.8 Hz, 1 H), 7.05–7.13 (m, 3
H), 7.20 (d, J = 8.1 Hz, 2 H), 7.21–7.35 (m, 6 H), 7.53 (s, 1 H), 7.58
(d, J = 8.1 Hz, 2 H), 8.05 (d, J = 8.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.8, 25.7, 28.3, 52.3, 62.9, 84.5,
112.1, 115.2, 119.5, 121.9, 123.0, 124.8, 126.7, 126.8, 128.7, 128.8,
128.9, 129.3, 129.7, 134.3, 135.2, 135.6, 143.5, 145.0, 149.4.
Anal. Calcd for C31H32N4O4S (556.67): C, 66.89; H, 5.79; N, 10.06.
Found: C, 66.98; H, 5.90; N, 10.18.
tert-Butyl 3-{2-[1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl]-1-[(4-
methylphenyl)sulfonyl]ethyl}-1H-indole-1-carboxylate (8b)
Yield: 78%; brown solid; mp 163–165 °C.
IR (KBr): 1739, 1377, 1156 cm–1.
Anal. Calcd for C33H34N4O4S (582.71): C, 68.02; H, 5.58; N, 9.61.
Found: C, 68.26; H, 5.51; N, 9.44.
1H NMR (400 MHz, CDCl3): d = 1.64 (s, 9 H), 2.35 (s, 3 H), 3.51
(dd, J = 11.3, 14.2 Hz, 1 H), 3.79 (dd, J = 3.8, 14.5 Hz, 1 H), 4.80
(dd, J = 4.3, 11.5 Hz, 1 H), 5.24 (s, 2 H), 6.85–6.92 (m, 3 H), 7.06–
7.10 (m, 2 H), 7.17 (d, J = 8.1 Hz, 2 H), 7.22–7.30 (m, 3 H), 7.49 (s,
1 H), 7.58 (d, J = 8.1 Hz, 2 H), 8.05 (d, J = 7.7 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 21.7, 25.7, 28.3, 53.3, 63.0, 84.6,
112.1, 115.3, 115.9, 116.4, 119.5, 122.2, 123.0, 124.9, 126.8, 129.3,
129.5, 129.6, 129.7, 130.5, 134.5, 135.2, 143.7, 145.0, 149.4, 160.4,
165.3.
tert-Butyl 3-(1-[(4-Methylphenyl)sulfonyl]-2-{1-[2-(tetrahydro-
2H-pyran-2-yloxy)ethyl]-1H-1,2,3-triazol-4-yl}ethyl)-1H-in-
dole-1-carboxylate (8f)
Yield: 75%; reddish solid; mp 106–109 °C.
IR (KBr): 1733, 1376, 1157 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.20–1.60 (m, 6 H), 1.63 (s, 9 H),
2.34 (s, 3 H), 3.31–3.36 (m, 1 H), 3.44–3.62 (m, 3 H), 3.82 (dd,
J = 4.2, 14.9 Hz, 1 H), 3.87–3.95 (m, 1 H), 4.23–4.42 (m, 3 H),
4.79–4.86 (m, 1 H), 7.05–7.10 (m, 1 H), 7.17 (d, J = 8.1 Hz, 2 H),
7.22–7.27 (m, 2 H), 7.38 (d, J = 8.1 Hz, 1 H), 7.50 (d, J = 9.8 Hz, 1
H), 7.57 (d, J = 8.1 Hz, 2 H), 8.03 (d, J = 8.1 Hz, 1 H).
Anal. Calcd for C31H31FN4O4S (574.67): C, 64.79; H, 5.44; N, 9.75.
Found: C, 64.62; H, 5.53; N, 9.88.
13C NMR (100 MHz, CDCl3): d = 19.4, 19.5, 21.8, 25.3, 25.5, 25.7,
28.3, 30.3, 30.4, 50.4, 50.5, 62.3, 62.4, 62.9, 63.0, 84.5, 98.9, 99.1,
112.1, 115.5, 119.6, 123.0, 123.1, 124.8, 126.7, 126.8, 129.4, 129.7,
134.3, 143.0, 145.1, 149.4, 152.8.
tert-Butyl 3-{2-[1-(3-Chlorobenzyl)-1H-1,2,3-triazol-4-yl]-1-[(4-
methylphenyl)sulfonyl]ethyl}-1H-indole-1-carboxylate (8c)
Yield: 77%; yellow oil.
IR (film): 1734, 1370, 1265, 1151 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.64 (s, 9 H), 2.36 (s, 3 H), 3.52
(dd, J = 11.2, 14.4 Hz, 1 H), 3.82 (dd, J = 3.8, 14.5 Hz, 1 H), 4.82
(dd, J = 4.3, 11.1 Hz, 1 H), 5.27 (s, 2 H), 6.88–6.92 (m, 1 H), 7.02–
7.12 (m, 4 H), 7.19 (d, J = 8.1 Hz, 2 H), 7.22–7.30 (m, 3 H), 7.50 (s,
1 H), 7.58 (d, J = 8.1 Hz, 2 H), 8.09 (d, J = 7.7 Hz, 1 H).
Anal. Calcd for C31H38N4O6S (594.72): C, 62.61; H, 6.44; N, 9.42.
Found: C, 62.78; H, 6.61; N, 9.27.
tert-Butyl 3-{2-[1-(4-Ethoxy-4-oxobutyl)-1H-1,2,3-triazol-4-yl]-
1-[(4-methylphenyl)sulfonyl]ethyl}-1H-indole-1-carboxylate
(8g)
13C NMR (100 MHz, CDCl3): d = 21.8, 25.7, 28.3, 53.4, 63.0, 84.6,
112.0, 115.4, 115.8, 116.3, 119.4, 122.4, 123.1, 124.9, 126.7, 129.4,
129.6, 129.7, 130.3, 135.3, 143.8, 145.1.
Yield: 75%; red oil.
IR (film): 1735, 1370, 1147 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.21 (t, J = 7.3 Hz, 3 H), 1.64 (s,
9 H), 1.97–2.02 (m, 2 H), 2.06–2.12 (m, 2 H), 2.35 (s, 3 H), 3.54
(dd, J = 11.1, 14.5 Hz, 1 H), 3.83 (dd, J = 3.9, 14.5 Hz, 1 H), 4.06
(q, J = 7.3 Hz, 2 H), 4.18 (t, J = 6.8 Hz, 2 H), 4.82 (dd, J = 4.3, 11.1
Hz, 1 H), 7.00 (s, 1 H), 7.06–7.09 (m, 1 H), 7.17 (d, J = 8.1 Hz, 2
H), 7.21–7.23 (m, 1 H), 7.31 (d, J = 8.1 Hz, 2 H), 7.58 (s, 1 H), 7.58
(d, J = 8.1 Hz, 1 H), 8.05 (d, J = 8.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.3, 21.7, 25.5, 25.7, 28.3, 30.6,
49.2, 60.8, 62.9, 85.5, 112.0, 115.3, 119.5, 122.3, 123.0, 124.8,
126.7, 129.3, 129.6, 129.7, 134.3, 135.2, 143.2, 145.0, 149.4, 172.4.
Anal. Calcd for C31H31ClN4O4S (591.12): C, 62.99; H, 5.29; N,
9.48. Found: C, 63.21; H, 5.18; N, 9.56.
tert-Butyl 3-{1-[(4-Methylphenyl)sulfonyl]-2-[1-(4-pentenyl)-
1H-1,2,3-triazol-4-yl]ethyl}-1H-indole-1-carboxylate (8d)
Yield: 78%; yellow solid; mp 134–136 °C.
IR (KBr): 1731, 1595, 1376, 1144 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.64 (s, 9 H), 1.72–1.84 (m, 4 H),
2.36 (s, 3 H), 3.53 (dd, J = 11.1, 14.5 Hz, 1 H), 3.83 (dd, J = 3.8,
14.5 Hz, 1 H), 4.07–4.14 (m, 2 H), 4.82 (dd, J = 3.9, 11.1 Hz, 1 H),
4.93 (dd, J = 10.7, 24.8 Hz, 2 H), 5.57–5.64 (m, 1 H), 6.94 (s, 1 H),
7.08–7.13 (m, 1 H), 7.19 (d, J = 8.1 Hz, 2 H), 7.21–7.26 (m, 1 H),
7.35 (d, J = 8.1 Hz, 1 H), 7.50 (s, 1 H), 7.60 (d, J = 8.1 Hz, 2 H),
8.05 (d, J = 8.1 Hz, 1 H).
Anal. Calcd for C30H36N4O6S (580.69): C, 62.05; H, 6.25; N, 9.65.
Found: C, 61.81; H, 6.14; N, 9.43.
tert-Butyl 3-{2-[1-(Cyanomethyl)-1H-1,2,3-triazol-4-yl]-1-[(4-
methylphenyl)sulfonyl]ethyl}-1H-indole-1-carboxylate (8h)
Yield: 77%; yellow solid; mp 160–162 °C.
Synthesis 2009, No. 18, 3143–3149 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-[2-(1-Alkyltriazol-4-yl)ethyl]indoles
3147
IR (KBr): 2222, 1730, 1370, 1151 cm–1.
Anal. Calcd for C30H36N4O4S (548.70): C, 65.67; H, 6.61; N, 10.21.
Found: C, 65.90; H, 6.83; N, 10.41.
1H NMR (400 MHz, CDCl3): d = 1.64 (s, 9 H), 2.36 (s, 3 H), 3.57
(dd, J = 11.1, 14.9 Hz, 1 H), 3.87 (dd, J = 4.3, 14.9 Hz, 1 H), 4.84
(dd, J = 4.7, 11.1 Hz, 1 H), 5.09 (d, J = 5.6 Hz, 2 H), 7.08–7.13 (m,
1 H), 7.17 (d, J = 8.5 Hz, 2 H), 7.20–7.23 (m, 2 H), 7.31 (d, J = 8.1
Hz, 1 H), 7.51 (s, 1 H), 7.56 (d, J = 8.5 Hz, 2 H), 8.06 (d, J = 8.1 Hz,
1 H).
13C NMR (100 MHz, CDCl3): d = 21.8, 25.5, 28.3, 37.5, 62.7, 84.7,
111.8, 112.5, 115.4, 119.5, 122.4, 123.1, 125.0, 126.8, 129.3, 129.8,
134.1, 135.2, 144.9, 145.2, 149.4.
tert-Butyl 3-(2-{1-[(6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-
d][1,3]dioxol-4-yl)methyl]-1H-1,2,3-triazol-4-yl}-1-[(4-methyl-
phenyl)sulfonyl]ethyl)-1H-indole-1-carboxylate (8l)
Yield: 81%; reddish oil.
IR (film): 1736, 1372, 1148 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.20 (s, 3 H), 1.33 (s, 3 H), 1.65
(s, 9 H), 2.36 (s, 3 H), 3.04 (s, 3 H), 3.45–3.56 (m, 1 H), 3.73–3.82
(m, 1 H), 4.05–4.15 (m, 1 H), 4.25–4.36 (m, 2 H), 4.47–4.58 (m, 2
H), 4.73–4.84 (m, 2 H), 7.01–7.09 (m, 2 H), 7.12 (d, J = 8.1 Hz, 2
H), 7.14–7.20 (m, 1 H), 7.35 (d, J = 8.0 Hz, 1 H), 7.45 (s, 1 H), 7.54
(d, J = 8.1 Hz, 2 H), 8.06 (d, J = 8.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.8, 25.0, 25.6, 26.5, 28.3, 53.1,
53.2, 55.4, 55.5, 62.9, 77.6, 81.8, 84.5, 85.1, 85.2, 110.1, 111.9,
113.0, 115.3, 119.6, 122.5, 123.0, 124.9, 126.9, 129.3, 129.5, 129.6,
129.8, 134.2, 135.3, 143.3, 145.1, 149.3.
Anal. Calcd for C26H27N5O4S (505.59): C, 61.77; H, 5.38; N, 13.85.
Found: C, 61.89; H, 5.24; N, 13.70.
tert-Butyl 3-{2-[1-(1-Methylhexyl)-1H-1,2,3-triazol-4-yl]-1-[(4-
methylphenyl)sulfonyl]ethyl}-1H-indole-1-carboxylate (8i)
Yield: 76%; reddish oil.
IR (film): 1735, 1371, 1148 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.74–1.00 (m, 5 H), 1.02–1.21 (m,
4 H), 1.28–1.40 (m, 3 H), 1.44–1.60 (m, 2 H), 1.64 (s, 9 H), 2.38 (s,
3 H), 3.48–3.57 (m, 1 H), 3.83 (dd, J = 3.8, 14.6 Hz, 1 H), 4.34–4.44
(m, 1 H), 4.83 (dd, J = 4.3, 11.1 Hz, 1 H), 6.93 (d, J = 3.4 Hz, 1 H),
7.09 (dt, J = 0.8, 7.5 Hz, 1 H), 7.19 (d, J = 8.1 Hz, 2 H), 7.23 (dt,
J = 0.8, 7.9 Hz, 1 H), 7.30–7.36 (m, 1 H), 7.52 (s, 1 H), 7.61 (d,
J = 8.1 Hz, 2 H), 8.05 (d, J = 8.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.1, 21.2, 21.5, 21.8, 22.4, 25.5,
25.9, 26.0, 28.4, 31.3, 37.1, 57.4, 63.1, 84.5, 115.3, 119.6, 119.9,
120.1, 123.0, 124.8, 126.8, 129.0, 129.4, 129.8, 131.2, 134.8, 142.9,
145.0, 149.4.
Anal. Calcd for C33H40N4O8S (652.76): C, 60.72; H, 6.18; N, 8.58.
Found: C, 60.96; H, 6.02; N, 8.77.
tert-Butyl 3-(2-{1-[4-(4-{2-[1-(tert-Butoxycarbonyl)-1H-indol-3-
yl]-2-[(4-methylphenyl)sulfonyl]ethyl}-1H-1,2,3-triazol-1-
yl)butyl]-1H-1,2,3-triazol-4-yl}-1-[(4-methylphenyl)sulfo-
nyl]ethyl)-1H-indole-1-carboxylate (8m)
Alkynylindole 6 (0.73 g, 1.75 mmol) was dissolved in a mixture of
THF (8 mL) and H2O (8 mL), and then azide 7m (0.07 g, 0.5 mmol),
sodium ascorbate (0.082 g, 0.4 mmol) and CuSO4·5H2O (0.032 g,
0.13 mmol) were sequentially added at r.t. The mixture was stirred
for 12 h at r.t., then was diluted with H2O (15 mL) and extracted
with CH2Cl2 (3 × 15 mL). The combined organic extracts were
washed with brine (2 × 5 mL) and then dried (MgSO4). Removal of
the solvent under reduced pressure gave crude 8m which was puri-
fied by column chromatography on silica gel (CHCl3–MeOH,
95:5).
Anal. Calcd for C31H40N4O4S (564.74): C, 65.93; H, 7.14; N, 9.92.
Found: C, 66.18; H, 7.27; N, 10.07.
tert-Butyl 3-{2-(1-Cyclopentyl-1H-1,2,3-triazol-4-yl)-1-[(4-
methylphenyl)sulfonyl]ethyl}-1H-indole-1-carboxylate (8j)
Yield: 80%; brown solid; mp 155–157 °C.
IR (KBr): 1736, 1375, 1144 cm–1.
Yield: 0.35 g (70%); brown solid; mp 120–121 °C.
IR (KBr): 1735, 1368, 1155 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.64 (s, 9 H), 1.65–1.82 (m, 6 H),
1.98–2.09 (m, 2 H), 2.35 (s, 3 H), 3.50 (dd, J = 11.1, 14.9 Hz, 1 H),
3.79 (dd, J = 4.3, 14.9 Hz, 1 H), 4.64–4.68 (m, 1 H), 4.82 (dd,
J = 4.3, 11.1 Hz, 1 H), 6.94 (s, 1 H), 7.07–7.11 (m, 1 H), 7.17 (d,
J = 8.5 Hz, 2 H), 7.21–7.26 (m, 1 H), 7.34 (d, J = 8.1 Hz, 1 H), 7.52
(s, 1 H), 7.59 (d, J = 8.1 Hz, 2 H), 8.05 (d, J = 8.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.7, 24.0, 25.8, 28.3, 33.2, 33.3,
61.7, 62.9, 84.4, 112.2, 115.2, 115.3, 119.6, 120.6, 122.9, 124.8,
126.7, 128.7, 129.3, 129.5, 129.6, 129.7, 134.4, 135.1, 142.8, 144.9,
149.4.
1H NMR (400 MHz, CDCl3): d = 1.37–1.44 (m, 4 H), 1.64 (s, 18
H), 2.34 (s, 6 H), 3.49 (dd, J = 11.1, 14.9 Hz, 2 H), 3.79 (dd, J = 4.7,
14.9 Hz, 2 H), 3.91–4.02 (m, 4 H), 4.82 (dd, J = 4.7, 11.1 Hz, 2 H),
6.90 (d, J = 5.5 Hz, 2 H), 7.02–7.13 (m, 2 H), 7.18 (d, J = 8.2 Hz, 4
H), 7.20–7.24 (m, 2 H), 7.28–7.35 (m, 2 H), 7.33 (d, J = 8.1 Hz, 2
H), 7.59 (d, J = 8.1 Hz, 4 H), 8.02 (d, J = 8.1 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 21.7, 25.7, 26.6, 28.2, 28.3, 49.1,
49.2, 62.8, 84.6, 112.1, 115.2, 119.5, 122.1, 122.9, 124.8, 126.7,
129.3, 129.5, 129.7, 134.3, 135.1, 143.3, 145.0, 149.3.
Anal. Calcd for C29H34N4O4S (534.67): C, 65.15; H, 6.41; N, 10.48.
Found: C, 64.91; H, 6.55; N, 10.32.
Anal. Calcd for C52H58N8O8S2 (987.20): C, 63.27; H, 5.92; N,
11.35. Found: C, 63.41; H, 6.09; N, 11.53.
tert-Butyl 3-{2-(1-Cyclohexyl-1H-1,2,3-triazol-4-yl)-1-[(4-meth-
ylphenyl)sulfonyl]ethyl}-1H-indole-1-carboxylate (8k)
Yield: 76%; yellow solid; mp 156–158 °C.
IR (KBr): 1739, 1375, 1145 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.14–1.40 (m, 4 H), 1.42–1.60 (m,
2 H), 1.64 (s, 9 H), 1.68–1.85 (m, 2 H), 1.90–2.03 (m, 2 H), 2.36 (s,
3 H), 3.51 (dd, J = 10.4, 14.5 Hz, 1 H), 3.82 (dd, J = 4.3, 14.4 Hz, 1
H), 4.14–4.23 (m, 1 H), 4.82 (dd, J = 4.3, 10.7 Hz, 1 H), 6.96 (s, 1
H), 7.08–7.12 (m, 1 H), 7.18 (d, J = 8.1 Hz, 2 H), 7.20–7.26 (m, 1
H), 7.35 (d, J = 8.1 Hz, 1 H), 7.50 (s, 1 H), 7.59 (d, J = 8.1 Hz, 2 H),
8.06 (d, J = 8.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.8, 25.2, 25.9, 28.3, 33.4, 33.5,
60.0, 63.0, 84.5, 112.3, 115.2, 119.6, 119.9, 123.0, 124.8, 124.9,
126.7, 128.8, 129.3, 129.7, 129.8, 134.5, 135.2, 142.7, 145.0, 149.5.
Diethyl [2-(1-Benzyl-1H-1,2,3-triazol-4-yl)-1-(1H-indol-3-
yl)ethyl]malonate (12a); Typical Procedure
N-Boc-1H-indole derivative 8a (0.27 g, 0.5 mmol) was dissolved in
a mixture of THF (2.5 mL) and CH2Cl2 (2.5 mL) and stirring was
continued for 3 h at r.t. After evaporation of the solvents under re-
duced pressure, the crude N-deprotected sulfonylindole was ob-
tained in nearly quantitative yield and was used for the next step
without further purification. To a stirred suspension of NaH (0.036
g, 1.5 mmol) in anhyd THF (6 mL), diethyl malonate (0.16 g, 1.0
mmol) was added at r.t. After the mixture was stirred for 20 min at
r.t., the crude sulfonylindole dissolved in anhyd THF (3 mL) was
added dropwise and the suspension was stirred for 2 h at r.t. The re-
action mixture was quenched with sat. NH4Cl (2 mL) and extracted
with CH2Cl2 (3 × 8 mL). The combined organic layer was dried
(MgSO4) and, after removal of the solvent under reduced pressure,
Synthesis 2009, No. 18, 3143–3149 © Thieme Stuttgart · New York

3148
M. Petrini, R. R. Shaikh
PAPER
the resulting crude product 12a was purified by column chromatog-
raphy on silica gel (hexane–EtOAc, 8:2).
Anal. Calcd for C20H20N6 (344.42): C, 69.75; H, 5.85; N, 24.40.
Found: C, 69.90; H, 5.68; N, 24.53.
Yield: 0.23 g (75%); yellow oil.
IR (film): 3248, 1728 cm–1.
Acknowledgment
1H NMR (400 MHz, CDCl3): d = 0.83 (t, J = 7.3 Hz, 3 H), 1.21 (t,
J = 7.3 Hz, 3 H), 3.24 (d, J = 6.8 Hz, 2 H), 3.80 (q, J = 7.3 Hz, 2 H),
3.89 (d, J = 9.8 Hz, 1 H), 4.05–4.12 (m, 1 H), 4.15 (q, J = 7.3 Hz, 2
H), 5.22 (dd, J = 14.9, 18.4 Hz, 2 H), 6.74 (s, 1 H), 6.86 (d, J = 2.6
Hz, 1 H), 6.91–6.93 (m, 1 H), 6.96–7.01 (m, 1 H), 7.04–7.09 (m, 1
H), 7.19–7.26 (m, 4 H), 7.48 (d, J = 8.1 Hz, 1 H), 8.83 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 13.6, 14.1, 30.1, 36.8, 53.7, 57.5,
61.2, 61.5, 111.4, 114.2, 118.9, 119.2, 121.7, 122.0, 123.1, 126.8,
127.7, 128.4, 128.9, 134.9, 136.1, 146.1, 168.3, 168.6.
Financial support from the University of Camerino and the MIUR
(National Project ‘Sintesi organiche ecosostenibili mediate da nuo-
vi sistemi catalitici’) is gratefully acknowledged.
References
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Anal. Calcd for C26H28N4O4 (460.53): C, 67.81; H, 6.13; N, 12.17.
Found: C, 68.05; H, 6.33; N, 12.38.
[2-(1-Benzyl-1H-1,2,3-triazol-4-yl)-1-(1H-indol-3-yl)ethyl]mal-
ononitrile (12b)
Yield: 76%; yellow oil.
IR (film): 3306, 2358 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.36–3.48 (m, 2 H), 4.06–4.20 (m,
1 H), 4.45–4.54 (m, 1 H), 5.22 (dd, J = 14.9, 18.4 Hz, 2 H), 7.06–
7.18 (m, 4 H), 7.20–7.29 (m, 2 H), 7.31–7.40 (m, 4 H), 7.57 (d,
J = 8.1 Hz, 1 H), 8.73 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 29.1, 29.2, 38.4, 54.3, 111.8, 111.9,
112.6, 112.7, 118.5, 120.5, 122.4, 123.0, 126.2, 128.1, 129.3, 134.6,
136.2, 144.2.
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Anal. Calcd for C22H18N6 (366.42): C, 72.11; H, 4.95; N, 22.94.
Found: C, 71.89; H, 5.16; N, 23.22.
Diethyl [2-(1-Cyclopentyl-1H-1,2,3-triazol-4-yl)-1-(1H-indol-3-
yl)ethyl]malonate (12c)
Yield: 73%; brownish oil.
IR (film): 3391, 1728 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.86 (t, J = 7.3 Hz, 3 H, rotamer
A), 0.88 (t, J = 7.3 Hz, 3 H, rotamer B), 1.24 (t, J = 7.3 Hz, 3 H, rot-
amer A), 1.26 (t, J = 7.3 Hz, 3 H, rotamer B), 1.56–1.82 (m, 6 H),
1.94–2.10 (m, 2 H), 3.23–3.34 (m, 2 H), 3.83 (q, J = 7.3 Hz, 2 H,
rotamer B), 3.85 (q, J = 7.3 Hz, 2 H, rotamer A), 3.94 (dd, J = 6.6,
9.8 Hz, 2 H), 4.09–4.16 (m, 1 H), 4.18 (q, J = 7.3 Hz, 2 H, rotamer
B), 4.20 (q, J = 7.3 Hz, 2 H, rotamer A), 4.65–4.69 (m, 1 H), 6.78
(d, J = 6.4 Hz, 1 H), 6.93–6.95 (m, 1 H), 7.02–7.12 (m, 2 H), 7.25–
7.32 (m, 1 H), 7.48–7.53 (m, 1 H), 8.82 (s, 1 H).
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13C NMR (100 MHz, CDCl3): d = 13.7, 14.2, 24.0, 30.4, 33.3, 36.9,
57.6, 61.3, 61.5, 61.7, 111.4, 114.5, 118.9, 119.3, 120.4, 121.8,
123.0, 127.0, 136.1, 145.5, 168.4, 168.7.
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Pappolla, M. A.; Böker, J.; Hardeland, R.; Pucci, B. J. Med.
Chem. 2006, 49, 2812. (b) Ateş-Alagöz, Z.; Coban, T.;
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Kremastinos, D. T. Chem. Pharm. Bull. 2002, 50, 165.
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Dorronsoro, I.; del Monte-Millán, M.; Valenzuela, R.; Usán,
P.; de Austria, C.; Bartolini, M.; Andrisano, V.; Bidon-
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Anal. Calcd for C24H30N4O4 (438.52): C, 65.74; H, 6.90; N, 12.78.
Found: C, 65.99; H, 6.83; N, 12.55.
[2-(1-Cyclopentyl-1H-1,2,3-triazol-4-yl)-1-(1H-indol-3-yl)eth-
yl]malononitrile (12d)
Yield: 75%; yellow solid; mp 160–163 °C.
IR (KBr): 3391, 2255 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.55–1.88 (m, 4 H), 1.90–2.05 (m,
2 H), 2.12–2.21 (m, 2 H), 3.35–3.48 (m, 2 H), 4.11–4.18 (m, 1 H),
4.55 (d, J = 5.1 Hz, 1 H), 4.78–4.87 (m, 1 H), 7.02–7.19 (m, 2 H),
7.24–7.33 (m, 2 H), 7.38–7.45 (m, 1 H), 7.50–7.62 (m, 1 H), 8.88
(s, 1 H).
13C NMR (100 MHz, CDCl3): d = 24.1, 29.1, 33.4, 38.4, 62.0, 111.9,
112.6, 118.4, 120.2, 121.0, 122.8, 123.0, 126.1, 129.1, 129.6, 134.3,
136.2, 143.5, 144.8.
Synthesis 2009, No. 18, 3143–3149 © Thieme Stuttgart · New York

PAPER
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Synthesis of 3-[2-(1-Alkyltriazol-4-yl)ethyl]indoles
3149
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(18) Thus, the presence of the first triazolyl group would provide
a sort of activation for the formation of the second group, as
evidenced by Finn and co-workers;17 however, this
activation is not strong enough to provide complete
formation of the bisadduct unless a large excess of alkyne is
used.
(19) The nature of the nucleophilic reagents amenable to react
with sulfonylindoles ranges from organometallic reagents
(Grignard and Reformatsky) to enolates and heteronucleo-
philes; see: (a) Shaikh, R. R.; Mazzanti, A.; Petrini, M.;
Bartoli, G.; Melchiorre, P. Angew. Chem. Int. Ed. 2008, 47,
8707. (b) Petrini, M.; Shaikh, R. R. Tetrahedron Lett. 2008,
49, 5645. (c) Ballini, R.; Palmieri, A.; Petrini, M.; Shaikh, R.
R. Adv. Synth. Catal. 2008, 350, 129. (d) Palmieri, A.;
Petrini, M. J. Org. Chem. 2007, 72, 1863. (e) Ballini, R.;
Palmieri, A.; Petrini, M.; Torregiani, E. Org. Lett. 2006, 8,
4093.
(11) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int.
Ed. 2001, 40, 2004.
(12) (a) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
For a recent application, see: (b) Ferrer, C.; Amijs, C. H. M.;
Echavarren, E. M. Chem. Eur. J. 2007, 13, 1358.
Propargylation of 1-acetyl-1H-indole-3-carbaldehyde is also
possible, albeit in low yield (48%); see: (c) Lee, A. S.-Y.;
Chu, S.-F.; Chang, Y.-T.; Wang, S.-H. Tetrahedron Lett.
2004, 45, 1551.
(20) (a) Blass, B. E. Tetrahedron 2002, 58, 9301. (b) Kabalka,
G. W.; Pagni, R. M. Tetrahedron 1997, 53, 7999.
Synthesis 2009, No. 18, 3143–3149 © Thieme Stuttgart · New York