Br?nsted acid catalyzed C3-selective propargylation and benzylation of indoles with tertiary alcohols

Article abstract of DOI:10.1055/s-2008-1072584

A Br?nsted acid catalyzed C3-selective tert-alkylation of indoles using tertiary propargylic and benzylic alcohols has been developed. New C3-propargylated indole derivatives with a quaternary carbon at the propargylic position have been efficiently synth

Full text of DOI:10.1055/s-2008-1072584

LETTER
975
Brønsted Acid Catalyzed C3-Selective Propargylation and Benzylation of
Indoles with Tertiary Alcohols
t
e
rt-Alkylation of
o
I
ndoles berto Sanz,*a Delia Miguel,a Julia M. Álvarez-Gutiérrez,a Félix Rodríguezb
a
Departamento de Química, Área de Química Orgánica, Facultad de Ciencias, Universidad de Burgos,
Pza. Misael Bañuelos s/n, 09001 Burgos, Spain
Fax +34(947)258831; E-mail: rsd@ubu.es
Instituto Universitario de Química Organometálica ‘Enrique Moles’, Universidad de Oviedo, C/Julián Clavería 8, 33006 Oviedo, Spain
b
Received 16 January 2008
lation of indoles at C3-position with tertiary propargylic
and benzylic alcohols under Brønsted acid catalysis.
Abstract: A Brønsted acid catalyzed C3-selective tert-alkylation of
indoles using tertiary propargylic and benzylic alcohols has been
developed. New C3-propargylated indole derivatives with a quater-
nary carbon at the propargylic position have been efficiently synthe-
sized. Reactions were performed in air with undried solvents, and
water was the only side product of the process.
First, we investigated the model reaction of N-methylin-
dole (1a) with tertiary alkynol 2a using some Brønsted
and Lewis acids as catalysts. Alkynol 2a was chosen be-
cause it is an ideal substrate to test the nucleophilic substi-
tution reaction versus the competitive elimination
reaction (which gives the corresponding enyne deriva-
tive). As shown in Table 1, the use of Brønsted acids such
as triflic acid (TfOH), 2,4-dinitrobenzenesulfonic acid
(DNBSA), or p-toluenesulfonic acid (PTSA) as catalysts
in MeCN at room temperature gave rise to the desired
alkylated indole derivative 3aa in good yields (entries 1–
3). Several Lewis acids also catalyzed the process (entries
4–6), but the substitution reactions were significantly
slower and/or less efficient. Finally, the substitution reac-
tion did not take place in the absence of catalyst (entry 7).
As expected, in the absence of the indole counterpart, and
by using any of the catalysts, we observed the exclusive
Key words: catalysis, indoles, alcohols, nucleophiles, alkylations
Facile access to substituted indoles is of general interest
because they are found as building blocks in many natural
products and because they have very important applica-
tions.1 Due to the nucleophilic nature of indolyl com-
pounds,2 there are different ways to perform their
alkylation.3 Among them, 1,2-addition to carbonyl deriv-
atives,4 Michael-type reactions,5 ring opening of epoxides
and aziridines,6 and the Pd-catalyzed allylic substitution
(Tsuji–Trost reaction)7 represent some of the most useful
approaches. Also, it should be noted that few methods for
the introduction of quaternary carbons at the C3-position
of indoles have been reported.8 From the synthetic point
of view, the direct catalytic substitution of indoles with al-
cohols is an attractive reaction due to the easy availability
of alcohols and due to the fact that water is the only by-
product of the process. Thus recently, some transition-
metal-9 and Lewis acid catalyzed10 methodologies for the
direct substitution reaction of alcohols with indoles have
been reported. However, the use of expensive, toxic and/
or moisture-sensitive reagents in most of these methods
limits their practical utility in large-scale synthesis. Much
more appealing is the use of Brønsted acids as catalysts to
perform this process.11 In this context, the development of
new methods for the alkylation of indoles with propargyl-
ic alcohols would be very interesting.12 It should be noted
that the synthesis of C3-propargylated indoles with a qua-
ternary carbon at the propargylic position has not been re-
ported. Moreover, no general method for the benzylation
of indoles with tertiary benzylic alcohols is known.13 Tak-
ing advantage of our experience in Brønsted acid catalysis
for the nucleophilic substitution of alcohols,14 we decided
to check the possibility of performing these new reactions.
Thus, in this paper we wish to report the successful alky-
Table 1 Evaluation of Brønsted or Lewis Acid Catalysts and Con-
ditions for the Nucleophilic Substitution Reaction of 2a with 1aa
Et
Ph
N
1a
catalyst (5 mol%)
solvent, r.t., time
Ph
Me
+
OH
N
Ph
Me
Ph
Et
3aa
2a
Entry
Catalyst
TfOH
DNBSA
PTSA
FeCl3
InBr3
I2
Solvent
MeCN
Time (h)b Yield (%)c
1
2
3
4
5
6
7
2
3
75
68
78
64
70
68
0
MeCN
MeCN
2
MeNO2
Cl(CH2)2Cld
MeCN
24
15
14
24
none
MeCN
a All reactions were carried out with 2a (1.2 equiv).
b Time needed for complete consumption of 1a determined by GC–
MS analysis.
SYNLETT 2008, No. 7, pp 0975–0978
Advanced online publication: 31.03.2008
DOI: 10.1055/s-2008-1072584; Art ID: D01308ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
8
c Isolated yield of 3aa after column chromatography.
d The reaction was carried out at reflux under an N2 atmosphere.

976
R. Sanz et al.
LETTER
formation of the enyne derivative coming from an elimi- followed and analyzed by GC–MS and we did not ob-
nation process in 2a.
serve, in the crude of the reactions, the presence of any by-
product in a significant amount. So, in the cases where the
yield of the isolated product was moderate, we suspect
that this was due to the decomposition of the final indole
derivative 3 under the reaction or purification conditions.
Due to the availability and easiness of handling, PTSA
was selected as catalyst in the following experiments.
Thus, we explored the generality of the reaction by using
different indole derivatives 1a–e and tertiary alkynols 2a–
k15 under the best reaction conditions previously estab- We were also interested in studying the reactivity of ter-
lished, i.e. PTSA as catalyst and MeCN as solvent at room tiary vinyl-substituted alkynols 4.18 Thus, their reaction
temperature (Table 2).
with 1a, under PTSA catalysis, regioselectively gave the
corresponding C3-alkylated indole derivatives 5 in high
yields (Scheme 1).19 A SN2¢-type attack of the indole,
probably favored by the conjugation of the phenyl group
with the enyne moiety, accounts for the formation of these
compounds.
As shown in Table 2, several indoles, including those with
electron-withdrawing substituents at the benzenoid moi-
ety as well as N-unsubstituted ones, were successfully
coupled. As for the alkynol counterpart, internal alkynes
with either an aromatic or heteroaromatic group at the
propargylic position (R3 group),17 or with an aromatic or Having successfully developed an efficient C3-propargy-
alkyl group at the terminal position (R5 group), gave good lation of indoles with tertiary propargylic alcohols, we fi-
results allowing the synthesis of C3-propargylated indoles nally checked the possibility of applying this
in generally high yields (Table 2). All the reactions were methodology to the synthesis of C3-benzylated indoles
Table 2 Propargylation Reactions of Indoles 1 with Tertiary Alkynols 2a,16
R4
R3
R2
OH
R2
R5
PTSA (5 mol%)
MeCN, r.t., time
+
R3
R5
N
R1
R4
N
R1
1
2
3
Entry
1
Indole
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1c
R1
R2
H
Alkynol
2a
2b
2c
R3
Ph
Ph
Ph
Ph
R4
Et
Me
R5
Product
3aa
3ab
3ac
3ad
3ae
3af
Time (h) Yield (%)b
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
Ph
2
78
81
60
80
72
85
57
80
81
70
64
83
46
74
58
81
54
52
2
H
Ph
2
3
H
n-Pr
i-Pr
Me
Me
Me
n-Pr
i-Pr
Me
n-Pr
Me
Me
Me
n-Pr
Me
Et
Ph
2
4
H
2d
2e
Ph
0.5
8
5
H
4-ClC6H4
2-Thc
4-ClC6H4
Ph
Ph
6
H
2f
Ph
1
7
H
2g
2h
2i
n-Bu
n-Bu
n-Bu
Ph
3ag
3ah
3ai
2
8
H
1
9
H
Ph
3
10
11
12
13
14
15
16
17
18
H
2b
2c
Ph
3bb
3bc
3bf
2
H
H
Ph
Ph
6
H
H
2f
2-Thc
4-ClC6H4
Ph
Ph
2.5
5
H
H
2g
2b
2h
2b
2j
n-Bu
Ph
3bg
3cb
3ch
3db
3dj
H
NO2
NO2
1
1c
H
Ph
n-Bu
Ph
1
1d
1d
1e
H
CO2Me
CO2Me
Br
Ph
1
H
Ph
n-Bu
n-Bu
3
H
2k
Ph
Me
3ek
2
a Reaction conditions: 1 (2 mmol), 2 (2.4 mmol), PTSA (0.1 mmol) in MeCN (2 mL) at r.t.
b Isolated yield after column chromatography.
c 2-Thienyl.
Synlett 2008, No. 7, 975–978 © Thieme Stuttgart · New York

LETTER
tert-Alkylation of Indoles
977
Table 3 Benzylation Reactions of Indoles 1 with Tertiary Benzylic Alcohols 6a
Ph Me
R4
R3
OH
R3
PTSA (5 mol%)
MeCN, r.t., time
R2
+
R2
Ph
Me
R4
N
R1
N
R1
1
6
7
Entry
Indole
1a
R1
R2
H
R3
H
H
H
Alcohol
6a
R4
Product
7aa
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
Me
Me
Me
H
Me
n-Bu
Ph
36
20
6
77
62
83
60
71
89
80
72
1a
H
6b
7ab
7ac
1a
H
6c
1d
H
CO2Me
6b
n-Bu
Ph
7db
7dc
25
6c
24
2
1d
H
H
CO2Me
6c
1f
H
Me
Ph
Ph
H
H
H
6c
Ph
7fc
1g
H
6a
Me
n-Bu
7ga
1g
H
6b
7gb
2
a Reaction conditions: 1 (2 mmol), 6 (2.4 mmol), PTSA (0.1 mmol) in MeCN (2 mL) at r.t.
b Isolated yield after column chromatography.
c The reaction was carried out at 50 ºC.
friendly process for the synthesis of C3-substituted in-
doles.
N
Ph
n
Me
R
1a
PTSA (5 mol%)
MeCN, r.t.
Acknowledgment
+
Ph
We gratefully thank Junta de Castilla y León (BU012A06 and
BU029A07) and Ministerio de Educación y Ciencia (MEC) and FE-
DER (CTQ2007-61436/BQU) for financial support. D.M. thanks
MEC for a FPU predoctoral fellowship. J.M.A.-G. and F.R. are gra-
teful to MEC and Fondo Social Europeo (’Ramón y Cajal’ con-
tracts).
N
HO
Me
4a: R = H; n = 1
4b: R = Me; n = 1
4c: R = H; n = 2
5aa (75%)
5ab (68%)
5ac (77%)
n
R
Scheme 1 Reaction of indole 1a with 1-propargylated 2-cycloal-
ken-1-ols 4
References and Notes
(1) Sundberg, R. J. Indoles; Academic Press: San Diego, 1996.
(2) Lakhdar, S.; Westermaier, M.; Terrier, F.; Goumont, R.;
Boubaker, T.; Ofial, A. R.; Mayr, H. J. Org. Chem. 2006, 71,
9088.
(3) For a review, see: Bandini, M.; Melloni, A.; Tommasi, S.;
Umani-Ronchi, A. Synlett 2005, 1199.
with a quaternary carbon at the benzylic position. So, the
reaction of several indoles 1 with tertiary benzylic alco-
hols 6,20 under PTSA catalysis, afforded the correspond-
ing indole derivatives 7 in high yields (Table 3). As
shown in Table 3, indoles 1 with substituents at different
positions were appropriate nucleophiles. Furthermore,
differently substituted tertiary benzylic alcohols 6 could
be coupled without any problems.
(4) For a recent example, see: Kang, Q.; Zhao, Z.-A.; You, S.-L.
J. Am. Chem. Soc. 2007, 129, 1484.
(5) For a review, see: Saracoglu, N. Top. Heterocycl. Chem.
2007, 11, 1.
In summary, we have shown that a simple Brønsted acid,
such as PTSA, is an efficient catalyst for the direct nucleo-
philic substitution of tertiary propargylic and benzylic al-
cohols with indoles. This method allows the preparation
of new C3-propargylated indole derivatives with a quater-
nary center at the propargylic position. Although tertiary
alcohols were used, the competitive elimination reaction
was avoided under the optimized reaction conditions. The
availability of the reagents used, the mild conditions and
the fact that only water was generated as a side product,
make this method an attractive and environmentally
(6) See, for instance: Bandini, M.; Cozzi, P. G.; Melchiorre, P.;
Umani-Ronchi, A. J. Org. Chem. 2002, 67, 5386.
(7) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Org. Lett.
2004, 6, 3199.
(8) See, for instance: (a) Reddy, R.; Jaquith, J. B.; Neelagiri, V.
R.; Saleh-Hanna, S.; Durst, T. Org. Lett. 2002, 4, 695.
(b) Bhuvaneswari, S.; Jeganmohan, M.; Cheng, C.-H. Chem.
Eur. J. 2007, 13, 8285. (c) Jia, Y.-X.; Zhong, J.; Zhu, S.-F.;
Zhang, C.-M.; Zhou, Q.-L. Angew. Chem. Int. Ed. 2007, 46,
5565.
(9) (a) Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Hidai, M.;
Uemura, S. J. Am. Chem. Soc. 2002, 124, 11846.
(b) Kennedy-Smith, J. J.; Young, L. A.; Toste, F. D. Org.
Lett. 2004, 6, 1325. (c) Zaitsev, A. B.; Gruber, S.; Pregosin,
Synlett 2008, No. 7, 975–978 © Thieme Stuttgart · New York

978
R. Sanz et al.
LETTER
P. S. Chem. Commun. 2007, 4692. (d) Whithney, S.; Grigg,
R.; Derrick, A.; Keep, A. Org. Lett. 2007, 9, 3299.
(e) Matsuzawa, H.; Kanao, K.; Miyake, Y.; Nishibayashi, Y.
Org. Lett. 2007, 9, 5561.
(15) Alkynols 2 were synthesized by nucleophilic addition of the
alkynylcerium reagents to the corresponding aryl alkyl
ketones as previously described: Imamoto, T.; Sugiura, Y.;
Takiyama, N. Tetrahedron Lett. 1984, 25, 4233.
(10) (a) Yasuda, M.; Somyo, T.; Baba, A. Angew. Chem. Int. Ed.
2006, 45, 793. (b) Yadav, J. S.; Subba Reddy, B. V.;
Raghavendra Rao, K. V.; Narayana Kumar, G. G. K. S.
Tetrahedron Lett. 2007, 48, 5573. (c) Jana, U.; Maiti, S.;
Biswas, S. Tetrahedron Lett. 2007, 48, 7160. (d) Yadav, J.
S.; Subba Reddy, B. V.; Raghavendra Rao, K. V.;
Narayana Kunar, G. G. K. S. Synthesis 2007, 3205.
(e) Srihari, P.; Bhunia, D. C.; Sreedhar, P.; Mandal, S. S.;
Shyam Sunder Reddy, J.; Yadav, J. S. Tetrahedron Lett.
2007, 48, 8120.
(11) (a) Shirakawa, S.; Kobayashi, S. Org. Lett. 2007, 9, 311.
(b) Motokura, K.; Nakagiri, N.; Mizugaki, T.; Ebitani, K.;
Kaneda, K. J. Org. Chem. 2007, 72, 6006. (c) Le Bras, J.;
Muzart, J. Tetrahedron 2007, 63, 7942.
(12) (a) While preparing this manuscript some works about this
reaction using different Lewis acids as catalysts appeared
(see ref. 10b–e). We have also reported a single example
about the Brønsted acid catalyzed alkylation of indoles with
propargylic alcohols: Sanz, R.; Martínez, A.; Álvarez-
Gutiérrez, J. M.; Rodríguez, F. Eur. J. Org. Chem. 2006,
1383. (b) Remarkably, in all these reactions only secondary
propargylic alcohols are used.
(13) The absence of examples where tertiary alcohols are used is
probably due to their high tendency to undergo elimination
processes under the acidic conditions. Only the alkylation of
N-methylindole with 2-phenylpropan-2-ol has been
reported. See ref. 10c and 11a.
(16) Typical Procedure for the Synthesis of 3-Alkylated
Indole Derivatives 3, 5, and 7; Synthesis of 3-(1,3-
Diphenylpent-1-yn-3-yl)-1-methyl-1H-indole(3aa;Table
2, Entry 1): To a mixture of alcohol 2a (0.567 g, 2.4 mmol)
and N-methylindole (1a; 0.262 g, 2.0 mmol) in analytical
grade MeCN (2 mL), PTSA (0.019 g, 0.1 mmol) was added.
The reaction was stirred at r.t. for 2 h (the completion of the
reaction was monitored by GC–MS and TLC). The solvent
was removed under reduced pressure and the residue was
purified by silica gel column chromatography (eluent:
hexane–Et2O, 10:1) to afford 3aa (0.545 g, 78%) as a white
solid, which was recrystallized in hexane–Et2O (2:1); mp
124–126 ºC. 1H NMR (400 MHz, CDCl3): d = 1.32 (t, J = 7.3
Hz, 3 H), 2.56 (dq, J = 7.2, 14.3 Hz, 1 H), 2.83 (dq, J = 7.2,
14.3 Hz, 1 H), 3.82 (s, 3 H), 7.16–7.24 (m, 2 H), 7.35–7.54
(m, 2 H), 7.66–7.74 (m, 2 H), 7.81 (d, J = 8.0 Hz, 1 H), 7.86
(d, J = 7.2 Hz, 2 H). 13C NMR (100.6 MHz, CDCl3): d = 10.1
(Me), 32.7 (Me), 34.8 (CH2), 45.4 (C), 84.9 (C), 93.7 (C),
109.3 (CH), 118.8 (CH), 119.5 (C), 121.3 (CH), 121.6 (CH),
124.0 (C), 126.3 (C), 126.4 (CH), 126.5 (CH), 127.3 (2 ×
CH), 127.8 (CH), 128.1 (2 × CH), 128.3 (2 × CH), 131.7
(2 × CH), 137.7 (C), 144.6 (C). IR (KBr): 2962, 2930, 1488,
1463, 1326, 758, 741, 701 cm–1. LRMS (EI): m/z = 349 (9)
[M+], 320 (100). HRMS: m/z calcd for C26H23N: 349.1830;
found: 349.1836.
(17) A dialkyl-substituted alkynol, such as 2-methyl-4-phenyl-3-
butyn-2-ol, gave a low yield (28%) of the corresponding
propargylated indole when reacted with 1a.
(18) Alkynols 4 were prepared by addition of phenylethynyl-
lithium to the corresponding 2-cycloalken-1-one at low
temperature in THF.
(19) Trace amounts of the corresponding product coming from a
direct attack of the indole on the propargylic position were
observed in the crude of the reactions when alcohols 4b and
4c were used.
(20) Alcohols 6a and 6c are commercially available. Alcohol 6b
was synthesized by addition of n-BuLi to acetophenone at
low temperature in THF.
(14) See ref. 12 and also: (a) Sanz, R.; Martínez, A.; Miguel, D.;
Álvarez-Gutiérrez, J. M.; Rodríguez, F. Adv. Synth. Catal.
2006, 348, 1841. (b) Sanz, R.; Miguel, D.; Martínez, A.;
Álvarez-Gutiérrez, J. M.; Rodríguez, F. Org. Lett. 2007, 9,
727. (c) Sanz, R.; Miguel, D.; Martínez, A.; Álvarez-
Gutiérrez, J. M.; Rodríguez, F. Org. Lett. 2007, 9, 2027.
(d) Sanz, R.; Martínez, A.; Álvarez-Gutiérrez, J. M.;
Rodríguez, F. Synthesis 2007, 3252. (e) Sanz, R.; Martínez,
A.; Guilarte, V.; Álvarez-Gutiérrez, J. M.; Rodríguez, F.
Eur. J. Org. Chem. 2007, 4642.
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