Bronsted acid catalyzed alkylation of indoles with tertiary propargylic alcohols: Scope and limitations

Article abstract of DOI:10.1002/ejoc.201001055

Direct alkylation of indoles with a wide variety of tertiary propargylic alcohols under Bronsted acid catalysis conditions has been studied. A general and environmentally friendly method for the synthesis of 3-propargylated indoles with quaternary carbon

Full text of DOI:10.1002/ejoc.201001055

FULL PAPER
DOI: 10.1002/ejoc.201001055
Brønsted Acid Catalyzed Alkylation of Indoles with Tertiary Propargylic
Alcohols: Scope and Limitations
Roberto Sanz,*[a] Delia Miguel,[a] Alberto Martínez,[a] Mukut Gohain,[a]
Patricia García-García,[a] Manuel A. Fernández-Rodríguez,[a] Estela Álvarez,[a] and
Félix Rodríguez[b]
Keywords: Indoles / Alkylation / Brønsted acids / Alcohols / Nucleophilic substitution
Direct alkylation of indoles with a wide variety of tertiary
propargylic alcohols under Brønsted acid catalysis conditions
has been studied. A general and environmentally friendly
method for the synthesis of 3-propargylated indoles with
quaternary carbon atoms at their propargylic positions has
been developed. The reactions are highly regioselective with
regard both to the indole and to the alkynol components.
Only with N-unsubstituted 2-arylindoles do competitive SNЈ
reactions take place to afford 3-dienyl- or 3-allenylindoles,
depending on the alkynol moiety. The reactions were carried
out in air with undried solvents, and water was the only side
product.
electrophilic attack of carbocations or related electrophiles
onto aromatic systems[5]) is one of the most useful C–C
bond-forming reactions in organic synthesis, and many ef-
forts have been devoted to the development of improved
procedures for the catalytic Friedel–Crafts alkylations of
indoles.[6] The large amounts of conventional Lewis acids
usually required to promote typical Friedel–Crafts alk-
ylation processes represent serious drawbacks (poor regio-
selectivities, undesired side-reactions of the electrophile, en-
vironmental concerns, etc.). In addition, the alkylation of
indolyl compounds is usually performed with typical elec-
trophiles such as carbonyl compounds,[7] imines,[8] electron-
deficient C=C bonds,[9] epoxides, and aziridines,[10] whereas
the well-known Pd-catalyzed allylic substitution (Tsuji–
Trost reaction) also represents a useful approach.[11] More-
over, enantioselective Friedel–Crafts reactions between
indoles and readily available prochiral electrophilic starting
materials constitute a simple strategy for the preparation of
optically active indole derivatives.[12]
As mentioned above, alkylation of indoles is usually car-
ried out with typical electrophiles. However, direct catalytic
functionalization of indoles with alcohols is an attractive
reaction, due not only to the availability of the starting
materials and the environmentally benign character of
alcohols, but also to the fact that water is the only by-prod-
uct of the process. Recently, the use of π-activated
alcohols[13] (benzylic, propargylic, allylic) has led to the de-
velopment of new catalytic methodologies for Friedel–
Crafts reactions. In this field, several reports in which dif-
ferent Lewis acids[14] and late transition metal salts/com-
plexes[15] have been used as catalysts for direct alkylations
of indoles with alcohols, including few examples of intra-
molecular cycloalkylations,[16] have appeared in recent
Introduction
The indole nucleus is one of the most ubiquitous hetero-
cyclic structures found in nature, and it is a fundamental
constituent of a number of natural and synthetic products
displaying biological activity.[1] The synthesis and function-
alization of indoles has therefore been a major area of focus
for synthetic organic chemists, and numerous methods for
the preparation of indoles have been developed.[2] In this
context, functionalization of the indole ring at the 3-posi-
tion is a fundamental synthetic task in the preparation of
relevant molecules containing indole nuclei.[3]
Indoles are electron-rich heteroaromatic systems that
react with electrophiles much more rapidly than most ben-
zene derivatives. The position in indole most reactive
towards electrophilic substitution is the 3-site, and this
susceptibility of indoles to electrophilic attack makes direct
3-alkylation by carbocations or ion pairs a feasible reac-
tion.[4] However, this nucleophilic nature of indolyl com-
pounds makes them quite reactive to protic and Lewis
acids, and consequently only procedures in which carbo-
cations are generated under relatively mild conditions are
likely to be successful. The Friedel–Crafts reaction (i.e.,
[a] Área de Química Orgánica, Departamento de Química,
Facultad de Ciencias, Universidad de Burgos,
Pza. Misael Bañuelos s/n, 09001 Burgos, Spain
Fax: +34-947-258831
E-mail: rsd@ubu.es
http://www.ubu.es/paginas/grupos_investigacion/cien_biotec/
sintorg/uk/index
[b] Instituto Universitario de Química Organometálica “Enrique
Moles”, Universidad de Oviedo,
C/Julián Clavería 8, 33006 Oviedo, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001055.
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R. Sanz et al.
FULL PAPER
years. However, the use of expensive, toxic, and/or moist- testing nucleophilic substitution vs. competitive elimination,
ure-sensitive catalysts in some of these methods limits their as well as for checking the regioselective outcome of the
practical usefulness in large-scale syntheses. Much more ap- process. As shown in Table 1, reactions in MeCN at room
pealing is the use of Brønsted acids as catalysts in these temperature in the presence of simple Brønsted acid cata-
processes as simple alternatives to some toxic and precious lysts such as triflic acid (TfOH), 2,4-dinitrobenz-
metals.[17]
enesulfonic acid (DNBSA), or p-toluenesulfonic acid
Among π-activated alcohols, propargylic alcohols are ap- (PTSA) took place to afford the desired alkylated indole
propriate substrates for catalyzed propargylic substitution derivative 3aa in good yields and with short reaction times
reactions, which have emerged as useful synthetic tools.[18] (Entries 1–3). Several Lewis acids also catalyzed the process
However, the risk of competing allene formation due to the (Entries 4–6); however, the substitution reactions were sig-
nature of propargylic cations, which are better represented nificantly slower and/or less efficient. As would be expected,
by the corresponding allenium species, as well as the ten- the substitution reaction did not take place in the absence
dency to undergo competitive elimination, are issues that of catalyst (Entry 7), whereas treatment of 2a with PTSA
need to be considered mainly in the case of tertiary propar- (5 mol-%) in the absence of the indole counterpart gave rise
gylic alcohols (Figure 1). In most reports of catalyzed pro- to the stereoselective formation of the enyne derivative –
pargylation reactions, secondary benzylic propargylic (Z)-1,3-diphenylpent-3-en-1-yne – originating from an eli-
alcohols (1-arylprop-2-yn-1-ol derivatives) are therefore mination process in 2a. It is also interesting to note the
usually employed as alkylating agents.
complete regioselectivity observed for this process with re-
gard both to the nucleophile (only 3-attack takes place) and
to the alkynol (exclusive substitution at the α-position of
the propargylic moiety is observed). The absence of forma-
tion of allenic products is significant because the use of ter-
tiary propargylic alcohols or their derivatives in nucleo-
philic substitution reactions usually affords mixtures of re-
gioisomers or mainly the allenyl derivatives.[24]
Table 1. Evaluation of Brønsted and Lewis acid catalysts for the
alkylation of N-methylindole (1a) with the tertiary alkynol 2a.
Figure 1. Propargylic cations from tertiary propargylic alcohols.
Although some methods for the preparation of 3-prop-
argylindoles have been reported,[14c,14e,14g,14h] no prepara-
tively useful synthesis of such compounds with quaternary
centers at their propargylic positions had been described
until our preliminary reports.[19,20] Moreover, it should be
noted that few general methods for the direct introduction
of quaternary carbon atoms at the 3-position of indoles are
known.[21] In addition, the usefulness of 3-propargylindoles
for subsequent gold-catalyzed transformations involving
1,2-indole migration has also been pointed out by our re-
search group.[22] In an extension of our interest in the devel-
opment of strategies for catalytic direct nucleophilic substi-
tutions with alcohols,[23] we wish to report our studies in
this field with indoles as nucleophiles and tertiary prop-
argylic alcohols as electrophiles.
Entry
Catalyst
Solvent
t [h][a]
Yield [%][b]
1
2
3
TfOH
DBNSA
PTSA
FeCl3
InBr3
I2
MeCN
MeCN
MeCN
MeNO2
DCE
MeCN
MeCN
DCM
2
3
2
24
15
14
24
3
75
68
78
64
70[d]
68
–
4
5[c]
6
7
8
9
–
PTSA
PTSA
75
80
MeNO2
2.5
[a] Time needed for complete consumption of 1a as determined by
GC–MS analysis. [b] Isolated yield of 3aa after column chromatog-
raphy. [c] Reaction performed at reflux under N2. [d] The elimi-
nation product (ca. 15%) was also formed.
We selected PTSA as the catalyst for screening of dif-
ferent solvents, due to its ready availability and ease of
handling. Although the alkylation process was also efficient
in CH2Cl2 and MeNO2, no significant improvements in
yield or reactivity with respect to our initial experiment
Results and Discussion
Optimization Studies
We initially selected the reaction between N-methylindole with MeCN (Entries 8–9) were observed. We therefore set-
(1a) and the tertiary alkynol 2a as a model system to assess tled on PTSA as catalyst and MeCN as solvent at room
the catalytic activities of several Brønsted and Lewis acids temperature as the best reaction conditions for exploring
and to determine the optimum reaction conditions. The the scope and limitations of this Friedel–Crafts alkylation
alkynol 2a was chosen because it is an ideal substrate for of indoles with alkynols.
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Alkylation of Indoles with Tertiary Propargylic Alcohols
Alkylation of 2-Unsubstituted Indoles
indoles 3. Significantly, we were able to reduce the reaction
times dramatically by performing the processes under mi-
crowave irradiation conditions (Entries 13–14). The indoles
3am and 3an were isolated in moderate yields.
Reactions with the Benzylic Alkynols 2
The results obtained from the reactions between a series
of 2-unsubstituted indoles 1 and the benzylic tertiary alkyn-
ols 2, catalyzed by PTSA (5 mol-%) under the optimized
reaction conditions, are summarized in Table 2. N-Meth-
ylindole (1a) was successfully coupled with different benz-
ylic alkynols bearing either aromatic (Entries 1–7), het-
eroaromatic (Entry 8), or alkyl substitution (Entries 9–12)
at their terminal positions (R4). Moreover, a wide variety
of alkyl groups, linear (Entries 1–3, 6–9, 11) or branched
(Entries 4–5, 10, 12), are tolerated at the propargylic posi-
tions (R3). In all cases the corresponding 3-propargylated
indoles are obtained regioselectively, generally in high
yields. Whereas functional groups, such as chlorine atoms,
could be present at the aromatic group at the propargylic
position (Entries 6, 11, and 18), when we tested the hin-
dered alkynols 2m and 2n, each bearing a substituent at the
ortho-position of this aromatic group, no conversion was
Not only N-methylindole (1a), but also N-unsubstituted
indoles (Entries 15–25), including those with electron-with-
drawing substituents at C-5 (consequently less nucleophilic;
Entries 20–25) were successfully coupled. Again, the benz-
ylic alkynols 2 with different substitution patterns, both at
the terminal (R4) and propargylic (R3) positions, were ap-
propriate counterparts for the reaction. All the reactions
were monitored and analyzed by GC–MS, and we did not
observe the presence of any byproduct in significant
amounts. The moderate yields obtained in some cases are
probably due to decomposition of the final indole derivative
3 under the reaction or purification conditions.
Reactions with the Dialkyl-Substituted Alkynols 4
We next examined the alkylation of the 2-unsubstituted
observed under the standard conditions. In these cases it indoles 1 with the alkynols 4, each bearing two aliphatic
was necessary to heat the mixture in MeCN at reflux for substituents at the propargylic position (Table 3). Under the
24 h in order to obtain the corresponding functionalized conditions described in Table 2 the reactions were slow, and
Table 2. Alkylation of the indoles 1 with the benzylic alkynols 2; synthesis of the 3-(1-arylpropargyl)indoles 3 (2-Th = 2-thienyl, 3-Th =
3-thienyl).[a]
Entry
1
R1
R2
2
Ar
R3
R4
t [h]
3
Yield [%][b]
1
2
3
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
1c
1d
1d
1d
1e
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
Ph
Ph
Ph
Ph
Et
Me
nPr
iPr
cC3H5
Me
Me
Me
nPr
iPr
Me
cC3H5
Me
Me
Me
nPr
Me
Me
Me
Me
nPr
Me
Me
Et
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3-Th
nBu
nBu
nBu
nBu
Ph
nBu
Ph
Ph
2
2
2
0.5
0.5
8
1
2
1
3
2
2
0.5
0.5
2
6
2.5
5
0.5
1
1
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
78
81
60
80
89
72
85
75
80
81
60
82
54
35[d]
70
64
83
51
62
74
63
81
65
61
59
4
5[c]
6
4-ClC6H4
2-Th
Ph
7
8
9
Ph
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
2j
2k
2l
3aj
4-ClC6H4
Ph
2-BrC6H4
2,6-F2C6H3
Ph
3ak
3al
2m
2n
2b
2c
2g
2k
2o
2b
2i
2b
2o
2p
2o
3am
3an
3bb
3bc
3bg
3bk
3bo
3cb
3ci
3db
3do
3dp
3eo
Ph
2-Th
4-ClC6H4
Ph
Ph
H
H
nBu
nBu
Ph
nBu
Ph
nBu
nBu
nBu
NO2
NO2
CO2Me
CO2Me
CO2Me
Br
Ph
Ph
Ph
Ph
Ph
Ph
1
1
3
2
H
H
Me
[a] Reaction conditions: 1 (2 mmol), 2 (2.4 mmol), PTSA (0.1 mmol) in MeCN (2 mL) at room temp. [b] Isolated yield of 3 after column
chromatography. [c] Carried out at 100 °C under microwave irradiation conditions (see the Supporting Information for details). [d] Isolated
along with 1a.
Eur. J. Org. Chem. 2010, 7027–7039
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R. Sanz et al.
FULL PAPER
heating in MeCN at reflux was required to achieve reason- Table 3. Alkylation of the indoles 1 with the dialkyl-substituted
alkynols 4a–e; synthesis of the 3-(1,1-dialkylpropargyl)indoles 5
able conversions. The difference in reactivity between the
alkynols 2 and the alkynols 4a–e is not surprising, because
(cC6H9 = cyclohex-1-enyl).[a]
the stabilities of the propargylic carbocations proposed as
intermediates for the substitution reactions should be sig-
nificantly decreased when an aryl group at the propargylic
position is changed for an alkyl group (see Figure 1). Once
again, as in the reactions of the hindered alkynols 2m and
2n, microwave irradiation proved to be an advantageous
methodology, particularly in terms of reaction times. Al-
though both N-methylindole (1a, Entries 1–5) and indole
Yield
Entry
1
R1
4
R2 R3
R4
t [min]
5
[%][b]
(1b, Entries 6–7) could be coupled under these conditions,
better results were obtained in the former case, probably
due to its higher nucleophilicity. With regard to the alkynol
counterpart, both linear (Entries 1–2, 4–7) and cyclic (En-
try 3) aliphatic substituents are tolerated at the propargylic
positions. In addition, the triple bond can variously bear an
aromatic (Entries 1–3, 6–7), an alkenyl (Entry 5), or an
alkyl group (Entry 4) at the terminal position. Although an
excess of alkynol is always used,[25] the corresponding 3-
propargylated indoles 5 were obtained only in moderate
yields in all cases.
1
2
3
4
5
6
7
1a Me 4a Me Me
1a Me 4b
1a Me 4c
1a Me 4d Me Me nC5H11
1a Me 4e Me Me cC6H9
1b
1b
Ph
Ph
Ph
20
20
70
50
30
60
60
5aa
5ab
5ac
5ad
5ae
5ba
5bb
42
47
Et
Et
–(CH2)5-
38
36[c]
41[c]
30
H
H
4a Me Me
4b Et Et
Ph
Ph
40[c]
[a] Reaction conditions:
1 (2 mmol), 2 (2.4 mmol), PTSA
(0.1 mmol) in MeCN (2 mL) at 100 °C under microwave irradiation
conditions (see the Supporting Information for details). [b] Isolated
yield of 5 after column chromatography. [c] Yield estimated from
the mixture of the corresponding propargylated indole 5 and the
starting indole 1.
Because the lower reactivities of the dialkyl-substituted
alkynols 4 relative to the benzylic alkynols 2 are probably
due to the inferior stabilities of the positively charged inter-
mediates, and in view of the known ability of the cyclopro-
pyl group to stabilize carbocations,[26] we envisaged that the tions between different 2-unsubstituted indoles 1 and a
cyclopropyl-substituted alkynols 6 might be appropriate series of cyclopropylalkynols 6 took place in short times
substrates for nucleophilic substitutions with the indoles 1 at room temperature to afford the corresponding alkylated
under mild conditions. Gratifyingly, we found out that reac- indoles 7 in high yields (Table 4).
Table 4. Alkylation of the indoles 1 with the cyclopropyl-substituted alkynols 6; synthesis of the 3-(1-cyclopropylpropargyl)indoles 7 (2-
Th = 2-thienyl, 3-Th = 3-thienyl, cC6H9 = cyclohex-1-enyl).[a]
Entry
1
R1
R2
6
R3
R4
t [h]
7
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1d
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
6a
6b
6c
6d
6e
6f
Me
Me
Me
Me
Me
Me
Me
Me
Me
cC3H5
2-Th
Me
Me
Me
Ph
3-Th
cC3H5
nBu
1
0.5
2
13
0.5
2
2
0.5
1
1.5
1
1
3
14
24
7aa
7ab
7ac
7ad
7ae
7af
7ag
7ah
7ai
85
93
73
77
92
85
79
60
82
81
95
71
62
50
87
cC6H9
C(Me)=CH2
(CH2)2Ph
SiMe3
2-PhC6H4
Ph
Ph
Ph
(CH2)2Ph
tBu
2-PhC6H4
6g
6h
6i
6j
7aj
6k
6a
6g
6l
7ak
7ba
7bg
7bl
H
H
H
H
CO2Me
6i
Me
7di
[a] Reaction conditions: 1 (1 mmol), 2 (1.2 mmol), PTSA (0.05 mmol) in MeCN (2 mL) at room temp. [b] Isolated yield of 7 after column
chromatography.
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Alkylation of Indoles with Tertiary Propargylic Alcohols
Furthermore, the process is broadly general, and so both
N-methylindole (1a, Entries 1–11) and N-unsubstituted ind-
oles such as 1b (Entries 12–14), as well as those with elec-
tron-withdrawing substituents at the benzenoid moiety (En-
try 15), are suitable nucleophiles for the coupling. With re-
gard to the cyclopropyl-substituted alkynol component,
aryl (Entries 1, 9–12, 15), heteroaryl (Entry 2), alkenyl (En-
tries 5–6), linear alkyl (Entries 4, 7, 13), branched alkyl (En-
try 14), and cyclic alkyl systems (Entry 3), and also silyl
(Entry 8) groups, are well tolerated at the terminal positions
of the triple bonds, whereas the presence of a methyl or an
additional cyclopropyl or heteroaromatic group at the other
propargylic position leads to similar results (Entry 1 vs. 10–
11). It is interesting to note that the alkylation reactions
Scheme 1. Reaction between 2-phenylindole (1f) and the alkynol 2b
take place with complete regioselectivity in all the cases in- under PTSA catalysis conditions.
volving the cyclopropyl-substituted alkynol. No products
arising from a competitive ring-opening pathway, as occurs
in other related catalyzed nucleophilic substitution pro- thus confirming our hypothesis (Table 5, Entry 1). There
cesses,[27] were observed.
are no known methods for the direct synthesis of 3-dienyl-
indole derivatives from unfunctionalized starting indole
compounds,[28] so we decided to evaluate the scope of this
procedure for the synthesis of 3-dienylindoles. It should be
noted that these compounds have been used as precursors
for the synthesis of alkaloids through Diels–Alder cycliza-
tions.[29]
We first studied the reactions between the different 2-
arylindole derivatives 1f–l and tertiary benzylic alkynols 2
possessing linear substituents sterically more demanding
than methyl (R2 ϶ H) at their propargylic positions
(Table 5). When the alkynol 2a was tested against 2-phen-
ylindoles containing electron-donating (Entry 2) or elec-
tron-withdrawing (Entry 3) groups on their benzenoid moi-
eties, the corresponding dienylindole derivatives 8 were ex-
clusively obtained in good yields.[30] In addition, aryl
groups with different electronic natures and substitution
patterns (Entries 6–8, 12) as well as a heteroaryl group (En-
try 9), are tolerated well at C-2 of the indole, also exclu-
Alkylation of 2-Substituted NH-Indoles
Once we had established the scope of the propargylation
of 2-unsubstituted indoles, we turned our attention to the
alkylation of 2-substituted ones. We were interested in
evaluating the effects that the additional groups could have
in the substitution reactions and in the possibility of syn-
thesizing 2,3-disubstituted indoles by the developed meth-
odology. We first decided to use 2-arylindoles, because aro-
matic substituents at C-2 significantly increase the nucleo-
philic character of the indole nucleus.
Alkylation of N-Unsubstituted 2-Arylindoles
a) Reactions with the Benzylic Alkynols 2
We started our studies by treating the commercially avail- sively yielding 3-dienyl derivatives. With regard to the sub-
able 2-phenylindole (1f) with the tertiary alkynol 2b under stituent at the terminal position of the triple bond, it was
the conditions previously established as optimal for 2-un- found that the alkynol 2i, bearing an alkyl group at this
substituted indoles (Scheme 1). Although the expected 3- position, mainly afforded the 3-propargylated derivative 3fi
propargylated indole 3fb was obtained as major product, (Entry 5). This seems to indicate that an aryl group is re-
we found that in this case the reaction was not completely quired at the terminal position of the acetylene moiety in
selective, and a significant amount of the 3-dienyl derivative order to favor the formation of 3-dienylindoles over that of
8fb was also isolated. The generation of 8fb could be ex- 3-propargylindoles. In addition, functionalized aryl (En-
plained in terms of a competitive SNЈ substitution reaction tries 10–12) and heteroaromatic groups (Entry 13) can be
leading to an allene derivative such as 9fb, which could un- present at one of the propargylic positions, whereas dif-
dergo further isomerization to the corresponding 1,3-diene. ferent linear alkyl groups can be located at the other pro-
The driving force for this acid-promoted isomerization pargylic position.
could be the extension of the conjugated system that now
reaches from the phenyl group at the 2-position of the 2-phenylindole (1f) and the alkynol 2d, bearing an isopropyl
indole to the terminal alkene. group instead of a linear alkyl group at the propargylic po-
On the other hand, when we tested the reaction between
We reasoned that the allenylation pathway should be fa- sition, as in the examples shown in Table 5, the allene deriv-
vored if the steric hindrance at the propargylic position in ative 9fd was isolated after purification on alumina (Table 6,
the starting alkynol were increased, and so we performed Entry 1). This result is consistent with the idea that the al-
the reaction between 1f and the alkynol 2a, bearing a bulk- lenylation pathway is favored over the propargylation path-
ier substituent than 2b (Et instead of Me). In this case the way when bulky substituents are present at the propargylic
3-dienylindole 8fa was exclusively obtained in good yield, positions of the tertiary alkynols. Moreover, the isomeriza-
Eur. J. Org. Chem. 2010, 7027–7039
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Table 5. Alkylation of the 2-arylindoles 1f–l with the benzylic α-monosubstituted alkylalkynols 2; synthesis of the 3-dienylindoles 8[a] (2-
Th = 2-thienyl).
Entry
1
R1
Ar1
2
Ar2
R2
R3
t [h]
8
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
1f
1g
1h
1f
1f
1i
H
OMe
Cl
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
2a
2a
2a
2c
2i
2a
2a
2a
2a
2q
2r
2q
2s
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Et
Ph
Ph
Ph
Ph
nBu
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
0.5
1
1
0.5
1.5
4
1
1
3
2
8fa
8ga
8ha
8fc
70
69
67
66
–
70
60
65
61
73
67
72
58
[c]
Et
–
4-FC6H4
4-MeOC6H4
2-MeOC6H4
2-Th
Ph
Ph
4-FC6H4
Ph
Me
Me
Me
Me
Me
Et
8ia
8ja
8ka
8la
8fq
8fr
8iq
8fs
1j
1k
1l
1f
1f
1i
4-ClC6H4
4-ClC6H4
4-ClC6H4
2-Th
H
H
H
2
2
2
Me
Et
1f
[a] Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), PTSA (0.025 mmol) in MeCN (2 mL) at room temp. [b] Isolated yield of 8 after
column chromatography. [c] The 3-propargylindole 3fi was the major isomer in the crude reaction mixture, and it was isolated in 65%
yield.
tion of the allene to the diene seems to be slowed down
In view of the potential interest of 3-allenylindoles and
when the substituent is branched instead of linear, thus al- the fact that no direct route to these compounds had been
lowing the isolation of the corresponding 3-allenylindole described previously, we decided to synthesize a collection
derivatives 9 in these particular cases.
of allene derivatives 9 through PTSA-catalyzed reactions
Table 6. Alkylation of 2-arylindoles of type 1 with benzylic (branched alkyl)alkynols of type 2; synthesis of the 3-allenylindoles 9 (2-Th
= 2-thienyl).[a]
Entry
1
Ar1
2
Ar2
R
t [h]
9
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1f
1i
1j
1l
1f
1j
1j
1f
1f
1f
1i
1j
1j
1l
Ph
4-FC6H4
4-MeOC6H4
2-Th
2d
2d
2d
2d
2t
2e
2t
2u
2v
2w
2w
2v
2w
2v
Ph
Ph
Ph
Ph
iPr
iPr
iPr
iPr
cC3H5
cC3H5
cC3H5
cC4H7
cC5H9
cC6H11
cC6H11
cC5H9
cC6H11
cC5H9
1
1
1
2
4
3
4
1
2
2
2
3
2
2
9fd
9id
9jd
9ld
9ft
9je
9jt
9fu
9fw
9fw
9iy
9jv
9jw
9lv
65
67
82[c]
70[d]
75[c]
80[c]
75[c]
69
Ph
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
Ph
Ph
4-MeOC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
70
81
4-FC6H4
4-MeOC6H4
4-MeOC6H4
2-Th
82
65[c]
82[c]
68
[a] Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), PTSA (0.025 mmol) in MeCN (2 mL) at room temp. [b] Isolated yield of 9. [c] PTSA
(20 mol-%, 0.1 mmol). [d] The corresponding 3-propargylindole 3ld (ca. 10%) was also detected.
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Eur. J. Org. Chem. 2010, 7027–7039

Alkylation of Indoles with Tertiary Propargylic Alcohols
between 2-arylindoles of type 1[31] and a series of benzylic tion to their behavior towards the tertiary cyclopropyl-sub-
(branched alkyl)alkynols (Table 6). Indoles with different stituted alkynols 6, bearing no aromatic groups at their pro-
aryl substituents at their 2-positions, including electron- pargylic positions (Table 7). Different cyclopropyl-substi-
withdrawing (Entry 2), electron-donating (Entry 3), and tuted alkynols 6 were coupled under the standard condi-
heteroaromatic (Entry 4) groups, were efficiently coupled tions with indoles bearing either an aryl (Entries 1, 3–5) or
with the alkynol 2d to yield the corresponding allene deriva- a heteroaryl (Entry 2) group at C-2, to yield the 2-aryl-3-
tives 9. Furthermore, it is not only the isopropyl group that propargylindoles 10 in good yields. Even in the cases of the
is tolerated at the propargylic position: cyclopropyl- (En- alkynols 6j and 6m, bearing groups sterically more de-
tries 5–7), cyclobutyl- (Entry 8), cyclopentyl- (Entries 9, 12, manding than methyl at their other propargylic positions,
14), and cyclohexyl-substituted alkynols (Entries 10, 11, 13) the direct substitution pathway was preferred (Entries 4–5).
also behave in the same way to afford the 3-allenylindoles These direct propargylation reactions contrast with the al-
9 in good yields and with short reaction times. In most lenylation pathway observed for the benzylic alkynols 2,
cases, the indole derivatives 9 were easily isolated by simple showing how the regioselectivity of the substitution (SN vs.
filtration as they precipitated from the reaction medium, SNЈ) in 2-arylindoles is controlled by the structure of the
whereas variable amounts of the corresponding dienes 8 re- starting propargylic alcohol.[33] The SNЈ substitution lead-
main in solution. In some cases the starting compounds are ing to allenes or dienes seems to be favored only for tertiary
not soluble in MeCN, in which cases larger amounts of propargylic alcohols with aryl substituents at both the
PTSA (20 mol-%) had to be added to ensure completion of propargylic and the terminal positions, and with a bulky
the reaction.
substituent at the other propargylic position.
In addition, the acid-catalyzed isomerization of the all-
enes 9 to the dienes 8 was also examined. The 3-allenyl-
indoles 9fd, 9id, and 9jd were transformed into the corre-
sponding 3-dienylindoles 8 (Scheme 2) in almost quantita-
tive yields on heating of acetonitrile solutions of the allenyl
derivatives at reflux in the presence of PTSA (5 mol-%).
These results provide further evidence for the mechanism
outlined in Scheme 1, supporting the intermediacy of the
allenes 9 in the formation of the dienes 8.
Table 7. Reactions between 2-arylindoles of type 1 and cyclopropyl-
substituted alkynols of type 6; synthesis of the 2-aryl-3-(1-cyclo-
propyl)propargylindoles 10 (2-Th = 2-thienyl).[a]
Entry
1
Ar
Ph
6
R1
R2 t [h] 10 Yield [%][b]
1
2
3
4
5
1f
6a
6a
6c
Me
Me
Me cC3H5
Ph
Ph
1
1
1
1
2
10a
10b
10c
10d
10e
67
77
80
76
75
1l 2-Th
1f
1f
1f
Ph
Ph
Ph
6j cC3H5 Ph
6m
Et
Ph
[a] Reaction conditions:
(0.05 mmol) in MeCN (2 mL) at room temp. [b] Isolated yield of
10 after column chromatography.
1
(1 mmol), 6 (1.2 mmol), PTSA
Scheme 2. Synthesis of the 3-dienylindoles 8 from the 3-allenyl-
indoles 9.
In addition, if the alkylation of a 2-arylindole, such as
the functionalized indole 1m, with a benzylic branched-
alkyl alkynol such as 2d was carried out at reflux instead
of room temperature, the corresponding 3-dienylindole 8md Alkylation of 2-Methylindole (1n)
was directly obtained and isolated in high yield
At this point, we wondered if 2-alkylindoles would follow
(Scheme 3).[32]
the same behavior as observed for 2-arylindoles or if, in
contrast, the regioselectivity of the substitution would also
be controlled by the nature of the substituent at C-2 in the
indole component. To this end, we started by performing a
reaction, under the standard conditions, between the com-
mercially available 2-methylindole (1n) and the benzylic al-
kynol 2b, bearing a methyl group at the propargylic posi-
tion. As in the alkylation of 2-phenylindole (1f), the corre-
sponding 3-propargylated derivative 11a was obtained in
good yield (Table 8, Entry 1). However, a distinctive out-
come was observed for the alkynols 2a and 2d, possessing
a larger linear substituent (Entry 2) or a larger branched
Scheme 3. Synthesis of the 4-bromo-3-dienylindole 8md.
b) Reactions with the Cyclopropyl-Substituted Alkynols 6
Once we had established the reactivity of 2-arylindoles substituent (Entry 3) at their propargylic positions. Whereas
with the tertiary benzylic alkynols 2, we turned our atten- the 3-allenylindoles 9 had been obtained with 2-phenyl-
Eur. J. Org. Chem. 2010, 7027–7039
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7033

R. Sanz et al.
FULL PAPER
indole (1f), the 3-propargylindoles 11 were now formed as tions of their triple bonds (Entries 4 and 5) and those bear-
major products in the reactions of 2-methylindole (1n). Not ing two alkyl groups at their propargylic positions (En-
surprisingly, the direct substitution pathway is also pre- try 6).
ferred for alkynols with alkyl groups at the terminal posi-
Alkylation of 1,2-Disubstituted Indoles
Table 8. Reactions between 2-methylindole (1n) and the benzylic
alkynols 2 or the cyclopropyl-substituted alkynol 6a; synthesis of
Because only the alkylation of 2-substituted indoles with
the 2-methyl-3-propargylindoles 11.[a]
a free NH moiety had so far been discussed, we next evalu-
ated the influence of substitution at the nitrogen atom.
Coupling between 1,2-dimethylindole (1o) and tertiary pro-
pargylic alcohols with different selected substitution pat-
terns thus led in all cases to the 3-propargylindoles 12 in
moderate to good yields (Table 9, Entries 1–6).
We next studied the reaction behavior of 1-methyl-2-
phenylindole (1p), and again the direct substitution path-
Entry Alkynol
R1
R2
R3
t [h]
11
Yield [%][b]
way (SN) was preferred for all the alcohols tested (Table 9,
Entries 7–15), including benzylic alkynols with alkyl groups
bulkier than methyl at their propargylic positions and aryl
groups at the terminal positions of their triple bonds (En-
tries 7 and 10). In contrast, when coupled with 2-phenyl-
indole (1f), these alkynol derivatives had exclusively led to
the corresponding allene or diene derivatives 8 or 9
(Tables 5 and 6). In these cases, the higher nucleophilicity
of this indole 1p probably accounts for the high obtained
yields of the corresponding 1-methyl-2-phenyl-3-prop-
argylindoles 13. It therefore seems that the presence of a
1
2
3
4
5
6
2b
2a
2d
2i
Ph
Ph
Ph
Ph
Ph
Me
Et
iPr
nPr nBu
iPr
Ph
Ph
Ph
2.5
2
1
3
2
11a
11b
11c
11d
11e
11f
72
64[c]
80
73
2j
nBu
Ph
60
6a
cC3H5 Me
2
71[d]
[a] Reaction conditions: 1n (1 mmol), 2 or 6 (1.2 mmol), PTSA
(0.05 mmol) in MeCN (2 mL) at room temp. [b] Isolated yield of 11
after column chromatography. [c] The corresponding 3-dienylindole
8na was also isolated (14%) and characterized. [d] Isolated along
with trace amounts of 1n.
Table 9. Reactions between the 1,2-disubstituted indoles 1o–q and the alkynols 2, 4, and 6; synthesis of the 1,2-disubstituted 3-propargyl-
indoles 12–14 (2-Th = 2-thienyl).[a]
Entry
1
R1
R2
Alkynol
R3
R4
R5
t [h]
12–14
Yield [%][b]
1
2
3
1o
1o
1o
1o
1o
1o
1p
1p
1p
1p
1p
1p
1p
1p
1p
1q
1q
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a
2b
2i
2m
4a
6n
2a
2b
2i
2x
4d
6c
6d
6l
6n
2a
2w
Ph
Ph
Ph
Et
Me
nPr
Me
Me
cC3H5
Et
Me
nPr
cC3H5
Me
cC3H5
cC3H5
cC3H5
cC3H5
Et
Ph
Ph
nBu
nBu
Ph
nBu
Ph
Ph
2
8.5
4
1
1
1
3
4
8.5
2
0.3
2
2
2
0.5
2
12a
12b
12c
12d
12e
12f
13a
13b
13c
13d
13e
13f
13g
13h
13i
59[c]
69
61
4
Ph
81
5[d]
6
Me
cC3H5
Ph
Ph
Ph
2-Th
Me
Me
Me
Me
cC3H5
Ph
40
60[e]
84
7
8
9
82
64
nBu
Ph
10
11[d]
12
13
14
15
16
17
81
nC5H11
cC3H5
nBu
tBu
nBu
Ph
50[f]
86
88
80
92
89
14a
14b
Ph
Ph
cC6H11
Ph
1
84
[a] Reaction conditions: 1 (1 mmol), alkynol (1.2 mmol), PTSA (0.05 mmol) in MeCN (2 mL) at room temp. [b] Isolated yield of 12–14
after column chromatography. [c] The 3-dienylindole 8oa was also isolated (20%). [d] Carried out under microwave irradiation conditions
at 100 °C (see the Supporting Information for details). [e] The corresponding 3-dienylindole was detected in trace amounts in the crude
mixture. [f] Isolated along with small amounts of 1p.
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Alkylation of Indoles with Tertiary Propargylic Alcohols
substituent at the nitrogen atom favors the SN reaction over ditions were generally used, and reaction times were kept
the SNЈ reaction. This hypothesis was further confirmed short. Moreover, reactions were performed with undried
when the reaction with 1,2-diphenylindole (1q) was exam- solvents under air, and water was the only side product. We
ined and the 3-propargylindoles 14a and 14b were exclu- can therefore conclude that a general, operationally simple,
sively obtained in high yields (Table 9, Entries 16 and 17), and environmentally friendly procedure with wide scope for
thus confirming that substitution at the nitrogen atom, the synthesis of 3-propargylated indoles with quaternary
either with an aryl or an alkyl group, suppresses the allenyl- carbon atoms at their propargylic positions has been estab-
ation (SNЈ) pathway.
lished.
Alkylation of Indoles with the Tertiary Terminal
Propargylic Alcohols 15
Experimental Section
General Procedure for the Syntheses of the 3-Propargyl-1H-indoles
3, 7, 10–14, and 16 and of the 3-Dienyl-1H-indoles 8: PTSA (5 mol-
Finally, the alkylation of a variety of N-unsubstituted 2-
substituted and 1,2-disubstituted indoles with the more
%) was added to
a mixture of the corresponding alkynol
challenging terminal benzylic alkynols 15a and 15b was (1.2 equiv.) and the indole derivative (1 equiv.) in analytical-grade
MeCN (2 mLmmol–1). The reaction mixture was stirred at room
temperature until the indole had been consumed, as determined by
considered (Table 10).
Table 10. Reactions between the indoles 1 and the terminal alkyn-
ols 15.[a]
GC–MS and/or TLC. The crude mixture was neutralized by the
addition of concd. NaOH (2 drops); H2O (20 mL) and EtOAc
(15 mL) were added. The separated aqueous phase was extracted
with EtOAc (3ϫ15 mL). The combined organic layers were dried
with anhydrous Na2SO4 and concentrated under reduced pressure.
Alternatively, after the addition of concd. NaOH, the solvent was
removed under reduced pressure, and the residue was purified by
silica gel column chromatography (eluent: mixtures of hexane/
Et2O) to afford the corresponding 3-alkylated indoles.
Synthesis of 1-Methyl-3-(4-methyl-1,3-diphenylpent-1-yn-3-yl)-1H-
indole (3ad): This compound (Table 2, Entry 4) was produced ac-
cording to the General Procedure from 4-methyl-1,3-diphenylpent-
1-yn-3-ol (2d, 601 mg, 2.4 mmol) and N-methylindole (1a, 262 mg,
2 mmol) in MeCN (4 mL) with PTSA (19 mg, 0.1 mmol) as cata-
lyst. The reaction mixture was stirred at room temp. for 30 min,
and the residue was purified by column chromatography on silica
gel (eluent: hexane/Et2O, 10:1) to afford 3ad (581 mg, 80%) as a
white solid, which was recrystallized from hexane/Et2O (2:1). M.p.
Yield
Entry
1
R1
R2
H
15
R3
R4
t [h] 16
[%][b]
1
2
1a
1f
1f
1n
1n
1o
Me
H
H
H
H
15a Ph cC3H5
1
1
16aa
16fa
74
77
51
70
53
69
Ph 15a Ph cC3H5
Ph 15b Ph Et
Me 15a Ph cC3H5
Me 15b Ph Et
3[c]
4
0.5 16fb
16na
0.5 16nb
16oa
1
5[c]
6
Me Me 15a Ph cC3H5
1
1
3
110–112 °C. H NMR (300 MHz, CDCl3): δ = 1.04 [d, J(H,H) =
[a] Reaction conditions:
1 (1 mmol), 15 (1.2 mmol), PTSA
6.5 Hz, 3 H, CH3CHCH3], 1.39 [d, 3J(H,H) = 6.5 Hz, 3 H,
(0.05 mmol) in MeCN (2 mL) at room temp. [b] Isolated yield of
16 after column chromatography. [c] Reaction performed under mi-
crowave irradiation conditions at 100 °C (see the Supporting Infor-
mation for details).
3
CH3CHCH3], 2.97 [sept, J(H,H) = 6.5 Hz, 1 H, CH(CH3)2], 3.79
(s, 3 H, NCH3), 7.07 [t, 3J(H,H) = 7.5 Hz, 1 H, ArH], 7.15–7.23
(m, 2 H, ArH), 7.25 (s, 1 H, NCH), 7.26–7.47 (m, 6 H, ArH), 7.55–
3
7.68 (m, 2 H, ArH), 7.77 [d, J(H,H) = 7.5 Hz, 2 H, ArH], 7.87 [d,
3J(H,H) = 8.1 Hz, 1 H, ArH] ppm. 13C NMR (75.4 MHz, CDCl3):
δ = 19.1 (CH3), 20.3 (CH3), 32.9 (CH3), 36.3 (CH), 50.8 (C), 86.3
(C), 92.0 (C), 109.2 (CH), 118.7 (C), 118.8 (CH), 121.5 (CH), 121.6
(CH), 124.2 (C), 126.2 (CH), 126.68 (C), 126.74 (CH), 127.4
(2ϫCH), 127.8 (CH), 127.9 (2ϫCH), 128.3 (2ϫCH), 131.8
Regardless of the structure of the indole, we isolated the
3-propargylated indole derivatives 16 as main products in
moderate to good yields after short reaction times. In the
case of the less reactive alkynol 15b it was necessary to heat
the reaction mixture by microwave irradiation to obtain
good conversions in short reaction times.
(2ϫCH), 137.5 (C), 144.8 (C) ppm. IR (KBr): ν = 2972, 2950,
˜
1486, 1324, 763, 745, 721, 696 cm–1. LRMS (70 eV, EI): m/z (%) =
320 (100) [M – C3H7]+. HRMS (70 eV, EI): calcd. for C27H25N
363.1987; found 363.1990. C27H25N (363.2): calcd. C 89.21, H 6.93,
N 3.85; found C 89.04, H 6.96, N 3.82.
Conclusions
Synthesis of 3-[2-Cyclopropyl-4-(thiophen-3-yl)but-3-yn-2-yl]-1-
methyl-1H-indole (7ab): This compound (Table 4, Entry 2) was pro-
duced according to the General Procedure from 2-cyclopropyl-4-
(thiophen-3-yl)but-3-yn-2-ol (6b, 230 mg, 1.2 mmol) and N-meth-
ylindole (1a, 131 mg, 1 mmol) in MeCN (2 mL) with PTSA
(9.5 mg, 0.05 mmol) as catalyst. The reaction mixture was stirred
at room temp. for 30 min, and the residue was purified by column
chromatography on silica gel (eluent: hexane/Et2O 25:1) to afford
7ab (284 mg, 93%) as a yellow oil: Rf = 0.29 (hexane/Et2O, 20:1).
The scope and limitations of Brønsted acid catalyzed di-
rect alkylation reactions between indoles and tertiary pro-
pargylic alcohols have been studied. The effects of the na-
ture of the substituents both on the indole and on the
alcohol components have been analyzed. Direct substitu-
tion leading to 3-propargylated indoles was found to be the
preferred reaction pathway in most cases, and only with N-
unsubstituted 2-arylindoles does a competitive SNЈ reaction
take place to afford 3-dienyl- or 3-allenylindoles. Mild con- 1H NMR (300 MHz, CDCl3): δ = 0.62–0.70 [m, 2 H, CH(CHH)2],
Eur. J. Org. Chem. 2010, 7027–7039
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7035

R. Sanz et al.
FULL PAPER
0.77–0.88 [m, 2 H, CH(CHH)2], 1.46–1.60 [m, 1 H, CH(CH2)2], mixture was stirred at room temp. for 3 h, and the residue was
1.96 (s, 3 H, CH3), 3.81 (s, 3 H, NCH3), 7.15–7.17 (m, 1 H, ArH), purified by column chromatography on silica gel (eluent: hexane/
7.18 (s, 1 H, ArH), 7.21–7.30 (m, 2 H, ArH), 7.31–7.37 (m, 1 H,
Et2O, 7:1) to afford 11d (251 mg, 73%) as a yellow foam. Rf = 0.41
(hexane/Et2O, 4:1). 1H NMR (300 MHz, CDCl3): δ = 0.95–1.05 [m,
6 H, (CH2)2CH3 and (CH2)3CH3], 1.44–1.68 [m, 6 H, CH2CH2CH3
3
3
ArH), 7.40 [d, J(H,H) = 8.1 Hz, 1 H, ArH], 7.44 [dd, J(H,H) =
2.9, 1.1 Hz, 1 H, ArH], 8.13 [d, 3J(H,H) = 8.0 Hz, 1 H, ArH] ppm.
13C NMR (75.4 MHz, CDCl3): δ = 2.2 (CH2), 3.2 (CH2), 21.2
(CH), 29.6 (CH3), 32.7 (CH3), 37.1 (C), 77.3 (C), 92.1 (C), 109.5 CH2(CH2)2CH3 and NCCH3], 2.63 [td, J(H,H) = 12.3, 4.5 Hz, 1
(CH), 118.8 (CH), 120.4 (C), 121.2 (CH), 121.5 (CH), 122.9 (C), H, CHHCH2CH3], 6.98–7.05 (m, 1 H, ArH), 7.11 [td, J(H,H) =
and CH2(CH2)2CH3], 2.28–2.44 [m,
6
H, CHHCH2CH3,
3
3
125.0 (CH), 125.6 (CH), 126.2 (C), 127.8 (CH), 130.2 (CH), 137.8
(C) ppm. LRMS (70 eV, EI): m/z (%) = 305 (59) [M]+, 290 (77),
277 (56), 264 (92), 157 (45), 144 (100), 133 (51), 115 (54), 89 (48).
HRMS (70 eV, EI): calcd. for C20H19NS 305.1238; found 305.1234.
9.3 Hz, 1 H, ArH], 7.18–7.25 (m, 2 H, ArH), 7.27–7.34 (m, 2 H,
ArH), 7.54–7.60 (m, 3 H, ArH), 7.73 (br. s, 1 H, NH) ppm. 13C
NMR (75.4 MHz, CDCl3): δ = 13.8 (CH3), 14.4 (CH3), 14.5 (CH3),
18.2 (CH2), 19.2 (CH2), 22.2 (CH2), 31.2 (CH2), 45.0 (CH2), 45.5
(C), 84.7 (C), 84.9 (C), 110.2 (CH), 115.1 (C), 119.0 (CH), 120.5
(CH), 120.9 (CH), 126.0 (CH), 127.2 (2ϫCH), 127.9 (2ϫCH),
Synthesis of 5-Methoxy-2-phenyl-3-[(1Z,3E)-1,3-diphenylpenta-1,3-
dienyl]-1H-indole (8ga): This compound (Table 5, Entry 2) was pro-
duced according to the General Procedure from 1,3-diphenylpent-
1-yn-3-ol (2a, 123 mg, 0.52 mmol) and 5-methoxy-2-phenyl-1H-in-
dole (1g, 112 mg, 0.5 mmol) in MeCN (2 mL) with PTSA (5 mg,
0.025 mmol) as catalyst. The reaction mixture was stirred at room
temp. for 30 min, and the residue was purified by column
chromatography on silica gel (eluent: hexane/Et2O 5:1) to afford
8ga (152 mg, 69%) as a white solid. M.p. 95–97 °C. 1H NMR
(300 MHz, CDCl3): δ = 1.58 [d, 3J(H,H) = 7.1 Hz, 3 H, CH3], 3.68
(s, 3 H, OCH3), 5.48 [dq, 3J(H,H) = 6.9, 1.1 Hz, 1 H, CHCH3],
6.49 [d, 3J(H,H) = 2.3 Hz, 1 H, ArH], 6.73–6.80 (m, 3 H, ArH),
6.85 [dd, 3J(H,H) = 6.7, 3.0 Hz, 2 H, ArH], 7.01 [d, 3J(H,H) =
8.7 Hz, 1 H, ArH], 7.13 (s, 1 H, ArH), 7.47–7.20 (m, 9 H, ArH),
132.2 (C), 134.8 (C), 147.4 (C) ppm. IR (KBr): ν = 3396, 2955,
˜
2926, 1699, 1682 cm–1. LRMS (70 eV, EI): m/z (%) = 343 (11) [M]+,
320 (100). HRMS (70 eV, EI): calcd. for C25H29N, 343.2300; found
343.2299.
Synthesis
of 1,2-Dimethyl-3-(4-phenyldec-5-yn-4-yl)-1H-indole
(12c): This compound (Table 9, Entry 3) was produced according
to the General Procedure from 4-phenyldec-5-yn-4-ol (2i, 276 mg,
1.2 mmol) and 1,2-dimethyl-1H-indole (1o, 145 mg, 1 mmol) in
MeCN (2 mL) with PTSA (9.5 mg, 0.05 mmol) as catalyst. The re-
action mixture was stirred at room temp. for 4 h, and the residue
was purified by column chromatography on silica gel (eluent: hex-
ane/Et2O, 20:1) to afford 12c (218 mg, 61%) as a yellow foam. Rf
= 0.46 (hexane/Et2O, 10:1). 1H NMR (300 MHz, CDCl3): δ = 1.10
3
7.62 [dd, J(H,H) = 7.8, 1.6 Hz, 2 H, ArH], 7.76 (br. s, 1 H, NH)
3
3
ppm. 13C NMR (75.4 MHz, CDCl3): δ = 15.2 (CH3), 55.8 (CH3),
102.7 (CH), 111.0 (CH), 113.0 (C), 121.1 (CH), 125.4 (CH), 126.2
(2ϫCH), 126.7 (2ϫCH), 126.9 (2ϫCH), 127.3 (CH), 127.4
(2ϫCH), 127.5 (CH), 127.6 (CH), 127.9 (CH), 128.3 (2ϫCH),
128.4 (2ϫCH), 129.6 (C), 131.0 (C), 132.8 (C), 136.9 (C), 137.3
(C), 139.9 (C), 141.9 (C), 142.4 (C), 153.9 (C) ppm. LRMS (70 eV,
EI): m/z (%) = 441 (24) [M]+, 412 (100), 380 (9). HRMS (70 eV,
EI): calcd. for C32H27NO, 441.2093; found 441.2072.
[t, J(H,H) = 7.2 Hz, 3 H, (CH2)nCH3], 1.13 [t, J(H,H) = 7.4 Hz,
3 H, (CH2)nCH3], 1.51–1.80 [m, 6 H, CH2CH2CH3 and CH2-
(CH2)2CH3], 2.43 (s, 3 H, NCCH3), 2.47 [t, 3J(H,H) = 7.0 Hz, 2
H, CH2(CH2)2CH3], 2.53 [td, 3J(H,H) = 12.2, 4.7 Hz, 1 H,
CHHCH2CH3], 2.81 [td, 3J(H,H)
CHHCH2CH3], 3.68 (s, 3 H, NCH3), 7.15 [t, J(H,H) = 7.5 Hz, 1
H, ArH], 7.25 [d, J(H,H) = 8.1 Hz, 1 H, ArH], 7.31 [d, J(H,H)
=
12.2, 4.2 Hz,
1
H,
3
3
3
3
= 7.1 Hz, 1 H, ArH], 7.34–7.43 (m, 3 H, ArH), 7.67 [d, J(H,H) =
7.5 Hz, 2 H, ArH], 7.85 [d, 3J(H,H) = 8.0 Hz, 1 H, ArH] ppm. 13
C
Synthesis of 3-(2-Cyclopropyl-4-phenylbut-3-yn-2-yl)-2-(thiophen-2-
yl)-1H-indole (10b): This compound (Table 7, Entry 2) was pro-
duced according to the General Procedure from 2-cyclopropyl-4-
phenylbut-3-yn-2-ol (6a, 224 mg, 1.2 mmol) and 2-(thiophen-2-yl)-
1H-indole (1l, 199 mg, 1 mmol) in MeCN (2 mL) with PTSA
(9.5 mg, 0.05 mmol) as catalyst. The reaction mixture was stirred
at room temp. for 1 h, and the residue was purified by column
chromatography on silica gel (eluent: hexane/Et2O 10:1) to afford
10b (283 mg, 77%) as a white solid. M.p. 70–72 °C. 1H NMR
(300 MHz, CDCl3): δ = 0.30–0.42 (m, 1 H, CHHCHCH2), 0.47–
0.53 (m, 1 H, CH2CHCHH), 0.72–0.86 [m, 2 H, CH(CHH)2], 1.38–
NMR (75.4 MHz, CDCl3): δ = 12.1 (CH3), 13.8 (CH3), 14.5 (CH3),
18.9 (CH2), 19.3 (CH2), 22.2 (CH2), 29.3 (CH3), 31.3 (CH2), 45.7
(CH2), 46.0 (C), 84.6 (C), 85.2 (C), 108.7 (CH), 114.9 (C), 118.8
(CH), 120.0 (CH), 120.7 (CH), 125.9 (CH), 126.8 (C), 127.1
(2ϫCH), 127.8 (2ϫCH), 134.7 (C), 136.4 (C), 148.0 (C) ppm.
LRMS (70 eV, EI): m/z (%) = 357 (41) [M]+, 314 (100), 300 (17),
145 (30). HRMS (70 eV, EI): calcd. for C26H31N 357.2456; found
357.2455. C25H29N (343.5): calcd. C 87.41, H 8.51, N 4.08; found
C 87.29, H 8.56, N 4.05.
Synthesis of 3-(2-Cyclopropyl-5,5-dimethylhex-3-yn-2-yl)-1-methyl-
2-phenyl-1H-indole (13h): This compound (Table 9, Entry 14) was
produced according to the General Procedure from 2-cyclopropyl-
5,5-dimethylhex-3-yn-2-ol (6l, 200 mg, 1.2 mmol) and 1-methyl-2-
phenyl-1H-indole (1p, 207 mg, 1 mmol). The reaction mixture was
stirred at room temp. for 2 h, and the residue was purified by col-
umn chromatography on silica gel (eluent: hexane/Et2O, 20:1) to
afford 13h (284 mg, 80%) as a white solid. M.p. 122–124 °C. 1H
3
1.52 [m, 1 H, CH(CH2)2], 1.86 (s, 3 H, CH3), 7.08 [dd, J(H,H) =
5.1, 3.6 Hz, 1 H, ArH], 7.14–7.38 (m, 9 H, ArH), 7.42 [dd, 3J(H,H)
3
= 5.1, 1.0 Hz, 1 H, ArH], 7.95 (br. s, 1 H, NH), 8.33 [d, J(H,H)
= 8.0 Hz, 1 H, ArH] ppm. 13C NMR (75.4 MHz, CDCl3): δ = 2.9
(CH2), 4.3 (CH2), 22.0 (CH), 30.5 (CH3), 38.3 (C), 83.3 (C), 93.1
(C), 110.8 (CH), 119.5 (CH), 120.0 (C), 122.3 (CH), 122.6 (CH),
124.0 (C), 125.9 (C), 126.7 (CH), 127.1 (CH), 127.3 (C), 127.6
(CH), 128.1 (2ϫCH), 130.1 (CH), 131.7 (2ϫCH), 135.5 (C), 135.6
(C) ppm. LRMS (70 eV, EI): m/z (%) = 367 (53) [M]+, 352 (80),
338 (48), 326 (100), 291 (84), 223 (77), 199 (62), 152 (75), 127 (76).
HRMS (70 eV, EI): calcd. for C25H21NS 367.1395; found 367.1393.
NMR (300 MHz, CDCl3):
δ = –0.08 to 0.05 (m, 1 H,
CHHCHCH2), 0.16–0.31 (m, 1 H, CH2CHCHH), 0.48–0.64 [m, 2
H, CH(CHH)2], 0.82–0.94 [m, 1 H, CH(CH)2], 1.18 [s, 9 H,
C(CH3)3], 1.55 (s, 3 H, CH3), 3.33 (s, 3 H, NCH3), 7.14 [t, 3J(H,H)
3
= 7.4 Hz, 1 H, ArH], 7.25 [d, J(H,H) = 7.1 Hz, 1 H, ArH], 7.29
Synthesis of 2-Methyl-3-(4-phenyldec-5-yn-4-yl)-1H-indole (11d):
This compound (Table 8, Entry 4) was produced according to the
General Procedure from 4-phenyldec-5-yn-4-ol (2i, 276 mg,
1.2 mmol) and 2-methyl-1H-indole (1n, 131 mg, 1 mmol) in MeCN
(2 mL) with PTSA (9.5 mg, 0.05 mmol) as catalyst. The reaction
[d, 3J(H,H) = 5.5 Hz, 1 H, ArH], 7.32–7.46 (m, 5 H, ArH), 8.33
[dd, 3J(H,H) = 8.1, 0.6 Hz, 1 H, ArH] ppm. 13C NMR (75.4 MHz,
CDCl3): δ = 2.6 (CH2), 4.3 (CH2), 21.9 (CH), 27.5 (C), 30.2 (CH3),
31.3 (3ϫCH3), 32.1 (CH3), 37.5 (C), 81.3 (C), 90.8 (C), 109.1 (CH),
117.9 (C), 118.6 (CH), 121.5 (CH), 122.6 (CH), 126.8 (C), 127.80
7036
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 7027–7039

Alkylation of Indoles with Tertiary Propargylic Alcohols
(CH), 127.84 (CH), 128.4 (CH), 131.5 (CH), 131.7 (CH), 135.0 (C), MeCN (2 mL). The reaction mixture was stirred at room temp. for
135.8 (C), 136.7 (C) ppm. LRMS (70 eV, EI): m/z (%) = 355 (30)
1 h (completion of the reaction was monitored by GC-MS and
[M]+, 340 (100), 327 (79), 314 (41), 298 (18), 282 (15), 268 (15), 233 TLC), after which a solid had precipitated. This was filtered to
(13), 220 (13). HRMS (70 eV, EI): calcd. for C26H29N, 355.2300;
found 355.2294. C26H29N (355.5): C 87.84, H 8.22, N 3.94; found
C, 87.71, H 8.25, N 3.92.
afford 9id (149 mg, 67%) as a pale yellow solid. M.p. 168–170 °C.
3
1H NMR (300 MHz, CDCl3): δ = 1.02 [d, J(H,H) = 6.5 Hz, 3 H,
3
CH3CHCH3], 1.23 [d, J(H,H) = 6.5 Hz, 3 H, CH3CHCH3], 2.83–
2.97 [m, 1 H, CH(CH3)2], 6.94 [t, 3J(H,H) = 8.4 Hz, 2 H, ArH],
7.10 [t, 3J(H,H) = 7.4 Hz, 1 H, ArH], 7.16–7.35 (m, 9 H, ArH),
7.38–7.57 (m, 6 H, ArH), 8.19 (br. s, 1 H, NH) ppm. 13C NMR
(75.4 MHz, CDCl3): δ = 22.2 (CH3), 22.5 (CH3), 29.6 (CH), 104.7
(C), 109.3 (C), 110.9 (CH), 115.6 (CH), 115.8 [d, 2J(C,F) = 25.4 Hz,
2ϫCH], 120.4 [d, 3J(C,F) = 3.8 Hz, 2ϫCH], 122.7 (CH), 126.5
(2ϫCH), 126.9 (CH), 127.1 (2ϫCH), 128.4 (2ϫCH), 128.7
(2ϫCH), 128.78 (C), 127.82 (C), 129.6 (CH), 129.7 (CH), 134.5
Synthesis of 3-(1-Cyclopropyl-1-phenylprop-2-ynyl)-1-methyl-1H-
indole (16aa): This compound (Table 10, Entry 1) was produced ac-
cording to the General Procedure from 1-cyclopropyl-1-phen-
ylprop-2-yn-1-ol (15a, 207 mg, 1.2 mmol) and 1-methylindole (1a,
131 mg, 1 mmol) in MeCN (2 mL) with PTSA (9.5 mg, 0.05 mmol)
as catalyst. The reaction mixture was stirred at room temp. for 1 h,
and the residue was purified by column chromatography on silica
gel (eluent: hexane/Et2O, 10:1) to afford 16aa (211 mg, 74%) as a
white solid. M.p. 114–116 °C. 1H NMR (300 MHz, CDCl3): δ =
1
(C), 136.0 (C), 136.5 (C), 137.2 (C), 162.5 [d, J(C,F) = 247.6 Hz,
1 C], 206.3 (C) ppm. LRMS (70 eV, EI): m/z (%) = 443 (16) [M]+,
400 (100), 366 (19), 322 (42). HRMS (70 eV, EI): calcd. for
C32H26FN 443.2049; found 443.2061. C32H26FN (443.6): C 86.65,
H 5.91, N 3.16; found C, 86.80, H 5.93, N 3.13.
0.56–0.66 (m,
1 H, CHHCHCH2), 0.69–0.78 (m, 1 H,
CH2CHCHH), 0.80–0.90 [m, 2 H, CH(CHH)2], 1.60–1.75 [m, 1 H,
CH(CH2)2], 2.45 (s, 1 H, CϵCCH), 3.84 (s, 3 H, NCH3), 6.92–7.05
(m, 1 H, ArH), 7.17–7.38 (m, 7 H, ArH), 7.57–7.65 (m, 2 H, ArH)
ppm. 13C NMR (75.4 MHz, CDCl3): δ = 2.5 (CH2), 3.8 (CH2), 21.2
(CH), 32.9 (CH3), 45.5 (C), 72.7 (CH), 84.6 (C), 109.3 (CH), 118.9
(CH), 119.3 (C), 121.2 (CH), 121.7 (CH), 126.0 (C), 126.6 (CH),
127.2 (2ϫCH), 127.3 (CH), 128.1 (2ϫCH), 137.8 (C), 145.2 (C)
ppm. LRMS (70 eV, EI): m/z (%) = 285 (78) [M]+, 270 (21), 257
(100), 244 (90), 202 (22), 157 (43), 144 (82). HRMS (70 eV, EI):
calcd. for C21H19N 285.1517; found 285.1511.
Typical Procedure for the Synthesis of the 3-(Buta-1,3-dienyl)-1H-
indoles 8 from the 3-(Propa-1,2-dienyl)-1H-indoles 9. Synthesis of
3-[(Z)-4-Methyl-1,3-diphenylpenta-1,3-dienyl]-2-phenyl-1H-indole
(8fd): PTSA (6 mg, 0.03 mmol) was added to a mixture of 3-(4-
methyl-1,3-diphenylpenta-1,2-dienyl)-2-phenyl-1H-indole
(9fd,
128 mg, 0.3 mmol) in analytical-grade MeCN (1 mL). The reaction
mixture was stirred at reflux for 5 h (until the isomerization reac-
tion was complete, as determined by GC–MS). The solvent was
removed under reduced pressure, and the residue was purified by
column chromatography on silica gel (eluent: hexane/Et2O, 10:1)
to afford 8fd (121 mg, 95%) as a pale yellow solid. M.p. 53–55 °C.
1H NMR (300 MHz, CDCl3): δ = 1.55 (s, 3 H, CH3), 1.75 (s, 3 H,
CH3), 6.60–6.75 (m, 5 H, ArH), 6.94 [ddd, 3J(H,H) = 7.9, 6.6,
1.2 Hz, 1 H, ArH], 7.02 [d, 3J(H,H) = 7.9 Hz, 1 H, ArH], 7.13
[ddd, 3J(H,H) = 8.1, 6.6, 1.4 Hz, 1 H], ArH, 7.16–7.22 (m, 1 H,
General Procedure for the Synthesis of the 3-(1,1-Dialkylpropargyl)-
1H-indoles 5: In a heavy-walled 10 mL vial, PTSA (5 mol-%) was
added to a mixture of the corresponding alkynol (2.4 mmol) and
indole derivative (2 mmol) in MeCN (2 mL). The reaction vessel
was sealed and subjected to microwave irradiation (50 W) at 100 °C
with stirring for the required time (see Table 3) until the alkynol
had disappeared, as determined by GC–MS and/or TLC. The reac-
tion mixture was allowed to cool to room temperature and neutral-
ized by the addition of 2 drops of concd. NaOH. The solvent was
removed under reduced pressure, and the residue was purified by
silica gel column chromatography to afford the corresponding 3-
propargylindoles.
3
ArH), 7.27–7.38 (m, 7 H, ArH), 7.50 [dd, J(H,H) = 8.2, 1.5 Hz, 2
H, ArH], 7.58 [dd, 3J(H,H) = 8.0, 1.7 Hz, 2 H, ArH], 7.89 (br. s, 1
H, NH) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 21.6 (CH3), 22.2
(CH3), 110.2 (CH), 113.5 (C), 119.3 (CH), 120.7 (CH), 122.0 (CH),
124.6 (CH), 126.3 (2ϫCH), 126.8 (2ϫCH), 127.0 (2ϫCH), 127.1
(CH), 127.2 (CH), 128.29 (2ϫCH), 128.33 (2ϫCH), 128.6
(2ϫCH), 129.4 (C), 132.1 (CH),132.8 (C), 134.25 (C),134.30 (C),
135.31 (C), 135.34 (C), 135.7 (C),141.3 (C), 142.7 (C) ppm. LRMS
(70 eV, EI): m/z (%) = 425 (45) [M]+, 410 (12), 348 (100), 293 (23),
293 (69). HRMS (70 eV, EI): calcd. for C32H27N 425.2143; found
425.2155.
Synthesis of 1-Methyl-3-(2-methyl-4-phenylbut-3-yn-2-yl)-1H-indole
(5aa): This compound (Table 3, Entry 1) was produced according
to the General Procedure from 2-methyl-4-phenylbut-3-yn-2-ol (4a,
384 mg, 2.4 mmol) and N-methylindole (1a, 262 mg, 2 mmol) in
MeCN (2 mL) with PTSA (19 mg, 0.1 mmol) as catalyst. The reac-
tion mixture was stirred under microwave irradiation conditions
(50 W) at 100 °C for 20 min, and the residue was purified by col-
umn chromatography on silica gel (eluent: hexane/Et2O, 15:1) to
afford 5aa (219 mg, 40%) as a yellow foam. Rf = 0.30 (hexane/
Et2O, 10:1). 1H NMR (300 MHz, CDCl3): δ = 2.08 (s, 6 H,
2ϫCH3), 3.84 (s, 3 H, NCH3), 7.18 (s, 1 H, NCH), 7.41–7.53 (m,
Supporting Information (see footnote on the first page of this arti-
cle): Complete experimental procedures, characterization data, and
1H and 13C NMR spectra for all the compounds, COSY and
NOESY spectra of 8fa and 8ga, and ORTEP diagram for com-
pound 8md.
3
6 H, ArH), 7.67–7.73 (m, 2 H, ArH), 8.30 [d, J(H,H) = 7.9 Hz, 1
H, ArH] ppm. 13C NMR (75.4 MHz, CDCl3): δ = 30.8 (2ϫCH3),
31.2 (CH3), 32.5 (C), 80.4 (C), 97.2 (C), 109.5 (CH), 118.8 (CH),
120.9 (C), 121.0 (CH), 121.5 (CH), 124.1 (C), 124.7 (CH), 125.9
(C), 127.6 (CH), 128.2 (2ϫCH), 131.7 (2ϫCH), 137.8 (C) ppm.
LRMS (70 eV, EI): m/z (%) = 273 (23) [M]+, 258 (100). HRMS
(70 eV, EI): calcd. for C20H19N 273.1517; found 273.1513.
Acknowledgments
We gratefully thank the Junta de Castilla y León (BU021A09 and
GR-172) and the Ministerio de Educación y Ciencia (MEC) and
FEDER (CTQ2007-61436/BQU and CTQ2009-09949/BQU) for fi-
nancial support. D. M. and A. M. thank the MEC for MEC-FPU
predoctoral fellowships. M. G. thanks the MEC for a “Young For-
eign Researchers” contract (SB2006-0215). M. A. F.-R. and P. G.-
G. also thank the MEC for “Ramón y Cajal” and “Juan de la Ci-
erva” contracts.
Typical Procedure for the Synthesis of the 3-(Propa-1,2-dienyl)-1H-
indoles 9. Synthesis of 2-(4-Fluorophenyl)-3-(4-methyl-1,3-di-
phenylpenta-1,2-dienyl)-1H-indole (9id): Table 6, Entry 2. PTSA
(5 mg, 0.025 mmol) was added to a mixture of 4-methyl-1,3-di-
phenylpent-1-yn-3-ol (2d, 130 mg, 0.52 mmol) and 2-(4-fluo-
rophenyl)-1H-indole (1i, 106 mg, 0.5 mmol) in analytical-grade
Eur. J. Org. Chem. 2010, 7027–7039
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7037

R. Sanz et al.
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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the (1Z,3Z) isomer were detected in the crude mixtures. After
column chromatographic purification, we usually isolated the
major isomer slightly contaminated with the minor one, proba-
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[32] The structure of 8md was confirmed by single-crystal X-ray
diffraction analysis: CCDC-773561 (8md·THF) contains the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[33] In addition, the reaction between the dialkyl-substituted alk-
ynol 4a and 2-phenylindole (1f) also afforded the 3-propargyl-
indole derivative, although it could not be completely purified.
Received: July 26, 2010
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Published Online: November 12, 2010
Eur. J. Org. Chem. 2010, 7027–7039
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7039