Three-component indium-mediated domino allylation of 1H-indole-3- carbaldehyde with electron-rich (hetero)arenes: Highly efficient access to variously functionalized indolylbutenes

Article abstract of DOI:10.1002/ejoc.200701160

We have developed a three-component, one-pot domino reaction that combines the allylindation of 1H-indole-3-carbaldehyde with the dehydrative alkylation of stabilized C nucleophiles (e.g., electron-rich heteroarenes, electron-rich aromatics, and stabilized enols) or N nucleophiles (e.g., azoles). Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200701160

FULL PAPER
DOI: 10.1002/ejoc.200701160
Three-Component Indium-Mediated Domino Allylation of 1H-Indole-3-
carbaldehyde with Electron-Rich (Hetero)arenes: Highly Efficient Access to
Variously Functionalized Indolylbutenes
Francesca Colombo,[a] Giancarlo Cravotto,[b] Giovanni Palmisano,*[a] Andrea Penoni,[a] and
Massimo Sisti[a]
Keywords: Indium / Domino reactions / Aldehydes / Allylation / Heterocycles / Nitrogen heterocycles
We have developed a three-component, one-pot domino re-
aromatics, and stabilized enols) or N nucleophiles (e.g.,
action that combines the allylindation of 1H-indole-3-carbal- azoles).
dehyde with the dehydrative alkylation of stabilized C
nucleophiles (e.g., electron-rich heteroarenes, electron-rich
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
The ubiquitous presence of the indole skeleton in a large
number of naturally occurring and biologically important
compounds has elicited intense research aimed to facilitate
its synthesis and functionalization. Moreover, the indole
unit has been recognized as a component of highly specific
information-transmitting molecules, a role it plays because
it can bind to many receptors with a high degree of affinity.
Consequently, much efforts is being devoted to develop ef-
ficient methods for the installation of a variety of functional
groups on the indole scaffold.[1]
Following our interest in this area we revisited the
Barbier-type indium-mediated allylation[2,3] (hereafter
called allylindation) of 1H-indole-3-carbaldehyde (1) in the
presence of azoles (e.g., pyrazole). At variance with results
previously reported by others,[4] we anticipated that adduct
2 could be obtained by a three-component, one-pot domino
process (as shown in the Scheme 1)[5,6]
Inspired by successful and ready reaction with N nucleo-
philes, we proceeded to develop a C–C bond-forming reac-
tion by merging allylindation with a dehydrative Friedel–
Crafts-type alkylation. If successful, this approach would
facilitate the access (via common intermediate 3) to a vari-
ety of structurally diverse products by simply changing the
C nucleophile chosen to react with it. The present report
Scheme 1.
describes the results of this study and their applications to
the synthesis of nonsymmetrical bis(indolyl)-, heteroaryl-
(indolyl)-, and alkyl(indolyl)butenes.[6,7]
[a] Dipartimento di Scienze Chimiche e Ambientali, Università Results and Discussion
dell’Insubria,
Via Valleggio 11, 22100 Como, Italy,
Fax: +39-031-2386449
We started from the allylindation of 1 in the presence of
indole (as a neutral C nucleophile, i.e. one possessing rela-
tively high-lying HOMOs) to obtain the already-known in-
dole 5; standard conditions were used as described by Ku-
mar et al.[4] Treatment of 1 with allyl bromide (1 equiv.) and
indole (1 equiv.) in the presence of indium metal (0.7 equiv.)
E-mail: giovanni.palmisano@uninsubria.it
[b] Dipartimento di Scienza e Tecnologia del Farmaco, Università
di Torino,
Via Giuria 9, 10125 Torino, Italy
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Table 1. Optimization of reaction conditions for allylindation of aldehyde 1 in the presence of indole.
FULL PAPER
Entry
Solvents
1/allyl bromide/In/indole
Temperature [°C]
t [h]
Yield [%][a]/[%][b]
1
2
THF/H2O (2:1)
THF/H2O (1:1)
CH2Cl2
DMF
MeOH
MeCN/H2O (1:1)
MeCN/H2O (1:1)
MeCN
MeOH
THF/H2O (1:1)
MeCN/H2O (1:1)
1:1:0.7:1
1:2:1.4:1
1:2:1.4:1
1:2:1.4:1
1:2:1.4:1
1:3.3:1.1:1
1:3.3:1.1:1
1:3.3:1.1:1
1:3.3:1.1:1
1:2:1.4:1
1:3.3:1.1:1
room temp.
50
40
50
3
2
2
2
2
4
4
6
6
2
6
40–55[c]/11–17[c]
86/10
35/21
33/25
15/25
73/12
25/20
49/16
57/21
3
4[d]
5
50
6[e]
7
room temp.
room temp.
50
50
50
50
8[e]
9[e]
10[f]
11[f]
61/11
65/13
[a] Isolated yields based on aldehyde 1. [b] Isolated yields of 6. [c] Yield range over three runs. [d] KI (1 equiv.) was added. [e] HCOOH
(0.1 equiv.) was added. [f] High-intensity ultrasonic irradiation (20 kHz, 250 W).
in THF/H2O (2:1) at 30 °C for 3 h afforded the desired ad- looked particularly promising on the basis of previous work
duct 5. In our hands, however, the reaction often failed to by Whitesides.[9] In fact, treatment of 1 with this catalyst
go to completion and its isolated yield varied from 40 to (0.1 equiv.) at room temperature cleanly afforded 5 (Table 1,
55% (three runs; Table 1, Entry 1). As conversions were un- Entry 6) in a pleasing 73% yield; no unreacted aldehyde
satisfactory, we undertook an investigation to find how they remained (TLC). In the absence of HCOOH, the reaction
could be improved. We identified five main factors that in- was slower and led to a mixture of products (Table 1, En-
fluenced reaction efficiency and selectivity: (1) the solvent, try 7). In the presence of HCOOH (0.1 equiv.), MeCN or
(2) the stoichiometric ratio of reactants, (3) the temperature, MeOH also performed well as solvent, and significantly in-
(4) the presence of acid catalysts, and (5) ultrasonic irradia- creased conversions and yields were observed (Table 1, En-
tion. We experimented with a wide range of solvents (in- tries 8 and 9, respectively). Finally, carrying out the reaction
cluding THF, MeCN, CH2Cl2, DMF, and MeOH), either in an ultrasonic bath (20 kHz, 250 W) under the conditions
neat or mixed with H2O, and found that the highest yield detailed in Entries 2 and 6 (Table 1) had no significant ef-
(86%) was achieved in THF/H2O (1:1) and at 50 °C. Dif- fect on either conversions or overall yields (Table 1, En-
ferent temperatures for the allylindation reactions were in- tries 10 and 11, respectively). Although the 1:1:1 adduct 5
vestigated during our previous work on this subject.[2]
A
was obtained in good yield at room temperature with the
complete survey led us to carry out the three-component use of 1.1 equiv. of indium (Table 1, Entry 6), 1.4 equiv. of
reactions at 50 °C in THF/H2O (1:1). So, we report here the indium at 50 °C in THF/H2O (1:1) worked even better
results with optimized experimental procedures.
(Table 1, Entry 2).
Under these conditions, an excess amount of allyl bro-
Having established an optimal set of conditions (Table 1,
mide (2 equiv.) and indium (1.4 equiv.) was also required Entry 2) for the allylindation reaction, our procedure was
for the reaction to go to completion (Table 1, Entry 2). tested on a range of nucleophilic probes (e.g., electron-rich
With other solvents (i.e., CH2Cl2 and DMF) the reaction heterocycles, electron-rich arenes, and stabilized enols).
was slower (Table 1, Entries 3 and 4, respectively), whereas
MeOH gave very low conversions (Table 1, Entry 5).
As shown in Table 2, the use of skatole (3-methyl indole)
as nucleophile did not significantly affect the yield but di-
rected the alkylation at C-2 (Table 2, Entry 3) leading to 8.
Increasing the steric bulk at the 3-position decreased the
selectivity. Thus, tryptophol (Table 2, Entry 4) gave both C-
and N-alkylation products (9 and 10, respectively) in a 1.3:1
ratio, whereas tetrahydrocarbazole (Table 2, Entry 5) under-
went N alkylation exclusively (to afford 11).
The presence of an electron-withdrawing group at C-3 of
the indole system had a detrimental effect on the reaction.
Indeed, 3-bromo- and 3-phenylindole failed to give any de-
Under these conditions, however, the process was rivatives, even under drastic conditions. On the contrary,
plagued by a side reaction, that is, the condensation of 1 under our conditions bis(alkylation) complicated the reac-
with indole to give 6[8] in yields ranging from 10 to 25%. tion of highly activated nucleophiles. In the case of pyrrole,
By carrying out the reaction with the use of THF as solvent some bis(adduct) 14 (7%) was obtained besides a mixture
or cosolvent the formation of 6 was minimized. Other sup- of 12 (56%) and 13 (17%). The most probable pathway for
plementary surveys regarding the effects of the single sol- the formation of 13 appears to be an indium-mediated
vent or the solvent mixtures will be studied in the future. Barbier reaction of primary product 12, as observed by Ya-
We then proceeded to screen three Brønsted acid catalysts dav[12] with pyrrole and indole. The 2:1 adduct 14 was
1
(HCOOH,[9] AcOH,[10] and NH4Cl[11]) that had previously found by H and 13C NMR spectra to be an inseparable
worked well for indium-mediated reactions. HCOOH diastereomeric mixture (C2/meso ca. 1:1). Formation of 13
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Efficient Access to Variously Functionalized Indolylbutenes
Table 2. Domino allylindation–alkylation reaction[a] of aldehyde 1 with nucleophiles.
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FULL PAPER
Table 2. (Continued).
[a] Reaction conditions: aldehyde 1 (1 mmol), nucleophile (1 mmol), In (1.4 mmol), allyl bromide (2 mmol), THF/H2O (1:1), 50 °C, 8 h
(except for Entry 1). [b] Isolated yields based on aldehyde 1. [c] Mixture of diastereomers.
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Efficient Access to Variously Functionalized Indolylbutenes
and 14 could be partially (but not entirely) suppressed by
To assess the scope of our procedure, we examined the
using an excess amount of pyrrole, typically 5 equiv. reactivity of 3 towards a number of electron-rich benzenoid
(Table 2, Entry 6). Bulky substituents (e.g., tBu) on the pyr- compounds. A single alkyl substituent on the ring appar-
role system[13] caused an inversion of the inherent regio- ently did not suffice to promote Friedel–Crafts-type alkyl-
chemical preference, giving 15 and 16 in a 2.3:1 ratio ation. Surprisingly, no reaction was observed with phenols
(Table 2, Entry 7), although the 1-phenyl-1-carbomethoxy- and anilines, although these substrates are regarded as
methyl group[14] directed the alkylation process on C-2 (to strongly activated arenes. Because electronic effects alone
17 as ca. 1:1 diastereomeric mixture) with complete regiose- cannot account for such a dramatic lack of reactivity, other
lectivity (Table 2, Entry 8). Interestingly, meso-octamethyl- factors must be responsible (deactivation of the aromatic
calix[4]pyrrole,[15] which belongs to a well-known class of ring by coordination of InIII species arising from allylin-
anion receptors,[16] afforded exclusively monoalkylated de- dation?). To address this issue, we turned to doubly acti-
rivative 18 in good yields (Table 2, Entry 9). This finding vated aromatics (e.g., polyphenols, aminophenols). Under
paves the way to a new class of calixpyrroles, possibly en- our conditions, polyphenols (Table 2, Entries 22–26) gave
dowed with interesting selective affinities for anions, to be the corresponding monoalkylated derivatives 34–39 in mod-
obtained by varying the structures of functional groups.
erate-to-good yields. Although 2-naphthol and 2,7-dihy-
When thiophene and its 2-methyl derivative were em- droxynaphthalene were inert, the reaction of 2,3-dihydroxy-
ployed as nucleophiles, not even a trace amount of the naphthalene proceeded smoothly to afford compound 37
three-component adducts could be detected. By comparing (Table 2, Entry 25) in 55% yield. Interestingly, the naturally
nucleophilicity parameters N (as defined by Mayr) of het- occurring (+)-catechin[29] gave 38 (Table 2, Entry 26) in
eroarenes, we could rationalize these findings.[17,18] Whereas 86% yield. In recent years interest in polyphenolic com-
thiophene and its 2-Me derivative have N = –1.01 and N = pounds has been growing due to their wide-ranging bio-
1.26,[19] respectively, indoles and pyrroles, which success- logical activities. By our method, the 8-position of (+)-cate-
fully behaved as π nucleophiles in the present work, had N chin can reliably be functionalized under mild conditions;
values in the 4–7 range.[20] The N value of 2-methylfuran, the access is thus opened to a new class of derivatives, poss-
3.61,[18] may well mark the “threshold” of π-nucleophilic ibly susceptible of interesting pharmacologic applications.
reactivity that is required for three-component adduct 19 Needless to say, aromatics bearing electron-withdrawing
(Table 2, Entry 10) to be formed from intermediates 3 or 4 groups proved inert under these reactions, which is consis-
in an aqueous solvent (see Scheme 1).
tent with the affirmed nucleophilic role of the aromatic
Pyrrolo[1,2-a]pyridines (or indolizines) and their aza- ring.
analogues (viz. imidazo[1,2-a]pyridines and imidazo[1,5-a]-
Alkylation of enolates derived from 1,3-dicarbonyls has
pyridine) result from the juxtaposition of electron-rich and been widely employed in the synthesis of a variety of com-
electron-poor heterocyclic rings; their electrophilic substitu- plex molecules.[30] These nucleophiles can undergo C and/
tion reactions take place on the five-membered ring at C- or O alkylation; the conditions that enhance the ambidose-
3.[21] Thus, 2-phenyl- and 2-(4-bromophenyl)indolizine[22,23] lectivity of the reaction have been well established. Under
gave, in good-to-excellent yields, the corresponding our conditions, the putative 3-alkylidene-3H-indolium cat-
3-alkylated compounds 20 and 21 (Table 2, Entries 11 and ion 3 was efficiently intercepted by 1,3-dicarbonyls to give
12); likewise 2-(4-bromophenyl)imidazo[1,2-a]pyridine[24] C-alkylated derivatives 40–45 in fair-to-good yields, regard-
(Table 2, Entry 13) yielded solely the 3-substituted deriva- less of the nature of the two carbonyl groups (Table 2, En-
tive 22 in 75% yield. Imidazo[1,5-a]pyridine[25] (Table 2, En- tries 28–33). The intermediacy of 3-alkylidene-3H-indolium
try 14) proved less selective, giving a 4:1 mixture of 3- and cation 3 was further proven by carrying out the allylin-
1-substituted compounds (23 and 24, respectively). In this dation of 1 in the presence of a suitable reducing agent (e.g.
instance, however, the 1,3-bis(alkylated) analogue 25 was Hantzsch ester) to lead to 3-but-3-enyl-1H-indole (5a).
the major product (isolated as an inseparable dia-
It is interesting to note that no acid and/or base were
stereomeric mixture), reflecting the enhanced reactivity of required to promote substrate enolization. The formation of
the five-membered ring. In the case of 6-phenylimidazo[2,1- O-alkylation products was not observed. Gratifyingly, these
b]thiazole[26] (Table 2, Entry 15), electrophilic attack oc- results further expand the synthetic potential of our method
curred at the expected 5-position, leading to 26.
for assembling variously functionalized alkyl(indolyl)but-
Electron-poor azoles, for example, triazoles and benzo- enes.
fused analogues (Table 2, Entries 16–21), exhibited a similar
Taken together, the foregoing results leave little doubt
reactivity towards 3, affording the respective N-alkylated that 4 is involved in this reaction. Under acid catalysis, in-
derivatives 27–33 in moderate-to-good yields; no trace doles of this type are thought to generate 3-alkylidene-3H-
amounts of C-alkylation products were detected.
indolium cations (viz. stabilized benzylic-type cations),
These findings are consistent with the well-known chem- which can be trapped by heteronucleophiles and stabilized
istry of azoles. Accordingly, in free(NH) azole, where (neu- C nucleophiles[31] in a three-component one-pot domino
tral) pyrrole-like and (base/nucleophilic) pyridine-like N allylation–dehydrative Friedel–Crafts-type process. Notably,
atoms occur in the same molecule, an electrophile will al- in all the examples listed in Table 2 the reaction proceeded
ways react with the latter.[27] The structure of 28 and 33 was well with 1.4 equiv. of indium. The metal plays a twofold
confirmed by single-crystal X-ray diffraction analysis.[28]
role: to promote both the Barbier reaction [as In0] and the
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F. Colombo, G. Cravotto, G. Palmisano, A. Penoni, M. Sisti
FULL PAPER
subsequent dehydrative alkylation step [as InIII species]. In-
deed, InIII salts have been recently shown to be effective
Lewis acids in many chemical transformations both in
aqueous and organic media under mild conditions.[32] In
particular, InBr3 has attracted increasing attention as a
green Lewis acid catalyst by virtue of its water stability, ease
of recovery, operational simplicity, and good tolerance of
oxygen- and nitrogen-containing substrates.[33]
Because of its electrophilic character, the exocyclic alk-
ylidene carbon atom of 3 is a likely candidate for the inter-
molecular addition of C nucleophiles. To test this hypothe-
sis, we treated it with InBr3 (0.1 equiv.) homoallylic alcohol
4 (obtained from 1 by reaction with allylmagnesium bro-
mide)[34] in the presence of indole (1 equiv.) in THF/H2O
(1:1) at 50 °C. Bis(indole) adduct 5 was isolated in 83%
yield, which convincingly argues for the intermediacy of 3.
In an analogous vein, the catalytic activation of allylic and
benzylic alcohols by InIII salts has been recently re-
ported.[35] When no InIII salt was added, messy reaction
mixtures were reported.
Homoallylic alcohol 4 was unstable when stored at room
temperature for several days. Its lability extended to silica
gel chromatography such that its purification was not pos-
sible. Under our optimized conditions and in the absence
of competing nucleophiles, attempts to prepare 4 by allylin-
dation of 1 were thwarted by its proclivity to undergo
subsequent addition (via 3) of allylInI[36] leading to 46
(42%)[2,4] as the major product, along with a plethora of
byproducts (Scheme 1).
after 8 h. Distilled water (15 mL) was added to the flask, and the
mixture was extracted with ethyl acetate (3ϫ10 mL). The com-
bined organic extract was washed with water (2ϫ15 mL) and dried
with anhydrous sodium sulfate, and the solvents were evaporated
under vacuum. Crude products 5b–45 were purified by flash silica
gel chromatography.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, compound characterization, and an-
alytical data (1H NMR, 13C NMR, MS, elemental analyses) for all
new compounds.
Acknowledgments
We thank Dr. T. Pilati, CNR – Istituto di Scienze e Tecnologie
Molecolari, Milano for single-crystal X-ray diffraction analyses.
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Conclusions
We developed a three-component one-pot domino reac-
tion combining the allylindation of 1H-indole-3-carbal-
dehyde with the dehydrative alkylation of stabilized C nu-
cleophiles (e.g., electron-rich heteroarenes, electron-rich
aromatics, and stabilized enols) and N nucleophiles (e.g.,
azoles) to generate a library of variously functionalized in-
dolylbutenes. Biological activities of some of these com-
pounds are currently being evaluated.
The method meets the requirements of high-throughput
parallel synthesis. As demonstrated above, product design
is susceptible to numerous variations through the choice of
C and N nucleophiles. An even greater synthetic flexibility
can be achieved through the choice of other allylic and pro-
pargylic halides. Furthermore, the synthetic potential must
be addressed of the C–C double bond ubiquitous in these
substrates. Preliminary studies along these lines are encour-
aging and results will be reported in due course.
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Experimental Section
Typical Experimental Procedure for the Synthesis of 5b–45: To a
solution of 1H-indole-3-carbaldehyde (0.145 g, 1 mmol) in THF/
H2O (1:1, 12 mL) was added allylbromide (0.176 mL, 2 mmol), the
chosen nucleophile (1 mmol), and indium powder (0.161 g,
1.4 mmol). The resulting mixture was stirred at 50 °C and stopped
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Efficient Access to Variously Functionalized Indolylbutenes
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I
It is stated that allylIn is formed by reaction of allyl halides
and indium in aqueous media (T. H. Chan, Y. Yang, J. Am.
Chem. Soc. 1999, 121, 3228–3229 and references cited therein.
Received: December 6, 2007
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Structure, Reactions, Synthesis and Uses of Heterocyclic Com-
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Published Online: April 9, 2008
Eur. J. Org. Chem. 2008, 2801–2807
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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