Reaction of 3-(1-arylsulfonylalkyl)-indoles with easily enolisable derivatives promoted by potassium fluoride on basic alumina

Article abstract of DOI:10.1002/adsc.200700410

Active methylene compounds and nitro derivatives react with 3-(1-arylsulfonylalkyl)-indoles in the presence of potassium fluoride on basic alumina at room temperature leading to the corresponding adducts in good yields. Under basic conditions, sulfonylind

Full text of DOI:10.1002/adsc.200700410

FULL PAPERS
DOI: 10.1002/adsc.200700410
Reaction of 3-(1-Arylsulfonylalkyl)-indoles with Easily Enolisable
Derivatives Promoted by Potassium Fluoride on Basic Alumina
Roberto Ballini,a Alessandro Palmieri,a Marino Petrini,a,* and Rafik R. Shaikha
a
Dipartimento di Scienze Chimiche, Universitàdi Camerino, via S. Agostino 1, 62032 Camerino, Italy
Fax : (+39)-0737-402-297; e-mail: marino.petrini@unicam.it
Received: August 22, 2007; Published online: December 14, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Active methylene compounds and nitro promptly adds stabilized carbanions. The obtained 3-
derivatives react with 3-(1-arylsulfonylalkyl)-indoles indolyl derivatives are pivotal intermediates for the
in the presence of potassium fluoride on basic alumi- synthesis of indole-based alkaloids and amino acids.
na at room temperature leading to the corresponding
adducts in good yields. Under basic conditions, sulfo-
nylindoles suffer elimination of arenesulfinic acid Keywords: basic alumina; carbanions; conjugate ad-
leading to an intermediate vinylogous imine that dition; heterogeneous catalysis; indoles
Introduction
long time, gramine derivatives (1, X=NR2) have rep-
resented the most viable substrates to prepare com-
Functional group implementation on 3-substituted in- pounds 3 following this approach.[3] Gramines that
doles represents a subtle device in many synthetic are usually prepared exploiting a Mannich reaction
plans oriented to the preparation of indole-based bio- on indoles, eliminate the dialkylamino moiety under
logically active compounds.[1] This strategy nicely basic conditions at high temperature (reflux in tolu-
complements direct functionalization at the 3-position ene or xylene) leading to intermediate 2. Alkylation
of indoles using strong electrophilic reagents, a pro- of the tertiary amino group in gramines affords a qua-
cess widely known as the Friedel–Crafts reaction.[2] ternary ammonium salt which, being a better leaving
The synthetic approach consists in the introduction of group, can be eliminated in mild conditions.[4] Other
a leaving group at the ꢀbenzylicꢁ position of 3-substi- derivatives such as 3-(1-hydroxyalkyl)-indoles (1, X=
tuted indoles 1 that can be subsequently eliminated OH, OR) have found only occasional utilisation for
under both acidic and basic conditions. The obtained this purpose,[5] although these compounds are certain-
intermediate 2 closely resembles a vinylogous imino ly involved as intermediates in the synthesis of bisin-
derivative that upon nucleophilic addition affords the doles and related compounds.[6] The arylsulfonyl
corresponding 1’-substituted indole 3 (Scheme 1).
group is recognised as a good leaving group in many
Practically, this procedure may constitute a valid synthetic processes,[7] but its utilisation in indolyl de-
option to the venerable Friedel–Crafts reaction pro- rivatives of type 1 has been somewhat hampered by
viding that an efficient access to 3-substituted indoles the paucity of procedures to access these com-
1 is possible and a rapid elimination step leading to pounds.[8]
the vinylogous intermediate 2 is achievable. For a
Recently, we have introduced two complementary
procedures to efficiently prepare 3-(1-arylsulfonylalk-
yl)-indoles starting from simple precursors. Reaction
of a-amidosulfones 4[9] with indoles 5 in the presence
of Montmorillonite K-10 under solventless conditions
affords sulfonylindoles 7 (Scheme 2, Method A).[10]
Alternatively, a simplified method involving a three-
component coupling of carbonyls 6, indoles 5 and ar-
enesulfinic acids leads to the same compounds 7 in
comparable yields (Scheme 2, Method B).[11] The ef-
fectiveness of sulfonylindoles 7 as precursors of vinyl-
Scheme 1. Synthetic approach to functionalized 3-substituted
indoles.
Adv. Synth. Catal. 2008, 350, 129 – 134
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129

Roberto Ballini et al.
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both elimination of arenesulfinic acid from 8 and eno-
lisation of the nitroalkane 9 (Table 1, Method A).[14]
Nitroalkylindoles 10 are obtained in good yields (78–
91%) using nitromethane and nitroethane, but this
procedure has proved to be quite unsatisfactory when
homologous and functionalised nitroalkanes are em-
ployed for the same purpose. Other bases working
under homogeneous conditions such as trialkylphos-
phines, potassium tert-butoxide, alkaline metal hy-
droxides, DBU and guanidines also gave disappoint-
ing results when tested on the same reaction. The ac-
tivating properties of KF on basic alumina have been
demonstrated in a consistent number of processes,[15]
and we were delighted to observe that this solid basic
system is also able to promote the addition of differ-
ent nitroalkanes 9 to sulfonylindoles 8 at room tem-
perature (Table 1, Method B).[16] The reaction is usu-
ally carried out in dichloromethane in such a mini-
mum amount that is needed to completely dissolve
Scheme 2. General syntheses of 3-(1-arylsulfonylalkyl)-in-
doles.
ogous imino derivatives 2 has been proved in the re- the reactants before the addition of the basic promot-
action with Grignard and Reformatsky reagents as er. A work-up procedure of the resulting heterogene-
well as in different reductive removals of the arene- ous mixture is avoided since purification of the final
sulfonyl group.[10,11]
products 10 is easily performed by adding a small
Stabilised carbanions which can be readily obtained amount of silica and, after removal of the solvent, by
from easily enolisable precursors represent a formida- direct application of the solid mixture to the head of
ble source of functionalised nucleophiles in the reac- a chromatographic column followed by elution with
tion with various electrophilic systems. The enhanced an appropriate solvent system. The results displayed
acidity of the hydrogen atoms in these compounds in Table 1, show that a consistent number of simple
allows the utilisation of basic promoters of moderate and functionalised nitroalkanes 9 efficiently add to
strength under mild reaction conditions. In this con- various sulfonylindoles 8 leading to the corresponding
text, solid bases are particularly appealing reagents 3-(2-nitroalkyl)-indoles 10 in good yields. Substitution
since their activity can be suitably tuned by the appro- at the 2-position of the indole ring in compounds 8
priate choice of the base-solid support couple. Fur- does not provide any reduction in the reactivity even
thermore, the heterogeneous conditions in which when phenyl or ester groups are present (Table 1, en-
these bases are employed favours the development of tries 5, 6, 9, 15). w-Nitro esters as well as O-protected
environmentally friendly chemical processes working b-nitro alcohols are effective in the reaction with sul-
with a limited amount of solvent or even in solvent- fonylindoles allowing the introduction of an addition-
less conditions. This paper reports on the utilisation al functional group in the molecular framework
of KF on basic alumina as solid base for the reaction (Table 1, entries 13–17). When nitromethane is used
of 3-(1-arylsulfonylalkyl)-indoles 7 with readily enolis- as reagent, dichloromethane must be replaced by
able compounds leading to functionalised 3-substitut- THF as a solvent in order to ensure a complete con-
ed indoles 3.
sumption of the sulfonylindole. Particularly interest-
ing is the reaction of secondary nitroalkanes such as
2-nitropropane and nitrocyclopentane that maintain a
satisfactory reactivity with different substrates 8
(Table 1, entries 8, 9, 12).
Results and Discussion
Nitroalkanes can be easily converted into the corre-
The obtained 3-(2-nitroalkyl) indoles 10h, i and l
sponding nitronate anions using a wide range of bases belong to a rather unknown class of tertiary nitro
and then used as effective nucleophiles with carbon- compounds that are not accessible through the very
yls, Michael acceptors and other electrophilic sub- popular Friedel–Crafts reaction of indoles with nitro-
strates.[12] Furthermore, the nitro group, once intro- alkenes.[17] The interest in 3-(2-nitroalkyl)-indoles 10
duced in a molecular framework, is amenable to sev- mainly stems from the subsequent reduction of the
eral synthetic transformations including reduction, nitro group that generates the corresponding trypta-
conversion into carbonyls and reductive removal.[13]
A
mines 11, a class of biologically active compounds
preliminary study on the reaction of sulfonylindoles 8 that also provide a prompt access to b-carboline alka-
with nitroalkanes 9 was carried out using NaH in loids 12 by means of a Pictet–Spengler reaction
THF at reflux, a basic system that is able to promote (Scheme 3).[18]
130
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Reaction of 3-(1-Arylsulfonylalkyl)-indoles with Easily Enolisable Derivatives
FULL PAPERS
Table 1. Potassium fluoride on basic alumina-promoted additions of nitroalkanes 9 to sulfonylindoles 8.
Entry
Product 10
R
R1
R2
R3
R4
Time [h]
Yield[a] [%]
1
2
3
4
5
6
7
8
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
10o
10p
10q
H
H
H
MeO
H
H
H
H
H
H
H
H
H
H
H
H
H
H
n-C5H11
n-C5H11
c-C6H11
Et
H
H
H
H
H
H
H
Me
Me
H
H
H
H
H
4
4
4
4
3
6
3
5
15
3
15
3
3
15
4
75[b] (81)
Me
Me
H
CO2Et
CO2Et
Me
Me
Ph
Me
Me
H
Me
Me
Ph
76[b] (85)
85[b,c] (88)
75[b]
87
88
89
Et
Me
Me
Et
Me
Me
Ph
Ph
-(CH2)4-
THPOCH2
THPOCH2
EtO2C
EtO2C
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C5H11
c-C6H11
n-C5H11
n-C5H11
c-C6H11
n-C5H11
n-C5H11
n-C5H11
77
73
9
10
11
12
13
14
15
16
17
G
G
85
H
77[c]
71
H
H
H
H
H
77
70[c]
81
ACHTREUNG
A
H
Me
2
4
86
83
MeO2C
A
[a]
Isolated yields after column chromatography using method B (KF/basic alumina, dichloromethane at room temperature).
Yields in parentheses were obtained using Method A (NaH in THF at reflux, see ref.[14]).
Reaction was carried out in THF at room temperature.
[b]
[c]
Phenylsulfonylindole was used.
other than the nitro one (Table 2). The results ob-
tained using the heterogeneous basic promoter (KF/
basic alumina, dichloromethane at room temperature,
Method B) when compared with those achieved using
NaH in THF at room temperature (Method A), show
the superior activity of the former system in produc-
ing adducts 14 (Table 2).
Diethyl malonate and malononitrile are particularly
reactive toward a large number of sulfonylindoles 8
including that prepared from 2-methylindole and ace-
tone which presents a certain steric crowding at the
electrophilic tertiary centre (Table 2, entries 9 and
23). Similarly, malonate derivatives bearing methyl or
amido groups at the 2-position, provide adducts 14l–n
in good yields (Table 2, entries 12–14). Mixed malonic
acid esters are particularly interesting reagents since
the presence of a tert-butyl group in the obtained in-
doles 14j and k would allow an easy chemoselective
Scheme 3. Synthetic elaboration of 3-(2-nitroalkyl)-indoles
10.
The effectiveness of KF on basic alumina as pro- cleavage of a single ester group (Table 2, entries 10
moter in nucleophilic additions on sulfonylindoles 8 and 11). The resulting mono esters 15 undergo a Cur-
has been subsequently tested using active methylene tius rearrangement via acyl azide leading to trypto-
reagents 13 bearing electron-withdrawing groups phan analogues 16 (Scheme 4).[19] Hydrolysis and de-
Adv. Synth. Catal. 2008, 350, 129 – 134
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Roberto Ballini et al.
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Table 2. KF on basic alumina-promoted additions of active methylene compounds 13 to indoles 8.
Entry
Product 14
R
R1
R2
R3
R4
EWG1
EWG2
Yield[a,b] [%]
1
2
3
4
5
6
7
8
14a
14b
14c
14d
14e
14f
14g
14h
14i
H
H
H
MeO
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
n-C5H11
n-C5H11
c-C6H11
Et
Et
n-C5H11
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
COMe
CO2Et
CO2Et
CN
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2-t-Bu
CO2-t-Bu
CO2Et
CO2Et
CO2Et
COMe
COMe
CN
CN
CN
CN
CN
CN
CN
NC
86 (70)
95 (65)
90 (86)[c]
88 (À)
67 (66)
83 (72)
84
84
68 (65)
82
Me
Me
H
CO2Et
Ph
Me
Me
Me
H
Me
H
H
H
H
H
H
H
Ph
A
9
Me
H
H
H
Me
NHCHO
NHCOMe
H
H
H
H
H
H
H
H
H
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
14j
14k
14l
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C5H11
c-C6H11
Et
84 (70)
83[d] (63)
78[d]
14m
14n
14o
14p
14q
14r
14s
14t
14u
14v
14w
14x
84
86[e]
87[e]
88
87[e] (76)
83[e] (70)
87[c]
Me
Me
CO2Et
Ph
Me
Me
CN
CN
CN
CN
CN
TolSO2
71[d]
n-C5H11
Me
n-C5H11
85 (74)
73
63
[a]
Isolated yields after column chromatography using method B (KF/basic alumina, dichloromethane at room temperature).
Unless otherwise stated reaction time was 2 h at room temperature
Yields in parentheses were obtained using method A (NaH in THF 2 h at room temperature).
Phenylsulfonylindole was used.
Reaction time was 15 h at room temperature.
Reaction time was 4 h at room temperature.
[b]
[c]
[d]
[e]
carboxylation on compounds 14m and n also provides action of easily enolisable reagents such as nitro com-
a straightforward entry to the same amino acid deriv- pounds, malonic acid derivatives, diketones and keto
atives.[20] Other active methylene derivatives tested esters with 3-(1-arylsulfonylalkyl)-indoles. The reac-
such as 2,4-pentanedione, ethyl 3-oxobutanoate and tivity of these sulfonylindoles toward nucleophiles is
ethyl 2-cyanoacetate also give satisfactory results in- due to the formation of an intermediate vinylogous
cluding p-toluenesulfonyl isocyanide which affords imine caused by a base-assisted elimination of arene-
adduct 14x, although only in moderate yield (Table 2, sulfinic acid. The obtained adducts are interesting
entries 15–17 and 24).
building blocks that allow a rapid entry to biologically
active indole derivatives endowed of practical inter-
est. This process is operationally simple since it
occurs at room temperature under heterogeneous
conditions and requires enough solvent needed to dis-
Conclusions
Potassium fluoride supported on basic alumina has solve the reactants before addition of the solid base.
been demonstrated as a superior promoter in the re- Removal of the solvent and application of the solid
132
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Reaction of 3-(1-Arylsulfonylalkyl)-indoles with Easily Enolisable Derivatives
FULL PAPERS
reduced pressure. The resulting solid mixture was directly
charged on a chromatography column and eluted (hexane-
ethyl acetate, 8:2) to afford pure products 10 and 14.
Acknowledgements
Financial support from University of Camerino and MIUR
(National Project “Sintesi organiche ecosostenibili mediate
da nuovi sistemi catalitici“) is gratefully acknowledged.
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dry THF (10 mL) the active methylene compound 13
(2.0 mmol) was added at room temperature. After stirring
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