Solventless clay-promoted Friedel-Crafts reaction of indoles with α-amido sulfones: Unexpected synthesis of 3-(1-arylsulfonylalkyl) indoles

Article abstract of DOI:10.1021/ol061604w

Friedel-Crafts reaction of indoles with α-amido sulfones in the presence of montmorillonite K-10 leads unexpectedly to 3-(1-arylsulfonylalkyl) indoles in good yield. The obtained products can be further desulfonylated under reductive or alkylative conditi

Full text of DOI:10.1021/ol061604w

ORGANIC
LETTERS
2006
Vol. 8, No. 18
4093-4096
Solventless Clay-Promoted
Friedel Crafts Reaction of Indoles with
-Amido Sulfones: Unexpected
Synthesis of 3-(1-Arylsulfonylalkyl)
Indoles
−
r
Roberto Ballini, Alessandro Palmieri, Marino Petrini,* and Elisabetta Torregiani
Dipartimento di Scienze Chimiche, UniVersita` di Camerino, Via S. Agostino, 1
I-62032 Camerino, Italy
marino.petrini@unicam.it
Received June 29, 2006
ABSTRACT
Friedel−Crafts reaction of indoles with r-amido sulfones in the presence of montmorillonite K-10 leads unexpectedly to 3-(1-arylsulfonylalkyl)
indoles in good yield. The obtained products can be further desulfonylated under reductive or alkylative conditions giving linear and branched
3-substituted indoles.
The introduction of functionalized alkyl frameworks at the
3-position in indole systems is a common practice directed
to the synthesis of biologically active compounds.1 Apart
from few notable exceptions,2 the vast majority of the
available methods to attain this result use a Friedel-Crafts
(F-C) reaction exploiting the electron-rich nature of the
indole nucleus.3
A common feature of all these procedures resides in the
utilization of highly electrophilic reagents generated under
Lewis or Brønsted acidic conditions.4 Activation by acid
promoters is particularly needed when poor electrophiles,
such as imines 2, are used for this purpose (Scheme 1).
Conversion of these nitrogen derivatives into iminium ions
ensures a rapid reaction with various indoles 1 to give
3-indolyl methanamines 3 that are pivotal intermediates in
alkaloid syntheses.
The efficiency of this process is affected by the reaction
conditions since the amino group in the benzylic position
can eliminate to give bisindoles as byproducts.5 This apparent
drawback represents a useful synthetic opportunity since
(3) Review: (a) Bandini, M.; Melloni, A.; Tommasi, S.; Umani-Ronchi,
A. Synlett 2005, 1199-1222. For some very recent examples see: (b) Jia,
Y.-X.; Zhu, S. F.; Yang, Y.; Zhou, Q.-L. J. Org. Chem. 2006, 71, 75-80.
(c) Yamazaki, S.; Iwata, Y. J. Org. Chem. 2006, 71, 739-743. (d) Lu,
S.-F.; Du, D.-M.; Xu, J. Org. Lett. 2006, 8, 2115-2118. (e) Li, D.-P.; Guo,
Y.-C.; Ding, Y.; Xiao, W.-J. Chem. Commun. 2006, 799-801. (f) Evans,
D. A.; Fandrick, K. R.; Song, H.-J. J. Am. Chem. Soc. 2005, 127, 8942-
8943. (g) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem.,
Int. Ed. 2005, 44, 6576-6579. (h) Palomo, C.; Oiarbide, M.; Kardak, B.
G.; Garcia, J. M.; Linden, A. J. Am. Chem. Soc. 2005, 127, 4154-4155.
(4) Acid catalysis can be sometimes avoided when particularly reactive
electrophiles are used in the reaction with indoles: (a) Jiang, B.; Huang,
Z.-G. Synthesis 2005, 2198-2204. (b) Dessole, G.; Herrera, R. P.; Ricci,
A. Synlett 2004, 2374-2378.
(1) (a) Faulkner, D. J. Nat. Prod. Rep. 2002, 1-48. (b) Saxton, J. E. In
The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1998. (c)
Sundberg, R. J. Indoles; Academic Press: New York, 1997. (d) Saxton, J.
E. Nat. Prod. Rep. 1997, 559-590.
(2) (a) Ballini, R.; Rabanedo Clemente, R.; Palmieri, A.; Petrini, M. AdV.
Synth. Catal. 2006, 348, 191-196. (b) Wynne, J. H.; Stalick, W. M. J.
Org. Chem. 2002, 67, 5850-5853. (c) Mahboobi, S.; Wiegrebe, W.; Popp,
A. J. Nat. Prod. 1999, 62, 577-579. (d) Koike, T.; Takeuchi, N.; Hagiwara,
M.; Yamazaki, K.; Tobinaga, S. Heterocycles 1999, 51, 2687-2695. (e)
Koike, T.; Hagiwara, M.; Takeuchi, N.; Tobinaga, S. Heterocycles 1997,
45, 1271-1280.
(5) (a) Mi, X.; Luo, S.; He, J.; Cheng, J.-P. Tetrahedron Lett. 2004, 45,
4567-4570. (b) Xie, W.; Bloomfield, K. M.; Jin, Y.; Dolney, N.; Wang,
P. G. Synlett 1999, 498-500.
10.1021/ol061604w CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/10/2006

Scheme 1
Scheme 2
the presence of TiCl4 at low temperature following our usual
procedure.11b Unexpectedly, the major product obtained in
this reaction was 3-substituted indole 9f bearing a tolylsul-
fonyl group instead of the carbamoyl moiety (Table 1, entry
1).
elimination of the amino framework from 3 leads to reactive
vinylogous imino derivatives 4 that may add nucleophilic
species giving branched 3-substituted indoles 5.6
Table 1. Reaction of Indole 1b with R-Amido Sulfone 6a
Compared with N-alkylimines, N-acylimines and their
corresponding iminium ions7 are considerably more reactive
toward nucleophiles and can be profitably used in a number
of synthetic applications, including catalytic enantioselective
processes.8 The poor stability of N-acylimino derivatives
makes preferable their in situ formation from suitable
R-substituted amido precursors that, by acid-promoted
elimination of a good leaving group, furnish the azomethine
electrophile ready to react with the appropriate indole.9
Concerning the nature of the acid promoter for the F-C
reaction, Lewis acids formerly used for this purpose can be
replaced by less hazardous and eco-friendly solid acid
compounds.10 Working under heterogeneous conditions, solid
acids can be often used without any added solvent and allow
easy workup of the corresponding reaction mixture. Recently,
we have demonstrated that R-amido sulfones 6 are useful
precursors of N-acyliminium ions 7 that, once they formed,
can react with several nucleophiles, such as allylsilanes, silyl
ketene acetals, and electron-rich aromatics, leading to the
corresponding adducts 8 (Scheme 2).11
acid promoter
(g/mmol 1b)
T
(°C)
time
(h)
yield
entry
solvent
9f (%)d
1
2
TiCl4 (2 equiv)
none
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
none
none
none
none
-78c
40
40
40
20
55
55
55
6
18
4
3
9
3
3
3
55
traces
51
95
traces
94
3a
4b
5b
6b
7b
8
HSZ-360 (1.7)
K-10 (1.7)
K-10 (1.7)
K-10 (1.7)
K-10 (0.9)
SiO2 (1.2)
88
73
a Zeolite. b Montmorillonite. c For 0.5 h at -78 °C then 5.5 h at rt.
d Isolated yields. All reactions were carried out on 1 mmol scale.
The absence of the acidic promoter does not produce any
appreciable result (Table 1, entry 2), but interestingly, solid
acid compounds are effective in promoting the same process
under various conditions. Zeolite HSZ-360 gives modest
results, but less expensive montmorillonite K-10 leads to the
formation of sulfone 9f in good yield using the same
conditions (Table 1, entries 3 and 4). At room temperature,
in the absence of any solvent, the conversion becomes
ineffective, while increasing the temperature up to 55 °C
produces substituted indole 9f in good yield (Table 1, entries
5 and 6). The amount of the acid promoter clearly affects
the efficiency of the process; although montmorillonite K-10
is a quite inexpensive support, its loading can be reduced to
0.9 g/mmol of substrate with only a modest lowering of the
indole chemical yield (Table 1, entry 7). Finally, silica gel
is also active as acid support for this process, but it is more
expensive and gives lower yield of product 9f than mont-
morillonite K-10 (Table 1, entry 8).
With the aim of searching for a new route to 3-substituted
indoles, we reacted indole 1b with R-amido sulfone 6a in
(6) (a) Semenov, B. B.; Novikov, K. A.; Lysenko, K. A.; Kachala, V.
V. Tetrahedron Lett. 2006, 47, 3479-3483. (b) Freed, J. D.; Hart, D. J.;
Magomedov, N. A. J. Org. Chem. 2001, 66, 839-852. (c) Dubois, L.;
Dorey, G.; Potier, P.; Dodd, R. H. Tetrahedron: Asymmetry 1995, 6, 455-
462.
(7) (a) Fisˇera, L. Science of Synthesis; Padwa, A., Ed.; Thieme: Stuttgart,
2004; Vol. 27, p 349. (b) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.;
Turchi, I. J.; Maryanoff, C. A. Chem. ReV. 2004, 104, 1431-1628. (c)
Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817-3856.
(8) (a) Wang, Y.-Q.; Song, W. J.; Hong, R.; Li, H.; Deng, L. J. Am.
Chem. Soc. 2006, 128, 8156-8157. (b) Jia, Y.-X.; Xie, J.-H.; Duan, H.-F.;
Wang, L.-X.; Zhou, Q.-L. Org. Lett. 2006, 8, 1621-1624. (c) Johannsen,
M. Chem. Commun. 1999, 2233-2234.
(9) DeNinno, M. P.; Eller, C.; Etienne, J. B. J. Org. Chem. 2001, 66,
6988-6993.
(10) (a) Singh, D. U.; Singh, P. R.; Samant, S. D. Synth. Commun. 2006,
36, 1265-1271. (b) Bartoli, G.; Bosco, M.; Giuli, S.; Giuliani, A.; Lucarelli,
L.; Marcantoni, E.; Sambri, L.; Torregiani, E. J. Org. Chem. 2005, 70,
1941-1944. (c) Bandini, M.; Fagioli, M.; Umani-Ronchi, A. AdV. Synth.
Catal. 2004, 346, 545-548. (d) Bartoli, G.; Bartolacci, M.; Bosco, M.;
Foglia, G.; Giuliani, A.; Marcantoni, E.; Sambri, L.; Torregiani, E. J. Org.
Chem. 2003, 68, 4594-4597. (e) Chakrabarty, M.; Basak, R.; Ghosh, N.
Tetrahedron Lett. 2001, 42, 3913-3915.
This unprecedented synthetic process represents a valuable
and general method to prepare several 3-(1-arylsulfonylalkyl)
indoles 9 starting from indoles 1 and various R-amido
sulfones 6 as displayed in Table 2.
The yields of the obtained sulfonyl indole derivatives 9
are usually satisfactory, and there is no clear relationship
(11) (a) Petrini, M. Chem. ReV. 2005, 105, 3949-3977. (b) Petrini, M.;
Torregiani, E. Tetrahedron Lett. 2005, 46, 5999-6003.
4094
Org. Lett., Vol. 8, No. 18, 2006

Scheme 3
Table 2. Synthesis of 3-Substituted Indoles 9 by Reaction of
Indoles 1 with Sulfones 6 Promoted by Montmorillonite K-10a
R-amido
sulfone 6
product
time
(h)
yield
(%)b
entry
indole 1
9
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
1d
1e
1f
6a
6b
6c
6d
6e
6a
6b
6c
6d
6e
6a
6a
6a
6b
6a
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
9o
6
7
7
7
15
3
6
6
7
9
71
70
72
80
71
88
90
79
69
70
46
62
76
70
80
a fast and reversible process; in addition, product 9 is
probably thermodynamically more stable than bisindole 14.
As a matter of fact, bisindole 14 can be observed during the
course of the reaction by TLC analysis, and its complete
disappearance usually announces the end of the process.
Furthermore, variable amounts of bisindole 14 can be isolated
from the reaction mixture after 0.5 h at 55 °C.14
6
6
5
6
The ready availability of sulfonyl indoles 9 opens new
synthetic opportunities for a suitable functionalization of
indoles at the 3 position, exploiting the well-known aptitude
of the arenesulfonyl moiety to act as a good leaving group.15
Substitution of the arenesulfonyl group with a hydrogen atom
would lead to the 3-alkyl indole derivative formally arising
from an alkylation reaction of the indole ring. Removal of
the arenesulfonyl group in benzylic and allylic positions is
usually best effected under radical conditions, taking advan-
tage of the stability of the corresponding radical intermedi-
ate.16
Therefore, reduction of sulfones 9 using Bu3SnH in toluene
at reflux gives the corresponding indole derivatives 16 in
satisfactory yield (Table 3, method A, entries 1, 3, 4, and
7). A comparison of this procedure with the classical
desulfonylation using 6% Na-Hg amalgam (Table 3, method
B) shows that the former reaction is more efficient in
1f
5
a Reaction conditions: sulfone 6 (3 mmol), indole 1 (3.2 mmol), and
montmorillonite K-10 (2.7 g) heated at 55 °C. b Isolated yields
between the nature of the reagent substituents and the
efficiency of the process, except in the case of 2-phenyl
indole 1c that gives a poor conversion into indole 9k
probably because of the steric hindrance exerted by the
phenyl group with respect to the hydrogen or methyl group
(Table 2, entry 11). The nature of the alkoxy group in the
carbamoyl moiety in R-amido sulfones is also important since
early attempts to use benzyloxy and tert-butyloxycarbamoyl
sulfones gave unreliable results.12
A plausible mechanism that explains the formation of
compounds 9 starts from the N-acyliminium ion 10 that is
formed by elimination of arenesulfinic acid from the R-amido
sulfone 6 under acid conditions (Scheme 3).
Reaction of the strong electrophile 10 with indole 1 gives
the F-C product 11 that is protonated and suffers elimination
of ethyl carbamate, leading to vinylogous iminium ion 13.13
At this point, the iminium ion 13 can react with indole 1 in
a second F-C reaction giving bisindole 14 or adds ArSO2H
to afford product 9. Formation of compound 9 is favored
because the F-C reaction leading to bisindole 14 is probably
(14) Under certain circumstances, the bisindole is stable enough with
respect to the sulfonyl indole that it may become the main product as in
the reaction of indole 1b with imino ester precursor 6f that gives
predominantly bisindole 15.
(15) (a) Na´jera, C.; Yus, M. Tetrahedron 1999, 55, 10547-10658. (b)
Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon Press: Oxford,
1993.
(16) (a) Padwa, A.; Muller, C. L.; Rodriguez, A.; Watterson, S. H.
Tetrahedron 1998, 55, 9651-9666. (b) Morimoto, Y.; Mikami, A.; Kuwabe,
S.; Shirahama, H. Tetrahedron: Asymmetry 1996, 7, 3371-3390. (c)
Giovannini, R.; Petrini, M. Synlett 1995, 973-974. (d) Smith, A. B., III;
Hale, K. J.; McCauley, J. P., Jr. Tetrahedron Lett. 1989, 30, 5579-5582.
(12) Extensive decomposition of the R-amido sulfone has been observed
in this process, especially for tert-butyloxycarbamoyl sulfones.
(13) Ke, B.; Qin, Y.; He, Q.; Huang, Z.; Wang, F. Tetrahedron Lett.
2005, 46, 1751-1753.
Org. Lett., Vol. 8, No. 18, 2006
4095

Table 3. Reductive Desulfonylation of Indoles 9 under Various
Conditionsa
Table 4. Reaction of Indoles 9 with Grignard Reagents 17a
Grignard reagent 17
R4
time
(h)
yield
(%)b
entry
indole 9
product 16
methoda
entry indole 9
product 18 yield (%)b
1
2
3
4
5
6
7
9d
9d
9f
9g
9g
9i
16a
16a
16b
16c
16c
16d
16e
A
B
A
A
C
B
A
4
2
3
8
2
4
8
86
61
85
77
85
62
56
1
2
3
4
5
9d
9f
9f
9g
9g
Me
n-Bu
CHdCH2
Me
n-Bu
17a
17b
17c
17a
17b
18a
18b
18c
18d
18e
75
94
77
85
91
a Reaction conditions: sulfonyl indole 9 (1 mmol) in THF (12 mL),
Grignard reagent (3 mmol) added dropwise at -35 °C. b Isolated yields.
9j
a Reaction conditions. Method A: sulfonyl indole 9 (1 mmol), Bu3SnH
(2 mmol), and AIBN (0.3 mmol) in toluene (12 mL) at reflux. Method B:
9 (1 mmol), 6% Na-Hg amalgam (1.5 g), and Na2HPO4 (4 mmol) in EtOH
(10 mL) at rt. Method C: 9 (1 mmol) and LiAlH4 (3 mmol) in THF (12
mL) at rt. b Isolated yields.
In summary, we have devised an unprecedented procedure
for the synthesis of 3-(1-arylsulfonylalkyl) indoles by
Friedel-Crafts reaction of R-amido sulfones with indoles
in the presence of montmorillonite K-10 under solventless
conditions. These rather unknown sulfonyl indole deriva-
tives18 can be desulfonylated under reductive conditions
giving 3-alkyl indoles or alkylated upon reaction with
Grignard reagents giving branched 3-alkyl indoles. Further
studies of reactions of 3-(1-arylsulfonylalkyl) indoles with
other nucleophilic systems are currently underway in our
laboratory.
providing indole 16a (Table 3, entries 1 and 2).17 Complex
hydride LiAlH4 is seldom used for this purpose, but the basic
character of this reagent makes possible a mechanism already
outlined in Scheme 1 that involves elimination to the imino-
like derivative 4 followed by its reduction to compound 5
(Nu ) H). Thus reduction of sulfone 9g using LiAlH4 in
THF affords the corresponding indole derivative 16d with a
considerable degree of efficiency (Table 3, method C, entry
5).
The success of the reductive cleavage of the ArSO2 group
by LiAlH4 clearly suggests the possibility of using Grignard
reagents in a strictly related fashion to obtain alkylation of
the indole side chain. Some preliminary results concerning
the reaction of simple Grignard reagents 17 with sulfones 9
at -35 °C show that this process is possible and leads to
the corresponding substituted indoles 18 in good yield (Table
4).
Acknowledgment. Financial support from University of
Camerino (National Project “Sintesi e Reattivita`-attivita` di
Sistemi Insaturi Funzionalizzati”) is gratefully acknowledged.
Supporting Information Available: General experimen-
tal procedures, spectroscopic data, and copies of 1H and 13
C
NMR spectra for all new compounds prepared. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL061604W
(18) (a) Krasovsky, A. L.; Druzhinin, S. V.; Nenajdenko, V. G.;
Balenkova, E. S. Tetrahedron Lett. 2004, 45, 1129-1132. (b) Licari, J. J.;
Dougherty, G. J. Am. Chem. Soc. 1954, 76, 4039-4040.
(17) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1345-
1353.
4096
Org. Lett., Vol. 8, No. 18, 2006