Simplified synthesis of 3-(1-arylsulfonylalkyl) indoles and their reaction with reformatsky reagents

Article abstract of DOI:10.1021/jo062538e

A simple procedure for the preparation of 3-(1-arylsulfonylalkyl) indoles by three-component condensation of indoles, carbonyls, and arenesulfinic acids is presented. The obtained products undergo a Reformatsky reaction leading to alkyl 3-(3-indolyl) alka

Full text of DOI:10.1021/jo062538e

SCHEME 1
Simplified Synthesis of 3-(1-Arylsulfonylalkyl)
Indoles and Their Reaction with
Reformatsky Reagents
Alessandro Palmieri and Marino Petrini*
Dipartimento di Scienze Chimiche, UniVersita di Camerino,
Via S. Agostino, 1, I-62032 Camerino, Italy
marino.petrini@unicam.it
ReceiVed December 12, 2006
Nitroalkenes usually require little activation to be introduced
into the indole ring because of their intrinsic reactivity as
electrophiles. Conversely, R,â-unsaturated esters, especially
when substituted at the â-position, must be activated using
strong Lewis acids to efficiently produce the corresponding
adduct, unless an intramolecular process is realized.4 A comple-
mentary indirect approach to obtain adducts 2 consists of the
reaction of indole 1 with an aldehyde in the presence of a
suitable reagent HX in which anion X- is able to intercept the
intermediate benzylic carbocation leading to 3-substituted indole
3 (Scheme 1, path b). Reaction of indolyl derivative 3 with a
base would produce an elimination of HX, providing that X-
is a good leaving group, leading to vinylogous imino derivative
4. Nucleophilic addition of carbanionic reagents to imine 4
affords the same compound 2 obtained by the direct method.5
Elimination of amino groups from derivatives 3 (X ) NR2)
obtained from Mannich-type reactions on indoles has long
constituted the only available entry to imino intermediates 4 to
be used in subsequent nucleophilic additions.6
Recently, we have demonstrated that reaction of various
indoles 1 with R-amidoalkylphenyl sulfones 5, in the presence
of montmorillonite K-10 as an acid promoter, gives 3-(1-
arylsulfonylalkyl) indoles 6 instead of the expected 3-(1-
aminoethoxycarbonylalkyl) indoles 7 (Scheme 2).7
Sulfonyl derivatives of type 5 are known to undergo elimina-
tion of the arenesulfinic group under both acidic and basic
conditions leading to reactive N-acilimino species that can be
profitably employed in the reaction with different nucleophilic
systems.8 In our process, the amido derivative 7 which is initially
A simple procedure for the preparation of 3-(1-arylsulfonyl-
alkyl) indoles by three-component condensation of indoles,
carbonyls, and arenesulfinic acids is presented. The obtained
products undergo a Reformatsky reaction leading to alkyl
3-(3-indolyl) alkanoates and (3-indolyl) ketones.
The electron-rich indole nucleus shows an enhanced reactivity
toward carbon electrophiles that generally results in the forma-
tion of 3-substituted indole derivatives. The alkylation process
occurs by way of a Friedel-Crafts (F-C) reaction exploiting
electron-poor alkenes as electrophilic reagents (Scheme 1, path
a).1 Such substitution reactions are usually promoted by Lewis
or Brønsted acids that can be nowadays employed even in a
catalytic amount.2 This feature makes the F-C reaction
particularly suited for enantioselective processes using different
catalytic systems.3 The acidity level of the promoter needed for
the F-C reaction is clearly affected by the electrophilic character
of the olefin used.
(1) Bandini, M.; Melloni, A.; Tommasi, S.; Umani-Ronchi, A. Synlett
2005, 1199-1222.
(2) (a) Ye, M.-C.; Yang, Y.-Y.; Tang, Y.; Sun, X.-L.; Ma, Z.; Qin,
W.-M. Synlett 2006, 1240-1244. (b) Li, D.-P.; Guo, Y.-C.; Ding, Y.; Xiao,
W.-J. Chem. Commun. 2006, 799-801. (c) Bartoli, G.; Bosco, M.; Giuli,
S.; Giuliani, A.; Lucarelli, L.; Marcantoni, E.; Sambri, L.; Torregiani, E.
J. Org. Chem. 2005, 70, 1941-1944. (d) Zhan, Z.-P.; Yang, R.-F.; Lang,
K. Tetrahedron Lett. 2005, 46, 3859-3862. (e) Ma, S.; Yu, S.; Peng, Z.
Org. Biomol. Chem. 2005, 3, 1933-1936. (f) Firouzabadi, H.; Iranpoor,
N.; Nowrouzi, F. Chem. Commun. 2005, 789-791. (g) Bandini, M.; Fagioli,
M.; Umani-Ronchi, A. AdV. Synth. Catal. 2004, 346, 545-548. (h) Dessole,
G.; Herrera, R. P.; Ricci, A. Synlett 2004, 2374-2378.
(3) (a) Evans, D. A.; Fandrick, K. R. Org. Lett. 2006, 8, 2249-2252.
(b) Yamazaki, S.; Iwata, Y. J. Org. Chem. 2006, 71, 739-743. (c) Palomo,
C.; Oiarbide, M.; Kardak, B. G.; Garc´ıa, J. M.; Linden, A. J. Am. Chem.
Soc. 2005, 127, 4154-4155. (d) King, H. D.; Meng, Z.; Denhart, D.;
Mattson, R.; Kimura, R.; Wu, D.; Gao, Q.; Macor, J. E. Org. Lett. 2005, 7,
3437-3440.
(4) Angeli, M.; Bandini, M.; Garelli, A.; Piccinelli, F.; Tommasi, S.;
Umani-Ronchi, A. Org. Biomol. Chem. 2006, 4, 3291-3296.
(5) For a related strategy using vinylogous nitrone derivatives, see:
Nicolaou, K. C.; Estrada, A. A.; Lee, S. H.; Freestone, G. C. Angew. Chem.,
Int. Ed. 2006, 45, 5364-5368.
(6) (a) Shirakawa, S.; Kobayashi, S. Org. Lett. 2006, 8, 4939-4942. (b)
Semenov, B. B.; Novikov, K. A.; Lysenko, K. A.; Kachala, V. V.
Tetrahedron Lett. 2006, 47, 3479-3483. (c) Freed, J. D.; Hart, D. J.;
Magomedov, N. A. J. Org. Chem. 2001, 66, 839-852. (d) Dubois, L.;
Dorey, G.; Potier, P.; Dodd, R. H. Tetrahedron: Asymmetry 1995, 6, 455-
462.
(7) Ballini, R.; Palmieri, A.; Petrini, M.; Torregiani, E. Org. Lett. 2006,
8, 4093-4096.
(8) Petrini, M. Chem. ReV. 2005, 105, 3949-3977.
10.1021/jo062538e CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/09/2007
J. Org. Chem. 2007, 72, 1863-1866
1863

TABLE 1. Synthesis of 3-(1-Arylsulfonylalkyl) Indoles 6 by
Condensation of Carbonyl Derivatives 8 in the Presence of
Arylsulfinic Acids 12
SCHEME 2
SCHEME 3
indole carbonyl sulfinic acid product
yielda
(%)
entry
3
8
12
6
solvent
1
2
3
4
5
6
7
8
9
1a
1a
1b
1b
1b
1b
1c
1c
1d
1e
1f
8b
8c
8b
8d
8g
8e
8b
8f
8b
8b
8a
8c
12a
12a
12a
12b
12a
12a
12a
12a
12a
12a
12a
12a
6a
6b
6c
6d
6e
6f
6g
6h
6i
EtOAc
EtOAcb
EtOAcb
EtOAc
CH2Cl2
EtOAc
EtOAc
EtOAc
EtOAc
CH2Cl2
80
68
75
82
70
95
67
81
80
79
71
75
10
11
12
6j
6k
6l
b
CH2Cl2
CH2Cl2
b
1f
a
b
Yield of pure isolated products. At reflux.
2.5 h formation of 3-(1-arylsulfonylalkyl) indoles 6 in good yield
(Table 1). Ethyl acetate is generally the solvent of choice for
most of the substrates tested; however, it has been observed
that in some instances the yield may be improved by performing
the reaction in dichloromethane. The acidity level provided by
arylsulfinic acids is often unable to allow for an efficient
decomposition of the intermediate bisindole 11, so addition of
p-toluenesulfonic acid is necessary to ensure better yields of
products 6. Indole as well as its substituted derivatives efficiently
react with aliphatic and aromatic aldehydes thus avoiding the
need for using R-amido sulfones as reagents for the preparation
of compounds 6. Furthermore, 2-substituted indoles such as
2-phenylindole 1c which react sluggishly under the previous
conditions can be readily transformed into sulfones 6g,h in
satisfactory yields (Table 1, entries 7 and 8). Interesting results
are also obtained using acetone 8g as a carbonyl derivative that
reacts even at room temperature (Table 1, entry 5); however,
the procedure would probably require optimization for other
ketones that give rather disappointing outcomes in these
conditions.
formed by reaction of 1 with 5 probably suffers an acid-
promoted elimination of ethyl carbamate giving a vinylogous
iminium ion that by reaction with arylsulfinic acid released from
5 produces the final compound 6. Sulfonyl indoles 6 are
effective precursors of imino derivatives of type 4, and their
utility has been demonstrated in the preparation of linear and
branched 3-alkyl indoles by reductive desulfonylation or reaction
with Grignard reagents.7 While monitoring the formation of
compounds 6 using the former procedure, the presence in the
reaction mixture of bisindole derivatives that slowly disappear
has always been observed along with the increasing formation
of the final products 6. It is known that aldehydes 8 react with
indoles 1 under F-C conditions to afford bisindoles 11 as main
products (Scheme 3).
Formation of bisindoles 11 is possible because the initially
formed indolylalkanols 9 in acidic conditions suffer elimination
of water giving a vinylogous iminium ion 10 that reacts with a
second molecule of indole.9 Therefore, we considered the
possibility of accessing sulfonyl indoles 6 using a related
procedure in which arylsulfinic acids 12 act as promoters and
effective trapping nucleophiles of the intermediate iminium ions
10. Upon mixing an indole 1 with an appropriate carbonyl
derivative 8 and arylsulfinic acids 12 in the presence of
p-toluenesulfonic acid (50% mol), it is possible to observe after
At this point, to further develop the chemistry of compounds
6, we decided to test the reactivity of these sulfonyl derivatives
toward stabilized carbanions with the aim to implement the
functional array of the original molecular structure. Among
various metal enolates, Reformatsky reagents are certainly those
of more practical use being generated using R-halo carbonyl
derivatives in the presence of zinc metal in various solvents.10
Furthermore, imines as well as iminium ions have been
demonstrated to react quite efficiently with these organozinc
(9) (a) Deb, M. L.; Bhuyan, P. J. Tetrahedron Lett. 2006, 47, 1441-
1443. (b) Gibbs, T. J. K.; Tomkinson, N. C. O. Org. Biomol. Chem. 2005,
3, 4043-4045. (c) Mo, L.-P.; Ma, Z.-C.; Zhang, Z.-H. Synth. Commun.
2005, 35, 1997-2004.
1864 J. Org. Chem., Vol. 72, No. 5, 2007

TABLE 2. Synthesis of 3-Indolylpropanoates 14 by Reformatsky
Reaction of 3-(1-Arylsulfonylalkyl) Indoles 6 with 2-Bromo
Carbonyl Derivatives 13
SCHEME 4
sulfonyl
indole 6
2-bromo
carbonyl 13
product
14
yielda
(%)
entry
Tricyclic â-keto esters of type 16 are pivotal intermediates for
the synthesis of tetracyclic lactam compounds that are of
potential interest as neurotransmitters.13
1
2
3
4
5
6
7
6a
6b
6c
6c
6c
6f
13a
13d
13a
13c
13e
13b
13b
14a
14b
14c
14d
14e
14f
80
75b
90
89
88c
66
67
In summary, a new procedure for the preparation of 3-(1-
arylsulfonylalkyl) indoles by a three-component coupling of
simple and commercially available reagents has been devised.
The synthetic significance of these sulfonyl derivatives is
demonstrated for their reaction with Reformatsky reagents that
efficiently produces 3-indolylpropanoate esters which are
amenable of other synthetic manipulations. Because in principle
many other nucleophilic systems can be made to react with these
reactive sulfonyl indoles, further studies are currently underway
in our laboratory.
6j
14g
a
b
c
Yield of pure isolated products. Diastereomeric mixture (3:2). At
reflux, 2.5 h.
derivatives.11 Refluxing a THF solution of sulfonyl indoles 6
with 2-bromo carbonyl compounds 13 in the presence of zinc
metal and a catalytic amount of iodine for 1 h ensures a complete
conversion of the indole 6 to the corresponding 3-indolylpro-
panoates 14 and 3-indolylpropanone 14e (Table 2).
Experimental Section
An excess of the Reformatsky reagent is obviously needed
to promote the elimination of the arenesulfinic acid giving the
imino derivative 4 which acts as an effective electrophile in
the reaction with the organozinc reagent. Different 2-bromo-
acetates have been tested for this procedure with satisfactory
results; reaction using methyl 2-bromopropanoate 13d leads to
the corresponding 3-indolylpropanoate 14b with good yield but
poor diastereoselectivity (3:2) (Table 2, entry 2). 2-Bromo-
acetophenone 13e can also be employed in this procedure,
although 2.5 h at reflux is needed to observe a complete
conversion of sulfonyl indole 6c into 3-indolyl ketone 14e (Table
2, entry 5).
3-Sulfonyl indoles 6k,l obtained from ethyl 2-indolecarboxy-
late 1f have been proven to be poorly reactive in the above-
cited conditions for the Reformatsky reaction; a different form
of activated zinc, namely, the zinc copper couple in dichlo-
romethane at reflux, is needed to obtain the desired diesters 15
(Scheme 4).12
General Procedure for the Preparation of Sulfonyl Indoles
6. To a stirred solution of indole 1 (3.2 mmol), arylsulfinic acid 12
(3.6 mmol), and p-toluenesulfonic acid monohydrate (1.5 mmol)
in EtOAc or CH2Cl2 (10 mL) (see Table 1) was added the carbonyl
compound 8 (3 mmol). The resulting reaction mixture was stirred
at rt or at reflux for 2.5 h (see Table 1) and was then treated with
saturated NaHCO3 (7 mL). The aqueous layer was extracted with
CH2Cl2 (3 × 20 mL), and the combined organic extracts were dried
over Na2SO4 and treated with activated charcoal. The crude product
6 obtained after filtration through a short celite pad and removal
of the solvent at reduced pressure was purified by flash chroma-
tography (hexanes/ethyl acetate 80:20).
1-Methyl-1-(2-methyl-1H-3-indolyl)ethyl (4-Methylphenyl) Sul-
fone (6e). Yield: 70%. White solid, mp 165-167 °C. IR (cm-1
,
nujol): 3331, 1115. 1H NMR (CDCl3, 400 MHz) δ: 2.00 (s, 6H),
2.15 (s, 3H), 2.33 (s, 3H), 6.92-6.98 (m, 1H), 7.02-7.09 (m, 3H),
7.21 (d, 1H, J ) 7.7 Hz), 7.30 (d, 2H, J ) 8.1 Hz), 7.61 (d, 1H,
J ) 8.1 Hz), 8.01 (bs, 1H). 13C NMR (CDCl3, 100 MHz) δ: 16.0,
21.7, 25.0, 65.9, 108.1, 110.4, 119.9, 121.3, 122.2, 128.7, 128.9,
130.4, 132.8, 134.7, 135.3, 144.2. GC-MS (70 eV): m/z 171 (100),
156, 129, 77. Anal. Calcd for C19H21NO2S (327.44): C, 69.69; H,
6.46; N, 4.28. Found: C, 69.74; H, 6.49; N, 4.25.
These 1,6-difunctionalized derivatives 15 are ideal substrates
for a Dieckmann condensation that can be carried out using
sodium hydride in THF at reflux leading to â-keto ester 16.
General Procedure for the Preparation of Esters 14. To a
stirred solution of 2-bromo derivative 13 (2.1 mmol), Zn dust (5
mmol), and I2 (0.2 mmol) in dry THF (12 mL) was added the
appropriate sulfonyl indole 6 (1 mmol). The resulting suspension
was stirred at reflux for 1 h and then treated with 2 N HCl (5 mL).
The aqueous layer was extracted with CH2Cl2 (3 × 20 mL), and
the combined organic extracts were dried over Na2SO4. The crude
(10) (a) Ocampo, R.; Dolbier, W. R., Jr. Tetrahedron 2004, 60, 9325-
9374. (b) Rathke, M. W.; Weipert, P. In ComprehensiVe Organic Synthesis;
Heathcock, C, H., Ed.; Pergamon Press: Oxford, 1991; Vol. 2, pp 277-
299.
(11) (a) Moumne, R.; Lavielle, S.; Karoyan, P. J. Org. Chem. 2006, 71,
3332-3334. (b) Awasthi, A. K.; Boys, M. L.; Cain-Janicki, K. J.; Colson,
P.-J.; Doubleday, W. W.; Duran, J. E.; Farid, P. N. J. Org. Chem. 2005,
70, 5387-5397. (c) Ross, N. A.; MacGregor, R. R.; Bartsch, R. A.
Tetrahedron 2004, 60, 2035-2041.
(12) (a) Santaniello, E.; Manzocchi, A. Synthesis 1977, 698-699. (b)
Mecozzi, T.; Petrini, M. Tetrahedron Lett. 2000, 41, 2709-2712.
(13) (a) Maertens, F.; Van den Bogaert, A.; Compernolle, F.; Hoornaert,
G. J. Eur. J. Org. Chem. 2004, 4648-4656. (b) Bennasar, M.-L.; Roca, T.;
Griera, R.; Bosch, J. J. Org. Chem. 2001, 66, 7547-7551.
J. Org. Chem, Vol. 72, No. 5, 2007 1865

product 14 obtained after removal of the solvent at reduced pressure
was purified by flash chromatography (hexanes/ethyl acetate
90:10).
GC-MS (70 eV) m/z: 317, 244, 242, 230, 184, 170, 156 (100),
140, 128, 115, 29. Anal. Calcd for C18H23NO4 (317.38): C, 68.12;
H, 7.30; N, 4.41. Found: C, 68.17; H, 7.34; N, 4.43.
tert-Butyl 3-(2-Methyl-1H-3-indolyl)octanoate (14d). Yield:
Ethyl 1-Ethyl-3-oxo-1,2,3,4-tetrahydrocyclopenta[b]indole-2-
carboxylate 16. To a stirred suspension of NaH (0.06 g, 2.5 mmol)
in dry THF (6 mL) was added diester 15a (0.32 g, 1 mmol) at
room temperature. The resulting mixture was stirred at reflux for
5 h and after cooling was treated with 2 N HCl (3 mL). The aqueous
layer was extracted with CH2Cl2 (3 × 20 mL), and the combined
organic extracts were dried over Na2SO4. The crude product
obtained after removal of the solvent at reduced pressure was
purified by flash chromatography (hexanes/ethyl acetate 90:10)
1
89%. Waxy solid. IR (cm-1, nujol): 3360, 1712, 1150. H NMR
(CDCl3, 400 MHz) δ: 0.78-0.85 (m, 3H), 1.10-1.28 (m, 6H),
1.24 (s, 9H), 1.65-1.77 (m, 1H), 1.81-1.93 (m, 1H), 2.38 (s, 3H),
2.70 (d, 2H, J ) 7.6 Hz), 3.26-3.35 (m, 1H), 7.00-7.11 (m, 2H),
7.25 (d, 1H, J ) 7.7 Hz), 7.58 (d, 1H, J ) 7.3 Hz), 7.75 (bs, 1H).
13C NMR (CDCl3, 100 MHz) δ: 12.4, 14.3, 22.8, 27.9, 28.1, 32.0,
34.2, 35.1, 42.1, 80.0, 110.4, 113.6, 119.0, 119.5, 120.7, 127.7,
131.4, 135.7, 172.9. GC-MS (70 eV) m/z: 329, 273, 258, 214 (100),
202, 157, 144, 130, 57. Anal. Calcd for C21H31NO2 (329.48): C,
76.55; H, 9.48; N, 4.25. Found: C, 76.60; H, 9.51; N, 4.27.
General Procedure for the Preparation of Compounds 15.
To a stirred solution of ethyl 2-bromo acetate 13b (2.1 mmol) and
Zn-Cu couple (200 mg) in dry CH2Cl2 (8 mL) was added the
appropriate sulfonyl indole 6 (1 mmol). The resulting suspension
was stirred at reflux for 1.5 h and then treated with 2 N HCl (5
mL). The aqueous layer was extracted with CH2Cl2 (3 × 20 mL),
and the combined organic extracts were dried over Na2SO4. The
crude product 15 obtained after removal of the solvent at reduced
pressure was purified by flash chromatography (hexanes/ethyl
acetate 90:10).
giving 0.17 g of ketoester 16 as an oil (yield 61%). IR (cm-1
,
nujol): 3350, 1374, 1136. 1H NMR (CDCl3, 400 MHz) δ: 1.06 (t,
3H, J ) 7.7 Hz), 1.30 (t, 3H, J ) 7.3 Hz), 1.71-1.86 (m, 1H),
2.06-2.20 (m, 1H), 3.67 (d, 1H, J ) 2.1 Hz), 3.75-3.81 (m, 1H),
4.25 (q, 2H, J ) 7.3 Hz), 7.16 (t, 1H, J ) 7.3 Hz), 7.38 (d, 1H,
J ) 7.3 Hz), 7.50 (d, 1H, J ) 8.5 Hz), 7.71 (d, 1H, J ) 8.1 Hz),
9.86 (bs, 1H). 13C NMR (CDCl3, 100 MHz) δ: 11.9, 14.4, 27.7,
41.1, 61.7, 64.3, 114.1, 121.0, 122.2, 123.1, 127.9, 137.0, 144.7,
150.0, 170.1, 187.9. GC-MS (70 eV) m/z: 199, 170 (100), 140,
115. Anal. Calcd for C16H17NO3 (271.31): C, 70.83; H, 6.32; N,
5.16. Found: C, 70.88; H, 6.34; N, 5.13.
Ethyl 3-(3-Ethoxy-1-ethyl-3-oxopropyl)-1H-2-indolecarboxyl-
ate (15a). Yield: 61%. Oil. IR (cm-1, neat): 3400, 1722. 1H NMR
(CDCl3, 400 MHz) δ: 0.49 (t, 0.3H, J ) 7.3 Hz), 0.81 (t, 2.7H,
J ) 7.3 Hz), 1.09 (t, 3H, J ) 7.3 Hz), 1.44 (t, 2.7H, J ) 7.3 Hz),
1.53 (t, 0.3H, J ) 7.3 Hz), 1.81-2.07 (m, 2H), 2.91 (d, 2H, J )
7.7 Hz), 4.00 (q, 2H, J ) 7.3 Hz), 4.11-4.27 (m, 1H), 4.37-4.48
(m, 2H), 7.07-7.17 (m, 1H), 7.25-7.33 (m, 1H), 7.37 (d, 0.9H,
J ) 8.1 Hz), 7.44 (d, 0.1H, J ) 8.5 Hz), 7.79 (d, 0.9H, J ) 8.5
Hz), 8.16 (d, 0.1H, J ) 8.1 Hz), 8.96 (bs, 1H). 13C NMR (CDCl3,
100 MHz) δ: 12.7, 14.2, 14.5, 27.9, 35.1, 40.3, 60.3, 61.1, 112.1,
119.6, 120.0, 122.2, 123.3, 123.8, 125.4, 125.7, 136.2, 162.5, 172.9.
Acknowledgment. Financial support from the University of
Camerino (National Project “Sintesi e Reattivita`-attivita` di
Sistemi Insaturi Funzionalizzati”) is gratefully acknowledged.
Supporting Information Available: Spectral and physical data
for compounds not included in the Experimental Section and copies
of 1H and 13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO062538E
1866 J. Org. Chem., Vol. 72, No. 5, 2007