Synthesis of C2-symmetric bis-indolyl sulfones

Article abstract of DOI:10.1016/j.tetlet.2009.08.001

A new class of C₂-symmetric bis-indole derivatives with 2,2′-linkage has been synthesized from bis-propargyl sulfones. The method involves treatment of the sulfones with catalytic amount of triethylamine to form the indole derivatives presumabl

Full text of DOI:10.1016/j.tetlet.2009.08.001

Tetrahedron Letters 50 (2009) 5846–5849
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of C2-symmetric bis-indolyl sulfones
*
Tapobrata Mitra, Sanket Das, Amit Basak
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
a r t i c l e i n f o
a b s t r a c t
A new class of C2-symmetric bis-indole derivatives with 2,20-linkage has been synthesized from bis-prop-
argyl sulfones. The method involves treatment of the sulfones with catalytic amount of triethylamine to
form the indole derivatives presumably via the intramolecular Michael addition to the intermediate bis-
allenic sulfones. Interestingly, the expected Garratt-Braverman pathway was not followed.
Ó 2009 Elsevier Ltd. All rights reserved.
Article history:
Received 20 May 2009
Revised 30 July 2009
Accepted 5 August 2009
Available online 9 August 2009
Bis-indole derivatives are important targets for drug design.1
This is mainly because of recent reports of various activities exhib-
ited by various bis-indoles2,3 as well as their presence in many bio-
active natural products.4 A variety of methods exist for the
synthesis of indole systems including bis-indole. The newer meth-
ods of indole synthesis mainly include metal-catalyzed intramolec-
ular cyclization to propargylic systems.5 For the bis-indoles, most
of the methods start from indole derivatives itself in which two in-
dole units are joined directly or through a suitable linker.6 The
usual linkage pattern is 3,30 which are the preferential sites for
electrophilic substitution in indoles.7 Recently, a gold (I)-catalyzed
sequential cycloisomerization/bis-addition of o-ethynylanilines to
3,30-bis-(indolyl)methanes has been reported.8 Simple and efficient
ways for constructing bis-indole derivatives with 2,20-linker are
still in demand. While trying to induce a Garratt-Braverman (GB)
cyclization9 to study the stereo-differentiation, if any, during the
formation of the atropisomers, we prepared a series of bis-propar-
gyl sulfones of the type A with an ortho aminoacyl amino acid
(Scheme 1). We found that the major pathway followed was isom-
erization followed by intramolecular addition of the amide nucle-
ophile via the nitrogen to form the indoles in high yields. A close
look at the structure of the sulfones reveals an interesting feature:
the bis-allenic sulfone obtained via base-induced isomerization of
the corresponding propargylic analog can either undergo GB-rear-
rangement or can be intramolecularly trapped by the nucleophilic
amide.
Our first task was to make the starting materials 1a–d. Thus
EDC-mediated coupling of 2-iodo aniline with N-Boc amino acids
produced the N-acyl derivatives. Sonogashira coupling10 with
propargyl alcohol followed by mesylation (mesyl chloride, Et3N)
and bromination (LiBr, THF)11 gave the bromide. The latter upon
treatment with Na2S in methanol afforded the sulfide which on
oxidation with mCPBA produced the sulfone (Scheme 2). The sim-
ple aryl sulfone 3 was similarly prepared from the intermediate
bromide 6a.
O
O
S
S
C
O
C
O
O
O
O
O
N
H
R1* R1*
N
H
N
H
R1*
R1*
N
H
A
B
NHCOR1*
O
GB Products
NH
R1*
S
HN
R1*
O
O
C
O
C
NHCOR1*
S
O
O
C
D
S
O O
O as nucleophile
O
O
However, in reality, the nucleophilic addition was found to be
the only pathway followed which led to the formation of bis-in-
doles F in high yields. Neither the phenyl-substituted naphthalene
sulfolenes D (GB product) nor any oxazepine derivative E could be
isolated in these reactions. The method is very general and works
with various amino acid derivatives. Herein, we report the results
in detail along with a probable explanation for such a preference.
N
N
R1* R1*
E
B
O
O
S
N
N as nucleophile
R
N
R1*
O
O
R1*
F
R1*
=
H
R = Me, CHMe2, CH2CHMe2, CH2Ph
NHBoc
* Corresponding author. Tel.: +91 3222283300; fax: +91 3222282252.
E-mail address: absk@chem.iitkgp.ernet.in (A. Basak).
Scheme 1. Possible reaction pathways via the bis-allenic sulfone.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.001

T. Mitra et al. / Tetrahedron Letters 50 (2009) 5846–5849
5847
OH
Br
50%
I
i
NH
81%
NH2
NH
4
R
6a-6d
SPh
R
O
5a-5d
O
NHBoc
iii
NHBoc
70%
NH
ii
70%
R
O
NHBoc
3a (R = Me)
iv 85%
S
S
SO2Ph
O
O
NH
HN
iv
NH
HN
NH
R
R
85%
R
R
O
R
O
O
O
O
NHBoc NHBoc
NHBoc
NHBoc NHBoc
3 (R = Me)
2a-2d
1a-1d
Scheme 2. Synthesis of the target bis-propargyl sulfones. Reagents and conditions: (a) R = Me; (b) R = CHMe2; (c) R = CH2CHMe2; (d) R = CH2Ph; i = MsCl, NEt3, 0 °C, DCM;
LiBr, THF; ii = Na2S, MeOH; iii = PhSH, NEt3, DCM; iv = mCPBA, DCM.
With the starting bis-propargyl sulfones in hand, the stage was
set to check their reactivity under basic conditions. As an initial
experiment, the sulfone 1a was dissolved in CDCl3 in an NMR tube
and triethylamine was added and the 1H NMR was recorded at dif-
ferent time points (Fig. 1). With time, the broad signal for the
methylenes in the substrate at ꢀd 4.4 was slowly replaced by a pair
of doublets at d 4.90 and 5.16 (J = 14.2 Hz) characteristic of an dia-
stereotopic methylene. At the same time, a new singlet started to
appear at d 6.86 which was assigned to the 3 and 30 hydrogens of
indole. The reaction was complete within 2 h. It was repeated on
a larger scale in CHCl3 and Et3N and the product was isolated in
a pure form in >95% yield by column chromatography over silica
gel using hexane–EtOAc (1:1) as eluent. That the product was
not a result of Garratt-Braverman cyclization was apparent from
the symmetrical nature of its structure (like appearance of AB pair
of doublets, each integrating to 2H and absence of the amide NH
signal. The other alternative oxazepine structure, however, could
not be ruled out on the basis of NMR or mass spectra.12 Repeated
attempts to obtain single crystal from any of these products failed.
The structures were finally confirmed to be the indole derivatives
by facile base-mediated deprotection of the acyl groups to form
the known free indole derivatives (Scheme 3). Spectral data com-
pletely matched with those reported.7,13
The generality of this methodology for the synthesis of bis-in-
dole derivatives was demonstrated by carrying out the reaction
with various other sulfones. In each case the indole derivatives
were obtained in excellent yields. The reaction also works with
monopropargyl sulfones 3. The results are shown in Table 1.
We would like to put forward a probable reason for such pref-
erence of nucleophilic attack over GB cyclization. Although the fi-
nal products of both the reactions are the creation of aromatic
system, namely indole and naphthalene, the GB cyclization in-
volves a series of steps as shown in Scheme 4. The first step, being
likely to be the rate determining step, does not lead to an aromatic
system and hence is endothermic. In case of the Michael pathway,
the addition of nucleophile is concomitant with the generation of
S
O
O
R
O
i
O
S
N
N
NH
HN
R
O
O
R
R
NHBoc
NHBoc
O
O
NHBoc NHBoc
1a-1d
7a-7d
ii
SO2Ph
O
O
S
NH
R
N
H
N
H
O
9
NHBoc
3
i
ii
SO2Ph
N
SO2Ph
N
H
R
O
10
NHBoc
8
Scheme 3. Results of base treatment of sulfones. Reagents and conditions: (a)
R = Me; (b) R = CHMe; (c) R = CH2CHMe2; (d) R = CH2Ph; i = Et3N, CHCl3, 0.5–2 h;
ii = Et3N, CHCl3, 24 h.
Figure 1. 1H NMR at different time points upon base treatment of sulfone 1a.

5848
T. Mitra et al. / Tetrahedron Letters 50 (2009) 5846–5849
2. (a) Andreani, A.; Burnelli, S.; Granaiola, M.; Leoni, A.; Locatelli, A.; Morigi, R.;
Table 1
Rambaldi, M.; Varoli, L.; Landi, L.; Prata, C.; Berridge, M. V.; Grasso, C.; Fiebig,
H.-H.; Kelter, G.; Burger, A. M.; Kunkel, M. W. J. Med. Chem. 2008, 51, 4563; (b)
Young, S. D.; Amblard, M. C.; Britcher, S. F.; Grey, V. E.; Tran, L. O.; Lumma, W.
C.; Huff, J. R.; Schleif, W. A.; Emini, E. E.; O’Brien, J. A.; Pettibone, D. J. Bioorg.
Med. Chem. Lett. 1995, 5, 491; (c) Regina, G. L.; Coluccia, A.; Piscitelli, F.;
Bergamini, A.; Sinistro, A.; Cavazza, A.; Maga, G.; Samuele, A.; Zanoli, S.;
Novellino, E.; Artico, M.; Silvestri, R. J. Med. Chem. 2007, 50, 5034; (d) Ragno, R.;
Artico, M.; Martino, G. D.; Regina, G. L.; Coluccia, A.; Pasquali, A. D.; Silvestri, R.
J. Med. Chem. 2005, 48, 213; (e) Silvestri, R.; Martino, G. D.; Regina, G. L.; Artico,
M.; Massa, S.; Vargiu, L.; Mura, M.; Loi, A. G.; Marceddu, T.; Colla, P. L. J. Med.
Chem. 2003, 46, 2482; (f) Cancio, R.; Silvestri, R.; Ragno, R.; Artico, M.; Martino,
G. D.; Regina, G. L.; Crespan, E.; Zanoli, S.; Hü bscher, U.; Spadari, S.; Maga, G.
Antimicrob. Agents Chemother. 2005, 49, 4546; (g) Hu, W.; Guo, Z.; Chu, F.; Bai,
A.; Yi, X.; Cheng, G.; Li, J. J. Bioorg. Med. Chem. 2003, 11, 1153; (h) Silvestri, R.;
Artico, M.; Martino, G. D.; Regina, G. L.; Loddo, R.; Colla, M. L.; Colla, P. L. J. Med.
Chem. 2004, 47, 3892; (i) Williams, T. M.; Ciccarone, T. M.; MacTough, S. C.;
Rooney, C. S.; Balani, S. K.; Condra, J. H.; Emini, E. A.; Goldman, M. E.; Greenlee,
W. J.; Kauffman, L. R.; O’Brien, J. A.; Sardana, V. V.; Schleif, W. A.; Theoharides,
A. D.; Anderson, P. S. J. Med. Chem. 1993, 36, 1291.
Compilation of the results of base treatment of various sulfones
Substrate
Product
Time (min)
Yield (%)
Yield of deprotected
indole (%)
1a
1b
1c
1d
3
7a
7b
7c
7d
8
120
50
33
81
90
98
97
98
95
95
95 (for 9)
95 (for 10)
O
O
S
R1*OC
COR1*
S
NH
C
C HN
O
O
GB Cyclization
3. Kam, T.-S.; Yoganathan, K.; Li, H.-Y. Tetrahedron Lett. 1996, 37, 8811.
4. (a) Wahlstrom, N.; Slatt, J.; Stensland, B.; Ertan, A.; Bergman, J.; Janosik, T. J. Org.
Chem. 2007, 72, 5886; (b) Gul, W.; Hamann, M. T. Life Sci. 2005, 78, 442; (c)
Newman, D. J.; Cragg, G. M.; Snader, K. M. Nat. Prod. Rep. 2000, 17, 215; (d)
Fernandez, L. S.; Buchanan, M. S.; Carroll, A. R.; Feng, Y. J.; Quinn, R. J.; Avery, V.
M. Org. Lett. 2009, 11, 329; (e) Shirani, H.; Stensland, B.; Bergman, J.; Janosik, T.
Synlett 2006, 15, 2459; (f) Ovenden, S. P. B.; Capon, R. J. J. Nat. Prod. 1999, 62,
1246.
5. (a) Naohiro Isono, N.; Lautens, M. Org. Lett. 2009, 11, 1329; (b) Yin, Y.; Ma, W.;
Chai, Z.; Zhao, G. J. Org. Chem. 2007, 72, 5731; (c) Saito, A.; Oda, S.; Fukaya, H.;
Hanzawa, Y. J. Org. Chem. 2009, 74, 1517; (d) Sakai, N.; Annaka, K.; Fujita, A.;
Sato, A.; Konakahara, T. J. Org. Chem. 2008, 73, 4160; (e) Ackermann, L. Org. Lett.
2005, 7, 439.
NH
HN
R1*OC
COR1*
Michael Addition
O
O
R1*OC
NH
COR1*
HN
O
O
S
S
C
C
NH
COR1*
HN
H H
COR1*
R1*OC
NH
O
O
6. Gibbs, T. J. K.; Tomkinson, N. C. O. Org. Biomol. Chem. 2005, 3, 4043.
7. 2,20Bis indoles have previously been synthesized from an indole Mannich base
in only 27% yield: Messinger, P.; Greve, H. Synthesis 1977, 259.
S
O
O
S
N
δ+
N
δ+
H
N
δ-
δ-
8. Praveen, C.; Wilson, Y.; Perumal, S. P. T. Tetrahedron Lett. 2009, 50, 644.
9. (a) Garratt, P. J.; Neoh, S. B. J. Org. Chem. 1979, 44, 2667; (b) Cheng, Y. S. P.;
Garratt, P. J.; Neoh, S. B.; Rumjanek, V. H. Isr. J. Chem. 1985, 26, 101; (c)
Braverman, S.; Duar, Y.; Segev, D. Tetrahedron Lett. 1979, 17, 3181; (d) Zafrani,
Y.; Gottlieb, H. E.; Sprecher, M.; Braverman, S. J. Org. Chem. 2005, 70, 10166.
10. (a) Sonogashira, K.; Tohoda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467;
(b) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N. Synthesis 1980,
627.
COR1*
H
H
R1*
O
O
R1*
O
O
S
N
N
R1*
O
R1*
O
11. (a) Jones, G. B.; Weight, J. M.; Hynd, G.; Wyatt, J. K.; Rarner, P. M.; Huber, R. S.;
Li, A.; Kilgore, M. W.; Sticca, R. P.; Pollenz, R. S. J. Org. Chem. 2002, 67, 5727; (b)
Basak, A.; Bag, S. S.; Das, A. K. Eur. J. Org. Chem. 2005, 7, 1239.
Scheme 4. Mechanism of GB and nucleophilic addition.
12. Selected spectral data: All 1H and 13C NMR spectra were recorded at 400 and
100 MHz, respectively, in CDCl3 unless mentioned otherwise.
the stable indole system and is thought to be exothermic. We be-
lieve that it is the endothermicity of the first step in GB cyclization
which is responsible for the observed selectivity (Scheme 4).
In conclusion, we have developed a simple method for the
preparation of 2,20-bis-indole derivatives connected via a func-
tional linker involving double Michael-type addition to bis-allenic
sulfone, generated in situ from bis-propargyl sulfone. We have also
demonstrated that intramolecular nucleophilic addition of amides
is more facile than the Garratt-Braverman cyclization pathway
which occurs at room temperature in aryl-substituted allenes.
Our observation is in line with the reported cleavage of DNA14 by
allenic sulfones via alkylation pathway (Nicolaou15).
For 7a: White solid; yield 98%, mp 130 °C; dH 7.78 (d, J = 8.8 Hz, 2H), 7.57 (d,
J = 7.6 Hz, 2H), 7.38 (dt, J = 6.4, 1.2 Hz, 2H), 7.30–7.26 (m, 2H), 6.86 (s, 2H),
5.49–5.42 (m, 4H), 5.16 (d, J = 14 Hz, 2H), 4.96 (d, J = 14.4 Hz, 2H), 1.50 (d,
J = 6.4 Hz, 6H), 1.46 (s, 18H); dC 175.1, 155.3, 135.9, 128.8, 127.1, 125.6, 123.4,
121.5, 115.6, 114.1, 80.2, 53.1, 51.7, 28.3, 18.6; ½aꢁD ꢂ90.5 (c 0.20, CHCl3); MS:
m/z = 689.28 [MNa+], 667.31 [MH+]; HRMS: calcd for C34H42N4O8S + H+
667.2804; found 667.2799.
For 7b: White solid; yield 97%, mp 178 °C; dH 7.86 (d, J = 8.4 Hz, 2H), 7.53 (d,
J = 7.6 Hz, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.28–7.24 (m, 2H), 6.87 (app. d, J = 8.0 Hz,
2H), 5.40–5.38 (m, 4H), 5.17 (dd, J = 22.1, 14.4 2H), 4.98 (dd, J = 22.1, 14.4 Hz,
2H), 2.19 (br s, 2H), 1.46 (s, 18H), 1.01 (app. d, J = 5.2 Hz, 6H), 0.86 (app. d,
J = 5.2 Hz, 6H); dC 174.1, 156.0, 136.0, 129.1, 127.4, 125.6, 123.6, 121.5, 115.9,
114.3, 80.1, 59.7, 53.6, 31.5, 28.3, 19.7, 16.4; ½aꢁD ꢂ121.32 (c 0.20, CHCl3); MS:
m/z = 745.32 [MNa+], 723.23 [MH+]; HRMS: calcd for C38H50N4O8S + H+
723.3430; found 723.3427.
For 7c: White solid; yield 98%, mp 75 °C; dH 7.92 (d, J = 8.4 Hz, 2H), 7.54 (d,
J = 7.6 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.27–7.24 (m, 2H), 6.84 (app. d,
J = 10.0 Hz, 2H), 5.48 (br s, 2H), 5.29–5.12 (m, 4H), 4.84 (dd, J = 27.2, 14.4 Hz,
2H), 1.78–1.75 (m, 2H), 1.45 (s, 18H), 1.33–1.25 (m, 4H), 0.98 (d, J = 6.4 Hz, 6H),
0.87 (d, J = 4.4 Hz, 6H); dC 175.7, 155.8, 135.9, 128.9, 127.2, 125.5, 123.5, 121.4,
Acknowledgments
T.M. and S.D. are grateful to CSIR, Government of India, for a fel-
lowship. D.S.T. is thanked for providing funds for the project and
creating 400 MHz NMR facility under the IRPHA programme.
115.3, 114.2, 80.1, 54.3, 53.0, 41.8, 28.3, 24.8, 23.2, 21.5; ½aꢁD ꢂ28.3 (c 0.20,
CHCl3); MS: m/z = 773.36 [MNa+], 751.06 [MH+]; HRMS: calcd for
C40H54N4O8S + H+ 751.3743; found 751.3738.
For 7d: White solid; yield 95%, mp 125 °C; dH 7.88 (d, J = 8.4 Hz, 2H), 7.53 (app.
t, J = 6.8 Hz, 2H), 7.36 (app. t, J = 8.0 Hz, 2H), 7.27–7.09 (m, 12H), 6.81 (app. d,
J = 4.8 Hz, 2H), 5.68 (b, 2H), 5.37 (app. t, J = 8.0 Hz, 2H), 4.96–4.86 (m, 4H),
3.28–3.21 (m, 2H), 2.96–2.89 (m, 2H), 1.35 (s, 18H); dC 174.0, 155.3, 136.0 (2C),
129.4, 128.9, 128.4, 127.0, 126.9, 125.6, 123.6, 121.5, 115.4, 114.3, 80.2, 56.7,
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.08.001.
53.1, 39.2, 28.2; ½a D
ꢁ
ꢂ30.8 (c 0.20, CHCl3); MS: m/z = 841.31 [MNa+], 819.25
[MH+]; HRMS: calcd for C46H50N4O8S + H+ 819.3430; found 819.3425.
For 8: White solid; yield 95%, mp 150 °C; dH 7.76 (d, J = 7.6 Hz, 3H), 7.64 (t,
J = 7.2 Hz, 1H), 7.50 (t, J = 8.0, 3H), 7.35 (app. t, J = 7.2 Hz, 1H), 7.26–7.23 (m,
1H), 6.57 (s, 1H), 5.46–5.43 (m, 2H), 5.26 (d, J = 14.4 Hz, 1H), 4.89 (d, J = 14 Hz,
1H), 1.52 (d, J = 6.4 Hz, 3H), 1.44 (s, 9H); dC 175.0, 155.3, 138.6, 136.0, 133.9,
129.1, 128.7, 128.4, 127.4, 125.6, 123.4, 121.6, 115.6, 114.1, 80.1, 56.2, 51.7,
References and notes
1. (a) Bergman, J.; Janosik, T.; Wahlstrom, N. Adv. Heterocycl. Chem. 2001, 80, 1; (b)
Knolker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303; (c) Prudhomme, M. Curr.
Pharm. Des. 1997, 3, 265; (d) Sanchez, C.; Mendez, C.; Salas, J. A. Nat. Prod. Rep.
2006, 23, 1007.
28.3, 18.9; ½a D
ꢁ
+403.6 (c 0.20, CHCl3); MS: m/z = 465.17 [MNa+], 443.13 [MH+];
HRMS: calcd for C23H26N2O5S + H+ 443.1642; found 443.1637.

T. Mitra et al. / Tetrahedron Letters 50 (2009) 5846–5849
5849
For 9: White crystalline solid; yield 95%, mp 220–222 °C; dH (MeOH-d4) 7.56
(dd, J = 8.0, 0.8 Hz, 2H), 7.37 (dd, J = 8.0, 0.8 Hz, 2H), 7.14 (dt, J = 7.2, 1.2 Hz, 2H),
7.04 (dt, J = 6.8, 0.8 Hz, 2H), 6.61 (s, 2H), 4.60 (s, 4H); dC (MeOH-d4) 137.2,
128.0,124.6, 121.7, 119.8, 119.1, 110.7, 104.3, 50.8; MS: m/z = 347.07 [MNa+],
325.01 [MH+]; HRMS: calcd for C18H16N2O2S + H+ 325.1012; found 325.1008.
For 10: Yellow solid; yield 95%, mp 191–192 °C; dH 8.80 (br s, 1H), 7.66 (d,
J = 8.0 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.49–7.39 (m, 4H), 7.22 (t, J = 7.6 Hz, 1H),
7.09 (t, J = 7.6 Hz, 1H), 6.14 (s, 1H), 4.54 (s, 2H); dC 137.3, 136.8, 134.0, 129.0,
128.3, 127.5, 124.4, 122.9, 120.6, 120.1, 111.1, 105.6, 56.2; MS: m/z = 294.07
[MNa+], 272.17 [MH+]; HRMS: calcd for C15H13NO2S + H+ 272.0746; found
272.0743.
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