Reactions of electron-rich indoles with triflic anhydride

Article abstract of DOI:10.1016/j.tetlet.2009.03.052

The reaction of electron-rich 3-aryl-substituted 4,6-dimethoxyindoles in the presence of base with triflic anhydride results in biaryl coupling, producing both 2,2′- and 2,7′-biindoles. Further, if acetone is present, the corresponding vinyl triflate is f

Full text of DOI:10.1016/j.tetlet.2009.03.052

Tetrahedron Letters 50 (2009) 2501–2504
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Tetrahedron Letters
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Reactions of electron-rich indoles with triflic anhydride
c
c
Nageshwar R. Yepuri a, Rachada Haritakul b, Paul A. Keller a, , Brian W. Skelton , Allan H. White
*
a School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia
b National Centre for Genetic Engineering and Biotechnology (BIOTEC), 113 Thanland Science Park, Phaholyothin Rd, Klong 1, Klong Luang, Pathumanthani 12120, Thailand
c School of Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, WA 6009, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of electron-rich 3-aryl-substituted 4,6-dimethoxyindoles in the presence of base with triflic
anhydride results in biaryl coupling, producing both 2,20- and 2,70-biindoles. Further, if acetone is present,
the corresponding vinyl triflate is formed and subsequent reaction yields the known indolylpyrroloin-
doles and dimeric spiroindoles. This is the first reported synthesis of these compounds under basic
conditions.
Received 18 December 2008
Revised 4 March 2009
Accepted 9 March 2009
Available online 13 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Biindoles
Triflic anhydride
Oxidative coupling
Anti-malarial
Anti-tuberculosis
1. Introduction
gave only 2,70-dimers. These results clearly show that the p-OMe
group is strongly 2,20-directing whereas the mildly deactivating
As part of our ongoing investigations into the biological activi-
ties of homo- and hetero-dimeric aromatic systems,1 we have been
investigating biindoles as bioisosteres of binaphthyl units. We pre-
viously reported the synthesis of 2,20-biindoles under thallium(III)
trifluoroacetate-mediated oxidative coupling conditions,2 and as
part of the mechanistic investigations, we required access to in-
doles that were N-protected with non-aromatic electron-with-
drawing protecting groups. While these mechanistic studies were
successfully completed,2 our initial attempts to generate N-trifly-
lindole monomers yielded unexpected results. Therefore, our
investigations into the reactions of electron-rich indoles with triflic
anhydride are reported here.
bromo group favoured the formation of 2,70 and 2,20-dimers, with
p-NO2 indole and the derivative having no para substituent on
the 3-aryl indole giving only the 2,70-dimer. This demonstrates
the influence of the 3-aryl para substituent in the formation of
the 2,70- over the 2,20-dimer, and has been observed previously
during the thallium(III) trifluoroacetate oxidative coupling of these
monomers.2
Although no experiments were performed investigating the
mechanism, we speculate that the initial step involves the known
electron transfer from substrate to triflic anhydride (Scheme 2).3
The longer reaction times and poorer yields in the absence of
NaH could possibly be attributed to a greater ease of this electron
transfer from the indole anion versus the neutral form. The elec-
tron transfer is also clearly influenced by the presence of substitu-
ents of differing electronic nature. The basic mechanism outlined
in Scheme 2 also suggests the possibility of the formation of 7,70-
dimers, even though these were not isolated from the reactions.
Presumably, the balance of electron distribution of the two pro-
posed intermediates favoured the use of the radical in the C2 posi-
tion for subsequent reaction. Alternatively, the electrophilic radical
intermediates could react with the indole anion at the activated C2
position giving rise to both dimers. Although both indole C2 and C7
positions are activated, the later by the presence of the two meth-
oxy groups, higher yields are generally observed in these indole
system by reaction at C2.2
2. Results and discussion
Initial treatment of 3-aryl-4,6-dimethoxyindoles with NaH fol-
lowed by addition of triflic anhydride yielded both the correspond-
ing 2,20-dimer and/or the 2,70-dimer in overall reasonable yield
(Scheme 1) with no requirement for chromatography when sole
products were formed. There was no indication of the formation
of the N-triflylindole. The optimisation of this dimerisation is sum-
marised in Table 1. Interestingly, the 3-(p-bromophenyl)indole 2
gave the 2,20-dimer as well as the 2,70-dimer, whereas the 3-(p-
nitrophenyl)indole derivative and the 3-phenylindole derivative
During the previously mentioned optimisation reactions, con-
tamination of the solvent led to the observation of the formation
* Corresponding author. Tel.: +61 2 4221 4692; fax: +61 2 4221 4287.
E-mail address: keller@uow.edu.au (P.A. Keller).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.052

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N. R. Yepuri et al. / Tetrahedron Letters 50 (2009) 2501–2504
i. NaH, DCM
ii. triflic anhydride
OMe
X
OMe
H
OMe
X
X OMe
OMe
OMe
N
+
OMe
X
N
MeO
N
N
H
MeO
MeO
H
X
H
HN
2,2'-dimer
X
2,7'-dimer
Yield %
Yield %
1:
X = p-MeOC6H4
: X = p-BrC6H4
: X = Ph
5
6
7
8
9
70
15
0
p-MeOC6H4
p-BrC6H4
Ph
0
2
3
4
10
11
12
55
60
47
: X = p-O2NC6H4
0
p-O2NC6H4
Scheme 1. Dimerisation of dimethoxyindoles using triflic anhydride yielding 2,20- and 2,70-biindoles.
11 containing an unsubstituted 3-phenyl ring showed no anti-
Table 1
Optimisation of the formation of 2,20- and 2,70-indole dimers
malarial activity in this assay. In contrast, when tested for their
anti-tuberculosis activity, 11 was the only compound to show
any activity, albeit only weakly.
3-Aryl unit
NaH (equiv)
Tf2O (equiv)
Isolated yield (%)
2,20-Dimer 2,70-Dimer
Time (h)
In conclusion, this is the first report of triflic anhydride-medi-
ated dimerisation of 3-substituted-4,6-dimethoxyindoles with
the formation of 2,20- and 2,70-dimers. We report here for the first
time the anti-malarial activity of this compound class with the
2,20-dimer 5, the 2,70-dimer 10 and the indolylpyrroloindole 16
found to have moderate activity. Only one spiro compound with
the same carbon skeleton has been previously reported8 albeit con-
taining two ketone moieties. The reactions can be controlled to a
degree to produce the 2,20 or 2,70-dimers by using the appropriate
para-substituted 3-phenyl substituents.
p-MeOC6H4
0
1
2
1
1
2
25
40
70
0
0
0
96
72
72
p-BrC6H4
p-O2NC6H4
Ph
0
1
2
1
1
2
0
5
15
15
30
55
72
72
48
0
1
2
1
1
2
0
0
0
10
30
47
72
96
72
0
1
2
1
1
2
0
0
0
15
50
60
72
72
48
3. Experimental
3.1. Biological assays
The assay used the microculture radioisotope technique at a
starting concentration of 10 lg/ml and was performed at the Na-
tional Centre for Genetic Engineering and Biotechnology (BIOTEC),
Pathumthani, Thailand.
OMe
X
OMe
X
Tf2O
NaH
+
Tf2O
1-4
N
MeO
N
MeO
The parasite Plasmodium falciparum (K1, multidrug-resistant
strain) was cultured continuously according to the method of Trag-
er and Jensen.9 Quantitative assessment of anti-plasmodial activity
in vitro was undertaken by means of the microculture radioisotope
technique based upon the method described by Desjardins et al.10
Inhibition concentration (IC50) represents the concentration which
causes 50% reduction in parasite growth as indicated by uptake of
[3H]-hypoxanthine by P. falciparum.
OMe
OMe
X
X
N
N
MeO
MeO
X
indole
anion
2,2'-biindole
7,7'-biindole 2,7'-biindole
The anti-mycobacterial activity was assessed against Mycobac-
terium tuberculosis H37Ra using the Microplate Alamar Blue Assay
(MABA) according to Collins.11 Standard drugs, isoniazid (MIC of
Scheme 2. Proposed mechanism for the triflic anhydride-mediated dimerisation of
electron-rich indoles in the presence of NaH leading to a 7,70-biindole and a 2,20-
biindole.
0.40–0.090 lg/ml) and kanamycin sulfate (MIC of 2.0–5.0 lg/ml)
were used as reference compounds for the anti-mycobacterial
assay.
of a different product. Investigation of this reaction revealed that
treatment of 4,6-dimethoxy-3-arylindoles 1 and 3 with triflic
anhydride in acetone produced the pyrroloindole spirodimer 13
and the indolylpyrroloindoles 14 and 16 (Scheme 3).4,5 These het-
erocyclic scaffolds have been previously reported starting from
analogous 4,6-dimethoxyindoles and various aldehydes and ke-
tones, but under acidic conditions. We report here that the corre-
sponding heterocycles are accessible under basic conditions with
the likely mechanism involving the generation of a vinyl triflate6
from acetone. The structure of 14 was confirmed by an X-ray crys-
tallographic study (Fig. 1).7
4. General procedures
4.1. Synthesis of dimers
To
a solution of 4,6-dimethoxy-3-(4-methoxyphenyl)indole
(1 mmol) in CH2Cl2 (10 ml) was added sodium hydride (2 mmol,
60% dispersion in mineral oil) and the suspension stirred for
5 min. Triflic anhydride (2 mmol) was then added to the reaction
mixture. After stirring for 72 h at 25 °C, ice cold water (50 ml)
was added carefully. The resulting mixture was partitioned with
CH2Cl2 (3 ꢀ 50 ml) and the combined organic layers dried (MgSO4)
and concentrated. The residue was either subjected to crystallisa-
tion from methanol to give the dimer 9 or was subjected to flash
The indole dimers synthesised in this study were screened for
their anti-malarial activity (Table 2) with most 2,20- and 2,70-in-
doles showing moderate activity. Surprisingly, the 2,70-derivative

N. R. Yepuri et al. / Tetrahedron Letters 50 (2009) 2501–2504
2503
OMe
X
OMe
X
OMe
X
NaH, acetone,
triflic anhydride, RT
N
MeO
N
MeO
OMe+
X
N
N
MeO
OMe
H
HN
1
3
and
X
OMe
OMe
Yield %
X
Yield %
70
70
13
15
14
16
20 p-MeOC6H4
Ph
0
Scheme 3. Formation of spiropyrroloindoles and indolopyrroloindoles using NaH and triflic anhydride.
4.2. Synthesis of spiropyrroloindoles and indolylpyrroloindoles
13 and 14
To a solution of 4,6-dimethoxy-3-(4-methoxyphenyl) indole
(1 mmol) in acetone (15 mL) was added sodium hydride (2 mmol)
and the suspension was stirred for 5 min. Triflic anhydride
(2 mmol) was then added slowly. The reaction mixture was heated
at reflux for 12 h. Ice cold water (50 ml) was added carefully, and
the resultant mixture was partitioned with CH2Cl2 (3 ꢀ 50 ml).
The combined organic layers were dried (MgSO4), then concen-
trated and the residue was subjected to silica gel flash chromatog-
raphy and elution with 80:20, hexane/ethyl acetate gave 13 as an
off-white powder in 20% yield; further elution gave 14 in 70% yield
as a pale yellow powder.
4.2.1. 2,20-Spirobi(1,2-dihydro-3,3-dimethyl-5,7-dimethoxy-4-
(4-methoxyphenyl)-1H-pyrrolo[1,2-a]indole) 13
White solid, mp 232–234 °C. 1H NMR (300 MHz, CDCl3) d: 7.37
(4H, d, J = 5.1 Hz, C4-ArH3, ArH5 and C40-ArH30, ArH50), 6.92 (4H, d,
J = 5.1 Hz, C4-ArH2 and C40-ArH6, ArH60), 6.06 (2H, d, J = 1.5 Hz, H6
and 60), 5.47 (2H, d, J = 1.5 Hz, H8 and H80), 3.87 (6H, s, C4-ArC4-
OCH3 and C40-ArC40-OCH30 ), 3.59 (6H, s, C5-OCH3 and C50-OCH3),
3.51 (6H, s, C7-OCH3 and C70-OCH3), 3.28 (2H, d, J = 13.2 Hz, H2a
and H20 ), 2.77 (2H, d, J = 13.2 Hz, H2b and H20b), 1.51 (6H, s,
a
C3(CH3a 2
)
and C30(CH3a)2), 1.40, (6H, s, C3(CH3b 2
)
and C30
13
(CH3b)2). C NMR (75 MHz, CDCl3) d: 158.1 (ArC40), 156.6 (C7),
155.0 (C5), 143.8 (C3a), 132.1 (2 ꢀ C, ArC30 and 50), 131.0 (C8a),
128.4 (ArC10), 116.8 (C4a), 108.3 (C4), 92.6 (C8), 85.4 (C6), 79.7
(C2 spiro), 58.3 (C1), 55.4 (3 ꢀ C, ArC40-OCH3, C5-OCH3, C7-
OCH3); 38.5 (C3), 31.5 (C3(CH3a)2), 28.3 (C3(CH3b 2 2
) ) . ES-MS m/z:
687 [M+1]+ (35), 364 (100%), 350 (20), 324 (70), 312 (10) 257
(10), 123 (20), 101 (40). ES-HRMS m/z: calcd for [M+1]+
C43H47N2O6 687.3425; found 687.3434.
Figure 1. X-ray structure of 5,7-dimethoxy-2,3-dihydro-1-[4,6-dimethoxy-3-(4-
methoxyphenyl)indol-2-yl]-1,3,3-trimethyl-4-(4-methoxyphenyl)-1H-pyrrolo[1,2-
a]indole 14.
4.2.2. 5,7-Dimethoxy-2,3-dihydro-1-[4,6-dimethoxy-3-(4-methoxy-
phenyl)indol-2-yl]-1,3,3-trimethyl-4-(4-methoxyphenyl)-1H-
pyrrolo[1,2-a]indole 14
White solid, mp 229–231 °C. 1H NMR (300 MHz, CDCl3) d: 7.81
(1H, s, NH0), 7.35 (4H, d, J = 8.7 Hz, ArH30 and 50 and ArH300 and 500),
6.84 (4H, d, J = 8.7 Hz, ArH20 and 60 and ArH200 and 600), 6.34 (1H, d,
J = 1.8 Hz, H6), 6.31 (1H, d, J = 1.8 Hz, H70), 6.22 (1H, d, J = 1.8 Hz,
H50), 6.14 (1H, d, J = 1.8 Hz, H8), 3.86 (3H, s, ArC400-OCH3), 3.84
(3H, s, ArC40-OCH3), 3.78 (3H, s, C40-OCH3), 3.72, (3H, s, C5-
OCH3), 3.66, (3H, s, C7-OCH3), 3.57 (3H, s, C60-OCH3), 2.84 (1H, d,
J = 7.8 Hz, H2), 2.39 (1H, d, J = 7.8 Hz, H2), 1.77 (3H, s, C1-CH3),
1.18 (3H, s, C3-(CH3)2), 1.12 (3H, s, C3-(CH3)2). 13C NMR (75 MHz,
CDCl3) d: 158.4 (ArC400), 158.0 (ArC40), 157.4 (C60), 156.7 (C7),
155.2 (C5), 155.0 (C40), 146.1 (C3a), 135.9 (C7a0), 135.2 (C8a),
132.4 (ArC100), 132.2 (ArC10), 128.4 (C20), 118.0 (C4a), 114.5
(C3a0), 112.8 (C30), 112.5 (C4), 92.5 (C70), 92.1 (C8), 87.1
(C6), 86.8 (C50), 62.4 (C1), 56.6 (C2), 55.1 (ArC400-OCH3), 55.8
Table 2
Anti-malarial and anti-tuberculosis activity of 2,20- and 2,70-biindoles and indo-
lopyrroloindole 16
Indole
Anti-malarial activity
IC50
Anti-tuberculosis activity
IC50
5
2.8
4.5
11.2
l
l
g/ml
g/ml
Inactive
Inactive
Inactive
10
16
11
lg/ml
Inactive
200 lg/ml
All other derivatives tested showed no activity in these assays.
column chromatography (hexane/EtOAc, 4:1 up to 1:1) for the sep-
aration of 6 and 10 and for the isolation of 11 and 12. Spectral data
for dimers 5–12 were identical to that previously reported.2

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N. R. Yepuri et al. / Tetrahedron Letters 50 (2009) 2501–2504
(ArC40-OCH3), 55.5 (C5-OCH3), 55.5 (C4-OCH30 ), 54.1 (C7-OCH3),
Acknowledgements
55.3 (C6-OCH0 ), 38.2 (C3), 30.4 (C3-(CH3)2), 29.1 (C3 (CH3)2), 28.2
3
(C1-CH3). ES-MS m/z: 647.2 [M+1]+ (15%), 546, (40), 364 (4), 264
(2), 147 (50), 103.9 (100). ES-HRMS m/z: calcd for [M+1]+
C40H43N2O6 647.3141; found 647.3121.
The authors would like to thank the University of Wollongong
for a postgraduate scholarship (NRY) and Professors J. Bremner
and S. Pyne for useful discussions.
4.2.3. 5,7-Dimethoxy-2,3-dihydro-1-[4,6-dimethoxy-3-
phenylindol-2-yl]-1,3,3-trimethyl-4-phenyl-1H-pyrrolo[1,2-
a]indole 16
References and notes
1. (a) Black, D. S.; Keller, P. A.; Kumar, N. Tetrahedron Lett. 1989, 30, 5807; (b)
Keller, P. A.; Birch, C.; Leach, S. P.; Tyssen, D.; Griffith, R. J. Mol. Graphics 2003,
21, 365; (c) Bremner, J. B.; Coates, J. A.; Coghlan, D. R.; David, D. M.; Keller, P. A.;
Pyne, S. G. New J. Chem. 2002, 26, 1549.
2. Keller, P. A.; Yepuri, N. R.; Kelso, M. J.; Mariani, M.; Skelton, B. W.; White, A. H.
Tetrahedron 2008, 64, 7787.
3. Creary, X.; Wang, Y. X.; Gill, W. Tetrahedron Lett. 1991, 32, 729.
4. Banerji, J.; Mustafi, R.; Shoolery, J. N. Heterocycles 1983, 20, 1355.
5. Black, D. S. C.; Craig, D. C.; Kumar, N. Tetrahedron Lett. 1991, 32, 1587.
6. Baranenok, I. L.; Nenajdenko, V. G.; Balenkova, S. Tetrahedron 2000, 56,
3077.
White solid, mp 199–202 °C. 1H NMR (300 MHz, CDCl3) d: 7.85
(1H, s, NH0), 7.46–7.26 (10H, Ar0 and Ar00 H2, 3, 4, 5 and 6), 6.38 (1H,
d, J = 1.2 Hz, H70), 6.34 (1H, d, J = 1.2 Hz, H8), 6.25 (1H, d, J = 1.2 Hz,
H6), 6.16 (1H, d, J = 1.2 Hz, H50), 3.79 (3H, s, C4-OCH03), 3.75, (3H, s,
C5-OCH3), 3.67, (3H, s, C7-OCH3), 3.57, (3H, s, C6-OCH0 ), 2.86, (1H,
3
d, J = 7.8 Hz, H2), 2.41, (1H, d, J = 7.8 Hz, H2), 1.78, (3H, s, C1-CH3),
1.21 (3H, s, C3-(CH3)2), 1.13, (3H, s, C3-(CH3)2). 13C NMR (75 MHz,
CDCl3) d: 157.5 (C60), 155.8 (C7), 155.0 (C5), 154.8 (C40), 146.6 (3a),
137.3 (ArC100, ArC10), 136.1 (C20), 135.7 (C7a0), 135.2 (C8a), 132.0
(ArC10), 132.1 (ArC200 and 600), 127.4 (ArC30), 127.0 (ArC300), 126.6
(C40 and C50), 126.0 (C400 and C500), 126.7 (C30), 117.9 (C4a), 114.3
(C3a0), 113.7 (C9), 108.0 (C4), 92.5 (C70), 92.1 (C8), 87.1 (C6), 86.8
(C50), 62.4 (C1), 61.9 (C20), 56.6 (C2), 50.8 (C5-OCH3), 50.5 (C40-
OCH3), 50.19 (C7-OCH3), 50.1 (C60-OCH3), 38.9 (C3), 33.2 (C3),
25.2 (C3-(CH3)2), 23.8 (C3-CH3)2), 22.8 (C1-CH3). ES-MS m/z:
587.4 [M+1]+ (90%). ES-HRMS m/z: calcd for [M+1]+ C38H39N2O4
587.2933; found 587.2950.
1
ꢀ
7. Crystals of 14 (C40H42N2O6, M = 646.8) are triclinic, space group P1 ðCi ; No: 2Þ ,
a = 9.486(2), b = 12.416(2), c = 14.833(2) Å,
a = 92.824(2)°, b = 107.427(2)°,
c
= 95.291(2)°, V = 1654 Å.3 Dc (Z = 02) = 1.29 g cmꢁ3
.
l ;
Vo = 0.087 mmꢁ1
specimen: 0.32 ꢀ 0.07 ꢀ 0.05 mm; ‘T min,max = 0.82 (‘empirical0/multiscan
‘correction0). 2hmax = 50°; Ntotal = 16018, N = 6789 (Rint = 0.029), No
(I > 2r(I)) = 4945; R1 = 0.056, wR2 = 0.15. T ca. 153 K. CCDC 711437.
8. Sakakibara, H.; Kobayashi, T. Tetrahedron 1966, 22, 2475.
9. Trager, W.; Jensen, J. B. Science 1976, 193, 673.
10. Desjardins, R. E.; Canfield, C. J.; Haynes, J. D.; Chulay, J. D. Antimicrob. Agents
Chemother. 1979, 16, 710.
11. Collins, C. H. Brit. J. Biomed. Sci. 2001, 58, 137.