The synthesis of 2- and 3-aryl indoles and 1,3,4,5-tetrahydropyrano[4,3-b]indoles and their antibacterial and antifungal activity

Article abstract of DOI:10.1016/j.bmcl.2009.07.091

A series of 2- and 3-aryl substituted indoles and two 1,3,4,5-tetrahydropyrano[4,3-b]indoles were synthesized from indole and 5-methoxyindole. The 2-aryl indoles were synthesized from the 1-(phenylsulfonyl)indole derivatives using magnesiation followed by iodination. The 2-iodinated compounds were then subjected to Suzuki-Miyaura reactions. In addition, the 3-aryl indoles were made from the corresponding 3-bromoindoles using Suzuki-Miyaura reactions. The 1,3,4,5-tetrahydropyrano[4,3-b]indoles were also synthesized from 1-(phenylsulfonyl)indole by magnesiation followed by treatment with allylbromide. The product was then converted into [2-allyl-1-(phenylsulfonyl)-1H-indol-3-yl]methanol which upon exposure to Hg(OAc)₂ and NaBH₄ afforded tetrahydropyrano[4,3-b]indoles. A number of the 2- and 3-aryl indoles displayed noteworthy antimicrobial activity, with compound 13a displaying the most significant activity (3.9 μg/mL) against the Gram-positive micro-organism Bacillus cereus.

Full text of DOI:10.1016/j.bmcl.2009.07.091

Bioorganic & Medicinal Chemistry Letters 19 (2009) 4948–4951
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The synthesis of 2- and 3-aryl indoles and 1,3,4,5-tetrahydropyrano[4,3-b]ind-
oles and their antibacterial and antifungal activity
Tlabo C. Leboho a, Joseph P. Michael a, Willem A. L. van Otterlo a, Sandy F. van Vuuren b,
Charles B. de Koning a,
*
a Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Wits 2050, South Africa
b Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown 2193, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 2- and 3-aryl substituted indoles and two 1,3,4,5-tetrahydropyrano[4,3-b]indoles were syn-
thesized from indole and 5-methoxyindole. The 2-aryl indoles were synthesized from the 1-(phenylsul-
fonyl)indole derivatives using magnesiation followed by iodination. The 2-iodinated compounds were
then subjected to Suzuki–Miyaura reactions. In addition, the 3-aryl indoles were made from the corre-
sponding 3-bromoindoles using Suzuki–Miyaura reactions. The 1,3,4,5-tetrahydropyrano[4,3-b]indoles
were also synthesized from 1-(phenylsulfonyl)indole by magnesiation followed by treatment with allyl-
bromide. The product was then converted into [2-allyl-1-(phenylsulfonyl)-1H-indol-3-yl]methanol
which upon exposure to Hg(OAc)2 and NaBH4 afforded tetrahydropyrano[4,3-b]indoles. A number of
the 2- and 3-aryl indoles displayed noteworthy antimicrobial activity, with compound 13a displaying
Received 4 June 2009
Revised 16 July 2009
Accepted 17 July 2009
Available online 22 July 2009
Keywords:
Synthesis
Antibacterial and antifungal activity
Indoles
Tetrahydropyrano[4,3-b]indoles
Palladium catalysis
Magnesiation of arylindoles
the most significant activity (3.9
l
g/mL) against the Gram-positive micro-organism Bacillus cereus.
Ó 2009 Elsevier Ltd. All rights reserved.
Indole and its derivatives play an important role as biologically
active compounds.1 As part of our research programme of particu-
lar interest to us is their role in combating bacterial and fungal
infections. For example, 5-nitro-2-phenylindole (INF55, 1) is a
promising lead in helping a wide range of antibiotics stay in bacte-
rial cells (Fig. 1).2 This is because efflux pumps in particularly,
Gram-positive bacteria are capable of extruding a wide range of
antibiotics.
Other 2-aryl substituted indoles such as 2 have been implicated
in inhibition of bacterial histidine kinases.3 Another example of an
active compound of this class would be 3-phenylindole 3 which is
an inhibitor of brassinin glucosyltransferase, a phytoalexin detoxi-
fying enzyme from the fungus, Sclerotinia sclerotiorum.4
Indoles containing a fused pyran at the 2- and 3-positions such
as (S)-etodolac 4 (Fig. 2), are also of importance, but not necessarily
for research related to the discovery of antibacterial and fungal
agents. For example, (S)-4 is a clinically effective anti-inflamma-
tory agent and has the potential to retard the progression of skel-
etal changes in rheumatoid arthritis.5,6 Other examples would
include (R)-5 which is a selective hepatitis C virus NS5B polymer-
ase inhibitor.7
F
O2N
N
N
H
1
H
3
H2N
N
H
NH
2
NH2
HN
Figure 1.
CN
Me
O
O
N
H
N
Pr
Et
CO2H
CO2H
H
Et
5
4
* Corresponding author. Tel.: +27 11 7176724; fax: +27 11 7176749.
E-mail address: Charles.deKoning@wits.ac.za (C.B. de Koning).
Figure 2.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.07.091

T. C. Leboho et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4948–4951
4949
R3
X
X
(i)
(ii)
R2
R1
R=R1=R2=R3=H,
I
N
N
SO2Ph
SO2Ph
14e
B(OH)2
8
B(OH)2
X= H,
(iv)
X= H, 6
X= OMe, 9
7
X= OMe,
R
X
X
14a
(iii)
R=Me, R1=R2=R3=H, 14b
Ar
Ar
R=H, R1=R2=R3=OMe,
14c
N
N
H
R2=OMe, R=R1=R3=H,14d
1,4-Dibromo-2,5-dimethoxybenzene 14f
R=CHO, R1=R2=R3=H,14g
SO2Ph
X= H,
X= OMe, 11a-f
10a-f
12a-f
X= H,
X= OMe, 13a-f
R=MeCO, R1=R2=R3=H,
14h
Scheme 1. Reagents and conditions: (i) (a) iPrMgCl, (iPr)2NH, THF, I2, X = H, 79%,
X = OMe, 89%; (ii) 10% Pd(PPh3)4, DME/EtOH, aq Na2CO3, Aryl boronic acid 14a–e
(Fig. 3), reflux, for yields see Table 1; (iii) K2CO3, MeOH, for yields see Table 1; (iv)
(a) iPrMgCl, (iPr)2NH, THF; (b) 5% Pd(PPh3)4, 2 equiv 1,4-dibromo-2,5-dimethoxy-
benzene 14f for the preparation of 10f and 11f.
Figure 3.
acids 14a–e gave 11a–e in fair to good yield (60–78%). Exposure of
each of these substrates 10a–e and 11a–e to potassium carbonate
in methanol resulted in the formation of the desired 2-aryl substi-
tuted indoles 12a–e and 13a–e that could be tested against a range
of bacterial and fungal cell lines. In addition, as shown in Scheme 1,
utilising the Dinsmore magnesiation conditions on compound 6
and 7, followed by the addition of 1,4-dibromo-2,5-dimethoxyben-
zene resulted in the direct formation of 10f and 11f without pro-
Therefore the synthesis of 2- and 3-substituted indoles and
their pyran fused analogues are important targets for organic syn-
thesis. These compounds can then be tested as potential bacterial
and fungal inhibitors.
In this Letter the synthesis of a series of 2- and 3-aryl substi-
tuted indoles and their testing against bacterial and yeast cell lines
are reported. The synthesis of two pyran fused indoles by using re-
lated synthetic methods is also disclosed.
ceeding via the corresponding indole iodides
Subsequently, both 10f and 11f were also efficiently converted into
12f and 13f in yields of 52% and 40%, respectively.
8
or 9.
To place a halogen in the 3-position of the indole nucleus, com-
pound 6 was treated with bromine in acetic acid to yield 15
(Scheme 2). In addition, indole 7 was subjected to NBS and benzoyl
peroxide in CCl4 to afford 16. Both 15 and 16 were then subjected
to Suzuki–Miyaura reactions with the boronic acids 14a–d used
previously, as well as the carbonyl containing boronic acids 14g
and 14h (Fig. 3), to afford 14 3-aryl substituted indoles 17 and
18 in good yields. All of these products were subsequently treated
with potassium carbonate in methanol to remove the phenylsul-
fone group resulting in the formation of the desired 3-aryl substi-
tuted indoles 19 and 20 (64–94%).
It was then desired to extend the methodology to the synthesis
of 1,3,4,5-tetrahydropyrano[4,3-b]indoles11 in a series of simple re-
lated steps. Starting from the same protected indole as used earlier
in the work, compound 6 was reacted under the magnesiation con-
ditions used previously, followed by quenching with allyl bromide
to afford 21 in a mediocre yield (Scheme 3). Subjecting 21 to
Cl2CHOCH3 and TiCl4 at low temperature then gave 22 in good
The magnesiation of indoles was reported in 1996 by Kondo and
Sakamoto8 as a useful method for adding substituents onto the 2-
position of the indole nucleus. More recently in the group of Dins-
more, the magnesiation has been extended to N-phenylsulfonyl-
pyrroles and made catalytic.9 As a result it was decided to take
advantage of this development to make a series of 2-aryl substi-
tuted indoles.
Treatment of both 1-(phenylsulfonyl)indole 6 and the methoxy-
indole derivative 7 with the catalytic magnesiation conditions
developed by Dinsmore, followed by reaction with iodine resulted
in the formation of the two iodinated precursors 8 and 9. These
compounds, containing an iodine atom in the 2 position of the in-
dole nucleus, proved to be suitable for palladium-catalysed Suzu-
ki–Miyaura reactions (Scheme 1). As shown in Table 1, exposure
of 8 to a range of aromatic boronic acids 14a–e (for structures
see Fig. 3) in the presence of palladium catalyst Pd(PPh3)4 afforded
the required 2-aryl substituted indoles 10a–e in mediocre to good
yields (44–82%).10 In a similar manner, treatment of 9 with boronic
Table 1
Yields of compounds formed in Scheme 1
Entry
Ar
C6H5
2-MeC6H4
3,4,5-(MeO)3C6H2
4-MeOC6H4
1-Naphthyl
2,5-(MeO)2-4-BrC6H2
1
2
X = H, 10
X = OMe, 11
10a, 82%
11a, 60%
10b, 44%
11b, 78%
10c, 56%
11c, 77%
10d, 60%
11d, 61%
10e, 60%
11e,a
10f, 21%
11f, 35%
3
4
X = H, 12
X = OMe, 13
12a, 78%
13a, 61%
12b, 82%
13b, 67%
12c, 51%
13c, 86%
12d, 52%
13d, 51%
12e, 52%
13e,a
12f, 52%
13f, 40%
a
Reaction not performed.
Table 2
Yields of compounds formed in Scheme 2
Entry
Ar
C6H5
2-MeC6H4
3,4,5-(MeO)3C6H2
4-MeOC6H4
2-(CHO)C6H4
2-(CH3CO)C6H4
1
2
X = H, 17
X = OMe, 18
17a, 89%
18a, 86%
17b, 68%
18b, 95%
17c, 83%
18c, 60%
17d, 82%
18d, 83%
17g, 67%
18g, 76%
17h, 84%
18h, 77%
3
4
X = H, 19
X = OMe, 20
19a, 81%
20a, 85%
19b, 64%
20b, 86%
19c, 65%
20c, 72%
19d, 79%
20d, 72%
19g, 72%
20g, 94%
19h, 92%
20h, 82%

4950
T. C. Leboho et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4948–4951
Br
Ar
(i)
(ii)
X
X
(i)
(ii)
N
N
SO2Ph
SO2Ph
N
N
6
21
SO2Ph
SO2Ph
OH
CHO
X= H, 17a-d,g-h
X= OMe, 18a-d,g-h
15
X= H,
X= OMe, 16
(iii)
Ar
N
N
X
SO2Ph
SO2Ph
22
23
25
(iv)
N
H
(v)
19a-d,g-h
X= H,
X= OMe,
OH
O
20a-d,g-h
Scheme 2. Reagents and conditions: (i) 10% Pd(PPh3)4, DME/EtOH, aq Na2CO3, aryl
boronic acid 14a–d, g–h (Fig. 3), reflux, for yields see Table 2; (ii) K2CO3, MeOH, for
yields see Table 2.
N
N
SO2Ph
O
SO2Ph
24
(vi)
yield. This product 22 was subsequently reduced with NaBH4 to
yield primary alcohol 23. Alternatively, the aldehyde 22 was ex-
posed to MeMgBr to afford the secondary alcohol 24. Both alcohol
23 and 24 were separately treated with Hg(OAc)2, followed by
reduction with NaBH4 to furnish the desired pyran fused indoles
25 and 26. As expected, pyran 26 was produced as a mixture of
cis- and trans-diastereoisomers.12
26
N
SO2Ph
Antimicrobial and antifungal testing: A range of the 2-and 3-
substituted indoles of general structure 12, 13, 19 and 20 were
quantitatively evaluated for antimicrobial activity using the mini-
mum inhibitory concentration (MIC) assay.13 These compounds
were tested against a number of reference test organisms including
Gram-positive (Staphylococcus aureus ATCC 6538 and Bacillus cer-
eus ATCC 11778), Gram-negative (Escherichia coli ATCC 8739 and
Klebsiella pneumoniae ATCC 8739) and yeasts (Candida albicans
ATCC 10231 and Cryptococcus neoformans ATCC 90112).14
Scheme 3. Reagents and conditions: (i) iPrMgCl, (iPr)2NH, THF, CH2@CHCH2Br,
31%; (ii) Cl2CHOMe, TiCl4, CH2Cl2, À78 °C, 81%; (iii) NaBH4, EtOH, 71%; (iv) MeMgBr,
Et2O, 76%; (v) (i) Hg(OAc)2, THF, (ii) NaBH4, aq NaOH, 31% (vi) (i) Hg(OAc)2, THF; (ii)
NaBH4, aq NaOH, 25%.
The highest activities noted against both Gram-positive patho-
gens (S. aureus and B. cereus) were shown by compounds 19a,
20a and 20b. Selective antimicrobial activity against B. cereus
was only observed for compounds 12c, 13a and 20g having MIC
values of 3.9, 78 and 20 lg/mL, respectively. These compounds
are all structurally similar. The most significant antimicrobial
The in vitro antimicrobial MIC screening results for compounds
12, 13, 19 and 20 are given in Table 3. Compounds with antimicro-
bial activities of 64–100 lg/mL were accepted as having clinical
relevance15 and compounds with activities 10
lg/mL or less were
activity noted, was for compound 13a having an MIC value of
3.9 lg/mL against B. cereus (see Fig. 4).
considered significant.16 All compounds indicating notable antimi-
crobial activity are indicated in bold (Table 3).
Table 3
Antimicrobial and antifungal activity of selected indole compounds
Compound
Pathogen (MIC
lg/mL)
Staphylococcus aureus Bacillus cereus ATCC
Escherichia coli ATCC Klebsiella pneumoniae Candida albicans
Cryptococcus neoformans
ATCC 6538
11778
8739
ATCC 13831
ATCC 10231
ATCC 90112
12a
12c
469
469
635
625
156
235
313
625
39.0
*
469
156
39.1
29.3
313
313
156
625
0.3
625
20
156
625
3.9
156
156
313
19.5
235
625
235
15.6
19.5
156
156
78
1250
313
625
938
*
468
625
*
313
391
313
313
469
313
313
313
469
313
208
313
313
313
313
261
313
313
0.8
156
117
156
156
469
313
156
235
19.5
313
156
156
78
117
313
156
156
235
2.5
625
313
58.5
625
*
ND
32.5
ND
65.1
29.3
78
261
235
625
29.3
29.3
313
39
12d
12e
13a
13b
13c
13d
19a
19c
19d
19f
20a
20b
20c
156
313
*
469
625
313
313
521
235
313
0.08
20d
20g
20h
Control17
156
0.08
2.5
ND = Not determined due to insufficient sample.
*
= Not active at highest concentration tested (1250 lg/mL).

T. C. Leboho et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4948–4951
4951
C. Leboho. Mr. R. Mampa and M. Brits are also thanked for provid-
ing the NMR and MS spectroscopy services, respectively.
R
MeO
References and notes
1. See for example: (a) Husson, H.-P.. In Brossi, A., Ed.; The Alkaloids, Chemistry
and Pharmocology; Academic Press: Amsterdam, 1986; Vol. 26, pp 1–46.
Chapter 1; (b) Lounasmaa, M.; Hanhihen, P.. In Cordell, G. A., Ed.; The Alkaloids,
Chemistry and Biology; Academic Press: Amsterdam, 2000; Vol. 55, pp 1–88.
Chapter 1; (c) Álvarez, M.; Joule, J. A.. In Cordell, G. A., Ed.; The Alkaloids,
Chemistry and Biology; Academic Press: Amsterdam, 2001; Vol. 57, pp 235–
272. Chapter 3; (d) Sundberg, R. J.; Smith, S. Q.. In Cordell, G. A., Ed.; The
Alkaloids, Chemistry and Biology; Academic Press: Amsterdam, 2002; Vol. 59,
pp 281–376. Chapter 2.
2. (a) Samosorn, S.; Bremner, J. B.; Ball, A.; Lewis, K. Bioorg. Med. Chem. 2006, 14,
857; (b) Ambrus, J. L.; Kelso, M. J.; Bremner, J. B.; Ball, A. R.; Casadei, G.; Lewis,
K. Bioorg. Med. Chem. Lett. 2008, 18, 4294.
3. Deschenes, R. J.; Lin, H.; Ault, A. D.; Fassler, J. S. Antimicrob. Agents Chemother.
1999, 43, 1700.
N
H
N
H
20b
19a
R= Me,
20g
R=CHO,
20a
R=H,
MeO
N
H
13a
OMe
OMe
OMe
4. Pedras, M. S. C.; Hossain, M. Bioorg. Med. Chem. 2007, 15, 5981.
5. Demerson, C. A.; Humber, L. G.; Abraham, N. A.; Schilling, G.; Martel, R. R.; Pace-
Asciak, C. J. Med. Chem. 1983, 26, 1778.
6. Sugimoto, T.; Aoyama, M.; Kikuchi, K.; Sakaguchi, M.; Deji, N.; Uzu, T.; Nishio,
Y.; Kashiwagi, A. Intern. Med. 2007, 46, 1055.
N
H
12c
Figure 4.
7. Gopalsamy, A.; Lim, K.; Ciszeski, G.; Park, K.; Ellingboe, J. W.; Bloom, J.; Insaf, S.;
Upeslacis, J.; Mansour, T. S.; Krishnamurthy, G.; Damarla, M.; Pyatski, Y.; Ho, D.;
Howe, A. Y. M.; Orlowski, M.; Feld, B.; O’Connell, J. J. Med. Chem. 2004, 47, 6603.
8. Kondo, Y.; Yoshida, A.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1996, 2331.
9. Dinsmore, A.; Billing, D. G.; Mandy, K.; Michael, J. P.; Mogano, D.; Patil, S. Org.
Lett. 2000, 2, 293.
10. Standard conditions for Suzuki–Miyaura used in our laboratories were
followed see for example: Moleele, S. S.; Michael, J. P.; de Koning, C. B.
Tetrahedron 2008, 64, 10573.
11. The first synthesis of the basic 1,3,4,5-tetrahydropyrano[4,3-b]indole skeleton
is described in: Nazare, M.; Schneider, C.; Lindenschmidt, A.; Will, D. W. Angew.
Chem., Int. Ed. 2004, 34, 4526.
12. For related benzo-fused examples see: Mmutlane, E. M.; Green, I. R.; Michael, J.
P.; de Koning, C. B. Org. Biomol. Chem. 2004, 2, 2461 or de Koning, C. B.; Giles, R.
G. F.; Green, I. R. J. Chem. Soc., Perkin Trans. 1 1991, 2743.
OMe
OMe
MeO
OMe
OMe
OMe
MeO
R
N
N
H
H
R=OMe, 13c
19c
R=H,
13. NCCLS. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria
that Grow Aerobically. Approved Standard-Sixth Edition. NCCLS document M7-
A6, Pennsylvania, USA, pp 15–17.
R=OMe, 20c
Figure 5.
14. Compounds at a starting concentration of 5 mg/mL, dissolved in acetone, were
introduced (100
lL) into the first well of a microtitre plate containing 100 lL
sterile water. Serial doubling dilutions were then performed so that
concentrations of the compound were reduced by half with each dilution. A
All compounds were poorly active against the Gram-negative
pathogens. This has been noted previously for other indole
derivatives.18
For the yeasts, in general the compounds tested were more ac-
tive against C. neoformans. For example, compounds 13c, 19c and
20c all containing a number of methoxy substituents (Fig. 5)
showed similar antifungal activity against C. neoformans with
fixed concentration of microbial culture (100 lL) yielding an inoculum size of
1 Â 106 colony forming units/mL was added to all wells and incubated at 37 °C
for 24 h. The yeasts were incubated for
iodonitrotetrazolium violet (INT) solution was prepared and 40
a
further 24 h.
A
0.2 mg/mL p-
lL transferred
to all inoculated wells. The plates were examined after 6 h or 24 h for either
bacteria or yeasts, respectively to determine a colour change in relation to
concentration of microbial growth .The MIC was calculated as the lowest
concentration having no evidence of microbial growth. Negative controls
(acetone solvent) were included to confirm that the diluents had no effect on
the antimicrobial activity. Positive controls (ciprofloxacin for bacteria and
amphotericin B for yeasts at starting concentrations of 0.01 mg/mL) were
included to confirm susceptibility of test organisms. Assays were repeated at
least in triplicate on consecutive days.
MIC values of 29.3, 32.5 and 29.3 lg/mL, respectively.
Acknowledgments
This work was supported by the National Research Foundation
(NRF, GUN 2053652 and the IRDP of the NRF (South Africa) for
financial support provided by the Research Niche Areas pro-
gramme), Pretoria, and the University of the Witwatersrand (Sci-
ence Faculty Research Council). We also gratefully acknowledge
the NRF scarce skills programme for generous funding to Mr. T.
15. Gibbons, S. Nat. Prod. Rep. 2004, 21, 263.
16. Rios, J. L.; Recio, M. C. J. Ethnopharmacol. 2005, 100, 80.
17. Both a positive control using the antibiotic ciprofloxacin for bacteria and
amphotericin B for yeasts as well as a negative control (media and solvent
only) were used for the antibacterial and fungal testing shown in Table 3.
18. Chikvaidze, I. S.; Megrelishvili, N. S.; Samsoniya, S. A.; Suvorov, N. N.; Gus’kova,
T. A.; Radkevich, T. P.; Baklanova, O. V. Pharm. Chem. J. 1998, 32, 29.