Regioselective dibromination of methyl indole-3-carboxylate and application in the synthesis of 5,6-dibromoindoles

Article abstract of DOI:10.1039/c1ob05522d

Treatment of methyl indole-3-carboxylate with bromine in acetic acid gives methyl 5,6-dibromoindole-3-carboxylate regioselectively, from which the parent 5,6-dibromoindole can be accessed via a one-pot, microwave-mediated ester hydrolysis and decarboxylation. Application of these building blocks in syntheses of natural and non-natural 5,6-dibromoindole derivatives, including meridianin F and 5,6-dibromo-2′-demethylaplysinopsin, is reported. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob05522d

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Regioselective dibromination of methyl indole-3-carboxylate and application
in the synthesis of 5,6-dibromoindoles†
Thomas B. Parsons, Ce´dric Ghellamallah, Louise Male, Neil Spencer and Richard S. Grainger*
Received 4th April 2011, Accepted 12th May 2011
DOI: 10.1039/c1ob05522d
Treatment of methyl indole-3-carboxylate with bromine in
acetic acid gives methyl 5,6-dibromoindole-3-carboxylate
regioselectively, from which the parent 5,6-dibromoindole
can be accessed via a one-pot, microwave-mediated ester
hydrolysis and decarboxylation. Application of these build-
ing blocks in syntheses of natural and non-natural 5,6-
dibromoindole derivatives, including meridianin F and 5,6-
dibromo-2¢-demethylaplysinopsin, is reported.
Indoles are one of the most important classes of aromatic
heterocycle, widespread in nature and in medicinal chemistry,
where they are regarded as privileged structures.1 Brominated
indoles have been isolated from a range of marine sources, and
have been shown to possess interesting biological activities.2
The 5,6-dibromoindole substructure is common to a number
of natural products,3–10 the syntheses of which have barely been
addressed.3b One possible reason for this is the paucity of effective
methods for the concise chemo- and regioselective incorporation
of multiple halogen substituents on the indole ring. We were
therefore intrigued by a 1930 report on the dibromination of
ethyl indole-3-carboxylate to give 5,6-dibromoindole 1 in high
yield.11 The regioselectivity of this reaction was determined by a
3-step degradation of 1 to 3,4-dibromoaniline, and comparison of
melting points with an authentic sample (Scheme 1). Analytical
data for 1 was unsurprisingly sparse given available techniques of
the period, with only microanalysis reported. Surprisingly, given
its obvious potential application in organic synthesis, this report
has never been followed up.12 Given the fact that the apparently
related bromination of 3-formylindole is reported to be non-
regioselective,13 we decided to reinvestigate this reaction as part
of a programme of research directed towards the syntheses of 5,6-
dibromoindole-containing natural and non-natural products.
Bromination of commercially available methyl indole-3-
carboxylate under the reported conditions did indeed give the 5,6-
dibromoindole2 ina gratifying70%yield. The indole 2 precipitates
Scheme 1 Regioselective bromination of indole-3-carboxylates.
from the reaction mixture, requiring minimal purification. The re-
giochemical outcome of this reaction was initially based on NMR
analysis, and further confirmed by X-ray crystallography.‡ Hence
the regiochemistry of bromination is consistent with the literature,
as originally reported for 1.
With the structure of 2 confirmed, our attention turned to
the application of this compound in natural product synthesis.
The meridianins are marine natural products that have attracted
some interest from the synthetic community due to their promis-
ing biological activity, including protein kinase inhibition and
antitumour activity.2a,4 However, a synthesis of meridianin F
has not been previously reported, presumably because of the
inaccessibility of the 5,6-dibromoindole substitution pattern. A
concise, 5-step synthesis of meridianin F (6),4 containing the
characteristic 2-aminopyrimidine ring at C-3 common to all the
meridianins, is shown in Scheme 2. Protection of 2 as the N-
Boc carbamate 3‡ (Boc2O, 96% yield) was followed by conversion
of the ester to the Weinreb amide 4.14 Treatment of 4 with
lithium(trimethylsilyl)acetylide gave the terminal alkyne 5 directly.
Direct conversion of the alkynyl ketone 5 to meridianin F (6) was
achieved using the conditions of Mu¨ller, developed for the syn-
thesis of related meridianins and analogues.15 This methodology,
which occurs with concomitant Boc deprotection, was previously
reported on TMS-protected acetylenes and extended to alkyl and
aryl substituted alkynes, with reaction times of 38 h at 80 ◦C,
or more generally 120 ◦C overnight. The shorter reaction time
in the case of 5 (2 h, 80 ◦C) is presumably due to the use of
the non-TMS protected compound. Analytical data for 6 were in
agreement with those previously reported, and the route shown
in Scheme 2 therefore represents the first synthesis of meridianin
F (6).
School of Chemistry, University of Birmingham, Edgbaston, Birmingham,
B15 2TT, UK. E-mail: r.s.grainger@bham.ac.uk; Fax: +44 (0)121 4144403;
Tel: +44 (0)121 4144465
† Electronic supplementary information (ESI) available: Experimental
procedures and analytical data for all compounds; determination of double
bond geometry for 19 and 21; X-ray crystal structures of 2, 3, 7, 10 and
11, CCDC reference numbers 818707–818711; copies of 1H and 13C NMR
spectra. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c1ob05522d
Although the ester at C-3 of 2 represents a useful func-
tional group for further transformations, we recognized that
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We have found that ester hydrolysis and decarboxylation can
be achieved in a single step through treatment of 2 with 3
equivalents of KOH in THF/MeOH/H2O under microwave
heating, providing 5,6-dibromoindole (7)‡ in 94% isolated yield
(Scheme 3).
We have used 7 in the synthesis of both natural and non-
naturally occuring 5,6-dibromoindole derivatives (Scheme 3).16
Iodination at the 3-position of 7 occurs readily using iodine and
KOH in DMF. The resulting iodide 8 can be used in a palladium-
catalyzed Sonogashira cross-coupling reaction with but-4-yn-1-ol
to give 9 in 68% yield (unoptimized). Bromination of 7 using
NBS gave 3,5,6-tribromoindole (10),‡ which upon N-methylation
gave 11.‡ Further bromination of 10 and 11 using NBS occurs
regioselectively at C-2 to give the tetrabromides 12 and 13,
respectively. Bromoindoles 10–13 are all natural products,17–19
with only the preparation of 12 and 13 having been previously
reported.13,20–22
Scheme 2 Synthesis of meridianin F.
Mannich reaction of 7 and the corresponding N-methylated
indole 14 gave dimethylaminomethyl indoles 15 and 16 re-
spectively, both brominated analogues of gramine. Brominated
its removal would permit access to the wealth of aromatic
substitution chemistry known for the 3-position of indole.
Scheme 3 Synthesis and reactions of 5,6-dibromoindole.
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gramine derivatives have previously been investigated for anti-
inflammatory and analgesic activity.23
calculations. The final R1 was 0.0234 (I > 2s(I)) and wR(F2) was 0.0621
(all data); CCDC 818711.†
Vilsmeier–Haack formylation of 7 gave the C-3 aldehyde 17
in high yield. Condensation of 17 with creatinine (18) gave the
non-natural 5,6-dibromo-4¢-demethylaplysinopsin 19, isolated as
a single double bond isomer. The (E)-double bond geometry in
19 was elucidated by NMR analysis (see ESI for details†). The
5 days reaction time can be reduced to 1 h through heating
a solution of 17 and 18 in piperidine in a microwave reactor
(200 W, 150 ◦C), with a slight erosion in selectivity (61% yield,
22 : 1 E : Z).
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The naturally occurring 5,6-dibromo-2¢-demethylaplysinopsin
21 has been shown to selectively inhibit the neoronal isozyme
of nitric oxide synthase (nNOS).8 3-Formylindole 17 was readily
converted into 21 through condensation with the known 2-
aminoimidazolone hydrochloride salt 20.24 The (Z)-double bond
geometry was obtained exclusively, and confirmed through NMR
analysis (see ESI for details†). The 5 day reaction time could again
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11 R. Majima and M. Kotake, Ber., 1930, 63B, 2237.
12 In the course of preparing this manuscipt for publication, Boyd and
Sperry reported their own investigation of the bromination of methyl
indole-3-carboxylate, and applied it to a synthesis of 5,6-dibromo-2¢-
demethylaplysinopsin 21: E. M. Boyd and J. Sperry, Synlett, 2011, 826.
Appeared online 15.03.2011.
◦
be reduced to 1 h using microwave irradiation (200 W, 150 C),
with 21 isolated in 68% yield as a 21 : 1 Z : E mixture of double
bond isomers.
In conclusion, the use of a reaction first reported in 1930,
but which has since lain dormant in the literature, has allowed
ready access to a range of both natural and non-natural 5,6-
dibrominated indoles. This work should pave the way for future
synthetic applications and biological studies.
Acknowledgements
We thank the EPSRC for funding, and acknowledge the UK
National Crystallography Service for X-ray crystallographic data
collection on compounds 2 and 3. The NMR spectrometers
used in this research were obtained through Birmingham Science
City: Innovative Uses for Advanced Materials in the Modern
World (West Midlands Centre for Advanced Materials Project
2), with support from Advantage West Midlands (AWM) and
part funded by the European Regional Development Fund
(ERDF).
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‡ Crystallographic data: 2: C10H7Br2NO2, M = 332.99, Triclinic, a =
˚
7.1280(4), b = 7.3609(4), c = 10.9238(6) A, a = 90.492(3), b = 98.609(3), g =
◦
3
¯
˚
112.463(3) , U = 522.34(5) A , T = 120(2) K, space group P1, Z = 2, 9706
reflections measured, 2390 unique (Rint = 0.0302) which were used in all
calculations. The final R1 was 0.0276 (I > 2s(I)) and wR(F2) was 0.0598
(all data); CCDC 818707. 3: C15H15Br2NO4, M = 433.10, Triclinic, a =
˚
7.0596(3), b = 10.6930(4), c = 11.4729(4) A, a = 96.062(2), b = 94.194(2),
◦
3
¯
˚
g = 106.037(2) , U = 822.95(5) A , T = 120(2) K, space group P1, Z = 2,
17723 reflections measured, 3762 unique (Rint = 0.0561) which were used in
all calculations. The final R1 was 0.0387 (I > 2s(I)) and wR(F2) was 0.0763
(all data); CCDC 818708. 7: C8H5Br2N, M = 274.95, Orthorhombic, a =
3
˚
˚
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space group Pbca, Z = 8, 14874 reflections measured, 1491 unique (Rint
=
20 O. R. Sua´rez-Castillo, L. Beiza-Granados, M. Mele´ndez-Rodr´ıguez, A.
0.0310) which were used in all calculations. The final R1 was 0.0279 (I >
2s(I)) and wR(F2) was 0.0778 (all data); CCDC 818709. 10: C8H4Br3N,
´
Alvarez-Herna´ndez, M. S. Morales-R´ıos and P. Joseph-Nathan, J. Nat.
˚
M = 353.85, Monoclinic, a = 8.8688(4), b = 6.0886(3), c = 16.8852(8) A,
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◦
3
˚
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4, 8715 reflections measured, 1603 unique (Rint = 0.0396) which were used
in all calculations. The final R1 was 0.0251 (I > 2s(I)) and wR(F2) was
0.0666 (all data); CCDC 818710. 11: C9H6Br3N, M = 367.88, Triclinic, a =
2546.
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˚
7.6033(4)◦, b = 8.0327(4), c = 9.6610(5) A, a = 68.061(3), b = 66.835(3), g =
3
¯
˚
73.873(3) , U = 497.24(4) A , T = 120(2)K, space group P1, Z = 2, 4842
reflections measured, 1695 unique (Rint = 0.0172) which were used in all
24 N. Roue´ and J. Bergman, Tetrahedron, 1999, 55, 14729.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 5021–5023 | 5023
©