Concise, efficient and practical assembly of bromo-5,6-dimethoxyindole building blocks

Article abstract of DOI:10.1016/j.tetlet.2011.01.076

A concise, efficient and simple route to a series of bromoindole building blocks is described. The synthetic routes are highlighted by purification-free preparation of o-nitrocinnamate intermediates and clean, modified Cadogan indole syntheses. The scope of this indole synthesis has been explored and expanded through the use of a range of solvents and easily removable phosphine reagents.

Full text of DOI:10.1016/j.tetlet.2011.01.076

Tetrahedron Letters 52 (2011) 1339–1342
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Concise, efficient and practical assembly of bromo-5,6-dimethoxyindole
building blocks
Paul B. Huleatt a, , Jacelyn Lau a, Sheena Chua a, Yun Lei Tan a, Hung Anh Duong a, Christina L. L. Chai a,b,
⇑
⇑
a Institute of Chemical and Engineering Sciences, Agency for Science, Technology and Research (A⁄STAR), 8 Biomedical Grove, Neuros, #07-01, Singapore 138665, Singapore
b Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise, efficient and simple route to a series of bromoindole building blocks is described. The synthetic
routes are highlighted by purification-free preparation of o-nitrocinnamate intermediates and clean,
modified Cadogan indole syntheses. The scope of this indole synthesis has been explored and expanded
through the use of a range of solvents and easily removable phosphine reagents.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 30 November 2010
Revised 31 December 2010
Accepted 14 January 2011
Available online 20 January 2011
Keywords:
Indoles
Nitrocinnamates
Nitrostyrenes
Phosphines
Microwaves
The indole moiety is well recognized as a ‘privileged structure’
and is undoubtedly one of the most important structural subunits
for drug discovery efforts. Moreover, indole core structures are
abundant in many naturally occurring compounds from the
essential amino acid, tryptophan to alkaloids.1 Two interesting
examples, 5,6-dihydroxyindole (DHI, 1) and 5,6-dihydroxyindole-
2-carboxylic acid (DHICA, 2) are the basic building blocks found
in the photoprotective mammalian pigment, eumelanin.2 Whilst
DHI and DHICA are of little utility due to their propensity to under-
go oxidative polymerization in an uncontrolled fashion, it is be-
lieved that appropriately protected derivatives of 1 and 2 could
be used in the controlled assembly of synthetic eumelanin-like
oligomers. The bromo-5,6-dimethoxy derivatives of DHI and DHI-
CA 3–9 shown in Figure 1 typify such building blocks and we have
recently demonstrated their utility in biindolyl syntheses via
Suzuki–Miyaura cross-coupling.3 However, current approaches to
such building blocks are not ideal. For example, previously re-
ported approaches to DHICA derivatives have utilized the Hemets-
berger–Knittel indole synthesis.4 Drawbacks with this approach
include hazards associated with the synthesis and manipulation
of organic azides on a multigram scale, moderate yielding steps
and the potential for side-product formation (e.g., 2H-azirines
and indole regioisomers) in the thermolysis of azidocinnamates
to indoles. In order to address such issues and to develop a
standard synthetic strategy for both DHI and DHICA building
blocks geared to maximize synthetic efficiency and practical sim-
plicity, we sought to access o-nitrostyrene and o-nitrocinnamate
HO
HO
HO
HO
CO2H
N
H
N
H
1
2
Br
Br
MeO
MeO
MeO
MeO
CO2Me
N
N
H
H
6
3
Br
MeO
MeO
MeO
MeO
MeO
MeO
CO2Me
N
H
N
H
7
Br
4
CO2Me
N
H
8
Br
Br
Br
MeO
MeO
N
H
MeO
MeO
CO2Me
Br
N
H
9
⇑
5
Corresponding authors. Tel.: +65 6799 8525; fax: +65 6464 2102 (P.B.H.); tel.:
Br
+65 6799 8522; fax: +65 6464 2102 (C.L.L.C.).
E-mail addresses: Paul_Huleatt@ices.a-star.edu.sg (P.B. Huleatt), Christina_
Chai@ices.a-star.edu.sg (C.L.L. Chai).
Figure 1. 5,6-Dihydroxyindole, 5,6-dihydroxyindole-2-carboxylic acid and bromo-
5,6-dimethoxyindole derivatives.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.076

1340
P. B. Huleatt et al. / Tetrahedron Letters 52 (2011) 1339–1342
Effective dibromination of 6-nitroveratraldehyde (14) was achieved
with NBS in concentrated sulfuric acid affording 2,5-dibromo-
6-nitroveratraldehyde (15) in good yield.
1) Me2SO4, K2CO3
DMF (94%)
MeO
HO
CHO
CHO
MeO
MeO
CHO
NO2
2) Ac2O, H2SO4
65% HNO3 (78%)
With the requisite bromo-o-nitroveratraldehydes in hand,
attention was turned to the synthesis of the key indole precursors
16–23 (Table 1). A Horner–Wadsworth–Emmons protocol utilizing
methyl diethylphosphonoacetate and sodium hydride in THF was
employed to convert 6-nitroveratraldehyde (14) into cinnamate
16 in good yield. Similarly, aldehydes 11, 13 and 15 were each con-
verted into the corresponding cinnamates 17–19 in excellent
yields. The efficiency of this concise sequence from commercial
starting materials 10, 12 and 14 to cinnamates 16–19 is notable.
It can be performed on a multigram scale, no chromatographic
purification steps or recrystallizations are required and compounds
16–19 are obtained analytically pure.
Br
Br
10
11
Br
Br
1) Me2SO4, K2CO3
DMF (95%)
HO
MeO
MeO
CHO
NO2
2) Ac2O, H2SO4
65% HNO3 (88%)
MeO
12
13
Br
MeO
MeO
CHO
NO2
NBS, H2SO4
(84%)
MeO
MeO
CHO
NO2
A Wittig methylenation protocol was adopted for the synthesis
of styrenes 20–23. Aldehydes 14 and 11 were smoothly converted
into the corresponding styrenes 20 and 21 using n-butyllithium
and methyltriphenylphosphonium bromide in THF at ꢀ78 °C.
When the synthesis of o,o0-disubstituted styrenes 22 and 23 was
attempted under similar conditions, the starting aldehydes 13
and 15 were cleanly converted through to 1-bromo-2,3-dime-
thoxy-5-nitrobenzene and 1,4-dibromo-2,3-dimethoxy-5-nitro-
benzene, respectively. These products presumably arise from an
ylide-mediated deformylation reaction. Similar deformylation of
sterically congested 2-halo-6-nitrobenzaldehydes under basic con-
ditions has been previously reported.7 Styrenes 22 and 23 could,
however, be accessed in modest yield when the ylide was formed
with NaHMDS. At this juncture, multigram quantities of all indole
precursors 16–23 could be readily obtained and conditions for
their conversion into indole building blocks 3–9 were explored.
The classical conditions for a Cadogan type cyclisation involve
heating the substrate with a large excess of a trivalent phospho-
rous reagent at elevated temperatures.5 When we attempted the
conversion of cinnamate 17 into the indole 8 with any one of tri-
methyl, triethyl, tributyl or triphenyl phosphite under conven-
tional or microwave heating, complications ensued. Triethyl and
tributyl phosphite led to mixtures of 8 and indole side products
arising from transesterification reactions. In the case of trimethyl
phosphite, the reagent degraded to dimethyl methylphosphonate
at the expense of the desired conversion of 17 into 8. When
triphenyl phosphite was employed conversion of 17 into 8 was
extremely sluggish and both the starting material and product
were observed to decompose over several hours. The use of
Br
14
15
Scheme 1. Synthesis of bromo-o-nitroveratraldehydes.
intermediates which could be converted into indoles in a manner
akin to the Cadogan carbazole synthesis.5 The protocol was de-
signed to tolerate various reaction conditions with minimal purifi-
cation steps in order to facilitate optimization and modification
during follow-up studies. Accordingly, we herein describe the
development of an expedient and practical route to a series of
DHI and DHICA derivatives 3–9.
We initiated our study with the synthesis of the bromo-o-nitro-
veratraldehydes (Scheme 1) required for elaboration into the key
o-nitrostyrene and o-nitrocinnamate intermediates. Commercially
available 5-bromovanillin (10) was methylated using standard con-
ditions to afford 5-bromoveratraldehyde. Subsequent nitration
using either 65% nitric acid or 65% nitric acid in acetic acid led to
mixtures of compound 11 and the regioisomer 5-bromo-2-nitrov-
eratraldehyde along with 3-bromo-4,5-dinitroveratrole and 3-
bromo-5-nitroveratrole which were likely formed through
a
sequential oxidation/decarboxylation/nitration process similar to
the Hunsdiecker reaction. The use of other nitrating conditions such
as Claycop in dichloromethane/acetic anhydride also led to mixtures
of products.6 Gratifyingly, nitration of 5-bromoveratraldehyde
using Menke conditions (Ac2O/65% HNO3), afforded 11 cleanly as a
single product in 78% yield. A similar alkylation, nitration sequence
was also used to convert 2-bromoisovanillin (12) into compound 13.
Table 1
Synthesis of o-nitrocinnamates and o-nitrostyrenes and conversion into the corresponding indoles
MoO2Cl2(dmf)2
(5 mol%)
PPh3 (2 equiv)
R1
R1
R1
R2
conditions
i, ii or iii
MeO
MeO
CHO
NO2
MeO
MeO
R3
NO2
MeO
MeO
R3
toluene, 200 o
C
N
H
R2
R2
1 h, microwave
Aldehyde
Alkene
Indole
Entry
Aldehyde
Conditionsa
R1
R2
R3
Alkene (yield)
Indole (yield)
1
2
3
4
5
6
7
8
14
11
13
15
14
11
13
15
i
i
i
i
ii
ii
iii
iii
H
H
Br
Br
H
H
Br
Br
H
Br
H
Br
H
Br
H
CO2Me
CO2Me
CO2Me
CO2Me
H
H
H
H
16 (80%)
17 (99%)
18 (99%)
19 (90%)
20 (90%)
21 (89%)
22 (25%)
23 (32%)
24 (63%)
8 (85%)
7 (92%)
9 (91%)
25 (65%)
4 (81%)
3 (80%)
5 (80%)
Br
a
Conditions: (i) methyl diethylphosphonoacetate, NaH, THF, 100 °C, 1 h; (ii) methyltriphenylphosphonium bromide, n-BuLi, THF, ꢀ78 °C; (iii) methyltriphenylphospho-
nium bromide, NaHMDS, THF, 25 °C.

P. B. Huleatt et al. / Tetrahedron Letters 52 (2011) 1339–1342
1341
Table 2
Evaluation of the conditions for the MoO2Cl2(dmf)2-mediated conversion of cinnamate 18 into indole 7
Entry
Solvent
Phosphinea
Temperature (°C)
Time (h)
Yield
b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Toluene
Toluene
Toluene
Toluene
Toluene/THF
Toluene
Toluene
Toluene
MeCN
MeCN
EtOAc
EtOAc
THF
THF
THF
THF
Acetone
Acetone
CH2Cl2
CH2Cl2
CH2Cl2
i
ii
iii
iv
v
PPh3
iii
iv
PPh3
iii
PPh3
iii
PPh3
ii
iii
iv
PPh3
iii
PPh3
iii
200
200
200
200
160
160
160
160
160
160
160
160
160
160
160
160
140
140
120
120
120
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1.5
2
2
—
51%
65%
72%
74%
74%
3.3 (7):1 (18)c
8.6 (7):1 (18)c
85%
78%
88%
79%
95%
92%
95%
94%
84%
79%
76%
77%
iv
2 (7):1 (18)c
a
Phosphines: (i) tris(3-sulfonatophenyl)phosphine trisodium salt hydrate, (ii) diphenyl-2-pyridylphosphine, (iii) 2-(diphenylphosphino)benzoic acid, (iv) 200–400 mesh,
2% divinylbenzene cross-linked, polystyrene-bound triphenylphosphine, (v) 4-diphenylphosphanylbenzoic acid 2-(trimethylsilyl)ethyl ester.
b
<5% Conversion of 18 into 7, 18 recovered.
c
Ratio of product (7) to starting material (18) determined by analysis of the 1H NMR spectrum of the crude reaction mixture.
triphenylphosphine in refluxing o-dichlorobenzene, as described
by Freeman et al.,8 was also attempted but resulted only in con-
sumption of 17 with no formation of tractable products. However,
the desired transformation was smoothly effected with triphenyl-
phosphine in refluxing toluene over 24 h in the presence of a
dioxomolybdenum(VI) catalyst.9,10
removing the solvent. Conversely, the use of water soluble tris
(3-sulfonatophenyl)phosphine trisodium salt13 (entry 1) resulted
in poor conversion of 18 probably due to the insolubility of the
reagent in toluene. When diphenyl-2-pyridylphosphine14 was used
in toluene (entry 2), indole 7 was isolated in moderate yield,
though in THF an excellent yield of 7 was obtained (entry 14). Both
4-diphenylphosphanylbenzoic acid 2-(trimethylsilyl)ethyl ester15
and 2-(diphenylphosphino)benzoic acid (o-DPPBA) could be used
to good effect in most cases (entries 5, 10, 12, 15, 18 and 20), how-
ever, the use of o-DPPBA was preferred for both economic and
practical reasons. In addition to being commercially available,
o-DPPBA can be readily prepared from inexpensive bulk chemicals
using a large scale, single-step synthesis.16 Furthermore, it gives
rise to an insoluble phosphine oxide by-product which can be eas-
ily removed by simple filtration. Significantly, o-DPPBA can be used
effectively in solvents such as acetonitrile, ethyl acetate and ace-
tone whereas polystyrene-supported triphenylphosphine cannot
and thus, it represents a highly valuable and complementary alter-
native to the polymer-bound reagent for this reaction.
We envisaged that the efficiency of this modified Cadogan in-
dole synthesis could be improved significantly through the use of
microwave heating. Thus, when an homogenous solution of cinna-
mate 17, triphenylphosphine (2 equiv) and MoO2Cl2(dmf)2
(5 mol %) in toluene in a sealed vessel was heated at 200 °C using
microwave heating for 1 h, complete consumption of 17 and clean
formation of indole 8 along with triphenylphosphine oxide was
observed by GC–MS analysis of the reaction mixture. Gratifyingly,
using this protocol, all cinnamates 16–19 and styrenes 20–23
could be readily converted into the corresponding indoles (3–5,
7–9, 24 and 25) in excellent isolated yields (Table 1). The conver-
sion of o-nitrostyrenes into indoles described here is particularly
noteworthy as similar transformations using classical conditions
have been low yielding.11 Moreover, this method provides a conve-
nient alternative to analogous palladium-mediated processes
which often require long reaction times at high temperatures un-
der high pressures of carbon monoxide.12 Conversion of indole
24 to the 3-bromo derivative 6 as previously described4 completed
the rapid compilation of the requisite DHI and DHICA derivatives
3–9.
In conclusion, we have described a concise, efficient and practi-
cally simple route to a series of DHI and DHICA derivatives 3–9.17
The syntheses described are highlighted by (a) the preparation of
o-nitrocinnamates on multigram scale without purification steps,
(b) a clean, microwave-mediated, Cadogan type indole synthesis
and (c) the use of triphenylphosphine surrogates to simplify isola-
tion of the pure indole products.
With a view to expanding the conditional scope and practical
convenience of this indole synthesis, the conversion of cinnamate
18 into indole 7 was studied with a variety of solvent and phos-
phine combinations (Table 2). Initial investigation of solvent and
temperature effects (entries 6, 9, 11, 13, 17 and 19) indicated that
the reaction could be carried out efficiently with triphenylphos-
phine in a variety of polar and non-polar organic solvents at
temperatures as low as 120 °C. Most significantly, a variety of other
phosphines, which form easily removable phosphine oxide by-
products (e.g., by acid wash, base wash or filtration), could be used
instead of triphenylphosphine. The use of polystyrene-supported
triphenylphosphine (entries 4, 8, 16 and 21) allowed the pure
indole 7 to be isolated by simply filtering off the polymer and
Acknowledgement
This work was supported by the Science and Engineering Re-
search Council of A⁄STAR (Agency for Science, Technology and Re-
search), Singapore.
Supplementary data
Supplementary data (physical data, spectroscopic data and 1H
and 13C APT NMR spectra for compounds 3–9, 11, 13 and 15–25)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.01.076.

1342
P. B. Huleatt et al. / Tetrahedron Letters 52 (2011) 1339–1342
was triturated with n-hexane containing a few drops of EtOAc and filtered to
References and notes
afford 15 as a light yellow solid (1.81 g, 84%).
General procedure for Horner–Wadsworth–Emmons reaction: To a solution of
methyl diethylphosphonoacetate (10 mmol) in dry THF (100 mL) at 0 °C was
added NaH (1 equiv, 60% dispersion in mineral oil). When the evolution of H2
had ceased (ꢁ5 min), the appropriate o-nitrobenzaldehyde (11, 13, 14 or 15)
was added and the reaction mixture was heated at reflux for 1 h. After cooling,
the solvent was removed in vacuo and the residue was partitioned between
EtOAc (100 mL) and H2O (30 mL). The organic phase was separated, dried
(MgSO4), filtered and the solvent removed in vacuo. The residue was triturated
with n-hexane containing a few drops of EtOAc and filtered to afford the
corresponding cinnamates 16–19.
1. (a) Higuchi, K.; Kawasaki, T. Nat. Prod. Rep. 2007, 24, 843–868; (b) Sundberg, R.
J. Indoles; Academic Press: London, 1996; (c) Kochanowska-Karamyan, A. J.;
Hamann, M. T. Chem. Rev. 2010, 110, 4489–4497.
2. (a) d’Ischia, M.; Napolitano, A.; Pezzella, A.; Meredith, P.; Sarna, T. Angew.
Chem., Int. Ed. 2009, 48, 3914–3921; (b) Meredith, P.; Sarna, T. Pigment Cell Res.
2006, 19, 572–594; (c) Prota, G. Melanins and Melanogenesis; Academic: San
Diego, 1992.
3. Duong, H. A.; Chua, S.; Huleatt, P. B.; Chai, C. L. L. J. Org. Chem. 2008, 73, 9177–
9180.
4. Huleatt, P. B.; Choo, S. S.; Chua, S.; Chai, C. L. L. Tetrahedron Lett. 2008, 49, 5309–
5311.
5. Cadogan, J. I. G.; Cameron-Wood, M.; Mackie, R. K.; Searle, R. J. G. J. Chem. Soc.
1965, 4831–4837.
6. (a) Laszlo, P.; Pennetreau, P. J. Org. Chem. 1987, 52, 2407–2410; (b) Laszlo, P.;
Cornelis, A. Aldrichim. Acta 1988, 21, 97–103; (c) Gigante, B.; Prazeres, A. O.;
Marcelo-Curto, M. J.; Cornelis, A.; Laszlo, P. J. Org. Chem. 1995, 60, 3445–3447.
7. Lock, G. Ber. Dtsch. Chem. Ges. 1935, 68B, 1505–1511.
8. Freeman, A. W.; Urvoy, M.; Criswell, M. E. J. Org. Chem. 2005, 70, 5014–5019.
9. Sanz, R.; Escribano, J.; Pedrosa, M. R.; Aguado, R.; Arnaiz, F. J. Adv. Synth. Catal.
2007, 349, 713–718.
10. Sanz, R.; Pedrosa, M. R. Curr. Org. Synth. 2009, 6, 239–263.
11. Somei, M.; Yamada, F.; Kaneko, C. Chem. Lett. 1978, 11, 1249–1250.
12. (a) Söderberg, B. C.; Shriver, J. A.; Wallace, J. M. Org. Synth. 2003, 80, 75–84; (b)
Tollari, S.; Penoni, A.; Cenini, S. J. Mol. Catal. A: Chem. 2000, 152, 47–54; (c)
Söderberg, B. C.; Shriver, J. A. J. Org. Chem. 1997, 62, 5838–5845.
13. For a review on the use of water soluble phosphines, see: Pinault, N.; Bruce, D.
W. Coord. Chem. Rev. 2003, 241, 1–25.
Compounds 20 and 21: To
a suspension of pre-dried methyltriphen-
ylphosphonium bromide (3.5 mmol) in THF (10 mL) at ꢀ78 °C was added
dropwise a solution of n-BuLi (2.5 M, 1 equiv). The resultant mixture was
stirred at ꢀ78 °C for 2 h before a solution of 14 or 11 (2.71 mmol) in THF was
added. The mixture was allowed to warm to room temperature and stirring
was continued for 16 h. Saturated NH4Cl solution (15 mL) was added and the
mixture was extracted with EtOAc (3 ꢂ 50 mL), the organic phase was dried
over Na2SO4 and concentrated in vacuo. Flash chromatographic purification of
the residue (n-hexane–EtOAc) afforded 20 or 21.
Compounds 22 and 23: To a suspension of pre-dried methyltriphenylphos-
phonium bromide (3.5 mmol) in THF (10 mL) at 0 °C was added dropwise a
solution of NaHMDS (1 M in THF, 1 equiv). The resultant mixture was stirred at
0 °C for 1 h before a solution of 13 or 15 (2.71 mmol) in THF (10 mL) was added
dropwise. The mixture was then stirred at room temperature for 16 h.
Saturated NH4Cl solution (15 mL) was added and the mixture was extracted
with EtOAc (3 ꢂ 50 mL). The organic phase was dried over Na2SO4 and then
concentrated in vacuo. Flash chromatographic purification of the residue
(n-hexane–EtOAc) afforded 22 or 23.
14. Camp, D.; Jenkins, I. D. Aust. J. Chem. 1988, 41, 1835–1839.
15. Yoakim, C.; Guse, I.; O’Meara, J. A.; Thavonekham, B. Synlett 2003, 473–476.
16. Kemme, S. T.; Schmidt, Y.; Gruenanger, C. U.; Laungani, A. C.; Herber, C.; Breit,
B. Synthesis 2010, 924–1928.
General procedure for the microwave-mediated Cadogan indole synthesis (Tables 1
and 2): (NOTE: Microwave reactions were performed using a Biotage Initiator™
in 2–5 mL reaction vessels).
A stirred suspension of the appropriate o-
nitrostyrene or o-nitrocinnamate (0.3 mmol) and phosphine (2.4 equiv) in
dry solvent (5 mL) in a microwave reactor vial was purged of oxygen by
bubbling argon through the mixture. MoO2Cl2(dmf)2 (5 mol %) was added and
the vessel sealed. The reaction mixture was heated under microwave
irradiation (at the appropriate temperature for the time listed). Work-up for
reactions with triphenylphosphine involved removal of the solvent in vacuo
and purification by column chromatography (n-hexane–EtOAc). Work-up for
reactions with polystyrene-supported triphenylphosphine involved filtration
and removal of the solvent in vacuo to afford the pure indole. Work-up for
reactions with 2-(diphenylphosphino)benzoic acid involved filtration, and if
necessary, base washing as previously described.15 Work-up for reactions with
other phosphines were as previously described.14,15
17. General procedure for nitration under Menke conditions: To a solution of 5-bromo
or 2-bromoveratraldehyde (20 mmol) in Ac2O (20 mL) was added one drop of
concentrated H2SO4. The resultant solution was stirred at room temperature
for 1 h then cooled to 0 °C. HNO3 (65%, 25 mL) was then added dropwise and
the reaction mixture was stirred for 16 h. Cold H2O was added to the thick
reaction mixture and the suspension was filtered and dried. The residue was
triturated with n-hexane containing a few drops of EtOAc and filtered to afford
11 or 13.
Compound 15: To a solution of 14 (1.23 g, 5.83 mmol) in concentrated H2SO4
(5 mL), NBS (3.11 g, 17.48 mmol) was added portion wise over a period of
30 min and the reaction vessel was stoppered and wrapped in aluminium foil
to exclude light. The reaction mixture was stirred for 16 h, poured onto cold
H2O (20 mL) and the resultant precipitate filtered and dried. The crude product