One-pot synthesis of camalexins and 3,3′-biindoles by the Masuda borylation-Suzuki arylation (MBSA) sequence

Article abstract of DOI:10.1002/ejoc.201300133

The Masuda borylation/Suzuki arylation (MBSA) sequence starting from N-protected 3-iodoindoles has successfully been extended to the coupling of five-membered heterocycles and indoles in the arylation step, which could not be achieved with previously developed MBSA methods. By this approach the one-pot nature of the method as well as the use of a simple catalyst system has been retained. The applicability of the method has been demonstrated by the facile synthesis of camalexins and 3,3′-biindoles, compounds of special interest due to their pronounced antifungal, antimicrobial and cytotoxic activities. The Masuda borylation/Suzuki arylation sequence furnishes in a concise one-pot manner camalexins and 3,3′-biindoles, compounds that show pronounced antifungal, antimicrobial, and cytotoxic activities. Copyright

Full text of DOI:10.1002/ejoc.201300133

FULL PAPER
DOI: 10.1002/ejoc.201300133
One-Pot Synthesis of Camalexins and 3,3Ј-Biindoles by the Masuda
Borylation–Suzuki Arylation (MBSA) Sequence
Boris O. A. Tasch,[a] Dragutin Antovic,[a] Eugen Merkul,[a] and Thomas J. J. Müller*[a]
Dedicated to Professor Dr. Manfred Braun on the occasion of his 65th birthday
Keywords: Synthetic methods / C–C coupling / Arylation / Palladium / Boron / Alkaloids
The Masuda borylation/Suzuki arylation (MBSA) sequence
starting from N-protected 3-iodoindoles has successfully
of a simple catalyst system has been retained. The applica-
bility of the method has been demonstrated by the facile syn-
been extended to the coupling of five-membered heterocy- thesis of camalexins and 3,3Ј-biindoles, compounds of special
cles and indoles in the arylation step, which could not be
achieved with previously developed MBSA methods. By this
approach the one-pot nature of the method as well as the use
interest due to their pronounced antifungal, antimicrobial
and cytotoxic activities.
Introduction
As part of our program to develop user-friendly one-pot
methods to access such substance classes, we are particu-
larly interested in the conceptual development of sequential
Pd-catalyzed processes.[3] Within this approach, the consec-
utive one-pot cross-coupling of two aryl halides by the Ma-
suda borylation/Suzuki arylation (MBSA) sequence in the
presence of a single Pd catalyst without further catalyst ad-
dition and by using equimolar amounts of reactants ap-
pears to be challenging and rewarding (Scheme 1).[4] In ad-
dition, Miyaura borylation/Suzuki arylation reactions have
also been considered and developed.[5]
Indoles bearing heteroaromatic substituents at the 3-po-
sition are commonly encountered scaffolds with remarkable
biological activities and significant prevalence in nature.[1]
As a consequence, this structural motif has received con-
siderable attention in the development of leads in medicinal
chemistry addressing a wide spectrum of pharmaceutical
activity. For example, structurally simple marine indole alk-
aloids such as meridianins and hyrtinadine A (Figure 1)
bear pyrimidinyl substituents and display remarkable cyto-
toxicity against several cancer cell lines.[2]
Scheme 1. Sequential Pd-catalyzed one-pot Masuda borylation/
Suzuki arylation (MBSA) sequence.
Starting from iodo-(7-aza)indoles, furans, thiophenes,
pyrroles, and arenes, a plethora of six-membered haloge-
nated carbo- and heterocycles can be cross-coupled in a
one-pot manner by using the same simple catalyst system
without the need for further catalyst addition in the con-
cluding Suzuki step.[6] In addition, this straightforward pro-
tocol has been successfully applied to the concise total syn-
theses of the marine indole alkaloids meridanin A and G
and the marine bis-indole alkaloid hyrtinadine A.[6,7] How-
ever, under the standard conditions, the use of five-mem-
bered heterocycles as coupling partners in the Suzuki step
Figure 1. 3-Heteroaryl-substituted indoles as structural motifs in
natural products.
[a] Institut für Organische Chemie und Makromolekulare Chemie
Heinrich-Heine-Universität Düsseldorf,
Universitätsstr. 1, 40225 Düsseldorf, Germany
Fax: +49-211-81-14324
E-mail: ThomasJJ.Mueller@uni-duesseldorf.de
Homepage: http://www.tjjmueller.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300133.
4564
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Synthesis of Camalexins and 3,3Ј-Biindoles
astoundingly only proceeded in low yield or did not occur biindoles have been studied for treating protein folding dis-
at all in the case of Boc-protected 3-iodoindoles.
order, for example, in Alzheimer’s disease, dementia, Park-
The loss of crops due to infection with pathogens has inson’s disease, Huntington’s disease, and Creutzfeldt-
become a serious problem worldwide. One answer to this Jakob’s disease.[20]
could be the utilization of phytoalexins,[8] secondary metab-
Published syntheses of 3,3Ј-biindoles most often use the
olites that are produced as part of a plant’s defense against isatin route.[21] In addition, Pd-catalyzed cross-coupling, in-
abiotic stress or infection. However, many of these small cluding a one-pot symmetrical dimerization by Miyaura bo-
molecules are also known to show significant antioxidant, rylation and Suzuki coupling,[22] Pd-catalyzed cycliza-
anticarcinogenic, or anti-inflammatory activity. The detoxi- tion,[23] and the reductive cyclization of substituted indole
fication of phytoalexins by pathogens has become a major derivatives,[24] have also been applied to the synthesis of the
problem for plants, which are left defenseless against infec- 3,3Ј-biindole scaffold.
tion.
Among the known phytoalexins, camalexin[9] has been
intensively studied. First isolated together with 6-methoxy-
camalexin from Camelina sativa infected with Alternaria
brassicae, it can also be found in various other Cruciferae[10]
and shows interesting antifungal,[11] antimicrobial,[9] and
cytotoxic activity against various human cancer cell lines
including the human breast cancer cell line SKBr3 (IC50
=
2.7 μm).[12] Several total syntheses of camalexin based on
organometallic (Kharasch,[13] Negishi,[14] and McMurry[15]
coupling reactions) and biomimetic key steps[16] have been
reported.
3,3Ј-Biindoles are scaffolds in natural products such as
rivilarine C,[17] folicanthine, and chimonanthine.[18] In par-
ticular, 1H,1ЈH-3,3Ј-biindole, a secondary metabolite iso-
lated from the fungus Gliocladium catenulatum,[19] has
shown very promising biological activity against Paeni-
bacillus larvae, which is responsible for the American foul-
brood disease among honey bees, a significant factor in
commercial apiculture due to the lack of specific antibiotic
Scheme 2. Retrosynthetic analysis of camalexins and 3,3Ј-biindoles
treatment. Furthermore, unsymmetrically substituted 3,3Ј- based upon the MBSA sequence.
Scheme 3. Synthesis of camalexin (3a) in a one-pot reaction.
Table 1. Optimization of the reaction conditions for the MBSA synthesis of camalexin (3a) in a one-pot reaction.
Entry
Conditions for the Masuda borylation[a]
Conditions for the Suzuki arylation
Isolated yield of 3a [%]
1
2
3
4
5
6
7
8
9
10
3 mol-% [Pd(PPh3)4], 1.0 mL NEt3
3 mol-% [PdCl2(PPh3)2], 1.0 mL NEt3
3 mol-% [PdCl2(PPh3)2], 0.5 mL NEt3
3 mol-% [PdCl2(PPh3)2], 0.5 mL NEt3
3 mol-% [Pd(PPh3)4], 0.5 mL NEt3
3 mol-% [PdCl2(PPh3)2], 0.5 mL NEt3
2.5 equiv. Cs2CO3, MeOH
2.5 equiv. Cs2CO3, MeOH
2.5 equiv. Na2CO3, MeOH
2.5 equiv. CsF, MeOH
2.5 equiv. Na2CO3, H2O
2.5 equiv. Na2CO3, H2O
2.5 equiv. Na2CO3, H2O
2.5 equiv. Na2CO3, 6 mol-% PPh3, H2O
2.5 equiv. Na2CO3, H2O
41
10
29
20
65[b]
n.i.[c]
39
3 mol-% [Pd(PPh3)4], 6 mol-% PPh3, 0.5 mL NEt3
3 mol-% [Pd(PPh3)4], 0.5 mL NEt3
74
2 mol-% PdCl2, 4 mol-% cataCXium® AHI, 0.5 mL NEt3
3 mol-% [PdCl2(CH3CN)2], 12 mol-% SPhos, 0.5 mL NEt3
n.i.[d]
n.i.[e]
2.5 equiv. Na2CO3, H2O; then 24 h, 110 °C
[a] An excess of 3.6 or 7.2 equiv. NEt3 was used. [b] The reaction mixture contained many byproducts (monitored by TLC). [c] The
reaction mixture appeared to be similar to that of entry 5 (monitored by TLC), but isolation was not attempted. [d] A mixture of starting
material and products was formed according to TLC and GC-MS; no isolation was attempted. [e] The desired product 3a was formed
in only trace amounts with the dehalogenated indole the major product (monitored by TLC).
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B. O. A. Tasch, D. Antovic, E. Merkul, T. J. J. Müller
FULL PAPER
Herein we report the extension of the MBSA sequence to Table 2. MBSA one-pot synthesis of camalexin derivatives 3.
bromothiazoles and iodoindoles as representative coupling
partners in the final Suzuki step illustrating this methodol-
ogy with one-pot syntheses of the indole alkaloids cama-
lexin, 6-methoxycamalexin, and 3,3Ј-biindole.
Results and Discussion
The retrosynthetic scheme for the Masuda borylation/
Suzuki arylation sequence with concomitant Boc cleavage
as the key step for the synthesis of camalexins and 3,3Ј-
biindoles is shown in Scheme 2.
Based upon our experience of the MBSA sequence with
brominated pyrimidines or dihalogenated diazines as Su-
zuki substrates we set up a model reaction to optimize the
synthesis of camalexin (3a) by using tert-butyl 3-iodo-1H-
indole-1-carboxylate (1a) and 2-bromothiazole (2a)
(Scheme 3, Table 1).
First, the standard conditions[6,7] were applied to give
compound 3a in a moderate 41% yield (Table 1, entry 1).
Upon changing the precatalyst to [PdCl2(PPh3)2], the yield
of 3a decreased considerably (Table 1, entry 2). In the
course of our work we found that concomitant Boc depro-
tection significantly affected the Suzuki coupling if the rate
of this reaction was lower than the base-mediated deprotec-
tion. However, variation of the base under otherwise the
same conditions revealed that sodium carbonate as base
gave higher yields (Table 1, entries 3, 5, 7, and 8). In ad-
dition, the use of methanol as co-solvent in the final step
to quench excessive pinacolborane and to enhance the solu-
bility of the base was replaced by water (Table 1, entries 5–
10). Finally, the addition of catalytic amounts of tri-
phenylphosphane to prevent precipitation of palladium in
the second step led to the formation of camalexin (3a) in
74% isolated yield (Table 1, entry 8). Note that two other
tested precatalyst systems based upon sterically hindered
phosphane ligands that have proven to considerably acceler-
ate cross-coupling in many other cases[25] completely failed
in the MBSA sequence (Table 1, entries 9 and 10).
With the optimized conditions in hand (Table 1, entry 8),
camalexin analogues 3 were synthesized in a concise one-
pot manner, always maintaining an equimolar ratio of the
iodoindoles 1 and the bromothiazoles 2. The reaction of
variously substituted, easily accessible N-Boc-3-iodoindoles
1[26] with pinacolborane (HBpin) and subsequent Suzuki
arylation with bromothiazoles 2 furnished camalexin ana-
logues 3 in good overall yields (Scheme 4, Table 2).
[a] The reaction was performed with 1.0 equiv. indole and 0.5 equiv.
dibromothiazole. [b] The desired bis-indole was formed in only
trace amounts (by HRMS).
Scheme 4. MBSA one-pot synthesis of camalexin derivatives 3.
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Synthesis of Camalexins and 3,3Ј-Biindoles
Table 3. Optimization of the reaction conditions for the one-pot synthesis of 3,3Ј-biindole (5a).
Entry
Conditions for the Masuda borylation
Conditions for the Suzuki arylation
Isolated yield of 5a [%]
1
2
3
4
5
6
7
2 mol-% PdCl2, 4 mol-% cataCXium® AHI, 60 °C, 4 h
2 mol-% PdCl2, 4 mol-% cataCXium® AHI, 80 °C, 4 h
2 mol-% PdCl2, 4 mol-% cataCXium® AHI, 80 °C, 4 h
2 mol-% PdCl2, 4 mol-% cataCXium® AHI, 80 °C, 4 h
2 mol-% PdCl2, 4 mol-% cataCXium® AHI, 80 °C, 4 h
2 mol-% PdCl2, 4 mol-% cataCXium® AHI, 80 °C, 4 h
3 mol-% [Pd(PPh3)4], 80 °C, 4 h
2.5 equiv. Cs2CO3, MeOH, 80 °C, 20 h
2.5 equiv. Na2CO3, H2O, 80 °C, 20 h
2.0 equiv. Ag2O, MeOH, 80 °C, 20 h
2.0 equiv. CsF, MeOH, 80 °C, 20 h
2.0 equiv. KF, MeOH, 80 °C, 20 h
2.0 equiv. K3PO4, MeOH, 80 °C, 20 h
2.5 equiv. Cs2CO3, MeOH, 80 °C, 20 h
n.i.[a]
n.i.[a]
n.i.[a]
n.i.[a]
n.i.[a]
n.i.[a]
83
[a] No product was observed (monitored by GC–MS). Therefore deprotection was not performed.
In addition to camalexin (3a), the 4-thiazolyl isomer 3b tion by GC–MS showed that the borylation step was suc-
and the hitherto unknown isomer 3c were synthesized in cessful, but the Suzuki arylation failed under these condi-
comparable good yields (Table 2, entries 1–3). Furthermore, tions. Even the modified conditions for the Suzuki arylation
the fluoro- (3d), chloro- (3e), and methoxy-substituted (3f as established for the synthesis of camalexins 3 did not fur-
and 3g) derivatives of camalexin were readily obtained
(Table 2, entries 4–7). The thiazole analogue 3h of the bio-
logically highly active marine alkaloid nortopsentin[27] is a
thiazole-bridged bis-indole derivative that was also isolated
in good yield (Table 2, entry 8). Interestingly, the regioiso-
meric 2,5-dibromothiazole (2e) only furnished the corre-
sponding bis-indole in trace amounts; the main product was
the monocoupled bromo derivative 3i (Table 2, entry 9).
All attempts to use N-Boc-protected 7-azaindoles in the
Masuda borylation or N-Boc-protected pyrroles in the Su-
zuki arylation met with failure.
Table 4. MBSA one-pot synthesis of 3,3Ј-biindoles 5.
The desired 3,3Ј-biindoles could not be isolated with N-
Boc-protected 3-iodoindoles 1 as coupling partners in the
terminal Suzuki step. Therefore we reasoned that the fragile
Boc group should be replaced by the Suzuki coupling-
robust tosyl group. For optimization studies, the stepwise
homocoupling of N-tosyl-3-iodoindole 4a[28] to furnish
3,3Ј-biindole (5a) was chosen (Scheme 5, Table 3). For sub-
sequent detosylation in the same reaction vessel, KOH and
methanol were added and the mixture was heated at 100 °C
for 3 h.
Scheme 5. One-pot synthesis of 3,3Ј-biindole 5a.
First, the precatalyst system based upon the ligand
cataCXium® AHI with PdCl2 as the palladium source was
screened and the bases and solvent additives in the Suzuki
step were varied (Table 3, entries 1–6). Monitoring the reac-
Eur. J. Org. Chem. 2013, 4564–4569
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B. O. A. Tasch, D. Antovic, E. Merkul, T. J. J. Müller
FULL PAPER
Then, after cooling to room temperature (water bath), water
(5.0 mL), Na2CO3 (266 mg, 2.5 mmol), triphenylphosphane
(16 mg, 0.06 mmol), and heteroaryl halide 2 (1.0 mmol) were suc-
cessively added. The mixture was stirred at 100 °C for 20 h (pre-
heated oil bath). After cooling to room temperature, the solvents
were removed under reduced pressure. The residue was absorbed
onto Celite® and purified chromatographically on silica gel (for
experimental details and analytical data, see the Supporting Infor-
mation).
nish 3,3Ј-biindole (5a). Returning to the original precatalyst
[Pd(PPh3)4] without additional ligands led to the isolation
of the detosylated compound 5a in 83% yield (Table 3, en-
try 7).
These optimized conditions (Table 3, entry 7) were ap-
plied to a three-step, one-pot MBSA sequence for the syn-
thesis of unsymmetrically substituted 3,3Ј-biindoles 5 in a
very straightforward fashion and in good overall yields
(Scheme 6, Table 4).
General Procedure for the Synthesis of 3,3Ј-Biindoles 5 by the
MBSA Sequence: [Pd(PPh3)4] (35 mg, 0.03 mmol) and the 3-iodo-
1-tosyl-1H-indole 4 (1.0 mmol) were placed under argon in a dry
screw-cap vessel equipped with septum and dissolved in dry 1,4-
dioxane (2.0 mL). Dry triethylamine (0.5 mL) and 4,4,5,5-tet-
ramethyl-1,3,2-dioxaborolane (0.22 mL, 1.50 mmol) were success-
ively added to the mixture, which was then stirred at 80 °C (pre-
heated oil bath) for 4 h (monitored by TLC). Then, after cooling
to room temperature (water bath), dry methanol (2.0 mL), Cs2CO3
(815 mg, 2.5 mmol), and another 3-iodo-1-tosyl-1H-indole 4Ј
(1.0 mmol) were successively added. The mixture was stirred at
80 °C for 20 h (preheated oil bath). After cooling to room tempera-
ture (water bath), potassium hydroxide (198 mg, 3.0 mmol) and dry
methanol (2.0 mL) were successively added to the reaction mixture,
which was then sealed and stirred at 100 °C for 3 h (preheated oil
bath). Finally, after cooling to room temperature, 0.1 n aqueous
HCl (30 mL) was added to the reaction mixture. A colorless pre-
cipitate was formed. The aqueous phase was then extracted with
dichloromethane (3ϫ 35 mL, monitored by TLC). The combined
organic layers were dried with anhydrous sodium sulfate and the
solvents were removed under reduced pressure. The residue was
adsorbed onto Celite® and purified chromatographically on silica
gel (for experimental details and analytical data, see the Supporting
Information).
Scheme 6. MBSA one-pot synthesis of 3,3Ј-biindoles 5.
Conclusions
The Masuda borylation/Suzuki arylation (MBSA) se-
quence starting from N-Boc- and N-tosyl-3-iodoindoles has
been successfully extended to the coupling of five-mem-
bered heterocycles in the Suzuki step, as illustrated by the
synthesis of camalexin analogues and symmetrically and
unsymmetrically substituted 3,3Ј-biindoles.
A detailed
screening of the reaction conditions showed that a simple
commercial precatalyst system could be successfully used.
However, it was necessary to modify the additives and bases
as well as co-solvents. In the case of the synthesis of 3,3Ј-
biindoles, the traditional Boc protecting group had to be
replaced by the more robust N-tosyl group. The ease of per-
forming this sequential palladium-catalyzed one-pot se-
quence as well as the building block character of the strat-
egy and the equimolar ratio of the reactants ensure that it
is highly sustainable. This straightforward methodology has
potential applications in alkaloid synthesis and medicinal
chemistry, especially because no complex ligands are re-
quired and the access to starting materials is short and elab-
orated. Further studies on one-pot sequences based upon
the Masuda borylation/Suzuki arylation as a key step are
underway.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details for the synthesis of compounds 3 and 5,
1H, 13C, and 135-DEPT NMR spectra of compounds 3 and 5.
Acknowledgments
The authors cordially thank the Fonds der Chemischen Industrie
(scholarship to B. O. A. T.) for financial support.
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Received: January 24, 2013
Published Online: March 19, 2013
Eur. J. Org. Chem. 2013, 4564–4569
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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