Angewandte
Chemie
We next turned our attention to the installation of the C7
À
substituent with the intention of utilizing the indole N H
À
motif to direct an iridium-catalyzed C H borylation, as
previously described by Maleczka, Smith and co-workers,[12]
that could be directly combined with a Suzuki–Miyaura
À
coupling to complete the C H arylation in a one-pot process.
À
The C H borylation at the C7 position of indole 6 was
successfully implemented using [{IrCl(cod)}2] (1.5 mol%) as
the catalyst with B2pin2 (1.5 equiv) in THF at 908C in a sealed
tube and afforded boronic ester 15 on a gram scale (see also
Scheme 2). Adding [PdCl2(dppf)] (5 mol%), 4-iodoanisole
Scheme 3. Selective electrophilic bromination at the C6 position.
*
Viable sites for electrophilic bromination are indicated ( ).
24 hours, direct addition of a sodium methoxide solution in
methanol (4m) and copper(I) iodide to the bromination
reaction mixture led to the formation of the methyl ether,[14]
completing a two-step one-pot etherification process from 11
and affording 12 in 81% yield on a 1.5 gram scale.
The choice of the nitro group was also important to
provide maximum flexibility in the carbazole ring-closure
À
Scheme 2. Iridium-catalyzed C H borylation at the C7 position.
À
process that we hoped to achieved by a C H amination
process. Despite considerable efforts, we were unable to
(3 equiv), and an aqueous solution of KOH (3m) directly to
the reaction mixture and stirring at 808C for 30 minutes
afforded 7 in 63% yield. We were able to scale up this
reaction to 4.7 gram batches, enabling effective material
effect a
phosphite-mediated Cadogen cyclization[15a] or
Merckꢁs reductive palladium-catalyzed process directly from
the nitro group.[15b] Attempts to use Buchwaldꢁs catalytic C H
À
carbazole synthesis (from a corresponding acetamide)[15c] as
well as our own palladium-catalyzed method (from a corre-
sponding benzylamine) also failed.[15d] Finally, we found that
the transformation of the nitro group into the azide by a two-
step reduction/diazotization/azidation process provided 13 in
95% yield on 1.5 gram scale (Scheme 1 and Scheme 4a).[16]
À
throughput. With the indole N H moiety having served its
À
purpose for directing the C H arylation, we next performed
the N-alkylation, which also served to prevent this nucleo-
philic motif from interfering with any subsequent metal-
catalyzed processes. Treatment of compound 7 with commer-
cial 4-methoxyphenethyl bromide (8) and K2CO3 afforded the
desired product 9 in 83% yield; this process could be
conducted in batches of two grams.
À
Although we investigated metal-catalyzed C H insertion
processes using the azide, none of these reactions resulted in
the desired heterocycle.[17] Carbazole 14 could be isolated
using Tokuyamaꢁs batch conditions for the thermal decom-
position of the azide;[4f–g] however, this approach is not
without issues, and we sought to address some of the problems
associated with this procedure that may preclude a larger
scale reaction. For instance, the sudden and exothermic
production of nitrogen gas on scale can be very dangerous,
and solvents with high boiling points are often required to
Suzuki–Miyaura coupling of the C4 bromide was next
investigated to incorporate the final aryl component into the
structure of dictyodendrin B (Scheme 1). The nitrophenol-
derived boronic ester 10 could be assembled in two steps from
a commercial building block, and subsequent cross-coupling
was performed using relatively standard conditions. These
involved the dropwise addition of the aryl boronic ester[13] to
a mixture of [PdCl2(dppf)] (5 mol%) and an aqueous solution
of K2CO3 (2m) in dioxane at 908C to furnish the C4-arylated
product 11 in 93% yield on a 1.5 gram scale. The dropwise
addition was important to avoid the competing deleterious
protodeboronation process that we observed when the aryl
boronic ester was present in the reaction mixture from the
outset.
The nitro group of the arena at the C4 position was critical
to successful oxygenation at the C6 position (Scheme 1).
À
Unfortunately, all attempts to secure a direct C H oxygen-
ation at this position failed. However, with the nitro group
deactivating the C4 aryl moiety, we found that electrophilic
bromination at the C6 position of the indole occurred with
exclusive selectivity at room temperature using a slight excess
of N-bromosuccinimide (see Scheme 3). All other nitrogen-
based substituents (azide, amide, and amine moieties)
resulted in bromination on the C4 aryl substituent. After
À
Scheme 4. C H amination for carbazole formation.
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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