One-shot indole-to-carbazole π-extension by a Pd-Cu-Ag trimetallic system

Article abstract of DOI:10.1039/c3sc51447a

We have developed a Pd-Cu-Ag trimetallic system that can convert indoles to carbazoles using electron-deficient alkenes as two-carbon units. Investigation of the reaction mechanism revealed that this one-shot indole-to-carbazole π-extension is likely to proceed through the sequence of (i) Pd/Cu-catalyzed indole C-H alkenylation, (ii) Ag-promoted Diels-Alder reaction and dehydrogenative aromatization. The successful one-pot synthesis of a granulatimide derivative, an interesting class of Chk1 kinase inhibitor, highlights the potential of the present reaction for further development and applications.

Full text of DOI:10.1039/c3sc51447a

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One-shot indole-to-carbazole p-extension by a
Pd–Cu–Ag trimetallic system†
Cite this: DOI: 10.1039/c3sc51447a
a
b
a
bc
ad
*
*
and Kenichiro Itami
Kyohei Ozaki, Hua Zhang, Hideto Ito, Aiwen Lei
We have developed a Pd–Cu–Ag trimetallic system that can convert indoles to carbazoles using electron-
deficient alkenes as two-carbon units. Investigation of the reaction mechanism revealed that this one-shot
indole-to-carbazole p-extension is likely to proceed through the sequence of (i) Pd/Cu-catalyzed indole
C–H alkenylation, (ii) Ag-promoted Diels–Alder reaction and dehydrogenative aromatization. The
successful one-pot synthesis of a granulatimide derivative, an interesting class of Chk1 kinase inhibitor,
highlights the potential of the present reaction for further development and applications.
Received 23rd May 2013
Accepted 18th June 2013
DOI: 10.1039/c3sc51447a
www.rsc.org/chemicalscience
Introduction
Direct p-extension of simple aromatics is one of the most rapid
and divergent ways to obtain fused p-conjugated molecules
such as polycyclic aromatic hydrocarbons (PAHs) and their
heteroatom-containing analogues.1 In particular, synthetic
methodologies that do not require any pre-functionalization of
aromatic substrate are strongly desired in terms of efficiency
and convenience.2 Recently, we have developed palladium-
catalyzed direct arylation of PAHs, such as pyrene, phenan-
threne, uoranthene, perylene, and corannulene.3 Further-
more, subsequent ring-fusion of arylated PAHs enables
p-expansion to extended PAHs that are otherwise difficult to
make. Our next challenge was to develop a method for single-
step direct p-extension of simple heteroaromatics such as
indoles to furnish fused heteroaromatics such as carbazoles.
Fig. 1 Carbazoles found in bioactive natural products.
Carbazoles are
a common structural motif found in
numerous biologically active natural products (Fig. 1).4
Furthermore, carbazoles are also widely used in photorefractive
materials and organic dyes for solar cells.5 Typically, C–C and
C–N bond-forming coupling reactions, cyclizations, and Diels–
Alder reactions are used for the synthesis of carbazoles.6
In recent years, indole-to-carbazole transformations have
attracted much attention, as indoles are readily available. For
Fig. 2 Alkenylations and p-extension of indoles.
example, Miura reported the Pd-catalyzed [2 + 2 + 2]cycloaddi-
tion of indoles with diarylacetylenes to give tetraarylated
carbazoles.7,8 Although there are other reports on the direct
p-extension of indoles to carbazoles,9 the synthetic utility and
the substrate scope remain relatively unexplored. A pioneering
aDepartment of Chemistry, Graduate School of Science, Nagoya University, Chikusa,
Nagoya 464-8602, Japan. E-mail: itami.kenichiro@a.mbox.nagoya-u.ac.jp; Fax: +81
52-788-6098
bCollege of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei,
430072, P.R. China
cState Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of study of indole alkenylation in a formal C–H/C–H coupling
Chemical Physics, Chinese Academy of Sciences, Lanzhou, 730000, P.R. China
dInstitute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Chikusa,
fashion was reported by Gaunt in 2005.10 They elegantly ach-
ieved C2- or C3-selective introduction of various alkenyl groups
to indoles (Fig. 2).11,12 Herein we report an indole-to-carbazole
Nagoya 464-8602, Japan
† Electronic supplementary information (ESI) available: Experimental procedures,
p-extension with vinyl compounds as two-carbon units. An
characterization of data for all new compounds, details of modication of reaction
interesting Pd–Cu–Ag trimetallic system allows us to conduct
this otherwise difficult transformation in one shot.
conditions. CCDC 940718. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c3sc51447a
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Table 1 Influence of reaction parametersa
Results and discussion
One-shot indole-to-carbazole p-extension by Pd–Cu–Ag
system
Pd(OAc)2 Cu(OAc)2
Entry (mol%)
(mol%)
AgOCOCF3 (equiv.) Yield of 3aab (%)
We began our study by examining various metal salts, ligands,
and additives in the reaction of N-methylindole (1a) and methyl
vinyl ketone (2a). Aer extensive screening, we determined that
the combination of Pd(OAc)2/Cu(OAc)2/AgOCOCF3 serves as an
efficient catalytic system to achieve the one-shot indole-to-
carbazole p-extension. For example, the p-extension product,
N-methyl-1,3-diacetylcarbazole (3aa), was obtained in 70% iso-
lated yield when a mixture of 1a (1.0 equiv.) and 2a (10 equiv.)
in toluene–DMSO (v/v ¼ 100 : 5) was treated with Pd(OAc)2
(10 mol%), Cu(OAc)2 (20 mol%), and AgOCOCF3 (4 equiv.)
at 100 ꢀC under air, representing our standard conditions
(Scheme 1).13 The structure of 3aa was unambiguously deter-
mined through single-crystal X-ray diffraction analysis (see the
ESI† for details).14
1
2
3
4
10
0
20
20
0
20
20
20
20
20
20
20
4
4
4
2
0
4
4
4
4
4
70
35
33
30
0
39
52
44
40
41
10
10
10
10
10
10
10
10
5
6c
7d
8e
9 f
10g
a
Reaction conditions: 1a (0.20 mmol), 2a (10 equiv.), Pd(OAc)2 (10 mol%),
Cu(OAc)2 (20 mol%), AgOCOCF3 (4.0 equiv.), toluene (1.0 mL), DMSO
b
c
(50 mL), air, 100 ꢀC, 14 h. Isolated yield. Toluene (1.0 mL) was used
d
e
as solvent. DMSO (1.0 mL) was used as solvent. 1,4-Dioxane
(1.0 mL) was used as solvent. Reaction at 80 ꢀC. g Reaction at 120 ꢀC.
f
Listed in Table 1 are some examples of variations from the
standard conditions (entry 1). The presence of both palladium
and copper is necessary to furnish the product 3aa in high yield
(entries 2 and 3). Decreasing the amount of AgOCOCF3 to 2
equiv. and 0 equiv. resulted in 30% and 0% yields of 3aa,
respectively (entries 4 and 5). The use of a toluene–DMSO mixed
solvent system is also critical for high-yield production of 3aa;
the use of toluene, DMSO, or 1,4-dioxane as a solvent led to
decreased yields (entries 6–8). Conducting the reaction at lower
moderate yields. The reactions of indoles bearing electron-
donating groups (1d, 1e and 1f) proceeded smoothly to provide
the products (3da, 3ea and 3fa). The tolerance of the reactions
for C–Cl and C–F bonds makes it attractive for further trans-
formations at these bonds of the products (3ga and 3ha).
Similarly, the reaction using N-methyl-7-azaindole (1i) provided
the corresponding a-carboline 3ia in 45% yield.
ꢀ
temperature (80 C) resulted in a signicant decrease in yield
(entry 9). On the other hand, considerable decomposition and
One-pot synthesis of a granulatimide analogue
polymerization of 1a were observed at higher temperature
(120 C), resulting in a decrease of yield (entry 10).
Granulatimide and its analogues, carbazoles having one or two
imide moieties, are well known as Chk1 kinase inhibitors
(Scheme 3).15 In particular, bisimide analogue shows much
higher activities than other derivatives.16 However, a previously
reported four-step synthetic procedure provided these struc-
tures in less than 10% overall yield. Thus we conducted the
ꢀ
Next we investigated the substrate scope of the reaction with
respect to vinyl compounds. In addition to methyl vinyl ketone,
aryl and alkyl vinyl ketones were found to be applicable to the
indole-to-carbazole p-extension reaction (Fig. 3). Employing a
series of phenyl vinyl ketones (2b–e) gave the corresponding 1,3-
dibenzoylcarbazoles (3ab, 3ac, 3ad and 3ae) in 37–61% isolated
yields. The reaction with cyclohexyl vinyl ketone (2f) afforded
the corresponding carbazole 3af in somewhat lower yield (24%
yield). Interestingly, we found that the p-extension using methyl
acrylate (2g) as a two-carbon unit proceeded well to give the
carbazole 3ag, bearing two ester groups that are potentially
transformable and removable (Scheme 2).
The present one-shot indole-to-carbazole p-extension proved
to be applicable to other indoles (Fig. 4). For example, the
reactions of N-benzylindole (1b) and unsubstituted indole (1c)
with 2a furnished the corresponding carbazoles (3ba and 3ca) in
Fig. 3 p-Extension of N-methylindole (1a) with various aryl/alkyl vinyl ketones
(2b–f). Reaction conditions: 1a (0.20 mmol), 2 (10 equiv.), Pd(OAc)2 (10 mol%),
Cu(OAc)2 (20 mol%), AgOCOCF3 (4.0 equiv.), toluene (1 mL), DMSO (50 mL), air,
100 ꢀC, 14 h. Indicated yields are isolated yields.
Scheme 1 One-shot p-extension of N-methylindole with methyl vinyl ketone.
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Mechanistic consideration
To investigate the reaction mechanism of the present p-exten-
sion reaction, we conducted the reactions of possible interme-
diates. Inspired by the work of Gaunt,10 we investigated the
reaction of C3-alkenylated product 4 (Scheme 4), which might
be formed from 1a and 2a under Pd catalysis (through an
oxidative Heck-like process). Indeed, compound 4 reacted with
2a to give carbazole 3aa in 56% GC yield under the standard
conditions using Pd(OAc)2, Cu(OAc)2, and AgOCOCF3.17 Taking
the observed regioselectivity into account, we assume that 3aa is
produced by the Diels–Alder reaction of 4 and 2a, and subse-
quent dehydrogenative aromatization (oxidation).18 To further
identify the real promoter for each step, the reactions were
carried out with omission of Pd, Cu, or Ag (Scheme 4). The
reaction without Pd or Pd/Cu resulted in higher yield of 3aa
(77% and 80% GC yields, respectively). On the other hand,
omission of all metals (Pd, Cu, Ag) led to a dramatic decrease in
the yield of 3aa (4% GC yield), albeit with full consumption of 4.
These results not only indicate (i) the intermediacy of 4 in the
reaction and (ii) the C3-alkenylation/Diels–Alder/oxidation
sequence as a possible mechanism of indole-to-carbazole p-
extension, but also (iii) the role of metal promoters (Pd and Cu
for C3-alkenylation, and Ag for Diels–Alder reaction and
oxidation).
Scheme 2 p-Extension with methyl acrylate.
The Michael addition product (5) of indole 1a to 2a could
also be a possible intermediate.19 Thus, alkylated indole 5 was
treated with 2a under the standard conditions (Scheme 5).
While the both starting materials (5 and 2a) were consumed
completely with or without Pd catalyst, carbazole 3aa was
produced in much lower yields (11% and 23% yield, respec-
tively). Although it may be assumed that 5 is oxidized to 4
entering the above-mentioned sequence, other pathways could
also be possible in the formation of 3aa. Nevertheless, we
surmise that pathway through 5 is not the major one for the
indole-to-carbazole p-extension under the current reaction
conditions.
Fig. 4 p-Extension of indoles (1b–i) with methyl vinyl ketone (2a). Reaction
conditions: 1 (0.20 mmol), 2a (10 equiv.), Pd(OAc)2 (10 mol%), Cu(OAc)2 (20 mol%),
AgOCOCF3 (4.0 equiv.), toluene (1 mL), DMSO (50 mL), air, 100 ꢀC, 14 h. Indicated
yields are isolated yields. atoluene (0.50 mL) and DMSO (0.50 mL) were used as
solvent.
Taking these results into consideration, the proposed major
reaction pathway is depicted in Fig. 5. An indole derivative 1
rst reacts with Pd(II) to provide a 3-indolylpalladium(II) species
by C–H palladation. The thus-formed organopalladium species
then undergoes a Mizoroki–Heck-like reaction with an electron-
decient alkene 2 to produce a C3-alkenylated indole interme-
diate.10 In this C–H alkenylation process, we assume that copper
salt and silver salt are acting as a Pd(0) / Pd(II) oxidation
Scheme 3 One-pot synthesis of bisimide analogue 3jh.
one-pot synthesis of bisimide analogue, employing our p-
extension reaction. Gratifyingly, the reaction of N-n-propy-
lindole (1j) with maleimide (2h) under the inuence of the Pd–
Cu–Ag trimetallic system yielded bisimide carbazole 3jh in 24%
yield in one pot (Scheme 3).
Scheme 4 Reactions of alkenylated indole 4 with 2a under various conditions.
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catalyzed indole C–H alkenylation, (ii) Ag-promoted Diels–Alder
reaction, and (iii) Ag-promoted dehydrogenative aromatization.
The successful one-pot synthesis of a granulatimide analogue
highlights the potential of the present reaction for further
development and applications. Expansion of the scope of this
reaction, elucidation of the reaction mechanism, and the
application to other aromatic systems are ongoing in our
laboratory.
Scheme 5 Reactions from the Michael adduct 5.
Acknowledgements
This work was supported by the Funding Program for Next
Generation World-Leading Researchers from JSPS (220GR049 to
K.I.) H.I. thanks JSPS for a postdoctoral fellowship.
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`
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Synthesis of 3aa is chosen as the representative procedure. A
7 mL screw-top test tube containing a magnetic stirring bar was
dried in vacuo with heating from a heat-gun. Aer cooling,
Pd(OAc)2 (4.5 mg, 20 mmol), Cu(OAc)2 (7.3 mg, 40 mmol), AgO-
COCF3 (176 mg, 0.80 mmol), methyl vinyl ketone (2a: 140 mg,
2.0 mmol), N-methylindole (1a: 26 mg, 0.20 mmol), toluene
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for 14 h with stirring. Aer cooling to room temperature, the
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alkenes as two-carbon units. Investigation of reaction mecha-
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