Oxidative C-H/C-H coupling of azine and indole/pyrrole nuclei: Palladium catalysis and synthesis of eudistomin U

Article abstract of DOI:10.1246/cl.2011.555

We have developed a palladium-catalyzed C-H/C-H coupling reaction of indoles or pyrroles with azine N-oxides. The reaction proceeds selectively at the C3 position of indoles/pyrroles and the C2 position of azine N-oxides. Furthermore, we have accomplished

Full text of DOI:10.1246/cl.2011.555

doi:10.1246/cl.2011.555
Published on the web April 21, 2011
555
Oxidative C-H/C-H Coupling of Azine and Indole/Pyrrole Nuclei:
Palladium Catalysis and Synthesis of Eudistomin U
Atsushi D. Yamaguchi, Debashis Mandal, Junichiro Yamaguchi,* and Kenichiro Itami*
Department of Chemistry, Graduate School of Science, Nagoya University, Nagoya, Aichi 464-8602
(Received April 8, 2011; CL-110292; E-mail: junichiro@chem.nagoya-u.ac.jp, itami.kenichiro@a.mbox.nagoya-u.ac.jp)
We have developed
a
palladium-catalyzed C-H/C-H
recently, Chang and co-workers reported the coupling of
benzene with pyridine N-oxide.9g Inspired by these findings,
we attempted the coupling of N-protected indole with pyridine
N-oxide12 as a synthon of pyridine. Employing Fagnou’s and
Chang’s reaction conditions, to a 1,4-dioxane solution of N-
pivaloylindole (1.0 equiv) were added pyridine N-oxide 2a (4.0
equiv), Pd(OAc)2 (10 mol %), Ag2CO3 (3.0 equiv), and pyridine
(1.0 equiv), and the reaction mixture was stirred for 5 h at 105 °C
to give the desired coupling product in 39% yield. Despite its
low yield, this reaction furnished the C3-substituted indole-
azine coupling product selectively. After extensive screening of
conditions including Pd sources, oxidants, additives, solvents,
and N-protecting groups on the indole,13 the yield of the
coupling product was increased to 73%, using MOM-protected
indole 1a as the substrate, 2,6-lutidine14 and AgOAc9c,15 as
additives (Table 1, Entry 1).
coupling reaction of indoles or pyrroles with azine N-oxides.
The reaction proceeds selectively at the C3 position of indoles/
pyrroles and the C2 position of azine N-oxides. Furthermore, we
have accomplished the synthesis of marine indole alkaloid
eudistomin U by utilizing this newly developed C-H/C-H
coupling reaction.
Compounds containing indole-azine and pyrrole-azine
moieties are prevalent in natural products and bioactive
molecules (Scheme 1).1-5 Therefore, the development of effi-
cient methods to construct these frameworks has been a topic
of considerable interest in organic chemistry. The fields of
biochemistry and medicinal chemistry should also benefit from
such a synthetic campaign, since these disciplines may see the
use of these coupled heterocycles as lead compounds in drug
discovery. Currently, the most reliable synthetic method for
making indole/pyrrole-azine compounds is by way of palla-
dium-catalyzed cross-coupling reactions of organometallic com-
pounds with haloarenes.2,4,5 However, each coupling partner
must be synthesized from its parent heteroaromatic compound,
occasionally requiring several steps. Although the direct C-H
bond arylation of heteroarenes6,7 has emerged as an attractive
methodology that can streamline overall synthesis, successful
examples of direct C-H bond arylation of electron-deficient
nitrogen heterocycles such as azines are rare.7b,8 Herein, we
report our finding of palladium-catalyzed indole-azine and
pyrrole-azine C-H/C-H coupling reactions.9-11
With the optimized conditions for regioselective indole
pyridylation in hand, we investigated the scope of direct indole-
Table 1. Pd-catalyzed C-H/C-H coupling of indoles/pyrroles
1a-1j with pyridine N-oxide (2a)a
Entry
Product
3 (Yield/%)b
1
1
2
3
1a R1 = MOM
1a R1 = MOM
1b R1 = Ts
3aa (73)
3aa (54)c
3ba (67)
First, we examined the C-H/C-H coupling of an indole
derivative and unfunctionalized pyridine. Under palladium
catalysis, the coupling product was observed but only in trace
amounts. Meanwhile, Fagnou and co-workers reported an
indole-benzene C-H/C-H coupling reaction,9d,9e and more
4
5
1c R2 = 5-CN
3ca (52)
3da (38)
1d R2 = 6-OMe
6
7
8
1e R2 = 5-NO2
1f R2 = 6-NO2
1g R2 = 6-CO2Me
3ea (56)
3fa (49)
3ga (55)
9
3ha (46)
1h
1i R2 = H
3ia (42)
3ja (47)
10
11
1j R2 = Ac
aConditions: 1a-1j (0.4 mmol), 2a (1.6 mmol), Pd(OAc)2 (0.04
mmol), 2,6-lutidine (0.4 mmol), AgOAc (1.2 mmol), 1,4-diox-
ane (1.2 mL), 120 °C, 16 h. bIsolated yield. c2 mol % of
Pd(OAc)2 was used. The reaction time was 43 h.
Scheme 1. Natural products containing indole-azine moieties.
Chem. Lett. 2011, 40, 555-557
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

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Table 2. Scope of azine N-oxidesa
Scheme 2. Regioselectivity switch in C-H arylation of pyrroles.
azine N-oxide coupling using various indoles and pyridine N-
oxide (2a) (Table 1). A decrease in catalyst loading was found to
be possible while maintaining reasonable yield (Entry 2).
Although the yield was slightly lower, tosyl-protected indole
1b also gave a similar result (Entry 3). This reaction tolerated
substitutions on indole ring such as cyano (Entry 4), methoxy
(Entry 5), nitro (Entries 6 and 7), and ester (Entry 8) groups.
This coupling reaction even proceeded when using azaindole
(Entry 9), which is more electron-deficient. Furthermore, we
found that the C-H/C-H coupling of pyrroles with 2a also
proceeded, albeit in a lower yield (Entries 10 and 11).
Interestingly, it was revealed that the reaction selectively
afforded the 3-pyridinated pyrrole product (the same selectivity
observed with indoles), adding to the small but growing
repertoire of ¢-selective arylations of five-membered hetero-
arenes.7i-7k
aConditions: 1a (0.4 mmol), 2a-2i (1.6 mmol), Pd(OAc)2 (0.04
mmol), 2,6-lutidine (0.4 mmol), AgOAc (1.2 mmol), 1,4-diox-
ane (1.2 mL), 120 °C, 16 h. bAcOH was used instead of 2,6-
lutidine.
To further investigate the interesting C3-regioselectivity of
pyrroles, the coupling reaction of various pyrroles with pyridine
N-oxide (2a) was carried out. As a result, we found that the
C2/C3 regioselectivity can be controlled by merely manipulat-
ing protecting group on the nitrogen atom (Scheme 2). For
example, when using methyl pyrrole-2-carboxylate (1k) as the
substrate, the reaction proceeded at the C2 position of the
pyrrole to give 3ka in 44% yield, whereas the use of tosyl-
protected pyrrole 1l gave C3-substituted pyrrole 3la in 47%
yield.16
We next examined the scope of the reaction with respect
to azine N-oxide. Representative results are shown in Table 2.
Some modifications on pyridine N-oxide such as methyl, nitro,
and cyano groups were tolerated and the corresponding coupling
products were obtained in moderate yields. When pyrazine N-
oxide was used, the reaction proceeded smoothly in the presence
of acetic acid.17 Notably, the use of quinoxaline N-oxide gave
rise to coupling product 3af in even higher yield than the parent
indole-pyridine N-oxide coupling reaction. Furthermore, we
also obtained the corresponding coupling products with iso-
quinoline, phthalazine, and pyrimidine N-oxides and their
regioselective outcomes were consistent with the parent cou-
pling reaction.
Scheme 3. Synthesis of eudistomin U through C-H/C-H coupling.
(i) MOMCl (1.1 equiv), NaH (1.3 equiv), DMF, rt, 8 h (89%). (ii)
MeReO3 (3 mol %), H2O2 aq (2.0 equiv), rt, CH2Cl2, 14 h, (79%).
(iii) 1a (1.0 equiv), 6 (4.0 equiv), Pd(OAc)2 (10 mol %), 2,6-lutidine
(1.0 equiv), AgOAc (3.0 equiv), 1,4-dioxane, 120 °C, 23 h (41%).
(iv) PCl3 (3.0 equiv), CH2Cl2, rt, 11 h (79%). (v) HCO2H, H2O,
125 °C, 39 h (49%).
with a MOM protection of commercially available ¢-carboline
followed by MTO (methyltrioxorhenium)-catalyzed pyridine
oxidation19 to afford the corresponding N-oxide 4 in 70% yield
over two steps. Subsequent C-H/C-H coupling of indole 1a and
4 under the key palladium catalysis delivered the desired
framework of eudistomin U in 41% yield. Although the yield
of coupling product 5 was not high, this coupling reaction
proceeded at the C3 position of indole and the C1 position of
¢-carboline regioselectively. After reduction of the N-oxide by
PCl3,20 and the follow-up deprotection of MOM groups with
HCO2H in water completed the synthesis of eudistomin U.
Finally, we applied our C-H/C-H coupling to the synthesis
of marine indole alkaloid eudistomin U,18 which possesses
DNA-binding activity (Scheme 3). This short synthesis begins
Chem. Lett. 2011, 40, 555-557
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

557
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In summary, we have developed a palladium-catalyzed
C-H/C-H coupling reaction of indoles/pyrroles and azine
N-oxides, proceeding selectively at the C3 position of indoles/
pyrroles and the C2 position of azine N-oxides. Furthermore, we
have accomplished the synthesis of eudistomin U, utilizing the
newly developed C-H/C-H coupling reaction. Total syntheses
of more complex natural products based on this oxidative C-H/
C-H coupling as well as mechanistic studies are ongoing in our
laboratory.
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology (MEXT), Japan, and the Asahi Glass
Foundation.
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Chem. Lett. 2011, 40, 555-557
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www.csj.jp/journals/chem-lett/