Palladium-catalyzed direct C3-selective arylation of n-unsubstituted indoles with aryl chlorides and triflates

Article abstract of DOI:10.1021/acs.orglett.7b02669

The direct C3-arylation of N-unsubstituted indoles with aryl chlorides and triflates has been realized using a palladium-dihydroxyterphenylphosphine (DHTP) catalyst. The site selectivity is different from that obtained with other structurally related ligands. This unique feature of the DHTP ligand is attributed to complex formation between the lithium salts of the ligand and the indole. The method was applied to the late-stage derivatization of pharmaceuticals having a chloro group.

Full text of DOI:10.1021/acs.orglett.7b02669

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Direct C3-Selective Arylation of
N‑Unsubstituted Indoles with Aryl Chlorides and Triflates
Miyuki Yamaguchi, Kohei Suzuki, Yusuke Sato, and Kei Manabe*
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
S
* Supporting Information
ABSTRACT: The direct C3-arylation of N-unsubstituted
indoles with aryl chlorides and triflates has been realized
using a palladium−dihydroxyterphenylphosphine (DHTP)
catalyst. The site selectivity is different from that obtained
with other structurally related ligands. This unique feature of
the DHTP ligand is attributed to complex formation between
the lithium salts of the ligand and the indole. The method was
applied to the late-stage derivatization of pharmaceuticals
having a chloro group.
Scheme 1. Pd-Catalyzed Arylation of N-Unsubstituted
Indoles with Aryl Halides and Triflates
rylindoles are key structural components of many natural
Aproducts and pharmaceuticals, and considerable effort has
been devoted to developing efficient synthetic methods for their
preparation.1 C3-arylated indoles are a particularly important
class of compounds with diverse biological activities such as
antimicrobial,2 anti-inflammatory,3 and anticancer activities.4
Late-stage functionalization by direct arylation of indoles
provides a powerful tool for the synthesis of C3-arylated
indoles.5 The introduction of an aromatic moiety at the C-3
position of indoles is typically achieved by transition-metal-
catalyzed cross-coupling reactions,6 such as palladium-catalyzed
direct C−H functionalization. Transition-metal-free processes
have also been reported; however, some drawbacks, such as the
need for highly reactive arylating agents (e.g., hypervalent iodine
reagents7 and diazonium salts8) and low regioselectivity due to
benzyne-like intermediates,9 limit their application. In Pd-
catalyzed direct C−H functionalization reactions, aryl halides
are often used as reactants. However, in the reaction of N-
unsubstituted indoles, control of site selectivity is an important
issue, as arylation occurs also at the C-2 or N-1 position of the
indole moiety (Scheme 1a).5a,b In addition, arylating agents for
the C3-arylation of N-unsubstituted indoles are limited to aryl
iodides and bromides,10 and only a few reactions with less
reactive but readily available aryl chlorides have been
reported,9,11 which usually result in N-arylation (Scheme
1b).12 Recently, Veisi and co-worker reported the direct
arylation of indoles at the C-3 position with aryl chlorides
using a catalyst derived from palladium nanoparticles immobi-
lized on single-wall carbon nanotubes.11 However, the develop-
ment of efficient methods with a broad substrate scope for the
synthesis of C3-arylated indoles is still highly desirable.
Moreover, no examples of C3-arylation using aryl triflates as
arylating agents, which are readily prepared from the
corresponding phenols, have been reported, as the reaction
provides exclusively the corresponding N-arylated product
(Scheme 1b).12b
Over the past decade, we have developed various hydroxy-
lated terphenylphosphine ligands such as dihydroxyterphenyl-
phosphine (DHTP), which have been successfully applied to
site-selective Pd-catalyzed cross-coupling reactions of halophe-
nols and haloanilines.13 In these reactions, the Pd−DHTP
catalyst and halophenol or haloaniline form a heteroaggregate
via a metal phenoxide or anilide intermediate, bringing the
halogen in the ortho position to the hydroxy or amino group
close to the palladium atom for site-selective oxidative addition.
In our investigations, we have now found that Cy-DHTP
(1a)13e,j also enables site-selectivity switching in Pd-catalyzed
arylation reactions of indoles (Scheme 1c). Herein, we report a
Pd−1a-catalyzed C3-selective direct arylation of N-unsubsti-
tuted indoles with aryl chlorides and triflates.
Received: August 28, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02669
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
First, the effect of ligands and bases was studied (Table 1).
Unsubstituted indole (2) and 4-chlorotoluene (3) were selected
11). Hydroxyterphenylphosphine 1c13a,f bearing one hydroxy
group did not show C3-selectivity (entry 12), demonstrating the
superiority of 1a over 1c, which was also observed in our
previous studies on Kumada−Tamao−Corriu13e and Sonoga-
shira couplings.13h,k,l Next, the effect of base was examined using
the Pd−1a catalyst. Interestingly, no reaction occurred when
sodium or potassium tert-butoxide was used instead of lithium
tert-butoxide (entries 13 and 14), which prompted us to screen
other lithium bases. However, the reaction in the presence of
Li2CO3 or LiOH gave only small amounts of 4 (entries 15 and
16), and the use of Li3PO4 was found to be ineffective (entry
17).
Table 1. Effect of Ligands and Bases in the Pd-Catalyzed C3-
Arylation of N-Unsubstituted Indole with Chlorotoluene
With the optimized conditions in hand, the scope of the
arylating agents was examined (Scheme 2). First, the reaction
a
yield (%)
entry
ligand
base
4
5
6
a
Scheme 2. Scope of Aryl Chlorides and Triflates
1
no ligand
PCy3
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuONa
t-BuOK
Li2CO3
LiOH
1
nd
6
nd
2
18
nd
nd
nd
nd
nd
nd
nd
trace
nd
nd
4
3
P(t-Bu)3·HBF4
PPh3
nd
nd
4
b
5
Cy-JohnPhos
XPhos
86
62
76
b
b
6
8
7
SPhos
2
8
Xantphos
DPPE
nd
nd
1
nd
nd
3
9
b
10
11
12
13
14
15
16
17
1a·HBF4
1b
85 (81)
19
12
nd
nd
1
1
trace
2
1c·HBF4
1a·HBF4
1a·HBF4
1a·HBF4
1a·HBF4
31
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
2
1a·HBF4
Li3PO4
nd
a
b
NMR yield. Isolated yield. nd = not detected.
as model substrates, and the reactions were carried out under
the conditions based on our previous study of site-selective
cross-couplings,13h,i,k using catalysts derived from palladium
acetate and a phosphine ligand, lithium tert-butoxide as a base,
and toluene as a solvent. In the absence of ligand, the arylation
reaction did not proceed (entry 1). When tricyclohexyl-
phosphine was used, the desired C3-arylated product 4 was
obtained in low yield along with a small amount of N-arylated 5
(entry 2). Under these conditions, tri-tert-butylphosphine and
triphenylphosphine were ineffective (entries 3 and 4). More-
over, the use of Cy-JohnPhos,14 XPhos,12c or SPhos15 afforded
N-arylated 5 selectively in good yield (entries 5−7), whereas the
reaction using bidentate ligands failed to provide arylated
products (entries 8 and 9). On the other hand, when the HBF4
salt of Cy-DHTP (1a) was used, the C3-selective reaction
proceeded smoothly to give the desired 4 in good yield (entry
10). Notably, although structurally related, 1a and 2-
phosphinobiphenyl ligands such as Cy-JohnPhos gave opposite
selectivities. DHTP 1b13e,j bearing a diphenylphosphino group
also promoted the arylation reaction at the C-3 position
selectively, although the yield of 4 was significantly lower (entry
a
b
c
Isolated yield. 1 mmol scale. 1.2 equiv of 3-chlorobenzotrifluoride
d
e
were used. 1.2 equiv of 2 were used. Pd(OAc)2 (4 mol %), 1a·HBF4
(8 mol %). 1.5 equiv of 2 were used. 48 h.
f
using 4-bromotoluene or p-tolyl triflate instead of 3 was carried
out. In both cases, the arylation proceeded selectively at the C-3
position, with p-tolyl triflate giving the desired 4 in higher yield
(75%). To the best of our knowledge, this is the first example
using aryl triflates in Pd-catalyzed direct C3-arylation of N-
unsubstituted indoles. Moreover, chlorobenzene and aryl
chlorides bearing an electron-donating group reacted smoothly
with 2 to afford C3-arylated 7−10 in high yields. Next, aryl
chlorides having an electron-withdrawing group were tested. 1-
B
DOI: 10.1021/acs.orglett.7b02669
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Organic Letters
Letter
Chloro-4-fluorobenzene and 1-chloro-3-(trifluoromethyl)-
benzene gave 11 and 12, respectively, in moderate yields,
whereas 1-chloro-4-nitrobenzene did not give the desired
product 13. The reactions using heteroaryl chlorides afforded
C3-arylated 14−16; however, 16 was accompanied by a
significant amount of the corresponding N-arylated product
(25%), which was separable from the desired product. The
arylation of 2 using various aryl triflates was also carried out.
Notably, higher yields of 10 and 11 were obtained with 4-
methoxyphenyl and 4-fluorophenyl triflate than with the
corresponding aryl chlorides. In addition, benzo[d][1,3]dioxole,
tetrahydronaphthalene, and Indane moieties could be success-
fully introduced into the 3-position of indoles using triflates as
arylating agents, which were readily prepared from the
corresponding hydroxy compounds, to afford the desired 17−
19, respectively.
Scheme 4. C3-Arylation of Indole with Pharmaceuticals
Containing an Aryl Chloride Moiety
Next, the scope of indoles was investigated (Scheme 3).
Indoles bearing substituents at various positions were reacted
a
Scheme 3. Scope of Indoles
yield along with a small amount of N-arylated product. In the
case of ( )-chlorpheniramine (30), C3-arylated product 31 was
obtained in 53% yield without formation of the N-arylated
product, although a longer reaction time was required. Chlorine
is one of the frequently used elements in pharmaceuticals, much
more frequently than bromine or iodine, and the majority of the
chlorine atoms are attached to an aromatic carbon.17 Therefore,
this catalytic system will find further synthetic applications in
late-stage introduction of an indole moiety to pharmaceuticals.
A catalytic cycle is proposed in Scheme 5. First, the NH of
indole 2 and the hydroxy groups of ligand 1a are deprotonated
Scheme 5. Proposed Catalytic Cycle
a
b
Isolated yield. Pd(OAc)2 (4 mol %), 1a·HBF4 (8 mol %), t-BuOLi
(3.5 equiv). The yield was determined after reduction to the
corresponding indoline with NaBH3CN.16b
with 3 using the Pd−1a catalyst. 5-Methoxyindole and 5-
fluoroindole gave the corresponding products 20 and 21 in high
and moderate yield, respectively. Indoles bearing substituents at
the C-7 position also afforded the desired products (22 and 23)
in moderate to good yields. When C2-substituted indoles were
used, the yields of products (24 and 25) decreased, suggesting a
steric hindrance effect on the reaction. On the other hand, N-
methylindole did not react, and 26 was not formed. Surprisingly,
the reaction of 3-methylindole also proceeded, and 3,3-
disubstituted indolenine 27 was obtained. Although the yield
and site selectivity of the reaction still need to be improved, to
the best of our knowledge, this is the first example of C3-
arylation of 3-substituted indoles to synthesize 3,3-disubstituted
compounds with simple aryl halides.16
by t-BuOLi, and the obtained lithium salts form heteroaggregate
A.18 Oxidative addition of aryl chloride or triflate to Pd gives
intermediate B, in which the C-3 position of indole is close to
the Pd atom thus promoting selective palladation to form
intermediate C. This intermediate, which would be formed
without significant strain according to a molecular model,
The utility of this catalytic system was demonstrated by
reacting indole with pharmaceuticals containing an aryl chloride
moiety (Scheme 4). When 1 equiv of chlorpromazine (28) was
used as a reactant, arylation proceeded selectively at the C-3
position of the indole to afford the desired product 29 in 65%
C
DOI: 10.1021/acs.orglett.7b02669
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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methylindole (Scheme 3).
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unsubstituted indoles with aryl chlorides and triflates using the
Pd−1a catalyst. Complex formation between the Pd−1a catalyst
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achieve C3-selectivity. This method enables the C3-functional-
ization of N-unsubstituted indole with readily available aryl
chlorides and triflates, including bioactive compounds such as
pharmaceuticals.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02669.
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1
Experimental procedures and characterization data, H
and 13C NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: manabe@u-shizuoka-ken.ac.jp.
ORCID
Kei Manabe: 0000-0002-9759-1526
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Ryoya Hagiwara (University of Shizuoka) for
his assistance in the indolenine synthesis. This work was
partially supported by JSPS KAKENHI (Grant Numbers
15H04634, 15K18833, and 17K08214), the Society of Synthetic
Organic Chemistry (Japan), the Uehara Memorial Foundation,
and the Platform Project for Supporting in Drug Discovery and
Life Science Research (Platform for Drug Discovery,
Informatics, and Structural Life Science) from the Ministry of
Education, Culture, Sports, Science and Technology (MEXT)
and Japan Agency for Medical Research and Development
(AMED).
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homoaggregates through a four-membered Li−O(N)−Li−O(N)
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DOI: 10.1021/acs.orglett.7b02669
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