Regiocontrolled Direct C?H Arylation of Indoles at the C4 and C5 Positions

Article abstract of DOI:10.1002/anie.201612599

An effective and practical strategy has been established for the direct and site-selective arylation of indoles at the C4 and C5 positions with the aid of a readily accessible, cheap, and removable pivaloyl directing group at the C3 position. This transfo

Full text of DOI:10.1002/anie.201612599

Angewandte
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Chemie
International Edition: DOI: 10.1002/anie.201612599
German Edition: DOI: 10.1002/ange.201612599
Regioselectivity
À
Regiocontrolled Direct C H Arylation of Indoles at the C4 and C5
Positions
Youqing Yang+, Pan Gao+, Yue Zhao, and Zhuangzhi Shi*
Abstract: An effective and practical strategy has been estab-
lished for the direct and site-selective arylation of indoles at the
C4 and C5 positions with the aid of a readily accessible, cheap,
and removable pivaloyl directing group at the C3 position. This
transformation shows good functional-group tolerance and
could serve as a powerful synthetic tool for the synthesis of
medicinally relevant compounds. This method and those
developed in previous research together enable the regiocon-
À
trolled direct arylation of indole at each C H bond without
prefunctionalization of the reactive sites.
T
he indole motif is a ubiquitous feature of bioactive natural
products and an important structural element in pharmaceut-
ical applications.[1] Consequently, there is continuing interest
À
in reactions that enable the C H functionalization of indoles.
À
There are six C H bonds in the indole motif that can be
functionalized: positions C2 and C3 (pyrrole core), and C4–
À
C7 (benzene core). However, these C H bonds are inequi-
valent, and it is quite difficult to access each of them
regioselectively. During the past decade, great effort has
Figure 1. Regioselective direct arylation of indoles at each position.
Bn=benzyl, DG=directing group, PG=protecting group, Py=pyri-
dine.
À
been devoted to the transition-metal-catalyzed C H func-
tionalization of indoles at the C2 and C3 positions.[2] The
implicit challenge of a developing a strategy for the direct
catalyzed direct arylation of indoles at the C6 position
(Figure 1B).[7] Until now, only direct arylation at the C4 and
C5 positions of indoles remained unsolved. We speculated
that simple indole building blocks could form the starting
point for a strategy that would involve the convenient
introduction and removal of a directing group to append
aryl substituents at C4 and C5 positions. Herein, we show that
the installation of a suitable directing group at the C3 position
of indoles enables direct arylation at the C4 and C5 positions
in a straightforward manner (Figure 1C).
À
functionalization of C H bonds on the benzene core rather
than the pyrrole core is evident.[3]
Although traditional cross-coupling methods, namely,
Suzuki, Negishi, and Stille coupling reactions, have been
widely utilized to build aryl–indolyl bonds at each position of
indoles in the total synthesis of natural products,[4] direct
arylation is undoubtedly the most desirable route. The direct
site-selective arylation of indoles at the C3 and C2 positions
has been well developed (Figure 1A).[5] The introduction of
a directing group on the N atom has been used as a reliable
strategy to ensure direct C2 selectivity. Recently, we achieved
a major breakthrough by introducing an aryl group at the C7
position of the indole.[6] The key to this success was the
appropriate choice of a N-P(O)tBu2 directing group for
C7 selectivity with a palladium-catalyzed system. On the
basis of this directing group, we also disclosed a copper-
Typically, an N-pivaloyl substituent is a good directing
group for C2 selectivity in the functionalization of indoles.[5g]
À
Recently, rhodium- and iridium-catalyzed direct C H olefi-
nation[3h] and amidation reactions[3i–k] of N-pivaloylindoles at
the C7 position have also been developed. We considered that
a bulky pivaloyl group at the C3 position of indoles might also
promote C4 and C5 selectivity. With AlEt2Cl in dichloro-
methane (DCM)[8a] or just by the use of hexafluoro-2-
propanol (HFIP)[8b] as a solvent, a pivaloyl group can be
selectively installed at the C3 position by a Friedel–Crafts
acylation process. To begin our investigation, we synthesized
the C3-pivaloyl-substituted indoles 2a, 2a’, and 2a’’ [Eq. (1)].
We first investigated the reaction of N-benzyl-3-pival-
oylindole (2a) with iodobenzene (3a; Table 1). When the
reaction was carried out with Pd(OAc)2 (5 mol%) in HFIP at
808C, we indeed observed the C4-arylation product 6aa,
which was formed in 12% yield along with the by-product 5aa
(5% yield; Table 1, entry 1). Remarkably, in the presence of
the oxidant Ag2O (1.2 equiv), the yield of 6aa was improved
[*] Y. Yang,[+] P. Gao,[+] Dr. Y. Zhao, Prof. Dr. Z. Shi
State Key Laboratory of Coordination Chemistry
School of Chemistry and Chemical Engineering, Nanjing University
Nanjing, 210093 (China)
E-mail: shiz@nju.edu.cn
Homepage: http://hysz.nju.edu.cn/zzshi/
[+] These authors contributed equally.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201612599.
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80% yield with complete regioselectivity (Table 1, entry 12).
Other copper sources, such as CuCl and Cu(OTf)2, were also
found to be effective in this reaction, although lower
reactivity was observed (entries 13 and 14).
We found that the pivaloyl group could be readily
removed from the two products 6aa and 7aa by a reverse
Friedel–Crafts reaction in the presence of p-toluenesulfonic
acid and glycol to give 8aa and 9aa in 92 and 98% yield,
respectively [Eqs. (2) and (3)]. The ready removal of the
directing group from the products under mild reaction
conditions demonstrates the full synthetic utility of this
method.
to 54%, and the arylation proceeded with high regioselectiv-
ity (entry 2). [Pd(PPh3)2Cl2] was a very effective catalyst,
providing the desired product in 64% yield with an encour-
aging level of C4 selectivity (C2/C4/C5 1:64:0; entry 3).
Further screening of additives showed that they had a signifi-
cant influence. When both 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) and 4 ꢀ molecular sieves (MS) were added, the
reaction gave 6aa in 86% yield with excellent C4 selectivity
(Table 1, entries 4 and 5).
Interestingly, the diaryliodonium salt[9] Ph2IOTf (4a) was
also very effective as an arylation reagent, resulting in 82%
yield with 1:82:0 C2/C4/C5 regioselectivity (Table 1, entry 6).
With this reagent, we found that changing the oxidant to CuO
led to a lower yield of 6aa (entry 7). Gratifyingly, the
regioselectivity was tuned to the C5 position in the nonpolar
solvent DCM (C2/C4/C5 3:0:35; entry 8). Examination of the
catalytic system revealed that [Pd(PPh3)2Cl2] and the addi-
tives were not necessary for this C5 arylation (entry 9), and
a catalytic amount of CuO (10 mol%) was enough to furnish
7aa in 42% yield at 408C (entry 10).[10] An immediate
improvement in the C5 arylation was observed when copper-
(I) thiophene-2-carboxylate (CuTc) was used as the catalyst
(64% yield; entry 11). The addition of the base 2,6-di-tert-
butylpyridine (dtbpy; 1.0 equiv) led to the formation of 7aa in
We next explored the scope of the direct C4 arylation
under the optimized conditions (Table 2). Cross-coupling
reactions of indole 2a with a broad range of aryl iodides were
first examined. Iodoarenes containing a methyl group on the
aryl ring at ortho, meta, and para positions afforded the
desired products 6ab–ad in 72–
83% yield. The regioselectivity
profile of this method was nicely
Table 1: Reaction development.[a]
illustrated by the fact that
methoxy- (product 6ae), phenyl-
(product 6af), and ester-substi-
tuted substrates (product 6ag), as
well as those containing fluoro
groups (products 6ah–aj), could
Entry
Catalyst [M] (mol%)
3/4
Oxidant
Solvent
Yield [%][b]
6aa
5aa
7aa
all be accommodated equally well.
In particular, chloro- and bromo-
substituted aryl iodides were very
effective substrates (products 6ak–
am), thus highlighting the potential
of this process in combination with
further conventional cross-cou-
pling transformations. With iodo-
benzene (3a) as the coupling part-
ner, reactions of indoles with
methyl (product 6ba), methoxy
(product 6ca), phenyl (product
6da), fluoro (product 6ea), chloro
(product 6 fa), and bromo substitu-
ents (product 6ga) afforded the
corresponding 4-aryl indoles in
moderate to excellent yields.
Among these substrates, the C5-
1
2
Pd(OAc)2 (5)
Pd(OAc)2 (5)
[Pd(PPh3)2Cl2] (5)
[Pd(PPh3)2Cl2] (5)
[Pd(PPh3)2Cl2] (5)
[Pd(PPh3)2Cl2] (5)
[Pd(PPh3)2Cl2] (5)
[Pd(PPh3)2Cl2] (5)
–
CuO (10)
CuTc (10)
CuTc (10)
CuCl (10)
3a
3a
3a
3a
3a
4a
4a
4a
4a
4a
4a
4a
4a
4a
–
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
DCM
DCM
DCM
DCM
DCM
DCM
DCM
5
3
1
0
0
1
2
3
4
4
1
0
3
3
12
54
64
0
0
0
0
0
0
1
35
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
CuO
CuO
CuO
–
–
–
–
–
3
4[c]
78
5[c,d]
6[c,d]
7[c,d]
8[c,d]
9
86 (84)[e]
82
13
0
0
0
0
0
0
0
48
42
64
10[f]
11[f]
12[f,g]
13[f]
14[f]
80 (74)[e]
58
Cu(OTf)2 (10)
55
[a] Reaction conditions: 2a (0.20 mmol), 3a (0.40 mmol) or 4a (0.28 mmol), solvent (1.0 mL), 12 h,
808C, Ar atmosphere. [b] Yields were determined by GC analysis of the crude reaction mixture. [c] The
reaction was carried out with DBU (1.0 equiv). [d] The reaction was carried out with 4 ꢀ MS (200 mg).
[e] The yield of the isolated product is given in parentheses. [f] The reaction was carried out at 408C.
[g] The reaction was carried out with dtbpy (1.0 equiv). Tf=trifluoromethanesulfonyl.
2
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Table 2: Direct arylation of indoles at the C4 position.[a]
substituted indoles 2c and 2e with the steric effect of
a substituent adjacent to the C4 position also delivered the
coupled products 6ca and 6ea in good yields. Furthermore,
lilolidine derivative 2h was also compatible with the reaction
conditions and afforded the desired product 6ah in 69%
yield.
We then tested the generality of directing-group removal.
The selected substrates bearing various substituents on the
aromatic ring such as methyl (product 8ab), trifluoromethoxy
(product 8ai) and halides (products 8al, 8am, 8ea–ga) were
tolerated, and the corresponding products were obtained in
good to excellent yields.
We next examined the scope of the arylation reaction with
diaryliodonium triflate salts, which ensured high regioselec-
tivity for the formation of 5-aryl indoles (Table 3). A wide
range of diaryliodonium triflate salts incorporating electron-
donating and electron-withdrawing substituents at the meta
and para positions were effective C5-arylation reagents
(products 7ab, 7ac, 7ae–am). However, the ortho-methyl-
substituted aryl derivative 4d could not generate the corre-
sponding arylation product 7ad, thus implying that increased
steric congestion affects reactivity. Regarding the indole
framework, various substituents at the C6 and C7 positions
were tolerated well (Table 3, products 7ba–ha). We also
successfully removed the directing group from selected
products (Table 3).
To confirm the importance of the sterically demanding
pivaloyl moiety for this high regioselectivity, we conducted
some control experiments under the optimized reaction
conditions (Figure 2). Indoles bearing smaller directing
groups at the C3 position, such as formyl (substrate 2a-I),[11]
acetyl (substrate 2a-II), and isobutyryl substituents (substrate
2a-III), underwent C4 and C5 arylation in lower yield. We
also evaluated the influence of the indole N-protecting group.
As compared to the N-benzylindole 2a, N-methylindole 2a’
underwent C4 arylation in slightly higher yield and C5
arylation in lower yield. Even the unprotected indole 2a’’
gave the C5-arylation product in modest yield, although the
corresponding C4-arylation product was not detected. How-
ever, for 2a’’’ with N-Ts protection, no product of either C4 or
C5 arylation was observed. These results indicated that when
the sterically hindered pivaloyl substituent is used as a direct-
ing group, an N-Bn- or N-Me-type protecting group is
[a] Reaction conditions I: 2 (0.20 mmol), 3 (0.40 mmol), [Pd(PPh3)2Cl2]
(5 mol%), Ag2O (1.2 equiv), DBU (1.0 equiv), 4 ꢀ MS (200 mg), HFIP
(1.0 mL), 808C, 12 h, Ar atmosphere.
Figure 2. Evaluation of different directing and N-protecting groups.
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Table 3: Direct arylation of indoles at the C5 position.[a]
Our approach clearly enables the rapid and modular
construction of C4- and C5-arylated products from simple and
available indole substrates with minimal prefunctionalization.
To demonstrate the synthetic importance of the present
protocol, we targeted the key intermediate in the synthesis of
two potent inhibitors, SETin-1[12] and tiplaxtinin,[13] in which
aryl groups are located at the indole C4 and C5 position,
respectively (Scheme 1). The reaction of indole 2a on
a 5.0 mmol scale with aryl iodide 3h, followed by removal
of the protecting group, gave 8ah (0.93 g) in 43% yield; 2a
and 4i generated 9ai (1.30 g) in 71% yield. Compound 8ah
Scheme 1. Synthesis of two inhibitors from one substrate. Reagents
and conditions: a) PivCl, AlEt2Cl, DCM, 08C; b-I) 3h, [Pd(PPh3)2Cl2],
Ag2O, DBU, 4 ꢀ MS, HFIP, 808C; b-II) 4i, CuTc, dtpby, DCM, 408C;
c) TsOH, glycol, 1008C; d) KOtBu, O2, DMSO, RT; e) Oxalyl chloride,
THF; f) MeOH; g) KOH, acetone, water, HCl. DMSO=dimethyl sulf-
oxide.
can be further converted into the SET inhibitor SETin-
1 through several known steps, whereas the sequential
treatment of 9ai with oxalyl chloride, MeOH, and KOH
gave tiplaxtinin (11; 1.15 g) in good yield.
We propose two catalytic cycles to account for the
selectivity of the arylation reactions (Figure 3). In the
palladium catalysis, PdII coordinates to the pivaloyl group of
À
the substrate, followed by 1) C H activation at the indole C4
position, 2) oxidative addition by ArI, 3) reductive elimina-
tion to give C4-arylation products, and 4) regeneration of the
active PdII species by Ag2O (Figure 3, left).[14] In the copper
catalysis, the reaction may proceed through the following
steps: 1) oxidative addition of the diaryliodonium salt to
CuTc to afford the CuIII species, 2) coordination of the
pivaloyl group, 3) aryl migration to the C5 position via
a Heck-type four-membered-ring transition state, and 4) E2-
type elimination to deliver the product and regenerate the
active Cu catalyst (Figure 3, right).[15]
[a] Reaction conditions II: 2 (0.20 mmol), 4 (0.28 mmol), CuTc
(10 mol%), dtpby (0.20 mmol), DCM (1.0 mL), 408C, 12 h, Ar atmos-
phere.
a prerequisite for achieving high levels of C4 and C5
regioselectivity.
In summary, we have reported the C4- and C5-selective
direct arylation of indoles with the aid of a readily accessible,
4
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Figure 3. Proposed catalytic cycles.
cheap, and removable pivaloyl directing group installed at the
C3 position. This method complements our previously
developed methods for C7 and C6 direct arylation and
mature reactions for direct arylation at C2 and C3, so that
À
now a simple indole can be selectively arylated at each C H
bond without prefunctionalization of the reactive sites.
Current studies are focused on the development of further
cross-coupling reactions at the benzene core of indoles.
Acknowledgements
We thank the “1000 Youth Talents Plan”, the “Jiangsu
Specially Appointed Professor Plan”, and the NSF of China
(Grants 2167020084, 21401099) for financial support.
Conflict of interest
The authors declare no conflict of interest.
Keywords: arylation · copper · indoles · palladium ·
regioselectivity
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[10] R. J. Phipps, M. J. Gaunt, Science 2009, 323, 1593.
[11] During the preparation of this manuscript for submission,
À
[13] H. Elokdah, M. Abou-Gharbia, J. K. Hennan, G. McFarlane,
C. P. Mugford, G. Krishnamurthy, D. L. Crandall, J. Med. Chem.
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[14] G. Chen, Z. Zhuang, G.-C. Li, T. G. Saint-Denis, Y. Xiao, C. L.
Joe, J.-Q. Yu, Angew. Chem. Int. Ed. 2017, 56, 1506 – 1509;
Angew. Chem. 2017, 129, 1528 – 1531.
a
method for the diverse ortho-C H functionalization of
benzaldehydes with transient directing groups was reported, by
which the direct arylation of 3-formylindole at the C4 position
with methyl 4-iodobenzoate was demonstrated with an amino
acid as a transient directing group: X.-H. Liu, H. Park, J.-H. Hu,
Y. Hu, Q.-L. Zhang, B.-L. Wang, B. Sun, K.-S. Yeung, F.-L.
Zhang, J.-Q. Yu, J. Am. Chem. Soc. 2017, 139, 888.
[15] B. Chen, X.-L. Hou, Y.-X. Li, Y.-D. Wu, J. Am. Chem. Soc. 2011,
133, 7668.
[12] S. Kashyap, J. Sandler, U. Peters, E. J. Martinez, T. M. Kapoor,
Bioorg. Med. Chem. 2014, 22, 2253.
Manuscript received: December 28, 2016
Final Article published: && &&, &&&&
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 7
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Regioselectivity
Y. Yang, P. Gao, Y. Zhao,
Z. Shi*
&&&& — &&&&
À
Regiocontrolled Direct C H Arylation of
Indoles at the C4 and C5 Positions
Grand Slam: An effective and practical
strategy has been established for the
direct site-selective arylation of indoles at
the C4 or C5 position (see scheme) by the
use of a readily available and removable
pivaloyl directing group (DG) at the
indole C3 position. Now the direct site-
selective arylation of indoles at any given
À
C H bond is possible by the appropriate
choice of this or a previously developed
complementary method.
Angew. Chem. Int. Ed. 2017, 56, 1 – 7
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!