Synthesis of C4-Aminated Indoles via a Catellani and Retro-Diels-Alder Strategy

Article abstract of DOI:10.1021/jacs.9b05009

Highly functionalized 4-aminoindoles were synthesized via the three-component cross-coupling of o-iodoaniline, N-benzoyloxyamines, and norbornadiene. The Catellani and retro-Diels-Alder strategy was used in this domino process. o-Iodoaniline, with electron-donating and sterically hindered protecting groups, made the reaction selective toward o-C-H amination. On the basis of density functional theory calculations, the intramolecular Buchwald coupling of this reaction underwent a dearomatization and a 1,3-palladium migration process. The reasons for the control of the chemical selectivity by the protecting groups are given. Moreover, synthetic applications toward 4-piperazinylindole and a GOT1 inhibitor were realized.

Full text of DOI:10.1021/jacs.9b05009

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Article
Synthesis of C4-Aminated Indoles via a
Catellani and Retro-Diels-Alder Strategy
Bo-Sheng Zhang, Yuke Li, Zhe Zhang, Yang An, Yu-Hua Wen,
Xue-Ya Gou, Si-Qi Quan, Xin-Gang Wang, and Yong-Min Liang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b05009 • Publication Date (Web): 28 May 2019
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Synthesis of C4-Aminated Indoles via a Catellani and Retro-Diels-Alder
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Bo-Sheng Zhang,1‡ Yuke Li,2‡ Zhe Zhang,1 Yang An,1 Yu-Hua Wen,1 Xue-Ya Gou,1 Si-Qi Quan,1 Xin-
Gang Wang,1 and Yong-Min Liang*1
1State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
2Department of Chemistry and Centre for Scientific Modeling and Computation, Chinese University of Hong Kong,
Shatin, Hong Kong, China
KEYWORDS. Indole, Norbornene, Retro-Diels–Alder Strategy, Domino Reaction, C4-Amination
ABSTRACT: Highly functionalized 4-aminoindoles were synthesized via the three-component cross-coupling of o-
iodoaniline, N-benzoyloxyamines and norbornadiene (NBD). The Catellani and retro-Diels–Alder strategy was used in this
domino process. o-Iodoaniline, with electron-donating and sterically hindered protecting groups (PGs), made the reaction
selective toward ortho-C-H amination. Based on density functional theory (DFT) calculations, the intramolecular Buchwald
coupling of this reaction underwent a dearomatization and a 1,3-palladium migration process. The reasons for the control
of the chemical selectivity by the protecting groups are given. Moreover, synthetic applications toward 4-piperazinylindole
and a GOT1 inhibitor were realized.
pendent on the glutamate oxaloacetate transaminase 1
1. INTRODUCTION
(GOT1) metabolic pathway. Fortunately, 4-(1H-indol-4-yl)-
N-phenylpiperazine-1-carboxamide was identified as an
inhibitor of GOT1 via a high throughput screening of
800,000 molecules.11 Moreover, the c-Jun N-terminal ki-
nase (JNK) inhibitor still has this C4-Aminated Indole skel-
eton (Scheme 1b).12 Although compounds with the 4-
aminoindole skeleton are generally biologically active, the
development of their synthetic methodology has been slow.
To synthesize 4-aminoindole, 2-methyl-1,3-dinitrobenzene
was synthesized from o-nitrotoluene by further nitration.
Then 2-methyl-1,3-dinitrobenzene underwent a nucleo-
philic addition with N,N-dimethylformamide dimethyl ace-
tal (DMFDMA) and a transition metal catalysis reduction to
give 4-aminoindole (in a yield less than 5%).13 The reac-
tion conditions of the entire process were relatively harsh,
and it was difficult to synthesize the highly functionalized
4-aminoindole. Therefore, the development of a series of
C-H amination reactions to construct a 4-aminoindole
skeleton from simple raw materials in one step is highly
valuable.
The indole heteroaromatic scaffold has been one of the
most popular organic templates of the past century.1 It is
common in a wide variety of organisms and biologically
active structures,2 and the review "Rings in Drugs" report-
ed that 24 drugs currently on the market contain indole
rings.3 Due to the high nucleophilic activity of the indole
pyrrole side, selective C-H functionalization of the indole at
the C2 or C3 position has been successfully obtained.4 Re-
cently, some sophisticated methods have been developed
for introducing functional groups into the indole at the C6
or C7 sites by using removable directing groups (DGs) on
the indole nitrogen atom.5 Naturally, C4 C-H indole func-
tionalization requires a directing group at the indole’s C3
position (Scheme 1a).6 Therefore, the direct construction
of C4 position functionalized indoles is an unsolved prob-
lem that has attracted much attention.
4-Aminoindole is a widely bioactive molecular skeleton.
4-Piperazinylindole was identified and subsequently co-
crystallized with the stabilized β1AR, yielding structures at
2.8 Å. This demonstrates that 4-piperazinylindole can be
used as a molecular fragment applied to the G protein-
coupled receptor (GPCR) target.7 GPCR targets have been
an important focus of research for the pharmaceutical in-
dustry, and over 60 new GPCR drugs have been launched
in the past 10 years.8 In addition, the 5-HT7 receptor is a
member of a GPCR family, and a 5-HT7 receptor ligand
may be used to treat depression.9 It is important to note
that the 5-year survival rate of pancreatic ductal adenocar-
cinoma (PDAC) is less than 1%, and this malignant tumor
has one of the worst prognoses.10 PDAC tumors are de-
In 1991, R. C. Larock first reported the construction of
indole via the palladium-catalyzed cyclization coupling of
o-haloaniline with substituted alkynes, and the reaction is
now widely used and has been named the "Larock indole
synthesis" by chemists.14 In 2009, M. Lautens improved the
"Larock indole synthesis" for the first time.15 They used
norbornadiene (NBD) instead of alkynes, and C2, C3-
nonsubstituted indoles were successfully achieved via a
retro-Diels-Alder strategy16. When the protecting group on
the nitrogen of o-iodoaniline is electron-withdrawing, the
reaction proceeds selectively toward the Buchwald cou-
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pling. When halogenated alkanes were added, it was still
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as the substrate, using gas chromatography-mass spec-
trometry (GCMS), we found that a small amount of desired
product was generated and that some direct intramolecu-
lar Buchwald coupling product 5ab was converted to the
product 4ab via a retro-Diels-Alder reaction. Therefore, we
conjectured that the electron-donation group on the nitro-
gen atom could make the reaction proceed toward ortho-
amination and promote the retro-Diels-Alder reaction.
Therefore, we used N-methyl-o-iodoaniline as the sub-
strate. Surprisingly, we obtained the 4-aminoindole prod-
uct 3ac in 57% yield, and almost all 5ac was converted to
4ac. Subsequently, we further investigated the use of iso-
propyl and tert-butyl as protecting groups to understand
the effect of steric hindrance on the reaction direction.
Gratifyingly, when we used tert-butyl as the protecting
group, 4-aminoindole 3a was obtained in 87% yield, and
no other byproducts were detected by GCMS (Table 1). In
addition, polysubstituted benzyl groups (1ae) can be used
as protecting groups. Finally, monodentate phosphines
were screened and triphenylphosphine is still the best lig-
and (Supporting Information, SI).
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impossible to change the direction of the reaction and pro-
duce the ortho-C-H functionalized products. Therefore,
promotion of the reaction to first react in the direction of
ortho-C-H functionalization and then successfully complete
the intramolecular Buchwald coupling is an important un-
solved problem.
Scheme 1. Approaches to Access C4-Aminated Indoles
and its Biological Activity
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Table 1. Study on the Types of Protective Groups of o-
Iodoanilinea
The Catellani reaction was discovered in 1997 and
Pd/NBE chemistry was established.17 In 2000, Lautens first
used phosphorus ligands to broaden the chemical compat-
ibility of Pd/NBE and established the Catellani-Lautens
reaction system.18 Thirteen years later, the Dong group
achieved ortho-amination for the first time by using elec-
trophilic amination reagents, providing a powerful tool for
designing and constructing 4-aminoindole.19 In 2016, Yu
first developed a meta-C–H amination with pyridine-type
DGs, which can be used to synthesize 3-fluoro-5-
morpholinoaniline (an important synthetic intermediate of
a BRAF inhibitor).20 Over the past 20 years, Lautens and
other research groups have developed a series of intramo-
lecular Pd/NBE reactions to construct various heterocyclic
or nonheterocyclic skeleton structures.21 However, the
construction of a C4-functionalized indole skeleton via
domino reactions in a single step has not been reported to
date.
a
Reaction conditions: substrate 1 (0.2 mmol), 2 (0.4 mmol,
2.0 equiv.), Pd(OAc)2 (10 mol%), PPh3 (20 mol%), norborna-
diene (0.7 mmol, 3.5 equiv.), Cs2CO3 (0.8 mmol, 4.0 equiv.),
toluene (3.0 mL), 140 °C, 36 h. Isolated yields.
(2) Investigation of Substrate Scope.
We first investigated the substrate scope of o-
iodoanilines. o-Iodoanilines, with a halogen (-F, Cl) and a
strongly electron-withdrawing group (-NO2), were compat-
ible with the reaction conditions and afforded the desired
4-aminoindole products in excellent yields (Table 2, 3b-3f).
It is worth mentioning that the heteroaromatic substrate
3-iodopyridin-2-amine reacted smoothly, and 4-amino-7-
azaindole 3g was obtained in 79% yield. Subsequently, we
expanded the scope of the groups on the nitrogen atom of
o-iodoaniline. Adamantane 3h with a large steric hin-
drance, dihydroindene 3i, tetrahydronaphthalene 3j and 4-
phenylbutan-2-yl 3k containing aromatic hydrocarbons
obtained the target products in high yield. These examples
showed that a series of N-alkyl substituted indoles can be
synthesized by this reaction. Notably, the coupling reaction
of the indole with secondary or tertiary carbon is a difficult
problem at present,22 and this method provides a conven-
ient route for the synthesis of these indole derivatives.
2. RESULTS AND DISCUSSION
(1) Reaction Optimization.
Initially, we used the removable t-butyloxycarbonyl (Boc)
group as the protecting group of o-iodoaniline to synthe-
size the 4-aminoindole skeleton structure in one step.
Norbornadiene (NBD) was used instead of norbornene
(NBE) as the ortho-C-H amination transient mediator for
the Catellani reaction. Unfortunately, no desired product
was detected, and the reaction proceeded toward the in-
tramolecular Buchwald coupling without the retro-Diels-
Alder reaction. When we used unprotected o-iodoaniline
Table 2. Investigation of Substrate Scopea
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a
Reaction conditions: substrate 1 (0.2 mmol), 2 (0.4 mmol,
1
2
3
2.0 equiv.), Pd(OAc)2 (10 mol%), PPh3 (20 mol%), norborna-
diene (0.7 mmol, 3.5 equiv.), Cs2CO3 (0.8 mmol, 4.0 equiv.),
toluene (3.0 mL), 140 °C, 36 h. Isolated yields.
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We continued to expand the substrate scope for electro-
philic amination reagents. Piperidine substituted with dif-
ferent sites and groups, thiomorpholine, and Boc-protected
piperazine-derived amination reagents all afforded the
desired products in excellent yields (Table 3). Nonhexacy-
clic amination reagents, such as azepane, pyrrolidine, di-
methylamine and methylbenzyl ammonia, also afforded
the target products in high yields, in contrast to the very
low yields obtained for these substrates in the previous
work. In addition, large volume amination reagents can
also be used to obtain the products smoothly. In particular,
the antidepressant drug paroxetine can be directly derived
by this method (6q).
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Table 4. Investigation of substrate scope for other elec-
trophilic reagentsa
a
Reaction conditions: substrate 1 (0.2 mmol), 2 (0.4 mmol,
2.0 equiv.), Pd(OAc)2 (10 mol%), PPh3 (20 mol%), norborna-
diene (0.7 mmol, 3.5 equiv.), Cs2CO3 (0.8 mmol, 4.0 equiv.),
toluene (3.0 mL), 140 °C, 36 h. Isolated yields.
Bromoaniline instead of o-iodoaniline.
b
o-
Table 3. Investigation of substrate scope for electro-
philic amination reagentsa
a
Conditions a: substrate 1 (0.2 mmol), 2 (1 mmol, 5.0
equiv.), Pd(OAc)2 (10 mol%), PPh3 (20 mol%), norbornadiene
(0.8 mmol, 4.0 equiv.), Cs2CO3 (0.8 mmol, 4.0 equiv.), DMF (3.0
mL), 140 °C, 36 h. Conditions b: substrate 1 (0.2 mmol), 2 (1
mmol, 5.0 equiv.), Pd(OAc)2 (10 mol%), TFP (20 mol%), nor-
bornadiene (0.8 mmol, 4.0 equiv.), K2CO3 (0.8 mmol, 4.0
equiv.), DMF (3.0 mL), 140 °C, 36 h. Isolated yields.
To further prove the practical value of this method, we
expanded the scope of electrophilic reagents. We used al-
kyl and aryl bromides as electrophilic reagents, and the
reaction conditions were reoptimized. When N,N-
dimethylformamide was used as the solvent instead of
toluene, 4-alkyl and aryl-substituted indoles were success-
fully obtained. Unfortunately, heterocyclic indole deriva-
tives could not be synthesized by this method (Table 4).
(3) Synthetic Applications.
To demonstrate the industrialization potential of this
method, the reaction was conducted on a 4 mmol scale,
and 1.10 grams of 1a was afforded (79% yield of isolated
product). In addition, pharmaceutical compounds and nat-
ural products often have unprotected NH bonds, and there-
fore we carried out a deprotection experiment on 4-
aminoindole. We tried to use trifluoroacetic acid, hydro-
chloric acid and a Lewis acid for deprotection. Finally, we
found that the deprotected product 3ab was obtained in
76% yield when aluminum chloride was used as the Lewis
acid and DCM was used as the solvent at 55 ℃. It is note-
worthy that isobutylene can be produced when deprotec-
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tion occurs under Lewis acid conditions. Therefore, when Scheme 3. Synthesis of Drug Building Blocks and GOT1
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sealed reaction tubes were used, some C3-tert-butyl sub-
stituted 4-aminoindoles were produced, and the yield of
the desired products was reduced. In addition, we per-
formed iodization and Friedel-Crafts fluoroacetylation on
indole 3a. Finally, we tried to use diphenylacetylene and
norbornene instead of norbornadiene according to Ca-
tellani’s work,17i but only a trace amount of the desired
product 10 was produced. This may be due to de-
norbornene reaction rate being much lower than the in-
tramolecular Buchwald coupling (Scheme 2).
Inhibitor.
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Scheme 2. Deprotection and Derivatization of Produc-
tion.
(4) Mechanistic Studies.
The DFT calculations were used to study the reaction of
o-iodoaniline with different protecting groups (Boc, t-Bu).
Cs2CO3 was taken into consideration in the whole mecha-
nism study.23 Before the C-H activation process, the re-
moval of CsI released 3.2 kcal/mol for the t-Bu group in-
termediate A and 2.4 kcal/mol for the Boc intermediate F
forming B1 and G1. The barriers are 25.3 and 24.5
kcal/mol for C-H activation process, respectively. The ben-
zene rings of intermediates B1 and G1 could be rotated to
obtain intermediates B2 and G2. It is noteworthy that the
energy of B2 is 0.6 kcal/mol larger than that of B1 due to
the high steric resistance of the t-butyl group. This is one
of the reasons why the reaction moves towards C-H activa-
tion when the protecting group is t-butyl.
Scheme 4. C-H Bond Activation and Buchwald Coupling.
The utility of this method was further demonstrated in
the formal synthesis of 4-piperazinylindole used as a mo-
lecular fragment applied to the G protein-coupled receptor
(GPCR) target, and we utilized it to further synthesize the
GOT1 inhibitor used to treat pancreatic ductal adenocarci-
noma (PDAC). In the past, the synthesis of 4-
piperazinylindole required further nitrosation of o-
Subsequently, we studied the mechanism of the intramo-
lecular C(sp3)-N Buchwald coupling. For the intermediate
B2, the distance between O in carbonate and H in the tert-
butyl is 2.35 Å. Therefore, the steric hindrance between
carbonate and tert-butyl prevents the Pd from attacking
nitrogen atoms directly. According to a hydrogen bond
between carbonate and amine and the coordination mode
of Buchwald ligand and palladium,24 we speculate that the
coordination of benzene with palladium may cause the
carbonyl group of the carbonate to leave. The results were
surprising, the carbonate can remove the proton from the
amine with a 16.1 kcal/mol barrier and the benzene ring
can coordinate with the palladium forming intermediate
D.25 Then 1,3-Pd migration was occurred to obtain inter-
mediate E (Scheme 5). After ortho-amination, the barriers
of Buchwald coupling process decreased significantly. This
may be due to the conjugation of secondary amine group
(Scheme 7).
nitrotoluene
and
purification
of
2-methyl-1,3-
dinitrobenzene from a variety of polynitrotoluene prod-
ucts, which was extremely uneconomical and environmen-
tally unfriendly. In this case, 3-5 steps are required for the
synthesis of 4-piperazinylindole, including a transition
metal catalyzed reduction and the nucleophilic addition to
N,N-dimethylformamide dimethyl acetal (DMFDMA).
Through our strategy, we synthesized 4-piperazinylindole
via a single step three-component tandem reaction and a
simple deprotected process. Then, we stirred 4-
piperazinylindole and 4-chlorophenyl isocyanate for 30
minutes in the presence of triethylamine as the base, and
obtained the GOT1 inhibitor in 46% yield.
Scheme 5. Computed Gibbs Free Energy Profile (t-
Butyl).
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Scheme 8. Computed Gibbs Free Energy Profile (Boc).
Scheme 6. The Steric Hindrance Between Tert-Butyl
Groups and Carbonate in Intermediate B2 and G2.
When the protecting group is Boc, we calculated it in the
same way. But no dearomatization intermediates were
formed similar to the intermediate D. Instead, the inter-
mediate I was directly formed. This may be due to the little
steric hindrance between Boc and carbonate (Scheme 6).26
Therefore, we speculated that the process was a concerted
metalation process, and then we found the TS5 (Scheme 8).
CONCLUSIONS
In a short summary, when the protecting group is t-butyl,
the barrier of the Buchwald coupling is 0.9 kcal/mol larger
than that of the C-H activation. When the protecting group
is Boc, the energy of the Buchwald coupling is 7.6 kcal/mol
lower than that of the C-H activation. The calculated re-
sults are in agreement with the experimental results.
In summary, highly functionalized 4-aminoindoles were
synthesized via the three-component cross-coupling of o-
iodoaniline, N-benzoyloxyamines and norbornadiene. The
Catellani and retro-Diels–Alder strategy was used in this
domino process. Based on the DFT calculations, the intra-
molecular Buchwald coupling of this reaction underwent a
dearomatization and 1,3-palladium migration process. The
reasons for the control of chemical selectivity by protect-
ing groups are given. Moreover, synthetic applications to-
ward 4-piperazinylindole and a GOT1 inhibitor were real-
ized.
Scheme 7. Computed Gibbs Free Energy Profile (After
Ortho-Amination).
ASSOCIATED CONTENT
Supporting Information
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Page 6 of 9
Experimental procedures, compound characterization, and
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
(7) (a) Christopher, J. A.; Brown, J.; Doré, A. S.; Errey, J. C.;
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Tehan, B.; Warne, T.; Congreve, M. Biophysical Fragment
Screening of the β1-Adrenergic Receptor: Identification of
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Drug Design. J. Med. Chem. 2013, 56, 3446-3455. (b)
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A.; Mazandarani, H.; Brennan, J. A.; Marquis, K. L.; Coupet, J.;
Andree, T. H. New generation dopaminergic agents. 5.
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AUTHOR INFORMATION
Corresponding Author
* E-mail: liangym@lzu.edu.cn
Author Contributions
‡These authors contributed equally.
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Funding Sources
National Natural Science Foundation of China (NSF 21472073，
21772075 and 21532001).
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ACKNOWLEDGMENT
Computations reported in this paper were performed on the
computer clusters at the Centre for Scientific Modeling and
Computation, CUHK. We would like to thank ACS ChemWorx
Authoring Services for providing linguistic assistance during
the preparation of this manuscript.
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