New Friedel-Crafts strategy for preparing 3-acylindoles

Article abstract of DOI:10.1039/c8ob02094a

A selective Friedel-Crafts acylation of indoles via an unusual cleavage of the amide C-N bond was achieved by triflic anhydride activation. This method offers rapid efficient access to high-biological-value 3-acylindoles, performs a series of scrupulous mechanistic studies and offers a strong courage that amide synthons can form new C-C bonds under transition-metal-free conditions.

Full text of DOI:10.1039/c8ob02094a

Organic &
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New Friedel–Crafts strategy for preparing
3-acylindoles†
Cite this: Org. Biomol. Chem., 2018,
16, 7792
Lian-Hua Li, Zhi-Jie Niu and Yong-Min Liang
*
Received 27th August 2018,
Accepted 2nd October 2018
DOI: 10.1039/c8ob02094a
rsc.li/obc
A selective Friedel–Crafts acylation of indoles via an unusual clea- reaction system provides one of the strongest inductive elec-
vage of the amide C–N bond was achieved by triflic anhydride acti- tron-withdrawing and leaving groups, namely the OTf
vation. This method offers rapid efficient access to high-biologi- (OSO2CF3) intermediate. This breakthrough has great potential
cal-value 3-acylindoles, performs a series of scrupulous mechanis- for the cleavage of strong amide C–N bonds in organic chem-
tic studies and offers a strong courage that amide synthons can istry toward the synthesis of more valuable medicinal and bio-
form new C–C bonds under transition-metal-free conditions.
active compounds. Given our interest in Tf2O-activated amides
as synthons, we hypothesized that the higher electrophilicity
could be used to develop a general Friedel–Crafts acylation15
of indoles, which has barely been reported (Scheme 1b).
Herein, we present the preliminary results of the Tf2O-acti-
vated acylation of indoles using amides as the acyl group
source. Our method offers rapid, efficient access to 3-acylin-
doles from simple precursors via an unusual C–N bond clea-
vage strategy.
Based on our hypothesis, we optimized the acylation of
indole 1a using tertiary amide 2a as the coupling partner. The
results are compiled in Table 1. Several bases were investigated
and Cs2CO3 was identified as the best option. Toluene was a
particularly efficient solvent and the desired product was iso-
lated in 60% yield (Table 1, entry 5). The yield increased
noticeably when the reaction temperature reached 70 °C with
CsF as an additive. Micro-adjustments in the ratio of indole
1a, amide 2a, Cs2CO3, and Tf2O were also performed.
Ultimately, the following standard reaction conditions to form
3-Acylindoles and their derivatives are key structural units in
alkaloids and pharmaceuticals and are versatile precursors for
synthesizing heterocycles. These compounds have been used
as anti-diabetic and anti-cancer compounds, inhibitors of
HIV-1 integrase,1 and as unusual intermediates in functional
group transformations.2 Thus, the synthesis of 3-acylindoles
has attracted intense attention.3 The conventional methods of
preparing 3-acylindoles, including Friedel–Crafts reactions,4
Vilsmeier–Haack acylations,5 and Grignard reactions,6 often
involve uncommon acylated reagents or harsh reaction
conditions.7–10 Although the 3-position of indole is the most
reactive site for electrophilic attack,7 the low yields encoun-
tered are usually attributed to the competitive formation of
1-acylated and 1,3-diacylated products due to the ambident
character of the indole system. Therefore, an efficient, simple
acylation reaction to access various 3-acylindoles is highly
desirable.
The amide bond is a ubiquitous structural motif, which
exerts various effects on the biological and material properties
of a vast range of compounds.11 The resonance stabilization of
amides (Scheme 1a) reduces the susceptibility of the molecules
to nucleophilic attack, and makes the amide C–N bond sur-
prisingly difficult to cleave.12 The triflic anhydride-mediated
(Tf2O) activation of amides to enhance their intrinsic electro-
philicity has been developed over recent decades,13,14 and the
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and
Chemical Engineering, Lanzhou University, Lanzhou 730000, P. R. China.
E-mail: liangym@lzu.edu.cn
†Electronic supplementary information (ESI) available. CCDC 1857322, 1857189,
1857188 and 1857187. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c8ob02094a
Scheme 1 Amide C–N bond and the new activation method.
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Table 1 Optimization of the reactiona
Table 2 Scope of acylating reagentsa
Entry Base (equiv.)
Temp (°C) Solvent
Yielde (%)
1
2
3
2,6-Dichloropyridine −78 to 40
DCM
DCM
DCM
DCE
Toluene
1,4-Dioxane N.D.
CH3NO2
Toluene
Toluene
N.D.
<5%
24
45
60
NaOH
−78 to 40
−78 to 40
−78 to 70
−78 to 70
−78 to 70
−78 to 70
−78 to 70
−78 to 70
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
4b
5b
6b
7b
8c
9c,d
N.D.
72
85
a Reaction conditions: Tf2O (2.0 equiv.) was added to a mixture of
indole 1a (0.2 mmol, 1.0 equiv.), amide 2a (1.0 equiv.) and base (2.2
equiv.) in solvent (3.0 mL) at −78 °C under an Ar atmosphere. After
20 min, the reaction mixture was stirred at the reported temperature
for another 12 h. b Amide (1.5 equiv.) was used. c Amide (1.6 equiv.)
and base (2.6 equiv.) were used, and the reaction was conducted for
14 h. d Additive CsF (0.5 equiv.) was used. e Isolated yields. Tf = trifluor-
omethanesulfonyl, TMS = trimethylsilyl, DCE = 1,2-dichloroethane,
DCM = dichloromethane.
the desired product were identified. The treatment of indole
1a (1.0 equiv.) with amide 2a (1.6 equiv.) in the presence of
Cs2CO3 (2.6 equiv.), CsF (0.5 equiv.) and Tf2O (2.0 equiv.) in
toluene at 70 °C for 14 h gave desired product 3aa in 85% yield
(Table 1, entry 9).
a All reactions were carried out on 0.2 mmol scale under an Ar atmo-
sphere for 14 h. Isolated yields are given.
Under the optimal conditions in Table 1, the scope of
amides as acylating reagents was examined. A series of pro-
ducts with representative substrates was synthesized. As sum-
marized in Table 2, amides with chain alkyl groups coupled and diverse acylated indoles were obtained in good yields
smoothly with indole 1a and afforded corresponding products (Table 3, 3ba–3ka). The acylated indoles bearing halogens
3aa–3ai in moderate to good yields. The α-substituted chain could be used in further coupling reactions. Likewise, benzyl
alkyl groups showed good compatibility with this transform- N-protected indole 3la was obtained in acceptable yields.
ation to provide acylated indoles 3aj–3al. Even though the reac- When the utility of this method was expanded to non-N-pro-
tion was affected by increased steric bulk, the tert-butyl amide tected indoles, the desired products were produced in moder-
generated desired product 3am. However, the adamantyl ate yields (Table 3, 3ma–3sa). The reactions to obtain 2-substi-
amide did not react. Additional attempts to use the strained tuted products 3ta and 3ua proceeded smoothly to give yields
cycloalkyl moiety were successful and gave satisfying yields of of 46% and 78%, respectively. These non-N-protected acylated
the desired products (Table 2, 3an–3ap). These results clearly products displayed high biological value and demonstrated
display the superior acylating capability of the aliphatic func- that this method has multiple potential uses in pharmaceuti-
tional group in this reaction. Importantly, substituted aryl cals. The structures of 3ga and 3ua were confirmed by X-ray
amides were tolerated in this transformation, albeit giving crystal structure analysis.
lower yields of the corresponding products, which could be
After our success in demonstrating our method, we were
used in medicinal chemistry directly due to their biological intrigued to see how far the range of N-leaving groups of
activities, particularly through interactions with the cannabi- amides could be extended (Table 4). Substrates with alkyl,
noid receptor.16 N,N-Dimethylformamide gave desired product branched alkyl, and aryl chains were compatible with the reac-
3as in 79% yields, and the method could be applied to the syn- tion, and desired product 3aa was obtained in excellent yields
thesis of aldehyde compounds. The molecular structures of (Table 4, 2A–2N). These results indicate different N-substituted
3aa and 3al were unambiguously confirmed by X-ray crystal amides can be used to acylate the indoles in this reaction and
structure analysis (Table 2).
the utility of this method can be easily expanded in synthesis
To evaluate the broad utility of this method, we turned our and retro-synthesis.
attention to investigating indole substrates (Table 3). The reac-
To explore the synthetic utility of this chemistry further, we
tions were conducted with amide 2a as the reaction partner, performed a further series of acylations17 (Scheme 2). As
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Table 3 Scope of indole substratesa
Scheme 2 Further applications. Reactions were carried out on 0.2 mmol
scale under an Ar atmosphere for 14 h. Isolated yields are given.
expected, the acylations of N,N-dimethyl aniline (4a), pyrrole
(6a), 1,2,3-trimethoxybenzene (8a) and veratrole (10a) with
amide 2a afforded the desired products in acceptable yields.
These results showcase the potential to apply the Friedel–
Crafts C–H acylation to active nucleophiles.
a All reactions were carried out on 0.2 mmol scale under an Ar atmo-
sphere for 14 h. Isolated yields are given.
Based on these results, a reasonable mechanism was pro-
posed (Scheme 3). The Tf2O-mediated activation of amide 2
generates highly electrophilic adduct I. The subsequent
nucleophilic attack of indole on adduct I produces intermedi-
ate II, which is converted to acylated indole 3 via the elimin-
ation of TfOH. The reaction allowed complete control of the
substitution pattern and was a one-pot reaction using a wide
range of readily available amides and indole substrates.
Table 4 Scope of N-leaving groupsa
To further understand this chemistry, parallel deuterium
labelling reactions were conducted between 1a/1a–3d and 2k
(Scheme 4a), and a kinetic isotope effect value of KH/KD = 1.11
was observed. This result suggests the unlikely involvement of
the cleavage of the C–H bond in the turnover-limiting step.
In addition, the mechanism of the transformation of 3ak
was monitored by 13C nuclear magnetic resonance (NMR)
spectroscopy (Scheme 4b). At different times, we tracked the
conversion from signal A (169 ppm) from the carbonyl carbon
of 2k to signal B (173 ppm) and signal C (171 ppm), which cor-
responded to intermediates I and II after Tf2O activation
(Scheme 3, for more details, see the ESI†), while signal
a All reactions were carried out on 0.2 mmol scale under an Ar atmo-
sphere for 14 h. Isolated yields are given.
Scheme 3 The proposed mechanism.
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Acknowledgements
Financial support was received from the National Natural
Science Foundation of China (NSF21472073, NSF21532001,
NSF21772075). We would like to thank LetPub (http://www.
letpub.com) for providing linguistic assistance during the
preparation of this manuscript.
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Conflicts of interest
There are no conflicts to declare.
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