C HAPTER I
II. A.1. Introduction
C−H Bond functionalization processes have provided a great impetus to modern organic synthesis. Such functionalizations have led to the possibility of molecular diversities through the constructions of either C−C or C−X (X = hetero atoms) bonds via the cleavage of ubiquitous C−H bonds.1 The two strategies usually followed are directing group assisted C−H bond functionalization2 and the cross dehydrogenative coupling (CDC).3 However, in recent times, the cross dehydrogenative coupling (CDC) strategy has had an upsurge because it is step and atom economic. The CDC approach has mostly been applied towards C−C bond forming reactions which are important in creating several significant building blocks.
Tertiary amines possessing alkyl groups are useful precursors for the sp3 C−H bond functionalizations α to the nitrogen atom.3b,3d,3e,3h,4 These functionalizations in most cases have been stimulated by various transition metal salts in combination with organic peroxides through a single electron transfer process.4 However a review of the literature reveal that these functionalizations occurred via an intermolecular attack of various C, N or O nucleophiles at the iminium ion generated in situ. Following these reports, we reasoned that if the nucleophile attacks intramolecularly, they could be useful towards the synthesis of nitrogeneous heterocycles. N,N-Dialkylamines are known to undergo intermolecular cross dehydrogenative coupling (CDC) with terminal alkynes under Cu catalyzed condition producing propargylic amines through nucleophilic attack at the iminium ion generated from N,N-dialkylamines (path-a, Scheme II.A.1.1).5 If the same alkynyl moiety is anchored at the ortho position of the tertiary amine, upon treatment to similar condition it may attack intramolecularly onto the iminium ion generated in situ leading to either a
five membered ring or a six membered ring. A trial reaction pursued to attain the intramolecular coupling of o-alknylated-N,N-dimethyl amine in the presence of a copper catalyst and a radical initiator resulted in the formation of 3-aroylindole via an intramolecular attack of the alkynyl carbon onto the iminium carbon and simultaneous oxidation of the other alkynyl carbon atom to a carbonyl functionality (path-b, Scheme II.A.1.1).
Scheme II.A.1.1. Copper catalyzed oxidative coupling of tertiary amines
II.A.2. Strategies for the synthesis of 3-aroylindoles
Among various nitrogenous heterocyclic scaffolds, the indolyl moiety, particularly the 3-acylindole has immense importance because of its relevance in natural products and pharmaceutical entities.6 Many compounds having 3-acylindole as the core unit are reported to exhibit biological activities such as antidiabetic, anti-inflammatory, anticancer, inhibitor of HIV-1 integrase etc.7 Apart from their bioactive nature they also serve as useful precursors to various other indole based compounds through easy functional group transformations of its carbonyl group.8
A myriad of applications of 3-aroylindoles led to the development of various protocols for their synthesis. Traditional routes to 3-acylindoles include Friedel–Crafts acylations,9 Vilsmeier–Haack acylations,10 and the reactions of indole salts with acyl chlorides.11 Friedel-Crafts acylations require stoichiometric metal salts as Lewis acid promoters and strict exclusion of moisture. Use of stoichiometric amount of Lewis acid makes the
procedure environmentally unfriendly owing to the production of large quantities of salt waste. Vilsmeier-Haack acylations use equivalent amount of hazardous POCl3, and suffer from lack of the amides used as carbonyl sources. The reactions of indole salts with acyl chlorides cannot tolerate the functional group sensitive to strong nucleophiles because Grignard reagents are used in these reactions. These limitations associated with the traditional methods led to the development of various transition metal catalyzed approaches for their synthesis most of which are based on C−H activation strategy.
Transition metal catalyzed methodologies can be broadly categorized in two parts: (i) coupling of preformed indoles with different aroylating sources and (ii) synthesis from non-indole starting materials.
(i) Coupling of preformed indoles with aroylating sources (a) Aniline as aroyl source
Su group developed a convenient and general method for formylation and aroylation of free (N−H) indoles via Ru- or Fe-catalyzed oxidative coupling of indoles with aniline derivatives (Scheme II.A.2.1).12a Formylation of indoles was also reported using N- methylaniline under metal free conditions.12b
Scheme II.A.2.1. Synthesis of 3-aroylindoles using N-benzylanilines as aroyl surrogate
(b) Nitrile as an aroyl source
Nitriles under Pd catalyzed condition form ketimine intermediates through carbopalladation which on subsequent hydrolysis produces aryl ketones. This strategy project nitriles to be a promising aroyl source under Pd catalyzed condition and this methodology has attracted much attention from the Larock group,13 the Lu group,14 and others in recent years.15 Song group developed a highly selective and operationally simple approach to 3-acylindoles following the aforementioned strategy which is applicable to both N-protected and unprotected indoles.16a Two similar Pd-catalyzed protocols have been
reported by Wang group and Sarkar group independently using appropriate ligands and additives (Scheme II.A.2.2).16b,c
Scheme II.A.2.2. Synthesis of 3-aroylindoles using nitriles as aroyl surrogate
(c) 1,3-Diketone as aroyl source
Li and co-workers demonstrated a novel solvent free triflic acid catalyzed synthesis of 3-acylindoles using 1,3-diones as acylating reagents. The reaction advances via C–C bond cleavage of 1,3-diketone accompanied by heterocyclic C–H bond functionalization to form new C–C bonds and is a greener and cheaper alternative route to 3-acylindoles (Scheme II.A.2.3).17
Scheme II.A.2.3. Acid catalyzed C3-aroylation of indoles with 1,3-diones
(d) Carbonylative coupling of indoles
Guan group has recently developed a facile and efficient Pd-catalyzed carbonylation of indoles with CO and aromatic boronic acids for the synthesis of indol-3-yl aryl ketones.
The reaction tolerates a wide range of functional groups and provided 3-aroyl indoles in high yields under mild conditions (Scheme II.A.2.4).18
Scheme II.A.2.4. Synthesis of 3-aroylindoles from arylboronic acids
(e) α-Oxoacid as aroyl source
α-Oxoacids are susceptible to undergo decarboxylation under oxidative conditions for which they are employed as aroyl sources in various transition metal catalyzed ketone synthesis. Wang et al reported a Cu-promoted decarboxylative direct C(3)–H acylation of N-substituted indoles with α-oxocarboxylic acids (Scheme II.A.2.5).19a Two analogous decarboxylative C3-acylation methodologies of free (N–H) indoles with α-oxocarboxylic acids were described by Zhang group and Wang group under Cu/Ag2CO3 and Pd catalyzed conditions respectively.19b,c
Scheme II.A.2.5. Synthesis of 3-aroylindoles from α-oxoacids
(ii) From non-indole starting materials (a) From N-aryl enaminones
Cacchi group reported an efficient copper-catalyzed approach for the construction of multi-substituted 3-aroylindoles utilizing readily available N-aryl enaminone as the starting material (Scheme II.A.2.6).20a An analogous Cu-catalyzed C−C bond forming reaction leading to 3-aroylindoles was developed by the same group starting from N-(2-iodoaryl)- enaminones.20b
Scheme II.A.2.6. Synthesis of 3-aroylindoles from N-aryl enaminones
(b) From o-alkynylated isocyanides and aryl halide
A palladium-catalyzed protocol for the synthesis of 3-acyl-2-arylindole derivatives has been developed by Takemoto et al via a Pd mediated isocyanide insertion followed by
oxypalladation of alkyne.21 Imidoylpalladium generated by isocyanide insertion is thought to be a key intermediate in this reaction (Scheme II.A.2.7).
Scheme II.A.2.7. Synthesis of 3-aroylindoles from o-alkynylisocyanides and aryl iodides
(c)From o-alkynylated-N,N-dialkylamines:
o-Alkynylated-N,N-dialkylamines has been realized to be a promising starting material for the synthesis of 3-aroylindoles through the sp3 C−H functionalization of amines α to nitrogen atom under oxidative conditions. A Pd–Cu co-catalyzed oxidative intramolecular Mannich type reaction for the formation of 3-acylindoles has been reported by Liang group using o-alkynylated-N,N-dialkylamines in which tert-butyl hydroperoxide serve as an oxidant.22a Zhou et al developed a photocatalytic pathway for their synthesis by adopting the same strategy (Scheme II.A.2.8).22b
Scheme II.A.2.8. Synthesis of 3-aroylindoles from o-alkynyl-N,N-dialkylamines