Synthesis of New Highly Functionalized 1H-Indole-2-carbonitriles via Cross-Coupling Reactions

An approach for the preparation of polysubstituted indole-2-carbonitriles through a cross-coupling reaction of compounds 1-(but-2-ynyl)-1H-indole-2-carbonitriles and 1-benzyl-3-iodo-1H-indole-2-carbonitriles is described. The reactivity of indole derivatives with iodine at position 3 was studied using cross-coupling reactions. The Sonogashira, Suzuki–Miyaura, Stille and Heck cross-couplings afforded a variety of di-, tri- and tetra-substituted indole-2-carbonitriles.


Introduction
Indole skeletons exist as key building blocks in drugs, natural products, pharmaceuticals, alkaloids and agrochemicals and exhibit potent and wide-ranging biological activities [1][2][3][4][5]. The indole scaffold represents probably one of the most important structural subunits for the discovery of new drug candidates [6][7][8][9]. In particular, the derivatives of 2-cyanoindoles gained considerable attention in recent years because of their great importance in biological sciences, and they are also of interest thanks to this nitrile function [10][11][12]. The 2-cyanoindole unit is an example of structural motif building blocks and effective precursors for the synthesis of various indole-fused polycycles [13][14][15][16][17][18][19], substituted 2-cyanoindoles [20][21][22][23][24], addition to nitriles [25,26] and indole heterocycle substitution [27,28]. These compounds exhibit a wide range of biological activities ( Figure 1). They are widely used in medicinal chemistry and pharmacological research as antagonist molecules. For example, adrenergic antagonist A [14] is a drug that inhibits the function of adrenergic receptors. There are also α-adrenoreceptors that are located on vascular smooth muscle. Antagonists reduce or block the signals of agonists. They can be drugs, which are added to the body for therapeutic reasons, or endogenous ligands. Analog D [27] of firefly luciferin is a compound of the class of luciferins, light-emitting chemical compounds. It is found in many species of fireflies (Lampyridae). It is the substrate of luciferase, an enzyme that catalyzes its oxidation into oxyluciferin with concomitant hydrolysis of a molecule of ATP into AMP and PPi accompanied by the emission of a photon of yellow light characteristic of these insects. NMDA receptor antagonists E [25] are a class of drugs that work to antagonize or inhibit the action of the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induce is referred to as dissociative anesthesia. The dopamine D 4 receptor (D 4 R) F [20] plays important roles in cognition, attention and decision making. Novel D 4 R-selective ligands have promise in medication development for neuropsychiatric conditions, including Alzheimer's disease and substance use disorders. Prostaglandin E2 (PGE2)

Synthesis of 1H-Indole-2-carbonitriles
We began our studies with the reaction of thionyl chloride of 1a-d with a catalytic amount of DMF, which gives access to acyl chloride that reacts with a solution of 25% ammonia to give 1H-indole-2-carboxamide derivatives 2a-d in good yields (Scheme 1). The reaction with phosphorus(V) oxychloride on the carboxamide afforded the corresponding 1H-indole-2-carbonitriles derivatives 3a-d in good yields (65-85%), following a modified procedure (see Experimental Section) [28].   Due to their importance, the development of efficient methodologies for the preparation and functionalization of various cyanoindoles has been the subject of intense research efforts. Direct incorporation of the nitrile function to substituted indoles has been accomplished through a variety of methods. These methods involved various sources of a cyano group including: acetonitrile [30], tert-butylisocyanide [31], nitromethane [32], benzyl cyanide [33], Beller's NCTS (N-cyano-N-phenyl-p-toluenesulfonamide) [34] or Zn(CN) 2 [35,36]. Palladium-catalyzed cross-coupling reactions are among the most successful transformations in organic synthesis. Thanks to all research work carried out over the years, a large variety of C-C and C-X bond formations and numerous highly active catalytic combinations are currently available [37][38][39][40][41]. The broad interest of this cross-coupling methodology is thus found in many fields of application [42,43]. Driven by our interest in the preparation of substituted 2-cyanoindoles and in conjunction with our successful previous research on palladium cross-coupling reactions, we explored the reactivity of 3-iodo-indole-2-carbonitrile of the residual iodine. This approach allowed the preparation of novel substituted 2-cyanoindoles in position 3 ( Figure 1). The aim of this work was to synthesize new 1H-indole-2-carbonitrile derivatives, which could also be useful for drug design. Moreover, the substitution in this type of product in position 3 is important for the development of new molecules with biological interests. The reactivity of iodine in this position was studied using some cross-coupling reactions such as Sonogashira, Suzuki-Miyaura, Stille and Heck reactions, which provided a wide variety of molecules. We report the preparation of 3-iodo-2-carbonitrile derivatives as precursors through the use of the C-I bond in coupling reactions to access a molecular diversity ( Figure 1).

Synthesis of 1H-Indole-2-carbonitriles
We began our studies with the reaction of thionyl chloride of 1a-d with a catalytic amount of DMF, which gives access to acyl chloride that reacts with a solution of 25% ammonia to give 1H-indole-2-carboxamide derivatives 2a-d in good yields (Scheme 1). The reaction with phosphorus(V) oxychloride on the carboxamide afforded the corresponding 1H-indole-2-carbonitriles derivatives 3a-d in good yields (65-85%), following a modified procedure (see Experimental Section) [28].

Sonogashira Reaction on the 1-Benzyl-3-iodo-1H-indole-2-carbonitrile Derivatives
Sonogashira cross-coupling was performed using 7a-d as substrates (Scheme 4) [47,48]. The alkynyl substituent in position 3 has been formed with phenylacetylene derivatives, 10 mol% of palladium (II) and 10 mol% of copper iodide. The reaction of 1-benzyl-3iodo-1H-indole-2-carbonitrile with a variety of aromatic alkynes containing both electrondonating and electron-withdrawing substituents was also examined. Thus, compounds 8a-j were obtained in moderate to good yields (69-90%), and this reaction was carried out with various substituents, either in ortho (F, OMe), meta (Me) or para (Et, F, OMe) and also with pyridine derivatives. These products were purified either by crystallization or by chromatography on silica gel. rivatives, 10 mol% of palladium (II) and 10 mol% of copper iodide. The reaction of 1-benzyl-3-iodo-1H-indole-2-carbonitrile with a variety of aromatic alkynes containing both electron-donating and electron-withdrawing substituents was also examined. Thus, compounds 8a-j were obtained in moderate to good yields (69-90%), and this reaction was carried out with various substituents, either in ortho (F, OMe), meta (Me) or para (Et, F, OMe) and also with pyridine derivatives. These products were purified either by crystallization or by chromatography on silica gel. Previously, our group reported on the access to iodo-imidazodipyridines from imidazopyridine-2-carbonitriles promoted by Grignard reagent in the presence of iodine and ZnI2 through a 6-endo-dig cyclization [49]. We wished to extend these results to the indole core. Some additional tests of magnesium ethyl bromide on compound 8b either in diethyl ether or in cyclopentylmethylether (CPME) were made. Changing reaction times and temperatures were carried out. The 6-endo-dig cyclization product was not isolated, and the addition of Grignard reagent on the cyano group provided the corresponding ketone in a very low yield (4%). However, a test with n-BuLi as the organometallic agent yielded the corresponding ketone 8b' with a full conversion rate, and no cyclization product was observed (Scheme 5). Further efforts to studies on the mechanism and synthetic applications for this type of cyclization are underway in our laboratory. Previously, our group reported on the access to iodo-imidazodipyridines from imidazopyridine-2-carbonitriles promoted by Grignard reagent in the presence of iodine and ZnI 2 through a 6-endo-dig cyclization [49]. We wished to extend these results to the indole core. Some additional tests of magnesium ethyl bromide on compound 8b either in diethyl ether or in cyclopentylmethylether (CPME) were made. Changing reaction times and temperatures were carried out. The 6-endo-dig cyclization product was not isolated, and the addition of Grignard reagent on the cyano group provided the corresponding ketone in a very low yield (4%). However, a test with n-BuLi as the organometallic agent yielded the corresponding ketone 8b' with a full conversion rate, and no cyclization product was observed (Scheme 5). Further efforts to studies on the mechanism and synthetic applications for this type of cyclization are underway in our laboratory.

Suzuki Reaction on the 1-Benzyl-3-iodo-1H-indole-2-carbonitrile Derivatives
Suzuki cross-coupling is one of the most efficient methods for the construction of C-C bonds. Although several other methods are available for this purpose, the Suzuki crosscoupling reaction, which produces biaryls, has proven to be the most popular in recent times. The key advantages of this coupling are the commercial availability of diverse boronic acids that are environmentally safer than other organometallic reagents. Another cross-coupling on nitrile compounds was also performed. The Suzuki reaction was carried out herein with a slight excess of boronic acid using NaHCO3 as base and tetrakistriphenylphosphine (10 mol%) as a catalyst in toluene/water mixture as a solvent (Scheme 6) [50][51][52]. Several compounds were synthesized with different ortho-, meta-or para-aryls substituted by electron donor groups (Me, Et, tBu, OMe) or electron-drawing groups (F, Cl) and with naphthalene derivative. Good yields (79-93%) were also obtained when substituted phenyl groups were used in this cross-coupling reaction (9a-p). These products were purified either by crystallization or by chromatography on silica gel.

Suzuki Reaction on the 1-Benzyl-3-iodo-1H-indole-2-carbonitrile Derivatives
Suzuki cross-coupling is one of the most efficient methods for the construction of C-C bonds. Although several other methods are available for this purpose, the Suzuki cross-coupling reaction, which produces biaryls, has proven to be the most popular in recent times. The key advantages of this coupling are the commercial availability of diverse boronic acids that are environmentally safer than other organometallic reagents. Another cross-coupling on nitrile compounds was also performed. The Suzuki reaction was carried out herein with a slight excess of boronic acid using NaHCO 3 as base and tetrakistriphenylphosphine (10 mol%) as a catalyst in toluene/water mixture as a solvent (Scheme 6) [50][51][52]. Several compounds were synthesized with different ortho-, metaor para-aryls substituted by electron donor groups (Me, Et, tBu, OMe) or electron-drawing groups (F, Cl) and with naphthalene derivative. Good yields (79-93%) were also obtained when substituted phenyl groups were used in this cross-coupling reaction (9a-p). These products were purified either by crystallization or by chromatography on silica gel.

Stille Reaction on the 1-Benzyl-3-iodo-1H-indole-2-carbonitrile Derivatives
Stille coupling was performed using an organotin compound and a catalytic amount of dichlorobis(acetonitrile)palladium(II) in DMF at 40°C (Scheme 8) [54,55]. Under these conditions, the coupling with compound 7a was successfully achieved, and two examples of coupling products (11b and 11c) were obtained in low to moderate yields (35-40%). No coupling product with tributyl(vinyl)stannane could be obtained (11a, 0%). Finally, these compounds were purified by column chromatography with a stationary phase composed of 10% powdered anhydrous K2CO3 and silica to remove all traces of organotin impurities [56].

Stille Reaction on the 1-Benzyl-3-iodo-1H-indole-2-carbonitrile Derivatives
Stille coupling was performed using an organotin compound and a catalytic amount of dichlorobis(acetonitrile)palladium(II) in DMF at 40 • C (Scheme 8) [54,55]. Under these conditions, the coupling with compound 7a was successfully achieved, and two examples of coupling products (11b and 11c) were obtained in low to moderate yields (35-40%). No coupling product with tributyl(vinyl)stannane could be obtained (11a, 0%). Finally, these compounds were purified by column chromatography with a stationary phase composed of 10% powdered anhydrous K 2 CO 3 and silica to remove all traces of organotin impurities [56].

Stille Reaction on the 1-Benzyl-3-iodo-1H-indole-2-carbonitrile Derivatives
Stille coupling was performed using an organotin compound and a catalytic amount of dichlorobis(acetonitrile)palladium(II) in DMF at 40°C (Scheme 8) [54,55]. Under these conditions, the coupling with compound 7a was successfully achieved, and two examples of coupling products (11b and 11c) were obtained in low to moderate yields (35-40%). No coupling product with tributyl(vinyl)stannane could be obtained (11a, 0%). Finally, these compounds were purified by column chromatography with a stationary phase composed of 10% powdered anhydrous K2CO3 and silica to remove all traces of organotin impurities [56].

General Information
The reagents were purchased from commercial suppliers and used without further purification. Melting points were determined on Büchi B-540 apparatus and are uncorrected. All solvents were dried following the procedure described by Armarego et Chai [57]. 1 H NMR and 13 C NMR spectra (from supplementary) were recorded on a Bruker Avance 300 MHz at 300 and 75 MHz, respectively. 1 H NMR spectra were recorded in CDCl 3 or referenced the residual CHCl 3 at 7.26 ppm (2.50 ppm for DMSO-d 6 ); 13 C NMR and J-mod spectra were referenced to the central peak of CDCl 3 at 77.0 ppm (39.52 ppm for DMSO-d 6 ). 19 F NMR was recorded at 282 MHz on the same instrument, using the CFCl 3 as internal reference (δ 0.0). Chemical shifts were reported in parts per million (ppm, δ), and coupling constants (J) were given in Hertz (Hz). Abbreviations for signal coupling are as follows: s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; sextuplet; sext, dd, doublet of doublets; dq, doublet of quartets; m, multiplet. High-resolution mass spectra (HRMS) were obtained by the electrospray ionization time-of-flight (ESI) mass spectrometry. Thin-layer chromatography (TLC) was performed on TLC silica gel 60 F 254 . Compounds were visualized under UV light (λ = 254 nm) and/or by immersion in a KMnO 4 solution followed by heating. Products were purified by flash column chromatography on silica gel (0.04-0.063 mm) using various mixtures of EtOAc and petroleum ether (35-60 • C fraction) as eluent. Heating was performed using a magnetic stirrer hotplate and an appropriate-sized heating block. Tributyl(vinyl)stannane was prepared from vinylmagnesium bromide and bis(tributyltin) oxide [58,59]. (E)-1-(Tributylstannyl)-2-(trimethylsilyl)ethene was prepared by hydrostannation of (trimethylsilyl)acetylene [60]. (E)-Tributyl(3-methylbut-1-en-1-yl)stannane was prepared by the method described by Chong [61]. The compound's name follows the IUPAC recommendations.