Base-Mediated Hydroamination of Alkynes - Accounts of Chemical

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Base-Mediated Hydroamination of Alkynes Monika Patel, Rakesh K. Saunthwal, and Akhilesh K. Verma* Department of Chemistry, University of Delhi, Delhi-110007, India CONSPECTUS: Inter- or intramolecular hydroamination reactions are a paradigmatic example of modern sustainable organic chemistry, as they are a catalytic, 100% atom-economical, and waste-free process of fundamental simplicity in which an amine is added to an alkyne substrate. Many enamines are found in many natural and synthetic compounds possessing interesting physiological and biological activities. The development of synthetic protocols for such molecules and their transformation is a persistent research topic in pharmaceutical and organic chemistry. Hydroamination is conspicuously superior to the other accessible methods, such as the imination of ketones or the aminomercuration/demercuration of alkynes, that involve the stoichiometric use of toxic reagents. Additionally, the hydroamination of alkyne substrates has been successfully employed as a key step in synthesizing target molecules through total syntheses containing substituted indoles, pyrroles, imidazoles, and other heterocycles as core moieties. Many research groups have explored inter- or intramolecular hydroamination of alkynes for the synthesis of diversely substituted nitrogen heterocycles using expensive metal catalysts. However, in contrast to metal-catalyzed hydroamination, the basemediated hydroamination of alkynes has not been extensively studied. Various inorganic (such as hydroxides, phosphates, and carbonates) and organic bases have been proven to be valuable reagents for achieving the hydroamination process. This method represents an attractive strategy for the construction of a broad range of nitrogen-containing compounds that prevents the formation of byproducts in the creation of a C−N linkage. The presence of a base is thought to facilitate the attack of nitrogen nucleophiles, such as indoles, pyrroles, and imidazoles, on unsaturated carbon substrates through the activation of the triple bond and thus transforming the electron-rich alkyne into an electrophile. In the past few years, we have been involved in the development of methods for the nucleophilic addition of N-heterocycles onto terminal and internal alkynes using alkali base catalysts to achieve new carbon−nitrogen bond-forming reactions. During our study, we discovered the regioselective preferential nucleophilic addition of N-heterocycles onto the haloarylalkyne over N-arylation of the aryl halide. In this Account, we summarize our latest achievements in regio-, stereo-, and chemoselective hydroamination chemistry of Nnucleophiles with alkynes using a superbasic medium to produce a broad range of highly functionalized vinyl and styryl enamines, which are valuable and versatile synthetic intermediates for the synthesis of bioactive compounds. Interestingly, the stereoselectivity of the addition products (kinetically stable Z and thermodynamically stable E isomers) was found to be dependent upon time. It is worthwhile to note that hydroaminated products formed by the addition reaction can further be utilized for the synthesis of indolo-/pyrrolo[2,1-a]isoquinolines, naphthyridines, and bisindolo/pyrrolo[2,1-a]isoquinolinesvia tandem cyclization. This chemistry is expected to find application in organic synthesis for constructing a diverse variety of fused π-conjugated compounds, enaminones, and C−C coupled products.

1. INTRODUCTION Base-mediated hydroamination reactions have emerged as a powerful tool for the synthesis of enamine-containing heterocyclic compounds due to the intriguing selectivity and exceptional ability to activate π-systems, especially alkynes, toward inter- and intramolecular nucleophilic attack. Hydroamination constitutes a significant challenge due to the repulsion between a nitrogen lone pair and the alkyne π-system, and it is also intricate to control the regioselectivity toward the Markovnikov and antiMarkovnikov products.1Due to the thermodynamic and kinetic constraints, the direct addition of amines to C−C multiple bonds is difficult.2This sort of nucleophilic addition reaction to unsaturated substrates is essential for the assembly of a wide variety of natural products, agrochemicals, pharmaceuticals and key intermediates in a number of industrial processes.3 The hydroamination of alkynes has been documented as both an © 2017 American Chemical Society

intra- and intermolecular reaction proceeding in the presence of various metal salts,4 including lanthanides, transition-metals, and alkaline earth metals; however, a cost-effective strategy remains elusive. The use of late-transition-metals5 as catalysts is thought to facilitate the attack of a nitrogen nucleophile onto the triple bond such that the electron-rich alkyne is transformed into an electrophile; however, employing an expensive metal catalyst limits the efficacy of the reaction. Therefore, base-mediated hydroamination is in high demand. Base-assisted6,7 C−N bond formation has been broadly classified as inorganic and organic base-catalyzed reactions. Among these, alkali base-promoted hydroamination reactions are the most popularly studied, as these bases can easily deprotonate the amines to provide more Received: September 5, 2016 Published: January 27, 2017 240

DOI: 10.1021/acs.accounts.6b00449 Acc. Chem. Res. 2017, 50, 240−254

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Accounts of Chemical Research nucleophilic species, which can readily attack the unsaturated substrate. The direct formation of a new C−N bond is thermodynamically feasible under basic conditions, but there is a high reaction energy barrier, which is usually avoided by employing the use of catalysts.8 The nucleophilic addition of amines to nonactivated alkynes is found to be unfavorable, which might be due to the following thermodynamic and kinetic aspects: (i) the nucleophilic attack of the amine nitrogen, bearing the lone pair, on the electron-rich alkyne leads to electrostatic repulsion; (ii) the large energy difference between π (CC) and σ (N−H) orbitals forbids the thermal addition of the −NH bond onto the alkyne; and (iii) the hydroamination reactions are slightly exothermic or even thermo-neutral. In this regard, the hydroamination9 of alkynes has become an active area of research due to the synthetic interest in the achieved products (enamines or imines) as well as the theoretical studies of their mechanisms. Although the intramolecular version of this transformation is well established, the intermolecular counterpart remains underdeveloped. Thus, most of the methodologies rely on the use of transition-metal-based catalysts. From a synthetic point of view, the stereocontrolled synthesis of enamines with a selective configuration is an interesting challenge. The present report addresses the stereocontrolled intra/intermolecular hydroamination mediated by easily accessible bases. Further elaboration of this working strategy has been successfully demonstrated by the annulation chemistry for the tandem synthesis of indolo- and pyrrolo[2,1-a]isoquinolines via hydroamination. All these reactions readily provide imine and enamine core motifs with assured atom- and step-economy. Pioneering studies in the area of base-assisted C−N bond formation by the Shostakovskii10a and Trofimov10b groups highlighted the nucleophilic addition of amines onto alkynes using potassium hydroxide (Scheme 1A and B). A base-catalyzed hydroamination of alkynes with substituted anilines and heterocyclic amines using cesium hydroxide (CsOH·H2O)has been investigated by Konochel et al. in 1999 (Scheme 1C).11 The research groups of Kondo,12a Mao,12b and Dodd12c employed phosphazene, K3PO4 and tBuONa bases, respectively, for the enamine synthesis (Scheme 1D−F); however, with the limited applications in this area, we focused our attention toward a direct and more practical synthetic method for the selective synthesis of an array of styryl and vinyl enamines.13

Scheme 1. Selected Examples of Base-Mediated Hydroamination of Alkynes

intramolecular cyclization of δ-iminoacetylenes using ammonia as a base for the synthesis of δ-iminoacetylenes (Scheme 2C). A facile route for the synthesis of disubstituted isoxazoles has been developed by the Bao group17 using triethylamine/DMSO as a basic medium (Scheme 2D). Cope-Type Hydroamination

The Beauchemin group18 has established a versatile chemistry of Cope-type hydroamination via a concerted 5-membered cyclic transition state for direct amination using hydroxylamine and hydrazine derivatives (Scheme 2E). In 2013, Bao et al.19 reported the synthesis of 3,5-disubstituted pyrazoles via nucleophilic attack of hydrazine onto 1,3-dialkyne through an allene intermediate, which further undergoes electrophilic cyclization to create a new C−N bond. The theoretical aspects of the mechanism of Cope-type hydroamination have been investigated by Tang et al.2 in 2014 (Scheme 2F).

2. PROGRESS IN BASE-MEDIATED HYDROAMINATION CHEMISTRY For decades, various research groups have made significant progress regarding the synthetic potential offered by inorganic and organic bases for inter- and intramolecular hydroamination. Remarkable strategies have been designed by the following: (a) employing sensitive bases such as BuLi, NH3, and Et3N; (b) Cope-type hydroamination; and (c) intramolecular C−N bond formation (Scheme 2). The efficacy of this reaction has been demonstrated for the diversification of polyheterocycles.

Intramolecular Hydroamination

Intriguingly, intramolecular animation has been explored using NaH,20 KOtBu21 and (dimethyl (oxo)-λ6-sulfanylidene) methane22 bases for the synthesis of isothiazoles, indoles and pyrrolidines, respectively (Scheme 2G−I). The Borhan group has established a tandem aza-Payne pathway followed by a hydroamination reaction via a latent nucleophile. These suggested methodologies for C−N bond formation have developed the interest of organic chemists in the field of hydroamination chemistry.

Organic Bases

Due to the significant application of hydroamination reactions, substantial interest is focused on developing new methodologies that are complementary to the widely used alkali bases, which enable the C−N bond formation. In this area, Suginome et al.14 and Tang et al.15 have made considerable progress by performing BuLi-catalyzed intramolecular hydroamination of conjugated enynes for the synthesis of substituted pyrrolidines (Scheme 2A and B). Subsequently, Abbiati et al.16 have developed the 241


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Accounts of Chemical Research Scheme 2. Hydroamination Strategies

3. INTERMOLECULAR HYDROAMINATION OF ALKYNES

In particular, for the internal alkyne, when an electrondonating group is attached at the para position of the alkyne, it increases the electron density at the distal end (Cp) of the triple bond. The proposed hypothesis was supported by density functional theory calculations that govern the formation of major and minor products (Figure 1B).24 To support our results, we recently proposed a plausible mechanistic pathway based on the superbase system, which revealed that the base abstracts the proton from the DMSO solvent and contributes to the styryl protons in the final product.

We predicted that the nature of the heterocyclic amine and electronic effect of the groups on the C−C triple bond are critical for a ccomplishing the hydroaminated products. The electronic biases and pKa value of the N-heterocyclic moiety play crucial roles in the formation of particularly the Z-isomer, and the prolonged reaction times can induce isomerization to the greater thermodynamically favorable E-product (Figure 1A).23 242


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Accounts of Chemical Research

Scheme 3. Scope of the Reactions of Indoles with Terminal Alkynes

Figure 1. Electronic effect.

thus demonstrating the generality of the designed protocol. The hydroamination of indoles with terminal alkynes, such as 4ethynyltoluene 2a and 4-ethynyl-N,N-dimethylaniline 2b, was successful in providing the addition products 3a,b. Heterocyclic amines with an electron-donating group such as 3-methylindole 1b and 2-methylindole 1c afforded the addition products 3c−i with Z-stereoselectivity in good yields. Furthermore, modification of the indole ring by substituting the -OMe/Br group at the C5-position made no appreciable changes in the reactivities of substrates 1d,e with the alkynes 2b,c and 2h and afforded the corresponding products 3j−m in significant yields. Interesting reactions in the indole ring via Suzuki coupling on 1e fruitfully provided the hydroaminated products 3n−p with terminal alkynes (Scheme 3). With these observations in hand, the reaction of indole(1a) and its derivatives such as 3-methylindole (1b), 2-methylindole (1c), 5-methoxyindole (1d) and 5-bromoindole (1e) with electronically symmetrical internal alkynes 4a−f were applied to the Nu-addition reaction (Scheme 4).13,24 Fortunately, the hydroamination process proceeded with excellent regio- and stereoselectivity when reacted with para-, meta-, ortho-, and heterocyclic-substituted internal alkynes and afforded a single isomer with Z-stereoselectivity. In contrast to the terminal alkyne, the internal alkyne requires a longer reaction time and a stoichiometric amount of base to provide the hydroamination product, probably due to the steric factor, which abandons the attack of the nucleophile at the triple bond site. Pyrrole is a light-sensitive substrate and is readily polymerized; therefore, the hydroamination of aryl acetylenes with pyrroles could be an extensive pathway for the synthesis of pyrrole analogs of enamines, as it exhibits certain advantages, particularly from the ease, safety, and environmental points. Indeed, during the past few decades, besides the Verma group, Trofimov and coworkers26,27 have developed a protocol for the synthesis of vinylic pyrroles with a superbasic system with indiscriminate hydroaminated products using terminal alkynes. Pyrrole (6), which is more nucleophilic, afforded the hydroaminated products 7a−e in a shorter reaction time. Terminal and symmetrical internal alkynes provided the hydroaminated product with Z-selectivity (Scheme 5). In contrast to the symmetrical internal alkynes, unsymmetrical alkynes provided a mixture of stereoisomers. The formation of major and minor products depends upon the electron density along the C(sp)−C(sp) bond of the alkyne. The discrete attack

The mechanism is initiated by the proton abstraction from the Nheterocycle followed by the nucleophilic addition onto the alkyne in an anti-Markovnikov fashion to form an alkenyl anion. Subsequently, deuteration of the alkenyl anion with DOH afforded the hydroaminated product (Figure 2).25

Figure 2. Mechanistic pathway.

Our preliminary investigation revealed that the optimal reaction conditions for the synthesis of diversely substituted Zstyryl enamines was 20 mol % of KOH in DMSO at 120 °C.24 The addition of substituted indoles 1a−g onto terminal alkynes 2a−j provided the corresponding Z-addition products 3a−p in good to excellent yields (Scheme 3). During the course of the reaction, it was noticed that the nature of the heteroarenes and the substituents attached to the aryl group of the triple bond were responsible for the success of the process. The reaction proceeds with a broad range of substituents (including electron-donating and electron-withdrawing groups), both on the N-heterocycles and acetylenes, 243


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There are certain thermodynamic and kinetic aspects that decide the stereochemistry of the hydroaminated products. The configuration of the addition product was established by NOESY studies. NOEs between vinyl-Hx and ortho-hydrogens Ha and Hb of the phenyl groupsareseen, while the contour for interactions between the vinyl-Hx and the hydrogen of the indole Hc was not observed. These two-dimensional studies provided evidence to judge the stereoselectivity in the enamine derivatives (Figure 3).24

Scheme 4. Hydroamination of Indoles with Internal Alkynes

Figure 3. NOESY studies of hydroaminated products.

During our studies, we observed that the formation of the E and Z isomers was dependent upon the reaction time. In Scheme 7, we have demonstrated the selective synthesis of Z-imidazolyl Scheme 7. Stereoselective Synthesis of Z-Imidazolyl Enamines Scheme 5. Synthesis of Stilbene Analogues of Pyrrole

of the N-nucleophile on the electrophilic carbon leads to the synthesis of vinylic heterocycles (Scheme 6).

enamines. Alkyne 2 bearing an electron-rich thiophene ring afforded the kinetically stable Z-addition product 9a in 1.5 h;

Scheme 6. Hydroamination of Unsymmetrical Internal Alkynes

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hydroamination, which contain primary and secondary amine groups. To gain insight into the chemoselective C−N bond forming event, we conducted the reaction of 5-aminoindole (14) with alkynes, which afforded the selective additionproducts 15a−l on the secondary amine without affecting the primary amine group (Scheme 10). Hitherto, the substituents attached on the alkynes have no significant effects on the yields of the products; however, the reaction time influences the stereochemistry. The Zselectivity (15a−h) was obtained by running the reaction for 0.5 h, while an increase in the reaction time to 1 h leads to mixtures of the stereoisomers 15i−l. Internal alkynes 4b,c afforded the addition products 15m,n in average yields using 2.0 equiv of KOH at 120 °C for 20 h. The presence of a free amino group in the enamines could be further utilized for the synthetic elaboration, which increases the synthetic utility of this developed procedure for the structural and biological assessment (Scheme 10).30 We envisioned that the reactivity of 5-aminoindole was increased due to the presence of an electron-rich system (+M effect of −NH2), which facilitates the formation of an addition product on the secondary heterocyclic amine and leaves the primary amine groupintact. We came across another chemoselective substrate tryptamine having a reactive aliphatic − NH2 group. The tryptamine framework is a significant substructure that is present both in natural products as well as remedial agents and has immense applications in biological and pharmaceutical chemistry.31 The intermolecular addition of tryptamine (16) onto electronneutral, electron-rich, electron-deficient, terminal and internal alkynes provided the chemoselective Z-styryl enamines 17a−n in modest to good yields (Scheme 11). It was interesting to note that the primary amine group remains unscathed. The elegant approach of KOH-DMSO has been useful to generate selectivity without incorporating any protecting group. Histamine, which plays a vital role in several immunological activities,32 was intentionally selected for chemoselective hydroamination. Due to the negative inductive effect of the tertiary nitrogen, the nucleophilicity of the histamine is decreased, and hence, it lowers the reactivity. Since the stereochemistry of enamine formation is time reliant, by varying the reaction time, the corresponding Z-addition product 19a was obtained in 2 h, a mixture of E/Z isomers 19b−d was obtained in 3 h, and the Eaddition product 19e was obtained in 4 h. The yields of the enamines containing a histamine nucleus were governed by the substituents present on alkyne groups (−Ph, m-tolyl, m-anisole,

however, after running the reaction for 3 h, the thermodynamically stable E-addition product 10a was obtained (see Scheme 8). Scheme 8. Stereoselective Synthesis of E-imidazolyl Enamines

A notable feature of our protocol was represented by the use of substrate 2 with electronic bias substitutions. Sterically hindered and fused imidazoles 8b−d underwent hydroamination to give the expected Z-styryl imidazoles in satisfactory yields (Scheme 7).28 A similar kind of chemistry has been described by Urabe29 and co-workers for the synthesis of styryl imidazoles using haloacetylenes. After attaining successful stereoselectivity, we endeavored to synthesize E-styrylimidazoles 10a−d by tuning the reaction time to 3 h. The C−N bond formation occurred efficiently in superbasic medium and provided general access to the thermodynamically stable trans-imidazole derivatives (Scheme 8). Substituted imidazoles are well-known for their rapid tautomerization (Scheme 9). Therefore, as a proof of this concept, we set out to devise base-catalyzed hydroamination of 4methyl-imidazole 11, and mixtures of tautomeric addition products were obtained.

4. CHEMOSELECTIVE HYDROAMINATION OF ALKYNES With the accomplishment of stereoselectivity, we made an effort to attain chemoselectivity in the reaction. The inter- and intramolecular hydroamination of primary amines onto alkynes have been well-recognized by using various bases and metal catalysts. Chemoselective substrates, such as 5-aminoindole, tryptamine, and histamine, were deliberately chosen for Scheme 9. Tautomerization in 4-Methylimidazole

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Accounts of Chemical Research Scheme 10. Chemoselective Addition of 5-Aminoindole

Scheme 11. Chemoselective Addition of Tryptamine

p-OCF3, and −CF3), which were used as another addition partner (Scheme 12). To validate our hypothesis of the stereocontrolled addition reaction, we performed the reactions of 5-aminoindole, trypt-

amine, and histamine with 3-ethynyltoluene. The formation of products with geometrically different entities was monitored at various time intervals of 25, 45, and 120 min. We observed that after 25 min, product 15a (only Z isomer) was acquired; however, after 45 min, a mixture of E:Z was obtained in a 40:60 stereoisomeric ratio, and after 2 h, the thermodynamically stable E-isomer was observed (Scheme 13A). Similarly, in another set of reactions, we performed the reaction of tryptamine and histamine; however, these reactions showed conversion at a slower pace (Scheme 13B and C). The intermolecular competition experiments highlighted the reactivity of the nucleophile. The antagonistic effect of N-, S-, and O-nucleophiles suggested that hydroamination is preferred over hydrothiolation and hydrophenoxylation (Scheme 14A).CarbaA).Carbazole would be a fascinating competitor in this case because it has a similar pKa compared to those of indoles, but its tricyclic character could alter its nucleophilicity (Scheme 14B).

Scheme 12. Chemoselective Addition of Histamine

5. REGIOSELECTIVE HYDROAMINATION OF DIALKYNES The remarkably broad scope of our catalytic system was exploited for dialkynes with N-heterocycles to deliver geometrically constrained enamines.The nucleophile has an equal tendency to attack both the alkyne centers; however, the proportionate stoichiometric ratio of the addition partner was responsible for the selectivity in the hydroamination reaction. In 246


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Accounts of Chemical Research Scheme 13. Kinetic and Thermodynamic Aspects of Hydroamination

Scheme 14. Competitive Experiments

addition to standard alkali base, Cs2CO3 proved to be a competent abstractor of the acidic proton in these types of reactions. The Gong group33 has also utilized Cs2CO3 for pyridine synthesis via hydroamination. The three arrays of selectivity including regio-, stereo-, and chemoselectivity were implemented in the reactions of N-heterocycles with 1,3- and 1,4diethynylbenzene providing the desired products 28 and 29 in moderate yields due to the formation of complex mixtures of other isomers (Scheme 15). Complementary to the single hydroamination, double hydroamination was also performed using a diethynylbenzene moiety. Reaction monitoring at incessant intervals of time and increasing the amount of heterocyclic substrate showed that the addition of the imidazole onto the alkyne occurs rapidly, leading to the transformation of the kinetically stable Z-isomer to the thermodynamically stable E-isomer30,followed by attack on another alkyne group present in substrate 26, whereas the

reaction of indole with 1,3-diethynylbenzene when ceased after 25 min yielded the desired cis-product 31 in an adequate yield (Scheme 16). The traditional substrates used for the synthesis of enaminones34 are amines and 1,3-diketones.These chalcones are an important class of biologically active compounds. The present strategy of C−N bond formation proved to be efficient for the synthesis of the corresponding enaminone derivatives by the reaction of heterocyclic amines with alkynones. During the course of the reaction of 1 and alkynone 32, it was observed that at elevated temperatures, an unidentified polar complex was formed. Thus, we performed the reaction by using 0.2 equiv of KOH at 80 °C. It was motivating to find that reaction of heterocycles 1a and 1b with alkynone 1-phenyl-3(trimethylsilyl)prop-2-yn-1-one 32a provided E-isomers 33a and 33b as major products via in situ hydrolysis of TMS within 10 min, while longer reaction times led to the decomposition of the product. The intermolecular addition of heterocycle 1b and 247


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Accounts of Chemical Research Scheme 15. Regioselective Hydroamination of 1,3- and 1,4-Diethynylbenzene

6. PREFERENTIAL NUCLEOPHILIC ADDITION OF N-HETEROCYCLES ONTO HALOARYLALKYNES OVER THE N-ARYLATION OF ARYL HALIDES The discovery of aryl/heteroaryl halides coupling with Nheterocycles and arylamines using metals and ligands is welldocumented in the literature.35 However, when the arylhalide competed with an alkyne, a new observation was the preferential addition of heterocyclic amines to haloalkynes over arylation reactions (Scheme 18).36 As evidence of our observation, we devised the KOH-catalyzed hydroamination of different bromo-substituted alkynes 34a−d under arylation and hydroamination conditions (Scheme 19). It was observed that electron-rich indoles, pyrrole, and electrondeficient imidazole reacted smoothly with ortho, meta, and parasubstituted bromoaryl trimethyl silane alkynes providing the hydroamination (addition product) over N-arylation. It was assumed that the trimethylsilyl group was eliminated in situ in the presence of base, and consequently, it can act as a terminal alkyne, which requires a shorter reaction time. In contrast to the electronically biased internal alkyne, reaction with the indolic nucleophile requires a longer reaction time (10−12 h), rendering the hydroaminated product in an appreciable yield (Scheme 19).36

Scheme 16. Double Hydroamination

1-phenyl-3-p-tolylprop-2-yn-1-one 32b yielded 33c as a mixture of Z and E isomers (Scheme 17). Scheme 17. Synthesis of Enaminones

7. APPLICATION OF HYDROAMINATION Hydroamination-triggered cyclizations have become a significant tool in organic chemistry, and they will probably be used for the proficient synthesis of numerous N-containing heterocyclic scaffolds. Despite the significant achievements already accomplished, we utilized the hydroamination chemistry for the synthesis of indolo and pyrrolo[2,1-a]isoquinolines, naphthyridines, and bisindolo- and pyrrolo[2,1-a]isoquinolines via the intermolecular addition of N-heterocycles onto ortho-haloarylalkynes followed by intramolecular C-2 arylation. The results of our studies on base-mediated regioselective hydroamination and the preferential addition of N-heterocycles 248


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Accounts of Chemical Research Scheme 18. Hydroamination vs N-Arylation

Scheme 19. Scope of the Bromo-Substituted TMS Alkynes

Scheme 20. Hydroamination Productsas Intermediates

onto halo-substituted arylalkynes suggests that the mechanism proceeds via the generation of an enamine intermediate followed by oxidative addition, which leads to the synthesis of fused heterocycles (Scheme 20). In comparison to 3-methylindole, indole afforded the cyclized product 41a in a lower yield due to the presence of a methyl group at the 3-position of indole, which increases the nucleophilicity at the C-2 position of the indole ring system

and facilitates the intramolecular cyclization via formation of a tertiary carbocation, whereas in the case of unsubstituted indole, decomposition occurred, which might be due to proton loss or polymerization. Heterocycles bearing electron-releasing groups, such as 4-ethylphenyl and 4-methoxyphenyl groupsat the 5position of indole, were also found to be suitable for the reaction. Electron-rich pyrrole 6 favored theannulation and afforded the desired products 41m−p in significant yields (Scheme 21). 249


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Accounts of Chemical Research Scheme 21. Tandem Synthesis of Indolo- and Pyrrolo[2,1-a]isoquinolines37

Scheme 22. Synthesis of Indolo- and Pyrrolo[2,1-f ][1,6]naphthyridines

Scheme 23. Synthesis of Bisindolo- and Pyrrolo[2,1-a]isoquinolines38

Naphthyridines are biologically and pharmaceutically important compounds and have always been an area of interest for synthetic chemists and biologists. Thus, we designed a variety of

substitutedindolo/pyrrolo[2,1-f ][1,6]naphthyridines via an enamine intermediate. Electron-rich heterocycles indoles 1 and pyrrole 6 were employed with 3-bromo-2-(arylethynyl)pyridine 250


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Accounts of Chemical Research Scheme 24. Plausible Mechanism

Scheme 25. Synthesis of Fused Heterocycles via Hydroamination

bisindolo[2,1-a]isoquinolines 43, regioisomers of bisindolo[2,1a]quinolines used as single-crystal field effect transistors. An array of bisindolo- and pyrrolo[2,1-a]isoquinolines 43a−f were synthesized by performing the reaction of N-heterocycleswith 2,5-dibromo-dialkyne 40 using a CuI/BtCH2OH catalytic system. Small heterocycles, such as pyrrole (6), afforded the biscyclized products in comparatively better yields with respect

39 to provide the desired naphthyridines 42a−e in satisfactory yields (Scheme 22). Our research group not only restricted our investigation toward the tandem cyclization for the synthesis of indolo, pyrrolo[2,1-a]isoquinolinesandnaphthyridines, we also explored our designed protocol for the double tandem synthesis of 251


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Accounts of Chemical Research Scheme 26. Palladium-Catalyzed Diversification

extraordinary research in current years has improved the synthetic potential of the base-assisted hydroamination methodology. An important synthetic consequence of preferential hydroamination over N-arylation of an ortho-haloaryl alkynes was the formation of indolo- and pyrrolo[2,1-a]isoquinolines, naphthyridines, and bisfused isoquinolines via ring closures of the in situ generated enamine followed by C-2 arylation in the presence of a copper catalyst. Annulations of enamines accomplished a scope of macrocyclic molecules beyond the limits of the conventional hydroamination manifold. On account of the sustainable nature of the direct C−N bond formation, along with increasingly the viable base-assisted intra- and intermolecular hydroamination, this method will be expected to provide further exciting results in this rapidly growing research area.

to indole and 3-methylindole. The reason for the low yields of the desired products 43 is probably due to the extensive site availability for C−N bond formation and the possible formation of a cyclized product (Scheme 23). Detailed mechanistic studies are essential to attain additional insight into the reaction pathways and disclose the nature of the addition steps occurring in tandem cyclization (Scheme 24). The results of the studies on the preferential addition of Nheterocycles onto halo-substituted aryl alkynes suggests that the transformation of the copper-catalyzed tandem synthesis of indolo- and pyrrolo[2,1-a]isoquinolines proceeds via regio- and stereoselective base-promoted hydroamination followed by oxidative addition (C).The copper complex D is formed by the intramolecular C-2 attack of nucleophile 1, which subsequently undergoes deprotonation, resulting in the formation of intermediate E. Reductive elimination of E affords the annulated product and regenerates copper complex A. Thus, our objective was not only to provide an attractive strategy for the synthesis of novel enamines but also a supportive protocol for the synthesis of a diverse library of heterocyclic motifs for medicinal chemists. Similar annulation chemistry has been demonstrated by the Wu and Kambe groups in 2013 for the synthesis of pyrazolo[5,1a]isoquinolines and imidazo/benzimidazo[2,1-a]-isoquinolines, respectively, via an enamine intermediate (Scheme 25).39,40 We believe that this approach to a variety of enamines is relatively functional for the synthesis of highly substituted polyheterocycles, predominantly by transforming the halide group into other substituents. For example, 5m is produced by base-catalyzed hydroamination, and the strategy can be further functionalized by applying palladium-catalyzed Suzuki, Heck and Sonogashira coupling reactions of the corresponding C−C coupled products, respectively (Scheme 26).

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Akhilesh K. Verma: 0000-0001-7626-5003 Notes

The authors declare no competing financial interest. Biographies Monika Patel has submitted her Ph.D. under the supervision of Prof. Akhilesh K. Verma at the University of Delhi. Her research interest was primarily focused on the synthesis of enamines and enaminones using the KOH-DMSO catalytic system. Rakesh K. Saunthwal has submitted his Ph.D. under the guidance of Prof. Akhilesh K. Verma at the University of Delhi. His research interest was mainly focused on the base-mediated synthesis of N-heterocycles.

8. CONCLUSION The KOH/DMSO combination is a robust catalytic system that has witnessed significant progress in achieving stereo-, chemoand regioselective hydroamination reactions. C−N bond linkage was exploited with various N-heterocycles and alkynes, leading to valuable enamines and enaminones in a step-economical fashion. The geometrical constraints of stereoselectivity were resolved by time regulation. An additional valuable asset of this chemistry, which encompasses inter- and intramolecular hydroamination, is that it offers numerous opportunities and many breakthrough discoveries for the construction of polyheterocycles. The

Akhilesh K. Verma received his Ph.D. from the Department of Chemistry, University of Delhi, India in 2000. He carried out his postdoctoral research at the University of Florida with Prof. A. R. Katritzky (January 2000 to December 2002) and Prof. R. C. Larock (June 2007 to August 2008) at Iowa State University. He is also a recipient of the BOYSCAST fellowship from DST, India. Presently he is serving at the Department of Chemistry, University of Delhi as a Professor. His current area of research focuses on heterocyclic synthesis, hydroamination of alkynes, tandem reactions, iodocyclization, C−H activation, and the development of new synthetic methods. 252


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ACKNOWLEDGMENTS A.K.V. is indebted to all of his past co-workers for their significant contributions to this project. We thank DST (SERB), CSIR, and the University of Delhi for their generous financial support at various stages of this project.

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