ortho-Halobenzyl Halides as Precursors for the Synthesis of Five- to Nine-Membered Ring Structures Employing Transition Metals as Catalysts

Abstract

This review highlights the multifaceted usefulness of o-halobenzyl halides as pivotal substrates for the construction of five- to nine-membered cyclic structures with the aid of transition metals as catalysts. These privileged entities engage dual active sites, enabling the combination of both intermolecular benzylation and intramolecular arylation strategies that directs the formation of a diverse repository of cyclic structures. The introduction of transition-metal catalysis in cross-coupling transformations sparked a revolution in forging aryl–heteroatom bonds, culminating in the evolution of more potent methodologies for the synthesis of a wide spectrum of valuable compounds. Furthermore, the associated pharmaceutical and biological attributes of these cyclic structures augment their significance in medicinal chemistry research. This review aims to showcase the importance of this synthetic methodology and its far-reaching applications in synthesis.

1 Introduction

2 Synthesis of Five-Membered Rings

3 Synthesis of Six-Membered Rings

4 Synthesis of Seven-Membered Rings

5 Synthesis of Eight- and Nine-Membered Rings

6 Conclusion

Biographical Sketches

Nayyef Al-Jaar (top row, left) received his B.Sc. (1995) from Yarmouk University, Jordan, his M.Sc. (2004) from Al al-Bayt University, Jordan, and his Ph.D. (2013) in organic chemistry from the University of Hohenheim, Germany, under the supervision of Professor Uwe Beifuss. He started his career as an assistant professor of organic chemistry at the Department of Pharmacy, Al-Ahiyya Amman University, Jordan (2013–2018), and then in 2018 he moved to the Department of Chemistry at the Hashemite University, Jordan. His current research interests focus on the development of novel transition-metal-catalyzed synthetic methodologies towards heterocyclic compounds.

Majed Shtaiwi (top row, second left) received his Ph.D. from The University of Queensland, Australia in 2002. In 2008, he joined the Faculty of Pharmacy at Al Zaytoonah Private University, Jordan. From 2010-2015, he worked at King Abdulaziz University, KSA. In 2015, he joined the Hashemite University, Jordan. His research interests are focused on the synthesis of heterocyclic compounds that have biological and pharmacological properties, including anti-AChE (for Alzheimer’s disease), sedative-hypnotic, anticancer, anti-oxidant, anti-inflammatory, antipsychotic, antibacterial, and antifungal.

Basem F. Ali (top row, center) received his Ph.D. from The University of New South Wales, Australia in 1999 under the supervision of Professor Ian Dance. He subsequently joined Al al-Bayt University, Jordan, as a lecturer. Currently, he is a professor of chemistry at the same institute. His research interests are focused on the synthesis, characterization and crystal supramolecularity of inorganic and organic compounds.

Mahmoud Al-Refai (top row, second right) obtained his B.Sc. from Yarmouk University, Jordan, in 1991, followed by his M.Sc. from Al al-Bayt University, Jordan, in 1999. He completed his Ph.D. in organic chemistry in 2008 at Georg-August-Universität Göttingen, Germany, under the supervision of Professor Hartmut Laatsch. In 2009, he joined Al al-Bayt University, Jordan, as an assistant professor of organic chemistry. Currently, he is a professor of chemistry at the same institute. His research focuses on the synthesis of bioactive heterocyclic compounds.

Kamal Kant (top row, right) completed his B.Sc. in 2018 at A.R.S.D College, Delhi University, India, and his M.Sc. in 2020 at Kirorimal College North Campus, Delhi University, India. In February 2021, he began his Ph.D. studies under the supervision of Dr. Chandi C. Malakar at the Department of Chemistry, National Institute of Technology Manipur, India. His research interests involve novel method development using organocatalysis, electrocatalysis and photocatalysis for the synthesis of N-heterocycles.

Ng Shereinai Bliss (bottom row, left) is a first-year postgraduate student at the Department of Chemistry at the National Institute of Technology, Manipur, India. She received her bachelor’s degree in chemistry (Honours) and mathematics (Generic Elective) from Dhanamanjuri University, Imphal, Manipur, India in 2023. She is currently pursuing her research project under Dr. Chandi C. Malakar. She is interested in organic synthesis, organocatalysis and metal catalysis. Upon the completion of her postgraduate studies, she intends to further extend her organic chemistry knowledge and progress towards a career as a researcher.

Mousa Al-Noaimi (bottom row, second left) received his Ph.D. from Carleton University, Canada, in 2004. He subsequently joined the Hashemite University, Jordan, as a lecturer in 2004, and is currently a professor of inorganic chemistry at the same institute. His research interests are focused on nanotechnology, the synthesis and physical characterization of organometallic complexes, the design of complexes with suitable oxidation potentials for oxidizing organic substrates, investigations on the inter-valence charge and electron-transfer processes between two metal centers in di-nuclear complexes and the design of metal complexes that exhibit luminescent properties at room temperature.

Lo’ay A. Al-Momani (bottom row, second right) completed his Ph.D. at Philipps University, Marburg, Germany in 2004, and his postdoctoral studies at Albert-Ludwigs University, Freiburg, Germany in 2005. He received a Fulbright scholarship in 2017 to undertake research at the University of Mississippi (Ole Miss), MS, USA. He was the Chair of the Chemistry Department (2007), the Dean of the Faculty of Science (2013), and the Dean of Academic Research and Higher Education (2020) at Tafila Technical University (TTU), Jordan. He is currently an associate professor at the Hashemite University, Jordan. He is interested in organocatalysis, green heterocyclic synthesis, and peptide chemistry.

Chandi C. Malakar (bottom row, right) obtained his M.Sc. in chemistry from the Indian Institute of Technology Kanpur in 2006. He subsequently completed his Ph.D. in 2011 at the University of Hohenheim, Stuttgart, Germany under the supervision of Professor Uwe Beifuss. After postdoctoral research with Prof. K. A. Tehrani at the University of Antwerp (2011–2012), Prof. Günter Helmchen at Ruprecht-Karls-Universität Heidelberg (2012–2014), Prof. P. S. Mukherjee at the Indian Institute of Science, Bangalore (2015) and industrial experience (2014–2015) as a Senior Principal Scientist at Signalchem Lifesciences Pvt. Ltd., he started his career at the National Institute of Technology Jalandhar as an assistant professor in July 2015. He then moved to the National Institute of Technology Manipur in October 2015, and currently he is an associate professor and Dean of Research & Consultancy. His current research interests are focused on C–H activation, asymmetric synthesis, transition-metal catalysis, electrocatalysis and organocatalysis.

Introduction

2-Halobenzyl halides are considered to be privileged moieties as they contain two reactive sites (the C(sp³)–X and C(sp²)–X bonds). In the first type of transformation, the substrate can undergo several substitution reactions that lead to O-, N-, S- and C-benzylation processes, and in the second strategy, O-, N-, S- and C-arylation reactions proceed in the presence of a transition metal for activation. These intermolecular benzylation and intramolecular arylation protocols direct the synthesis of several useful five-, six-, seven-, eight- and nine-membered rings. In addition, employing transition-metal catalysis to accomplish the cross-coupling reaction leads to the creation of C–A bonds (A = C, N, O, S), which have been routed to more effective synthetic methods for many compounds.[1] Generally, the formation of these bonds involves a nucleophilic aromatic substitution reaction, and is limited to electron-deficient aryl halides and diazotization protocols. Furthermore, the success in this field was dependent on the development of palladium-catalyzed cross-coupling methods, which resulted in synthetic protocols for the generation of aryl–carbon and aryl–heteroatom bonds.[2] The palladium-catalyzed procedures include Heck, Suzuki–Miyaura, Sonogashira, and Hartwig–Buchwald coupling reactions. It should be noted that copper-mediated Ullmann cross-coupling reactions, condensations and Castro–Stevens reactions were usually employed for the generation of C–C and carbon–heteroatom bonds.[3] Five- to eight-membered rings occur in nature in a large variety of natural products that exhibit a wide spectrum of pharmaceutical and biological properties. Representative examples of five- to eight-membered ring structures, which are prepared from 2-halobenzyl halides as starting materials, and that exhibit biological properties, include 4,5-diaryl-1H-pyrazole-3-ol derivatives as potential COX-2 inhibitors,[4] and compounds with anti-inflammatory,[5] antidiabetic,[6] antifungal[7] and anticancer activities.[8]

Synthesis of Five-Membered Rings

Due to the importance of five-membered ring structures,[9] methods for the construction of these moieties have been thoroughly investigated over past decades, and several routes have been elaborated for their efficient preparation. In 2000, Yee and Song described the formation of a range of 2-aryl-2H-indazoles 4. Their developed route relied upon the preparation of N-(o-bromobenzyl)-N-(p-tolyl)hydrazines 3 by the reaction of o-bromobenzyl halides 1 with phenyl hydrazines 2, followed by the intramolecular ring-closing reaction of adducts 3 in the presence of Pd(OAc)₂/dppf/ ^t BuONa (Scheme [1]).[10]

In 2021, Beifuss and co-workers overcame the drawbacks of the necessity of two steps for synthesizing 2H-indazoles, as described by Yee and Song,[10] by performing the reaction in one step. They obtained the desired products in higher yields and prepared a library of 18 examples. A direct domino regioselective preparation of 2-substituted 2H-indazoles 6 was achieved by the reaction of o-bromobenzyl bromides 1 with arylhydrazines 5 in the presence of PdCl₂ as the catalyst, ^t Bu₃PHBF₄ as the ligand, and Cs₂CO₃ as the base in DMSO as the reaction medium at 120 °C in a sealed tube. This innovative tactic is predicated on the intramolecular N-arylation and regioselective intermolecular N-benzylation, which are followed by aerial oxidation (Scheme [2]).[11]

Mechanistically, N-(o-bromobenzyl)-N-(p-tolyl)hydrazine I is formed by the intermolecular N-benzylation of o-bromobenzyl bromide 1 with aryl hydrazine 5. This is the first step in the proposed transformation. Subsequently, palladium adds to the intermediate I via the Buchwald–Hartwig oxidative process, resulting in intermediate II. This intermediate then undergoes intramolecular nucleophilic rearrangement, resulting in intermediate III. Finally, indoles 6 are obtained by reductive elimination of III and oxidation of the resulting intermediate IV with aerial oxygen (Scheme [3]).

Mori and co-workers succeeded in developing a different method for the synthesis of five-membered rings starting from 2-iodobenzyl bromides 1. Excellent yields of 1-(2-iodobenzyl)-1H-imidazoles 8 were obtained via the palladium-catalyzed reaction of imidazole (7) with 2-iodobenzyl bromides 1 in the presence of NaH. These compounds subsequently undergo intramolecular C–H arylation at 100 °C catalyzed by palladium, yielding 5H-imidazo[5,1-a]isoindoles 9 (Scheme [4]).[12]

Another class of five-membered rings that can be synthesized from 2-halobenzyl halides are benzofurans. Starting from syn-1,2-bis(2-bromoaryl)ethane-1,2-diols 11, catalytic quantities of Cu(II) oxinate as the copper source, K₃PO₄ as the base, and KI as the reductant in aqueous acetonitrile were used to produce 4b,9b-dihydrobenzofuro[3,2-b]benzofurans 12, in diastereomerically and enantiomerically pure forms, in yields of up to 90%. The precursor (E)-stilbenes 10, which were prepared from 2-bromobenzyl bromides 1 and LiHMDS, were catalytically dihydroxylated to yield diols 11 in both diastereomerically and enantiomerically pure forms (Scheme [5]).[13]

In 2018, Kang and co-workers established a novel protocol for synthesizing 2-substituted benzofurans 16 from the reaction of 2-halo-2-(phenoxymethyl)benzenes 14 with aldehydes 15 in the presence of ^t BuOK in DMF at 90 ℃. Compounds 14 were prepared from 2-bromobenzyl bromides 1 and alcohols 13 in THF using NaH as the base (Scheme [6]). This protocol involves a reaction with the aldehyde via a cascade radical addition/cyclization sequence, and offers a quick, versatile, and practical access to the medicinally active substituted benzofuran skeleton.[14]

Based on the experimental data, a plausible mechanism was proposed (Scheme [6]). The authors presented both anionic and radical pathways, and through control experiments, they proposed that the reported protocol may involve a radical pathway. Initially, intermediate A was formed by heating the starting substrate 14 in the presence of ^t BuOK and DMF. Subsequently, intermediate B was produced through the reaction between intermediate A and aldehyde 15. However, since intermediate B is not thermodynamically more stable, the reaction is likely reversible and shifts towards regenerating intermediate A. Intermediate B then underwent an intramolecular radical addition reaction, leading to the generation of intermediate C. Due to the greater stability of the allyl radical in intermediate C compared to the alkoxy radical in intermediate B, intermediate C undergoes elimination resulting in the formation of intermediate D, which then releases the final product 16 through an E2-elimination reaction.

Indoles are bicyclic heterocycles that contain a five-membered ring, and exhibit remarkable pharmaceutical properties. In this section, methods for the synthesis of indoles from 2-halobenzyl halides are presented. In 1991, Kozikowski and Ma elaborated the combination of 2-bromobenzyl bromides 1 and indoles 17 in the presence of KOH as a base to obtain the intermediate N-(o-bromobenzyl)indoles 18. Next, the addition of Pd(PPh₃)₄ and KOAc led to the formation of tetracyclic indole derivatives 19 with yields of up to 86% (Scheme [7]).[15]

Barbero and co-workers have looked into several methods for synthesizing indazoles from 2-bromobenzyl bromides 1. In order to generate the indolo[1,2-a]indole structural isomers 23 and isoindolo[2,1-a]indole skeletons 21, they devised a straightforward and effective synthetic method.[16] The primary pathway is based on C-aryl–C and C-aryl–N bond formation processes mediated by copper(I) (Scheme [8]). When indole 20 was heated with polyphosphoric acid (PPA), the 2-bromobenzyl group migrated from the nitrogen to the C2 position of the indole to yield the 2-benzyl product 22. Furthermore, rather than employing expensive palladium, rhodium, or ruthenium complexes as catalysts, the aforementioned arylation procedure is the first documented instance of a copper(I)-catalyzed intramolecular C–H functionalization of an indole.[17]

Laha and colleagues[18] have established a domino synthesis of annulated nitrogen heterocycles 25, as proposed by Ma (1991)[15] and Barbero (2009).[16] This was achieved by reacting 2-bromobenzyl bromides 1 and indoles 24 in the presence of Pd(OAc)₂, PPh₃, and NaH in DMF at 130 °C for 16 hours (Scheme [9]). This procedure has an advantage over the previously published protocols as the intermediate N-(o-bromobenzyl)indoles 20 and molecules 21 do not need to be prepared. Furthermore, a promising method for obtaining a variety of fused nitrogen heterocycles with multiple substitution patterns in good yields is via the palladium-catalyzed domino N-benzylation/C–H arylation of nitrogen heterocycles using 2-bromobenzyl bromides 1.[18]

With regards to the mechanism, it is suggested that the benzylic phosphonium salt I can be produced by nucleophilic attack at the benzylic C–Br link by PPh₃. The benzylic phosphonium group of intermediate I might then be replaced by the nucleophilic indole nitrogen, resulting in the production of N-benzylindole II and the regeneration of the PPh₃ molecule. Intermediate III is then formed by the oxidative addition of Pd⁰ to the aryl halide, which is followed by nucleophilic displacement to create the Pd(II)-aryl complex IV. Finally, a series of reductive elimination steps results in the final product 25 (Scheme [10]).[19]

In 1994, Guzman and co-workers prepared the indole derivatives 28, in two steps with yields ranging from 47–70%, by employing 2-bromobenzyl bromides 1 and pyrroles 26 as starting materials. The oxidative radical cyclization of 1-(2-bromobenzyl)pyrroles 27, which were prepared from 2-bromobenzyl bromides 1 and pyrroles 26, using Bu₃SnH/AIBN in benzene afforded indazoles 28 (Scheme [11]).[20]

Using tandem N-benzylation/C–H arylation reaction sequences, in 2017, Dodonova and Tumkevicius reported a simple synthesis of pyrimido[5′,4′:4,5]pyrrolo[2,1-a]isoindoles 30 from 2,4-diarylpyrrolo[2,3- d]pyrimidines 29 and o-bromobenzyl bromides 1. Palladium-catalyzed tandem N-benzylation and intramolecular C–H arylation reactions were easily carried out on all the substrates, resulting in the delivery of pyrimido[5′,4′:4,5]pyrrolo[2,1-a]isoindoles in 22–85% yields (Scheme [12]). The transformation allowed for the production of fused pyrrolo[2,3-d]pyrimidine derivatives and exhibited good regio- and chemoselectivity.[21]

In 2017, Chen and colleagues demonstrated that the 2,3′-spirobi[indolin]-2-ones 32 were formed by domino nucleophilic benzylation and successive CuBr-catalyzed intramolecular C(sp²)–N cross-coupling reaction sequences between 2-bromobenzyl bromides 1 and 3-aminooxindoles 31, with yields ranging from 47–88% (Scheme [13]). This work offers a new perspective on the synthesis of structurally varied spirocyclic oxindoles using 3-aminooxindoles 31 and 2-bromobenzyl bromides 1 as substrates.[22]

Also in 2017, Oh et al. reported the successful synthesis of spiro[indoline-2,3′-pyrrolidin]-2′-ones 35 via a three-component process that combined the actions of Pd⁰ and Cu(I). The Pd-catalyzed benzylation of α-isocyanolactams 33 with 2-bromobenzyl bromides 1 enabled the efficient creation of α-substituted α-isocyanolactams. This was followed by the in situ Cu-catalyzed addition of amines 34 to the isocyanide moiety, resulting in amidine intermediates. The combined action of Pd/Cu catalysis allowed for the easy intramolecular N-arylation of the amidine intermediates, which in turn facilitated the chiral resolution of the spirocyclic 2-indolines 35 (Scheme [14]).[23]

In 1995, Shim and colleagues found that the heterocyclization of 2-bromobenzyl bromides 1, primary amines 36, and carbon monoxide (CO) in the presence of palladium(0) in DMF at 100 °C was a suitable procedure for the synthesis of N-substituted isoindolin-l-ones 37. The yields of the products were reduced when an electron-withdrawing group, such as Cl, was present on the aromatic ring of the amines 36. It was also investigated whether a longer reaction time increased the yields of the resulting isoindolin-l-ones 37 (Scheme [15]).[24]

Ulven and Hansen presented a similar method for the synthesis of 2-benzylisoindolin-1-ones 39 starting from 2-bromobenzyl bromides 1, benzylamines 38 and (COCl)₂ in the presence of catalytic amounts of Pd(OAc)₂, XantPhos, DMAP and trimethylamine in dioxane at 90 ℃ for 17 hours (Scheme [16]). The advantage of this procedure is the use of oxalyl chloride as the CO source for the carbonylation.[25]

Optaz and Bachon, in 2016, devised an additional protocol for the synthesis of 2,3-disubstituted indole derivatives. Using microwave-assisted copper- or palladium-catalyzed intramolecular cross-coupling reactions, their route relies on the α-alkylation of deprotonated Strecker products 42, which are produced by the reaction of primary amines 40 and aromatic aldehydes 41, with 2-halobenzyl halides 1. These intermediate alkylated aminonitriles 43 can then be cyclized to give 1,2-disubstituted indoles 44 in moderate to excellent yields (Scheme [17]).[26]

A four-step method for producing imidazoisoindol-3-ones 49 from hydantoin (45) and 2-bromobenzyl bromides 1 was devised by Williams and Dandepally in 2009 (Scheme [18]). Hydantoin (45) was converted into the Boc-protected 2-bromobenzyl derivative of hydantoin 46 by first adding the 2-bromobenzyl group by reaction with 2-bromobenzyl bromide 1 and NaH as the base, followed by Boc protection. The resulting crude product was meticulously reduced in ethanol using NaBH₄, and then MsCl and an excess triethylamine were added. This process produced 3-(2-bromobenzyl)-2-oxo-2,3-dihydro-1H-imidazole-1-carboxylates 47. Subsequently, under standard conditions, the N-Boc-moiety on 47 was removed to provide 1-(2-bromobenzyl)-1H-imidazol-2(3H)-one 48. Finally, different imidazoisoindol-3-ones 49 were obtained via the palladium-catalyzed intramolecular C–H insertion process with substituted 2-haloaryl-imidazolin-2-ones 48.[27]

Han and colleagues developed a two-step reaction method in 2013 to create a pathway for the synthesis of 5H-imidazo[2,1-a]isoindoles 52. Beginning with the reaction of 2-bromobenzyl bromides 1 with imidazoles 50, the protocol initially produced 1-(2-bromobenzyl)-1H-imidazoles 51. Next, intramolecular C-arylation in the presence of CuI as the catalyst, 1,10-phenanthroline as the ligand, and K₃PO₄ as the base in DMF/o-xylene at 145 °C produced the 5H-imidazo[2,1-a]isoindoles 55 (Scheme [19]).[28]

Doucet and co-workers have offered a similar technique for synthesizing polycyclic imidazoles 55 over two steps. The process was initiated with the intermolecular benzylation of 2-benzyl bromides 1 with imidazole (53) to afford the 1-(2-bromobenzyl)imidazoles 54, which was followed by regioselective intramolecular cyclization at the C-5 position to produce imidazo[5,1-a]isoindoles 55 by employing 2.0 mol% of PdCl(C₃H₅)(dppb) in the presence of 2 equivalents of KOAc (Scheme [20]).[29]

In 2010, Heo and colleagues developed a practical and effective one-step method to produce pyrazolo[5,1-a]isoindoles 58 via Pd-catalyzed intramolecular C–H bond activation of 1-(2-halobenzyl)pyrazoles 57. Compounds 57 are prepared by reacting 2-bromobenzyl bromides 1 with pyrazoles 56 (Scheme [21]). In order to prevent additional C–H bond activation at the C-3 position of pyrazolo[5,1-a]isoindoles, LiCl must be used in these reactions. This approach has also been applied for the synthesis of pyrazolo[5,1-a]isoquinolines with six-membered rings.[30]

Furthermore, 2-bromobenzyl bromides are very important as a starting materials for the preparation of cyclic compounds. In 1993, Castedo and co-workers synthesized N-(phenylfluorenyl)-2-amino-l-indanones 62 in three steps from 2-bromobenzyl bromides 1 in yields ranging from 67–98% (Scheme [22]). The key step is the halogen–metal exchange enabling cyclization of aryl-substituted o-bromophenylalanine-derived oxazolidinones 61 using n-BuLi followed by in situ intramolecular acylation of the aryllithium intermediates.[31]

Using 2-bromobenzyl bromides 1 as precursors in 2000, Ishibashi and colleagues produced methylenecycloalkanes 66 in three steps. Originally, the aryl radical cyclization onto methylenecycloalkanes happened in a 5-exo fashion, and subsequent exo-cyclization and neophyl rearrangement resulted in the creation of endo-cyclization products 66 (Scheme [23]).[32]

In 1999, Halterman and Zhu reported an effective and novel pathway involving enolate alkylation/Cr(II)/Ni(II)-mediated carbonyl addition to produce 2- and 3-substituted indenes 69 from 2-bromobenzyl bromides 1. In order to create tethered bromoaryl ketones 68, which could be cyclized in the presence of CrCl₂/NiCl₂ to produce disubstituted indenes 69, the technique started with the reaction of 2-bromobenzyl bromides 1 and 3-pentanone (67) (Scheme [24]).[33]

A similar and convenient route has been utilized for the synthesis of methylenecycloalkanes 72 from 2-bromobenzyl bromides 1 in three-stages. Alkylation of the potassium enolate of cycloalkanone 70 using 2-bromobenzyl bromides in THF followed by Wittig olefination produced 2-(2-bromobenzyl)-1-methylenecycloalkanes 71. Next, t-BuLi was used at a low temperature for the cyclization of compounds 71 to give products 72 while adding TMEDA (Scheme [25]). The cyclization of the aryllithium species derived from 2-(o-bromobenzyl)-1-methylenecyclohexanes 71 represents an experimentally appropriate method towards the formation of stereoisomerically pure 4a-substituted cis-hexahydrofluorenes 72 in 60–90% yields.[34]

In 2003, Crow and Halterman reported a three-step protocol for synthesizing chiral annulated indenes 74, 76 and 78. In this process the nopinone 73, verbenone 75 and menthone 77 were transformed into their enolate forms, and then alkylated with 2-bromobenzyl bromides 1, followed by ring closure with CrCl₂/cat. NiCl₂ and dehydration with an acid (Scheme [26]).[35]

A further approach for synthesizing five-membered rings starting from 2-bromobenzyl bromides 1 in two steps was established by Muratake and co-workers. The protocol was initiated with the alkylation of the anions of N-cycloalkylidenecyclohexylamines 79 with 2-bromobenzyl bromides 1 to afford the substrates 80, which was followed by Pd-catalyzed intramolecular cyclization to produce the cyclic compounds 81 (Scheme [27]).[36]

In 2007, Sun and co-workers observed that 2-bromobenzyl bromides 1 reacted with Zn powder to produce the organozinc reagents 82, which was followed by the addition to alkynes 83 in the presence of a nickel catalyst to afford indenes 84 (Scheme [28]). The authors also found that the Ni(PPh₃)₂I₂-catalyzed carboannulation of 2-bromobenzyl zinc bromides with alkynes could be expanded to acrylate and styrene derivatives.[37]

Using catalytic amounts of Pd(PPh₃)₄ in the presence of Cs₂CO₃ and water in THF at 60 °C, in 2009, Shimizu and colleagues showed that 2-bromobenzyl bromides 1 reacted with (Z)-1,2-bis(pinacolatoboryl)stilbenes 85 to deliver 2,3-diphenylindenes 86 with yields of up to 88% (Scheme [29]). These reactions of vicinal diborylalkenes and -arenes with vicinal-bromo(bromomethyl)arenes via a Pd-catalyzed double cross-coupling process represent an effective and simple method for synthesizing (hetero)arene-fused cyclopentadienes.[38]

In 2011, Buchwald and co-workers described the reaction of 2-bromobenzyl bromides 1 with anisole derivatives 87. The obtained 4-(2-bromophenethyl)phenols 88 were exposed to arylative dearomatization to give 2′,3′-dihydrospiro[cyclohexa[2,5]diene-1,1′-inden]-4-ones 89 using a palladium catalyst (Scheme [30]). Initial data showed that the production of the spirocyclic quaternary carbon center could be achieved with high levels of enantiocontrol (up to 91% ee).[39]

In 2016, Song and colleagues demonstrated a straightforward synthesis of fluorenes 91 from 2-halobenzyl bromides 1 and substituted boric acid derivatives 90 (Scheme [31]). The reaction was performed in THF using K₃PO₄/PivOH as the base, LiCl as an additive and palladium as the catalyst at 120 °C for 12 hours. Moreover, this novel route could be used to obtain several fluorene derivatives 91 in moderate to good yields. The selectivity of substituted fluorenes 91 was studied by varying the halogen substituent on the 2-halobenzyl bromide 1 substrate, which reacts with the arylboronic acid.[40]

Regarding the likely reaction mechanism, it is suggested that the aromatic C–Br of 2-bromobenzyl bromide 1 underwent a cross-coupling reaction with arylboronic acid 90 in the first stage, resulting in the formation of intermediates I and II. This is then followed by the oxidative addition of Pd⁰ to the benzylic C–Br bond to form intermediate III. In order to produce the desired product, 2-substituted fluorenes 91, the intermediate III must lastly go through a cyclization reaction via a C–H activation process (Scheme [32], route A). It is suggested that the oxidative insertion of the benzylic C–Br bond into the Pd⁰ center is the initial step when using 2-chlorobenzyl bromides. This produces an intermediate I′ that can couple with the arylboronic acid 90 and eventually delivers the 3-substituted fluorenes 92 (Scheme [32], route B).

In 2022, Wang and co-workers developed a novel and essentially chemo- and regioselective route for the preparation of 3-(2,3-dihydro-1H-inden-1-yl)-N-(quinolin-8-yl)propenamides 94 by the reaction of 2-bromobenzyl chlorides 1 with unactivated alkenes 93 in NMP at 40 ℃ in 12 hours (Scheme [33]). Moreover, this protocol highlights is important for the synthesis of bioactive indane compounds.[41]

Synthesis of Six-Membered Rings

Owing to the significance of six-membered ring structures, numerous attempts have been made in recent decades towards their synthesis, and various strategies have been employed for the effective manufacture of these compounds.[42`] [b] [c] [d] [e] In this section, synthetic strategies for the generation of six-membered-ring-containing molecules starting from 2-halobenzyl halides under the influence of transition metals as catalysts are discussed. Chromenes are important six-membered heterocycles that exhibit remarkable biological activities.[42f–j] In 2000, Bowman and co-workers reported a novel route for the preparation of 1-methoxy-6H-benzo[c]chromenes 97 and 3-methoxy-6H-benzo[c]chromenes 98 via the Bu₃SnH-mediated cyclization of 1-iodo- and 1-bromo-2-(3-methoxyphenyloxymethyl)benzenes 96 through rearrangement of an intermediate spirodienyl radical. The 1-iodo- and 1-bromo-2-(3-methoxyphenyloxymethyl)benzenes 96 were prepared from the reaction of alcohol 95 and 2-halobenzyl bromides 1 using NaH as the base in THF (Scheme [34]).[43]

An analogous approach was also found to be suitable for the preparation of 6H-benzo[c]chromenes 101 in two steps starting from 2-halobenzyl bromides 1, as presented by Fagnou and co-workers.[44] It was found that the reaction between 2-bromobenzyl halides 1 and phenols 99 gave the intermediate 1-halo-2-phenoxymethylbenzenes 100. Subsequently, palladium hydroxide on carbon (Pearlman’s catalyst) efficiently catalyzes the intramolecular cyclization of 1-halo-2-phenoxymethylbenzenes 100 to afford the target products 101 (Scheme [35]). The nature of the active homogenous palladium species that is generated under the reaction conditions is compatible with this technique.[44]

An alternative transformation for the synthesis of benzofurans 104 and 105 was established by Daugulis and Bajracharya. Accordingly, the transformation was performed under metal-free reaction conditions using the t-BuOK-mediated intermolecular benzylation of phenols 102 with 2-halobenzyl halides 1 for the formation of 3-(2-halobenzyloxy)phenols 103, which underwent intramolecular cyclization to afford the 6H-benzo[c]chromenes 104 and 105 (Scheme [36]).[45]

Similar to the work reported by Fagnou in 2005[44] and Daugulis in 2008,[45] Kouznetsov and co-workers,[46] in 2017, established another procedure for the synthesis of benzofurans 108 in yields ranging from 56–96%. This two-step procedure started from the reaction of 2-bromobenzyl halides 1 and phenols 106 for the synthesis of the intermediate aryl benzyl ethers 107, followed by the intramolecular cyclization to afford products 108 via metal-free and palladium-catalysed synthesis of benzochromenes 108 (Scheme [37]). This straightforward arylation reaction was preferred as the most effective methodology to synthesize a library consisting of 17 novel benzo[c]chromenes 108, whilst resolving the main shortcomings of the existing procedures, which include the need for ligands and additives, sensitive, costly, and complicated catalysts, as well as the unselective synthesis of benzofuran derivatives.[46]

In 2007, Majumdar et al. reported a palladium(0)-catalyzed regioselective synthesis of substituted coumarin-annulated heterocycles. The reactions of 2-bromobenzyl halides 1 with hydroxycoumarins 109 gave aryl ethers 110, which underwent subsequent regioselective palladium(0)-catalyzed intramolecular annulation to give the corresponding coumarin-annulated products 111 in good to excellent yields (Scheme [38]).[47]

Majumdar and colleagues have also detailed a similar process for the synthesis of coumarins 114. Their method is based on the synthesis of 4-[(2-bromobenzyl)oxy]-6-methyl-2H-pyran-2-ones 113 via the reaction of 2-bromobenzyl halides 1 and 4-hydroxypyrones 112, which is then followed by the Pd-catalyzed intramolecular cyclization to produce coumarin derivatives 114. By using this technique, n-Bu₃SnH is not used as a radical initiator. Furthermore, the halogen-reduced acyclic products 115 were the primary result of the aryl-radical-mediated cyclization of precursors 113 (Scheme [39]).[48]

A similar strategy was established by Nolan et al. in 2014 for the preparation of pyrone derivatives 118. Their route relied upon the reaction of 2-bromobenzyl bromides 1 with 4-hydroxypyrones 116 for the preparation of compounds 117, followed by Pd(OAc)₂-catalyzed C–H functionalization to afford the coumarin derivatives 118 (Scheme [40]). They were able to create six-membered heterocyclic molecules containing oxygen, sulfur, or a sulfone by effectively extending the radical cyclization mediated by Bu₃SnH.[49]

In 2008, Islam and Majumdar reported the use of 2-bromobenzyl bromides 1 and 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one (119) in refluxing acetone in the presence of anhydrous potassium carbonate for the synthesis of 4-(2′-bromobenzyloxy)-1-phenyl-1,8-naphthyridin-2(1H)-ones 120. A subsequent regioselective Bu₃SnH/AIBN-mediated radical cyclization strategy then afforded the 1,8-naphthyridinone-annulated oxygen heterocycles 121 (Scheme [41]).[50]

Basu and co-workers have established a regioselective synthesis of spiro-quinolones and spiro-coumarin derivatives 124 via aryl radical cyclization of 3-(2′-bromobenzyloxy)benzopyran-7-ones 123 in the presence of n-Bu₃SnCl/Na(CN)BH₃-AIBN. 2-Bromobenzyl bromides 1 and 3-hydroxy-2H-chromen-2-one or 3-hydroxyquinolin-2(1H)-ones 122 reacted to form compounds 123 in the presence of anhydrous potassium carbonate acting as a base (Scheme [42]).[51]

A broad and effective synthesis of isochromans 127 via diastereoselective Pd⁰-catalyzed carboiodination of alkenyl ethers 126 has been demonstrated. The alkenyl ethers 126 were synthesized by the reaction of 2-halobenzyl iodides 1 with allylic alcohols 125 (Scheme [43]). These transformations afford generally good to excellent yields of the products with high diastereoselectivities and display broad functional group compatibility.[52]

A different procedure that uses the reaction of 2-halobenzyl bromides 1 with ethyl malonate (128) to create chroman derivatives 130 has been reported. With good yields and high enantiomeric selectivity, the intramolecular asymmetric aryl C–O coupling reactions of 2-(2-haloaryl)propane-1,3-diols 129 resulted in the enantioselective synthesis of chiral (3,4-dihydro-2H-chromen-3-yl)methanols 130 (Scheme [44]).[53]

An additional approach for the preparation of N-, O- and S-heterocyclic six-membered scaffolds 133 starting from 2-bromobenzyl bromides 1 and pyrazoles 131 was achieved by Lindsley and co-workers. Their method relies on the fast, universal and high-yielding synthesis of the tricyclic core via a Pd-catalyzed, microwave-assisted C–H heteroarylation process (Scheme [45]). This novel protocol demonstrates complete regioselectivity, and using this strategy, numerous previously unknown heterotricyclic and heterotetracyclic ring structures were generated in high yields.[54]

Using a palladium catalyst, PPh₃ as a ligand, and K₂CO₃ as a base in DMF at 120 °C, Opsenica and colleagues recently reported a one-pot, two-step synthesis of isochromene-fused CF₃-substituted pyrazoles 135 from the reaction of 2-bromobenzyl bromides 1 and pyrazolones 134 (Scheme [46]). A fused tricycle is produced by the direct C–H arylation of CF₃-substituted pyrazolones, which is followed by Pd catalysis.[55]

Another route to synthesize coumarin derivatives begins with 1,3-dicarbonyls 136 and 2-halobenzyl halides 1. The synthesis of α-(2-bromobenzyl)-β-keto esters 137 or δ-(2-bromophenyl)-β-keto esters 138 is dependent on the reactions of 2-bromobenzyl bromides 1 and 1,3-dicarbonyl compounds 136. This is followed by CuI-catalyzed intramolecular O-arylation of esters 137 at reflux in THF to give 4H-1-benzopyrans 139 in high yields, or the C-arylation of esters 138 to afford the 3,4-dihydronaphthalen-2(1H)-ones 140 (Scheme [47]). Thus, chemoselective O- or C-arylation can be accomplished effectively by using the appropriate substrates.[56]

In 2008, Majumdar and co-workers expanded the scope of the synthesis of chroman derivatives 143 from 2-bromobenzyl bromides 1 and phenols 141 to afford ethers 142, which were then cyclized via a Pd-catalyzed Heck reaction. This protocol showcased the ligand-free Heck coupling reaction of unactivated phenyl aryl ethers for synthesizing bis- and tris-heterocyclic compounds (Scheme [48]).[57]

Beginning with 2-bromobenzyl bromides 1 and β-ketoesters 144, in 2011, Beifuss and colleagues devised an effective domino Cu(I)-catalyzed procedure for the selective synthesis of 4H-chromenes 145 and naphthalenes 146. The ratio of the substrates and the reaction conditions determines which of the two compounds, 4H-chromenes 145 or naphthalenes 146, are synthesized. The 4H-chromenes 145 were produced via the reaction of 1.0 mmol of 1 and 2.0 mmol of 144 in the presence of 20 mol% of CuI and 4.0 mmol of K₃PO₄ in DMF or DMA at 110 °C over 24 hours in a sealed tube. However, when 0.5 mmol of 1 and 1.5 mmol of 144 under the influence of 10 mol% of CuI, 4.0 mmol of Cs₂CO₃ and 30 mol% of 2-picolinic acid in NMP were employed at 100 ℃ over 24 hours in sealed tube, the reaction afforded the naphthalenes 146 (Scheme [49]).[58]

A plausible mechanism for the synthesis of naphthalenes 146 starts with C-benzylation and then C-arylation with two different ester functionalities to give intermediate II. This is followed by 1,2-addition to afford intermediate III, which undergoes rearrangement to produce intermediate IV. Finally, 1,2 addition and aromatization gives the target compounds 146 (Scheme [50]).[58]

In 2012, Zhang and co-workers elaborated the one-pot synthesis of 4H-chromenes 148 from the reaction of 2-bromobenzyl bromides 1 and 1,3-carbonyl compounds 147 using CuI as the catalyst. The appropriate selection of solvent and base was critical to the success of this domino process. This novel approach to 4H-chromenes 148 creates chemical complexity from easily accessible starting materials by combining multiple processes in a single pot (Scheme [51]).[59]

A potent protocol for the synthesis of 4H-chromenes 150 was developed in 2012 by Beifuss and colleagues. It involves two steps: the synthesis of 2-[(2-bromophenyl)methyl]-3-hydroxy-2-cyclohexen-1-ones 149 through the reaction of 2-bromobenzyl bromides 1 and 1,3-dicarbonyl compounds 147, and the intramolecular cyclization of 149 catalyzed by Cu (Scheme [52]). A useful substitute for the domino approach is the two-step synthesis of 4H-chromenes 150, since it does not result in the creation of any side products. Under simple circumstances, 2-bromobenzyl bromides 1 and 1,3-diones 147 might react to selectively produce the necessary C-benzylated 1,3-diones 149, with yields ranging from 45–83%.[60]

In 2015, Wan et al. reported the reaction of 2-bromobenzyl bromides 1 with 1,3-dicarbonyl compounds 147 using CuO/oxalohydrazide and TBAB to obtain 4H-chromenes 151 in one pot (Scheme [53]). The reaction proceeds through a tandem C-benzylation and intramolecular O-arylation process for the sequential one-pot formation of functionalized 4H-chromenes 151. One-pot reaction conditions and the use of water as the solvent offer benefits for the synthesis of related O-heterocycles and 4H-chromenes.[61]

In 2002, Barluenga and co-workers established a two-step protocol to obtain 6H-dibenzo[b,d]pyrans or 6H-dibenzo[b,d]thiopyrans 154 starting from 2-bromobenzyl bromides 1 in yields ranging from 56–81% (Scheme [54]). The developed approach involved the reaction of 2-bromobenzyl bromides 1 and phenols or thiophenols 152, with subsequent addition of n-BuLi and suitable electrophiles affording the desired compounds 154.[62]

Majumdar and co-workers reported a strategy for the formation of quinolone-annulated sulfur heterocycles 158 in 2005. Their synthetic route relied on phase-transfer catalysis for the formation of sulfides 157 from the reaction of 2-bromobenzyl bromides 1 and 4-mercaptoquinolones 155 followed by n-Bu₃SnH/AIBN-mediated ring closure of sulfides 157 to afford quinolone-annulated sulfur heterocycles 158 regioselectively (Scheme [55]).[63]

In 2007, Majumdar and co-workers disclosed a novel route for the regioselective formation of benzofuran-annulated six-membered sulfur heterocycles 161 via the reaction of 3(2H)-benzothiofuranone (159) and 2-bromobenzyl bromides 1 to afford the sulfides 160, followed by cyclization after the addition of n-Bu₃SnH and AIBN (Scheme [56]). The radical cyclization of several sulfides under mild and neutral conditions was also explored.[64]

An approach to sulfur heterocycles has been described based on the cyclization of sulfides 165 to afford isothiochromans 166 using Stille or Suzuki–Miyaura cross-coupling reactions. The sulfides 165 were prepared from 2-bromobenzyl bromides 1 and potassium ethanethioate (162) via a two-step procedure (Scheme [57]).[65]

Among six-membered N-heterocycles, quinolones and isoquinolines are very important biologically active scaffolds that are abundant in natural products and pharmaceutical compounds.[66] In 2008, Majumdar et al. established a novel method for the preparation of quinolones 169 starting from 2-bromobenzyl bromides 1 and 6-(N-methylamino)coumarins or 6-(N-methylamino)quinolones 167 to give the precursor compounds 168, which were cyclized using a Heck coupling reaction. For the regioselective synthesis of quinolone-annulated linearly fused six-membered heterocyclic compounds, it was discovered that the intramolecular Heck coupling reaction was an efficient an simple method compared to intramolecular aryl radical cyclization (Scheme [58]).[67]

A novel method for synthesizing 3,4-dihydroquiolines-2-ones 170 and 12H-chromeno[2,3-b]quinolin-12-ones 171 was presented by Fan and colleagues in 2013. The process begins with the reaction between 2-bromobenzyl bromides 1 and cyanoacetamide. Their method relies on the N- and O-arylation of the acetamide by copper-catalyzed processes employing easily accessible 2-bromobenzyl bromides 1 (Scheme [59]).[68] The excellent efficiency, easily accessible starting materials, and simple reaction conditions make this process superior to alternative approaches.

According to a recent study by Fu et al., employing a copper catalyst and a superbase, 3-benzyl-1-methylindolin-2-imine hydrochlorides 172 and 2-iodobenzyl bromides 1 react to produce 6H-indolo[2,3-b]quinolines 173 (Scheme [60]). The main reasons behind the cleavage of the carbon–carbon single bond were the superbase produced by sodium tert-butoxide and dimethyl sulfoxide, as well as the intrinsic drive towards aromatization. Moreover, the N-heterocycles obtained are derivatives of indoloquinolines that exhibit a wide range of biological activity.[69]

A general and efficient synthesis of pyrimidino[3,2-c]tetrahydroisoquinolin-2,4-diones 176 was reported using 2-bromobenzyl bromides 1 and 1,3-dialkyl-5-N-methylaminopyrimidine-2,4-diones 174. The transformation was executed by the reaction of compounds 1 with 174 to give amines 175, and then, under the influence of Bu₃SnCl and AIBN, radical-mediated cyclization of compounds 175 gave the final products 176 (Scheme [61]).[70]

Another route for the synthesis of isoquinoline derivatives starting from 2-bromobenzyl bromides 1 was introduced by Sanz and co-workers. The combination of 2-bromobenzyl bromides 1 and indole (177) afforded the 1-(2-bromobenzyl)-1H-indoles 178, which, via subsequent addition of n-BuLi and a carboxylic ester, produced the indolo[1,2-b]isoquinoline derivatives 179 (Scheme [62]).[71]

In 2009, Alper and Chouhan reported that the Pd-catalyzed one-pot, three-component synthesis of pyrazoloisoquinolinones 182 could be accomplished by the reaction between benzenesulfonylmethyl-2-bromobenzenes 180, pyrazolidinones 181 and carbon monoxide in the presence of Cs₂CO₃ and a ligand in THF as the solvent at 80 ℃ in 4 hours (Scheme [63]). The benzenesulfonylmethyl-2-bromobenzenes 180 were prepared from 2-bromobenzyl bromides 1 and NaSO₂Ph in DMF at 80 ℃ over 2 hours. A variety of ring-fused pyrazoloisoquinolinones 182 were achieved from a series of active methylene compounds. Additionally, the developed strategy may find wide applications in pharmaceutical and medicinal chemistry research.[72]

Chen and colleagues described an effective nucleophilic substitution/C–H activation/aromatization cascade reaction in 2015. The reaction was catalyzed by Pd. In this transformation, 2-bromobenzyl bromides 1 and N-phenylmethanesulfonamides 183 were reacted in DMF at 160 °C for 24 to 48 hours with a Pd catalyst, a PPh₃ ligand, and Cs₂CO₃ as the base to produce phenanthridines 184 (Scheme [64]). A range of phenanthridines, exhibiting yields spanning from 31% to 85%, were synthesized. The careful synthesis of the naturally occurring alkaloid trisphaeridine further supported the utility of this protocol.[73]

The proposed reaction pathway indicates that the first step is the base-promoted N-benzylation of 2-bromobenzyl bromides 1 with N-phenylmethanesulfonamides 183 for the synthesis of the intermediate I. Next, oxidative addition of intermediate I to an in situ generated Pd⁰ species and subsequent intramolecular C–H activation forms the intermediate compound III, which, via reductive elimination, forms the intermediate IV. Finally, the fused heterocycles 184 are formed through an aromatization process (Scheme [65]).

In 2015, Xu and co-workers contributed a protocol for the formation of nitrogen-containing heterocyclic products 187–189 in good yields through the palladium-catalyzed intramolecular Heck coupling reaction of N-vinylacetamides 186, which were prepared from 2-bromobenzyl bromides 1 and vinylacetamides 185. The choice of ligand and base for the reaction determines the nature of the N-heterocyclic product (Scheme [66]). Tandem reactions are shown to be responsible for the selective synthesis of the products by sequential β-N-Pd elimination, 1,4-Pd migration, and acyl C–H bond functionalization.[74]

In 2017, Huo and co-workers reported the reaction of 2-bromobenzyl bromides 1 and 1-phenyl-1-propynes 190 using n-BuLi and HgCl₂ for the synthesis of 2-(4-phenylbut-3-ynyl)benzaldehyde oximes 191. This was followed by Pd(PPh₃)₂/PhCOOH-catalyzed intramolecular cyclization of oximes 191 to afford 3,4-dihydroisoquinoline N-oxides 192 (Scheme [67]). This study describes a new and valuable protocol for the construction of C–N bonds in the realm of organic synthesis.[75]

Chen and colleagues successfully synthesized spiro[oxindole-3,5′-pyrrolo[2,1-a]isoquinolines] 194 in 2017 by reacting 2-bromobenzyl bromides 1 and 3-pyrrolyl-2-oxindoles 193 in DMF at 140 °C for 48 hours with Pd acting as a catalyst, PPh₃ acting as a ligand, and sodium carbonate acting as a base (Scheme [68]). A variety of spiro[oxindole-3,5′-pyrrolo[2,1-a]isoquinolines] 194 were produced with yields as high as 92% using this approach.[76]

Mohan and co-workers developed a method for the synthesis of isoquinolines 196 in 2018. Their pathway is based on the N-benzylation/intramolecular coupling reactions of easily synthesized 4-quinolones 195 with commercially accessible 2-bromobenzyl bromide derivatives 1 (Scheme [69]), which are catalyzed by palladium. Moderate to good yields of the desired isoquinolines 196 were obtained and numerous functional groups were tolerated during the reactions.[77]

Further progress using 2-bromobenzyl bromides 1 as precursors for the construction of isoquinolines 202 was achieved by Ogoshi and co-workers in 2020. They conducted the reaction between 2-bromobenzyl bromides 1 and 1-heptyne (197) using n-BuLi in THF for the synthesis of 1-bromo-2-(oct-2-yn-1-yl)benzenes 198. Next, the addition of Mg in THF followed by DMF to compounds 198 provided alkynes 199. Subsequent addition of TsNH₂ (200) to compounds 199 afforded the tosylates 201, which under the influence of 20 mol% of quinuclidine in THF at 80 ℃ for 30 hours produced the isoquinoline derivatives 202 in high yields (Scheme [70]).[78]

Furthermore, Laha and colleagues have developed a potent approach for the production of dihydrophenanthridines 204 in moderate to good yields via the palladium-catalyzed tandem N-benzylation/intramolecular direct arylation between sulfonanilides 203 and 2-bromobenzyl bromides 1 (Scheme [71]). Moreover, it was also found that the analyzed reaction conditions were beneficial for the multistep literature-guided synthesis of 6,7-dihydro-5H-dibenzo[c,e]azepines 206.[79]

In 2012, Bisai and co-workers introduced a practical metal-free protocol for the formation of oxoassoanine using t-BuOK. The strategy was executed via the reaction between 2-bromobenzyl bromides 1 and isatin (207) to deliver the N-(6-bromo)benzyl-2-oxindoles 208, which was followed by t-BuOK-promoted intramolecular O-arylation to afford oxoassoanine (209a) and its derivative 209b in high yields (Scheme [72]).[80]

Quinazolines are another significant class of heterocyclic chemicals that can be synthesized from 2-halobenzyl halides. Using CuI as the catalyst, Cs₂CO₃ as the base, and l-proline as the ligand in THF at 85 °C for 6 hours, in 2011, Mondal and colleagues developed an effective approach for the synthesis of quinazolines 211 from reactions between 2-bromobenzyl bromides 1 and 2-aminopyridines 210 (Scheme [73]). The process produces the quinazolinone scaffolds 211 by nucleophilic aromatic substitution of the N-heteroaromatic cationic intermediate and subsequent in situ aerial oxidation at the benzylic site.[81]

In 2012, Beifuss and colleagues developed a simple procedure for the synthesis of quinazolines 213 from the reaction of benzamidines 212 and 2-bromobenzyl bromides 1 with Cu(I) acting as a catalyst (Scheme [74]). Using water as the solvent and mild reaction conditions, this unique Cu₂O-catalyzed process has guided the production of the target compounds selectively and with yields as high as 85%.[82]

Zhang and colleagues have reported a general and effective synthesis of quinazolines 216 and 1,2,3,4-tetrahydroquinazolines 218 starting from 2-bromobenzyl bromides 1, aldehydes 214 and aqueous ammonia 215 or amines 217 under the influence of a catalytic quantity of Cu(OAc)₂ and DMAP in DMSO at 80 °C (Scheme [75]).[83] This method is similar to that proposed by Beifuss and colleagues in 2012.[82] It should be mentioned that the quinazolines 216 were obtained when they employed aqueous ammonia 215 and that the 1,2,3,4-tetrahydroquinazolines 218 were the only products produced when they used aqueous amines 217. This technique has advantages over other protocols as it uses easily obtained starting materials, exhibits strong functional group tolerance, and produces the final products with a range of structural types.[83]

Starting from 2-bromobenzyl bromides 1, Perumal and Kiruthika have described a straightforward two-step technique for the synthesis of indolo[1,2-a]quinazolines 221, with good to exceptional yields. It was discovered that N-(2-bromobenzyl)-4-methylbenzenesulfonamides 219 were produced by the reaction of 2-bromobenzyl bromides 1 with aqueous ammonia and tosyl chloride. This was followed by a reaction with N-(2-(2,2-dibromovinyl)phenyl)acetamides 220 in the presence of copper iodide as the catalyst, 1,10-phenanthroline as the ligand, and Cs₂CO₃ as the base in THF at 80 °C, which produced the final products 221 (Scheme [76]). This new technique is more practical, atom-economic, and dependable in terms of reaction time, yields, and scalability.[84]

In 2017, Cho and co-workers[85] revealed another protocol similar to that developed by Beifuss and co-workers.[82] However, in this strategy, they used 1-bromo-2-(bromomethyl)cyclohex-1-enes 222 instead of 2-bromobenzyl bromides 1. The starting 1-bromoallyl bromides 222 were reacted with amidine hydrochlorides 223 under the influence of copper powder as well as a base to give the corresponding 2-phenyl-5,6,7,8-tetrahydroquinazolines 224 as the final products (Scheme [77]).[85]

Paul and associates have reported an alternative transformation that can be used to synthesize quinazolines 226 from 2-bromobenzyl bromides 1 and amidines 225 by employing tetra-coordinated nickel(II) complexes with redox-active diamine-based ligands as catalysts (Scheme [78]). This indicates that the transformation was achieved via the Ni-catalyzed direct C–N cross-coupling reaction of amidines 225 and 2-bromobenzyl bromides 1 under very mild circumstances. Numerous polysubstituted quinazolines 226 were synthesized in yields ranging from 23% to 72% under the indicated reaction conditions.[86]

Another class of heterocyclic scaffolds that can be produced from 2-bromobenzyl bromides are phthalazines. In 2014, Luong and colleagues reported the development of an effective Pd-catalyzed selective intramolecular arylation process utilizing functionalized N,N′-substituted 1-aminoindoles 229, which allowed for the production of fused indolo[2,1-a]phthalazines 230 in high yields. To prepare the N,N′-substituted 1-aminoindoles 229, which were subsequently cyclized using the Pd(OAc)₂/Dpephos catalytic system to produce the desired products 230, the reaction started with the coupling reaction of substituted 1-aminoindoles 227 with aryl chlorides 228 and N-benzylation with 2-bromobenzyl bromides 1 (Scheme [79]). Additionally, the process demonstrates strong functional group tolerance and yields a large number of N-aryl-N′-benzyl-1-aminoindoles.[87]

In 2012, Bao and colleagues developed a workable method to produce imidazobenzothiazines 232 by employing 2-bromobenzyl bromides 1 and 2-mercaptoimidazoles 231 with Cu(I) as a catalyst, l-proline as a ligand, and Cs₂CO₃ as a base in DMF at 110 °C for 20 hours (Scheme [80]). Moreover, a number of functional groups were successfully tolerated under the specified reaction conditions, with product yields as high as 95% being obtained. In addition to an intramolecular C–N cross-coupling cyclization, the reaction also involves an S_N2 mechanism.[88]

Moreover, 2-bromobenzyl halides 1 can be used for the synthesis of cyclic six-membered rings. In 1991, Ghatak and co-workers developed a protocol for procuring trans-octahydroanthracenes 234 from 2-bromobenzyl bromides 1 in several steps. The protocol was initiated with the reaction of 2-bromobenzyl bromide 1 and Hagemann’s ester 233, followed by alkaline hydrolytic decarboxylation to afford the corresponding cyclohexenones. Next, a Wittig reaction of the cyclohexenones gave the desired alkenes, followed by intramolecular cyclization using n-Bu₃SnH/AIBN to obtain the trans-octahydroanthracenes 234 (Scheme [81]).[89]

A novel method for producing a six-membered ring from 2-bromobenzyl bromides 1 via a proton-abstraction mechanism in a palladium-catalyzed intramolecular arylation process was reported by Echavarren and colleagues in 2006. They started with 1-bromo-2-(2-(phenyl)-2-phenylethyl)benzenes 236, formed by the reaction of 2-bromobenzyl bromides 1 with benzophenones 235. Palladium was then employed to catalyze the intramolecular cyclization of intermediates 236 to produce the phenanthrenes 237a and 237b (Scheme [82]). It was shown from experimental and theoretical results that an electrophilic aromatic substitution reaction was not involved in this Pd-catalyzed arylation process.[90]

For the production of benzo- and naphtho-fused bicyclo[n.3.1]alkanes 240, in 2011, Giorgi and colleagues presented a simple regioselective intramolecular α′-arylation of compounds 239 catalyzed by palladium (Scheme [83]). Using DBU as the base in THF at room temperature, the C-alkylation of α-nitroketones 238 with 2-bromobenzyl halides 1 produced compounds 239. A ring-closure reaction then produced the bicyclo[n.3.1]alkanes 240. When ester substituents were present on the aromatic moiety, the reaction showed good tolerance for functional groups such as nitro, halogen, and oxygen functionalities. A restriction noticed was the lack of intramolecular cyclization.[91]

Liu and colleagues explored a method for the production of 2-naphthols 243. Through the carbonylative Stille coupling of 2-halobenzyl halides 1 with tributylallylstannane, they have successfully synthesized 2-halobenzyl β,γ-unsaturated ketones 241 in acceptable to excellent yields. Next, it was shown that 2-halobenzyl α,β-unsaturated ketones 242 were produced under straightforward conditions by isomerizing 2-halobenzyl β,γ-unsaturated ketones 241. Finally, the 2-halobenzyl α,β-unsaturated ketones 242 were transformed into 2-naphthols 243 in moderate to good yields via an intramolecular Heck coupling reaction (Scheme [84]).[92]

In 2012, Nishiyama and co-workers elaborated a practical Pd-catalyzed synthesis of dibenz[a,h]anthracenes 247 via double-cyclization of (Z,Z)-p-styrylstilbenes 246, which were prepared in two steps. The first step involved the combination of 2-bromobenzyl bromides 1 with PPh₃ to form 2-bromobenzyltriphenylphosphonium bromides 244, and the second step consisted of the reaction of compounds 244 with terephthalaldehyde (245) (Scheme [85]).[93]

In 2013, Taillefer and co-workers reported a straightforward strategy for the formation of 9,10-dihydrophenanthrenes 248 from 2-bromobenzyl bromides 1 under very mild conditions by using a ligand-free iron catalytic system (Scheme [86]).[94]

In 2013, Yan and co-workers discovered that phenanthrenes 253 could be prepared by intramolecular cyclization of 1,1-biphenyl aldehydes 252 using t-BuOK in DMF. The 1,1-biphenyl aldehydes 252 were prepared starting from the addition between 2-bromobenzyl bromides 1 and N-methylanilines 249 to give amines 250, followed by the addition of 2-formylphenylboronic acids 251 in methanol (Scheme [87]).[95]

Wei et al. have disclosed an enantioselective access, via palladium-catalyzed desymmetrization, to cyclohexanones 256 that include γ-all-carbon quaternary centers. The method involves reacting ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylates 254 and 2-bromobenzyl bromides 1, then treating the obtained mixture in toluene at 80 °C with Pd₂(dba)₃, a ligand, benzylamine, and Cs₂CO₃ (Scheme [88]). Significantly, less reactive triflates, and aryl and alkenyl bromides were all appropriate substrates for this reaction. A number of dihydronaphthalenes with quaternary centers, lactones, tetralones, ring-fused indoles, and 6,6,5-tricycles efficiently produced the required products in moderate to good yields.[96]

A method for synthesizing dibenzocyclooctaphenanthrenes 262 from 2-bromobenzyl bromides 1 in multiple steps was recently presented by Jin and colleagues. This method was based on the combination of Cu(OTf)₂ as the catalyst and DDQ as the oxidant, which led to the selective oxidation of o-biphenyl-tethered methylenecirculenes 261 fused with a seven-membered ring (Scheme [89]). The equivalent eight-membered-ring structures 262 were created using these scaffolds. Through intramolecular spirocyclization, tandem selective single-electron oxidation of the benzylidene moieties and 1,2-aryl migration sequences, seven- to eight-membered rings were expanded.[97]

In 2012, You and co-workers established a practical strategy to obtain the spiroindolenine derivatives 265.[98] The authors revealed that 2-bromobenzyl bromides 1 reacted with indoles 263 to form dialkyl 2-((1H-indol-3-yl)methyl)-2-(2-bromobenzyl)malonates 264. Next, dearomatization of 2-((1H-indol-3-yl)methyl)-2-(2-bromobenzyl)malonates 264 in the presence of [Pd(C₃H₅)Cl]₂ as the catalyst, PPh₃ and K₂CO₃ in toluene afforded the spiroindolenines 265 (Scheme [90]). Several spiroindolenine derivatives 265 were produced in good to outstanding yields using easily obtainable triphenylphosphine as the ligand. An important aspect of the technique is the enantioselective control.

Synthesis of Seven-Membered Rings

Seven-membered rings are another important class of compounds which have a wide range of applications in organic synthesis, natural products and pharmaceutically active compounds.[99] Among these scaffolds, azepines are the most notable for their widespread applications. A novel method for the preparation of these moieties was developed by Yale and Petigara in 1974. They established a suitable and an efficient protocol for the generation of these scaffolds via the transformation of 2-bromobenzyl bromides 1 into 2-bromophenethyl bromides 266, followed by the reaction with 2-aminopyridine (267) to give 2-amino-1-(2-bromophenethyl)pyridinium bromides 268. Finally, intramolecular cyclization of compounds 268 into 1-(2-bromophenethyl)-2-iminopyridines 269 was conducted in the presence of sodium ethoxide in methanol under refluxing conditions for 5 hours (Scheme [91]).[100]

A further approach to azepines was developed by Harayama and co-workers in 2004. Their strategy relies upon the reaction of 2-bromobenzyl bromides 1 with N-methyl-1-naphthylamines 270 to afford the N-bromobenzylnaphthylamines 271, which were then cyclized to give benzonaphthazepines 272 by employing Pd(OAc)₂, P(o-Tol)₃ and K₂CO₃ in DMF (Scheme [92]). Using a Pd reagent, it was shown that the biaryl coupling reaction of N-bromobenzylnaphthylamines 271 results in regioselective C–H activation at the peri position with respect to the amine group on the naphthalene ring. This is caused by intramolecular coordination of the benzylamino group to the Pd center.[101]

In 2010, Heo and co-workers contributed a practical and efficient synthesis of 6,7-dihydro-5H-bibenz[c,e]azepine-5-ones 276 in three steps. In the first step, the conversion of 2-bromobenzyl bromides 1 into 2-bromobenzyl azides 273 was performed using sodium azide in DMF at room temperature for 3–6 hours. This was followed by a Suzuki–Miyaura coupling reaction of 273 with 2-(methoxycarbonyl)phenylboronic acid (274) to generate the biaryl ester-azides 275, which underwent intramolecular ring closure to afford the azepines 276 in the presence of PPh₃ in THF at room temperature over 10 hours (Scheme [93]).[102]

In 2011, Wallace et al. synthesized dibenz[c,e]azepines 280 in three steps from 2-bromobenzyl bromides 1 and N-Boc-protected amines 277 (Scheme [94]). As anticipated by molecular mechanics predictions, the cyclization reaction of derivatives 278 proceeded with strong atropo-diastereoselectivity because of strain effects that are influenced by the trigonalization of the nitrogen atom.[103]

In 2012, Rossi and Guastavino reported a two-step synthesis of benzo-fused azepines. They started with the base-promoted N-benzylation of 2-halobenzyl halides 1 with 2-acetylpyrrole (281) to afford 1-(2-halobenzyl)-2-acetylpyrroles 282, which were then treated with t-BuOK, pinacolone (as an electron donor) and FeCl₂ in DMSO to give the desired cyclized product 5H-benzo[e]pyrrolo[1,2-a]azepin-11(10H)-one (283) in 84% yield together with 3-acetyl-5H-pyrrolo[2,1-a]isoindole (284) (Scheme [95]).[104]

A workable approach for the efficient synthesis of dibenzo[b,e]azepin-6-ones 287 was described by Laha and colleagues in 2013. It involved ortho-benzylation of the C–H bond of 1 by utilizing a functionalizable (-CONH₂) directing group, in a process that was catalyzed by palladium and allowed for both chemo- and regioselectivity (Scheme [96]). Using Suzuki or Stille cross-coupling reactions, o-benzylation of primary benzamides 285 with 2-bromobenzyl bromides 1 yielded the 2-bromobenzyl benzamides 286. These were then subjected to intramolecular N-arylation using 10 mol% of Pd(OAc)₂, 13 mol% of Xant-Phos, and 2 equivalents of Cs₂CO₃ in dioxane at 110 °C for 18 hours to produce the desired products: dibenzoazepinones 287.[105]

Furthermore, oxepine derivatives are another important class of compounds that can be synthesized from 2-bromobenzyl bromides 1. Chattopadhyay and co-workers have elaborated an efficient conversion of 2-bromobenzyl bromides 1 and 1,2:5,6-di-O-isopropylidene glucofuranose (288) into the corresponding exo-methylene derivatives 290 in three steps. Compounds 290 were then cyclized to give 2-benzoxepines 291 in the presence of 1.8 equivalents of TBTH and catalytic AIBN in dry benzene under reflux conditions for 6 hours (Scheme [97]).[106]

Moreover, diazepines are another type of seven-membered ring molecules that have been found to have wide range of applications. In 2013, Chattopadhyay et al. developed a three-step synthetic route to imidazole-fused benzodiazepines 296 starting from 2-bromobenzyl bromides 1 and imidazole-2-carbaldehyde (292). The addition of 1 and 292 afforded N-benzylated imidazo-2-carbaldehydes 293, with subsequent addition of amines 294 producing the imidazo-N-alkylated amines 295. Finally, compounds 295 underwent intramolecular Buchwald–Hartwig cycloamination to afford the imidazole-fused benzodiazepines 296 by employing 10 mol% of Pd₂(dba)₃, 10 mol% of BINAP and 2 equivalents of t-BuOK in refluxing toluene (Scheme [98]). The reactions proceeded smoothly with both aliphatic and aromatic amines.[107]

In 2014, Laha and colleagues developed a domino method that starts with o-phenylenediamines 297 and 2-bromobenzyl bromides 1 or tosylates as substrates and ends with 10,11-dihydro-5H-dibenzo[b,e][1,4]diazepines 298 in yields of up to 91% (Scheme [99]). The N-benzylation of 1,2-diaminoarenes 297 with 2-bromobenzyl bromides 1 is catalyzed by Pd and this is followed by an intramolecular N′-arylation. It is noteworthy to emphasize that the reaction exhibits a high tolerance to functional groups and a wide range of substrates, making it a desirable method for obtaining diazepines 298.[108]

An effective approach for the synthesis of 3-substituted 1,3,4,5-tetrahydro-1,4-benzodiazepin-2-ones 300 was presented by Zeng and colleagues in 2015. It involves a cascade Cu-catalyzed/S_N2 coupling reaction between 2-halobenzyl halides 1 and l-phenylalaninamide (299) (Scheme [100]). Furthermore, the amide chirality was maintained throughout the process. This approach was appealing due to its many advantages, including the one-pot process, the simplicity, the inexpensive catalyst, the functional group tolerance, and the ability to utilize a variety of substrates.[109]

To prepare benzo[e]pyrrolo[1,2-a][1,4]diazepines 302, Al-Tel and colleagues treated 2-bromobenzyl bromides 1 with pyrrolidine-2-carboxamides 301 in 2017. First, compounds 1 and carboxamides 301 were reacted together in DMF at 70 °C for 12 hours. Next, CuI, l-proline, and the base Cs₂CO₃ were added to the reaction mixture, which was then heated for 30 minutes at 140 °C (Scheme [101]). A number of heterocyclic scaffolds, including benzodiazepin-2-ones, thiazapines, diazapines, diazocines, diazocinones, thiazocines, and diazepines were created using this one-pot procedure.[110]

In 1964, Yale and Sowinski revealed that the synthesis of 5,11-dihydrodibenz[b,e][1,4]oxazepine derivatives 304 could be accomplished starting from 2-bromobenzyl bromides 1 and 2-nitrophenols 303 in a five-step sequence (Scheme [102]).[111]

In 1970, Pluscec and Yale reported a successful synthesis of 6,11-dihydropyrido[3,2-b][4,1]benzoxazepines 308 starting from 2-bromobenzyl bromides 1 and 2-nitropyridin-3-ol (305) in three steps (Scheme [103]). The O-benzylation of compounds 1 with 305 in the presence of KOH afforded 3-(o-bromobenzyloxy)-2-nitropyridines 306, which further reacted with DCC in formic acid to give N-[3-(o-bromobenzyloxy)-2-pyridyl]formamides 307. Finally the ring closure of compounds 307 in the presence of K₂CO₃ in Et₂NH afforded 6,11-dihydropyrido[3,2-b][4,1]benzoxazepines 308.[112]

Analogous to the work reported by Yale in 1964[111] and 1970,[112] in 2003, Rogers and co-workers established a two-step strategy for the preparation of oxazepines 311 and thiazepines 314. The first step is the O-benzylation of 2-bromobenzyl bromides 1 with 2-nitrophenols 309 to give the ethers 310, or the reduction of disulfides 312 followed by S-benzylation to afford the thioethers 313. Next, intramolecular cyclization of 310 or 313 produces the oxazepines 311 and thiazepines 314 in the presence of Pd(dba)₂, P(t-Bu)₃ and NaO ^t Bu in toluene at 95 ℃ (Scheme [104]). The scope of this reaction was explored, and it was shown to be operative with a variety of substrates.[113]

Another approach to seven-membered biaryl sultams 316 was developed by Laha and co-workers in 2015. Their route relies on the use of Pd-catalyzed regio- and chemoselective reactions between 2-bromobenzyl bromides 1 and N-alkylbenzenesulfonamides 315 (Scheme [105]). It should be noted that this route featured a cascade reaction and involved an N-benzylation process, which, followed by an intramolecular direct C–H arylation, delivered the final compounds. In addition, the developed domino reaction exhibited good functional group tolerance and a wide substrate scope.[114]

In 1980, Bradsher and co-workers treated 2-bromobenzyl bromides 1 successively with n-BuLi and CO₂. The generated intermediate underwent Parham cycliacylation using n-BuLi leading to the synthesis of the corresponding dibenzosuberones 317 in satisfactory yields (Scheme [106]).[115]

Synthesis of Eight- and Nine-Membered Rings

Eight- and nine-membered ring scaffolds are significant molecules in the realms of synthetic organic chemistry and physiologically active moieties.[116] These scaffolds can be made using precursor compounds such as 2-halobenzyl halides. In 2009, Majumdar et al. developed a productive two-step reaction strategy for the production of dibenzoazocine derivatives 320 (Scheme [107]). The desired products were delivered by an intramolecular Heck coupling reaction via the 8-exo-trig mode of cyclization, an aza-Claisen rearrangement, and refluxing in acetone in the presence of anhydrous K₂CO₃ and a small amount of sodium iodide. The synthesis started with the reaction of 2-bromobenzyl halides 1 with C-allylanilines 318. This reaction tolerated a number of different substituents on substrates 1 and 318.[117]

Majumdar and co-workers have carried out an analogous process for the synthesis of heterocycle-annulated azocine derivatives 323. In order to produce the Heck precursors 322, they initiated the reaction between 2-bromobenzyl bromides 1 and 5-allyl-6-(ethylamino)coumarins 321 under Finkelstein conditions. Potassium acetate was used as a base, Bu₄NBr (TBAB) as a promoter, PPh₃ as a ligand, and Pd(OAc)₂ as the catalyst in anhydrous DMF. The reaction was carried out under a nitrogen atmosphere at 90 °C for six hours (Scheme [108]). Numerous substituted azocine-fused molecules 323 with aryl rings such as coumarin and quinolone moieties were investigated in detail.[118]

In 2013, Schubert and co-workers presented a novel one-pot synthesis of (Z)-5,6-dihydrodibenzo[b,f]azocines 325 in up to 33% yield via reactions between 2-bromobenzyl bromides 1 and 2-chloroanilines 324 using K₂CO₃, followed by the addition of boroxine, Pd⁰, and phosphine (Scheme [109]).[119]

Chattopadhyay and co-workers have demonstrated a successful synthesis of trans-furo[3,2-c][2]benzoxocines 329 in three steps. The protocol was realized via O-alkylation between 2-bromobenzyl bromides 1 and 1,2:5,6-di-O-isopropylidene-α-glucofuranoside derivative 326 in the presence of aqueous sodium hydroxide in a biphasic medium to afford the O-2-bromobenzylated glucofuranosides 327. Next, the successive addition of 75% acetic acid, PPh₃, I₂ and imidazole in refluxing toluene afforded the desired olefins 328 in satisfactory yields. Finally, the radical cyclization of 328 with Bu₃SnH and AIBN in refluxing benzene furnished the products 329 in yields ranging from 50–58% (Scheme [110]).[120]

Later, in 2010, Chattopadhyay reported the synthesis of chiral benzodiazocine derivatives 333 by intramolecular addition between aryl bromides and iodides 1 with compound 330 to give derivatives 331. Transformation into amines 332 was followed by cyclization using a palladium catalyst, various bulky biaryl phosphines as ligands and toluene as the solvent (Scheme [111]). Additionally, a number of electron-rich aryl halides were reacted with sugar-derived amines other than benzyl amine using the aforementioned intramolecular method, and high yields of the products were obtained.[121]

In 2007, Majumdar and co-workers contributed an effective and high-yielding procedure for the synthesis of naphthoxocines 338 and 339 in two steps. The reaction of 2-bromobenzyl bromides 1 and α- or β-naphthols 334 or 335 at reflux in dry acetone in the presence of K₂CO₃ and NaI delivered the ethers 336 or 337, which were subjected to Pd-catalyzed intramolecular Heck coupling reactions and cyclization to afford the naphthoxocines 338 and 339 (Scheme [112]).[122]

Using an intramolecular Heck coupling reaction and 9-endo-trig and 8-endo-trig cyclizations, respectively, the Majumdar’s group reported the synthesis of nine-membered oxa-heterocyclic compounds 342 in 2008 (Scheme [113]).[123]

In 2009, Majumdar also showcased two efficient three-step routes for the synthesis of naphthoxepines 346 and naphthoxocines 347 with yields ranging from 60–76%. The protocol began with the O-benzylation reactions of 2-bromobenzyl bromides 1 with 1-formyl-2-naphthols 343 to give 2-bromobenzyl 2-formylaryl ethers 344. A subsequent Wittig reaction produced the 2-bromobenzyl 2-vinylaryl ethers 345 that underwent regioselective Heck coupling and intramolecular ring closure under different reaction conditions to afford the final products 346 or 347 (Scheme [114]).[124]

In 2017, Ghosh described the synthesis of dibenzo[c,f]oxocines 351 framework in three steps. The reaction started with the O-benzylation of 2-bromobenzyl bromides 1 with 2-iodobenzyl alcohols 348 to give 1-bromo-2-((2-iodobenzyloxy)methyl)benzenes 349, which was followed by a Sonogashira cross-coupling reaction to afford 1-bromo-2-(((2-(phenylethynyl)benzyl)oxy)methyl)benzenes 350. Next, substrates 350 undergo a tandem Heck–Suzuki intramolecular ring closure reaction to give the desired products 351 (Scheme [115]). The synthesis of several dibenzoxocines 351 in good yields attests to the utility of this well-developed approach.[125]

In 2017, Shi and co-workers observed that the combination of cyclohexane-1,3-diones 352 and 2-bromobenzyl bromides 1 in the presence of aqueous Bu₄NOH in dioxane could be effectively employed for the synthesis of 2-(2-bromobenzyl)cyclohexane-1,3-diones 353, which then participated in enantioselective Pd-catalyzed intramolecular α-arylative desymmetrization reactions to afford the substituted bicyclo[m.n.1] skeletons 354 (Scheme [116]). In addition, this protocol was used as a key step during the synthesis of (–)-parvifoline.[126]

Conclusion

In summary, harnessing o-halobenzyl halides for generating five- to nine-membered ring structures by employing transition-metal catalysis epitomizes a robust and versatile approach in contemporary organic synthesis. The diverse array of synthetic procedures and the biological relevance of the resultant compounds underscore the pivotal role of this methodology in pharmaceutical endeavors. The prospect of generating innovative pharmaceutical agents by leveraging the synthesized structures represents an exciting frontier in medicinal chemistry, pointing towards further advances in drug discovery and development. This review aims to highlight the significance of this synthetic methodology and its far-reaching implications in the realms of organic and pharmaceutical chemistry.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The authors are grateful to all the co-workers whose names appear in references 9, 11, 42, 58, 60 and 82.

• References


For reviews on transition-metal-catalyzed C–X and C–C coupling reaction see:
• 1a Wegner H, Auzias M. Angew. Chem. Int. Ed. 2011; 50: 8236
  CrossrefPubMedSearch in Google Scholar
• 1b Bellina F, Rossi R. Chem. Rev. 2010; 110: 1082
  CrossrefPubMedSearch in Google Scholar
• 1c Yin L, Liebscher J. Chem. Rev. 2007; 107: 133
  CrossrefPubMedSearch in Google Scholar
• 1d Chinchilla R, Nájera C. Chem. Rev. 2007; 107: 874
  CrossrefPubMedSearch in Google Scholar
• 1e Fairlamb IJ. S. Annu. Rep. Prog. Chem., Sect. B 2006; 102: 50
  CrossrefSearch in Google Scholar
• 2a Stumer R. Angew. Chem. Int. Ed. 1999; 38: 3307
  CrossrefPubMedSearch in Google Scholar
• 2b Aranyos A, Old DW, Kiyomori A, Wolfe JP, Sadighi JP, Buchwald SL. J. Am. Chem. Soc. 1999; 121: 4369
  CrossrefSearch in Google Scholar
• 2c Metal-Catalyzed Cross-Coupling Reactions . Diederich F, Stang PJ. Wiley-VCH; Weinheim: 1998
  Search in Google Scholar
• 2d Old DW, Wolfe JP, Buchwald SL. J. Am. Chem. Soc. 1998; 120: 9722
  CrossrefSearch in Google Scholar
• 2e Beller M. Angew. Chem. Int. Ed. 1995; 34: 1316
  CrossrefSearch in Google Scholar
• 2f Hartwig JP. Synlett 1997; 329
• 2g Wagaw S, Rennels RA, Buchwald SL. J. Am. Chem. Soc. 1997; 119: 8451
  CrossrefSearch in Google Scholar
• 2h Wolfe JP, Wagaw S, Buchwald SL. J. Am. Chem. Soc. 1996; 118: 7215
  CrossrefSearch in Google Scholar
• 3a Ricordi VG, Fritas CF, Perin G, Lenardão EJ, Jacob RG, Savegnago L, Alues D. Green Chem. 2012; 14: 1030
  CrossrefSearch in Google Scholar
• 3b Jiao J, Zhang X.-R, Chang N.-H, Wang J, Wei J.-F, Shi X.-Y, Chen Z.-G. J. Org. Chem. 2011; 76: 1180
  CrossrefPubMedSearch in Google Scholar
• 3c Cortes-Salva M, Garvin C, Antilla JC. J. Org. Chem. 2011; 76: 1456
  CrossrefPubMedSearch in Google Scholar
• 3d Altman RA, Shafir A, Lichtor PA, Buchwald SL. J. Org. Chem. 2008; 73: 284
  CrossrefPubMedSearch in Google Scholar
• 3e Niu J, Zhou H, Li Z, Xu J, Hu S. J. Org. Chem. 2008; 73: 7814
  CrossrefPubMedSearch in Google Scholar
• 3f Zhang Q, Wang D, Wang X, Ding K. J. Org. Chem. 2009; 74: 7187
  CrossrefPubMedSearch in Google Scholar
• 3g Wolf C, Liu S, Mei X, August AT, Casimir MD. J. Org. Chem. 2006; 71: 3270
  CrossrefPubMedSearch in Google Scholar
• 3h Chen Y.-J, Chen H.-H. Org. Lett. 2006; 8: 5609
  PubMedSearch in Google Scholar
• 3i Cristau H.-J, Cellier PP, Hamada S, Spindler J.-F, Taillefer M. Org. Lett. 2004; 6: 913
  CrossrefPubMedSearch in Google Scholar
• 3j Ma D, Cai Q. Org. Lett. 2003; 5: 3799
  CrossrefPubMedSearch in Google Scholar
• 3k Ley SV, Thomas AW. Angew. Chem. Int. Ed. 2003; 38: 5400
  CrossrefPubMedSearch in Google Scholar
• 3l Kunz K, Scholz ZV, Ganzer D. Synlett 2003; 2428
• 3m Kwong FY, Klapars A, Buchwald SL. Org. Lett. 2002; 4: 581
  CrossrefPubMedSearch in Google Scholar
• 3n Stephens RD, Castro CE. J. Org. Chem. 1963; 28: 2163
  Search in Google Scholar
• 3o Stephens RD, Castro CE. J. Org. Chem. 1963; 28: 3313
  CrossrefSearch in Google Scholar
• 3p Ullmann F. Chem. Ber. 1903; 36: 2382
  CrossrefSearch in Google Scholar
• 3q Ullmann F, Sponagel O. Chem. Ber. 1903; 36: 2382
  CrossrefSearch in Google Scholar
• 3r Ullmann F. Chem. Ber. 1901; 34: 2174
  CrossrefSearch in Google Scholar
• 4 Patel MV, Bell R, Majest S, Henry R, Kolasa T. J. Org. Chem. 2004; 69: 7058
  CrossrefPubMedSearch in Google Scholar
• 5 Chai X, Guan Z, Yu S, Zhou Q, Hu H, Zou Y, Tao X, Wu Q. Bioorg. Med. Chem. Lett. 2012; 22, 5849
  PubMed
• 6 Saeedi M, Mohammadi-Khanaposhtani M, Pourrabia P, Razzaghi N, Ghadimi R, Imanparast S, Faramarzi MA, Bandarian F, Esfahani EN, Safavi M, Rastegar H, Larijani B, Mahdavi M, Akbarzadeh T. Bioorg. Chem. 2019; 83: 161
  CrossrefPubMedSearch in Google Scholar
• 7 Zou Y, Zhao Q, Liao J, Hu H, Yu S, Chai X, Xu M, Wu Q. Bioorg. Med. Chem. Lett. 2012; 22: 2959
  CrossrefPubMedSearch in Google Scholar
• 8 Zhang Y, Lv Z, Zhong H, Geng D, Zhang M, Zhang T, Li Y, Li K. Eur. J. Med. Chem. 2012; 53: 356
  CrossrefPubMedSearch in Google Scholar
• 9a Thangadurai A, Minu M, Wakode S, Agrawal S, Narasimhan B. Med. Chem. Res. 2012; 21: 1509
  CrossrefSearch in Google Scholar
• 9b Gaikwad DD, Chapolikar AD, Devkate CG, Warad KD, Tayade AP, Pawar RP, Domb AJ. Eur. J. Med. Chem. 2015; 90: 707
  CrossrefPubMedSearch in Google Scholar
• 9c Jia B.-X, Zeng X.-L, Ren F.-X, Jia L, Chen X.-Q, Yang J, Liu H.-M, Wang Q. Food Chem. 2014; 155: 31
  CrossrefPubMedSearch in Google Scholar
• 9d Hassanein HH, Khalifa MM, El-Samaloty ON, El-Rahim MA, Taha RA, Magda Ismail MF. Arch. Pharm. Res. 2008; 31: 562
  CrossrefPubMedSearch in Google Scholar
• 9e Xue N, Yang X, Wu R, Chen J, He Q, Yang B, Lu X, Hu Y. Bioorg. Med. Chem. 2008; 16: 2550
  CrossrefPubMedSearch in Google Scholar
• 9f Sheppeck JE. II, Gilmore JL, Tebben A, Xue C.-B, Liu R.-Q, Decicco CP, Duan JJ.-W. Bioorg. Med. Chem. Lett. 2007; 17: 2769
  CrossrefPubMedSearch in Google Scholar
• 9g Bringmann G, Mühlbacher J, Messer K, Dreyer M, Ebel R, Nugroho BW, Wray V, Proksch P. J. Nat. Prod. 2003; 66: 80
  CrossrefPubMedSearch in Google Scholar
• 9h Ferrari M, Goadsby P, Roon K, Lipton R. Cephalalgia 2002; 22: 633
  CrossrefPubMedSearch in Google Scholar
• 9i Naylor EM, Parmee ER, Colandrea VJ, Perkins L, Brockunier L, Candelore MR, Cascieri MA, Colwell LF. Jr, Deng L, Feeney WP, Forrest MJ, Hom GJ, MacIntyre DE, Strader CD, Tota L, Wang P.-R, Wyvratt MJ, Fisher MH, Weber AE. Bioorg. Med. Chem. Lett. 1999; 9: 755
  CrossrefPubMedSearch in Google Scholar
• 9j Reitz DB, Garland DJ, Norton MB, Collins JT, Reinhard EJ, Manning RE, Olins GM, Chen ST, Palomo MA, McMahon EG. Bioorg. Med. Chem. Lett. 1993; 3: 1055
  CrossrefSearch in Google Scholar
• 9k Kant K, Patel CK, Banerjee S, Naik P, Atta AK, Kabi AK, Malakar CC. ChemistrySelect 2023; 8: e202303988
  CrossrefSearch in Google Scholar
• 9l Kaldhi D, Vodnala N, Gujjarappa R, Malakar CC, Nayak S, Ravichandiran V, Gupta S, Hazra CK. Tetrahedron Lett. 2019; 60: 223
  CrossrefSearch in Google Scholar
• 9m Aljaar N, Ibrahim MM, Younes EA, Al-Noaimi M, Abu-Safieh KA, Ali BF, Kant K, Al-Zaqri N, Sengupta R, Malakar CC. Asian J. Org. Chem. 2023; 12: e202300036
  CrossrefSearch in Google Scholar
• 9n Kabi AK, Gujjarappa R, Vodnala N, Kaldhi D, Tyagi U, Mukherjee K, Malakar CC. Tetrahedron Lett. 2020; 61: 152535
  CrossrefSearch in Google Scholar
• 9o Kabi AK, Gujjarappa R, Roy A, Sahoo A, Musib D, Vodnala N, Singh V, Malakar CC. J. Org. Chem. 2021; 86: 14597
  CrossrefPubMedSearch in Google Scholar
• 10 Song JJ, Yee NK. A. Org. Lett. 2000; 2: 519
  CrossrefPubMedSearch in Google Scholar
• 11 Aljaar N, Al-Noaimi M, Conrad J, Beifuss U. J. Org. Chem. 2020; 86: 1408
  CrossrefPubMedSearch in Google Scholar
• 12 Arai N, Takahashi M, Mitani M, Mori A. Synlett 2006; 3170
• 13 Imrich H.-G, Conrad J, Beifuss U. Eur. J. Org. Chem. 2015; 7718
• 14 Zheng HX, Shan XH, Qu JP, Kang YB. Org. Lett. 2018; 20: 3310
  CrossrefPubMedSearch in Google Scholar
• 15 Kozikowski AP, Ma D. Tetrahedron Lett. 1991; 32: 3317
  CrossrefSearch in Google Scholar
• 16 Barbero N, SanMartin R, Dominguez E. Tetrahedron Lett. 2009; 50: 2129
  CrossrefSearch in Google Scholar
• 17a Alberico D, Scott ME, Lautens M. Chem. Rev. 2007; 107: 174
  CrossrefPubMedSearch in Google Scholar
• 17b Faust R, Garratt PJ, Jones R, Yeh L.-K, Tsotinis A, Panoussopoulou M, Calogeropoulou T, The M.-T, Sugden D. J. Med. Chem. 2000; 43: 1050
  CrossrefPubMedSearch in Google Scholar
• 17c Campeau L.-C, Thansandote P, Fagnou K. Org. Lett. 2005; 7: 1857
  CrossrefPubMedSearch in Google Scholar
• 17d A palladium-catalyzed indole alkenylation by C–H functionalization aided by copper oxidants is reported in: Grimser NP, Gaunlett C, Godfrey CR. A, Gaunt MJ. Angew. Chem. Int. Ed. 2005; 44: 3125
  CrossrefPubMedSearch in Google Scholar
• 17e Kakiuchi F, Chatani N. Adv. Synth. Catal. 2003; 345: 1077
  CrossrefSearch in Google Scholar
• 17f Norinder J, Matsumoto A, Yoshikai N, Nakamura E. J. Am. Chem. Soc. 2008; 130: 5858
  CrossrefPubMedSearch in Google Scholar
• 18 Laha JK, Dayal N, Singh S, Bhimpuria R. Eur. J. Org. Chem. 2014; 5469
• 19 Cacchi S, Fabrizi G. Chem. Rev. 2011; 111: 215
  CrossrefPubMedSearch in Google Scholar
• 20 Antonio Y, De La Cruz E, Galeazzi E, Guzman A, Bray BL, Greenhouse R, Kurz LJ, Lustig DA, Maddox ML, Muchowski JM. Can. J. Chem. 1994; 72: 15
  CrossrefSearch in Google Scholar
• 21 Dodonova J, Tumkevicius S. Synthesis 2017; 49: 2523
  Thieme ConnectSearch in Google Scholar
• 22 Cui B, Shan J, Yuan C, Han W, Wan N, Chen Y. Org. Biomol. Chem. 2017; 15: 5887
  CrossrefPubMedSearch in Google Scholar
• 23 George J, Kim HY, Oh K. Org. Lett. 2019; 21: 5747
  CrossrefPubMedSearch in Google Scholar
• 24 Shim SC, Jiang LH, Lee DY, Cho CS. Bull. Korean Chem. Soc. 1995; 16: 1064
  Search in Google Scholar
• 25 Hansen SV. F, Ulven T. Org. Lett. 2015; 17: 2832
  CrossrefPubMedSearch in Google Scholar
• 26 Bachon A.-K, Opatz T. J. Org. Chem. 2016; 81: 1858
  CrossrefPubMedSearch in Google Scholar
• 27 Dandepally SR, Williams AL. Tetrahedron 2009; 50: 1395
  CrossrefSearch in Google Scholar
• 28 Huang Y, Chen W, Zhao D, Chen C, Yin H, Zheng L, Jin M, Han S. Chin. J. Chem. 2013; 31: 1007
  CrossrefSearch in Google Scholar
• 29 Xu X, Zhao L, Li Y, Soulé J.-F, Doucet H. Adv. Synth. Catal. 2015; 357: 2869
  CrossrefSearch in Google Scholar
• 30 Choi YL, Lee H, Kim BT, Choi K, Heo JN. Adv. Synth. Catal. 2010; 352: 2041
  CrossrefSearch in Google Scholar
• 31 Paleo MR, Castedo L, Domínguez D. J. Org. Chem. 1993; 58: 2763
  CrossrefSearch in Google Scholar
• 32 Ishibashi H, Kobayashi T, Nakashima S, Tamura O. J. Org. Chem. 2000; 65: 9022
  CrossrefPubMedSearch in Google Scholar
• 33 Halterman RL, Zhu C. Tetrahedron Lett. 1999; 40: 7445
  CrossrefSearch in Google Scholar
• 34 Bailey WF, Daskapan T, Rampalli S. J. Org. Chem. 2003; 68: 1334
  CrossrefPubMedSearch in Google Scholar
• 35 Halterman RL, Crow LD. Tetrahedron Lett. 2003; 44: 2907
  CrossrefSearch in Google Scholar
• 36a Kong L, Han X, Jiao P. Chem. Commun. 2014; 50: 14113
  CrossrefPubMedSearch in Google Scholar
• 36b Muratake H, Natsume M, Nakai H. Tetrahedron 2004; 60: 11783
  CrossrefSearch in Google Scholar
• 37 Deng R, Sun L, Li Z. Org. Lett. 2007; 9: 5207
  CrossrefPubMedSearch in Google Scholar
• 38 Shimizu M, Tomioka Y, Nagao I, Hiyama T. Synlett 2009; 3147
• 39 Rousseaux S, García-Fortanet J, Del Aguila Sanchez MA, Buchwald SL. J. Am. Chem. Soc. 2011; 133: 9282
  CrossrefPubMedSearch in Google Scholar
• 40 Song J, Sun W, Li Y, Wei F, Liu C, Qian Y, Chen S. Chem. Asian J. 2016; 11: 211
  CrossrefPubMedSearch in Google Scholar
• 41 Wang H, Huang H, Gong C, Diao Y, Chen J, Wu S.-H, Wang L. Org. Lett. 2022; 24: 328
  CrossrefPubMedSearch in Google Scholar
• 42a Acharya A, Gautam V, Ila H. J. Org. Chem. 2017; 82: 7920
  CrossrefPubMedSearch in Google Scholar
• 42b Patel CK, Gujjarappa R, Kant K, Ghanta S, Singh V, Kabi AK, Al-Zaqri N, Malakar CC. Adv. Synth. Catal. 2023; 365: 2203
  CrossrefSearch in Google Scholar
• 42c Kant K, Banerjee S, Patel CK, Kalita S, Reetu R, Naik P, Aljaar N, Malakar CC. Heterocycles 2023; 106: 925
  CrossrefSearch in Google Scholar
• 42d Patel CK, Banerjee S, Kant K, Sengupta R, Aljaar N, Malakar CC. Asian J. Org. Chem. 2023; 12: e202300311
  CrossrefSearch in Google Scholar
• 42e Reetu R, Gujjarappa R, Malakar CC. Asian J. Org. Chem. 2022; 11: e202200163
  CrossrefSearch in Google Scholar
• 42f Bhattacharya P, Senapati K, Chattopadhyay K, Mandal SM, Basak A. RSC Adv. 2015; 5: 61562
  CrossrefSearch in Google Scholar
• 42g Pratap R, Ram VJ. Chem. Rev. 2014; 114: 10476
  CrossrefPubMedSearch in Google Scholar
• 42h Killander D, Sterner O. Eur. J. Org. Chem. 2014; 1594
• 42i Appendino G, Gibbons S, Giana A, Pagani A, Grassi G, Stavri M, Smith E, Rahman MM. J. Nat. Prod. 2008; 71: 1427
  CrossrefPubMedSearch in Google Scholar
• 42j Simon-Levert A, Aze A, Bontemps-Subielos N, Banaigs B, Genevière A.-M. Chem.-Biol. Interact. 2007; 168: 106
  CrossrefPubMedSearch in Google Scholar
• 43 Bowman WR, Mann E, Parr J. J. Chem. Soc., Perkin Trans. 1 2000; 2991
• 44 Parisien M, Valette D, Fagnou K. J. Org. Chem. 2005; 70: 7578
  CrossrefPubMedSearch in Google Scholar
• 45 Bajracharya GB, Daugulis O. Org. Lett. 2008; 10: 4625
  CrossrefPubMedSearch in Google Scholar
• 46 Ortiz Villamizar MC, Zubkov FI, Puerto Galvis CE, Vargas Méndez LY, Kouznetsov VV. Org. Chem. Front. 2017; 4: 1736
  CrossrefSearch in Google Scholar
• 47 Majumdar KC, Pal AK, Taher A, Debnath P. Synthesis 2007; 1707
• 48 Majumdar KC, Debnath P, Taher A, Pal AK. Can. J. Chem. 2008; 86: 325
  CrossrefSearch in Google Scholar
• 49 Nolan M.-T, Bray JT. W, Eccles K, Cheung MS, Lin Z, Lawrence SE, Whitwood AC, Fairlamb IJ. S, McGlacken GP. Tetrahedron 2014; 70: 7120
  CrossrefSearch in Google Scholar
• 50 Majumdar K, Islam R. Synth. Commun. 2008; 38: 4053
  CrossrefSearch in Google Scholar
• 51 Majumdar KC, Mukhopadhyay PP, Basu PK. Synth. Commun. 2005; 35: 1291
  CrossrefSearch in Google Scholar
• 52 Petrone DA, Malik HA, Clemenceau A, Lautens M. Org. Lett. 2012; 14: 4806
  CrossrefPubMedSearch in Google Scholar
• 53 Yang W, Yan J, Long Y, Zhang S, Liu J, Zeng Y, Cai Q. Org. Lett. 2013; 15: 6022
  CrossrefPubMedSearch in Google Scholar
• 54 Garrison AT, Childress ES, Davis DC, Lindsley CW. J. Org. Chem. 2019; 84: 5855
  CrossrefPubMedSearch in Google Scholar
• 55 Nikolić AM, Živković F, Selaković Ž, Wipf P, Opsenica IM. Eur. J. Org. Chem. 2020; 5616
• 56 Fang Y, Li C. J. Org. Chem. 2006; 71: 6427
  CrossrefPubMedSearch in Google Scholar
• 57 Majumdar KC, Chakravorty S, De N. Tetrahedron Lett. 2008; 49: 3419
  CrossrefSearch in Google Scholar
• 58 Malakar CC, Schmidt D, Conard J, Beifuss U. Org. Lett. 2011; 13: 1972
  CrossrefPubMedSearch in Google Scholar
• 59 Zhang XY, Fang LL, Liu N, Wu HY, Fan XS. Chin. Chem. Lett. 2012; 23: 1129
  CrossrefSearch in Google Scholar
• 60 Sudheendran K, Malakar CC, Conrad J, Beifuss U. J. Org. Chem. 2012; 77: 10194
  CrossrefPubMedSearch in Google Scholar
• 61 Mao Z, Zhu X, Wan Y. Catal. Lett. 2015; 145: 1612
  CrossrefSearch in Google Scholar
• 62 Barluenga J, Fanňanás FJ, Sanz R, Fernández Y. Chem. Eur. J. 2002; 8: 2034
  CrossrefPubMedSearch in Google Scholar
• 63 Majumdar K, Mukhopadhyay P, Biswas A. Tetrahedron Lett. 2005; 46: 6655
  CrossrefSearch in Google Scholar
• 64 Majumdar KC, Chattopadhyay B, Nath S. Synth. Commun. 2007; 37: 2907
  CrossrefSearch in Google Scholar
• 65 Castanheiro T, Donnard M, Gulea M, Suffert J. Org Lett. 2014; 16: 3060
  CrossrefPubMedSearch in Google Scholar
• 66a Ball M, Zhong Y, Wu Y, Schenck C, Ng F, Steigerwald M, Xiao S, Nuckolls C. Acc. Chem. Res. 2015; 48: 267
  CrossrefPubMedSearch in Google Scholar
• 66b Penning TM. Chem. Res. Toxicol. 2014; 27: 1901
  CrossrefPubMedSearch in Google Scholar
• 66c Ghinet A, Gautret P, Hijfte NV, Ledé B, Hénichart J.-P, Bîcu E, Darbost U, Rigo B, Daïch A. Chem. Eur. J. 2014; 20: 10117
  CrossrefPubMedSearch in Google Scholar
• 66d Castillo D, Sauvain M, Rivaud M, Jullian V. Planta Med. 2014; 80: 902
  Thieme ConnectPubMedSearch in Google Scholar
• 66e Jin Z. Nat. Prod. Rep. 2011; 28: 1126
  CrossrefPubMedSearch in Google Scholar
• 66f Nakanishi T, Suzuki M, Saimoto A, Kabasawa T. J. Nat. Prod. 1999; 62: 864
  CrossrefPubMedSearch in Google Scholar
• 66g Boulware RT, Stermitz FR. J. Nat. Prod. 1981; 44: 200
  CrossrefSearch in Google Scholar
• 66h Muth CW, Bhattacharya B, Mahaffey RL, Minigh HL. J. Med. Chem. 1973; 16: 303
  CrossrefPubMedSearch in Google Scholar
• 67 Majumdar K, Chattopadhyay B, Pal A. Lett. Org. Chem. 2008; 5: 276
  CrossrefSearch in Google Scholar
• 68 Zhang X, Guo X, Fang L, Song Y, Fan X. Eur. J. Org. Chem. 2013; 8087
• 69 Liu C, Zhu XJ, Han YZ, Yang HJ, Zhu CJ, Fu H. Org. Biomol. Chem. 2019; 17: 4984
  CrossrefPubMedSearch in Google Scholar
• 70 Majumdar KC, Mukhopadhyay PP. Synthesis 2003; 920
• 71 Sanz R, Ignacio JM, Castroviejo MP, Fañanásb FJ. ARKIVOC 2007; (iv): 84
  Search in Google Scholar
• 72 Chouhan G, Alper HJ. J. Org. Chem. 2009; 74: 6181
  CrossrefPubMedSearch in Google Scholar
• 73 Han W, Zhou X, Yang S, Xiang G, Cui B, Chen Y. J. Org. Chem. 2015; 80: 11580
  CrossrefPubMedSearch in Google Scholar
• 74 Wang M, Zhang X, Zhuang Y.-H, Xu Y.-H, Loh T.-P. J. Am. Chem. Soc. 2015; 137: 1341
  CrossrefPubMedSearch in Google Scholar
• 75 Song ZY, Luo J, Ren DZ, Fu J, Liu YJ, Jin FM, Huo ZB. ARKIVOC 2017; (v): 148
  CrossrefPubMedSearch in Google Scholar
• 76 Zhang T, Cui B, Han W, Wan N, Bai M, Chen Y. Eur. J. Org. Chem. 2017; 3179
• 77 Arasakumar T, Shyamsivappan S, Gopalan S, Ata A, Mohan PS. Synlett 2019; 30: 63
  Thieme ConnectSearch in Google Scholar
• 78 Hoshimoto Y, Nishimura C, Sasaoka Y, Kumar R, Ogoshi S. Bull. Chem. Soc. Jpn. 2020; 93: 182
  CrossrefSearch in Google Scholar
• 79 Laha JK, Dayal N, Jain R, Patel K. J. Org. Chem. 2014; 79: 10899
  CrossrefPubMedSearch in Google Scholar
• 80 De S, Ghosh S, Bhunia S, Sheikh JA, Bisai A. Org. Lett. 2012; 14: 4466
  CrossrefPubMedSearch in Google Scholar
• 81 Maity A, Mondal S, Paira R, Hazra A, Naskar S, Sahu KB, Saha P, Banerjee S, Mondal NB. Tetrahedron Lett. 2011; 52: 3033
  CrossrefSearch in Google Scholar
• 82 Malakar CC, Baskakova A, Conrad J, Beifuss U. Chem. Eur. J. 2012; 18: 8882
  CrossrefPubMedSearch in Google Scholar
• 83 Fan X, Li B, Guo S, Wang Y, Zhang X. Chem. Asian J. 2014; 9: 739
  CrossrefPubMedSearch in Google Scholar
• 84 Kiruthika SE, Perumal PT. Org. Lett. 2014; 16: 484
  CrossrefPubMedSearch in Google Scholar
• 85 Lee HK, Sohn H.-S, Cho CS. Synth. Commun. 2017; 47: 1046
  CrossrefSearch in Google Scholar
• 86 Sikari R, Sinha S, Chakraborty G, Das S, van Leest NP, Paul ND. RSC Adv. 2019; 18: 4342
  Search in Google Scholar
• 87 Luong TT. H, Brion JD, Alami M, Messaoudi S. J. Org. Chem. 2014; 80: 751
  CrossrefPubMedSearch in Google Scholar
• 88 Wang R, Qian W, Bao W. Tetrahedron Lett. 2012; 53: 442
  CrossrefSearch in Google Scholar
• 89 Pal S, Mukherjee M, Podder D, Mukherjee AK, Ghatak UR. J. Chem. Soc., Chem. Commun. 1991; 1591
• 90a García-Cuadrado D, Braga AA. C, Maseras F, Echavarren AM. J. Am. Chem. Soc. 2006; 128: 1066
  CrossrefPubMedSearch in Google Scholar
• 90b García-Cuadrado D, de Mendoza P, Braga AA. C, Maseras F, Echavarren AM. J. Am. Chem. Soc. 2007; 129: 6880
  CrossrefPubMedSearch in Google Scholar
• 91 Giorgi G, Maiti S, López-Alvarado P, Menendez JC. Org. Biomol. Chem. 2011; 9: 2722
  CrossrefPubMedSearch in Google Scholar
• 92 Dai Y, Feng X, Liu H, Jiang H, Bao M. J. Org. Chem. 2011; 76: 10068
  CrossrefPubMedSearch in Google Scholar
• 93 Umeda R, Miyake S, Nishiyama Y. Chem. Lett. 2012; 41: 215
  CrossrefSearch in Google Scholar
• 94 Toummini D, Ouazzani F, Taillefer M. Org. Lett. 2013; 15: 4690
  CrossrefPubMedSearch in Google Scholar
• 95 Chen Y, Zhang N, Ye L, Chen J, Sun X, Zhang X, Yan M. RSC Adv. 2015; 5: 48046
  CrossrefSearch in Google Scholar
• 96 Wei Q, Cai JH, Hu XD, Zhao J, Cong HJ, Zheng C, Liu WB. ACS Catal. 2020; 10: 216
  CrossrefSearch in Google Scholar
• 97 Yang L, Matsuyama H, Zhang S, Terada M, Jin T. Org. Lett. 2020; 22: 5121
  CrossrefPubMedSearch in Google Scholar
• 98 Wu K.-J, Dai L.-X, You S.-L. Org. Lett. 2012; 14: 3772
  CrossrefPubMedSearch in Google Scholar
• 99a Kalgutkar A, Jones R, Sawant A. Sulfonamide as an Essential Functional Group in Drug Design. In Metabolism Pharmacokinetics and Toxicity of Functional Groups: Impact of Chemical Building Blocks on ADMET. Smith DA. RSC Drug Discovery Series No. 1; RSC Publishing; Cambridge: 2010
  Search in Google Scholar
• 99b Olkkola KT, Ahonen J. Midazolam and Other Benzodiazepines . In Modern Anesthetics: Handbook of Experimental Pharmacology . Schîttler J, Schwilden H. Springer-Verlag; Berlin, Heidelberg: 2008: 335
  Search in Google Scholar
• 99c Hansch C, Sammes PG, Taylor JB. In Comprehensive Medicinal Chemistry . Pergamon Press; Oxford: 1990: 2
  Search in Google Scholar
• 100 Petigara RB, Yale HL. J. Heterocycl. Chem. 1974; 11: 331
  CrossrefSearch in Google Scholar
• 101 Harayama T, Sato T, Hori A, Abe H, Takeuchi Y. Synthesis 2004; 1446
• 102 Goh Y.-H, Kim G, Kim BT, Heo J.-N. Heterocycles 2010; 80: 669
  CrossrefSearch in Google Scholar
• 103 Cheetham CA, Massey RS, Pira SL, Pritchard RG, Wallace TW. Org. Biomol. Chem. 2011; 9: 1831
  CrossrefPubMedSearch in Google Scholar
• 104 Guastavino JF, Rossi RA. J. Org. Chem. 2012; 77: 460
  CrossrefPubMedSearch in Google Scholar
• 105 Laha JK, Shah PU, Jethava KP. Chem. Commun. 2013; 49: 7623
  CrossrefPubMedSearch in Google Scholar
• 106 Neogi A, Majhi TP, Ghoshal N, Chattopadhyay P. Tetrahedron 2005; 61: 9368
  CrossrefSearch in Google Scholar
• 107 Mitra S, Darira H, Chattopadhyay P. Synthesis 2013; 45: 85
  Search in Google Scholar
• 108 Laha JK, Satyanarayana Tummalapalli KS, Gupta A. Eur. J. Org. Chem. 2014; 4773
• 109a Biswas S, Batra S. Adv. Synth. Catal. 2011; 353: 2861
  CrossrefSearch in Google Scholar
• 109b Lu D, Ma C, Yuan S, Zhou L, Zeng Q. Adv. Synth. Catal. 2015; 357: 3491
  CrossrefSearch in Google Scholar
• 110 Srinivasulu V, Janda KD, Abu-Yousef IA, O’Connor MJ, Al-Tel TH. Tetrahedron 2017; 73: 2139
  CrossrefSearch in Google Scholar
• 111 Yale HL, Sowinski F. J. Med. Chem. 1964; 7: 609
  CrossrefPubMedSearch in Google Scholar
• 112 Yale HA, Pluscec J. J. Org. Chem. 1970; 35: 4254
  CrossrefSearch in Google Scholar
• 113 Margolis BJ, Swidorski JJ, Rogers BN. J. Org. Chem. 2003; 68: 644
  CrossrefPubMedSearch in Google Scholar
• 114 Laha JK, Sharma S, Dayal N. Eur. J. Org. Chem. 2015; 7885
• 115 Reames DC, Hunt DA, Bradsher CK. Synthesis 1980; 454
• 116a Vedejs E, Galante RJ, Goekjian PG. J. Am. Chem. Soc. 1998; 120: 3613
  CrossrefSearch in Google Scholar
• 116b Faulkner DJ. Nat. Prod. Rep. 1989; 5: 613
  CrossrefPubMedSearch in Google Scholar
• 116c Faulkner DJ. Nat. Prod. Rep. 1986; 3: 1
  CrossrefPubMedSearch in Google Scholar
• 116d Stillings MR, Freeman S, Myers PL, Readhead MJ, Welboum AP, Rance MJ, Atkinson DC. J. Med. Chem. 1985; 28: 225
  CrossrefPubMedSearch in Google Scholar
• 116e Faulkner DJ. Nat. Prod. Rep. 1984; 1: 251
  CrossrefSearch in Google Scholar
• 116f Faulkner DJ. Nat. Prod. Rep. 1984; 1: 551
  CrossrefSearch in Google Scholar
• 116g Devon TK, Scott AI. In Handbook of Naturally Occurring Compounds, Vol. II. Academic Press; New York: 1972
  Search in Google Scholar
• 116h Basil B, Coffee EC. J, Gell DL, Maxwell DR, Sheffield DJ, Wooldridge KR. H. J. Med. Chem. 1970; 13: 403
  CrossrefPubMedSearch in Google Scholar
• 117 Majumdar KC, Chattopadhyay B, Samanta S. Tetrahedron Lett. 2009; 50: 3178
  CrossrefSearch in Google Scholar
• 118 Majumdar KC, Nandi RK, Samanta S, Chattopadhyay B. Synthesis 2010; 985
• 119 Jäger M, Görls H, Günther W, Schubert US. Chem. Eur. J. 2013; 19: 2150
  CrossrefPubMedSearch in Google Scholar
• 120 Nandi A, Mukhopadhyay R, Chattopadhyay P. J. Chem. Soc., Perkin Trans. 1 2001; 3346
• 121 Adhikary ND, Chattopadhyay P. Eur. J. Org. Chem. 2010; 1754
• 122 Majumdar KC, Chattopadhyay B, Ray K. Tetrahedron Lett. 2007; 48: 7633
  CrossrefSearch in Google Scholar
• 123 Majumdar KC, Chattopadhyay B. Synlett 2008; 979
• 124 Majumdar KC, Ansary I, Sinha B, Chattopadhyay B. Synthesis 2009; 3593
• 125 Ghosh T. New J. Chem. 2017; 41: 2927
  CrossrefSearch in Google Scholar
• 126 Zhu C, Wang D, Zhao Y, Sun W.-Y, Shi Z. J. Am. Chem. Soc. 2017; 139: 16486
  CrossrefPubMedSearch in Google Scholar

Corresponding Authors

Publication History

Received: 10 March 2024

Accepted after revision: 22 April 2024

Accepted Manuscript online:
22 April 2024

Article published online:
16 May 2024

© 2024. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References


For reviews on transition-metal-catalyzed C–X and C–C coupling reaction see:
• 1a Wegner H, Auzias M. Angew. Chem. Int. Ed. 2011; 50: 8236
  CrossrefPubMedSearch in Google Scholar
• 1b Bellina F, Rossi R. Chem. Rev. 2010; 110: 1082
  CrossrefPubMedSearch in Google Scholar
• 1c Yin L, Liebscher J. Chem. Rev. 2007; 107: 133
  CrossrefPubMedSearch in Google Scholar
• 1d Chinchilla R, Nájera C. Chem. Rev. 2007; 107: 874
  CrossrefPubMedSearch in Google Scholar
• 1e Fairlamb IJ. S. Annu. Rep. Prog. Chem., Sect. B 2006; 102: 50
  CrossrefSearch in Google Scholar
• 2a Stumer R. Angew. Chem. Int. Ed. 1999; 38: 3307
  CrossrefPubMedSearch in Google Scholar
• 2b Aranyos A, Old DW, Kiyomori A, Wolfe JP, Sadighi JP, Buchwald SL. J. Am. Chem. Soc. 1999; 121: 4369
  CrossrefSearch in Google Scholar
• 2c Metal-Catalyzed Cross-Coupling Reactions . Diederich F, Stang PJ. Wiley-VCH; Weinheim: 1998
  Search in Google Scholar
• 2d Old DW, Wolfe JP, Buchwald SL. J. Am. Chem. Soc. 1998; 120: 9722
  CrossrefSearch in Google Scholar
• 2e Beller M. Angew. Chem. Int. Ed. 1995; 34: 1316
  CrossrefSearch in Google Scholar
• 2f Hartwig JP. Synlett 1997; 329
• 2g Wagaw S, Rennels RA, Buchwald SL. J. Am. Chem. Soc. 1997; 119: 8451
  CrossrefSearch in Google Scholar
• 2h Wolfe JP, Wagaw S, Buchwald SL. J. Am. Chem. Soc. 1996; 118: 7215
  CrossrefSearch in Google Scholar
• 3a Ricordi VG, Fritas CF, Perin G, Lenardão EJ, Jacob RG, Savegnago L, Alues D. Green Chem. 2012; 14: 1030
  CrossrefSearch in Google Scholar
• 3b Jiao J, Zhang X.-R, Chang N.-H, Wang J, Wei J.-F, Shi X.-Y, Chen Z.-G. J. Org. Chem. 2011; 76: 1180
  CrossrefPubMedSearch in Google Scholar
• 3c Cortes-Salva M, Garvin C, Antilla JC. J. Org. Chem. 2011; 76: 1456
  CrossrefPubMedSearch in Google Scholar
• 3d Altman RA, Shafir A, Lichtor PA, Buchwald SL. J. Org. Chem. 2008; 73: 284
  CrossrefPubMedSearch in Google Scholar
• 3e Niu J, Zhou H, Li Z, Xu J, Hu S. J. Org. Chem. 2008; 73: 7814
  CrossrefPubMedSearch in Google Scholar
• 3f Zhang Q, Wang D, Wang X, Ding K. J. Org. Chem. 2009; 74: 7187
  CrossrefPubMedSearch in Google Scholar
• 3g Wolf C, Liu S, Mei X, August AT, Casimir MD. J. Org. Chem. 2006; 71: 3270
  CrossrefPubMedSearch in Google Scholar
• 3h Chen Y.-J, Chen H.-H. Org. Lett. 2006; 8: 5609
  PubMedSearch in Google Scholar
• 3i Cristau H.-J, Cellier PP, Hamada S, Spindler J.-F, Taillefer M. Org. Lett. 2004; 6: 913
  CrossrefPubMedSearch in Google Scholar
• 3j Ma D, Cai Q. Org. Lett. 2003; 5: 3799
  CrossrefPubMedSearch in Google Scholar
• 3k Ley SV, Thomas AW. Angew. Chem. Int. Ed. 2003; 38: 5400
  CrossrefPubMedSearch in Google Scholar
• 3l Kunz K, Scholz ZV, Ganzer D. Synlett 2003; 2428
• 3m Kwong FY, Klapars A, Buchwald SL. Org. Lett. 2002; 4: 581
  CrossrefPubMedSearch in Google Scholar
• 3n Stephens RD, Castro CE. J. Org. Chem. 1963; 28: 2163
  Search in Google Scholar
• 3o Stephens RD, Castro CE. J. Org. Chem. 1963; 28: 3313
  CrossrefSearch in Google Scholar
• 3p Ullmann F. Chem. Ber. 1903; 36: 2382
  CrossrefSearch in Google Scholar
• 3q Ullmann F, Sponagel O. Chem. Ber. 1903; 36: 2382
  CrossrefSearch in Google Scholar
• 3r Ullmann F. Chem. Ber. 1901; 34: 2174
  CrossrefSearch in Google Scholar
• 4 Patel MV, Bell R, Majest S, Henry R, Kolasa T. J. Org. Chem. 2004; 69: 7058
  CrossrefPubMedSearch in Google Scholar
• 5 Chai X, Guan Z, Yu S, Zhou Q, Hu H, Zou Y, Tao X, Wu Q. Bioorg. Med. Chem. Lett. 2012; 22, 5849
  PubMed
• 6 Saeedi M, Mohammadi-Khanaposhtani M, Pourrabia P, Razzaghi N, Ghadimi R, Imanparast S, Faramarzi MA, Bandarian F, Esfahani EN, Safavi M, Rastegar H, Larijani B, Mahdavi M, Akbarzadeh T. Bioorg. Chem. 2019; 83: 161
  CrossrefPubMedSearch in Google Scholar
• 7 Zou Y, Zhao Q, Liao J, Hu H, Yu S, Chai X, Xu M, Wu Q. Bioorg. Med. Chem. Lett. 2012; 22: 2959
  CrossrefPubMedSearch in Google Scholar
• 8 Zhang Y, Lv Z, Zhong H, Geng D, Zhang M, Zhang T, Li Y, Li K. Eur. J. Med. Chem. 2012; 53: 356
  CrossrefPubMedSearch in Google Scholar
• 9a Thangadurai A, Minu M, Wakode S, Agrawal S, Narasimhan B. Med. Chem. Res. 2012; 21: 1509
  CrossrefSearch in Google Scholar
• 9b Gaikwad DD, Chapolikar AD, Devkate CG, Warad KD, Tayade AP, Pawar RP, Domb AJ. Eur. J. Med. Chem. 2015; 90: 707
  CrossrefPubMedSearch in Google Scholar
• 9c Jia B.-X, Zeng X.-L, Ren F.-X, Jia L, Chen X.-Q, Yang J, Liu H.-M, Wang Q. Food Chem. 2014; 155: 31
  CrossrefPubMedSearch in Google Scholar
• 9d Hassanein HH, Khalifa MM, El-Samaloty ON, El-Rahim MA, Taha RA, Magda Ismail MF. Arch. Pharm. Res. 2008; 31: 562
  CrossrefPubMedSearch in Google Scholar
• 9e Xue N, Yang X, Wu R, Chen J, He Q, Yang B, Lu X, Hu Y. Bioorg. Med. Chem. 2008; 16: 2550
  CrossrefPubMedSearch in Google Scholar
• 9f Sheppeck JE. II, Gilmore JL, Tebben A, Xue C.-B, Liu R.-Q, Decicco CP, Duan JJ.-W. Bioorg. Med. Chem. Lett. 2007; 17: 2769
  CrossrefPubMedSearch in Google Scholar
• 9g Bringmann G, Mühlbacher J, Messer K, Dreyer M, Ebel R, Nugroho BW, Wray V, Proksch P. J. Nat. Prod. 2003; 66: 80
  CrossrefPubMedSearch in Google Scholar
• 9h Ferrari M, Goadsby P, Roon K, Lipton R. Cephalalgia 2002; 22: 633
  CrossrefPubMedSearch in Google Scholar
• 9i Naylor EM, Parmee ER, Colandrea VJ, Perkins L, Brockunier L, Candelore MR, Cascieri MA, Colwell LF. Jr, Deng L, Feeney WP, Forrest MJ, Hom GJ, MacIntyre DE, Strader CD, Tota L, Wang P.-R, Wyvratt MJ, Fisher MH, Weber AE. Bioorg. Med. Chem. Lett. 1999; 9: 755
  CrossrefPubMedSearch in Google Scholar
• 9j Reitz DB, Garland DJ, Norton MB, Collins JT, Reinhard EJ, Manning RE, Olins GM, Chen ST, Palomo MA, McMahon EG. Bioorg. Med. Chem. Lett. 1993; 3: 1055
  CrossrefSearch in Google Scholar
• 9k Kant K, Patel CK, Banerjee S, Naik P, Atta AK, Kabi AK, Malakar CC. ChemistrySelect 2023; 8: e202303988
  CrossrefSearch in Google Scholar
• 9l Kaldhi D, Vodnala N, Gujjarappa R, Malakar CC, Nayak S, Ravichandiran V, Gupta S, Hazra CK. Tetrahedron Lett. 2019; 60: 223
  CrossrefSearch in Google Scholar
• 9m Aljaar N, Ibrahim MM, Younes EA, Al-Noaimi M, Abu-Safieh KA, Ali BF, Kant K, Al-Zaqri N, Sengupta R, Malakar CC. Asian J. Org. Chem. 2023; 12: e202300036
  CrossrefSearch in Google Scholar
• 9n Kabi AK, Gujjarappa R, Vodnala N, Kaldhi D, Tyagi U, Mukherjee K, Malakar CC. Tetrahedron Lett. 2020; 61: 152535
  CrossrefSearch in Google Scholar
• 9o Kabi AK, Gujjarappa R, Roy A, Sahoo A, Musib D, Vodnala N, Singh V, Malakar CC. J. Org. Chem. 2021; 86: 14597
  CrossrefPubMedSearch in Google Scholar
• 10 Song JJ, Yee NK. A. Org. Lett. 2000; 2: 519
  CrossrefPubMedSearch in Google Scholar
• 11 Aljaar N, Al-Noaimi M, Conrad J, Beifuss U. J. Org. Chem. 2020; 86: 1408
  CrossrefPubMedSearch in Google Scholar
• 12 Arai N, Takahashi M, Mitani M, Mori A. Synlett 2006; 3170
• 13 Imrich H.-G, Conrad J, Beifuss U. Eur. J. Org. Chem. 2015; 7718
• 14 Zheng HX, Shan XH, Qu JP, Kang YB. Org. Lett. 2018; 20: 3310
  CrossrefPubMedSearch in Google Scholar
• 15 Kozikowski AP, Ma D. Tetrahedron Lett. 1991; 32: 3317
  CrossrefSearch in Google Scholar
• 16 Barbero N, SanMartin R, Dominguez E. Tetrahedron Lett. 2009; 50: 2129
  CrossrefSearch in Google Scholar
• 17a Alberico D, Scott ME, Lautens M. Chem. Rev. 2007; 107: 174
  CrossrefPubMedSearch in Google Scholar
• 17b Faust R, Garratt PJ, Jones R, Yeh L.-K, Tsotinis A, Panoussopoulou M, Calogeropoulou T, The M.-T, Sugden D. J. Med. Chem. 2000; 43: 1050
  CrossrefPubMedSearch in Google Scholar
• 17c Campeau L.-C, Thansandote P, Fagnou K. Org. Lett. 2005; 7: 1857
  CrossrefPubMedSearch in Google Scholar
• 17d A palladium-catalyzed indole alkenylation by C–H functionalization aided by copper oxidants is reported in: Grimser NP, Gaunlett C, Godfrey CR. A, Gaunt MJ. Angew. Chem. Int. Ed. 2005; 44: 3125
  CrossrefPubMedSearch in Google Scholar
• 17e Kakiuchi F, Chatani N. Adv. Synth. Catal. 2003; 345: 1077
  CrossrefSearch in Google Scholar
• 17f Norinder J, Matsumoto A, Yoshikai N, Nakamura E. J. Am. Chem. Soc. 2008; 130: 5858
  CrossrefPubMedSearch in Google Scholar
• 18 Laha JK, Dayal N, Singh S, Bhimpuria R. Eur. J. Org. Chem. 2014; 5469
• 19 Cacchi S, Fabrizi G. Chem. Rev. 2011; 111: 215
  CrossrefPubMedSearch in Google Scholar
• 20 Antonio Y, De La Cruz E, Galeazzi E, Guzman A, Bray BL, Greenhouse R, Kurz LJ, Lustig DA, Maddox ML, Muchowski JM. Can. J. Chem. 1994; 72: 15
  CrossrefSearch in Google Scholar
• 21 Dodonova J, Tumkevicius S. Synthesis 2017; 49: 2523
  Thieme ConnectSearch in Google Scholar
• 22 Cui B, Shan J, Yuan C, Han W, Wan N, Chen Y. Org. Biomol. Chem. 2017; 15: 5887
  CrossrefPubMedSearch in Google Scholar
• 23 George J, Kim HY, Oh K. Org. Lett. 2019; 21: 5747
  CrossrefPubMedSearch in Google Scholar
• 24 Shim SC, Jiang LH, Lee DY, Cho CS. Bull. Korean Chem. Soc. 1995; 16: 1064
  Search in Google Scholar
• 25 Hansen SV. F, Ulven T. Org. Lett. 2015; 17: 2832
  CrossrefPubMedSearch in Google Scholar
• 26 Bachon A.-K, Opatz T. J. Org. Chem. 2016; 81: 1858
  CrossrefPubMedSearch in Google Scholar
• 27 Dandepally SR, Williams AL. Tetrahedron 2009; 50: 1395
  CrossrefSearch in Google Scholar
• 28 Huang Y, Chen W, Zhao D, Chen C, Yin H, Zheng L, Jin M, Han S. Chin. J. Chem. 2013; 31: 1007
  CrossrefSearch in Google Scholar
• 29 Xu X, Zhao L, Li Y, Soulé J.-F, Doucet H. Adv. Synth. Catal. 2015; 357: 2869
  CrossrefSearch in Google Scholar
• 30 Choi YL, Lee H, Kim BT, Choi K, Heo JN. Adv. Synth. Catal. 2010; 352: 2041
  CrossrefSearch in Google Scholar
• 31 Paleo MR, Castedo L, Domínguez D. J. Org. Chem. 1993; 58: 2763
  CrossrefSearch in Google Scholar
• 32 Ishibashi H, Kobayashi T, Nakashima S, Tamura O. J. Org. Chem. 2000; 65: 9022
  CrossrefPubMedSearch in Google Scholar
• 33 Halterman RL, Zhu C. Tetrahedron Lett. 1999; 40: 7445
  CrossrefSearch in Google Scholar
• 34 Bailey WF, Daskapan T, Rampalli S. J. Org. Chem. 2003; 68: 1334
  CrossrefPubMedSearch in Google Scholar
• 35 Halterman RL, Crow LD. Tetrahedron Lett. 2003; 44: 2907
  CrossrefSearch in Google Scholar
• 36a Kong L, Han X, Jiao P. Chem. Commun. 2014; 50: 14113
  CrossrefPubMedSearch in Google Scholar
• 36b Muratake H, Natsume M, Nakai H. Tetrahedron 2004; 60: 11783
  CrossrefSearch in Google Scholar
• 37 Deng R, Sun L, Li Z. Org. Lett. 2007; 9: 5207
  CrossrefPubMedSearch in Google Scholar
• 38 Shimizu M, Tomioka Y, Nagao I, Hiyama T. Synlett 2009; 3147
• 39 Rousseaux S, García-Fortanet J, Del Aguila Sanchez MA, Buchwald SL. J. Am. Chem. Soc. 2011; 133: 9282
  CrossrefPubMedSearch in Google Scholar
• 40 Song J, Sun W, Li Y, Wei F, Liu C, Qian Y, Chen S. Chem. Asian J. 2016; 11: 211
  CrossrefPubMedSearch in Google Scholar
• 41 Wang H, Huang H, Gong C, Diao Y, Chen J, Wu S.-H, Wang L. Org. Lett. 2022; 24: 328
  CrossrefPubMedSearch in Google Scholar
• 42a Acharya A, Gautam V, Ila H. J. Org. Chem. 2017; 82: 7920
  CrossrefPubMedSearch in Google Scholar
• 42b Patel CK, Gujjarappa R, Kant K, Ghanta S, Singh V, Kabi AK, Al-Zaqri N, Malakar CC. Adv. Synth. Catal. 2023; 365: 2203
  CrossrefSearch in Google Scholar
• 42c Kant K, Banerjee S, Patel CK, Kalita S, Reetu R, Naik P, Aljaar N, Malakar CC. Heterocycles 2023; 106: 925
  CrossrefSearch in Google Scholar
• 42d Patel CK, Banerjee S, Kant K, Sengupta R, Aljaar N, Malakar CC. Asian J. Org. Chem. 2023; 12: e202300311
  CrossrefSearch in Google Scholar
• 42e Reetu R, Gujjarappa R, Malakar CC. Asian J. Org. Chem. 2022; 11: e202200163
  CrossrefSearch in Google Scholar
• 42f Bhattacharya P, Senapati K, Chattopadhyay K, Mandal SM, Basak A. RSC Adv. 2015; 5: 61562
  CrossrefSearch in Google Scholar
• 42g Pratap R, Ram VJ. Chem. Rev. 2014; 114: 10476
  CrossrefPubMedSearch in Google Scholar
• 42h Killander D, Sterner O. Eur. J. Org. Chem. 2014; 1594
• 42i Appendino G, Gibbons S, Giana A, Pagani A, Grassi G, Stavri M, Smith E, Rahman MM. J. Nat. Prod. 2008; 71: 1427
  CrossrefPubMedSearch in Google Scholar
• 42j Simon-Levert A, Aze A, Bontemps-Subielos N, Banaigs B, Genevière A.-M. Chem.-Biol. Interact. 2007; 168: 106
  CrossrefPubMedSearch in Google Scholar
• 43 Bowman WR, Mann E, Parr J. J. Chem. Soc., Perkin Trans. 1 2000; 2991
• 44 Parisien M, Valette D, Fagnou K. J. Org. Chem. 2005; 70: 7578
  CrossrefPubMedSearch in Google Scholar
• 45 Bajracharya GB, Daugulis O. Org. Lett. 2008; 10: 4625
  CrossrefPubMedSearch in Google Scholar
• 46 Ortiz Villamizar MC, Zubkov FI, Puerto Galvis CE, Vargas Méndez LY, Kouznetsov VV. Org. Chem. Front. 2017; 4: 1736
  CrossrefSearch in Google Scholar
• 47 Majumdar KC, Pal AK, Taher A, Debnath P. Synthesis 2007; 1707
• 48 Majumdar KC, Debnath P, Taher A, Pal AK. Can. J. Chem. 2008; 86: 325
  CrossrefSearch in Google Scholar
• 49 Nolan M.-T, Bray JT. W, Eccles K, Cheung MS, Lin Z, Lawrence SE, Whitwood AC, Fairlamb IJ. S, McGlacken GP. Tetrahedron 2014; 70: 7120
  CrossrefSearch in Google Scholar
• 50 Majumdar K, Islam R. Synth. Commun. 2008; 38: 4053
  CrossrefSearch in Google Scholar
• 51 Majumdar KC, Mukhopadhyay PP, Basu PK. Synth. Commun. 2005; 35: 1291
  CrossrefSearch in Google Scholar
• 52 Petrone DA, Malik HA, Clemenceau A, Lautens M. Org. Lett. 2012; 14: 4806
  CrossrefPubMedSearch in Google Scholar
• 53 Yang W, Yan J, Long Y, Zhang S, Liu J, Zeng Y, Cai Q. Org. Lett. 2013; 15: 6022
  CrossrefPubMedSearch in Google Scholar
• 54 Garrison AT, Childress ES, Davis DC, Lindsley CW. J. Org. Chem. 2019; 84: 5855
  CrossrefPubMedSearch in Google Scholar
• 55 Nikolić AM, Živković F, Selaković Ž, Wipf P, Opsenica IM. Eur. J. Org. Chem. 2020; 5616
• 56 Fang Y, Li C. J. Org. Chem. 2006; 71: 6427
  CrossrefPubMedSearch in Google Scholar
• 57 Majumdar KC, Chakravorty S, De N. Tetrahedron Lett. 2008; 49: 3419
  CrossrefSearch in Google Scholar
• 58 Malakar CC, Schmidt D, Conard J, Beifuss U. Org. Lett. 2011; 13: 1972
  CrossrefPubMedSearch in Google Scholar
• 59 Zhang XY, Fang LL, Liu N, Wu HY, Fan XS. Chin. Chem. Lett. 2012; 23: 1129
  CrossrefSearch in Google Scholar
• 60 Sudheendran K, Malakar CC, Conrad J, Beifuss U. J. Org. Chem. 2012; 77: 10194
  CrossrefPubMedSearch in Google Scholar
• 61 Mao Z, Zhu X, Wan Y. Catal. Lett. 2015; 145: 1612
  CrossrefSearch in Google Scholar
• 62 Barluenga J, Fanňanás FJ, Sanz R, Fernández Y. Chem. Eur. J. 2002; 8: 2034
  CrossrefPubMedSearch in Google Scholar
• 63 Majumdar K, Mukhopadhyay P, Biswas A. Tetrahedron Lett. 2005; 46: 6655
  CrossrefSearch in Google Scholar
• 64 Majumdar KC, Chattopadhyay B, Nath S. Synth. Commun. 2007; 37: 2907
  CrossrefSearch in Google Scholar
• 65 Castanheiro T, Donnard M, Gulea M, Suffert J. Org Lett. 2014; 16: 3060
  CrossrefPubMedSearch in Google Scholar
• 66a Ball M, Zhong Y, Wu Y, Schenck C, Ng F, Steigerwald M, Xiao S, Nuckolls C. Acc. Chem. Res. 2015; 48: 267
  CrossrefPubMedSearch in Google Scholar
• 66b Penning TM. Chem. Res. Toxicol. 2014; 27: 1901
  CrossrefPubMedSearch in Google Scholar
• 66c Ghinet A, Gautret P, Hijfte NV, Ledé B, Hénichart J.-P, Bîcu E, Darbost U, Rigo B, Daïch A. Chem. Eur. J. 2014; 20: 10117
  CrossrefPubMedSearch in Google Scholar
• 66d Castillo D, Sauvain M, Rivaud M, Jullian V. Planta Med. 2014; 80: 902
  Thieme ConnectPubMedSearch in Google Scholar
• 66e Jin Z. Nat. Prod. Rep. 2011; 28: 1126
  CrossrefPubMedSearch in Google Scholar
• 66f Nakanishi T, Suzuki M, Saimoto A, Kabasawa T. J. Nat. Prod. 1999; 62: 864
  CrossrefPubMedSearch in Google Scholar
• 66g Boulware RT, Stermitz FR. J. Nat. Prod. 1981; 44: 200
  CrossrefSearch in Google Scholar
• 66h Muth CW, Bhattacharya B, Mahaffey RL, Minigh HL. J. Med. Chem. 1973; 16: 303
  CrossrefPubMedSearch in Google Scholar
• 67 Majumdar K, Chattopadhyay B, Pal A. Lett. Org. Chem. 2008; 5: 276
  CrossrefSearch in Google Scholar
• 68 Zhang X, Guo X, Fang L, Song Y, Fan X. Eur. J. Org. Chem. 2013; 8087
• 69 Liu C, Zhu XJ, Han YZ, Yang HJ, Zhu CJ, Fu H. Org. Biomol. Chem. 2019; 17: 4984
  CrossrefPubMedSearch in Google Scholar
• 70 Majumdar KC, Mukhopadhyay PP. Synthesis 2003; 920
• 71 Sanz R, Ignacio JM, Castroviejo MP, Fañanásb FJ. ARKIVOC 2007; (iv): 84
  Search in Google Scholar
• 72 Chouhan G, Alper HJ. J. Org. Chem. 2009; 74: 6181
  CrossrefPubMedSearch in Google Scholar
• 73 Han W, Zhou X, Yang S, Xiang G, Cui B, Chen Y. J. Org. Chem. 2015; 80: 11580
  CrossrefPubMedSearch in Google Scholar
• 74 Wang M, Zhang X, Zhuang Y.-H, Xu Y.-H, Loh T.-P. J. Am. Chem. Soc. 2015; 137: 1341
  CrossrefPubMedSearch in Google Scholar
• 75 Song ZY, Luo J, Ren DZ, Fu J, Liu YJ, Jin FM, Huo ZB. ARKIVOC 2017; (v): 148
  CrossrefPubMedSearch in Google Scholar
• 76 Zhang T, Cui B, Han W, Wan N, Bai M, Chen Y. Eur. J. Org. Chem. 2017; 3179
• 77 Arasakumar T, Shyamsivappan S, Gopalan S, Ata A, Mohan PS. Synlett 2019; 30: 63
  Thieme ConnectSearch in Google Scholar
• 78 Hoshimoto Y, Nishimura C, Sasaoka Y, Kumar R, Ogoshi S. Bull. Chem. Soc. Jpn. 2020; 93: 182
  CrossrefSearch in Google Scholar
• 79 Laha JK, Dayal N, Jain R, Patel K. J. Org. Chem. 2014; 79: 10899
  CrossrefPubMedSearch in Google Scholar
• 80 De S, Ghosh S, Bhunia S, Sheikh JA, Bisai A. Org. Lett. 2012; 14: 4466
  CrossrefPubMedSearch in Google Scholar
• 81 Maity A, Mondal S, Paira R, Hazra A, Naskar S, Sahu KB, Saha P, Banerjee S, Mondal NB. Tetrahedron Lett. 2011; 52: 3033
  CrossrefSearch in Google Scholar
• 82 Malakar CC, Baskakova A, Conrad J, Beifuss U. Chem. Eur. J. 2012; 18: 8882
  CrossrefPubMedSearch in Google Scholar
• 83 Fan X, Li B, Guo S, Wang Y, Zhang X. Chem. Asian J. 2014; 9: 739
  CrossrefPubMedSearch in Google Scholar
• 84 Kiruthika SE, Perumal PT. Org. Lett. 2014; 16: 484
  CrossrefPubMedSearch in Google Scholar
• 85 Lee HK, Sohn H.-S, Cho CS. Synth. Commun. 2017; 47: 1046
  CrossrefSearch in Google Scholar
• 86 Sikari R, Sinha S, Chakraborty G, Das S, van Leest NP, Paul ND. RSC Adv. 2019; 18: 4342
  Search in Google Scholar
• 87 Luong TT. H, Brion JD, Alami M, Messaoudi S. J. Org. Chem. 2014; 80: 751
  CrossrefPubMedSearch in Google Scholar
• 88 Wang R, Qian W, Bao W. Tetrahedron Lett. 2012; 53: 442
  CrossrefSearch in Google Scholar
• 89 Pal S, Mukherjee M, Podder D, Mukherjee AK, Ghatak UR. J. Chem. Soc., Chem. Commun. 1991; 1591
• 90a García-Cuadrado D, Braga AA. C, Maseras F, Echavarren AM. J. Am. Chem. Soc. 2006; 128: 1066
  CrossrefPubMedSearch in Google Scholar
• 90b García-Cuadrado D, de Mendoza P, Braga AA. C, Maseras F, Echavarren AM. J. Am. Chem. Soc. 2007; 129: 6880
  CrossrefPubMedSearch in Google Scholar
• 91 Giorgi G, Maiti S, López-Alvarado P, Menendez JC. Org. Biomol. Chem. 2011; 9: 2722
  CrossrefPubMedSearch in Google Scholar
• 92 Dai Y, Feng X, Liu H, Jiang H, Bao M. J. Org. Chem. 2011; 76: 10068
  CrossrefPubMedSearch in Google Scholar
• 93 Umeda R, Miyake S, Nishiyama Y. Chem. Lett. 2012; 41: 215
  CrossrefSearch in Google Scholar
• 94 Toummini D, Ouazzani F, Taillefer M. Org. Lett. 2013; 15: 4690
  CrossrefPubMedSearch in Google Scholar
• 95 Chen Y, Zhang N, Ye L, Chen J, Sun X, Zhang X, Yan M. RSC Adv. 2015; 5: 48046
  CrossrefSearch in Google Scholar
• 96 Wei Q, Cai JH, Hu XD, Zhao J, Cong HJ, Zheng C, Liu WB. ACS Catal. 2020; 10: 216
  CrossrefSearch in Google Scholar
• 97 Yang L, Matsuyama H, Zhang S, Terada M, Jin T. Org. Lett. 2020; 22: 5121
  CrossrefPubMedSearch in Google Scholar
• 98 Wu K.-J, Dai L.-X, You S.-L. Org. Lett. 2012; 14: 3772
  CrossrefPubMedSearch in Google Scholar
• 99a Kalgutkar A, Jones R, Sawant A. Sulfonamide as an Essential Functional Group in Drug Design. In Metabolism Pharmacokinetics and Toxicity of Functional Groups: Impact of Chemical Building Blocks on ADMET. Smith DA. RSC Drug Discovery Series No. 1; RSC Publishing; Cambridge: 2010
  Search in Google Scholar
• 99b Olkkola KT, Ahonen J. Midazolam and Other Benzodiazepines . In Modern Anesthetics: Handbook of Experimental Pharmacology . Schîttler J, Schwilden H. Springer-Verlag; Berlin, Heidelberg: 2008: 335
  Search in Google Scholar
• 99c Hansch C, Sammes PG, Taylor JB. In Comprehensive Medicinal Chemistry . Pergamon Press; Oxford: 1990: 2
  Search in Google Scholar
• 100 Petigara RB, Yale HL. J. Heterocycl. Chem. 1974; 11: 331
  CrossrefSearch in Google Scholar
• 101 Harayama T, Sato T, Hori A, Abe H, Takeuchi Y. Synthesis 2004; 1446
• 102 Goh Y.-H, Kim G, Kim BT, Heo J.-N. Heterocycles 2010; 80: 669
  CrossrefSearch in Google Scholar
• 103 Cheetham CA, Massey RS, Pira SL, Pritchard RG, Wallace TW. Org. Biomol. Chem. 2011; 9: 1831
  CrossrefPubMedSearch in Google Scholar
• 104 Guastavino JF, Rossi RA. J. Org. Chem. 2012; 77: 460
  CrossrefPubMedSearch in Google Scholar
• 105 Laha JK, Shah PU, Jethava KP. Chem. Commun. 2013; 49: 7623
  CrossrefPubMedSearch in Google Scholar
• 106 Neogi A, Majhi TP, Ghoshal N, Chattopadhyay P. Tetrahedron 2005; 61: 9368
  CrossrefSearch in Google Scholar
• 107 Mitra S, Darira H, Chattopadhyay P. Synthesis 2013; 45: 85
  Search in Google Scholar
• 108 Laha JK, Satyanarayana Tummalapalli KS, Gupta A. Eur. J. Org. Chem. 2014; 4773
• 109a Biswas S, Batra S. Adv. Synth. Catal. 2011; 353: 2861
  CrossrefSearch in Google Scholar
• 109b Lu D, Ma C, Yuan S, Zhou L, Zeng Q. Adv. Synth. Catal. 2015; 357: 3491
  CrossrefSearch in Google Scholar
• 110 Srinivasulu V, Janda KD, Abu-Yousef IA, O’Connor MJ, Al-Tel TH. Tetrahedron 2017; 73: 2139
  CrossrefSearch in Google Scholar
• 111 Yale HL, Sowinski F. J. Med. Chem. 1964; 7: 609
  CrossrefPubMedSearch in Google Scholar
• 112 Yale HA, Pluscec J. J. Org. Chem. 1970; 35: 4254
  CrossrefSearch in Google Scholar
• 113 Margolis BJ, Swidorski JJ, Rogers BN. J. Org. Chem. 2003; 68: 644
  CrossrefPubMedSearch in Google Scholar
• 114 Laha JK, Sharma S, Dayal N. Eur. J. Org. Chem. 2015; 7885
• 115 Reames DC, Hunt DA, Bradsher CK. Synthesis 1980; 454
• 116a Vedejs E, Galante RJ, Goekjian PG. J. Am. Chem. Soc. 1998; 120: 3613
  CrossrefSearch in Google Scholar
• 116b Faulkner DJ. Nat. Prod. Rep. 1989; 5: 613
  CrossrefPubMedSearch in Google Scholar
• 116c Faulkner DJ. Nat. Prod. Rep. 1986; 3: 1
  CrossrefPubMedSearch in Google Scholar
• 116d Stillings MR, Freeman S, Myers PL, Readhead MJ, Welboum AP, Rance MJ, Atkinson DC. J. Med. Chem. 1985; 28: 225
  CrossrefPubMedSearch in Google Scholar
• 116e Faulkner DJ. Nat. Prod. Rep. 1984; 1: 251
  CrossrefSearch in Google Scholar
• 116f Faulkner DJ. Nat. Prod. Rep. 1984; 1: 551
  CrossrefSearch in Google Scholar
• 116g Devon TK, Scott AI. In Handbook of Naturally Occurring Compounds, Vol. II. Academic Press; New York: 1972
  Search in Google Scholar
• 116h Basil B, Coffee EC. J, Gell DL, Maxwell DR, Sheffield DJ, Wooldridge KR. H. J. Med. Chem. 1970; 13: 403
  CrossrefPubMedSearch in Google Scholar
• 117 Majumdar KC, Chattopadhyay B, Samanta S. Tetrahedron Lett. 2009; 50: 3178
  CrossrefSearch in Google Scholar
• 118 Majumdar KC, Nandi RK, Samanta S, Chattopadhyay B. Synthesis 2010; 985
• 119 Jäger M, Görls H, Günther W, Schubert US. Chem. Eur. J. 2013; 19: 2150
  CrossrefPubMedSearch in Google Scholar
• 120 Nandi A, Mukhopadhyay R, Chattopadhyay P. J. Chem. Soc., Perkin Trans. 1 2001; 3346
• 121 Adhikary ND, Chattopadhyay P. Eur. J. Org. Chem. 2010; 1754
• 122 Majumdar KC, Chattopadhyay B, Ray K. Tetrahedron Lett. 2007; 48: 7633
  CrossrefSearch in Google Scholar
• 123 Majumdar KC, Chattopadhyay B. Synlett 2008; 979
• 124 Majumdar KC, Ansary I, Sinha B, Chattopadhyay B. Synthesis 2009; 3593
• 125 Ghosh T. New J. Chem. 2017; 41: 2927
  CrossrefSearch in Google Scholar
• 126 Zhu C, Wang D, Zhao Y, Sun W.-Y, Shi Z. J. Am. Chem. Soc. 2017; 139: 16486
  CrossrefPubMedSearch in Google Scholar