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Review Article Published: 03 Feb, 2020 SF Journal of Pharmaceutical and Analytical Chemistry Aromatic Substitution Reactions: An Overview

Kapoor Y1 and Kumar K1,2* 1School of Pharmaceutical Sciences, Apeejay Stya University, Sohna-Palwal Road, Sohna, Gurgaon, Haryana, India

2School of Pharmacy and Technology Management, SVKM’s NMIMS University, Hyderabad, Telangana, India

Abstract The introduction or replacement of ’s on aromatic rings by substitution reactions is one of the most fundamental transformations in . On the basis of the , these substitution reactions can be divided into electrophilic, nucleophilic, , and transition metal catalyzed. This article also focuses on electrophilic and nucleophilic substitution mechanisms.

Introduction The replacement of an , generally , or a group attached to the carbon from the ring by another group is known as aromatic substitution. The of these reactions depends upon the nature of the existing substituent and can be ortho, Meta or Para selective. Electrophilic Aromatic Substitution (EAS) reactions are important for synthetic purposes and are also among the most thoroughly studied classes of organic reactions from a mechanistic point of view. A wide variety of can effect aromatic substitution. Usually, it is a substitution of some other group for hydrogen that is of interest, but this is not always the case. For example, both silicon and mercury substituent’s can be replaced by electrophiles. The reactivity of a particular determines which aromatic compounds can be successfully substituted. Despite the wide range of electrophilic species and aromatic ring systems that can undergo substitution, a single broad mechanistic picture encompasses most EAS reactions. The identity of the rate-determining step and the shape of the reaction energy profile are specific to individual reactions, but the sequence of steps and the nature of the intermediates are very similar across a wide range of reactivity. OPEN ACCESS EAS: General Mechanism

* Correspondence: The EAS or electrophilic follows the below generalized two steps: Kapil Kumar, School of Pharmacy and Technology Management, SVKM’s 1. In the first step, the electrophilic reagent attacks on the π electrons of the aromatic ring to form an intermediate which is known as aronium cation, the sigma complex or the pentadienyl NMIMS University, Hyderabad, cation as shown in Scheme 1. Telangana, India. Tel: +91-8872041174 2. The second step of the reaction involves the elimination of a proton from the intermediate, by Fax: +91-1636-239515 an anionic species, to form a substituted as depicted in Scheme 2. E-mail: [email protected] The reaction of benzene nucleus in the product confers stability to the substituted product. Received Date: 04 Jan 2020 Thus, the electrophilic aromatic substitution reactions are bimolecular since the rate determining Accepted Date: 27 Jan 2020 (first) step involves two step mechanisms. Published Date: 03 Feb 2020 Role of σ and π Complex in EAS Citation: Kapoor Y, Kumar K. Aromatic Substitution Reactions: An Overview. Formation of σ complex follows the initial formation of a π complex in which electrophile is SF J Pharm Anal Chem. 2020; 3(1): loosely held near the π-electron cloud of aromatic ring, however in most of aromatic substitution, 1019. formation of a π-complex is found to be reversible and rapid step which is followed by the slow (rate ISSN 2643-8178 determining) and irreversible step of σ complex formation as shown in Scheme 3. Copyright © 2020 Kumar K. This is an Nitration Reaction open access article distributed under It is carried out with a mixture of HNO and H SO (nitrating agent) the reaction proceeds very the Creative Commons Attribution 3 2 4 slowly when HNO alone is used which indicate that H SO converts the HNO into a form that is License, which permits unrestricted 3 2 4 3 capable of reacting with benzene with great ease. Evidence shows that H2SO4 helps in converting the use, distribution, and reproduction in HNO3 into nitronium which the real nitrating agent as is shown in Scheme 4. any medium, provided the original work is properly cited. Like H2SO4 other strong acids (ex., BF3, HF) also serve the purpose (Scheme 5).

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Note: shown in Scheme 14. and are reactive toward aromatic , but Lewis acid catalysts are normally needed to • H SO has no action on benzene itself under the conditions of 2 4 achieve desirable rates. Elemental reacts very exothermically nitration. and careful control of conditions is required. Molecular can + • Presence of NO2 in mixture has been confirmed by the Raman effect substitution only on very reactive aromatics, but a number of spectra. more reactive iodination reagents have been developed. It takes place in the presence of a catalyst a carrier such as iron powder, • NO +is a powerful electrophile which attacks on the benzene 2 FeCl , ZnCl , AlBr , iodine, etc. The function of the catalyst ring as explained in Scheme 6. 3 2 3 is to facilitate the formation of the electrophile, halonium ion Lewis • Each successive nitro group reduces the reactivity of ring; it is Acid facilitates cleavage of halogen bond. easy to control conditions to obtain a mono nitration product, if poly Rate studies show that chlorination is subject to acid , nitration is desired more vigorous conditions are required. although the kinetics are frequently complex [20-23]. It is much more Effect of rapid in polar than in non-polar [24]. N-Bromosuccinimide (NBS) and N-chlorosuccinimide (NCS) are alternate halogenating In CH COOH and CH NO formation of NO + is often the rate 3 3 2 2 agents, both of which can halogenate moderately active aromatics controlling step [1]. HNO in acetic anhydride (CH CO) O generates 3 3 2 in nonpolar solvents by using HCl [25] or HClO [26] as a catalyst. acetyl nitrate which give high ortho: para ratios [2]. A convenient 4 are strongly catalysed by mercuric acetate or procedure involves reaction of the aromatic in chloroform or trifluroacetate which generate acylhypohalites which are the active dichloromethane with a nitrate and trifluoroacetic anhydride [3]. halogenating agents (Scheme 15). The trifluoroacetyl hypohalites Presumably trifluoroacetyl nitrate is generated under these conditions are very reactive reagents. Even nitrobenzene, for example, is readily as illustrated in Scheme 7. brominated by trifluoroacetyl hypobromite [27]. (CH CO) O and (CF CO) O have been used in conjugation with 3 2 3 2 A solution of Br in CCl containing H SO and mercuric-oxide HNO and zeolite-β which gives excellent para selectivity (Scheme 2 4 2 4 3 is also a reactive brominating agent [28]. Fluorination can be carried 8) [4,5]. The improved selectivity is thought to occur as a result of out using fluorine diluted with an inert gas. However, great care is nitration within the zeolite pores which may restrict access to the necessary to avoid uncontrolled reaction [29]. Acetyl hypofluorite ortho-position. can be prepared in situ from fluorine and sodium acetate [30]. It Nitration can be catalyzed by lanthanide salts (Scheme 9). shows a strong preference for o-fluorination of alkoxy and - For example, the nitration of benzene, , and substituted rings. N-Fluoro-bis-(trifluoromethansulfonyl) by aqueous nitric acid proceeds in good yield in the presence of (N-fluorotriflimide) display similar reactivity and can fluorinate benzene and activated aromatics as shown in Scheme 16 [31]. Yb(O3SCF3)3 [6]. The catalysis presumably results from an oxyphilic interaction of nitrate ion with the cation, which generates or transfers Iodination’s can be carried out by mixtures of iodine and + the NO2 ion [7]. This catalytic procedure uses a stoichiometric various oxidants such as periodic acid [32], I2O5 [33], NO2 [34] and amount of nitric acid and avoids the excess strong acidity associated Ce(NH3)2(NO3)6 [35]. A mixture of a cuprous iodide and a cupric salt with conventional nitration conditions. can also affect iodination as shown in Scheme 17 [36]. Catalysis results form an oxyphilic interaction of nitrate ion with Iodination of moderately reactive aromatics can be affected by + the cation, which generates or transfers the NO2 ion. This catalytic mixtures of iodine and silver or mercuric salts [37-41]. Hypoiodites procedure uses a stoichiometric amount of nitric acid and avoids are presumably the active iodinating species. Bis-(pyridine) iodonium the excess strong acidity associated with the conventional nitration salts can iodinate benzene and activated derivatives in the presence condition Scheme 10. of strong acids such as HBF4 or CF3SO3H [42]. Some representative Salts containing the nitronium ion can be prepared and are Halogenations reactions are illustrated in Scheme 18 [43-50]. reactive nitrating agents. The tetrafluroborate salt has been used Friedel-Crafts Alkylation most frequently, [8-10] but the trifluromethane sulphonate can also be prepared readily [11], heterocycles(pyridine, quinoline) Friedel-Crafts alkylation reactions are an important method form N-nitro salts on reaction with NO BF [12]. These N-nitro for introducing carbon substituent’s on aromatic rings. The 2 4 reactive electrophiles can be either discrete ’s or heterocycles can act as nitrating reagents in a reaction called transfer polarized complexes that contain a reactive . Various nitration as shown in Scheme 11. combinations of reagents can be used to generate alkylating species. Compounds such as phenyl acetate esters and phenyl ethyl ethers, Alkylations usually involve halides and Lewis acids as shown in which have substituent’s that can serve as directing groups, Scheme 19 or reactions of or with strong acids. show high ortho: para ratios under these conditions [13]. These Owing to the involvement of carbonation’s, Friedel-Crafts reactions are believed to involve coordination of the NO + at the 2 alkylation’s can be accompanied by rearrangement of the alkylation substituent oxygen, followed by intramolecular transfer (Scheme 12). group. For example, isopropyl groups are often introduced when Scheme 13 shows some representative Aromatic nitration reactions n-propyl reactants are used as shown in Scheme 20 [51]. [14-19]. Alkyl groups can also migrate from one position to another on the ring [52]. Such migrations are also thermodynamically controlled The introduction of the onto aromatic rings by and proceed in the direction of minimizing steric interactions electrophilic substitution is an important synthetic procedure as between substitutions as illustrated in Scheme 21.

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Methane sulfonate esters of secondary alcohols also give Friedel- Bimolecular substitution crafts products in the presence of Sc(O3SCF3)3 [53] or Cu(O3SCF3)2 as In bimolecular nucleophilic substitution reactions in which shown in Scheme 22 [54]. the substrate is attacked at a saturated carbon atom, the starting Friedel-crafts alkylation can occur intramolecular to form a fused material has a tetrahedral structure, and the transition state has a ring. Intramolecular Friedel-Crafts reactions provide an important trigonal bipyramidal structure. The mechanism of this reaction is method for constructing polycyclic frameworks. It is characterized by entry of the nucleophilic reagent from one side of the substrate and departure of the ion from the other side as somewhat easier to form six-member than five-member rings in such illustrated in Scheme 30. reactions as depicted in Scheme 23. Limitations Aryl diazonium as synthetic intermediates The first widely used intermediates for nucleophilic aromatic 1. Friedel-Crafts alkylation reaction does not proceed with substitution were the aryl diazonium salts. Aryl diazonium ions aromatic reactants having electron withdrawing group . are usually prepared by reaction of with nitrous acid, which 2. Each alkyl group that is introduced increases the reactivity of is generated in situ from a nitrite salt.Unlikealiphatic diazonium ring toward further substitution, so polyalkylation can be a problem. ion, which decompose very rapidly to molecular nitrogen and a It can be minimized by using the aromatic reactant in excess Scheme carbocation, aryl diazonium ions are stable enough to exist in solution at room temperature and below. They can also be isolated as salts with 24. non-nucleophilic anions, such as tetrafluroborate or trifluroacetate. Friedel-Craft Acylation Salts prepared with o-benzene disulfonimidate (Scheme 31) also appear to have potential for synthetic application [55]. It involves reaction of acid-chlorides or anhydrides in presence of

Lewis acids such as AlCl3, SbF5, or BF3. Bismuth (III) triflate is also a The steps in forming a diazonium ion are addition ofthe very active Acylation catalyst [55,56]. For example, a combination of nitrosonium ion, NO+, to the amino group, followed by elimination hafnium (IV) triflate and LiClO4 in nitro catalyzes acylation of as shown in Scheme 32. of moderately reactive aromatics by acetic-anhydride as shown in In addition to the aqueous method for diazotization in aqueous Scheme 25. solution, diazonium ions can be generated in organic solvents by Mixed anhydrides with trifluoroacetic acid are reactive acylating reaction with alkyl nitrites as shown in Scheme 33. agents. Scheme 26 showed the use of a mixed anhydride in the course Diazonium ions form stable adducts with certain of synthesis of the anticancer agent tamoxifen. such as sec. and sulfide-anions. These compounds can be used Regioselectivity in Friedel-craftsacylation’s can be quite as precursors of diazonium ion intermediates as illustrated in Scheme sensitive to reaction solvent. In general para attack predominates 34. for alkyl . The percentage of ortho attack increases with the There are several general mechanisms by which substitution electrophilicity of the acylium-ion. Moreover, by this method no can occur. One involves unimolecular thermal decomposition of rearranged alkylated product (ex.,Cumene) is formed as shown in the diazonium ion, followed by capture of the resulting aryl cation Scheme 27. by a . The phenyl cation is very unstable and therefore Nucleophilic Aromatic Substitution highly unselective [56]. Either the solvent or an anion can act as the nucleophile as shown in Scheme 35. The replacement of hydrogen or a substitution by a nucleophilic Another mechanism for substitution is adduct formation followed reagent is known as nucleophilic aromatic substitution as shown in by collapse of adduct with loss of nitrogen as shown in Scheme 36. Scheme 28. It doesn’t take place with the benzene itself but with its some substituted derivatives and with naphthalene. Synthetically A third mechanism involves redox processes, and it is particularly important substitutions of aromatic compounds can also be done likely to operate in reactions in which copper salts are used as catalysts by nucleophilic reagents. There are several general mechanisms for as shown in Scheme 37 [57]. substitution by nucleophiles. Unlike nucleophilic substitution at Reductive dediazonization: Replacement of a nitro or amino saturated carbon, aromatic nucleophilic substitution does not occur group by hydrogen is sometimes required to a synthetic operation in by a single-step mechanism. The broad mechanistic classes that can which the substituent was used to control the position selectivity of a be recognized include addition-elimination, elimination-addition, prior transformation. The best reagents for reductive dediazonationare and metal catalyzed processes. H3PO2, NaBH4, etc. The reduction by H3PO2 proceeds by one electron Unimolecular substitution reduction followed by loss of nitrogen and formation of the phenyl radical [58]. The hypophosphorous acid then serves as a hydrogen Unimolecular nucleophilic substitution reactions proceed by a atom donor. two-stage mechanism in which heterolysis precedes reaction with the nucleophileex, uncatalysed decomposition of aryl diazonium initiation ArN N + e Ar + N2 cation (Scheme 29). The unimolecular reaction is characterized Propagation experimentally by first-order kinetics-i.e., by a rate that depends only + Ar H3PO2 Ar H + [H2PO2] on concentration of the substrate (and not the nucleophile), by the ArN N + [H2PO2 ] absence of effects of steric hindrance, by powerful facilitation of the Ar + N2 + [H2PO2] H + H3PO3 + reaction by the presence of electron-releasing groups attached to the [H2PO2] H2O reaction center, and by variable, and often diagnostic, . form diazonium ion intermediates: Aryl diazonium

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O O + X X H H O O2N X Y N O2N Y + Z N CH + NO2 O N Y Z HC O O X Z X Figure 1: H+ ions can be converted to phenols by heating in water. Under these conditions, there is probably formation of a phenyl cation as shown ZCH2 NO2 in Scheme 38. Figure 2: Aryl halides from diazonium ion intermediates: Aryl bromides and chlorides are prepared by a reaction using appropriate Cu(I) salt which is known as the . The Sandmeyer reaction occurs by an oxidative of the diazonium ion with Cu(I) and halide transfer from a Cu(III) intermediate as illustrated in Scheme 39. Reaction of with alkyl nitrites and Cu(III) halides in Figure 3: Benzyne molecule the sideways overlap pi sp2 orbitals a sigma gives good yields of aryl-halides [59]. Fluorine substituents bonds out of the plane of the aromatic sigma-cloud. can also be introduced via diazonium ions. One procedure is to isolate aryl diazonium tetrafluroborate. These decompose thermally to give aryl-fluorides [60], Called the schiemann reaction, it probably X X NH + NH3 involves formation of an aryl cation that abstracts fluoride ion from + 2 the tetrafluroborate anion as shown in Scheme 40 [61]. Figure 4: Aryl diazonium ions are converted to iodides in high yield by reaction with iodide salts. This reduction for aryl-iodide formation is X initiated by reduction of the diazonium ion by iodide. The aryl radical + X - Benzyene then abstracts iodine from either I2 or I3 . A chain mechanism then - proceeds and consumes I and ArN2 evidence for the involvement Figure 5: of radicals includes the isolated of cyclized products from o-allyl derivativesas shown in Scheme 41. developed and known as vicarious nucleophilic aromatic substitution Introduction of Other Nucleophiles Using Diazonium Ion (Figure 2). Intermediates: Cyano and azido groups are also readily introduced Substitution by the elimination-addition mechanism via diazonium intermediates. Reaction of diazonium salts with azide The elimination-addition mechanism involves a highly unstable ion gives adducts that smoothly decompose to nitrogen and the aryl intermediate called dehydrobenzene or benzyne as shown in Scheme azide as shown in Scheme 42 and Scheme 43. 46 [62]. Meerwein arylation reactions: Aryl diazonium can be used to A unique feature of this mechanism is that the entering form certain types of C-C bonds. The copper-catalyzed reaction of nucleophile doesn't necessarily become bound to the carbon to which diazonium ions with conjugated alkenes results in arylation of , the leaving group was attached as shown in Scheme 47 and Scheme known as the Meerwein arylation reaction. The reaction sequence is 47(a) (Figure 3). initiated by reduction of the diazonium ion by Cu(I). The aryl radical adds to the alkene to give a new beta-aryl radical. The final step is a This new bond orbital lies along the side of the ring and has little ligand transfer that takes place in the copper coordination sphere. An interaction with the sigma cloud lying above and below the ring. The alternative course is oxidation deprotonation, which gives a styrene sideways overlap isn't very good, so bond is weak and benzyne is derivative as shown in Scheme 44. highly reactive molecule. Substitution by the addition-elimination mechanism Benzyne formation elimination step involves two steps; The addition of a nucleophile to an aromatic ring, followed by (1) Abstraction of hydrogen ion by the ion to form NH3 elimination of substituent results in nucleophilic substitution (Figure and (Figure 4). 1). (2) Carbanion loss halide ion to form benzyne (Figure 5). The addition-elimination mechanism has been used for arylation of oxygen and nitrogen nucleophiles. The pyridine family of Addition steps also involve two steps as shown in Scheme 48; heteroaromatic nitrogen compound is reactive toward nucleophile (a) Attachment of amide ion to form carbanion. substitution at the C(2) and C(4) positions. The nitrogen atom serves to activate the ring towards nucleophilic attack by stabilizing the (b) Carbanion abstracts a hydrogen ion form acid, NH3. addition intermediate this kind of substitution reaction is especially There are several methods for Benzyne generation such as; important in chemistry of Scheme 45. (1) Benzyne can also be generated from o-dihaloaromatic. A variation of the aromatic nucleophile substitution process in Reaction with Li-Hg or results in the formation which the leaving group is front of the entering nucleophile has been of transient organometallic compounds that decompose with

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F Li-Hg F + + Li Br major monor Figure 6: Figure 11:

O CO2H HONO C O O CO + N2 N2 + 2 + NH2 N N O H CO C CO2 3 2 H3CO2C Figure 7: Figure 12:

N N N N + 2N2 N N N X + X NH2

Figure 8: + :Nu Nu

+ N Nu + X Nu X + SO N 2 + N2 S O O Figure 13: Figure 9: substitution reaction. Different types of aromatic substitution

O H2,Pd reaction like nitration, halogenation, Friedel-Crafts alkylation + O + H ,-H2O and acylation reaction were also discussed. Nucleophilic aromatic diphenylene substation reactions were also covered in this review article. Figure 10: Acknowledgements elimination of halide (Figure 6). We acknowledge the faculty member of Apeejay Stya University and SVKM’s NMIMS, Hyderabad for their guidance and support. (2) Diazotization of o-amino benzoic acid, (Figure 7). (3) Oxidation of 1-aminobenzotriazole, (Figure 8). Conflict of Interest (4) By benzothiadiazide-1, 1-dioxide, (Figure 9). The author confirms that there is no conflict of interest for this publication. Reactions of benzyne, References (1) With [4+2] products are formed (Figure 1. (A) Hughes ED, Ingold CK, Reed RI. Kinetics and mechanism of aromatic 10). + nitration. Part II. Nitration by the nitronium ion, NO2 , derived from (2) Benzyne gives both [2+2] cycloaddition and end reaction nitric acid. J Chem Soc. 1950. products with simple alkenes, (Figure 11), Scheme 49. (B) Hoggett JG, Moodie RB, Schofield K. Electrophilic aromatic substitution. Part II. The nitration of some reactive aromatic compounds Substitution by the S 1 mechanism RN by nitric acid in sulpholan and nitromethane. J Chem Soc. 1969. The distinctive feature of the S 1 mechanism is an electron RN (C) Schofield K. Aromatic Nitration. Cambridge University Press, transfer between the nucleophile and the aryl-halide the overall Cambridge, 1980, Chap 2. reaction is mainly a chain process. 2. Sparks AK. in Aromatic Nitration. Nitration by Acyl Initiation: (Figure 12). Nitrates. J Org Chem. 1966; 31: 2299-2302. Propagation: (Figure 13). 3. Crivello JV. Nitrations and oxidations with inorganic nitrate salts in trifluoroacetic anhydride. J Org Chem. 1981; 46: 3056-3060. A potential advantage of the SRN1mechanism is that it is not particularly sensitive to the nature of other aromatic ring substitution 4. Smith K, Gibbins T, Millar RW, Claridge RP. A novel method for the although EWG substitution favors the nucleophile addition step. nitration of deactivated aromatic compounds. J Chem Soc. 2000; 16: 2495- 2842. Nucleophile which shows S 1 mechanism; ketone enolates, ester RN 5. Smith K, Musson A, DeBoos GA. A Novel Method for the Nitration of enolates, amide enolates, 2, 4 pentanediene dianion, pentadienyl and Simple Aromatic Compounds. J Org Chem. 1998; 63: 8448-8454. indenyl carbanion phenolates, phosphides and thiolates. 6. Walker FJ, Barrett AGM, Braddock DC, Ramprasad D. Novel Recyclable The reactions are frequently initiated by light, which promotes Catalysts for Atom Economic Aromatic Electrophilic Nitration. J Chem the initially electron transfer. As for other radical chain process the Soc Chem Commun. 1997. reaction is sensitive to substances that can intercept the propagation 7. Walker FJ, Barrett AGM, Braddock DC, McKinnell RM, Ramprasad intermediates Scheme 50. D. Lanthanide(III) and Group IV metal triflate catalysed electrophilic nitration: ‘nitrate capture’ and the rôle of the metal centre. J Chem Soc. Conclusion 1999; 8:835-1108. Based on our interest on organic chemistry [63A-U], we 8. (A) Kuhn SJ, Olah GA. Aromatic Substitution. VII.1Friedel-Crafts Type summarized the mechanism, different derivatives of aromatic Nitration of Aromatics2. J Am Chem Soc. 1961; 83: 4564-4571. (B) Olah

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54. Singh RP, Kamble RM, Chandra KL, Saravaran P, Singh VK. An efficient (I) Mittal M, Kumar K, Anghore D, Rawal RK. ICP-MS: Analytical method for aromatic Friedel–Crafts alkylation, acylation, benzoylation, Method for Identification and Detection of Elemental Impurities. Curr and sulfonylation reactions. Tetrahedron. 2001; 57: 241-247. Drug Discover Tech. 2017; 14: 106-120. 55. (A) Barbero M, Crisma M, Degani I, Fochi R, Perracino P. New Dry (J) Kaur R, Chaudhary S, Kumar K, Gupta MK, Rawal RK. Recent synthetic Arenediazonium Salts, Stabilized to an Exceptionally High Degree by the and medicinal perspectives of dihydropyrimidinones: A review. Eur J Med Anion of o-Benzenedisulfonimide. Synthesis. 1998; 8: 1171-1175; Chem. 2017; 132: 108-134. (B) Babero M, Degani I, Dughera S, Fochi R. Halodediazoniations of Dry (K) Kumar B, Singh V, Shankar R, Kumar K, Rawal RK. Synthetic and Arenediazonium o-Benzenedisulfonimides in the Presence or Absence of Medicinal Prospective of Structurally Modified Curcumins. Curr Topics an Electron Transfer Catalyst. Easy General Procedures to Prepare Aryl Med Chem. 2017; 17: 148-161. Chlorides, Bromides, and Iodides. J Org Chem. 1999; 64: 3448-3453. (L) Talwan P, Choudhary S, Kumar K, Rawal RK. Chemical and Medicinal 56. Swain CG, Sheats JE, Harbison KG. Evidence for phenyl cation as an Versatility of Substituted 1,4-Dihydropyridines. Curr Bioact Compd. intermediated in reactions of benzenediazonium salts in solution. J Am 2017; 13: 109-120. Chem Soc. 1975; 97: 783-790. (M) Kaur R, Rani V, Abbot V, Kapoor Y, Konar D, Kumar K. Recent 57. Cohen T, Lewarchik RJ, Tarino JZ. J Am Chem Soc. 1975. synthetic and medicinal perspectives of : An overview. J Pharm Chem Chem Sci. 2017; 1: 17. 58. Kornblum N, Cooper GD, Taylor JE. The Chemistry of Diazo Compounds. II. Evidence for a Free Radical Chain Mechanism in the Reduction of (N) Kapoor Y, Kumar K. Structural clinical impact of anti-allergy agents: Diazonium Salts by Hypophosphorous Acid. J Am Chem Soc. 1950; 72: An overview. Bioorg Chem. 2020; 94: 103351. 3013-3021. (O) Kumar K, More SS, Goyal S, Gangar M, Khatik GL, Rawal RK, et al. A 59. Doyle MP, Sigfried B, Dellaria JF. Alkyl nitrite-metal halide deamination convenient synthesis of 4-alkyl-3-benzyolpyrroles from α, β-unsaturated reactions. 2. Substitutive deamination of arylamines by alkyl nitrites ketone and tosylmethylisocyanide. Tetrahedron Lett. 2016; 57: 2315-2319. and copper(II) halides. A direct and remarkably efficient conversion of (P) Kumar K, Siddique J, Gangar M, Goyal S, Rawal RK, Nair VA. ZrCl arylamines to aryl halides. J Org Chem. 1977; 42: 2426-2431. 4 catalysed diastereoselective synthesis of spirocarbocyclicoxindolesvia 60. Roe A. Org React. 1949. [4+2] cycloaddition. Chemistry Select. 2016; 1: 2409. 61. Swain CG, Rogers RJ. Mechanism of formation of aryl fluorides from (Q) Kumar K, Konar D, Goyal S, Gangar M, Chouhan M, Rawal RK, et

arenediazonium fluoborates. J Am Chem Soc. 1975; 97: 799-800. al. ChemInform Abstract: AlCl3/Cyclohexane mediated electrophilic activation of isothiocyanates: An efficient synthesis of thioamides. 62. Hoffmann RW. Dehydrobenzene and . Academic Press New Chemistry Select. 2016; 1: 3228. York. 1967. (R) Kumar K, Konar D, Goyal S, Gangar M, Chouhan M, Rawal RK, et 63. (A) Kaur R, Kapoor Y, Manjal SK, Rawal RK, Kumar K. Diversity-Oriented al. Water promoted regiospecific azidolysis and copper catalysed azide Synthetic Approaches for Furoindoline: A Review. Curr Org Synth. 2019; cycloaddition: One-pot synthesis of 3-hydroxy-1-alkyl-3-[(4-aryl/ 16: 342-368. alkyl-1H-1,2,3-triazol-1-yl)methyl]indolin-2-one derivatives. J Org Chem. (B) Kaur R, Kumar K. Chem Heterocycl Compd. 2018; 54: 700. 2016; 81: 9757-9764. (C) Kapoor Y, Kumar K. Med Ana Chem Int J. 2019; 3: 136. (S) Kumar K, More SS, Khatik GL, Rawal RK, Nair VA. A highly stereoselective chiral auxiliary-assisted reductive cyclization to (D) Kaur R, Kumar K. J Med Chem Sci. 2019; 2: 110. furoindoline. J Heterocycl Chem. 2017; 54: 2696. (E) Kapoor Y, Kumar K. Quantitative Structure Activity Relationship in (T) Kumar K, Mudshinge S, Goyal S, Gangar M, Nair VA. ChemInform Drug Design: An Overview. SF J Pharm Anal Chem 2019; 2: 1015. Abstract: A catalyst free, onepot approach for the synthesis of quinoxaline (F) Kapoor Y, Dubey S, Kar S, Kumar K. CAR T Cell: A Novel Treatment derivatives via oxidative cyclizationof 1,2-diamines and phenacyl Regime for Cancer. SF J Pharm Anal Chem. 2018; 1: 1008. bromides. Tetrahedron Lett. 2015; 56: 1266. (G) Kaur R, Manjal SK, Rawal RK, Kumar K. Recent synthetic and (U) Manjal SK, Pathania S, Bhatia R, Kaur R, Kumar K, Rawal RK. medicinal perspectives of tryptanthrin. Bioorg Med Chem. 2017; 25: 4533- Diversified Synthetic Strategies for Pyrroloindoles: An Overview. J 4552. Heterocycl Chem. 2019; 56: 2318. (H) Manjal SK, Kaur R, Bhatia R, Kumar K, Singh V, Shankar R, et al. Synthetic and medicinal perspective of thiazolidinones: A review. Bioorg Chem. 2017; 75: 406-423.

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