key: cord-0020081-psy04q47 authors: Akhtar, Rabia; Zahoor, Ameer Fawad; Rasool, Nasir; Ahmad, Matloob; Ali, Kulsoom Ghulam title: Recent trends in the chemistry of Sandmeyer reaction: a review date: 2021-08-20 journal: Mol Divers DOI: 10.1007/s11030-021-10295-3 sha: ca9ec3e306275a428d59743d5bbb80ab3901b5c0 doc_id: 20081 cord_uid: psy04q47 Metal-catalyzed reactions play a vital part to construct a variety of pharmaceutically important scaffolds from past few decades. To carry out these reactions under mild conditions with low-cost easily available precursors, various new methodologies have been reported day by day. Sandmeyer reaction is one of these, first discovered by Sandmeyer in 1884. It is a well-known reaction mainly used for the conversion of an aryl amine to an aryl halide in the presence of Cu(I) halide via formation of diazonium salt intermediate. This reaction can be processed with or without copper catalysts for the formation of C–X (X = Cl, Br, I, etc.), C-CF(3)/CF(2), C–CN, C–S, etc., linkages. As a result, corresponding aryl halides, trifluoromethylated compounds, aryl nitriles and aryl thioethers can be obtained which are effectively used for the construction of biologically active compounds. This review article discloses various literature reports about Sandmeyer-related transformations developed during 2000–2021 which give different ideas to synthetic chemists about further development of new and efficient protocols for Sandmeyer reaction. An updated compilation of new approaches for Sandmeyer reaction is described in this review to construct a variety of carbon-halogen, carbon-phosphorous, carbon-sulfur, carbon-boron etc. linkages. [Image: see text] Aromatic diazonium salts, discovered by Griefs in 1858 [1] , have wide spread applications in organic synthesis as well as at industrial level. They are frequently used for the preparation of organic nanocompounds and grafted a variety of organic molecules on metallic surfaces [2] . Furthermore, Meerwein arylation [3, 4] , Balz-Schiemann [5, 6] and various metal-catalyzed reactions [7, 8] involve diazonium salts as starting precursors for the production of various halides, phenols, cyanides, azides and alkenes [9] which serve as effective intermediates for the synthesis of important molecules [10] [11] [12] [13] . Sandmeyer reaction is one of them, in which diazonium salts are used for the construction of carbon-halogen, carbon-phosphorous, carbon-sulfur, carbon-selenium, carbon-boron bond formation. Moreover, various trifluoromethylated compounds as well as a number of pharmaceutically important drugs can be synthesized via Sandmeyer approach [14] . Literature study reveals the importance of metal-catalyzed cross-coupling reactions which are extensively used in organic synthesis and in pharmaceutical industry. These reactions are carried out by the treatment of various organic halides with a suitable coupling partner using a variety of catalysts and ligands [15] [16] [17] [18] [19] . Sandmeyer approach, first discovered in 1884 by Sandmeyer [20, 21] , is one of these metal-catalyzed reactions which effectively converts benzenediazonium salts into bromo-, chlorobenzene, benzonitriles, etc., in the presence of different copper catalysts. Since 1884, different methods have been discovered to improve the efficacy of Sandmeyer reaction as an innovation of organic phase diazotization process reported by Doyle et al. in 1977 [22, 23] and the effective utilization of these diazonium salts in a variety of metal-catalyzed reactions (Kikukawa and Matsuda, 1977) [24, 25] , etc. Although the mechanism of this reaction is not yet clear however, a general mechanism reported by Waters [26] and later on by Kochi [27] is highlighted in Scheme 1 according to which diazonium salt readily undergoes homolytic dediazoniation in the presence of copper salt, resultantly affording aryl radical. This radical upon treatment with reactive species gives desired product with regeneration of copper(I) species. Owing to the extensive applications of Sandmeyer reaction, herein we describe an updated compilation of new approaches reported during 2000-2021 for Sandmeyer reaction. Marco-Contelles and colleagues reported copper-catalyzed Sandmeyer reaction of N-(prop-2-yn-1-ylamino) pyridines in the presence of organic nitrites afforded various bicyclic chlorinated pyridones [28] . For example, reaction of pyridine 3 in combination with isopentyl nitrite and cupric chloride gave pyridone 4 in 62% yield. Temperature was maintained at 65 °C to achieve maximum conversion in acetonitrile solvent. Mechanism of this reaction first involved the coordination of nitrosyl complex of cupric chloride with alkyne group followed by the breakage of RO-NO bond releasing alkoxy radical that captured hydrogen from NH 2 group to give ROH molecule. On the other side, breakage of NH 2 bond started the free radical chain reaction resultantly affording E-exo-chloromethylene intermediate which after hydrolysis gave targeted pyridone 4 (Scheme 2). A single report considering the importance and synthesis of monofluorinated polychlorinated biphenyls has been disclosed by Sott et al. [29] in which Suzuki and Sandmeyer reactions are the key steps. Table 1 presents some of these reactions performed under optimized conditions. Suzuki coupling between arylboronic acid 5 and Scheme 1 General mechanism of Sandmeyer reaction 2,3,5,6-tetrachloro-bromoaniline (6) was processed using 3% Pd(PPh 3 ) 4 as catalyst, sodium carbonate as base and toluene as solvent. As a result, biphenyl product 7 was obtained which subsequently subjected to Sandmeyer reaction in the presence of t-BuONO and CuCl 2 to obtain required PCB (polychlorinated biphenyls) 8 in 4% overall yield. Likewise, other two reactions were also performed; however, deamination in the absence of CuCl 2 gave desired PCB 11 and 12 in 26% and 7% overall yields, respectively, which could be used as analytical standards for PCB analysis. An approach for the synthesis of tetrasubstituted pyrazole derivatives and their fungicidal properties against Uncinula necator was investigated by Dumeunier et al. [30] . Their methodology started from the reaction of acetonitrile 13 with 4-chloro benzaldehyde (14) to afford 2,3-diarylacrylonitrile 15 which was subjected to ring closure reaction with hydrazine. Resultantly, pyrazoline derivative 16 was obtained which readily converted into desired pyrazole 17 by applying standard protocol of Sandmeyer reaction (HCl, NaNO 2 , CuCl) (Scheme 3). Hughes et al. [31] proposed a strategy for the synthesis of a variety of 4-aryl-5-cyano-2-aminopyrimidines which are effectively used as VEGF (vascular endothelial growth factor)-R2 kinase inhibitors. These inhibitors stop angiogenesis process successfully, resultantly inhibiting the growth of tumor cells. The synthetic protocol of these inhibitors started from the reaction of aryl methyl ester 18 with lithium salt of the acetonitrile to obtain corresponding α-cyanoketone which on treatment with N,N-dimethylformamide diethyl acetal afforded vinylogous amide. In the next step, pyrimidine ring 19 was obtained by the reaction of vinylogous amide with guanidinium salt. Sandmeyer reaction of pyrimidine 19 in the presence of antimony trichloride and tert-butyl nitrite gave 2-chloropyrimidine derivative 20 which was efficiently converted into targeted 4-aryl-5-cyano-2-aminopyrimidine derivative 21 by the displacement of chloro group with a variety of aliphatic amines in 73-95% yield range (Scheme 4). A quite efficient and simple way to synthesize different arylpiperazines involving Sandmeyer reaction as key step was demonstrated by Rancati et al. [32] . A reference pathway is described in Scheme 5 which started from the nitration of 1,4-benzodioxin-5-carboxylic acid 22 followed by catalytic hydrogenation provided hydrochloride form of amino derivative 23 in quantitative yield. This benzodioxine was subjected to Sandmeyer reaction in the Research group of Han disclosed the synthetic route of thienopyrimidine analogs which were found to be effective FLT3 inhibitors [33] . Standard conditions to carry out this protocol started from the Knoevenagel condensation Scheme 4 Sandmeyer reaction for the preparation of aminopyrimidines derivatives Scheme 5 Preparation of arylpiperazines using Sandmeyer reaction as key step of 2-acetylthiophene 27 with malononitrile 28 followed by the treatment with elemental sulfur to obtain corresponding thiophene, ready to produce thienopyrimidine 29 after treatment with formamide. Next, Sandmeyer reaction of thienopyrimidine 29 proceeded well at 70 °C in the presence of t-BuONO and CuCl 2 . THF/CH 3 CN was used as solvents to carry out maximum conversion. Later on, reaction of chloride 30 with hydrazine monohydrate and furan 31 afforded required thienopyrimidine 32 efficiently. By using same reaction pathway, a variety of thienopyrimidine derivatives were obtained in good yield range (Scheme 6). Ding et al. [34] presented a valuable approach to obtain biologically active isatin derivatives which play an important role in pharmaceutical industry due to their excellent antitumor properties against a variety of cell lines (K562, HepG2, HT-29, HL60, etc.). Focusing the synthesis of isatin derivatives, a quite simple and easy pathway is outlined in Scheme 7 involving the condensation of aniline 33 with hydroxylamine hydrochloride at 90 °C and chloral hydrate in 2 mol/L of HCl and water solution to afford oxime 34. Cyclization of this oxime (34) in the presence of sulfuric acid with subsequent bromination reaction afforded required isatin 36 in 86% yield. Player et al. [35] reported the synthesis of 2-(2-chloro-6-fluorophenyl)acetamides and proved their potential applicability as thrombin inhibitors. A reference synthetic protocol is highlighted in Scheme 8 which started from the reaction of nitrobenzene 37 with diethyl malonate followed by decarboxylation (in the presence of LiCl) and aromatic nucleophilic substitution reaction (with amine 38) provided aryl fluoride 39. Protection of -NH group of compound 39 with subsequent reduction (Zn, AcOH) and Sandmeyer reaction (tert-butyl nitrite, CuCl 2 , CH 3 CN) provided derivative 40. Later on, deprotection of the -NH and ester groups followed by the reaction with O-guanidine segment afforded desired 2-(2-chloro-6-fluorophenyl) acetamide 41. Lobana and colleagues reported a first example of Sandmeyer reaction for the conversion of 2-mercapto-1-methylimidazoline to 2-bromo-1-methyl-imidazole at ambient temperature [36] . Copper(I) bromide was selected as suitable catalyst for this purpose, and the reaction was carried out in CH 3 CN-CHCl 3 mixture. Plausible mechanism for this conversion is presented in Scheme 9 which started from the oxidation of Cu(I) to Cu(II) ion. This copper ion further used to oxidize thio moiety 42, resultantly produced disulfide imidazoline 44 which in the last step was converted into required 2-bromo-1-methyl-imidazole 45. This brominated imidazole (45) coordinated with bromide ions in the presence of Cu 2+ to obtain tetranuclear complex [Cu 4 (η 1 -N-(N 2 C 4 H 5 Br) 4 (μ 4 -O)(μ-Br) 6 ]. The research group of Laali performed Sandmeyer reaction for the bromodediazotization of the diazonium salt 46 [37] . Reaction performed under nitrogen atmosphere using [BMIM][PF 6 ] ionic liquid, as solvent. Copper(I) bromide was used as bromine source, and temperature was maintained at 65-75 °C. Resultantly, halogenated products were obtained and their formation ratio strictly depended upon the nature of the substituents of the diazonium salts. As depicted in Scheme 10, diazonium salts having electron-donating substituents gave mainly Schiemann product; however, electronwithdrawing substituents afforded Sandmeyer product predominantly along with the formation of hydrodediazoniation product. Evans and coworkers described an impressive reaction pathway to synthesize 5-amino-3-aryl-1-(tert-butyl)-1Hpyrazole-4-carboxamides in good yield range [38] . Reaction of potassium tricyanomethanide (50) with tertbutylhydrazine (51) in a mixture of HCl and water gave 41% yield of pyrazole 52 which was successfully subjected to Sandmeyer reaction. This reaction worked very well by using t-BuONO and CuBr 2 in acetonitrile solvent. As a result, corresponding 3-bromo regioisomer 53 was afforded in 59% yield. Later on, hydrolysis of cyano group of compound 53 followed by Suzuki-Miyaura reaction gave desired pyrazole-4-carboxamide 56 in 87% yield. By using similar reaction approach, a variety of targeted compounds were obtained in 25-87% yield range (Scheme 11). Özkan et al. [39] published a report on the facile synthesis of bromobenzenes by using Sandmeyer approach. In their methodology, a quick reaction of aniline with concentrated HCl produced corresponding anilinium salt which was diazotized in the presence of ethyl nitrite. In the next step, this diazonium salt was treated with bromine radical, obtained by the reaction of molecular bromine with ammonium persulfate. As a result, desired substituted bromobenzene was afforded in moderate to good yield range (55-80%). A reference example is highlighted in Scheme 12. Research group of Schäfer reported a simple, efficient and cost-effective synthetic pathway for ethyl 5-(2,4-dif luorophenyl)-1,3,4-thiadiazole-2-carboxylate (64) including Sandmeyer bromination and Suzuki-Miyaura couplings as key steps [40] . Reactions performed at gram scale and kilogram scale level under mild conditions. An outline of these reactions is presented in Scheme 13 which started first from the conversion of ethyl 5-amino-1,3,4-thiadiazole-2-carboxylate (61) into bromo thiadiazole 62 in 71% yield. Reaction processed at room temperature in the presence of tert-butyl nitrite Scheme 10 Sandmeyer reaction for the bromodediazotization of the diazonium salt 46 and 1.5 equivalents of copper bromide using acetonitrile as an effective reaction media. Later, compound 62 was subjected to Suzuki-Miyaura reaction using boronic acid 63 as another coupling partner. This palladium-catalyzed reaction along with xanthphos ligand afforded desired cross-coupled product 64 in 85% yield. A variety of pharmaceutical agents having cyclopropylpyridine scaffold are good inhibitors of interleukin Scheme 11 Synthesis of pyrazoles by adopting Sandmeyer and Suzuki-Miyaura approaches Scheme 12 Facile synthesis of bromobenzene 60 by using Sandmeyer protocol receptor-associated kinases, PDE4 enzyme inhibitors and have been widely used to synthesize canabinoid receptor 2 agonists. Considering their importance, Striela et al. [41] prepared bromocyclopropylpyridines by the reaction of aminocyclopropylpyridines (obtained via Suzuki reaction of aminobromopyridines) with amyl nitrite through Sandmeyer approach. Reaction proceeded at room temperature in dibromomethane solvent using 0.5 equivalent CuBr 2 to obtain good yield range. A competent method for the synthesis of aryl bromides involved the reaction of arenediazonium salts with KBr, resultantly affording a variety of aryl bromides in an excellent yield range. This Sandmeyer reaction was carried out at 20-25 °C in acetonitrile solvent. Maximum conversion was achieved by using equimolar (10 mol%) catalytic mixture of CuBr and CuBr 2 along with dibenzo-18-crown-6 as a phase transfer catalyst and 1,10-phenanthroline (phen) as ligand. This protocol covers a wide substrate scope by allowing the preparation of different electron-donating and withdrawing groups containing aryl bromides and dibromides in 56-99% yield range [42] . Siméon et al. [43] reported halogenation reactions of 2-amino-1,3-thiazoles in the presence of CuBr/CuBr 2 for the preparation of monohalo and dihalo 1,3-thiazole derivatives. Temperature played a vital part to achieve required products in reasonable yield. For instance, reaction of 2-aminothiazole 65 in the presence of CuBr, n-butyl nitrite and acetonitrile gave desired monohalogenated product 66 in 46% yield. This reaction was completed at 60 °C within 15 min. However, when the same reaction was performed first at 40 °C then at 25 °C (for 15-120 min) and 65 °C (for 15 min) using CuBr 2 as catalyst, dihalo product 67 was obtained in 79% yield. On the other hand, in the absence of n-butyl nitrite 2-aminothiazole 65 gave halogenated product 68 at room temperature within 10 h in 94% yield. In this methodology, all reactions were performed in a regioselective fashion under mild conditions which led to the formation of a variety of novel iodo, bromo and chloro derivatives (Scheme 14). Synthesis of a variety of hydroxycoumarin and pyranocoumarin derivatives and evaluation of their anti-proliferative activity was reported by Mao et al. [44] . 3,5-Dimethoxyaniline (69), starting precursor of this methodology first underwent Sandmeyer reaction in the presence of NaNO 2 , H 2 SO 4 and KI. Resultantly, iodine-substituted methoxy ether 70 was obtained in 75% yield which demethylated followed by the reaction with β-ketoester afforded iodo-substituted 5-hydroxycoumarin 71. Conversion of this coumarin (71) to chromene 72 by annulation with 3-methylbut-2-enal was achieved in 79-82% yield range. After that, these coumarin and chromene derivatives were successfully subjected to palladium-catalyzed Suzuki cross-coupling reaction using different arylboronic acids to obtain desired hydroxycoumarin and pyranocoumarin derivatives in good to excellent yield range (Scheme 15). Another application of Sandmeyer reaction was reported by Kim et al. [45] where they described [5, 5] -sigmatropic rearrangement reactions of N,N'-diaryl hydrazides, resultantly affording 4,4′-diamino-biphenyls (benzidines). Their methodology started from the copper-catalyzed coupling of bis(m-bromophenyl) ethers 73 followed by cyclization reaction in the presence of palladium catalyst furnished corresponding diaryl hydrazides which were then subjected to benzidine rearrangement in the presence of aq. HCl. As a result, benzidines 74 were obtained whose structures were confirmed by treating one of the derivatives with sodium nitrite and KI. As expected, corresponding diiodide 76 was obtained which confirmed the structural integrity of benzidines 74. Later, these benzidines 74 were readily converted Owing to the wide spread applications of conjugated compounds in optoelectronic devices due to their charge transfer and luminescent properties, synthesis of newly functionalized conjugated polymers and oligomers has fascinated a great deal of consideration. [2.2] Paracyclophane skeleton plays a main role in this regard and has been synthesized by different era of chemists due to its exclusive conjugated system. To carry out this research work, Gon et al. [46] synthesized tetrasubstituted [2.2]-paracyclophane core which involved Sonogashira-Hagihara coupling (PdCl 2 (PPh 3 ) 2 , PPh 3 , CuI, Et 3 N, THF) and Sandmeyer reactions (H 2 SO 4 , NaNO 2 , KI) as key steps. Results declared that targeted derivatives showed good optical properties due to their larger molar extinction coefficient and photoluminescence quantum efficiency. Liu et al. [47] proposed a complementary electrochemical method for Sandmeyer halogenation in which graphite can be used as cathode material which is an inexpensive metal as compared to platinum. This electrochemical reaction generated a variety of aryl halides by treating diazonium salts with different halogen sources such as CBrCl 3 , CH 2 I 2 , LiCl, CCl 4 , NaBr, NBS. Reaction processed at 20 °C in 5:1 mixture of MeOH/DMF using Bu 4 NClO 4 as an electrolyte. Moreover, this reaction can also be performed in a one-pot fashion by obtaining diazonium salt from different anilines in the presence of tert-butyl nitrite followed by halogenation under optimized conditions provided required aryl halides. The efficient synthesis of novel benzo-substituted phthalazines was reported by Tsoungas and Searcey [48] . Their synthetic pathway started from the catalytic hydrogenation of aldehyde 77 to obtain alcohol 78 in 74% yield which was then subjected to Sandmeyer reaction in the presence of sodium nitrite and trimethysilyl bromide. As a result, diazonium salt 79 was formed which readily converted into compound 80. After deprotection 58% yield of free alcohol 81 (from compound 78) was obtained that further underwent halogen lithium exchange process followed by oxidation (PCC, DCM) and cyclization (N 2 H 4 , EtOH) reactions to provide targeted phthalazine 82 in 82% yield (Scheme 17). An alternate route to obtain phthalazine 82, started from the reduction of aldehyde 77 followed by diazotization and Sandmeyer reaction (t-BuONO, CuBr, HBr), provided aldehyde 85 in 45% yield. This aldehyde after protection ((CH 2 OH) 2 , TSA) followed by lithium halogen exchange process gave resulting intermediate in 76% yield (over 2 steps). Deprotection in the presence of 3 N HCl and cyclization of 4-methoxyphthalaldehyde with N 2 H 4 provided required phthalazine 82 in 82% yield (Scheme 18). Buchtík et al. [49] reported a simple experimental procedure for the synthesis of polynuclear heterocyclic molecules based on 5-phenyl-6-azauracil scaffold. For this purpose, 3-[3-(6-azauracil-5-yl)-2-aminophenyl]-1,2-dihydro-quinoxaline-2-one (86) was used as starting precursor which first converted into diazonium salt that further produced a variety of heterocyclic N-H acids in good yield range. Two reference compounds, prepared via Sandmeyer reaction, are highlighted in Scheme 19. Reaction proceeded well when 6-azauracil 86 was reacted with sodium nitrite followed by the treatment with CuCl or CuBr in the presence of HCl/HBr provided 2-chloro (87) and 2-bromo (88) derivatives in 57 and 80% yield, respectively. Highlighting the medicinal importance of organofluorine compounds, research group of Zheng synthesized trifluoromethylated arenes via Sandmeyer trifluoromethylation process [50] . Simple and mild reaction conditions, easy availability of the reagents and wide functional groups tolerance are the prominent features of this methodology. The reaction proceeded first from the formation of diazonium Synthesis of polynuclear heterocyclic molecules based on 5-phenyl-6-azauracil scaffolds salt 90 which subsequently treated with Langlois' reagent and CuCl in the presence of sodium bicarbonate (additive). Maximum conversion was achieved within 20 h by carrying out reaction at room temperature in acetonitrile solvent. Proposed mechanism of this reaction is presented in Scheme 20 which started from the conversion of diazonium salt to diazo radical via Cu(I)-mediated singleelectron transfer process. This azo radical was further transformed into aryl radical 92 by releasing nitrogen gas. On the other side, Langlois' reagent upon treatment with TBHP produced trifluoromethyl radical whose reaction with CuCl generated Cu(II)CF 3 species that was used to insert CF 3 group in aryl radical 92 in the last step. Danoun et al. [51] designed convenient, competent and inexpensive practical procedures for the trifluoromethylthiolation of arenediazonium salts via Sandmeyer reaction. Optimized parameters of this reaction involved TMSCF 3 , CuSCN, Cs 2 CO 3 and sodium thiocyanate as sulfur source. Reaction worked very well at room temperature in acetonitrile solvent to obtain 23-98% yield range. Mechanism of this reaction is highlighted in Scheme 21. Later on, the same research group reported either one pot or sequential diazotization and trifluoromethylation as presented in Scheme 22 [52] . In method A, 4-methoxyaniline (98) was first diazotized in the presence of equimolar amount (2 equiv.) of t-BuONO and HBF 4 to produce diazonium salt 99 which was then dissolved in acetonitrile mixture containing TMSCF 3 , copper(I) thiocyanate and cesium carbonate. As a result, 81% yield of the targeted product 100 was achieved at room temperature. On the other side, in a one-pot procedure a reaction mixture containing diazotized aniline was added to a suspension of TMSCF 3 , copper(I) thiocyanate and cesium carbonate, resultantly afforded benzotrifluoride 100 in 85% yield. Yields of targeted derivatives were almost comparable of both pathways or sometimes higher in the later one. Wide functional group tolerance such as ether, ester, ketone and cyano groups and good yield range broadened the scope of this methodology. Another application of Sandmeyer reaction for the trifluoromethylation of arenediazonium tetrafluoroborates was disclosed by Danoun et al. [53] . Plausible mechanism of this reaction started first by the reaction of copper(I) thiocyanate with trimethylsilyl cyanide in the presence of cesium carbonate; as a result, trifluoromethyl copper(I) species was generated which reacted with diazonium salt to obtain corresponding benzotrifluoride as described in Scheme 23. The methodology covers wide substrate scope giving rise to 40-98% yield range. Goossen et al [54] provided detailed investigation of novel copper-catalyzed Sandmeyer reaction in which Ruppert-Prakash trifluoromethylating reagent produced a variety of trifluoromethylated arenes in good yield range without formation of CuCF 3 species. They began their investigation by treating 4-methoxyaniline with tert-butyl nitrite for the formation of diazonium salt. To select suitable acid for this conversion, the performance of eight acids (p-toluenesulfonic acid (p-TSA), p-TSA . H 2 O, trifluoroacetic acid (TFA), ethereal . HCl, acetic acid, methanesulfonic acid (MSA), trichloroacetic acid (TCA), benzenesulfonic acid (BSA)) was observed and concluded that p-TSA gave maximum yield (85%). In addition to this, TMSCF 3 , CuSCN, Cs 2 CO 3 and room temperature were the other parameters to carry out trifluoromethylation and trifluoromethylthiolation in 41-98% and 32-70% yield range, respectively. A new synthetic approach of trifluoromethylated arenes via copper-catalyzed Sandmeyer reaction in the presence of Umemoto's reagent was established by Dai et al. [55] . The potential applicability of Umemoto's reagent in combination with copper powder was proven by carrying out reaction using a variety of aryl amines; as a result, desired trifluoromethylated arenes were obtained in moderate to good yield range. Two equivalents Cu powder, 1.5 equivalents Umemoto's reagent 102, 3 equivalents of isoamyl nitrite and acetonitrile solvent are the optimized parameters of this methodology (Scheme 24). Matheis et al. [56] performed direct, simple and selective Sandmeyer reaction of diazonium salt 106 by using difluoromethyl-copper complex as difluoromethylating reagent. This complex can be formed by treating 2.5 equivalents of TMS-CF 2 H with 1 equivalent copper thiocyanate and 3 equivalents cesium fluoride in DMF solution. This successful difluoromethylation process tolerated a wide variety of functional groups by giving 34-86% yield range. It was observed that both electron-donating and withdrawing substituents afforded almost high yields. However, by In 2014, Wang et al. [57] have made a novel contribution toward Sandmeyer-type trifluoromethylation reaction by using trifluoromethyl-silver complex as CF 3 source. This methylating reagent was prepared by treating silver fluoride with TMSCF 3 in propionitrile. Temperature was first maintained at − 78 °C and then gradually raised to 25 °C. As a result, desired AgCF 3 complex obtained which was subjected to Sandmeyer process. This process started from the diazotization of the different aromatic amines via standard protocol (HCl, t-BuONO) followed by the oxidative addition of the trifluoromethyl-silver complex to diazonium salt, resultantly afforded high-valent silver intermediate which readily underwent reductive elimination reaction to obtain targeted trifluoromethylated product in 10-97% yield range. Later on, in 2015 Wu et al. [58] proposed one-pot difluoromethylthiolation approach via Sandmeyer reaction under mild conditions. Optimized parameters to carry out this conversion including [Cu(CH 3 CN) 4 ]PF 6 as copper salt, 2,2'-bipyridine as ligand, acetonitrile as solvent and [(SIPr) Ag(SCF 2 H)] as difluoromethylating reagent (Fig. 1) which could be easily prepared by treating [(SIPr)Ag(CF 2 H)] with sulfur in THF solvent. This methodology gave wide substrate scope by giving 32-92% yield range of difluoromethylthiolated heteroarenes within 24 h by maintaining temperature at 50 °C. In 2019, Hu and et al. [59] reported for the first time pentafluoroethylation reaction by utilizing Sandmeyer approach. In their methodology, CuC 2 F 5 was used as pentafluoroethylating reagent which obtained in a sequence manner first by treating TMSCF 3 with sodium iodide in THF solvent; as a result, tetrafluoroethylene species was attained. This species further reacted with cesium fluoride in the presence of copper thiocyanate at 70 °C to afford targeted CuC 2 F 5 . In the last step, diazonium salt 110 was treated with CuC 2 F 5 in acetonitrile solvent; resultantly, desired product 111 was obtained in 93% yield. This protocol covered wide substrate scope by giving targeted derivatives in 51-93% yield range within short reaction time (Scheme 26). Hong et al. [60] examined the use of Togni's reagent in one-pot Sandmeyer trifluoromethylation reaction. Their pathway started from the diazotization of the aromatic amines in the presence of HCl and t-BuONO. Then this salt was treated with Togni's reagent II and copper salt, Cu(MeCN) 4 BF 4 at 45 °C. Sodium bicarbonate was used as base in dichloroethane solvent. As a result, corresponding tifluoromethylated analogs were obtained in 42-90% yield range. A plausible mechanism is highlighted in Scheme 27 according to which Togni's reagent was used to produce CF 3 radical via copper(I)-mediated single-electron transfer (SET) approach. Some other reports on Sandmeyer-type fluoromethylation are presented in Table 2 . In 2014, Xu et al. [63] reported Cu 2 O-catalyzed Sandmeyer reaction of arenediazonium tetrafluoroborates with TMSCN. The reaction worked very well and gave maximum yield with 0.4 equivalent catalyst loading that was not even significantly increased by using 1 equivalent of Cu 2 O in acetonitrile solvent. Temperature was maintained at 55 °C to obtain targeted products in 38-92% yield range within 10 h. This ligand and halogen-free protocol provided many benefits over classic Sandmeyer reaction as nontoxic, mild reaction conditions, low catalyst loading and wide substrate scope are the salient features of this methodology. Later on, this research group presented another nontoxic palladium-catalyzed cyanation via Sandmeyer approach in which acetonitrile was used as nonmetallic CN source [64] . Reaction processed under ambient air in the presence of 0.1 equivalent of PdCl 2 and 1 equivalent of Ag 2 O (additive) at 55 °C. As a result, 30-64% yield range was obtained of the targeted derivatives. A plausible mechanism is highlighted in Scheme 28 which started from the reduction of divalent palladium to zero-valent palladium. In the next oxidative step, this zero-valent palladium added to ArN 2 + BF 4 − to obtain Ar-Pd species (A) followed by the cleavage of CH 3 -CN bond in the presence of Ag 2 O gave intermediate (C). Reductive elimination was the last step which provided aromatic nitrile along with zero-valent palladium. In order to develop new and efficient conditions for Sandmeyer cyanation, Barbero et al. [65] utilized arene and heteroarenediazonium o-benzenedisulfonimides as starting precursors and tetrabutyl ammonium cyanide as CN source. Reaction was carried out at room temperature in acetonitrile solvent. This approach under mild reaction conditions gave targeted compounds in 34-92% yield range. A reference example is presented in Scheme 29 which highlighted the mechanism of this copper-free protocol started by the transfer of electron from anionic part of the salt 119 toward cation. As a result, resonance-stabilized complex 119a was formed which reacted with CN − part of tetrabutyl ammonium cyanide to provide corresponding aryl nitrile 120. Da Silva et al. [66] designed an effective approach for the synthesis of 2-chloro-3-carbonitrile analogs which are wellknown intermediates and can be transformed into a variety of useful and biologically important heterocyclic molecules, for example the highly polyfunctionalized 4H-pyran, oxazolo, pyrazolo, 1,4-dihydropyridine or pyridines derivatives. The authors used 2-amino-3-carbonitriles as starting precursors to obtain corresponding 2-chloro-3-carbonitriles via Sandmeyer approach. The reaction was catalyzed by 1.5 equivalents of CuCl 2 in acetonitrile solvent. After the addition of isoamyl nitrile, temperature was maintained at 65 °C to obtain targeted derivatives in 10-69% yield range (Fig. 2) . For the construction of medicinally important indole-1,2,4-benzotriazine derivatives, Sandmeyer reaction seems to be a suitable methodology as elaborated by Xu et al. [67] . Their protocol started by the S N Ar reaction of the indole 133 with 2-nitrophenyl halide 134 in the presence of cesium carbonate to obtain respective indole derivative 135 which was subsequently reduced with stannous chloride dihydrate. As a result, indole 136 obtained (45% yield) that was cyclized by using tert-butyl nitrite via a modified Sandmeyer reaction to afford targeted indole-1,2,4-benzotriazine 137 (24% yield) which proved to be a promising lead compound against a variety of phytopathogenic fungi (Scheme 30). The research group of Beletskaya reported copper-catalyzed Sandmeyer cyanation approach with a variety of diazonium salts [68] . Reaction proceeded very well using potassium cyanide as CN source, equimolar amount (10 mol%) of CuCN as catalyst, 1,10-phenantroline as ligand, dibenzo-18-crown-6 as phase transfer catalyst and Cu(BF 4 ) 2 as cocatalyst. Maximum yield range (52-93%) was obtained by carrying out reaction at room temperature in acetonitrile solvent. Sulfonyl fluorides have gained tremendous interest in synthetic organic chemistry due to their unique characteristics such as stability, reactivity pattern and proton-mediated reactivity. They are extensively used for the construction of a variety of pharmacologically important scaffolds. Considering their importance, Lin et al. developed an efficient, cost-effective and copper-free methodology for the synthesis of arenesulfonyl fluorides via Sandmeyer approach. In their protocol, different arenediazonium salts having electrondonating and withdrawing substituents were treated with N-fluorobenzenesulfonimide (NFSI), a fluorine source and K 2 S 2 O 5 which plays dual role as a reductant and a sulfonyl source simultaneously. Reaction conducted very well under argon atmosphere in a mixture of acetonitrile, water and acetic acid (co-solvent). Maximum conversion was attained within 6 h at room temperature. Diaryl sulfones exhibit a wide range of biological activities; for example, they act as anticancer, antifungal, antibacterial agents and are efficient thymidylate synthase and HIV-1 reverse transcriptase inhibitors. Besides this, they play a vital role as synthetic intermediates in organic chemistry. Despite the discovery of various synthetic methods for diaryl sulfones, search of new and efficient conditions is still under process. In this regard, Yang et al. [70] reported a competent copper-catalyzed Sandmeyer approach for the synthesis of diaryl sulfones. For example, reaction of aryl amine 89 with arylsulfinic acid 138 in the presence of equimolar amounts (3 equivalents) of copper powder and isoamyl nitrite (diazotizating agent) gave 82% yield of the corresponding product 139. Reaction processed under nitrogen atmosphere by maintaining temperature at 0-25 °C in acetonitrile solvent. This approach depicted a wide substrate scope, allowing the preparation of a variety of diaryl sulfones in 47-82% yield range (Scheme 31). Research group of Goossen in 2015 reported difluoromethylthiolation of arene diazonium salts in 61-95% yield range [71] . Standard parameters to make this conversion effective included following steps: First a solution of diazonium salt 99 in acetonitrile solvent was mixed in sodium thiocyanate, cesium carbonate and copper thiocyanate mixture. Then cesium fluoride, copper thiocyanate and TMS-CF 2 H in DMF were added in the reaction mixture; as a result, desired product 140 was obtained in 95% yield within 12 h by carrying out reaction at room temperature. Later on, same research group presented trifluoromethylthiolation and pentafluoroethylthiolation by applying Sandmeyer conditions as described in Scheme 32. Reaction of 4-methoxybenzenediazonium tetrafluoroborate (99) was performed with 1.8 equivalents of Me 4 NSCF 3 in the presence of copper thiocyanate. Resultantly, trifluoromethyl thioether 141 was obtained in 97% yield [72] . However, when the same reaction was performed in the presence of 10 mol% elemental copper using Me 4 NSC 2 F 5 as SC 2 F 5 source, pentafluoroethyl thioether 142 was obtained in 98% yield. This methodology under mild reaction conditions tolerates a variety of functional groups by giving 61-99% yield range [73] . Zhang et al. [74] adopted a different approach for trifluoromethylation of arenediazonium tetrafluoroborates in the presence of Langlois reagent (NaSO 2 CF 3 ). Reaction worked very well at 45 °C using t-butyl hydroperoxide as oxidant, CuBF 4 (CH 3 CN) 4 as copper salt and 2,2′;6′,2′′-terpyridine (tpy) as ligand. As a result, 30-63% yield range of the corresponding trifluoromethylated derivatives was obtained in a mixture of acetonitrile/water solvent. Similarly, the authors Scheme 29 Sandmeyer cyanation, using arenediazonium o-benzenedisulfonimide 119 as starting precursor and tetrabutyl ammonium cyanide as CN source reported trifluoromethanesulfonylation of arenediazonium tetrafluoroborates in 45-90% yield range in the presence of NaSO 2 CF 3 and 10 mol% Cu 2 O. To carry out maximum conversion at room temperature, DMSO was selected as suitable solvent. Organothiophosphates are worthy of attention due to their outstanding insecticidal, antiviral and enzyme inhibition properties against acetylcholinesterase (AChE) enzyme. Their wide spread contribution in pharmaceutical chemistry encouraged Kovacs et al. [75] to disclose Ou et al. [76] in 2019 published a convenient procedure for the construction of (diethylphosphono)-difluoromethyl thioethers proceeding via two steps: Sandmeyer thiocyanation and subsequent fluoroalkylation reaction. Optimal reagents for thiocyanation included copper thiocyanate, cesium carbonate, sodium thiocyanate (sulfur source) and acetonitrile solvent. As a result, corresponding thiocyanate derivative was obtained which was subjected to fluoroalkylation reaction using TMS-CF 2 PO(OEt) 2 as the difluoroalkyl source. Plausible mechanism of this reaction is presented in Very recently, research group of Qing reported a similar methodology for fluorosulfonylation of arenediazonium Scheme 34 Mechanism of sequential Sandmeyer thiocyanation and fluoroalkylation reactions tetrafluoroborates [77] . However, they used Na 2 S 2 O 5 as sulfonyl source instead of K 2 S 2 O 5 . The other optimized parameters were N-fluorobenzenesulfonimide (NFSI), 2/0.1 mixture of acetonitrile/water, 60 °C temperature under nitrogen atmosphere. As a result, 43-81% yield range was obtained within 6 h. A plausible mechanism is highlighted in Scheme 35. Single-electron transfer reduction of aryldiazonium salt 149 provided aryl radical 114 which upon reaction with SO 2 (generated from Na 2 S 2 O 5 ) gave arenesulfonyl radical 150. In the last step, transfer of fluorine atom from N-fluorobenzenesulfonimide afforded targeted arenesulfonyl fluoride 151. In another report, various diazonium salts were subjected to fluorosulfonylation reaction by passing through Sandmeyer approach. For this purpose, Na 2 S 2 O 5 was used as sulfur dioxide source and Selectfluor 152 as fluorine source in methanol solvent. Temperature was maintained at 70 °C to attain maximum yield (85%) of sulfonyl fluoride 153. This methodology was applied on a variety of substrates; resultantly moderate to good yield range was obtained (Scheme 36) [78] . Tarkhanova et al. [79] demonstrated that copper catalysts incorporating ionic liquid on Silochrom support efficiently catalyzed Sandmeyer reaction. A highlighted example for the thiocyanation of 3-methyl-4-nitrophenyldiazonium tetrafluoroborate (154) is presented in Scheme 37. For this purpose, potassium thiocyanate was used as nucleophile and reaction was catalyzed with CuCl-Et 3 PrNCl in acetonitrile solvent. 96% Yield of the required product 155 was obtained by carrying out reaction at room temperature. Same methodology was adopted to attain 87-97% yield range of a variety of aryl bromides. Organotin reagents are highly important due to their usage in the synthesis of various C-N, C-F and C-OCF 3 bond formation reactions. They are also used for the generation of C-C bond by highly famous Stille cross-coupling reaction Scheme 35 Fluorosulfonylation of arenediazonium tetrafluoroborate 149 using Na 2 S 2 O 5 as sulfonyl source and N-fluorobenzenesulfonimide (NFSI) as fluorine source Scheme 36 Fluorosulfonylation reaction using Selectfluor 152 as fluorine source whose wide applications in organic synthesis create a dire need to develop new and efficient synthetic methods for aryl stannane compounds. On account of this, Qiu et al. [80] developed a Sandmeyer-type stannylation approach for the preparation of aryl trimethylstannanes. A highlighted example is presented in Scheme 38 in which amine 57 was treated with tert-butyl nitrite and (SnMe 3 ) 2 in dichloroethane solvent at 0 °C. Screening a variety of acidic additives such as TsOH, BF 3 . OEt 2 , AlCl 3 and AcOH which found to be helpful for diazotization process, maximum yield was obtained with p-toluenesulfonic acid. Overall, moderate to good yield range (36-86%) of the targeted products was obtained which were most likely subjected to different cross-coupling reactions without purification such as Stille reaction and can also be used for the synthesis of different pharmaceutical agents. Later on, the same research group developed another methodology for stannylation of aromatic amines, simultaneously generating trimethylstannyl arylboronate analogs which were effectively subjected to Stille and Suzuki-Miyaura cross-coupling reactions [81] . For example, conversion of p-nitroaniline 57 into arylboronate 157 was accomplished in the presence of tert-butyl nitrite, bis(pinacolato)diboron, benzoyl peroxide and acetonitrile solvent under metal-free conditions. Then reduction of nitro group to NH 2 group via palladium-catalyzed reaction generated boron-substituted aniline 158 in 98% yield which further converted into corresponding stannylation analog 159 under optimized Sandmeyer-type stannylation reaction conditions (t-BuONO, (SnMe 3 ) 2 , TsOH, DCE) (Scheme 39). In an effort to search diversified methods for aryl phosphonates which play a vital role in material science, organic Scheme 38 Sandmeyer-type stannylation approach for the preparation of aryl trimethylstannanes Scheme 39 Synthesis of trimethylstannyl arylboronate analog 159 and medicinal chemistry, Wang and their colleagues studied the applicability of Sandmeyer phosphorylation reaction for the synthesis of these aryl phosphonates [82] . They began their investigation by the reaction of ethyl 4-aminobenzoate with tert-butyl nitrite under different conditions. First of all, trimethyl phosphite, triethyl phosphite and triphenyl phosphite were screened as phosphorous source and results supported the use of triphenyl phosphite which gave significant yield (78%) as compared to the other phosphites. Reaction processed at 0 °C using TsOH . H 2 O as an additive which was selected among different acids such as HCl, TsOH . H 2 O, H 2 SO 4 and BF 3 . OEt 2 . Reaction completed within 8 h in acetonitrile solvent by giving 25-99% yield range. Matheis et al. [72] successfully utilized Sandmeyer approach for the preparation of trifluoromethylselenoethers under mild reaction conditions. For this purpose, Me 4 NSeCF 3 was used as SeCF 3 source which efficiently converted diazonium salt 99 to its corresponding selenoether 160 in 98% yield. Reaction processed at room temperature using CuSCN as copper salt in acetonitrile solvent. In order to evaluate substrate scope, maximum conversion was achieved within 1 h by giving 69-98% yield range of the desired trifluoromethylselenoethers. Similarly, a straightforward approach for the insertion of trifluoromethylseleno group into aromatic amines was reported by Nikolaienko and Rueping in 2016 [83] . Reaction was accomplished via two steps, first converting diazonium salt 99 to its respective selenocyanate in the presence of CuCl/CuCl 2 catalytic system. 1,10-Phenanthroline was used as additive, cesium carbonate as base and KSeCN as SeCN source in acetonitrile solvent. In the second step, this selenocyanate was treated with TMS-CF 3 for the insertion of CF 3 group. Reaction was completed within 12 h at room temperature and afforded corresponding trifluoromethylselenoether 160 in 74% yield. In this methodology, arenediazonium salts having both electron-donating and withdrawing substituents were readily converted into desired selenoethers in 40-88% yield range (Scheme 40). Focusing the green synthetic routes, Zhang et al. [84] published their report on Sandmeyer-type borylation for the synthesis of arylboronate esters. They began their investigation by treating 4-carboxylicphenyldiazonium tetrafluoroborate with bis(pinacolato)diboron as exemplary substrates. Reaction processed at room temperature in a mixture of solvents such as acetone-water, acetonitrile-water, dimethoxyethane-water, dioxane-water, water and acetone. Results revealed that 2:1 mixture of acetonitrile-water gave targeted arylboronate ester in 80% yield. Maximum conversion was achieved in the presence of 5 mol% CuBr which selected by observing the catalytic behavior of Cu(OAc) 2 , FeCl 3 , Co(Ac) 2 , CeCl 2 and CuBr. 24-85% Yield range of different arylboronate esters was obtained within 3-6 h. In continuation of this research work, Qiu et al. [85] in 2013 reported Sandmeyer-type borylation approach under metal-free condition. In this method, a variety of aryl amines were first diazotized in the presence of tert-butyl nitrite followed by the addition of bis(pinacolato)diboron in acetonitrile solvent afforded the desired pinacol arylboronates in 14-77% yield range by maintaining temperature at 80 °C. These aryl boronates further used for Suzuki-Miyaura crosscoupling reaction to obtain a variety of biaryl compounds in moderate to high yield range which proved the efficacy of this protocol. Some other reports on Sandmeyer-type borylation are presented in Table 3 . [91] . Their methodology started from the Suzuki cross-coupling of bis(arylation) of 3,5-dibromopyridine (164) with 4-methoxyphenylboronic acid under optimized conditions resultantly afforded corresponding arylated compound 165 in 71% yield which was subsequently subjected to Sandmeyer reaction in the presence of t-BuONO, CH 2 I 2 and I 2 . Consequently, iodopyridine 166 was obtained in 61% yield. In the next step, by applying Sonogashira reaction conditions followed by palladium-catalyzed hydrogenation and cyclization reactions afforded desired indolizidinium alkaloid 167 in 79% yield (Scheme 41). Later on, the same research group utilized their previously reported methodology for the synthesis of indolizidinium alkaloid ipalbidinium 171 and quinolizidinium alkaloid clathryimine B [92] . Their recommended approach is described in Scheme 42 which started from the Suzuki reaction of the bromopyridine 168 with boronic acid under standard conditions. As a result, corresponding arylpyridine 169 was obtained in 72% yield which subsequently subjected to Sandmeyer reaction in the presence of t-BuONO, CH 2 I 2 , CuI and I 2 , resultantly affording iodo compound 170 in 82% yield. Further, Sonogashira coupling followed by catalytic hydrogenation and cyclization reactions which after cleavage of the OMe group using BBr 3 afforded desired ipalbidinium 171 in 19% yield. Likewise, clathryimine B was also prepared by using the same reaction conditions of these key steps. Studies on biological activities of curcuphenol reveal that it can be used as antibacterial, antifungal, antimalarial as well as anticancer agent. Besides this, it plays a great role to inhibit proton-potassium ATPase enzyme, resultantly preventing/curing different stomach diseases such as gastroesophageal reflux disease and peptic ulcer disease. Remarkable pharmacological significance of curcuphenol has attracted researchers to develop various techniques for the efficient synthesis of this scaffold. On account of this, Kim and their colleagues proposed an enantioselective synthesis of ( +)-curcuphenol via Sandmeyer and Negishi cross-coupling reactions [93] . Their pathway started from the easily available starting precursor, m-anisidine (172) which was protected using benzyl bromide and potassium carbonate base. Insertion of aldehyde into this moiety using crotonaldehyde Scheme 41 Synthesis of alkaloid ficuseptine 167 using Suzuki, Sandmeyer and Sonogashira reactions as key steps 173 in the presence of imidazolidinone catalyst 174 provided corresponding aldehyde derivative in 90% yield. After reduction of this aldehyde with NaBH 4 followed by deprotection, reaction provided compound 175 in 90% yield. Compound 175 was then converted to derivative 176 by passing through Sandmeyer reaction. Optimized reagents for this conversion were sodium nitrite and copper bromide which gave resultant analog 176 in 55% yield. Next step was Negishi coupling for the replacement of bromo group to methyl group, and the resultant compound was treated with triphenylphosphine, imidazole and iodine to obtain iodo compound 177 in 84% yield. Last step was the reaction of compound 177 with 2-methyl-1-propenylmagnesium bromide (178) followed by the cleavage of the methyl ether functionality afforded (S)-( +)-curcuphenol (179) in 92% yield (Scheme 43). To synthesize a variety of aryl azides through green approach, Zarchi and Ebrahimi utilized polymer-supported Scheme 45 Synthesis of ceritinib (LDK378) 190, an anaplastic lymphoma kinase inhibitor nitrite ion ((poly(4-vinylpyridine)-supported nitrite ion, [P 4 -VP]NO 2 ) for diazotization process [100] . First, reaction of aromatic amines in the presence of NaNO 2 , [P 4 -VP] NO 2 and H 2 SO 4 provided corresponding diazonium salts which on reaction with NaN 3 afforded targeted aryl azides in 70-90% yield range. Later, in 2014 the authors used (poly(4vinylpyridine)-supported ethyl bromide ([P 4 -VP]Et-Br) for the diazotization-bromination of a variety of aromatic amines [101] . Reaction worked very well in the presence of CuBr and afforded 40-94% yield range. Simple recovery and reusability of polymeric reagent with good functional groups tolerance proved the efficacy of this Sandmeyer protocol. To highlight the importance of gold catalysis which is effectively used to activate carbon-carbon multiple bonds, Peng et al. [102] reported gold-catalyzed Sandmeyer reaction for the formation of C-Br, C-S and C-P linkages. For C-Br bond formation, different aryl diazonium salts were reacted with sodium bromide and 3% PPh 3 AuCl in acetonitrile solvent. As a result, desired derivatives were attained in 57-88% yield range at 50 °C. On the other hand, C-S cross-coupling reaction was accomplished by the treatment of aryldiazonium salt with (S)-methyl 2-((tertbutoxycarbonyl)amino)-3-mercaptopropanoate (a cysteine derivative used as sulfur nucleophile) in acetonitrile solvent. 3 Mol% catalyst loading using sodium carbonate as base completed this reaction within 3 h at room temperature. Furthermore, reaction of diazonium salts with HP(O)(OEt) 2 (a phosphorous source) in the presence of 5 mol% PPh 3 AuCl gave desired derivatives in 51-87% yield range. Reaction accomplished within 5 h with the help of 3-chloropyridine additive at 50 °C. Owing to the synthetic as well as pharmacological importance of 1,2-diamines, Gan et al. [103] performed a coupling reaction of ketimine 205 with N-Boc aldimine 206 by using 5 mol% mesitylcopper as catalyst and (R,R P )-TANIAPHOS as ligand in dimethoxyethane. As a result, 1,2-diamine Scheme 46 Preparation method for favipiravir 197, an anti-influenza drug compound 207 was obtained in 79% yield with 97% ee. After that, removal of ketimine moiety in acidic condition followed by protection of amino group with tosyl chloride and reduction of nitro group provided arylamine 208 which readily underwent Sandmeyer reaction to obtain 1,2-diaryldiamine 209, phenol 210, arylbromide 211, trifluoromethylated compound 212 and arylboronate 213 in 80%, 73%, 75%, 54% and 66% yields, respectively, under different reaction conditions as depicted in Scheme 48. In conclusion, we have collected a number of Sandmeyertype approaches with plausible mechanisms published during 2000-2021. This review has witnessed that significant efforts have been made for the conversion of aromatic amino group to boryl, stannyl, phosphoryl, and trifluoromethyl groups by adopting Sandmeyer protocol with or without copper catalysts. However, aryl halides and trifluoromethylated compounds were the most prevalent choices prepared via Sandmeyer reaction. These Sandmeyer-type conversions processed under mild reaction conditions using easily available starting materials proved to be helpful for synthesizing various biologically active compounds. Although many developments regarding Sandmeyer reaction have been made in the recent past yet a lot of improvements are required to address limitations and hindrances involved in its industrial scale use such as excessive use of metals and restricted choice of reagents in diazotization step. On further detailed mechanistic investigation of Sandmeyer reaction, adopting green synthetic methodologies, implementing electrochemical and photocatalytic approaches, incorporating simple reaction methods with minimum use of expensive metals, the researchers may be able to prepare novel biologically active molecules through Sandmeyer transformation in near future. Vorläufige Notiz über die Einwirkung von salpetriger Säure auf Amidinitro-und Diazotization-cyanation of aromatic amines with crosslinked poly(4-vinylpyridine)-supported cyanide ions Über die Einwirkung aromatischer Diazoverbindungen auf α, β-ungesättigte Carbonylverbindungen The photoredox-catalyzed Meerwein addition reaction: Intermolecular amino-arylation of alkenes Ein neues Verfahren zu ihrer Darstellung Ber Dtsch Chem Ges 60 1186 1190 A One-pot diazotation-fluorodediazoniation reaction and fluorine gas for Scheme 48 Sandmeyer reaction for the synthesis of 1,2-diamines (209-213) the production of fluoronaphthyridines Diazonium salts as substrates in palladium-catalyzed cross-coupling reactions Pentafluorosulfanyl)benzenediazonium tetrafluoroborate: a versatile launch pad for the synthesis of aromatic SF5 compounds via cross Coupling, azo coupling, homocoupling, dediazoniation, and click chemistry Removal of amino groups from anilines through diazonium salt-based reactions A mild and efficient palladium-catalyzed cyanation of aryl chlorides with K4[Fe(CN)6] Rhodium-catalyzed ortho-cyanation of symmetrical azobenzenes with N-cyano-N-phenyl-ptoluenesulfonamide Promotion of Sandmeyer hydroxylation (homolytic hydroxydediazoniation) and hydrodediazoniation by chelation of the copper catalyst: Bidentate ligands Rhodium(III)-catalyzed azidation and nitration of arenes by CH activation Angew Chem The mechanism of Sandmeyer's cyclization reaction by electrospray ionization mass spectrometry Development of environmental friendly synthetic strategies for Sonogashira cross coupling reaction: an update Synthetic Commun Transition metal catalyzed Glaser and Glaser-Hay coupling reactions: scope, classical/green methodologies and synthetic applications Syn Commun Development of green methodologies for Heck, Chan-Lam, Stille and Suzuki cross-coupling reactions Cross-coupling reactions towards the synthesis of natural products Mol Divers Synthetic applications and methodology development of Chan-Lam coupling: a review Mol Divers Ueber die Ersetzung der Amidgruppe durch Chlor in den aromatischen Substanzen Ber Dtsch Chem Ges 17 1633 1635 Ueber die Ersetzung der Amidgruppe durch Chlor, Brom und Cyan in den aromatischen Substanzen Ber Dtsch Chem Ges Alkyl nitrite-metal halide deamination reactions. 2. Substitutive deamination of arylamines by alkyl nitrites and copper(II) halides. A direct and remarkably efficient conversion of arylamines to aryl halides Reductive deamination of arylamines by alkyl nitrites in N, N-dimethylformamide. A direct conversion of arylamines to aromatic hydrocarbons Reaction of diazonium salts with transition metals. I. Arylation of olefins with arenediazonium salts catalyzed by zero valent palladium Reaction of diazonium salts with transition metals. II. Palladium catalyzed arylation of ethylene with arenediazonium salts Decomposition reactions of the aromatic diazo compounds. X. Mechanism of the Sandmeyer reaction The mechanism of the Sandmeyer and Meerwein reactions A practical two-step synthesis of imidazo[1,2-a]pyridines from N-(prop-2-yn-1-yl)pyridin-2-amines Synthesis of dioxin-like monofluorinated PCBs: For the use as internal standards for PCB analysis Synthesis of tetrasubstituted pyrazoles through different cyclization Strategies 4-Aryl-5-cyano-2-aminopyrimidines as VEGF-R2 inhibitors: Synthesis and biological evaluation 3-dihydro-1,4-benzodioxin-5-yl)-piperazine Discovery of thienopyrimidine-based FLT3 inhibitors from the structural modification of known IKK inhibitors Synthesis and antiproliferatory activities evaluation of multisubstituted isatin derivatives -Chloro-6-fluorophenyl)acetamides as potent thrombin inhibitors A Sandmeyer type reaction for bromination of 2-mercapto-1-methyl-imidazoline (N2C4H6S) into 2-bromo-1-methyl-imidazole (N2C4H5Br) in presence of copper(I) bromide Dalton Trans 40 11382 11384 Halo-and azidodediazoniation of arenediazonium tetrafluoroborates with trimethylsilyl halides and trimethylsilyl azide and Sandmeyer-type bromodediazoniation with Cu(I)Br in [BMIM][PF 6 ] ionic liquid A novel synthesis of bromobenzenes using molecular bromine Development of a scalable route for a key thiadiazole building block via sequential Sandmeyer bromination and room-temperature Suzuki-Miyaura coupling Synthesis of bromocyclopropylpyridines via the Sandmeyer reaction Synthesis and evaluation of novel substituted 5-hydroxycoumarin and pyranocoumarin derivatives exhibiting significant anti-proliferative activity against breast cancer cell lines Benzidine rearrangement reactions of polyether tethered cyclic N, N′-diaryl hydrazides Optically active cyclic compounds based on planar chiral [2.2]paracyclophane: extension of the conjugated systems and chiroptical properties A general electrochemical strategy for Sandmeyer reaction A convenient access to benzosubstituted phthalazines as potential precursors to DNA intercalators Polycyclic heterocycles with acidic N-H group VII 1 Synthesis of some polynuclear heterocyclic compounds derived from 5-phenyl-6-azauracil ARKIVOC Copper-promoted conversion of aromatic amines into trifluoromethylated arenes: onepot Sandmeyer trifluoromethylation Sandmeyer trifluoromethylthiolation of arenediazonium salts with sodium thiocyanate and Ruppert-Prakash reagent Sandmeyer trifluoromethylation of arenediazonium tetrafluoroborates One-pot Sandmeyer trifluoromethylation and trifluoromethylthiolation Copper-promoted Sandmeyer trifluoromethylation reaction Sandmeyer difluoromethylation of (hetero)arenediazonium salts Conversion of aromatic amino into trifluoromethyl groups through a Sandmeyertype transformation Copper-promoted Sandmeyer difluoromethylthiolation of aryl and heteroaryl diazonium salts Pentafluoroethylation of arenediazonium tetrafluoroborates using on-site generated tetrafluoroethylene Copper-promoted one-pot trifluoromethylation of aromatic amines with Togni's reagent ChemistrySelect A general, regiospecific synthetic route to perfluoroalkylated arenes via arenediazonium salts with RFCu(CH3CN) complexes Trifluoromethylation of arenediazonium salts with fluoroform-derived CuCF3 in aqueous media Copper(I)-oxidemediated cyanation of arenediazonium tetrafluoroborates with trimethylsilyl cyanide: A method for synthesizing aromatic nitriles Sandmeyer cyanation of arenediazonium tetrafluoroborate using acetonitrile as cyanide source Org Chem Front 2 231 235 Copper-free Sandmeyer cyanation of arenediazonium o-benzenedisulfonimide Org Biomol Chem The Sandmeyer reaction on some selected heterocyclic ring systems: Synthesis of useful 2-chloroheterocyclic-3-carbonitrile intermediates Synthesis and antifungal activities of novel indole[1,2-c]-1,2,4-benzotriazine derivatives against phytopathogenic fungi in vitro Catalytic Sandmeyer cyanation as a synthetic pathway to aryl nitriles Arenesulfonyl fluoride synthesis via copper-free Sandmeyertype fluorosulfonylation of arenediazonium salts Copper-mediated cascade synthesis of diaryl sulfones via the Sandmeyer reaction Synthesis of difluoromethyl thioethers from difluoromethyl trimethylsilane and organothiocyanates generated in situ Angew Chem 127 5845 5848 Sandmeyer-type trifluoromethylthiolation and trifluoromethylselenolation of (hetero)aromatic amines catalyzed by copper Convenient synthesis of pentafluoroethyl thioethers via catalytic Sandmeyer reaction with a stable fluoroalkylthiolation reagent Copper-promoted trifluoromethanesulfonylation and trifluoromethylation of arenediazonium tetrafluoroborates with NaSO2CF3 Practical reagents and methods for nucleophilic and electrophilic phosphorothiolations Copper-mediated synthesis of (diethylphosphono)difluoromethyl thioethers from diazonium salts, NaSCN, and TMS-CF2PO(OEt)2 Asian Fluorosulfonylation of arenediazonium tetrafluoroborates with Na2S2O5 and N-fluorobenzenesulfonimide Copperfree Sandmeyer-type reaction for the synthesis of sulfonyl fluorides Highly efficient Sandmeyer reaction on immobilized CuI/CuII-based catalysts Synthesis of aryl trimethylstannanes from aryl amines: a Sandmeyer-type stannylation reaction Angew Chem 125 11795 11798 Synthesis of trimethylstannyl arylboronate compounds by Sandmeyer-type transformations and their applications in chemoselective cross-coupling reactions Metal-free aromatic carbon-phosphorus bond formation via a Sandmeyer-type reaction Trifluoromethylselenolation of aryldiazonium salts: a mild and convenient copper-catalyzed procedure for the introduction of the SeCF3 group Sandmeyer-type reaction to Pinacol arylboronates in water phase: a green borylation process Synthesis of Pinacol arylboronates from aromatic amines: A metal-free transformation Transition-metal-free borylation of aryltriazene mediated by BF3 Metal-free, visible light-induced borylation of aryldiazonium salts: a simple and green synthetic route to arylboronates Borylation using group IV metallocene under mild conditions One-pot Suzuki coupling of aromatic amines via visible light photocatalyzed metal free borylation using t-BuONO at room temperature Convenient and general zinc-catalyzed borylation of aryl diazonium salts and aryltriazenes under mild conditions ChemistryOpen Total synthesis of the indolizidinium alkaloid ficuseptine Total syntheses of the alkaloids ipalbidinium and clathryimine B Monatsh Chem 134 573 583 https Efficient total synthesis of (+)-curcuphenol via asymmetric organocatalysis A facile synthesis of melatonergic antidepressant agomelatine An efficient synthesis of ceritinib (LDK378) using a Sandmeyer reaction The complete synthesis of favipiravir from 2-aminopyrazine Novel route for btaining isomeric benzo Synthesis and reductive reactions of 2,3-dioxo-2,3-dihydrobenzo Condensed tetracyclic systems with an isatin fragment in the molecule Facile and one-pot synthesis of aryl azides via diazotization of aromatic amine using cross-linked poly(4-vinylpyridine)-supported nitrite ion and azidation by a Sandmeyer-type reaction Iran Diazotization-bromination of aromatic amines using polymer-supported bromide via Sandmeyer-type reaction Nucleophile promoted gold redox catalysis with diazonium salts: C-Br, C-S and C-P bond formation through catalytic Sandmeyer coupling Synthesis of chiral anti-1,2-diamine derivatives through copper(I)-catalyzed asymmetric α-addition of ketimines to aldimines Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Acknowledgements Provision of facilities from Government College University, Faisalabad is highly acknowledged. The authors declare that they have no conflict of interest.