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A novel synthetic route to 3‐amino‐5‐halo‐2‐iodobenzoates, which are used as versatile starting materials in the synthesis of pharmaceuticals, was developed using commercially available 2‐aminobenzoates bearing a suitable halogen atom at the C5 position as the starting material. Synthesis was initiated with the introduction of a nitro group at the C3 position of the appropriate 2‐aminobenzoates, forming 2‐amino‐3‐nitrobenzoates with a C5‐halogen atom. The subsequent conversion of the C2‐amino group to an iodide yielded 5‐halo‐2‐iodo‐3‐nitrobenzoates, which were further converted into the desired 3‐amino‐5‐halo‐2‐iodobenzoates by reducing the C3‐nitro group to an amino group. It is worth noting that this transformation can be conducted on a 50 mmol scale, and the desired benzoate compounds were obtained in good yield, demonstrating the practical applicability of this protocol. [ABSTRACT FROM AUTHOR]

A new, improved 2nd generation route for the synthesis of 3‐ethyl‐4‐hydroxy‐5‐methylbenzonitrile has been developed. The original route started from 2‐ethyl‐6‐methylaniline, which was converted by a classical sequence of para‐bromination, cyanation and Sandmeyer hydroxylation into the desired phenol. This route was used on multi‐kg scale and delivered the product with the desired purity. However, the route was not ideal, as it featured safety critical steps (cyanation), employed undesirable solvents (DMF), included laborious workup and isolation procedures, and suffered from a low overall yield (40–45 %) and suboptimal green metrics (PMI: 210). We envisioned a new, non‐classical approach to the product by introducing the nitrile through a para‐selective formylation, followed by transformation of the intermediate aldehyde into the nitrile with hydroxylamine‐O‐sulfonic acid (HOSA). The new sequence of Sandmeyer hydroxylation, Duff formylation and HOSA‐promoted nitrile formation was thoroughly optimized and finally scaled up to 400 g. This novel 3‐step sequence delivered 3‐ethyl‐4‐hydroxy‐5‐methylbenzonitrile in 69 % overall yield with excellent purity (99.3 % a/a) and a vastly improved PMI of 81. [ABSTRACT FROM AUTHOR]

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-CF3/CF2, 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. [ABSTRACT FROM AUTHOR]

The synthesis of 4-phenylphenalenones, a group of phytoalexins exclusive from Musa acuminata (bananas), has been revisited to extend the scope of the derivatives that can be prepared. The discovery that 4-methoxyphenalenone participates in a selective substitution reaction allowed the preparation of 4-bromophenalenone, which proved to be an efficient substrate for Suzuki cross-couplings. The results solve the previously uncovered problem of preparing electron-rich 4-heteroarylphenalenones and provide a general synthesis of this type of phytoalexins.

In this paper, the high-yielding synthesis of 2-cyano-6-methoxybenzothiazole and 2-cyano-6-hydroxybenzothiazole through catalytic Sandmeyer cyanation was described. In this Sandmeyer type reaction, 2-amino-6-methoxybenzo-thiazole and 2-amino-6-hydroxybenzothiazole were converted to the corresponding diazonium tetrafluoroborate salt and subsequently cyanated in the presence of Cu(I)/Cu(II)/ N, N, N′, N′-tetramethyl ethylenediamine as a catalyst. This protocol features mild reaction conditions, high yielding, short reaction time and capability for large-scale synthesis. In addition, a direct, more efficient and economical approach for 2-cyano-6-hydroxybenzothiazole was presented. [ABSTRACT FROM AUTHOR]

An efficient method with a stable and convenient AgSCF 3 provides an additional way for the synthesis of trifluoromethylthiolated compound with arenediazonium salts, in very mild conditions and good yield. • The first example of the stable AgSCF 3 for trifluoromethylthiolation of arenediazonium salts. • An efficient method for trifluoromethylthiolation of arenediazonium salts was developed. • The mild reaction condition. • The trifluoromethylthiolated products with electron-withdrawing substituent were obtained in higher yields. An efficient method for trifluoromethylthiolation of arenediazonium salts has been developed in mild conditions with a stable and convenient AgSCF 3. It provides a straightforward and convenient way for the synthesis of trifluoromethylthiolated compound from diazonium salts in moderate to good yields. [ABSTRACT FROM AUTHOR]

Favipiravir was first synthesized from an inexpensive and commercially available starting material, 2-aminopyrazine. The preferred route embedded within Scheme 4 consisted of seven steps, and was highlighted by the novel and efficient synthesis of 3,6-dichloropyrazine-2-carbonitrile 8. This intermediate was prepared in four successive steps which were regioselective chlorination of the pyrazine ring, bromination, Pd-catalyzed cyanation, and Sandmeyer diazotization/chlorination. This protocol eliminated the hazardous POCl3 of previous synthetic methods and offered a better yield (48%) which was 1.3-fold higher than a recently published procedure. From intermediate 8, the subsequent nucleophilic fluorination, nitrile hydration and hydroxyl substitution efficiently afforded the target product. Another synthetic approach with the same starting material was also investigated to bypass the allergy-causing dichloro intermediate 8. However, the key step of monofluorination at the pyrazine C6 position of intermediate 19 or 22 was not achieved. [ABSTRACT FROM AUTHOR]

An expedient one‐pot synthesis of (diethylphosphono) difluoromethyl thioethers is described consisting of a Sandmeyer thiocyanation with in situ‐fluoroalkylation using TMS‐CF2PO(OEt)2 as the fluorine source. Both steps are mediated by copper(I) thiocyanate. The reaction is applicable to a wide range of functional groups, as demonstrated by 22 examples. [ABSTRACT FROM AUTHOR]

A series of multi-substituted isatin derivatives were synthesized using the powerful Sandmeyer reaction. The structures of these derivatives were confirmed by 1H-NMR, 13C-NMR, and HR-MS. Inhibition of proliferation activities of these derivatives against human leukemia cells (K562), human hepatocellular carcinoma cells (HepG2) and human colon carcinoma cells (HT-29) were evaluated in vitro using the MTT assay. Among the series, compound 4l exhibited strong antiproliferatory activities against K562, HepG2 and HT-29 cells with IC50 values of 1.75, 3.20, and 4.17 μM, respectively. The morphological, growth inhibitory and apoptosic effects of compound 4l in K562 cells, wound healing effect in HepG2 cells, and tube formating effect in matrix gel of HUVEC cells were evaluated consequently. All results indicated that compound 4l could be used as a potential antitumor agent in further investigations.

Abstract: New late‐stage phosphorothiolation methods are disclosed that allow the efficient transfer of SP(O)(OR)2 groups to diversely functionalized substrates using nucleophilic and electrophilic reagents. The nucleophilic reagent, tetramethylammonium O,O‐dimethyl phosphorothioate, was synthesized in near‐quantitative yield from Me3SiP(O)(OMe)2, elemental sulfur and Me4NF. Its umpolung with N‐bromophthalimide provided the electrophilic reagent, O,O‐dimethyl‐S‐(N‐phthalimido)phosphorothioate. Complementary methods based on these reagents enable the phosphorothiolation of diversely functionalized alkyl halides, arenediazonium salts, arylboronic acids and electron‐rich arenes in good yields under mild conditions. [ABSTRACT FROM AUTHOR]

The total synthesis of the biaryl ether natural product violaceic acid ( 1 ) in four steps is described. The steps included a S N Ar reaction between phenol 7 and flouroarene 12 to afford the biaryl ether 13 , selective reduction of a nitro group to an amine in the presence of an aldehyde, a Cu mediated Sandmeyer reaction and final hydrolysis to afford the target compound 1 . The amine 14 was also converted into the known iodide 18 which gave impure 1 on Pd mediated hydroxide cross coupling. [ABSTRACT FROM AUTHOR]

An efficient and environmentally benign method for the synthesis of aryl iodides have been developed by diazotization of aromatic amines with NaNO2 and nanosilica periodic acid (nano-SPIA) as a green catalyst via grinding followed by a sandmeyer iodination by KI under solvent-free conditions at room temperature. The ensuing aryl diazonium salts supported on nano-SPIA were sufficiently stable to be kept at room temperature in the dry state. This method is a novel, efficient, eco-friendly route for solvent-free synthesis of aryl iodides.

The compound 2-((1,3-dimethyl-1H-pyrazol-5-yl)(methyl)carbamoyl)benzene-diazonium hydrogen sulfate (10) was reacted with copper sulfate and sodium chloride, in the presence of ascorbic acid as reducing agent, to afford a mixture of the chlorinated epimers 4′-chloro-2,2′,5′-trimethyl-2′,4′-dihydrospiro[isoindoline-1,3′-pyrazol]-3-one (18) and (19), the epimers 4′-hydroxy-2,2′,5′-trimethyl-2′,4′-dihydrospiro[isoindoline-1,3′-pyrazol]-3-one (20) and (21), and N-(1,3-dimethyl-1H-pyrazol-5-yl)benzamide (22). Under the foregoing conditions, diazonium salt 10 affords neither the 2-chloro-N-(1,3-dimethyl-1H-pyrazol-5-yl)-N-methylbenzamide (23) nor the tricyclic derivative 24, the classical products of the Sandmeyer and Pschorr reactions, respectively. Finally, by heating 20 at 210 °C the compound 1,3-dimethylisochromeno[4,3-c]pyrazol-5(1H)-one (24) was obtained. The transformation under the above conditions of 2-((4-chloro-3-methyl-1-phenyl- 1H-pyrazol-5-yl)(methyl)carbamoyl)benzendiazonium hydrogen sulphate (11) afforded 4′,4′-dichloro-2,5′-dimethyl-2′-phenyl-2′,4′-dihydrospiro[isoindoline-1,3′-pyrazol]-3-one (29) as the sole reaction product.

Objective: The purpose of this study was to synthesize three new derivatives of metoclopramide by diazotization and replacement reactions and then to quantify in vitro their protection effects on blood cholinesterases using chlorpyrifos as a potent inhibitor. methods: The three new metoclopramide derivatives were synthesized via Sandmeyer reaction, the chemical structures of these derivatives were identified by physico-chemical and spectroscopic (U.V. and FTIR) techniques. Results and conclusion: The results of in vitro evaluation of their human cholinesterases inhibition and protection against chlorpyrifos indicated that the (OH) functional group binds to cholinesterase (ChE) at the same organophosphorous (OP) binding site and shows some competition and protection ability but not to a significant degree, while the (Cl and I) functional groups bind to the ChE at site differs from OP binding site, as well as the (I) functional group has more selectivity for enzyme moiety and binds more strongly than the (Cl) group, so that shows more ChE inhibiting ability

Certain substituted bromobenzenes have been synthesized in acceptable yieldsusing a novel Sandmeyer type reaction. The reactions are relatively quick and possiblyproceed via a radical mechanism.

A new tetrahalogenated benzoic acid 4-chloro-2,3,5-trifluorobenzoic acid was synthesized from methyl 2,3,4,5-tetrafluorobenzoate via three steps. The structure of the newly synthesized compound was established by FTIR, NMR, MS and elemental analysis.

A copper-mediated trifluoroacetylation of various arenediazonium salts with ethyl trifluoropyruvate is reported. The reaction proceeded smoothly under mild conditions at room temperature giving trifluoromethyl aryl ketones in moderate to good yields. A variety of functional groups, including methoxy, hydroxy, ester, ketone, trifluoromethyl, and halide groups, were well tolerated. A possible reaction mechanism involving an aryl radical intermediate was proposed and supported by experimental evidence. This reaction provides a new route to trifluoromethyl aryl ketones, notable synthetic targets, from the corresponding anilines. [ABSTRACT FROM AUTHOR]

Aromatic and heteroaromatic diazonium salts were efficiently converted into the corresponding trifluoromethylthio- or selenoethers by reaction with Me4NSCF3 or Me4NSeCF3, respectively, in the presence of catalytic amounts of copper thiocyanate. These Sandmeyer-type reactions proceed within one hour at room temperature, are applicable to a wide range of functionalized molecules, and can optionally be combined with the diazotizations into one-pot protocols. [ABSTRACT FROM AUTHOR]

It has been carried out the modification of Sandmeyer modification reaction by in-situ generated formaldehyde. The in-situ generated formaldehyde has been performed via heterogeneous phase reaction between 6.40 mL (0.10 mol) CH2Cl2 as organic phase with 40 mL 6.0 N KOH-alcoholic solution as aqueous phase and 2.56 g tetrabutylammonium perchlorate as phase transfer catalyst (PTC) by 40o C for 4 hours. Furthermore, 5.9 mL (0.05 mol) guaiacol 1 is dropwised to add to the reaction mixture. After the addition of guaiacol 1 finished, then reaction is allowed to run for 1 hour, so that the white crystal of vanillil alcohol 10 can be produced in 25.3%. Followed by oxidation of vanillil alcohol 10 with mixture of K2Cr2O7/conc. H2SO4 solution as oxidator, and 18-crown ether-6 as phase transfer catalyst (PTC) in heterogeneous phase at the room temperature for 5 hours, can be afforded vanillin 4 in 6.2% (calculated from starting material 1).

'Green' laboratory procedures have been developed for the synthesis and purification of 5-nitrotetrazole sodium salt, a key precursor of promising energetic compounds. The procedures can be safely scaled up. [ABSTRACT FROM AUTHOR]

Reactions of 5-carboxy and 4-methylphenylene-1,3-bisdiazonium tetrafluoroborates with amides and nitriles of acrylic and methacrylic acids in the presence of chloride, bromide, and thiocyanate anions proceed as anionarylation at one of the diazo groups and nucleophilic substitution at another one. With 4-methylphenylene- 1,3-bisdiazonium tetrafluoroborate as the arylating agent, the anionarylation and the Sandmeyer reaction occur involving para- and ortho-positioned diazo groups, respectively. [ABSTRACT FROM AUTHOR]

A copper-CF2H complex generated in situ from copper thiocyanate and TMS-CF2H smoothly converts organothiocyanates into valuable difluoromethyl thioethers. This reaction step can be combined with several thiocyanation methods to one-pot protocols, allowing late-stage difluoromethylthiolations of widely available alkyl halides and arenediazonium salts. This strategy enables the introduction of difluoromethylthio groups--a largely unexplored substituent with highly promising properties--into drug-like molecules. [ABSTRACT FROM AUTHOR]

Iodoarenes are important synthons for a wide range of organic transformations. Here we report a general strategy to prepare singly iodinated electron-rich aromatic compounds through the intermediacy of diaryliodonium salts. This process, which incorporates a phase separation that greatly simplifies product purification, is an attractive replacement for the Sandmeyer approach to iodoarenes that are otherwise difficult to access. [ABSTRACT FROM AUTHOR]

The reactions of 2-amino-5-cyclopropylpyridine with organic nitrites in the presence of copper(II) halides in various organic solvents were investigated. Optimal reaction conditions for the Sandmeyer reaction were developed and successfully applied to the synthesis of useful building blocks, bromo and chlorocyclopropylpyridines. Aminocyclopropylpyridines were synthesized in high yields from the corresponding aminobromopyridines under standard Suzuki coupling conditions. [ABSTRACT FROM AUTHOR]

A Cu2O-mediated cross coupling of arenediazonium tetrafluoroborates with trimethylsilyl cyanide to form aromatic nitriles is presented. This protocol tolerates a wide range of functional groups and gives good to excellent yields under mild conditions. Cu2O provides appealing and convenient access to aromatic nitriles compared with the traditional Sandmeyer reaction with toxic CuCN via nucleophilic substitution under relatively harsh conditions. [ABSTRACT FROM AUTHOR]

A range of benzotrifluorides are conveniently accessible in high yields from widely available (hetero)aromatic amines and the inexpensive trifluoromethylating agent TMSCF3 through a copper-mediated Sandmeyer trifluoromethylation reaction. Two practical procedures are presented. In the first, the diazonium salts are preformed in an extra reaction step, in the second approach the diazotization and the trifluoromethylation are combined into a one-pot procedure. [ABSTRACT FROM AUTHOR]

A novel strategy for aromatic trifluoromethylation by converting amino into trifluoromethyl groups via a Sandmeyer-type reaction is reported. The transformation involves diazotization of the aromatic amines with tert-butyl nitrite and hydrochloric acid to form aryldiazonium chlorides, followed by trifluoromethylation with trifluoromethylsilver at low temperature. Various readily available aromatic amines are smoothly converted under mild conditions. [ABSTRACT FROM AUTHOR]

Practical one-pot procedures were developed for both Sandmeyer-type trifluoromethylations and trifluoromethylthiolations. Starting from broadly available (hetero)aromatic amines, various benzotrifluorides were synthesized in high yields via in situ diazotization and copper-mediated trifluoromethylation using the inexpensive Ruppert-Prakash trifluoromethylating reagent. In the presence of sodium thiocyanate as a sulfur source, aryl trifluoromethyl thioethers are exclusively formed. [ABSTRACT FROM AUTHOR]

A convenient and efficient method for the copper-mediated cascade synthesis of diaryl sulfones via the Sandmeyer reaction has been developed. The protocol uses readily available aryl amines and arylsulfinic acids as the starting materials, isoamyl nitrite as the diazotizating reagent of the aryl amines, and the method shows mild reaction conditions and high tolerance towards various functional groups in the substrates. [ABSTRACT FROM AUTHOR]