2-Iodopyridine reaction with

Qudguiner s group enlisted a combination of directed metalation and a Pd-catalyzed crosscoupling reaction for the construction of heteroaryl natural products [49]. One example was the total synthesis of bauerine B (64), a -carboline natural product [50], Or/fio-lithiation of 2,3-dichloro-A-pivaloylaminobenzene (61) was followed by reaction with trimethylborate to provide boronic acid 62 after hydrolysis. The Suzuki reaction between 62 and 3-fluoro-4-iodopyridine led to the desired biaryl product 63 contaminated with the primary amine (ca. 30%), both of which were utilized in the total synthesis of bauerine B (64). Another p-carboline natural product, the antibiotic eudistomin T (65), and a few other hydroxy p-carbolines have also been synthesized in the same fashion [3,51]. 

The lack of reactivity of 3-halo substituents under non-radical nucleophilic substitution conditions allows differential functionalization of pyri-dines by 3-umpolung and 2-nucIeophilic substitution processes. Thus, treatment of 2-fluoro-3-iodopyridine (189) with oxygen or amine nucleophiles affords products 191 which, upon subjection of SRN1 reactions with carbon, phosphorus, and sulfur systems, give 2,3-difunctionalized pyri-dines 192 (Scheme 56) (88JOC2740). 

Tetrafluoropyridyl organometallic reagents can be prepared by reaction of 4-bromotetra-fluoro- or tctrafluoro-4-iodopyridine with zinc or cadmium in dimethylformamide at room temperature.83 Metathesis of these reagents with copper(l) bromide affords the (2.3,5,6-tetra-fluoro-4-pyridyl)copper reagent. The latter species undergoes high-yield substitution reactions with allyl halides, vinyl iodides, aryl iodides, and alkanoyl halides. 

Difficulties in preparing and handling complex bases, along with their exacting experimental conditions have limited their use. Kondo provided a solution to this with a report on the effectiveness of lithium di-ZerZ-butyltetramethylpiperidinozincate (TMP-zincate) as a highly chemoselective base [9]. It was determined that pre-complexation of LTMP 20 with di-zerz-butylzinc was required to generate the active species 21. The reaction with pyridine at room temperature was found to proceed smoothly to produce the 2-lithio species that could be treated with iodine to afford 2-iodopyridine 22. 

Phenyl-substituted propargyl alcohol couples with 3-iodopyridine to furnish (49) (Scheme 10). On reaction of the 2-iodopyridine (50), however, it was found that the initial alkynylation product (51) rearranged to form the corresponding chalcone (52). The same rearrangement occurs in pyrimidines when the iodine is located in an electrophilic position. In reactions with the corresponding methylpropargyl alcohol, the reaction stops after... 

A typical halogen-dance reaction from the work of Queguiner is shown in Scheme 7. In this example, treatment of 2-fluoro-3-iodopyridine (18) with LDA and methyl iodide provides pyridine 19, in which the iodine has migrated to the 4-position and a methyl group has been incorporated at the 3-position. The mechanism of related halogen-dance... 

Interestingly, reaction of aryl halides with long chain Q ,allylpalladium intermediates, which are trapped by nucleophiles. Treatment of 3-iodopyridine (362) with 1,12-trideca-diene (363) in the presence of amine 364 produced a mixture of 365 (62 %) and 366 (13 %). The reaction took 4 days showing that the elimination and readdition of H-Pd-X occurred back and forth many times along the long carbon chain, and was terminated by the formation of the 7r-allylpalladium intermediate [145],... 

Cyclization of iodopyiidinyl aUyl ethers derived fom dihalopyridines and sodium aUyUc oxides leads to formation of furo[2,3-fc]pyridines 292, furo[3,2-c]pyiidines 293, and furo[2,3-c]pyridines 294 by a Heck mode of reaction (Scheme 101). In the reaction sequences, the initial step in the preparation of iodopyridine aUyl ethers involves regioselective lithiation of 3-fluoro, 2-fluoro-, and 4-chloropyridines with LDA. Subsequently, the lithiated species are treated with iodine as electrophile. A variety of iodopyiidinyl ethers have been prepared from dihalopyridines and sodium aUyhc oxides and subjected to the Pd-catalyzed cyclization reactions with formation of the furoannulated pyridine products. When the allyl groups carry a 2-substituent as in stracture 295, hydridopaUadium elimination is prevented. Instead, sodium formate reductive elimination of the palladium substituent gives the product 296. The isomeric structures 297 and 298 are available similarly. ... 

DMSO solvent, requires the presence of a weak acid such as acetic or trifluorobenzoic and involves a significant kinetic isotope effect indicating that C-H bond cleavage is, at least partially, rate determining. " The trifiuoromethylation of iodoheteroaromatics, such as 4-iodopyridine, by copper-catalysed reaction with trifluoromethyldiphenylsul-fonium salts is likely to involve the intermediacy of trifiuoromethylcopper. " Copper catalysis has also been used in the synthesis of Ai-arylpurines, (59), by reaction of purines with diaryliodonium salts. 

The amino function in 4-amino-3-halopyridines belraves unexceptionally. Thus 4-amino-3-diloropyridine gives the 3-chloro-4-pyridinediazonium salt dien treated with nitrous acid the diazonium salt decomposes in the presence of potassium iodide to yield 3-chloro-4-iodopyridine. 4-Amino-2,3,5,6-tetrafluoropyridine is a very weak base but it can be diazotized in 80% hydrofluoric acid. The diazonium salt is converted to 4-bromo-2,3,5,6-tetrabromopyridine with cuprous bromide, but its reaction with water or with A, lV-dimethylaniline are complex. 4-Amino-2-chloro-3-nitropyridine is not converted to 2-chloro-3-nitro-4-pyridone (K-97) on diazotization with mineral acids and sodium nitrite or with isoamyl nitrite in glacial acetic acid with the latter reagent 2-chloro-3-nitropyri-dine (K-98) is formed." Nitrous acid reacts with 4-amlno-2-pyridone to give 4-amino-3-nitroso-2-pyridone instead of the diazonium salt. ... 

Interestingly, unsymmetrical amino-bipyridines were produced from the coupling reactions of 2-pyridylzinc bromides with halogenated aminopyri-dines under the conditions used previously. As shown in Scheme 3.11, 2-amino-5-iodopyridine reacted with PI to afford 2,3-bipyridine (s2a) in 59% isolated yield in the presence of lmol% of Pd(PPhs)4 catalyst (route A, Scheme 3.11). 

New anesthetic compound - tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c] pyrazole (104) has been prepared by reaction iodopyridine 103 with CsF in DMSO without change of stereochemistry at rather hard conditions (60 min. at 200 °C) [90] (Scheme 40). Compounds 104 are modulators of receptors of cannabinoids and can be used against a cancer and Alzheimer s and Parkinson s diseases [90]. 

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