Bromine Magnesium Exchange Research Articles

The reaction of unprotected 1,4-dihydropyridine Hantzsch esters with Grignard reagents: Preparation of unsymmetrical 1,4-dihydropyridine derivatives

The mild bromine-magnesium exchange reaction using i-PrMgBr in THF on the 2-bromomethyl-1,4-dihydropyridine Hantzsch esters allowed the synthesis of highly functionalized magnesiated 1,4-dihydropyridines with ester groups tolerance. Treatment of the resulting anionic intermediates with hard electrophile methyl iodide gave N-methylated product 6 and pyridine derivative 7 in 60 % and 10 % yields, respectively. In trapping the reaction mixture of magnesiated 1,4-dihydropyridine with ethyl bromide, pyridine derivative 8, and dimer 9 were obtained. Also, FeCl3-catalyzed cross-coupling reaction of allylMgBr, i-PrMgBr, and n-BuMgBr Grignard reagents with 2-bromomethyl-1,4-dihydropyridine derivative 2 afforded unsymmetrical 1,4-dihydropyridine derivatives 10a-c in good yields.

Formal Halogen Transfer of Bromoarenes via Stepwise Reactions.

A two-step halogen transfer of bromoarenes is reported. Mono-, di-, and tribromoaryllithiums generated through deprotonative lithiation were converted into organozinc species by in situ zincation, which were then subjected to bromination to provide the corresponding di-, tri-, and tetrabromoarenes, respectively, in 41-95% yields. Regioselective bromine-magnesium exchange with ethylmagnesium chloride followed by electrophilic trapping afforded benzene, pyridine, quinoline, pyrimidine, and thiazole derivatives with the bromo group translocated from the original position in 28-86% yields.

Synthesis of two potent glucocorticoid receptor agonists labeled with carbon‐14 and stable isotopes

Two potent glucocorticoid receptor agonists were prepared labeled with carbon-14 and with stable isotopes to perform drug metabolism, pharmacokinetics, and bioanalytical studies. Carbon-14 labeled (1) was obtained from an enantiopure alkyne (5) via a Sonogashira coupling to a previously reported 5-amino-4-iodo-[2-(14)C]pyrimidine [(14)C]-(6), followed by a base-mediated cyclization (1) in 72% overall radiochemical yield. Carbon-14 labeled (2) was prepared in five steps employing a key benzoic acid intermediate [(14)C]-(13), which was synthesized in one pot from enolization of trifluoromethylketone (12), followed by bromine-magnesium exchange and then electrophile trapping reaction with [(14)C]-carbon dioxide. A chiral auxiliary (S)-1-(4-methoxyphenyl)ethylamine was then coupled to this acid to give [(14)C]-(15). Propargylation and separation of diastereoisomers by crystallizations gave the desired diastereomer [(14)C]-(17) in 34% yield. Sonogashira coupling to iodopyridine (10) followed by cyclization to the azaindole [(14)C]-(18) and finally removal of the chiral auxiliary gave [(14)C]-(2) in 7% overall yield. For stable isotope syntheses, [(13)C6]-(1) was obtained in three steps using [(13)C4]-(6) and trimethylsilylacetylene-[(13)C2] in 26% yield, while [(2)H5]-(2) was obtained by first preparing the iodopyridine [(2)H5]-(10) in five steps. Then, Sonogashira coupling to chiral alkyne (24) and cyclization gave [(2)H5]-(2) in 42% overall yield.

Strategies To Prepare and Use Functionalized Organometallic Reagents

Polyfunctional zinc and magnesium organometallic reagents occupy a central position in organic synthesis. Most organic functional groups are tolerated by zinc organometallic reagents, and Csp(2)-centered magnesium organometallic reagents are compatible with important functional groups, such as the ester, aryl ketone, nitro, cyano, and amide functions. This excellent chemoselectivity gives zinc- and magnesium-organometallic reagents a central position in modern organic synthesis. Efficient and general preparations of these organometallic reagents, as well as their most practical and useful reactions, are presented in this Perspective. As starting materials, a broad range of organic halides (iodides, bromides, and also to some extent chlorides) can be used for the direct insertion of magnesium or zinc powder; the presence of LiCl very efficiently promotes such insertions. Alternatively, aromatic or heterocyclic bromides also undergo a smooth bromine-magnesium exchange when treated with i-PrMgCl·LiCl. Alternative precursors of zinc and magnesium reagents are polyfunctionalized aryl and heteroaryl molecules, which undergo directed metalations with sterically hindered TMP bases (TMP = 2,2,6,6-tetramethylpiperide) of magnesium and zinc. This powerful C-H functionalization method gives access to polyfunctional heterocyclic zinc and magnesium reagents, which undergo efficient reactions with numerous electrophiles. The compatibility of the strong TMP-bases with BF3·OEt2 (formation of frustrated Lewis pairs) dramatically increases the scope of these metalations, giving for example, a practical access to magnesiated pyridines and pyrazines, which can be used as convenient building blocks for the preparation of biologically active molecules.

Pyridylmagnesiates: generation by bromine–metal exchange and enantioselective addition to aldehydes

Butyl and dibutylmagnesiates incorporating chiral ligands have been prepared and their reactivity studied. The reagents were efficient to promote the clean bromine–magnesium exchange of azinyl bromides at room temperature and subsequent reaction with aldehydes affording pyridylcarbinols. (R,R)-TADDOL-based dibutylmagnesiate was the best reagent leading to acceptable to good enantioselectivities, depending on the substrate and on the aldehyde substitution. This is the first example of enantioselective addition of in situ generated pyridylmagnesiate to carbonyl electrophiles.

ChemInform Abstract: Synthesis of Functionalized Pyridazin‐3(2H)‐ones via Selective Bromine—Magnesium Exchange and Lactam Directed ortho C—H Magnesiation.

AbstractIn the presence of Mst‐MgBr the pyridazinone (I) can undergo selective substitution at C‐5 to afford products like (III), (V), and (VI).

Chiral Organomagnesiates as Dual Reagents for Bromine–Magnesium Exchange of 2‐Bromopyridine and Access to Chiral α‐Substituted 2‐Pyridylcarbinols

AbstractNew chiral ligand containing butyl and dibutylmagnesiates have been prepared from a range of ligands and their reactivity studied. The reagents were generally efficient in promoting the clean bromine–magnesium exchange of 2‐bromopyridine at room temperature and the subsequent reaction with aldehydes to afford α‐substituted 2‐pyridylcarbinols in good yields. (R,R)‐TADDOLate proved to be the best ligand, leading to acceptable to good enantioselectivities. To the best of our knowledge this is the first example of an organomagnesiate‐induced halogen–metal exchange followed by an enantioselective addition.

Synthesis of (Hetero)arylated Pyridazin-3(2H)-ones via Negishi Reaction Involving Zincated Pyridazin-3(2H)-ones

Zincated pyridazin-3(2H)-ones generated via bromine-magnesium exchange followed by transmetalation using ZnCl(2) or via lactam-directed ortho C4-H zincation with TMPZnCl·LiCl have been synthesized. These in situ created organometallics can be used in Negishi reactions with iodo(hetero)arenes delivering a new approach toward (hetero)arylpyridazin-3(2H)-ones.

Synthesis of Functionalized Pyridazin-3(2H)-ones via Selective Bromine–Magnesium Exchange and Lactam Directed Ortho C–H Magnesiation

Selective bromine-magnesium exchange on 2-benzyl-5-bromo-4-methoxypyridazin-3(2H)-one could be achieved when MesMgBr was used as reagent. With more nucleophilic RMgCl species (R = Bu, i-Pr, Ph) both nucleophilic addition-elimination at C-4 and bromine-magnesium exchange at C-5 occurred. In 2-benzyl-5-bromopyridazin-3(2H)-one, which does not contain a substituent at C-4, addition could not be suppressed. Less nucleophilic Mg amides (TMPMgCl·LiCl) allowed regioselective C-H magnesiation at the C-4 position in such substrates, as exemplified for 2-benzyl-5-chloro- and 2-benzyl-6-chloropyridazin-3(2H)-one. Quenching of the magnesiated pyridazinones with electrophiles gives access to a variety of hitherto unknown pyridazin-3(2H)-one derivatives.

ChemInform Abstract: 2,4‐Disubstituted Thiazoles by Regioselective Cross‐Coupling or Bromine—Magnesium Exchange Reactions of 2,4‐Dibromothiazole.

AbstractThe synthesis of 2‐substituted 4‐bromothiazoles from 2,4‐dibromothiazole (I) is achieved by regioselective Negishi and Stille cross‐coupling reactions.

2,4-Disubstituted Thiazoles by Regioselective Cross-Coupling or Bromine-Magnesium Exchange Reactions of 2,4-Dibromothiazole

Cross-coupling reactions occur on 2,4-dibromothiazole preferentiallyat the more electron-deficient 2-position. This fact can be favorablyused to prepare 2-substituted 4-bromothiazoles, which serve as precursorsfor 2,4-disubstituted thiazoles. Protocols for regioselective Negishiand Stille cross-coupling reactions are provided. Alternatively,the title compound can be metalated in 2-position by a halogen-metalexchange reaction. As a supplement to the well-established bromine-lithiumexchange, the regioselective bromine-magnesium exchangereaction is presented.

ChemInform Abstract: Magnesiation of Pyridine N‐Oxide via Iodine or Bromine—Magnesium Exchange: A Useful Tool for Functionalizing Pyridine N‐Oxides.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis and evaluation of a new polar, TIPNO type nitroxide for “living” free radical polymerization

The bromine–magnesium exchange of 2-bromopyridine provides an easy access to a new versatile TIPNO type nitroxide. The synthesis of four functionalized alkoxyamines have been achieved. Polymerizations of styrene and n-butyl acrylate mediated with this new nitroxide exhibited all the expected features of a controlled system. Because of its increase of polarity, this pyridine nitroxide is more efficient than TIPNO for the acrylate polymerization as no added free nitroxide is required, that confirms the strong influence of the polarity of the nitroxide on the efficiency of nitroxide-mediated radical polymerization, result already observed in the case of the polar SG1 nitroxide. Different block copolymers were synthesized. Polystyrene, poly(n-butyl acrylate) and poly(tert-butyl acrylate) blocks were successfully used as macroinitiators for the synthesis of various diblock and triblock copolymers. A representative example of such architecture is given by polystyrene-b-poly(n-butyl acrylate)-b-poly(tert-butyl acrylate) with a PDI of 1.2!

Kinetics of Bromine−Magnesium Exchange Reactions in Substituted Bromobenzenes

Competition experiments have been performed to determine the relative reactivities of substituted bromobenzenes, bromonaphthalenes, and 9-bromoanthracene toward i-PrMgCl x LiCl in THF at 0 degrees C. The rates of the bromine-magnesium exchange reactions are accelerated by electron-acceptor substituents, the activating efficiency of which increases in the order para < meta << ortho. The activation free enthalpies of the bromine-magnesium exchange reactions correlate fairly (r(2) = 0.83) with the proton affinities of analogously substituted aryllithiums (slope 0.8). The kinetics of two representative bromoarenes with i-PrMgCl x LiCl were found to be first-order in both bromoarene and i-PrMgCl x LiCl. Combination of the resulting second-order rate constants with the k(rel) values from competition experiments allowed us to calculate reaction times for the bromine-magnesium exchange reactions of a large variety of bromoarenes.

Cyano-Substituted 2-Carboxyimidazoles: Synthesis of 4-Cyano-1-{[2-(tri­meth­ylsilyl)ethoxy]methyl}-1H-imidazole-2-carboxylate Potassium Salt

The first example of a monocyano-substituted 2-carboxyimidazole is reported. A synthesis of potassium 4-cyano-1-{[2-(trimethylsilyl)ethoxy]methyl} -1 H-imidazole-2-carboxylate (2) is demonstrated where the carboxylate group is introduced via bromine-magnesium exchange on a SEM-protected cyanoimidazole followed by reaction with ethyl cyanoformate. The synthesis includes the equilibration of a regioisomeric mixture of SEM-protected imidazoles to give a single product.

Relative Rates of Bromine–Magnesium Exchange Reactions in Substituted Bromobenzene Derivatives

Relative Rates of Bromine–Magnesium Exchange Reactions in Substituted Bromobenzene Derivatives

The N-vinyl group as a protection group of the preparation of 3(5)-substituted pyrazoles via bromine–lithium exchange

Treatment of 3,4,5-tribromopyrazole with 1,2-dibromoethane and triethylamine gave 3,4,5-tribromo-1-vinylpyrazole, which underwent regioselective bromine–lithium exchange at the 5-position. Subsequent addition of an electrophile gave 5-substituted 3,4-dibromo-1-vinylpyrazoles. These underwent bromine–lithium or bromine–magnesium exchange predominantly at the 4-position, with the regioselectivity between the 3- and 4-positions being influenced by the nature of the metal and the 5-substituent. The 5-substituted products were de-vinylated by mild treatment with KMnO 4 affording 3-substituted pyrazoles. Alternatively, the 1-vinyl group could be used in ring-closing metathesis. Thus, 5-allylthio-1-vinylpyrazole produced 5 H-pyrazolo[5,1- b][1,3]thiazine upon treatment with Grubbs' second-generation catalyst.

Regioselective Functionalization of Trisubstituted Pyridines Using a Bromine—Magnesium Exchange.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Bromine—Magnesium Exchange of 5‐Bromo‐2‐picoline via an Organomagnesium Complex nBu2iPrMgLi: A New Preparation Methodology of Functionalized Picolines under Noncryogenic Conditions.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Synthesis and Utilization of Functionalized Polystyrene Resins

Abstract Co-polymerised 4-bromopolystyrene has been converted to a range of polymer-supported reagents and scavengers by bromine–magnesium exchange using Oshima's trialkylmagnesate complex followed by quenching with a variety of electrophiles. Mitsunobu, halogenation and Wittig reactions, were explored to assess the utility of the resins for target oriented and diversity oriented synthesis.