Reformatsky Reagent Research Articles

Synthesis of Naphthalene Amino Esters by the Blaise Reaction of o-Alkynylarenenitriles

The action of a Reformatsky reagent on o-alkynylarenenitriles provides a convenient access to naphthalene amino esters via tandem 6-endo-dig carbannulation of in situ generated Blaise reaction intermediates. The products are formed in moderate to good yields with high chemo- and regioselectivity.

ChemInform Abstract: Palladium‐Catalyzed α‐Arylation of Zinc Enolates of Esters: Reaction Conditions and Substrate Scope.

The intermolecular α-arylation of esters by palladium-catalyzed coupling of aryl bromides with zinc enolates of esters is reported. Reactions of three different types of zinc enolates have been developed. α-Arylation of esters occurs in high yields with isolated Reformatsky reagents, with Reformatsky reagents generated from α-bromo esters and activated zinc, and with zinc enolates generated by quenching alkali metal enolates of esters with zinc chloride. The use of zinc enolates, instead of alkali metal enolates, greatly expands the scope of the arylation of esters. The reactions occur at room temperature or at 70 °C with bromoarenes containing cyano, nitro, ester, keto, fluoro, enolizable hydrogen, hydroxyl, or amino functionality and with bromopyridines. The scope of esters encompasses acyclic acetates, propionates, and isobutyrates, α-alkoxyesters, and lactones. The arylation of zinc enolates of esters was conducted with catalysts bearing the hindered pentaphenylferrocenyl di-tert-butylphosphine (Q-phos) or the highly reactive dimeric Pd(I) complex {[P(t-Bu)3]PdBr}2.

A chemoselective Reformatsky–Negishi approach to α-haloaryl esters

A practical synthesis of α-haloaryl esters has been achieved via a chemoselective Negishi coupling of poly-halogenated aromatics and Reformatsky reagents in the presence of catalytic Pd(dba)2 and Xantphos. This chemistry tolerates a variety of aryl halides and was successfully applied to the synthesis of Ibuprofen. The α-haloaryl ester products, exemplified by ethyl 2-(4-bromo-2-chlorophenyl)acetate (3a), can be further functionalized via palladium or copper catalysis to afford an array of α-aryl esters.

Tandem Blaise/retro-Blaise Reaction for the Nitrile-Mediated Regioselective Intermolecular Addition of Unstabilized Zinc Ester Enolates (Reformatsky Reagents) to 1-Alkynes and 1,3-Enynes

We report the novel use of a nitrile as a mediator to achieve the regioselective intermolecular addition of unstabilized zinc ester enolates (Reformatsky reagents) to 1-alkynes and 1,3-enynes. This reaction is made possible by a reversible addition of enolates to a nitrile (Blaise reaction), generating a zinc aza-enolate that, unlike zinc ester enolates, can add intermolecularly to 1-alkynes and 1,3-enynes. Subsequent removal of the nitrile through a retro-Blaise reaction generates the targeted addition product. This method is combined with a Diels-Alder reaction and subsequent oxidative aromatization, providing a tandem one-pot de novo construction of α-arylated alkanoates from Reformatsky reagents.

Palladium-catalyzed α-arylation of zinc enolates of esters: reaction conditions and substrate scope.

The intermolecular α-arylation of esters by palladium-catalyzed coupling of aryl bromides with zinc enolates of esters is reported. Reactions of three different types of zinc enolates have been developed. α-Arylation of esters occurs in high yields with isolated Reformatsky reagents, with Reformatsky reagents generated from α-bromo esters and activated zinc, and with zinc enolates generated by quenching alkali metal enolates of esters with zinc chloride. The use of zinc enolates, instead of alkali metal enolates, greatly expands the scope of the arylation of esters. The reactions occur at room temperature or at 70 °C with bromoarenes containing cyano, nitro, ester, keto, fluoro, enolizable hydrogen, hydroxyl, or amino functionality and with bromopyridines. The scope of esters encompasses acyclic acetates, propionates, and isobutyrates, α-alkoxyesters, and lactones. The arylation of zinc enolates of esters was conducted with catalysts bearing the hindered pentaphenylferrocenyl di-tert-butylphosphine (Q-phos) or the highly reactive dimeric Pd(I) complex {[P(t-Bu)3]PdBr}2.

ChemInform Abstract: Cu(OAc)2‐Catalyzed Tandem Blaise/Pinner‐Type Reaction for One‐Pot Synthesis of Pyrimidin‐4‐ones.

AbstractA novel synthesis of the title compounds proceeds via reaction of nitriles with Reformatsky reagent followed by Co(O‐Ac)2‐catalyzed reaction of the Blaise‐type intermediate with a second nitrile.

ChemInform Abstract: Synthesis, Structure, and Biological Applications of α‐Fluorinated β‐Amino Acids and Derivatives

AbstractReview: 133 refs.

Reaction of organozinc halides with aryl isocyanates

Reformatsky reagent, benzylzinc bromide or alkylzinc iodides react with aryl isocyanates directly to give corresponding N-substituted carbamates under mild reaction conditions. However, the reaction of allylzinc bromide or propargylzinc bromide with aryl isocyanates produces the corresponding N-substituted amides. The reactions provide alternative methods for the synthesis of N-substituted carbamates or amides.

Enantiopure Trifluoromethylated β3,3-Amino Acids: Synthesis by Asymmetric Reformatsky Reaction with Stable Analogues of Trifluoromethyl N-tert-Butanesulfinylketoimines and Incorporation into α/β-Peptides

Addition of a Reformatsky reagent to α-aryl(alkyl) α-trifluoromethyl N-tert-butanesulfinyl hemiaminals, bench-stable surrogates of trifluoromethyl ketoimines, provided β-alkyl(aryl) β-trifluoromethyl β-amino acids derivatives in good yields and high diastereoselectivities. The N-tert-butanesulfinyl β(3,3)-amino esters were further utilized as versatile intermediates for the elaboration of heterodi- and -tripeptides.

Cu(OAc)2-Catalyzed Tandem Blaise/Pinner-Type Reaction for One-Pot Synthesis of Pyrimidin-4-ones

A novel tandem Blaise/Pinner-type reaction for the one-pot synthesis of pyrimidin-4-ones is described. The Blaise reaction intermediate, formed by addition of a Reformatsky reagent to a nitrile, reacted with a second nitrile chemoselectively in the presence of a catalytic amount of Cu(OAc)(2) to afford pyrimidin-4-ones.

Synthesis and Functionalization of Unsymmetrical Arylsulfonyl Bisindoles and Bisbenzazoles

AbstractA three‐component coupling of two different benzazole compounds with p‐toluenesulfinic acid allows the efficient preparation of unsymmetrical arylsulfonyl bisbenzazole derivatives. Substitution of the arylsulfonyl group from these adducts using sodium borohydride leads to the corresponding bisbenzazoles. Functional implementation of the bisbenzazole system can be achieved using Grignard and Reformatsky reagents.

Synthesis, Structure, and Biological Applications of α‐Fluorinated β‐Amino Acids and Derivatives

This review gives a broad overview of the state of play with respect to the synthesis, conformational properties, and biological activity of α-fluorinated β-amino acids and derivatives. General methods are described for the preparation of monosubstituted α-fluoro-β-amino acids (Scheme 1). Nucleophilic methods for the introduction of fluorine predominantly involve the reaction of DAST with alcohols derived from α-amino acids, whereas electrophilic sources of fluorine such as NFSI have been used in conjunction with Arndt-Eistert homologation, conjugate addition or organocatalyzed Mannich reactions. α,α-Difluoro-β-amino acids have also been prepared using DAST; however, this area of synthesis is largely dominated by the use of difluorinated Reformatsky reagents to introduce the difluoro ester functionality (Scheme 9). α-Fluoro-β-amino acids and derivatives analyzed by X-ray crystal and NMR solution techniques are found to adopt preferred conformations which are thought to result from stereoelectronic effects associated with F located close to amines, amides, and esters (Figs. 2-6). α-Fluoro amide and β-fluoro ethylamide/amine effects can influence the secondary structure of α-fluoro-β-amino acid-containing derivatives including peptides and peptidomimetics (Figs. 7-9). α-Fluoro-β-amino acids are also components of a diverse range of bioactive anticancer (e.g., 5-fluorouracil), antifungal, and antiinsomnia agents as well as protease inhibitors where such fluorinated analogs have shown increased potency and spectrum of activity.

ChemInform Abstract: Reaction of Alicyclic Reformatsky Reagents with 2,5‐Bis(arylmethylidene)cyclopentanones.

Reformatsky reaction of methyl 1-bromocyclobutane-, 1-bromocyclopentane-, 1-bromocyclohexane-, and 1-bromocycloheptanecarboxylates with 2,5-bis(arylmethylidene)cyclopentanones gave the corresponding 4′-aryl-7′-arylmethylidene-4′,5′,6′,7′-tetrahydro-2′H-spiro[cycloalkane-1,3-cyclopenta[b]pyran]-2′-ones.

Reaction of alicyclic reformatsky reagents with 2,5-bis(arylmethylidene)cyclopentanones

Reformatsky reaction of methyl 1-bromocyclobutane-, 1-bromocyclopentane-, 1-bromocyclohexane-, and 1-bromocycloheptanecarboxylates with 2,5-bis(arylmethylidene)cyclopentanones gave the corresponding 4′-aryl-7′-arylmethylidene-4′,5′,6′,7′-tetrahydro-2′H-spiro[cycloalkane-1,3-cyclopenta[b]pyran]-2′-ones.

ChemInform Abstract: Chemoselective Intramolecular Alkylation of the Blaise Reaction Intermediates: Tandem One‐Pot Synthesis of exo‐Cyclic Enaminoesters and Their Applications Toward the Synthesis of N‐Heterocyclic Compounds.

AbstractCoupling of nitriles (I) and (VII) with Reformatsky reagents, generated from bromides (II) and (V), followed by treatment with NaN(Tms)2 allows an efficient access to exo‐cyclic enaminoesters.

ChemInform Abstract: Tandem One‐Pot Synthesis of Polysubstituted Pyridines Using the Blaise Reaction Intermediate and 1,3‐Enynes.

AbstractSequential reaction of nitriles, Reformatsky reagents and 1,3‐enynes proceeds with complete regio‐ and chemoselectivity to provide the polysubstituted pyridines.

Chemoselective Intramolecular Alkylation of the Blaise Reaction Intermediates: Tandem One-Pot Synthesis of exo-Cyclic Enaminoesters and Their Applications toward the Synthesis of N-Heterocyclic Compounds

The intramolecular alkylative reactivity and N/C selectivity of the various Blaise reaction intermediates, which are formed from the reaction of the Reformatsky reagents with ω-chloroalkyl nitriles, did not reach the synthetic potential as an entry to exo-cyclic enaminoesters. To circumvent this issue, various additives were investigated, among which the addition of NaHMDS dramatically enhanced the reactivity and N/C selectivity. This modification provided a highly efficient route for the synthesis of various N-fused heterocyclic compounds, as it requires only two steps from nitriles.

Enantioselective Reformatsky reaction of ethyl iododifluoroacetate with ketones

Two approaches have been developed for the enantioselective Reformatsky reaction of ethyl iododifluoroacetate with ketones to form a quaternary carbon centre using (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol as the chiral ligand. Good yields and high enantioselectivities (80-91% ee) were achieved with a range of alkyl aryl ketones in a convenient one-pot protocol using ethyl iododifluoroacetate and diethylzinc to form the difluorinated Reformatsky reagent homogeneously. In the traditional two-step Reformatsky reaction using the preformed Reformatsky reagent generated from ethyl iododifluoroacetate and zinc dust, good yields and good enantioselectivities (75-84% ee) were also obtained.

Tandem One-Pot Synthesis of Polysubstituted Pyridines Using the Blaise Reaction Intermediate and 1,3-Enynes

A tandem one-pot method for the construction of a pyridine moiety with selective control of substitution patterns has been developed through the sequential reactions of nitrile with a Reformatsky reagent and 1,3-enyne involving regio- and chemoselective addition of the Blaise reaction intermediate to 1,3-enyne, followed by isomerization, cyclization, and an aromatization cascade.

Synthesis of spirotetrahydropyran-2,4-diones with ferrocenyl substituent

Methyl esters of 1-(2-bromo-2-methylpropanoyl)cycloalkanecarboxylic acids (Iа–Ic) and 2,2-dimethyl3-oxo-3-(1-bromocycloalkyl)propanoic acids (Vа–Vc) react with zinc and aromatic aldehydes to give spirotetrahydropyran-2,4-diones with the aryl substituent in the 6 position of the heterocycle [1–5]. In order to synthesize similar compounds with the ferrocenyl substituent we have studied the reaction of the Reformatsky reagents IIа–IIc and VIа–VIc prepared from bromooxoesters Iа–Ic, Vа–Vc and zinc with ferrocenecarbaldehyde. It was found that the Reformatsky reagents IIа–IIc and VIа–VIc add to the carbonyl group of ferrocenecarbaldehyde with the formation of bromozincalkoxides IIIа–IIIc and VIIа– VIIc. In the course of the reaction, the latter spontaneously underwent cyclization with the elimination of bromozincmethylate to give spirotetrahydropyran-2,4-diones with the ferrocenyl substituent in the 6 position of the heterocycle IV–VIII, which were isolated in 70–83% yield.