Allylic Grignard Reagents Research Articles

Sequential Diastereoselective Addition of Allylic and Homoallylic Grignard Reagents to 2‐Acyl‐perhydro‐1,3‐benzoxazines and Ring‐Closing Metathesis: An Asymmetric Route to Azepin‐3‐ol and Azocin‐3‐ol Derivatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Efficient Routes to Acenaphthylene‐Fused Polycyclic Arenes/Heteroarenes and Heterocyclic Fluoranthene Analogues.

The acenaphthenone-derived α-oxoketene dithioacetal 2 has been subjected to various [3 + 3] aromatic and heteroaromatic annulation and other heterocyclization reactions previously developed in our laboratory, providing short and efficient routes to a diverse range of known and unknown acenaphtho-annulated linear and angular PAHs, heteroaromatics and five-membered heterocycles in good yields. Thus, benzo- and naphthoannulation of 2 with various allyl and benzyl Grignard reagents afforded substituted fluoranthenes 4a–c and benzo[k]fluoranthene 8, respectively, in good yields. Similarly, the parent benzo[j]fluoranthene 15a and its substituted derivative 16b have been synthesized by base-induced conjugate 1,4-addition of arylacetonitriles to 2, followed by acid-induced cyclization of the conjugate adducts 12a–b to give 13a–b and subsequent further transformations. The adducts obtained by 1,4-addition of anions derived from acetophenone and acenaphthenone were subjected toheterocyclization in the presence of ammonium acetate to give 8-arylacenaphtho[1,2-b]pyridines 18a–b and bis(acenaphtho)-annulated pyridine 20. Heterocyclization of 2 with bifunctional nucleophiles such as 2-picolyllithium and guanidinium nitrate afforded the corresponding acenaphtho[1,2-b]quinolizinium salt 23 and acenaphtho[1,2-d]pyrimidine 24, respectively, in high yields. Finally, acenaphtho[1,2-c]-fused five-membered heterocycles such as 7-(methylthio)acenaphtho[1,2-c]thiophene (25), 7-(methylthio)acenaphtho[1,2-c]furan (27) and 7-(methylthio)acenaphtho[1,2-c]pyrrole-2-carboxylic acid (30) were obtained in good yields by subjection of 2 to Simmons–Smith reaction conditions or by treatment with dimethylsulfonium methylide or glycinate dianion. Some of these newly synthesized PAHs or fused heterocycles were subjected to Raney Ni desulfurization to furnish sulfur-free compounds. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Opening of Aryl-Substituted Epoxides To Form Quaternary Stereogenic Centers: Synthesis of (−)-Mesembrine

[reaction: see text] Cycloalkanones are easily converted into aryl-substituted cyclic alkenes by the addition of an aryl Grignard reagent followed by dehydration. These alkenes are good substrates for asymmetric epoxidation. We have found that the addition of allylic and benzylic Grignard reagents can occur preferentially at the benzylic position of the derived epoxides to give the quaternary stereogenic center. This approach led to a short synthesis of the nanomolar serotonin re-uptake inhibitor (-)-mesembrine.

Intramolecular Cyclopropanation of Epichlorohydrin-Derived Unsaturated Chlorohydrins

Concise stereoselective syntheses of bicyclo[3.1.0]hexan-2-ols and a bicyclo[4.1.0]heptan-2-ol are achieved via regioselective ring-opening of epichlorohydrin with allylic and homoallylic Grignard reagents, followed by lithium 2,2,6,6-tetramethylpiperidide-induced intramolecular cyclopropanation of the resulting unsaturated chlorohydrins.

Sequential Diastereoselective Addition of Allylic and Homoallylic Grignard Reagents to 2‐Acyl‐perhydro‐1,3‐benzoxazines and Ring‐Closing Metathesis: an Asymmetric Route to Azepin‐3‐ol and Azocin‐3‐ol Derivatives

AbstractChiral 2‐acyl‐3‐allyl‐substituted perhydrobenzoxazines derived from (–)‐8‐aminomenthol react with allyl or homoallyl Grignard reagents to provide the corresponding tertiary alcohols in very good yields and with excellent diastereoselectivities. The 1,8‐ and 1,9‐azadienes prepared in this way participate in RCM reactions to give good yields of seven‐ and eight‐membered nitrogen heterocycles. The yields of the RCM reaction increased when the hydrochlorides were used instead of the neutral azadienes. The removal of the chiral adjuvant allowed the preparation of enantiopure azepin‐3‐ol and azocin‐3‐ol derivatives. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Efficient Routes to Acenaphthylene‐Fused Polycyclic Arenes/Heteroarenes and Heterocyclic Fluoranthene Analogues

AbstractThe acenaphthenone‐derived α‐oxoketene dithioacetal 2 has been subjected to various [3 + 3] aromatic and heteroaromatic annulation and other heterocyclization reactions previously developed in our laboratory, providing short and efficient routes to a diverse range of known and unknown acenaphtho‐annulated linear and angular PAHs, heteroaromatics and five‐membered heterocycles in good yields. Thus, benzo‐ and naphthoannulation of 2 with various allyl and benzyl Grignard reagents afforded substituted fluoranthenes 4a–c and benzo[k]fluoranthene 8, respectively, in good yields. Similarly, the parent benzo[j]fluoranthene 15a and its substituted derivative 16b have been synthesized by base‐induced conjugate 1,4‐addition of arylacetonitriles to 2, followed by acid‐induced cyclization of the conjugate adducts 12a–b to give 13a–b and subsequent further transformations. The adducts obtained by 1,4‐addition of anions derived from acetophenone and acenaphthenone were subjected toheterocyclization in the presence of ammonium acetate to give 8‐arylacenaphtho[1,2‐b]pyridines 18a–b and bis(acenaphtho)‐annulated pyridine 20. Heterocyclization of 2 with bifunctional nucleophiles such as 2‐picolyllithium and guanidinium nitrate afforded the corresponding acenaphtho[1,2‐b]quinolizinium salt 23 and acenaphtho[1,2‐d]pyrimidine 24, respectively, in high yields. Finally, acenaphtho[1,2‐c]‐fused five‐membered heterocycles such as 7‐(methylthio)acenaphtho[1,2‐c]thiophene (25), 7‐(methylthio)acenaphtho[1,2‐c]furan (27) and 7‐(methylthio)acenaphtho[1,2‐c]pyrrole‐2‐carboxylic acid (30) were obtained in good yields by subjection of 2 to Simmons–Smith reaction conditions or by treatment with dimethylsulfonium methylide or glycinate dianion. Some of these newly synthesized PAHs or fused heterocycles were subjected to Raney Ni desulfurization to furnish sulfur‐free compounds. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Enantioselective Construction of Carbobicyclic Scaffolds.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Addition of Benzylic and Allylic Organozinc and Grignard Reagents to Resin-Bound Imines To Provide α-Branched Secondary Amines Bearing a Wide Variety of Functional Groups. Utility in the Synthesis of β-3 Adrenergic Receptor Agonists

Benzylic and allylic organozinc and Grignard reagents have been added to resin-bound imines to provide alpha-branched secondary amines. Many functional groups, including electrophilic groups, were compatible with this methodology. Three modules--a resin-bound primary amine, an aromatic aldehyde, and the organometallic--were independently varied to produce a combinatorial library of alpha-branched secondary amines designed as beta-3 adrenergic receptor agonists.

Cobalt-catalyzed cross-coupling reactions of alkyl halides with allylic and benzylic Grignard reagents and their application to tandem radical cyclization/cross-coupling reactions.

Details of cobalt-catalyzed cross-coupling reactions of alkyl halides with allylic Grignard reagents are disclosed. A combination of cobalt(II) chloride and 1,2-bis(diphenylphosphino)ethane (DPPE) or 1,3-bis(diphenylphosphino)propane (DPPP) is suitable as a precatalyst and allows secondary and tertiary alkyl halides--as well as primary ones--to be employed as coupling partners for allyl Grignard reagents. The reaction offers a facile synthesis of quaternary carbon centers, which has practically never been possible with palladium, nickel, and copper catalysts. Benzyl, methallyl, and crotyl Grignard reagents can all couple with alkyl halides. The benzylation definitely requires DPPE or DPPP as a ligand. The reaction mechanism should include the generation of an alkyl radical from the parent alkyl halide. The mechanism can be interpreted in terms of a tandem radical cyclization/cross-coupling reaction. In addition, serendipitous tandem radical cyclization/cyclopropanation/carbonyl allylation of 5-alkoxy-6-halo-4-oxa-1-hexene derivatives is also described. The intermediacy of a carbon-centered radical results in the loss of the original stereochemistry of the parent alkyl halides, creating the potential for asymmetric cross-coupling of racemic alkyl halides.

Total Synthesis of (+)‐Cylindricine C.

Abstract A stereoselective total synthesis of (+)-cylindricine C has been achieved starting with ( S )- N -Boc-2-pyrrolidinone. The key elements of this synthesis involve the sequence of reactions including BF 3 -mediated addition of the allyl Grignard reagent to the cyclic imine, spirocyclization via enamine formation, and intramolecular Michael addition to form the tricyclic core.

Enantioselective Construction of Carbobicyclic Scaffolds

Allylic and benzylic Grignard reagents smoothly open phenylalkynyl-activated cyclic trisubstituted epoxides at the more substituted carbon atom to give secondary alcohols with a chiral quaternary center. These alcohols are good substrates for the construction of enantiomerically pure carbobicyclic scaffolds through intramolecular alkylation.

Total synthesis of (+)-cylindricine C

A stereoselective total synthesis of (+)-cylindricine C has been achieved starting with (S)-N-Boc-2-pyrrolidinone. The key elements of this synthesis involve the sequence of reactions including BF3-mediated addition of the allyl Grignard reagent to the cyclic imine, spirocyclization via enamine formation, and intramolecular Michael addition to form the tricyclic core.

Manganese‐Catalyzed Carbomagnesation of Alkynes

AbstractFor Abstract see ChemInform Abstract in Full Text.

Titanocene‐Catalyzed Regioselective Carbomagnesation of Alkenes and Dienes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Total synthesis of (-)-microcarpalide, a novel microfilament disrupting metabolite.

The stereoselective total synthesis of (-)-microcarpalide, a recently discovered 10-membered lactone of fungal origin displaying a remarkable disrupting action on actin microfilaments, was accomplished by using ring-closing metathesis (RCM) as the key step for the formation of the medium-sized ring. The diene ester required for the macrocyclization reaction was assembled via DCC-mediated esterification of two suitable partners, each bearing a terminal alkene group. The alcohol fragment was synthesized from n-bromohexane through a seven-step sequence entailing two consecutive stereoselective homologations of chiral boronic esters as strategic transformations for the sequential insertion of the two stereocentres with the final S absolute configuration, using (+)-pinanediol as the chiral director; final elaboration to the desired C(11) framework envisaged treatment with an allyl Grignard reagent and oxidative cleavage of the boronic scaffold. In contrast, the acidic fragment was prepared in ten steps from d-tartaric acid, whose C(4) backbone was elongated to the required C(7) skeleton by means of two distinct Swern-Wittig oxidation-homologation sequences.

Titanocene-catalyzed regioselective carbomagnesation of alkenes and dienes.

A new method for regioselective carbomagnesation of alkenes and dienes has been developed by the use of a titanocene catalyst. This reaction proceeds efficiently at 0 degrees C in THF in the presence of Cp(2)TiCl(2) by the combined use of organic halides (R-X; R = alkyl, aryl and vinyl) and n-BuMgCl to afford benzyl, alpha-silylalkyl, or allyl Grignard reagents, which were trapped with various electrophiles. The present reaction involves (i) addition of carbon radicals toward alkenes or dienes in the carbon-carbon bond-forming step and (ii) transmetalation on Ti of benzyl-, alpha-silylalkyl-, or allyltitanocene with n-BuMgCl in the carbon-magnesium bond-forming step. The scope and limitations of this reaction have also been examined.

Preparation, properties and synthetic potentials of fluorous boronates

A fluorous approach to the chemistry of boronic acids and its application in fluorous-phase techniques are described. Treatment of fluorous bromosilane 2 with allyl Grignard reagent followed by dihydroxylation provided fluorous diol 1 . A series of boronic acids were attached to 1 by esterification. The formed fluorous boronates 4 were moisture sensitive and thus their synthetic potentials were limited. Thus a fluorous pinacol, 5 , was designed and synthesized by treatment of fluorous bromosilane 2 with excess 2,3-dimethyl-2-butyenylmagnesium bromide 9 to afford fluorous tetramethyl ethene 8 , and was dihydroxylated. Compound 5 was successfully used to prepare fluorous boronates in a one-pot process from organic bromides. We have demonstrated that olefin cross-metathesis can be carried out in a fluorous version. It is noteworthy that all of the fluorinated compounds reported in this paper were purified by simple liquid extraction.

A concise asymmetric route to Nuphar alkaloids. A formal synthesis of (-)-deoxynupharidine.

[reaction: see text] A stereocontrolled route to Nuphar alkaloids is described that employs a formal [3 + 3] cycloaddition strategy to assemble the piperidine nucleus. The addition of Pd-TMM complexes to aziridine 10 was found to be sluggish; however, the addition of a functionalized allyl Grignard reagent followed by a Mitsunobu condensation reaction provided 11 in high yield. The employment of this route in the formal synthesis of (-)-deoxynupharidine 1 is described.

Cobalt‐Catalyzed Coupling Reaction of Alkyl Halides with Allylic Grignard Reagents.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Manganese-Catalyzed Carbomagnesation of Alkynes

The development of manganese-catalyzed carbomagnesation of alkynes is reviewed. Manganese salts mediate the efficient addition of a variety of Grignard reagents to alkynes. Allyl, aryl, and alkyl Grignard reagents participate in these reactions. In many cases, a hetero atom such as oxygen or nitrogen in substrates facilitates the addition reaction. Stoichiometric carbometalation reactions with manganese ate complexes are also discussed, as is cyclization of 1,6-diynes and 1,6-enynes via carbometalation with triallylmanganate.