Reaction of magnesium alkylidene carbenoids with lithium acetylides and lithium thiolates: a novel synthesis of conjugated enynes and vinyl sulfides

Magnesium alkylidene carbenoids were generated from 1-chlorovinyl p-tolyl sulfoxides with i-PrMgCl at −78 °C in THF or toluene via the sulfoxide-magnesium exchange reaction. Reaction of the generated magnesium alkylidene carbenoids with lithium acetylides or lithium thiolates gave conjugated enynes or vinyl sulfides, respectively, in moderate to good yields. The intermediate of this reaction was found to be the alkenyl anion and it could be trapped with some electrophiles to give tetra-substituted conjugated enynes and vinyl sulfides.     

On the curious oxidations of 2-furylethanols

Rather than giving the corresponding aldehyde or carboxylic acid, Jones oxidation of 5-substituted-2-furylethanols gives rise to high yields of the corresponding dihydro-2-(2-oxoethyl)furan-3(2H)-ones, following Achmatowicz-type oxidative ring opening and subsequent reclosure by a 5-exo Michael addition of the pendant hydroxy group to the enedione function. Other oxidation methods such as a Swern reaction give lower yields of the same products while magnesium perphthalate tends to yield the intermediate enediones, and IBX tends to yield the furyl aldehydes.     

Cyclopropyl organyl sulfides

Conclusions Three methods were developed for the synthesis of cyclopropyl organyl sulfides, which are based on the reaction of cyclopropyl halides with either thiols or alkali metal thiolates in a superbasic medium, the reaction of cyclopropyllithium with diorganyl disulfides, and the reaction of cyclopropyl alkyl sulfides with lithium in liquid ammonia and subsequent reaction with organic bromo derivatives. In contrast, the cleavage of cyclopropyl aryl sulfides leads to the formation of lithium arylthiolates.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 1, pp. 1664–1667, July, 1983.     

Synthesis of difluorinated pseudopeptides using chiral α,α-difluoro-β-amino acids in the Ugi reaction

2,2-Difluoro-3-(2-hydroxy-1 R-phenylethylamino)-3 S-phenylpropionic acid 3, obtained by a Reformatsky-type reaction of ethyl bromodifluoroacetate with (4R)-2,4-diphenyloxazolidine, was used as a classical carboxylic acid in the Ugi reaction to prepare various difluorinated pseudopeptides 5a-n. Compounds 5 were then deprotected by hydrogenolysis to furnish difluorinated pseudopeptides 6.     

A synthesis of esters, amides, and sulfones bearing a 1-cyclopentenyl group at the α-position from cyclobutanones with one-carbon ring-expansion

Treatment of 1-chlorovinyl p-tolyl sulfoxides, derived from cyclobutanones and chloromethyl p-tolyl sulfoxide, with lithium enolate of carboxylic acid tert-butyl esters, lithium enolate of carboxylic acid N,N-dimethylamides, or lithium α-carbanion of alkyl phenyl sulfones gave adducts in high yields. The adducts were treated with isopropylmagnesium chloride or ethylmagnesium chloride in dry toluene to give esters, amides, and sulfones bearing a 1-cyclopentenyl group at the α-position in moderate to good yields with one-carbon ring-expansion via magnesium carbenoid 1,2-CC insertion reaction. The magnesium carbenoid 1,2-CC insertion reaction proved to be highly stereospecific. The reaction mechanism and origin of the specificity are described.     

Concise route to defined stereoisomers of the hydroxy acid of the chondramides

The use of Kobayashi vinylogous aldol reaction in the reaction with acetaldehyde led to anti-aldol product 11. After reductive removal of the chiral auxiliary, the primary alcohol was converted to the allyliodide 14. This compound could be engaged in an Evans alkylation reaction, leading eventually to hydroxy acid 19. Inclusion of a Mitsunobu inversion reaction on the sequence starting with ent-11 led to hydroxy ester 30, featuring a 6,7-syn-configuration. These hydroxy acids should help to elucidate the correct stereostructure of the chondramide depsipeptides.     

Identification and determination of carboxylic acids in food samples using 2-(2-(anthracen-10-yl)-1H-phenanthro[9,10-d]imidazol-1-yl)ethyl 4-methylbenzenesulfonate (APIETS) as labeling reagent by HPLC with FLD and APCI/MS

A new labeling reagent for carboxylic acids, 2-(2-(anthracen-10-yl)-1H-phenanthro[9,10-d]imidazol-1-yl)ethyl 4-methylbenzenesulfonate (APIETS) has been designed and synthesized. It was used to label eight fatty acids (lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, oleic acid, linoleic acid and linolenic acid) and four hydroxy pentacyclic triterpene acids (oleanolic acid, ursolic acid, betulinic acid and maslinic acid), successfully. APIETS could easily and quickly label carboxylic acids in the presence of K₂CO₃ catalyst at 85 °C for 35 min in N,N-dimethylformamide solvent. The carboxylic acids derivatives were separated on a C₈ reversed-phase column with gradient elution and fluorescence detection at λ_ex/λ_em = 315/435 nm. Identification of these derivatives was carried out by online mass spectrometry with atmospheric pressure chemical ionization in positive ion mode. The detection limits obtained were 13.37-30.26 fmol (signal-to-noise ratio of 3). The proposed method has been applied to the quantification of carboxylic acids in sultana raisin (Thompson seedless), hawthorn flake (Crataegus pinnatifida Bge.), Lycium barbarum seed oil and Microula sikkimensis seed oil with recoveries over 95.3%. It has been demonstrated that APIETS is a prominent labeling reagent for determining carboxylic acids with high performance liquid chromatography.     

Replacement of Methoxy by tert-Butyl on a Naphthalene Residue: An Unexpected Reaction During a Snieckus ortho-Lithiation

Summary.  When 1-methoxy-2-naphthalene carboxylic acid diethylamide was reacted with tert-butyl lithium in presence of TMEDA and 3,5-dimethoxybenzaldehyde was subsequently added to the reaction mixture, (P, S/M, R)- and (P, R/M, S)-1-tert-butyl-3-((3,5-dimethoxyphenyl)-hydroxymethyl)-naphthalene-2-carboxylic acid diethylamide were formed instead of the corresponding 1-methoxy derivative. The diastereomeric relationship of the products is due to a sterically severely hindered rotation around the amide-aryl bond. Received May 11, 2001. Accepted May 18, 2001     

An asymmetric synthesis of carboxylic acid derivatives,including lactic acid and α-amino acid derivatives,from optically active 1-chlorovinyl p-tolyl sulfoxides and ester lithium enolates with creation of chirality at the α-position

Treatment of optically active 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from symmetrical ketones or methyl formate and (R)-(−)-chloromethyl p-tolyl sulfoxide in three steps, with lithium enolate of carboxylic acid tert-butyl esters gave optically active adducts having a substituent (alkyl, alkoxy, or dibenzylamino group) at the α-position with high 1,4-chiral induction from the sulfur chiral center. The adducts were converted to optically active esters, lactic acid, and α-amino acid derivatives having a chiral center at the α-position. When this addition reaction was carried out with an ester enolate generated from excess carboxylic acid tert-butyl ester with LDA in the presence of HMPA, the diastereomer of the adduct was obtained. By using the two reaction conditions for the generation of the ester enolate, a new method for asymmetric synthesis of both enantiomers of carboxylic acid derivatives having a substituent at the α-position from the one chiral source, (R)-(−)-chloromethyl p-tolyl sulfoxide, was achieved.     

Replacement of Methoxy by tert -Butyl on a Naphthalene Residue: An Unexpected Reaction During a Snieckus ortho -Lithiation

 When 1-methoxy-2-naphthalene carboxylic acid diethylamide was reacted with tert-butyl lithium in presence of TMEDA and 3,5-dimethoxybenzaldehyde was subsequently added to the reaction mixture, (P, S/M, R)- and (P, R/M, S)-1-tert-butyl-3-((3,5-dimethoxyphenyl)-hydroxymethyl)-naphthalene-2-carboxylic acid diethylamide were formed instead of the corresponding 1-methoxy derivative. The diastereomeric relationship of the products is due to a sterically severely hindered rotation around the amide-aryl bond.     

Solution phase structures of enantiopure and racemic lithium N-benzyl-N-(α-methylbenzyl)amide in THF: low temperature 6Li and 15N NMR spectroscopic studies

The antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide are highly efficient enantiopure ammonia equivalents for the asymmetric synthesis of β-amino acid derivatives via conjugate addition to α,β-unsaturated esters. ⁶Li and ¹⁵N NMR spectroscopic studies of doubly labelled ⁶lithium (S)-¹⁵N-benzyl-¹⁵N-(α-methylbenzyl)amide in THF at low temperature reveal the presence of lithium amide dimers as the only observable species. Either a monomeric or dimeric lithium amide reactive species can be accommodated within the transition state mnemonic for this class of conjugate addition reaction. This enantiopure lithium amide offers unique opportunities over achiral (e.g., lithium dibenzylamide) and C₂-symmetric (e.g., lithium bis-N,N-α-methylbenzylamide) counterparts for further mechanistic study owing to the ready distinction of the various dimers formed.     

Efficient NMR chiral discrimination of carboxylic acids using rhombamine macrocycles as chiral shift reagent

Chiral rhombamine macrocycles 1a-b were prepared by a [2+2]cyclocondensation reaction of (R,R)-1,2-diaminocyclohexane with corresponding dialdehydes and were found to be useful as NMR chiral shift reagents for the determination of enantiomeric purity and the absolute configuration of a wide range of carboxylic acid and amino acid derivatives.     

Diastereoselective Michael addition of (S)-mandelic acid enolate to nitroalkenes. Enantioselective synthesis of α-hydroxy-α,β-diaryl-γ-lactams

The reaction of the lithium enolate of the (S,S)-cis-1,3-dioxolan-4-one derived from optically active (S)-mandelic acid and pivalaldehyde with several aromatic nitroalkenes in the presence of HMPA proceeds readily to give the corresponding Michael adducts in good yields and diastereoselectivities. Reduction of the nitro group with Zn/HCl/EtOH/H₂O with concomitant intramolecular aminolysis of the acetal moiety leads directly to enantiomerically pure α-hydroxy-α,β-diaryl-γ-lactams.     

A synthesis of bicyclo[n.1.0]alkanes having tert-butyl carboxylate or acetamide moiety via the intramolecular 1,3-CH insertion of magnesium carbenoids

Treatment of 1-chlorovinyl p-tolyl sulfoxides, derived from various cyclic ketones and chloromethyl p-tolyl sulfoxide, with lithium enolate of carboxylic acid tert-butyl esters or N,N-dimethylacetamide gave adducts in high yields. The adducts were treated with ether solution of isopropylmagnesium chloride in dry toluene to give bicyclo[n.1.0]alkane derivatives having tert-butyl carboxylate or acetamide moiety on the bridgehead carbon in high to quantitative yields via magnesium carbenoid 1,3-CH insertion reaction. The 1,3-CH insertion reaction proved to be regioselective and stereospecific. The reaction mechanism and origin of the selectivity and specificity are discussed.     

New synthetic methods : Volumes 4,5 and 6, Verlag Chemie,Weinheim/New York 1979; Volume 4, viii + 266 pages; Volume 5, viii + 270 pages; Volume 6, viii + 274 pages; DM 68 each.

trans-β-Phenylethenylboronic acid, trans-β-p-methylphenylethenylboronic acid and trans-β-p-methoxyphenylethenylboronic acid on treatment with catalytic amounts of palladium chloride in presence of excess of lithium chloride and triethylamine give the corresponding (E, E)-1,4-diaryl-1,3-butadienes in virtually quantitative yield.     

A novel method for asymmetric synthesis of both enantiomers of α-substituted carboxylic acid derivatives from optically active 1-chlorovinyl p-tolyl sulfoxides and lithium ester enolates with 1,4-chiral induction from the sulfur chiral center

Treatment of optically active 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from symmetrical ketones and (R)-(−)-chloromethyl p-tolyl sulfoxide in three steps, with lithium enolate of carboxylic acid tert-butyl esters gave optically active adducts having a substituent at the α-position with high 1,4-chiral induction from the sulfur chiral center in high yields. The adducts were converted to optically active esters and carboxylic acids having a chiral center at the α-position. When this addition reaction was carried out with the ester enolate generated from excess carboxylic acid tert-butyl ester with LDA in the presence of HMPA, the diastereomer of the adduct was obtained. By using the two reaction conditions for the generation of the ester enolates, a new method for asymmetric synthesis of both enantiomers of carboxylic acid derivatives having a substituent at the α-position from the one chiral source, (R)-(−)-chloromethyl p-tolyl sulfoxide, was realized.     

Synthesis and oxidation of thioglicosides underlain by neomenthanethiol,D-glucose,and D-fructose

Synthesis of sulfides proceeding from neomenthanethiol, 1,2-O-isopropylidene-α-D-glucofuranose and 2,3:4,5-di-O-isopropylidene-β-D-fructopyranose was performed to get 65 and 54% yield respectively. Oxidation of the sulfides afforded diastereomeric sulfoxides in the yields from 40 to 53%, and diastereomeric excess (de) up to 36%. After removing the isopropylidene protection from 1-deoxy-1-[(1S,2S,5R)-2-isopropyl-5-methylcyclohexylsulfanyl]-2,3:4,5-di-O-isopropylidene-β-D-fructopyranose a water-soluble sulfide was obtained.     

(E)-Selective Horner-Wadsworth-Emmons reaction of aryl alkyl ketones with bis(2,2,2-trifluoroethyl)phosphonoacetic acid

The stereoselective Horner-Wadsworth-Emmons reaction of aryl alkyl ketones with bis(2,2,2-trifluoroethyl)phosphonoacetic acid utilizing lithium hexamethyldisilazide in DMF afforded (E)-α,β-unsaturated carboxylic acids as the major products.     

The cooperative effect of a hydroxyl and carboxyl group on the catalytic ability of novel β-homoproline derivatives on direct asymmetric aldol reactions

Novel β-homoproline derivatives, 2-hydroxy-2-(pyrrolidin-2-yl)acetic acids (R,S)- and (S,S)-1a-d, were synthesized. All of the prepared compounds were used as organocatalysts in the direct asymmetric aldol reaction of 4-nitrobenzaldehyde with several ketones. Among these catalysts, (R)-2-hydroxy-2-((S)-pyrrolidin-2-yl)acetic acid (R,S)-1a showed good catalytic ability in the formation of aldol product 13 (up to 69% ee, 95% yield), which was similar to the results catalyzed by l-proline (71% ee, 96% yield). Relatively low yields and low enantioselectivities were observed in aldol reactions catalyzed by (S,S)-1a, for example, 13 was obtained in 55% yield and 13% ee. The aldol reaction catalyzed by the methyl-protected carboxylic acid 1b and esters 1c,d produced much lower chemical yields and enantioselectivities during the formation of 13. The cooperative effect of the (R)-configured hydroxyl group and the carboxyl group was found to play an important role in inducing enantioselectivity in the aldol reaction. Relatively high diastereoselectivities (anti:syn = 85:15) and enantioselectivity (anti, 83% ee) were observed in the aldol reactions of 4-nitrobenzaldehyde with cyclohexanone, which was catalyzed by (R,S)-1a.     

A facile access to thieno[2,3-b]indoles via sulfur-mediated decarboxylative cyclization of α, β-unsaturated carboxylic acids with indoles

An efficient synthesis of thieno[2,3-b]indoles via a one-pot three-component reaction was well established. By using inexpensive and commercial available indoles and α, β-unsaturated carboxylic acids in the presence of elemental sulfur, various functional groups were achieved in moderate to good yields.