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The reaction of cyclopropyl phenyl sulfoxide with a magnesium amide, generated from ethylmagnesium bromide and diisopropylamine, gave 1-(phenylthio)cyclopropanol in 72% yield. When the diisopropylmagnesium reagent was treated with a thiol prior to an interaction with cyclopropyl phenyl sulfoxides, symmetrical and unsymmetrical cyclopropanone dithioacetals were produced in fair yields along with small quantities of the corresponding 1-(phenylthio)cyclopropanols.

Cycloaddition of N-(benzoylmethylene)aniline N-oxide as a reactive nitrone to allyl alcohol dipolarophiles are accelerated either 1) by pretreatment of the dipolarophiles with an organometallic compound such as ethylmagnesium bromide or diethylzinc, or 2) in the presence of a Lewis acid such as magnesium bromide or zinc bromide. These cycloadditions are highly regio- and stereoselective, both selectivities depending upon the kind of metals included in the organometallics or Lewis acid employed. These reactions offer the first example of regio- and stereocontrol of nitrone cycloadditions to nonactivated olefins.

Development of an efficient synthesis of the C-D ring portion of streptonigrin is a key operation in the synthesis of this antibiotic and its analogues. A new method for the synthesis of 3-cyano-5,6-dimethyl-4-(3,4,5-trimethoxyphenyl)-2-pyridone (14), a compound having the requisite functionality for conversion into a streptonigrin analogue, has been established. It involves treatment of 3,4,5-trimethoxybenzonitrile with ethylmagnesium bromide and malononitrile to give propylenemalononitrile derivative 7, which is condensed with trimethyl orthoacetate to give a mixture of 9 and pyridine derivative 12. Demethylation of 12 then affords 14. The overall yield for this route was 50%, allowing for conversion of 9 to 12.

Cycloaddition of N-(benzoylmethylene)aniline N-oxide as a reactive nitrone to allyl alcohol dipolarophiles are accelerated either 1) by pretreatment of the dipolarophiles with an organometallic compound such as ethylmagnesium bromide or diethylzinc, or 2) in the presence of a Lewis acid such as magnesium bromide or zinc bromide. These cycloadditions are highly regio- and stereoselective, both selectivities depending upon the kind of metals included in the organometallics or Lewis acid employed. These reactions offer the first example of regio- and stereocontrol of nitrone cycloadditions to nonactivated olefins.

Tris(pentafluorophenyl) phosphine and bis (pentafluorophenyl) sulfide react with ethylmagnesium bromide to give products indicating cleavage of the pentafluorophenyl group from phosphorus and sulfur. Ethylated phosphorus and sulfur compounds as well as pentafluorophenylmagnesium bromide are the principal reaction products. Minor products from subsequent reaction between the Grignard reagents and cleavage products have also been detected.

The reaction ofRS(SR)-2,3-dibromo- and 2,3-dichlorotetrahydrofurans with ethylmagnesium bromide in ether was investigated. It was shown that the main reaction products are 2-ethyl-3-bromotetrahydrofuran (27%) and 3-bromo-2-(2-ethyl-3-tetrahydrofuryl)tetrahydrofuran (65%) in the first case and 2-ethyl-3-chlorotetrahydrofuran (33%) and 3-chloro-2-(3-chloro-2-tetrahydrofuryl)tetrahydrofuran (65%) in the second.

Sulfoxides carrying α-hydrogens were allowed to react with magnesium amides generated in situ by the treatment of ethylmagnesium bromide with secondary amines such as 2,2,6,6-tetramethylpiperidine or diisopropylamine in diethyl ether to give the corresponding dithioacetals in moderate to good yields.

A new method for synthesis of α-halo(C1, F)carboxylic acid derivatives and α-haloaldehydes is described. α-Halo-α-sulfinyl carboxylic acid, esters, and α-halo-α-sulfinyl aldehydes were easily prepared from aryl l-haloalkyl sulfoxides and alkyl chloroformate and ethyl formate, respectively, in good yields. α-Chloro-α-sulfinyl amides were synthesized from (p-tolylthio)acetic acid. Ligand exchange reaction of the sulfinyl group of these acids, esters, amides, and aldehydes with ethylmagnesium bromide gave the magnesium enolates, which were treated with water to give α-halocarboxylic acid derivatives and α-chloroaldehydes in good yields. The magnesium enolates derived from the α-chloro-α-sulfinyl acid derivatives were trapped with carbonyl compounds to afford the adducts, which were transformed to α, β-epoxy carboxylic acid derivatives. Thermal elimination of the sulfinyl group in the α-halo-α-sulfinyl acid derivatives and the α-halo-α-sulfinyl aldehydes gave α-halo-α, β-unsaturated carboxylic acid derivatives and α-halo-α, β-unsaturated aldehydes in high yields.

The reactions of sulfoxides with magnesium amides generated in situ from the reaction of ethylmagnesium bromide and secondary amines, such as diisopropylamine (DIPA) or 2,2,6,6-tetramethylpiperidine (TMP) in diethyl ether, were examined. Diaryl sulfoxides were heated with the diisopropylaminomagnesium reagent in diethyl ether to give the corresponding diaryl sulfides in 42—52% yields. Sulfoxides bearing hydrogens at the α-positon only (RSOCH2R1) reacted with the tetramethylpiperidinomagnesium reagent at room temperature to produce the corresponding dithioacetals (RSCHR1SR) in 47—86% yields. The treatment of sulfoxides bearing hydrogens both at the α- and β-positions (RSOCHR1CHR2R3) with the magnesium amides at room temperature afforded the corresponding vinyl sulfides (RSCR1=CR2R3) in 52—72% yields accompanying 2.3—27% yields of the corresponding dithioacetals. The pathways leading to the products involving the formation of the sulfur-stabilized carbonium ion intermediates are discussed.

It has been found that the reactions of sulfoxides bearing hydrogen(s) at the α-position (R1SOCHR2R3: R1 = alkyl or Ph; R2 = H, alkyl, or Ph; R3 = H or Me) with thiols (R4SH: R4 = alkyl or aryl) in the presence of the (diisopropylamino)magnesium reagent, generated in situ from the reaction of ethylmagnesium bromide and diisopropylamine, in diethyl ether gave unsymmetrical dithioacetals (R1SCR2R3SR4) in isolated yields ranging from 44 to 91%.

When 2-(methylamino)benzonitrile was treated successively with magnesium bis(diisopropylamide), generated in situ from the reaction of ethylmagnesium bromide and diisopropylamine, and α,β-unsaturated carboxylic acid esters in diethyl ether at 0 °C, conjugate addition and enolate–nitrile coupling proceeded sequentially to give the corresponding 4-amino-1,2-dihydro-3-quinolinecarboxylates in isolated yields ranging from 36 to 79%.

The isomerization-cyclization of tetrahydropyridine 7 by AcOH leads to 4-ethyloctahydroindolo[2,3-a]quinolizine-2-carbaldehydes (8). When the process is carried out with aqueous AcOH, indolizidinoindole 9 is formed as a by-product in a competitive way. Compound 7 is available via reductive cyanation of pyridinium salt 1 followed by treatment of nitrile 2 with ethylmagnesium bromide.

(Dialkylamino)magnesium reagents, derived from secondary amines and ethylmagnesium bromide, have been found to react with aromatic aldehydes to give 1,2-diaryl-1,2-bis(dialkylamino)ethenes in moder...

Primary aromatic amines are readily converted into arylimino-1,2,3-dithiazoles 2 and the derived cyanothioformanilides 6, both of which are rapidly cleaved by ethylmagnesium bromide in hot THF to give the corresponding isothiocyanates. The transformation 2→6→ArNCS can be performed as a ‘one-pot’ operation. The imines 2 are also converted, more slowly, into the isothiocyanates by sodium hydride in hot THF, via the cyanothioformanilides 6. Conversion of the anilides 6 into isothiocyanates is much faster under microwave irradiation in 2,6-lutidine. Mechanisms are proposed for these reactions.

The reactions of enamines with sulfoxides bearing α-hydrogens in the presence of a magnesium amide, generated in situ from the reaction of ethylmagnesium bromide with diisopropylamine, afforded the corresponding α-sulfenylalkylated ketones and aldehydes in isolated yields ranging from 39 to 76%. This procedure was successfully extended to the bis(methylthio)methylation with methyl (methylthio)methyl sulfoxide.

The synthesis of the two diasteromeric meso forms of 4-amino-3,5-heptanediol (3R,4r,5S)- 1a and (3S,4s,5R)- 1b and the two pseudo C 2 -symmetric enantiomers (3S,5S)- 1c and (3R,5R)- ent - 1c is described by stereocontrolled ethylmagnesium bromide or diethylzinc addition to diastereomeric α-amino-β-hydroxy pentanal derivatives 9 and 13 . These derivatives were prepared from (2S)-N,N-dibenzyl-O-TBS-serinal 2 , that in turn were obtained from (L)-serine.

Highly stereoselective boronic ester chemistry has been used for the synthesis of (4S,6S,7S)-7-hydroxy-4,6-dimethylnonanone (1), the pheromone of the cigarette beetle. 2-Bromo-1-butene (8) was made from 1-butyne via bromoboration and protodeboronation, and was converted to 1-ethylethenylmagnesium bromide. (R,R)-1,2-Dicyclohexyl-1,2-ethanediol [“(R)-DICHED”] methylboronate was treated with (dichloromethyl)lithium to yield (R)-DICHED (S)-1-chloroethylboronate (9), which with 1-ethylethenylmagnesium bromide yielded (R)-DICHED (R)−(2-ethyl-1-methyl-2-propenyl)boronate (10). Further chain extensions with (chloromethyl)lithium, (dichloromethyl)lithium followed by methylmagnesium bromide, and (dichloromethyl)lithium followed by ethylmagnesium bromide completed assembly of the carbon skeleton. Deboronation with hydrogen peroxide yielded (3S,5S,6S)-2-ethyl-3,5-dimethylocten-6-ol (14), which with osmium tetraoxide and sodium periodate yielded 1.

1,3-Dipolar cycloaddition reactions of nitrile oxides with olefins are very interesting reactions in organic synthesis due to their facile induction of stereocenters1 and easy conversion2 of the resulting isoxazolines to synthetically useful functional groups, such as β-hydroxyketones,1f,3 βhydroxyamines,4 α,β-unsaturated ketones,5 substituted tetrahydrofurans.6 Although the 1,3-dipolar cycloaddition reactions of nitrile oxides with α,β-unsaturated ketones generally afforded a mixture of two regioisomers, the cycloadditions of aryl nitrile oxides with 2-cyclopenten-1one could afford predominantly the corresponding 3-aryltetrahydrocyclopent[d]isoxazol-4-ones (1).7 The reductions of 3-alkyl-3a,5,6,6a-tetrahydro-4H-cyclopenta[d]isoxazol-4-ones by NaBH4 were reported8 to afford only 3a,4-cis isomers in quantitative yields. We have also found that the reduction of 3-methyl-3a,5,6,6a-tetrahydro4H-cyclopenta[d]isoxazol-4-one showed a similar diastereoselectivity and gave a 9:1 mixture of 3a,4-cis and 3a,4-trans isomer. However, there have been few studies on the reduction and Grignard reaction of carbonyl group in 1.1f,8 Herein we wish to report the diastereoselective reduction and Grignard reaction of 3-aryltetrahydrocyclopent-1,2-isoxazol-4ones (1). When the carbonyl group of 3-aryltetrahydrocyclopent[d] isoxazol-4-ones (1) were reduced to the corresponding 3aryltetrahydrocyclopent-1,2-isoxazol-4-ols (2) by sodium bo-rohydride in methanol, we isolated only 3a,4-cis-3a,6acis-isomers in excellent yields without any trace of 3a,4trans-3a,6a-cis-isomers. This excellent diastereoselectivity may result from the attack of reducing agent to the convex side of the cis-fused structure. Interestingly, the reduction of 3a,7a-cis-3-phenyl-3a,4,5,6,7,7a-hexahydro-1,2-benzisoxol7-one, a 6-membered ring-fused isoxazolinone by NaBH4 showed less diastereoselectivity and afforded a 2:1 mixture of 3a,4-cis and 3a,4-trans isomers.9 The relative stereochemistry of three stereocenters of 2a (Ar =phenyl) were confirmed by NOE experiments in 1H NMR. Irradiation of H-3a at 4.07 ppm showed 2.36% and 2.12% enhencement of signals for H-4 at 4.55 ppm and H-6a at 5.21 ppm, respectively. Grignard reactions of methylmagnesium chloride or ethylmagnesium bromide with 1 were examined in THF at 0 oC, and we observed the reactions proceeded very slow and afforded 3 in low yields with the complicated by-products probably due to the abstraction of acidic protons at C-3a or C-5 position. When Imamoto's method10 was applied in this Grignard reaction, we found that the reaction was completed within 3 h at -78 oC in excellent yield. All of the products obtained from the Grignard reactions of 1 were only 3a,4cis-3a,6a-cis-isomers as expected, which were confirmed by

Dialkoxytitanacyclopropane intermediates (or titanium (II)-olefin complexes) gen- erated in situ from ethylmagnesium bromide and titanium (IV) isopropoxide react with allylic alcohols and allylic ethers to afford S N2' allylic ethylation products. The reaction pro- ceeds with high regioselectivity and with low to high trans-/cis- stereoselectivity. This obser- vation and others suggest a reaction mechanism involving an EtMgBr-initiated formation of titanacyclopentane ate complex 10 from titanacyclopropane-olefin complex 7 as a key step. Based on this assumption, a modified mechanism of titanium-mediated cyclopropanation of esters with Grignard reagents is proposed.

Addition of magnesium ester and amide enolates, generated using an excess amount of a magnesium amide (from diisopropylamine and ethylmagnesium bromide), to o-isocyanobenzoates affords 4-hydroxy-3-quinolinecarboxylic esters and amides by a tandem Claisen-type condensation/cyclization sequence.

The reaction of N-benzyl α-amino acid ethyl esters with ethylmagnesium bromide in the presence of a catalytic amount of titanium tetraisopropoxide leads to formation of the corresponding 1-aminoalkyl- 1-cyclopropanols in high yields. Hydrogenation of the latter over palladium catalyst ensures selective removal of one or two protecting benzyl groups from the nitrogen atom.

Reaction of gem -dibromocyclopropanes with ethylmagnesium bromide at ambient temperature leads to very high yields of allenes; when cyclopropylidene–allene ring opening is suppressed, alternative carbenic products are observed, although other reactions compete. When the reactions are carried out at −60°C, a 1-bromo-1-(bromomagnesio)-cyclopropane is formed which may be trapped by a number of electrophiles.

The reaction of cyclopropyl phenyl sulfoxide with a magnesium amide, generated from ethylmagnesium bromide and diisopropylamine, gave 1-(phenylthio)cyclopropanol in 72% yield. When the diisopropylmagnesium reagent was treated with a thiol prior to an interaction with cyclopropyl phenyl sulfoxides, symmetrical and unsymmetrical cyclopropanone dithioacetals were produced in fair yields along with small quantities of the corresponding 1-(phenylthio)cyclopropanols.

Interaction of titanium(IV) isopropoxide with ethylmagnesium bromide and its higher homologs leads to the generation of alkoxytitanacyclopropane species, which are able to act in the reactions with unsaturated compounds as 1,2-dicarbanionic alkylating agents. The present review is focused on the processes of intermolecular regio- and stereoselective alkylation of carboxylic esters and allylic alcohol derivatives with alkoxytitanacyclopropane reagents. The oxophilicity of the titanium atom and its tendency to form sterically crowded ate complexes are probably the main factors providing a high level of selectivity of these transformations. © 2008 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 8: 269–278; 2008: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.20155

The authors of the present paper reported the synthesis of [11C]-ohmefentanyl in a symposium abstract in 1991(1). We here describe the results of synthesis and analysis in detail. Ohmefentanyl 1 is a novel, highly potent and selective agonist for opiate μ-receptors. In order to visualize the μ-receptor by Positron Emission Tomography (PET), this compound was labelled with carbon-11. The unlabelled cis-A-ohmefentanyl was prepared in a nine-step synthesis and two-step fractional crystallization, and the OH-precursor 11 for [11C]-ohmefentanyl labelling was obtained by hydrolysis of the 4-N-propionyl group of cis-A-ohmefentanyl in 6 N hydrochloric acid. The [11C]-propionyl chloride was prepared by carbonation of ethylmagnesium bromide with cyclotron-produced [11C]-carbon dioxide followed by direct treatment of the intermediate complex with phthaloyl dichloride and 2,6-di-t-butylpyridine. Reaction of the OH-precursor 11 with [11C]-propionyl chloride yields [11C]-ohmefentanyl separated by HPLC, with a high specific activity of 11.1 – 14.8 GBq μmol−1 (300−400 mCi μmol−1), 49 minutes after the end of bombardment. The keto-precursor 12, prepared by hydrolysis of the 4-N-propionyl group of cis-10 in 8 N hydrochloric acid, was also used for [11C]-ohmefentanyl labelling. Reaction of the [11C]-propionyl chloride with keto-precursor 12, followed by addition of sodium borohydride, yields [11C]-ohmefentanyl. The [11C]-labelled ohmefentanyl obtained using the OH-precursor 11 is a cis-A form, while that obtained using the keto-precursor is a mixture of cis-A and cis-B forms.

Tris(pentafluorophenyl) phosphine and bis (pentafluorophenyl) sulfide react with ethylmagnesium bromide to give products indicating cleavage of the pentafluorophenyl group from phosphorus and sulfur. Ethylated phosphorus and sulfur compounds as well as pentafluorophenylmagnesium bromide are the principal reaction products. Minor products from subsequent reaction between the Grignard reagents and cleavage products have also been detected.

α-Halo α-sulfinyl ketones were synthesized in two steps from 1-haloalkyl aryl sulfoxides and aldehydes in high yields. Desulfinylation of the α-halo α-sulfinyl ketones was performed with ethylmagnesium bromide in ether at low temperature to afford α-halo ketones via magnesium enolates in high yields. The magnesium enolate intermediates were trapped with various electrophiles such as deuterium oxide, ethyl chloroformate, and chlorotrimethylsilane. Trapping of the magnesium enolate intermediate with carbonyl compounds afforded a new type of the directed aldol reaction. Desulfinylation of the sulfinyl group of the α-halo α-sulfinyl ketones under thermal conditions gave α-halo α,β-unsaturated ketones or α-halo cross dienones.

The reaction ofRS(SR)-2,3-dibromo- and 2,3-dichlorotetrahydrofurans with ethylmagnesium bromide in ether was investigated. It was shown that the main reaction products are 2-ethyl-3-bromotetrahydrofuran (27%) and 3-bromo-2-(2-ethyl-3-tetrahydrofuryl)tetrahydrofuran (65%) in the first case and 2-ethyl-3-chlorotetrahydrofuran (33%) and 3-chloro-2-(3-chloro-2-tetrahydrofuryl)tetrahydrofuran (65%) in the second.

Methyl 3-bromomethylbut-3-enoate smoothly reacted with prenal, β-ionylideneacetaldehyde, benzyloxyacetaldehyde, and tributylchlorostannane in the presence of zinc and aqueous ammonium chloride in tetrahydrofuran to give the corresponding δ-hydroxy-β-methylidenecarboxylic acid esters. In the absence of ammonium chloride, satisfactory yields of the products were obtained only in the reactions with prenal and benzyloxyacetaldehyde; these reactions involved lactonization of intermediate δ-hydroxy-β-methylidenecarboxylic acid esters, and the double carbon-carbon bond migrated to the conjugated position with the lactone carbonyl group. The condensation of β-ionylideneacetaldehyde with methyl 3-bromomethylbut-3-enoate was successfully used to obtain isotretinoin. Initial methyl 3-bromomethylbut-3-enoate was synthesized in a good yield from readily accessible ethyl 3,3-diethoxypropionate via cyclopropanation with ethylmagnesium bromide in the presence of titanium tetra(isopropoxide), oxidation of the acetal moiety to ester, and cleavage of the cyclopropane ring in intermediate methyl (1-methylsulfonyloxycyclopropyl)acetate.

The α-phenylthio-substituted Grignard reagent 8 was generated in >95% ee by a sulfoxide/magnesium exchange reaction starting from the enantio- and diasteromerically pure α-phenylthio sulfoxide 6a. The α-thio-substituted Grignard reagenthas been trapped with benzaldehyde to give the syn-β-phenylthio-substituted alcohol 9b in very high diastereoselectivity and enantiomeric purity. α-Heterosubstituted alkylmetal reagents (1) are potentially useful chiral -synthons in organic synthesis On reaction with aldehydes two diastereomeric alcohols 2a and 2b are formed (Scheme 1). Simple diastereoselectivity is generally low using organolithium compounds There are indications that Grignard reagents of the type of 1 lead to higher diastereoselectivity possibly due to a change in the addition mechanismConfigurational stability of the organometallic reagents 1 is another issue. For instance, in the case of the arylthio-substituted derivatives of 1 the organolithium compounds are configurationally labile, racemizing rapidly even at -110°C–9 Substantially higher configurational stability can be expected for the corresponding Grignard reagents Thus, for both reasons Grignard reagents such as 8 would be of interest, provided they can be generated in enantiomerically pure form. Grignard reagents can be generated by a sulfoxide/magnesium exchange, a reaction studied extensively by Satoh and Takano We used this reaction previousl to generate enantiomerically pure α-chloroalkyl Grignard reagents. This led us to investigate the sulfoxide/magnesium exchange reaction of the α-arylthio alkyl sulfoxides 6.The starting sulfoxide 6 was prepared (Scheme 2) by reacting α-phenylthio methyllithium (4) with a menthyl aryl sulfinate following precedent from the Gennari group We chose the p-chlorobenzene sulfinate 314 instead of the more common p-toluene sulfinates in order to facilitate purification of the starting sulfoxides 6 by crystallization. Treatment of the menthyl sulfinate 3 with 4 at -78°C thus generated the (+)-(S)-α-phenylthio sulfoxide 5 as white crystals (mp 71–72°C) in 70% yield. The sulfoxide 5 was benzylated in 80% yield to furnish a 1:1 mixture of the diastereomeric sulfoxides 6a and 6b. The mixture was separated by column chromatography on silica gel to give 6a {mp 103°C, [α]D20=+17.9 (c=1.09, acetone)} and 6b {mp 75°C, [α]D20=-164.1 (c=1.56, acetone)}. The relative and absolute configuration of 6a was assigned as (S,S) by X-ray structure analysis,† cf. Fig. 1.When the stereochemically homogeneous sulfoxide 6a was treated with ethylmagnesium bromide at -78°C in THF (Scheme 3), rapid sulfoxide/magnesium exchange ensued to give the α-phenylthio alkyl Grignard reagent 8. The latter was trapped after 10 min by addition of benzaldehyde, providing 58% of the β-hydroxy thioether 9 along with 99% of the sulfoxide 7 of 99% ee. The β-hydroxy thioether was obtained as a single diastereomer (syn:anti >98: 98: 95%.Since the absolute configuration of the epoxide 1016 and the sulfoxide 717 is known, the stereochemical course of the sulfoxide/magnesium exchange can be shown to proceed with inversion at the sulfoxide sulfur atom and with retention of configuration in the formation of the carbon magnesium bond. This corresponds to our recent results found in the sulfoxide/magnesium exchange on α-chloroalkyl sulfoxidesThe present study shows that α-arylthio alkyl Grignard reagents of type 8 can be generated in enantiomerically pure form by a sulfoxide/magnesium exchange reaction, that these reagents are configurationally stable at -78°C for a sufficient period of time to be added to an aldehyde, and that this addition proceeds with very high (>98%) simple diastereoselectivity to provide the syn-diastereomer of 9. Experimental

The reactions of magnesium amides 4 derived from sec-aminoacrylates 3 and ethylmagnesium bromide with methyl propiolate (2) afforded α-pyridones. This provides an efficient heterocyclic annelation reaction.

Development of an efficient synthesis of the C-D ring portion of streptonigrin is a key operation in the synthesis of this antibiotic and its analogues. A new method for the synthesis of 3-cyano-5,6-dimethyl-4-(3,4,5-trimethoxyphenyl)-2-pyridone (14), a compound having the requisite functionality for conversion into a streptonigrin analogue, has been established. It involves treatment of 3,4,5-trimethoxybenzonitrile with ethylmagnesium bromide and malononitrile to give propylenemalononitrile derivative 7, which is condensed with trimethyl orthoacetate to give a mixture of 9 and pyridine derivative 12. Demethylation of 12 then affords 14. The overall yield for this route was 50%, allowing for conversion of 9 to 12.

In accord with the ligand coupling concept, an axial and an equatorial ligand are considered to be extruded from the valence-shell-expanded heteroatom in a concerted fashion which thus affords the coupling product. Therefore, the coupling ligands should retain the original configuration. Indeed, the ligand coupling product, p-(1 -Phenylethyl)phenylsulphonylbenzene (3) formed in the reaction of 1 -phenylethyl benzene-p-sulphonylphenyl sulphoxide (2) with ethylmagnesium bromide is found to retain completely the 1 -phenylethyl group configuration, as in our earlier example of the coupling reaction of optically active 1 -phenylethyl 2-pyridyl sulphoxide with Grignard reagents and that of allylic and vinylic sulphoxides with Grignard reagents. The absolute configuration of (+)-(2) and (+)-(3) are determined unequivocally to be SsRc and Rc, respectively, by X-ray methods.

Reaction of pinanediol boronates with (1,1-dichloroethyl)lithium generated in situ at −78°C followed by rearrangement of the resulting borate complex 2S in the presence of zinc chloride at 25°C has resulted in chirally biased insertion of the 1-chloroethyl group into the carbon–boron bond. (s)-Pinanediol phenylboronate (7) produced (s)-pinanediol (1S)-(1-chloro-1-phenylethyl)boronate (8S) in 92% DE. Nonstererospecific reaction with ethylmagnesium bromide to form (s)-pinanediol (1S)-(1-phenyl-1-methylpropyl)boronate (5S) reduced the DE to 88%. Peroxidic deboronation yielded (R)-(+)-2-phenyl-2-butanol (6R) (84% EE). (s)-Pinanediol ethylboronate (4) with (1,1-dichloroethyl)lithium showed the opposite chiral preference, yielding (s)-pinanediol (1R)-(1-chloro-1-methylpropyl)boronate (3R) (89% DE), which was converted by phenylmagnesium bromide followed by hydrogen peroxide to 6R (76% EE). Diastereoselections were small in reactions of (1,1-dichloroethyl)-lithium with n-alkylboronates 9a and 13 and with cyclohexylboronate 9c. The 13 was converted to the enantiomer of the insect pheromone frontalin (17) (21% EE). Good diastereoselections were found with α-substituted alkylboronates 9b and 18, but the configurations of the products could not be determined. (s)-Pinanediol (1,1-dichloroethyl)boronate (1) reacts with Grignard reagents via an intermediate borate 2R with negligible diastereoselection.

3-Butenyl-isoxazolines were known as good precursors for the syntheses of new types of 5-cyanomethyl-2iodomethyltetrahydrofuran derivatives. 5-Cyanomethyl-2iodomethyltetrahydrofuran was synthesized from isoxazolines by electrophilic iodoetheration using iodine or iodine monochloride, which was the first example of electrophilic cleavage of isoxazoline ring by iodoetheration reaction. From the combination of this reaction and diastereoselective formation of isoxazoline in the support of magnesium chelation effect, we synthesized 5-cyanomethyl-3-hydroxy2-iodomethyltetrahydrofuran from syn-5-(1-hydroxy-3butenyl)isoxazolines with diastereoselctivity. We expected better diastereoselectivity could be achieved by adding one more hydroxyl group at the 2-position of butenyl group in isoxazoline close to the reaction center. First, we prepared chiral 3-diphenylmethyl-5-(1,2-dihydroxy-3-butenyl)isoxazolines (3) by 1,3-dipolar cycloaddition reaction of diphenylacetohydroximoyl chloride (1) with (3R,4R)-1,5hexadiene-3,4-diol (2a) and meso-1,5-hexadiene-3,4-diol (2b) by the aid of magnesium chelation effect, and after Oprotection of isoxazolines, iodoetheration was examined to synthesize chiral 5-cyanomethyl-3,4-dihydroxy-2-iodomethyltetrahydrofurans 6. Diphenylacetohydroximoyl chloride (1), precursor of diphenylacetonitrile oxide was reacted with (3R,4R)-1,5hexadiene-3,4-diol (2a) in the presence of ethylmagnesium bromide as shown in Scheme 1. The more ethylmagnesium bromide was used, the more diadduct 4a was formed in this reaction. When 2.2 equiv of ethylmagnesium bromide was used, the best result of 3a was obtained (Entry 3 in Scheme 1). In case of meso-1,5-hexadiene-3,4-diol (2b), however, only 47% of 3b was obtained (Entry 4 in Scheme 1). The isolated 3a was a single stereoisomer that thought to be synisomer of 5-position and a-position due to the magnesium chelation effect, but 3b must be a racemic mixture of synisomers according to which double bond was reacted. The hydroxyl groups of 3a were protected with TBDMS and MOM group, and then reacted with iodine monochloride in dichloromethane to give 5-cyanomethyl-3,4dihydroxy-2-iodomethyltetrahydrofurans 6 in moderate yields as shown in Scheme 2. 5a (P=TBDMS) afforded only trans-6a (P=TBDMS) without any trace of cis-6a (P=TBDMS), while 5a (P=MOM) afforded a mixture of two isomers (trans/cis, 5/1). As we expected, the bulkier TBDMS group showed better diastereoselectivity in iodoetheration. We examined the energy minimizations of trans

When 2-(methylamino)benzonitrile was treated successively with magnesium bis(diisopropylamide), generated in situ from the reaction of ethylmagnesium bromide and diisopropylamine, and α,β-unsaturated carboxylic acid esters in diethyl ether at 0 °C, conjugate addition and enolate–nitrile coupling proceeded sequentially to give the corresponding 4-amino-1,2-dihydro-3-quinolinecarboxylates in isolated yields ranging from 36 to 79%.

A new and effective procedure was developed for the synthesis of 3-ethylquinoxalin-2(1H)-one from o-phenylenediamine and ethyl 2-oxobutanoate. The latter was prepared by the Grignard reaction of diethyl oxalate with ethylmagnesium bromide or iodide. The ethyl group in 3-ethylquinoxalin-2(1H)-one can readily be converted into various functional groups: α-bromoethyl, α-thiocyanato, α-azidoethyl, α-phenylaminoethyl, acetyl, and bromoacetyl. The reaction of 3-(bromoacetyl)quinoxalin-2(1H)-one with thiourea and hydrazine-1,2-dicarbothioamide gives the corresponding 3-(2-amino-4-thiazolyl) derivatives.

The addition of CH-active compounds to 6-aryl-1,2,4-triazine 4-oxide is reversible and occurs under conditions of kinetic control at position 5 of the heterocycle to form cyclic C(5)-σH adducts. Under conditions of thermodynamic control the nucleophilic attack is directed to position 3 of the heterocycle and is accompanied by its opening to form the more stable open chain addition products. Attack of ethylmagnesium bromide is directed exclusively to the 5 position of the 6-aryl-1,2,4-triazine 4-oxides as a result of the irreversibility of the given reaction.

Reductive cyclopropanation of triethyl methanetricarboxylate (4a) with ethylmagnesium bromide in the presence of titanium tetraisopropoxide furnished diethyl 2-(1′-hydroxycyclopropyl)malonate (5a) in 50% yield. Dehydromesylation of the mesylate of cyclopropanol 5a, generated in situ, by treatment with an excess of triethylamine gave diethyl cyclopropylidenemalonate 3-Et as a highly reactive, unstable compound, which could be isolated as an oil in 39% yield, but more favorably could also be generated in situ from the mesylate or the acetate 11 (prepared from 5a in 90% yield) and trapped without isolation with various N-, O-, S-, and C-nucleophiles. Thus, ammonia, dimethylamine, isopropylamine, diethylamine, dibenzylamine, morpholine, N-methylpiperazine, piperazine, aniline, p-cresol, 1-thionaphthol, and cyanide anion easily add to the double bond of the diester 3-Et generated in situ at ambient temperature, forming 1′-substituted cyclopropylmalonates 10a−i in 18−95% yields. The α,β-unsaturated diester 3-Et also easily enters into 1,3-dipolar and Diels−Alder cycloadditions with nitrones, ethyl diazoacetate, azide anion, and dienes to give the corresponding cycloadducts in 12−83% yields. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

It has been found that the reactions of sulfoxides bearing hydrogen(s) at the α-position (R1SOCHR2R3: R1 = alkyl or Ph; R2 = H, alkyl, or Ph; R3 = H or Me) with thiols (R4SH: R4 = alkyl or aryl) in the presence of the (diisopropylamino)magnesium reagent, generated in situ from the reaction of ethylmagnesium bromide and diisopropylamine, in diethyl ether gave unsymmetrical dithioacetals (R1SCR2R3SR4) in isolated yields ranging from 44 to 91%.

Enantiopure (3S,4R)- and (3S,4S)-3-amino-4-hydroxyhexanoic acids and (4S,5R)- and (4S,5S)-4-amino-5-hydroxyheptanoic acid derivatives have been prepared by stereodivergent synthesis from L-aspartic and L-glutamic acids, respectively. The stereochemistry at the carbon atom attached to the amino group was determined from the starting material, but the configuration at C-4 or C-5 is controlled by diastereoselective alkylation with diethylzinc or ethylmagnesium bromide. The protection of the carboxylic group as OBO orthoester improved the yields in the final products. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

(Z)-4-(Trimethylsilyl)-3-buten-1-ol intermediate: 4-(trimethylsilyl)-3-butyn-1-ol product: (Z)-4-(trimethylsilyl)-3-buten-1-ol Keywords: metal-catalyzed reactions, palladium; reduction, CC CC; silylation; assay methods, for ethylmagnesium bromide with 2-butanol, 1,10-phenanthroline indicator; catalysts, metal, lindlar catalyst, modified; chlorotrimethylsilane; tetrahydrofuran

Alkylations of aldehydes via reaction of the magnesioenamine salt of an aldehyde: 2,2-dimethyl-3-phenylpropionaldehyde intermediate: N-(2-methylpropylidene)-tert-butylamine product: 2,2-dimethyl-3-phenylpropionaldehyde byproduct: 2,4-dinitrophenylhydrazone Keywords: alkylation, C-alkylation; coupling; Grignard and related reactions; ethylmagnesium bromide, preparation of; tetrahydrofuran; bubbler, mercury; condenser, for low-boiling liquids

1-Phenyl-1,4-pentadiyne and 1-phenyl-1,3-pentadiyne reactant: 102 g. (1.00 mole) of phenylacetylene reactant: 96 g. (0.81 mole) of propargyl bromide product: 1-phenyl-1,4-pentadiyne product: 1-phenyl-1,3-pentadiyne Keywords: coupling; Grignard and related reactions; rearrangements; ethylmagnesium bromide, preparation of; phenylethynylmagnesium bromide, preparation of; tetrahydrofuran

Addition of an ethylcopper complex to 1-octyne: (E)-5-ethyl-1,4-undecadiene product: (E)-5-ethyl-1,4-undecadiene Keywords: addition, to CC; alkenylation, C-alkenylation; alkylation, C-alkylation; assay methods, for ethylmagnesium bromide with 2-butanol, 1,10-phenanthroline indicator; copper(I) bromide, dimethyl sulfide complex; diethyl ether; ethyl copper complex, preparation of; ethyl copper complex-1-octyne adduct, preparation of; sodium benzophenone ketyl, solution in diethyl ether; tetrahydro-1,3-dimethyl-2(1H)-pyrimidinone (DMPU); dimethyl sulfide, stench; hexamethylphosphoric triamide (HMPA), toxicity; bath, cooling, refrigerated; stopcock to allow simultaneous addition of liquid reagents and inert gases

Shortly after Ziegler’s disclosures, Anderson and Merkling reported the polymerisation of norbornene using titanium tetrachloride and ethylmagnesium bromide at 50°C. Subsequently it was established that the polymer was the result of a ring opening process rather than the expected vinyl addition polymerisation. Using isotopic labelling (Dall’ Asta and Motroni) it was established that in the polymerisation of cyclic olefins the reaction proceeded via complete cleavage of the carbon-carbon double bond.