Nitrones Grignard reagents

A variety of C-nucleophiles can be added to 3-thiazolines to give the corresponding substituted thiazolidines <83TL4503>. Among those nucleophiles are organolithium compounds, Grignard reagents, nitronates, and silyl and lithium enol ethers. 

The diastereoselectivity of the nucleophilic addition to nitrone 2 may be rationalized by assuming that magnesium bromide preferentially coordinates with the nitrone oxygen. The Grignard reagent is therefore forced to interact with the acetal oxygen in position 3. 

On the other hand, following the same sequences from the differently protected serine-derived nitrone 168, through the formation of hydroxylamines 169, C2 epimers of carboxylic acid and aldehydes are obtained, i.e., (2S,3R)-170 and (2S,3R)-171. Moreover, the syn adducts 164 were exclusively obtained in the addition of Grignard reagents to the nitrone 163, whereas the same reactions on nitrone 168 occurred with a partial loss of diastereoselectivity [80]. Q, j6-Diamino acids (2R,3S)- and (2R,3R)-167 can also be prepared from the a-amino hydroxylamines 164 and 169 by reduction, deprotection and oxidation steps. The diastereoselective addition of acetylide anion to N,N-dibenzyl L-serine phenyhmine has been also described [81]. 

Diastereoselective addition of a wide range of Grignard reagents to C -alkyl and C-aryl-A-[a.-phenyl- or u-methyl-j3-(benzyloxy)ethyl nitrones is determined by the presence of a stereogenic A -substituent (136, 137). High diastereoselectiv-ity in the addition of organometalic compounds to A-(( i-methoxyalkyl) nitrones can be explained by a simple chelation model (Scheme 2.132) (136). 

Table 2.10 Stereoselective additions of Grignard reagents to nitrone 292 ...

O - P h e n y 1 - /V - e r y t h r o s y 1 nitrone (336), as a Ci,C i-bis-electrophile, when subjected to the double addition of Grignard reagents (in a domino style), leads to acyclic hydroxylamine (338) via the formation of open-chain nitrone (337 ). The reaction proceeds at 0°C with variable diastereoselectivity ranging from medium to good, depending on the organometalic reagent used (Scheme 2.140) (564). 

As in all cases already mentioned, diastereoselective addition of Grignard reagents to j3-amino nitrones (a-aminoalkyl nitrones) is a key step in the stereo-controlled syntheses of O.,j3-diamino acids (Scheme 2.141) (565, 566), of unsym-metrical a-amino hydroxylamines and 1,2-diamines (Scheme 2.142) (209, 567). 

Recently, semiempirical PM3 computational analysis (568) and first ab initio study (569) of the nucleophilic addition to chiral nitrones of Grignard reagents have been carried out. The data revealed that all reactions are exothermic and proceed through /w-complexation of nitrones with the organometalic reagent. 

Addition of the Grignard reagent, prepared from 3-aryl-2-/.sopropyl-1 -chloropropane (340) to nitrone (339) is a very important step toward the synthesis of compound (342a) which is used in preparing the antihypertensive agent SPP-100B and its epimer (342b) (Scheme 2.143) (197). 

Recently, tert- butyl (phenylsulfonyl)alkyl-A-hydroxycarbamates (343), which are readily obtained from the reaction of aldehydes and tert -butyl-A -hydroxy-carbamate in an aqueous methanol solution, were used as an equivalent of N -(/iocprotected nitrones in the nucleophilic addition of Grignard reagents (Scheme 2.144) (571). 

Addition of the Grignard reagent, generated in situ from (375), to nitrone (373) or to 2,5-dimethyl-l-pyrroline-A-oxide, affords biradical (379) or nitrone containing monoradical (380). Furthermore, (380) can be transformed into biradical (381) and triradical (382) (Scheme 2.165) (620). 

Double addition of Grignard reagents to A-glycosyl nitrones (336), in a domino fashion, affords hydroxylamines. Their usefulness has been shown with the synthesis of pyrroloazepine (418) via a ring closing metathesis key step (Scheme 2.187) (564). 

Unlike alkyl nitronates (302), their silyl analogs react with Grignard reagents at the silicon atom rather than at the a-C atom (306). All these processes may be represented as electrocyclic. 

The same nitrone 241 was employed in a stereoselective alkylation with a Grignard reagent by Petrini et al. <1995JOC5706> for another synthesis of lentiginosine. 

Treatment of hydroxylamines 4 (R1 = cyclohexyl, Ph or 3,4-(MeO)2CgH3) with acetone gives nitrones 5, which are transformed by Grignard reagents R2MgBr (R2 = Me, Et, Bu, Ph or allyl) into the hydroxylamines 6 the latter are converted into the hindered secondary amines 7 by means of carbon disulphide10. 

The furoxan ring is more susceptible to nucleophilic attack and reduction than it is to reaction with electrophiles or oxidation. Grignard reagents react with disubstituted furoxans primarily at C-3 and, in most cases, the resulting adduct fragments to a nitrile and a nitronate salt which affords a ketone on workup. 

Mild alkaline hydrolysis of (186 R = Me) gave the l,4-benzodiazepin-2-one 4-oxide. Grignard reagents react with the nitrone (152 R = R1 = H) and similar compounds to give the 4-hydroxy-5-phenyl derivative (77ACS(B)70l). 

Cerium(IV) ammonium nitrate, 67 Grignard reagents, 138 Other nitro compounds Alumina, 14 Nitrones... 

NaOCl converts the alkyl nitronate adducts formed between nitroarenes and Grignard reagents, to alkyl chloroarenes814. tert-Butyl hypochlorite selectively chlorinates benzal-doximes to afford benzohydroximoyl chlorides8 5. 

Reactions of allylic and benzylic Grignard reagents with alkyl nitro compounds can, under the right conditions, provide an acceptable route to nitrones [11]. Lack of regio- and stereoselectivity may be a problem, though the former can be controlled to some extent by varying the acid used for protonation, e.g. 

Ketoximes from R CH NOj and R MgBr. Reaction of the Vilsmeier reagent with the lithium nitronate of a nitroalkane activates the -position to attack by Grignard reagents to form ketoximes (equation I). 

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