Monoalkylation synthesis

A special problem arises in the preparation of secondary amines. These compounds are highly nucleophilic, and alkylation of an amine with alkyl halides cannot be expected to stop at any specifle stage. Secondary amides, however, can be monoalkylated and lydrolyzed or be reduced to secondary amines (p. 11 If.). In the elegant synthesis of phenyl- phrine an intermediate -hydroxy isocyanate (from a hydrazide and nitrous acid) cyclizes to pve an oxazolidinone which is monomethylated. Treatment with strong acid cleaves the cyclic irethan. 

FORSTER - DECKER Amine Synthesis Selective monoalkylation of primary amines via imines An altemativa method is the reaction ol 1 and 2 in the preserve of NaCNBH4 or tnaceloxyborohydride (Borch reduction)/... 

Monoalkylated and dialkylated acetic acids can be prepared by the malonic ester synthesis, but trialkylated acetic acids (R3CCO2H) can t be prepared. Explain. 

Schreiber found that the monoalkylation of the lithium enolate of cyclonona-none with propene oxide could be cleanly effected by addition of AlMe3 to give the y-hydroxy ketone 145, a key intermediate for the synthesis of recifeiolide [69a]. 

The potential utility of cyclopentadienylthallium(I) in organic synthesis, and its advantages over the much more commonly employed sodium salt, have been illustrated recently 22). Treatment of (I) (Scheme 2) with chloromethyl methyl ether in dry ether resulted in smooth monoalkylation... 

Alkylation of dianions occurs at the more basic carbon. This technique permits alkylation of 1,3-dicarbonyl compounds to be carried out cleanly at the less acidic position. Since, as discussed earlier, alkylation of the monoanion occurs at the carbon between the two carbonyl groups, the site of monoalkylation can be controlled by choice of the amount and nature of the base. A few examples of the formation and alkylation of dianions are collected in Scheme 1.7. In each case, alkylation occurs at the less stabilized anionic carbon. In Entry 3, the a-formyl substituent, which is removed after the alkylation, serves to direct the alkylation to the methyl-substituted carbon. Entry 6 is a step in the synthesis of artemisinin, an antimalarial component of a Chinese herbal medicine. The sulfoxide serves as an anion-stabilizing group and the dianion is alkylated at the less acidic a-position. Note that this reaction is also stereoselective for the trans isomer. The phenylsulfinyl group is removed reductively by aluminum. (See Section 5.6.2 for a discussion of this reaction.)... 

Rapid monoalkylations are achieved in good yield compared with classical methods. Of particular interest is the synthesis of ot-amino acids by alkylation of aldimines with microwave activation. Subsequent acidic hydrolysis of the alkylated imine provides leucine, serine, or phenylalanine in preparatively useful yields within 1-5 min [50], Alkylation of phenylacetonitrile was performed by solid-liquid PTC in 1-3 min under microwave irradiation (Eq. 36 and Tab. 5.14). The nitriles obtained can subsequently be quickly hydrolyzed in a microwave oven to yield the corresponding amides or acids [56]. 

One of the interesting application of 12 (R= allyl, X=Br) will be the synthesis of cyclic amino acid, (S)-pipecolic acid, as its tert-butyl ester 271251 Monoalkylation of the O Donnell imine 23 with l-chloro-4-iodobutane afforded the alkylated product 26 with 99 % ee. The conversion of 26 to the tert-butyl ester of pipecolic acid 27 was achieved in high yield by the sequence imine reduction, cyclization, and hydrogenolytic removal, as shown in Scheme 8. 

The catalysed two-phase adaptation of the Atherton-Todd procedure is effective for the phosphorylation of primary alcohols and of phenols [6] to produce trialkyl phosphates and dialkyl aryl phosphates. Trialkyl phosphates have also be obtained in high yield (>75%) from the alkylation of preformed tctra-n-butylammonium di-/-butylphosphate [7], Subsequent cleavage of the /-butyl groups provide a simple synthesis of monoalkyl phosphates. 

It has been reported that the ease of A-alkylation of aromatic amines is enhanced by ultrasonics [9], and, predictably, the presence of mesomeric electron-withdrawing substituents at positions ortho or para to the amino function aids the A-alkylation of the aromatic amines [e.g. 10], see also, for example, the phase-transfer catalysed glycosidation of 2-cyanoaniline [11], Generally, the direct /V-monoalkylation of aminoarenes is not particularly satisfactory, but an alternative protocol [12] in which the N-acyl derivatives are alkylated and then hydrolysed leads to enhanced yields (>90%) (see Section 5.2). In a similar manner, a one pot synthesis converts 2-... 

Monoalkylation of a-isocyano esters by using tert-butyl isocyano acetate (R = fBu) has been reported by Schollkopf [28, 33]. Besides successful examples using primary halides, 2-iodopropane has been reported to produce the a-alkylated product (1) as well by this method (KOfBu in THF). In the years 1987-1991, Ito reported several methods for the monoalkylation of isocyano esters, including the Michael reaction under TBAF catalysis as described earlier [31], Claisen rearrangements [34], and asymmetric Pd-catalyzed allylation [35]. Finally, Zhu recently reported the first example of the introduction of an aromatic substituent by means of a nucleophilic aromatic substitution (Cs0H-H20, MeCN, 0°C) in the synthesis of methyl ot-isocyano p-nitrophenylacetate [36]. 

The quaternary ammonixim salt 73, thenium closylate, is an anthelmintic agent. Many substances of this general type are effective by interfering with nervous conduction, and thereby muscle tone, of intestinal worms. This allows their expulsion, not always in the dead state. The synthesis proceeds from 2-thienylamine (70) by monoalkylation with 2-phenoxyethyl bromide (71) to give secondary amine 72. 

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