Amides, Weinreb

A -Methoxy-A -methyl-amide. Due to the chelation effect, nucleophilic addition of an organometallic reagent adds only once to give ketone, whereas normal amides would have led to double addition to afford tertiary alcohol. 

---

Dimethylsulfoxonium methylide (1) is the reagent of choice for the cyclopropanation of a,p-unsaturated carbonyl substrates. The reaction is generally carried out at more elevated temperatures in comparison to that of 2, although exceptions exist. The method works for 0 ,P-unsaturated ketones, esters and amides. Representative examples are found in transformations of 2(5//)-furanone 55 to cyclopropane 56 and 0 ,P-unsaturated Weinreb amide 57 to cyclopropane 58. ... 

McCluskey et al. have also used [BMIM][BF4] as a solvent for the allylation of aldehydes and Weinreb amides [56]. Similar diastereoselectivities and similar or slightly lower yields were obtained in this ionic liquid, compared with reactions carried... 

The synthesis of the polyol glycoside subunit 7 commences with an asymmetric aldol condensation between the boron enolate derived from imide 21 and a-(benzyloxy)acetaldehyde (24) to give syn adduct 39 in 87 % yield and in greater than 99 % diastereomeric purity (see Scheme 8a). Treatment of the Weinreb amide,20 derived in one step through transamination of 39, with 2-lithiopropene furnishes enone 23 in an overall yield of 92 %. To accomplish the formation of the syn 1,3-diol, enone 23 is reduced in a chemo- and... 

A retrosynthetic analysis of fragment 152 can be completed through cleavage of the C16-C17 bond in enone 155, the projected precursor of epoxide 152. This retrosynthetic maneuver furnishes intermediates 156 and 157 as potential building blocks. In the forward sense, acylation of a vinyl metal species derived from 156 with Weinreb amide 157 could accomplish the construction of enone 155. Iodide 153, on the other hand, can be traced retrosynthetically to the commercially available, optically active building block methyl (S)-(+)-3-hydroxy-2-methyIpropionate (154). 

Uneyama et al. have shown that enantiopure trifluoromethyloxirane (193) can be lithiated and stereoselectively trapped with a variety of electrophiles to give substituted trifluoromethyloxiranes such as 195 (Scheme 5.46) [70] the use of a Weinreb amide as the electrophile is unusual. 

Weinreb amides of aziridinecarboxylic acids readily react with orfho-lithiated 0-methoxymethyl phenols. The thus produced benzoylaziridine 43 undergoes an intramolecular ring expansion upon treatment with acid in ethanol. Base treatment leads to benzofuranones as shown in Scheme 34 [44]. 

A New General Method for the Preparation of Weinreb Amides from Esters... 

The reaction of an ester with Weinreb amine and i-PrMgCl provides a general method for the preparation of Weinreb amides that has been widely used in the... 

Table 3.3 Preparation of Weinreb amides from esters.

The ketone 15 was eventually prepared by Grignard addition to Weinreb amide 21, as shown in Scheme 5.5. The Weinreb amide 21 was prepared from p-iodobenzoic acid (20). The phenol of readily available 3-hydroxybenzaldehyde (22) was first protected with a benzyl group, then the aldehyde was converted to chloride 24 via alcohol 23 under standard conditions. Preparation of the Grignard reagent 25 from chloride 24 was initially problematic. A large proportion of the homo-coupling side product 26 was observed in THF. The use of a 3 1 mixture of toluene THF as the reaction solvent suppressed this side reaction [7]. The iodoketone 15 was isolated as a crystalline solid and this sequence was scaled up to pilot plant scale to make around 50 kg of 15. 

After salt break chiral acid 11 was converted to the methyl ketone 13 in essentially quantitative yield via the intermediacy of the Weinreb amide and processed as an oil without further purification (Scheme 9.6). The carbonyl group in 13 was then reduced to the secondary alcohol 16 using L-Selectride as previously described in 97% assay yield. We were pleased to find that an attainable reaction temperature of-50°C was sufficient to obtain high selectivity of >98 2, and that, in the absence of the reactive nitrile group, no issues were observed or during... 

Mori later developed a shorter synthesis of these pheromones by employing a Weinreb amide A (Scheme 31) as the common intermediate [54]. The products 18-20, however, were less enantiomerically pure than those previously synthesized from the epoxy alcohol A of Schemes 29 and 30. 

Entry to the ugibohlin, phakellin, and isophakellin ABC ring systems was achieved via intramolecular N(l)-C(3) cyclizations of the Weinreb amide 169 of pyrrole-proline 168 or its brominated derivatives to give the bispyrrolopyr-azine 170 (Scheme 12) <2005TL249>. 

Cyclization of the Weinreb amide 356 under reductive conditions using lithium aluminium hydride (LAH) led to formation of the carbinolamine 357 which underwent elimination on treatment with methanesulfonic acid to give 358 in 72% yield as shown in Scheme 27 <2005TL249>. 

The preparation of 3-vinylpyrroles was investigated utilizing the Horner-Wads worth-Emmons reaction with 3-formyl-lV-tosylpyrrole <06S1494>. The intramolecular acylation of pyrrole-2-Weinreb amides provided access to novel indolizinone derivatives <06T6182>. The amidation of pyrrole-2-carbonyl chloride was utilized as a key step in the preparation of pyrrole-oxazole analogue 90 of the insecticide Pirate <06S1975>. 

There are several new methodologies based on the Julia olefination reaction. For example, 2-(benzo[t/Jthiazol-2-ylsulfonyl)-j -methoxy-i -methylacetamide 178, prepared in two steps from 2-chloro-iV-methoxy-jV-methylacetamide, reacts with a variety of aldehydes in the presence of sodium hydride to furnish the ajl-unsaturated Weinreb amides 179 <06EJOC2851>. An efficient synthesis of fluorinated olefins 182 features the Julia olefination of aldehydes or ketones with a-fluoro l,3-benzothiazol-2-yl sulfones 181, readily available from l,3-benzothiazol-2-yl sulfones 180 via electrophilic fluorination <06OL1553>. A similar strategy has been applied to the synthesis of a-fluoro acrylates 185 <06OL4457>. 

The cycloaddition of Weinreb amide functionalized nitrile oxide with a range of dipolarophiles has been studied. N-Methoxy-N-methylcarbonocyanidic amide, nitrile oxide 207 (i.e., a nitrile oxide of Weinreb amide type derivative) was generated from 2-chloro-2-(hydroxyimino)-N-methoxy-N-methylacetamide as intermediate and used in situ. Thus, addition of 3-bromo-l-propyne as dipolarophile to this precursor of 207, followed by quenching with triethylamine, gave 5-(bromo-methyl)-N-(methoxy)-N-methyl-3-isoxazolecarboxamide 208 in 55% to 60% yield (367). 

The unified highly convergent total and formal syntheses of ( + )-macro-sphelides B (441 X = O) and A (441 X = a-OH, p-H), respectively, have been described (483). Key features of the syntheses include the concise synthesis of the optically active S-hydroxy-y-keto a, 3-unsaturated acid fragment 442 via the direct addition of a fra/i.s-vinylogous ester anion equivalent to a readily available Weinreb amide, and the facile construction of the 16-membered macrolide core of the macrosphelide series via an INOC. 

Scheme 54 shows the synthesis reported by Cox et al. of the pyrazoline compound 198 [98]. The Weinreb amide (e.g., 199) was reacted with a terminal alkyne followed by a reaction of the resulting alkyl ketone (200) with an aryl cuprate to produce the pyrazoline 198. Cox et al. employed the use of microwave technology in this reaction. Kidwai and Misra also employed microwave technology to produce pyrazoline compounds [99]. 

In the presence of organometallic reagents (R1 MgX, R11u, diisobutylaluminium hydride (DIBAL-H)), the Weinreb amides 186 lead selectively to the corresponding carbonyl derivatives 187 as a mixture of Z/E isomers which spontaneously undergo partial cyclization to dihydropyrrolizines 188 (Scheme 42). This cyclization was completed by refluxing the cmde mixture in chloroform in the presence of silica gel <2002S2450>. 

The addition of allenyl ether-derived anions to Weinreb [4] or to morpholino amides [5] follows a slightly different pathway (Eq. 13.2). For example, the addition of lithioallene 6 to Weinreb amide 7 at -78 °C, followed by quenching the reaction with aqueous NaH2P04 and allowing the mixture to warm to room temperature leads to cyclopentenone 9 in 80% yield [6]. The presumed intermediate of this reaction, allenyl vinyl ketone 8, was not isolated, as it underwent cyclization to 9 spontaneously [7]. These are exceptionally mild conditions for a Nazarov reaction and are probably a reflection of the strain that is present in the allene function, and also the low barrier for approach of the sp and sp2 carbon atoms. What is also noteworthy is the marked kinetic preference for the formation of the Z-isomer of the exocyclic double bond in 9. Had the Nazarov cyclization of 8 been conducted with catalysis by strong acid, it is unlikely that the kinetic product would have been observed. 

---