Ketones, diazo synthesis

Photo-de-diazoniation has found relatively little application in organic synthesis, as is clearly evident from the annual Specialist Periodical Reports on Photochemistry published by the Royal Society of Chemistry. Since the beginning of these reports (1970) they have contained a section on the elimination of nitrogen from diazo compounds, written since 1973 by Reid (1990). In the 1980s (including 1990), at least 90% of each report is concerned with dediazoniations of diazoalkanes and non-quinon-oid diazo ketones, the rest being mainly related to quinone diazides and only occasionally to arenediazonium salts. 

The reaction between acyl halides and diazomethane is of wide scope and is the best way to prepare diazo ketones. Diazomethane must be present in excess or the HX produced will react with the diazo ketone (10-74). This reaction is the first step of the Amdt-Eistert synthesis (18-8). Diazo ketones can also be prepared directly from a carboxylic acid and diazomethane or diazoethane in the presence of dicyclohexyl-carbodiimide. ... 

A number of these alkylation reactions are illustrated in Scheme 9.2. Entries 1 and 2 are typical examples of a-halo ester reactions. Entry 3 is a modification in which the highly hindered base potassium 2,6-di-f-butylphenoxide is used. Similar reaction conditions can be used with a-halo ketones (Entries 4 and 5) and nitriles (Entry 6). Entries 7 to 9 illustrate the use of diazo esters and diazo ketones. Entry 10 shows an application of the reaction to the synthesis of an amide. 

A simple synthesis of a-amino ketones and esters 231 (R1 = EtO or Ph R2 = H or CO2EE R3 = Me or CH2C02Et R4 = PhCH2 or CH2C02Et) proceeds from diazo ketones and esters, respectively, tertiary amines and copper powder. The intermediate... 

The present procedure for the synthesis of an a-diazo ketone is a modification of the Forster reaction,which has been recently exploited by numerous workers.The synthesis is generally applicable to cyclic ketones, is convenient, and offers moderate yields (60-70%) of pure a-diazo ketones. 

One of the earliest uses for rhodium(II)-catalyzed dipoles was demonstrated in Davies furan synthesis [22]. Isomiinchnones were also shown to produce substituted furans [115]. Additional furan syntheses have been described using silylacetates [116], unsaturated esters [117], and fluoroalkyl diazo acetates [118]. The synthesis of furofuranones and indenofuranones 35 from a-diazo ketones having pendant alkynes has also been reported (Eq. 6) [119]. Other fused heterocyclic systems include furo[3,4-c]furans [120, 121] furo[2,3-b]furans [122] as well as thiobenzofurans [123], and benzoxazoles[124] have also been synthesized with this methodology. 

In more recent work, Chiu and co-workers [167, 168] have reported an intramolecular 1,3-dipolar cycloaddition approach toward the pseudolaric acids 85, in which the di-polarophile is an unactivated 1,1-disubstituted alkene. Hence, treatment of the diazo ketone 86 with catalytic Rh2(OAc)4 furnished a mixture of tricyclic products 87 and 88 in nearly equal proportions (Scheme 19.13). The synthesis of 2-pyridones [169] and their application to the ipalbidine core [170] has been described. The pentacyclic skeleton of the aspidosperma alkaloids was prepared via the cycloaddition of a push-pull carbonyl ylide [171]. The dehydrovindorosine alkaloids 89 have also been investigated, in which the a-diazo-/ -ketoester 90 undergoes a facile cycloaddition to furnish 91 in... 

Padwa has reported an approach to the ring system of the ribasine alkaloids 98 [174], using an intramolecular 1,3-dipolar cycloaddition of the a-diazo ketone 99 to produce the pentacyclic skeleton 100 (Scheme 19.17). Wood [175] used an intermolecular 1,3-dipolar cycloaddition of a carbonyl ylide for the total synthesis of ( )-epoxysorbicilli-nol 101 (Scheme 19.18). The key cycloaddition in this approach is the conversion of 102 to the natural product core 103, which sets the substitution pattern around the entire ring system in a single step. 

Diazocycloalkanones with five- to twelve-membered rings can be synthesized by the present procedure in good yields (Table I).4 Diazo transfer with deformylation can also be used for the preparation of bicyclic a-diazo ketones.10,11 A related procedure involving reaction of the sodium salt of an a-(hydroxy methylene)-ketone with p-toluenesulfonyl azide in ethanol has been applied to the synthesis of diazoalkyl ketones, a-diazo aldehydes, and a-diazo carboxylic esters.12... 

The crude diazo ketone (30.8-33.4 g) always contains about 10% of Boc-L-phenylalanine methyl ester formed by esterification of Boc-L-phenylalanine with diazomethane. This material can be carried through the synthesis and is removed during Step B. 

A regio- and stereospecific synthesis of modhephene has also been achieved beginning with the Weiss-Cook reaction As illustrated in Scheme XCVII, cyclo-pentai -l,2-dione can be readily crait l into a-diazo ketone 8(M), copper-catalyz l decomposition of which delivers tricyclic ketone 801. Following the dimethylation of this intermediate, carbomethoxylation was accomplished to give 802 and provide... 

Ring closure to an episulfide is a feasible reaction for thiocarbonyl ylides. In most cases, the sulfur is further extruded under the reaction conditions to afford an olefin as the final product. This cascade transformation has been utilized by Danishefsky and co-workers in their total synthesis of ( )-indolizomycin (Scheme 16)." In the Danishefsky s approach, diazo ketone 137 is treated with a catalytic amount of Rh2(OAc)4 to generate thiocarbonyl ylide 138, which cyclizes to give episulfide 139. This episulfide isomerizes to mercaptan 140, which is then desulfurized by partially deactivated W-2 Raney nickel. 

Among the methods described in Section 10.6.5, the syntheses reported by Umezawa et alJ78 and Garcfa-Lopez et al.179,80 have been most widely used. As summarized in Scheme 33, the synthesis is initiated with the preparation of a diazo ketone through the reaction between a N-protected a-amino acid and isobutyl chloroformate followed by treatment with diazomethane. The chloromethyl ketone is prepared by adding 2.5 M hydrochloric acid to the diazo ketone. Transhalogenation is exploited to obtain the iodomethyl ketone. Through in situ reaction with the sodium derivative of dimethyl malonate, the 4-oxo diester is obtained. 

Marti et alJ4"1 have used a similar approach involving Fmoc-protection. However, they have demonstrated that it is possible to use Fmoc-protected diazo ketones derived from a-amino acids together with a peptide on a solid support with a free N-terminus in a silver-promoted Amdt-Eistert procedure. Hence, homologation and peptide coupling are achieved in one step. This approach has led to the synthesis of a-peptides containing one (l3-amino acid (Scheme 19) and also, if the homologation procedure is used repetitively, to p3-peptides. 

Solid-Phase Synthesis of (53-Peptides Reaction of Fmoc-Protected Diazo Ketones with Concomitant (53-Peptide Formation on a Solid Support 1401... 

GRUNDMANN ALDEHYDE SYNTHESIS. Transformation of an acid into an aldehyde of the same chain length by conversion of the acid chloride via the diazo ketone to the acetoxy ketone, reduction with aluminum isopropoxide and hydrolysis to the glycol, and cleavage with lead tetraacetate. 

Peptidyl bromomethyl ketones (Scheme 2) are synthesized by the same method used to prepare chloromethyl ketones (Scheme 1) namely, the reaction of peptidyl diazomethyl ketones with HBr. 16-18 This reaction proceeds readily for either chloromethyl or bromomethyl ketones, although a contaminant, the N-methylated compound, is usually observed in the final reaction product. 1 A variation of this method involves the use of LiBr, which facilitates the formation of acid-sensitive protected amino acids. 1 As with the chloromethyl synthesis, only Z and Boc should be used to protect the amino acids. 3 Although the reaction of diazo ketones with HBr is well known and relatively simple, only a few compounds have been synthesized (Table 2). 

The cyclopropanation of alkenes, alkynes, and aromatic compounds by carbenoids generated in the metal-catalyzed decomposition of diazo ketones has found widespread use as a method for carbon-carbon bond construction for many years, and intramolecular applications of these reactions have provided a useful cyclization strategy. Historically, copper metal, cuprous chloride, cupric sulfate, and other copper salts were used most commonly as catalysts for such reactions however, the superior catalytic activity of rhodium(ll) acetate dimer has recently become well-established.3 This commercially available rhodium salt exhibits high catalytic activity for the decomposition of diazo ketones even at very low catalyst substrate ratios (< 1%) and is less capricious than the old copper catalysts. We recommend the use of rhodium(ll) acetate dimer in preference to copper catalysts in all diazo ketone decomposition reactions. The present synthesis describes a typical cyclization procedure. 

A study of the Staudinger synthesis of /3-lactams from a diazo ketone, an acid chloride, and an imine (under basic conditions) has explored the cis/trans selectivity as a function of time, temperature, solvent, and the order of addition of reagents.81... 

Enol ethers react with diazo ketones in the presence of Cu-catalysts to give cyclopropanes such as 24. Ring cleavage with acid and subsequent intramolecular aldol condensation constitutes a flexible route to cyclopentenones (Eq. 7) 12-13). This procedure has also been applied to a synthesis of cis-jasmone employing isopropenyl acetate as a donor olefin 14). 

Addition of a suitably substituted diazo ketone to diketene has served as a key step — albeit with low efficiency — in yet another synthesis of m-jasmone 30). 

---