2-Alkynal diethyl acetals

ALKYL-2-PYRAZOLIN-5-ONES, 55, 73 2-Alkynal diethyl acetals, 59,14 2-Alkynals, 59,14... 

The alkynylation of estrone methyl ether with the lithium, sodium and potassium derivatives of propargyl alcohol, 3-butyn-l-ol, and propargyl aldehyde diethyl acetal in pyridine and dioxane has been studied by Miller. Every combination of alkali metal and alkyne tried, but one, gives the 17a-alkylated products (65a), (65c) and (65d). The exception is alkynylation with the potassium derivative of propargyl aldehyde diethyl acetal in pyridine at room temperature, which produces a mixture of epimeric 17-(3, 3 -diethoxy-T-propynyl) derivatives. The rate of alkynylation of estrone methyl ether depends on the structure of the alkyne and proceeds in the order propar-gylaldehyde diethyl acetal > 3-butyn-l-ol > propargyl alcohol. The reactivity of the alkali metal salts is in the order potassium > sodium > lithium. 

ALKYNES VIA PHASE TRANSFER-CATALYZED DEHYDROHALOGENATION PROPIOLALDEHYDE DIETHYL ACETAL... 

Secondary and tertiary dialkylcuprates, lithium dialkenyl-, and even diphenyl-cuprates, add in very good yields to the reactive propionaldehyde diethyl acetal. The syn addition products may be trapped with a variety of electrophiles such as alkyl, alkenyl, alkynyl and aryl halides. The method has been used for the synthesis of several natural products. Substituted alkynic acetals also react with lithium dialkylcuprates in ether to furnish stable dialkenylcuprates of type (128) which do not eliminate to the corresponding alkoxy allenes (129) if the temperature is maintained below -20 C.164-179... 

Dehydrohalogenation [1, 1035-1037, at end]. In a general procedure for the conversion of alkenes into alkynes by bromination and dehydrobromination, Ward and van Dorp recommend sodium amide and liquid ammonia for the dehydrobromination step.103 The preparation of propargyl aldehyde diethyl acetal is an example ,cb... 

The challenge of the synthesis of the ene-diyene natural products was one of the factors that brought the Sonogashira reaction to prominence. Three Sonogashira reactions were used in a synthesis of the core of the esperamycin/calichemicin anti-tumour agents (Scheme 2.117). Two were employed in sequence to add two alkynes onto cw-l,2-dichloroethylene 2375 to form the ene-diyne 2376. Due to the sensitivity of propiolaldehyde, its diethyl acetal was employed. After hydrolysis of the acetal, a diene unit was installed. 

Tyrrell demonstrated a three step tandem sequence involving an intermolecular Nicholas reaction, intramolecular Nicholas reaction, and a cationic cyclization. Treatment of silyl enol ether 55 with hexacarbonyl(propiolaldehyde diethyl acetal) dicobalt and boron trifluoride provides cobalt-alkyne complex 56. Exposure of this material to tetrafluoroboric acid promotes an intramolecular Nicholas reaction to form the second six-membered ring. Alkyne decomplexation with ceric ammonium nitrate enables the final cyclization step to yield the target tricycle 57." ... 

The direct combination of selenium and acetylene provides the most convenient source of selenophene (76JHC1319). Lesser amounts of many other compounds are formed concurrently and include 2- and 3-alkylselenophenes, benzo[6]selenophene and isomeric selenoloselenophenes (76CS(10)159). The commercial availability of thiophene makes comparable reactions of little interest for the obtention of the parent heterocycle in the laboratory. However, the reaction of substituted acetylenes with morpholinyl disulfide is of some synthetic value. The process, which appears to entail the initial formation of thionitroxyl radicals, converts phenylacetylene into a 3 1 mixture of 2,4- and 2,5-diphenylthiophene, methyl propiolate into dimethyl thiophene-2,5-dicarboxylate, and ethyl phenylpropiolate into diethyl 3,4-diphenylthiophene-2,5-dicarboxylate (Scheme 83a) (77TL3413). Dimethyl thiophene-2,4-dicarboxylate is obtained from methyl propiolate by treatment with dimethyl sulfoxide and thionyl chloride (Scheme 83b) (66CB1558). The rhodium carbonyl catalyzed carbonylation of alkynes in alcohols provides 5-alkoxy-2(5//)-furanones (Scheme 83c) (81CL993). The inclusion of ethylene provides 5-ethyl-2(5//)-furanones instead (82NKK242). The nickel acetate catalyzed addition of r-butyl isocyanide to alkynes provides access to 2-aminopyrroles (Scheme 83d) (70S593). 

ALKYL SELENOCYANATES Triphenyl-phosphine-Diethyl azodicarboxylate. ALKYNES Acetic anhydride-Pyridine. Dimethyl) diazomethyl)phosphonate. OrganoUthium reagents. 

We have completed the first total synthesis of (-)-ichthyothereol (46) and its acetate 47 by the palladium-catalyzed coupling reaction between the ( )-iodoolefin 63 and the triyne derivative 66. The iodoolefin 63 was prepared from commercially available diethyl L-tartrate through the Co2(CO)8-mediated endo cyclization of the optically active c/.v-epoxy-alkyne derivative 60 in a highly stereoselective manner. 

Oxidation of diethyl a-benzylmalonate (25) by Mn(III) acetate in acetic acid at 70 °C in the presence of mono- or disubstituted alkynes leads to dihydronaphthalene derivatives (26) in moderate to good yields (equation 33). A mechanistic scheme involving the formation of the corresponding malonyl radical, its addition to a triple bond and intramolecular homolytic aromatic substitution of the vinyl radical adducts is discussed. Absolute rate constants, obtained from competitive studies, for the addition of a-benzylmalonyl radicals to a variety of alkynes cover few orders of magnitude e.g. the rate constants at 60 °C are 3x10 and 1 x 10 s for 4-octyne and phenylacetylene respectively. 

Phosphonylpyrazole 4 To a stirred solution of aldehyde (1 0.5 mmol) and diethyl(diazo-methyl)phosphonate (BOR 2 275 mg, 1.25 mmol) in dry EtOH (10 mL) was added CS2CO3 (480 mg, 1.5 mmol) at 0 °C and the resulting mixture was stirred at room temperature until complete consumption of aldehyde 1 (monitored by TLC). To the reaction mixture containing alkyne intermediate were then added Cul (19 mg, 0.10 mmol), BOR (2 165 mg, 0.75 mmol) and KOH (56 mg, 1 mmol) and stirring continued until all the alkyne intermediate was coti-sumed (monitored by TLC). Then the reaction mixture was concentrated in vacuo and the crude residue was directly subjected to silica gel column chromatography ( -hexane/ethyl acetate 3/ 7) to afford pure phosphonylpyrazole 4, characterized by spectral studies. 

A highly regioselective protocol was reported that delivered numerous 3,4-disubstituted indole derivatives with excellent yields by hydrazine-directed Rh-catalyzed C-H activation, in which the protected hydrazine acts as a directing group and as an internal oxidant (Eq. (5.14)) [11a]. The reaction was promoted by an acetic acid additive. Similarly, a Rh(IIl)-catalyzed reaction of an arylhydrazine salt, a diethyl ketone, and an alkyne to synthesize a 3,4-disubstituted indole was also reported by our group. The reaction proceeds by in situ condensation of an arylhydrazine with diethyl ketone to form an arylhydrazone intermediate (Eq. (5.15)) [11b]. 

Various [l- C]carboxylic acids have been prepared by carboxylation of carbanions stabilized by -I or -M substituents. The examples in Figure 5.7 have been selected here as prototypes, since they are of strategic interest. Deprotonation of diethyl methylphos-phonate (18 with n-BuLi followed by [ CJcarboxylation and esterification with diazoethane provided triethyl phosphonoll- Clacetate (19) in an overall radiochemical yield of 62%. Compound 19 has been widely exploited for chain extensions by a labeled two-carbon unit via its alkenylation reaction with carbonyl compounds (Homer-Wadsworth-Emmons reaction). Similarly, reaction of alkyl halides, tosylates or carbonyl compounds with LiC = CH or LiC=CH H2NCH2CH2NH2 followed by deprotonation and [ C]carboxylation of the resulting terminal alkynes has been used as a strategic tool for the incorporation of a labeled three-carbon unit, as exemphfied in a steroid platform (20 to 21). This chemistry provides outcomes complementary to those using [ C2]acetylene (Chapter 8, Section 5.1). Finally, the [ CJcarboxylation of lithiated dimethylsulfide provided an alkylthio[l- C]acetic acid 22 and thence a functionalized 2-alkylthio[l- C]ethyl derivative 23 useful, in this case, for elaboration into e.p. 

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