Sodium amide synthesis

Sodium Amide. Synthesis of j8-Keto Esters. J. Amer. chem. Soc. 66, 1768 (1944). 

An apparatus identical with that used for the preparation of sodium amide (synthesis 38) is set up, with a three-... 

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

The classical conditions for the Madelung indole synthesis are illustrated by the Organic Syntheses preparation of 2-methylindole which involves heating o-methylacetanilide with sodium amide at 250 C[1]. 

The Madelung Synthesis and Related Base-Catalyzed Condensations. The Madelung cyclization involves an intramolecular condensation of an o-aLkylanilide. A classic example of the Madelung synthesis is the high temperature condensation of o-methylacetanihde [120-66-1] to 2-methylindole [95-20-5] by sodium amide. 

The synthesis of 1-ethoxy-1-butjme has been reported previously, but the preparations have required multistep sequences. Two of the procedures use 1,2-dibromo-l-ethoxy butane which is dehydrohalogenated in two successive steps, first by an amine base and then by either powdered potassium hydroxide or sodium amide no yields are given. The... 

The most common conditions employed in the Madelung process are sodium/potassium alkoxide or sodium amide at elevated temperature (200-400 C). The Madelung reaction could be effected at lower temperature when -BuLi or LDA are employed as bases/ The useful scope of the synthesis is, therefore, limited to molecules which can survive strongly basic conditions. The process has been successfully applied to indoles bearing alkyl substituents. ... 

Scheme 6 Synthesis of P-amino-NHPs from P-chloro-precursors and sodium amide...

Sodium amide has been extensively used in the synthesis of a large number of acetylenic compounds by dehydrohalogenation. An example is ... 

A very significant mortality in Western countries is associated with cardiac arrhythmias Consequently an intensive search is underway for agents to combat this condition - particularly for compounds with an unusual mode of action A class Ic (local anesthetic-like) agent of interest in ihis context is Indecainide (50) One of several routes to this compound covered by patents begins with sodium amide mediated alkylation of 9 cyanofluorene (48) with 3 isopropylamino-1 chloropropane to give amine 49 The synthesis concludes by partial hydrolysis of the nitnle func tion to a carboxamide linkage with sulfunc acid to produce indecainide (50) [15]... 

Meperidine Meperidine, the ethyl ester of l-methyl-4-phenylpiperidine-4-carboxyhc acid (3.1.39), is a synthetic opioid analgesic. Its synthesis is accomphshed by the alkylation of benzyl cyanide using Af,Al-fcix-(2-chlorethyl)-iV-methylamine in the presence of sodium amide, which forms l-methyl-4-phenyl-4-cyanopiperidine (3.1.38), and its subsequent acidic ethanolysis into meperidine [30-32]. 

In the second, simpler scheme, synthesis begins with 7-chloro-5-phenyl-2,3-dihydro-l//-l,4-benzodiazepin-2-one (5.1.1), which is alkylated by cyclopropylmethylbromide in the presence of sodium amide into prazepam (5.1.11) [11,12]. 

The first way of synthesis is by the alkylation of 10,ll-dihydro-5//-dibenz[b,f]azepme using l-bromo-3-chloropropane in the presence of sodium amide into a chloro derivative (7.1.12) and the subsequent reaction of this with methylamine, giving desipramine (7.1.13) [18-20]. 

Subsequently, Kato and Goto have reported the synthesis of 2- and 4-pyridinecarbox-aldoximes from 2- and 4-picoline with potassium amide and amyl nitrite in liquid ammonia at — 33°C, although they failed to obtain either of these oximes when the reaction was carried ont with sodium amide in liquid ammonia at room temperature in a sealed tube. Finally, in 1964, aUcyl-substituted heteroaromatic compounds and allyl-substituted benzenes were oximated in liquid ammonia at —33 °C with sodamide and an alkyl nitrite . 

Phenylacetonitrile (pATDMSO = 21.9) is considerably more acidic than acetonitrile. Deprotonation can be done with sodium amide. Dialkylation has been used in the synthesis of meperidine, an analgesic substance.62... 

Thiols very readily add to diacetylene in the presence of bases, such as alkoxides, with formation of enyne sulfides HC=CCH=CHSR [175]. In strongly basic media, thiol can be eliminated from these enyne derivatives [2], Thus, functionalization of HChCCH=CHSR followed by treatment with an excess of sodium amide results in a derivative of butadiyne. This sequence of conversions permits the synthesis of some 1,3-diyne systems that are not otherwise easily accessible. 

The devastating mental deterioration that characterizes Alzheimer s disease has been attributed to a mishandling of the neurotransmitter acetylchohne. Inhibitors of acetylcholinesterase, the enzyme that catabolizes that substance, would be expected to help restore deficient acetylcholine levels. Several partly reduced acridines have shown some activity in treating Alzheimer s disease. At least one of these, tacrine (14-5), is now approved for use in patients. The initial step in the synthesis of the first of these consists of the sodium amide catalyzed condensation of isatin (14-1) with cyclohexanone. The reaction can be visualized by assuming the first step to involve an attack of amide on isatin to give an amido-amide such as (14-2) (note that no attempt has been made to account for charges). This can then react with... 

The synthesis of sodium amide, NaNH2 (or sodamide ), by passing ammonia over heated sodium metal, was first reported almost two centuries ago. A number of studies have since been made of its properties, but no crystal structure has been reported. Sodamide is used as a strong base in organic chemistry (often in liquid ammonia solution). In contrast, sodium bis(trimethylsilyl)amide NaN(SiMe3)2 (or sodium hex-amethyldisilazide , NaHMDS), whose crystal structure is discussed later, is widely used for deprotonation reactions or base catalysed reactions due to its solubility in a wide range of non-polar solvents. An overview of some of the types of chemical reactions in which NaHMDS is used is presented in Scheme 2.3. 

Exercise 18-39 Show a synthesis of 3-ethyl-2-pentanone from ethyl 3-oxobutanoate. What advantage would this route have over alkylation of 2-pentanone with sodium amide and ethyl iodide (Section 17-4A.)... 

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