Synthesis general

Knight, in General and Synthetic Methods , ed. G. Pattenden, (Specialist Periodical Reports), The Chemical Society, London, 1977, vol. 1, p. 111. 

Amides can be converted into acids by A-nitration followed by protonation and base hydrolysis,  

Carboxylic acid fluorides can be prepared from the free acids by treatment with hexafluoro-1,2-epoxypropane, and benzylidene chlorides are converted into the 

Variations in the 5-substituent of chiral oxazolines cause considerable fluctuations in the degree of asymmetrical alkylation of these substrates, showing that steric as well as chelation factors are important in this method of obtaining chiral carboxylic acids. An impressive example of asymmetric induction is the synthesis of 3-substituted-3-phenylpropionic acids (5) of ca. 99% optical purity, from the 1,4-oxazepine (4) (derived from a-ethoxycarbonylcinnamic acid and /-ephedrine hydrochloride), by Michael addition of Grignard reagents in the presence of nickel chloride, followed by hydrolysis and decarboxylation.  

The hydrogenation of various a/3-unsaturated acids in the presence of rhodium-phosphine complex catalysts whose ligands are chiral at both phosphorus and carbon gives saturated carboxylic acids with enantiomeric excesses up to 70%. The addition of carbon tetrachloride, catalysed by copper(ll) chloride, to (—)-men thy 1 acrylic and methacrylic esters, followed by hydrolysis, results in /3-tri-chloromethyl derivatives (6) having ca. 50% enantiomeric enrichment at the a-position.  

using either aqueous piperidine at 90°C or copper sulphate and 

Yields are especially high for oxidations of aromatic aldehydes, and 

Both alcohols and aldehydes can be oxidised to carboxylic acids using ruthenium tetroxide an efficient, two-phase (CCl4-aq.NaCl) electro-oxidation method has been developed for the generation of RuO which could be especially useful for oxidations of carbohydrate derivatives, partly protected as acetonides.5 Zinc dichromate 

2-Diols are efficiently cleaved to the corresponding carboxylic acids, usually in excellent yields ( 90%), simply by treatment with hydrogen peroxide (40% w/v) but in the presence of both tungstate (Na WO. 2H2O) and phosphate (H- PO ) catalysts at pH2. The method could be especially useful for large scale preparations. 

A new method for obtaining chiral -substituted carboxylic acids consists of S 2 ring openings of the tartramide-derived acetals (1) by trialkylaluminum reagents followed by cleavage of the major 

Almost without exception, azo dyes are made by diazotization of a primary aromatic amine followed by coupling of the resultant diazonium salt with an electron-rich nucleophile. The diazotization reaction is carried out by treating the primary aromatic amine with nitrous acid, normally generated in situ with hydrochloric acid and sodium nitrite. The nitrous acid nitrosates the amine to generate the A-nitroso compound, which tautomerises to the diazo hydroxide [Eq. (1)]. 

Protonation of the hydroxy group followed by the elimination of water generates the resonance-stabilised diazonium salt [Eq. (2)]. 

For weakly basic amines, i.e., those containing several electron-withdrawing groups, nitrosyl sulfuric acid (NO+HSO 4 ) is used as the nitrosating agent in sulfuric acid, which may be mixed with phosphoric, acetic, or propionic acid. 

A diazonium salt is a weak electrophile and hence reacts only with highly electron rich species such as amino and hydroxy compounds. Even hydroxy compounds must be ionized for reaction to occur. Consequently, hydroxy compounds such as phenols and naphthols are coupled in an alkaline medium (pH pKa of phenol or naphthol typically pH 7-11), whereas aromatic amines such as N,N-dialkylamines are coupled in a slightly acid medium, typically pH 1-5. This provides optimum stability for the diazonium salt (stable in acid) without deactivating the nucleophile (protonation of the amine). 

Microwave systems have promoted thermal preparation of heat-labile compounds, reactions that require high temperature, and they have aided optimization of established reactions known to require elevated temperature. Improved conditions obtained in comparison with literature methods have typically involved a combination of increased convenience, time savings, greater yields, greater selectivity, the need for less catalyst, or use of a more environmentally benign solvent or reaction medium [7, 8, 15]. 

Steven Ley and his group at Cambridge performed a microwave-assisted Claisen rearrangement of an allylaryl ether, to give the corresponding 2-allylphenolic deriv- 

The radical chain decarboxylation method (see below) has been adapted to a one-carbon homologation procedure for carboxylic acids by trapping the inteimiediate carbon radicals with 

Grignard reagents, and appears both practical and efficient. 

Full details have been given for the conversion of organomercurals (RHgX) into acids (RCO H) by palladium-catalysed 

Zinc iodide catalyses the addition of the tellurium reagent, PhTeSiMe, to lactones (10) leading to lo-telluro-acids (11) after an aqueous work-up yields are between 79 and 98%.. Substantial improvements have been made to the tungstate-catalysed epoxidation of o,8-unsaturated acids which should make a wide range of epoxy-acids (12) more readily available. 

Diacids.- Succinic acids have been obtained from olefins by a 

Asymmetric bromolactonization of the acylproline (76) gives the lactone (77) in good yield and high stereoselectivity (99%). A review article on 

A further example of the remarkable effect on the regiospecificity of alkylation caused by changing a carbanion counterion from lithium to copper has been reported in the elaboration of isoprenoid 2,6-dienoic acids from dienolates of a/3-unsaturated acids, and allyl halides. 

Formation of the trianion (7) using lithium di-isopropylamide as base in preference to LiNH2 NH3 has improved the yields of 3,5,7-triketo-acids obtained on carboxylation of (7). 

Phenylacetic acids have been prepared from 2,2-dichlorostyrenes by sequential hydroboration and oxidation (Cr03-H2S04) of the intermediate trialkyl borane, and benzoyl benzoic acids (8), not readily available by other routes, have been obtained in good yield by treatment of phthalic anhydride with aryl-lithiums at — lOO C. Syntheses of some bicyclo [1,1,0] butane-l-carboxylic acids (9) and a range of cyclopropane-1-carboxylic acids [(10) and (II)] have been described. 1-Hydroxy-cyclopropanecarboxylic acids (13) have been prepared from the hydroxy-cyclobutanone derivatives (12), following bromination and hydrolysis. 

Perfluoro alkanoic acids have been prepared from perfluoro alkyl iodides by carboxylation in the presence of a zinc-copper couple in DMSO, in yields of 50% or greater. 

Interest continues in the conversion of phenols to half esters of c/5,cw-muconic acid (14). Japanese workers have obtained (14) in 44% yield from phenol itself using copper(i) chloride and oxygen in methanol. However, it appears that copper(ii) species are the true catalysts since catechol can be converted to (14) in 80—85% yield in the absence of oxygen using copper(n) salts. The oxidation of phenol to c/. ,c/5 -muconic acid itself has also been effected using peracetic acid with both copper(n) and iron(in) species as catalysts catechol has been identified as an intermediate in the latter case. 

---

This is then a general synthesis for ketones and the corresponding disconnection is... 

An interesting general synthesis using repeating anellation procedures has been developed by E. Vogel (W. Wagemann, 1978). First cyclohepta-3,5,7-triene-l,3-... 

Reaction of perfluoroaLkenes and hypochlorites has been shown to be a general synthesis of perfluoroepoxides (32) (eq. 7). This appears to be the method of choice for the preparation of epoxides from internal fluoroalkenes (38). Excellent yields of HFPO from hexafluoropropylene and sodium hypochlorite using phase-transfer conditions are claimed (34). 

The direct oxidation of fluoroalkenes is also an excellent general synthesis procedure for the preparation of perfluoroepoxides (eq. 8). This method exploits the low reactivity of the epoxide products to both organic and inorganic free radicals. 

Aromatic Hydrazines. A general synthesis for aryUiydraziaes is via diazotization of aromatic amines, followed by reduction of the resulting diazonium salt (18) ... 

A general synthesis of tiisubstituted alkenes containing three different alkyl substituents is achieved by the following methodology (288) ... 

An efficient general synthesis of a-chiral (Z)- and (H)-a1kenes ia high enantiomeric purity is based on the hydroboration of alkynes and 1-bromoaIkynes, respectively, with enantiomericaHy pure IpcR BH readily available by the hydroboration of prochiral alkenes with monoisopiaocampheylborane, followed by crystallization (519). 

CovalentISPoncycIopentadienyl Compounds. The general synthesis of covalent non-Cp compounds, R TiX where R = alkyl or aryl... 

In 1888 Claisen (1888CB1149) first recognized a general synthesis of isoxazoles (283) by the condensation-cyclization of 1,3-diketones (280) with hydroxylamine. It is now generally accepted that the monoxime (281) of the 1,3-diketone and the subsequent 5-hydroxy-isoxazoline (282) are the intermediate products of the reaction. The isolation of the monoxime (281) and 5-hydroxyisoxazoline (282), which were both readily converted into the isoxazole (283) by treatment with acid or base, has been reported (62HC(17)l). 

Peracid oxidation of imines is the most general synthesis of oxaziranes (Section 5.08.4.1.1). Other peroxides and metal catalysis have also been employed. 

Flash thermolysis of compounds of the type (120), derivatives of Meldrum s acid , is a fairly general synthesis of ketenes (Scheme 103). Brown and coworkers (77AJC179) found that the spirooxirane (121) gave ketene, possibly via the expected carbonyloxirane (122) and probably by isomerization of carbenaoxirane (Scheme 104). 

Cyanohydrin trimethylsilyl ethers are generally useful as precursors of ctir-bonyl anion equivalents and as protected forms of aldehydes. Direct conversion of p-anisaldehyde into 0-TRIMETHYLSILYL-4-METH0XYMANDEL0-NITRILE employs a convenient in situ generation of trimethylsilyl cyanide from chlorotnmethylsilane A general synthesis of allemc esters is a variant of the Wittig reaction. Ethyl (triphenylphosphoranylidene)acetate converts pro-pionyl chloride into ETHYL 2,3-PENTADlENOATE. 

An interesting footnote to the general synthesis of macrocyclic crown ether-type esters is found in the work of Ors and Srinivasan . These workers used cinnamate esters and diesters as precursors to large ring lactones. Depending on orientation, either truxil-... 

In 1958 Simmons and Smith described a new and general synthesis of cyclopropanes by treatment of olefins with a reagent prepared from methylene iodide and a zinc-copper couple in ether solution. 

Diketo steroids have been prepared by air oxidation of 3-keto-5i5-steroids in potassium /-butoxide-t-butanoF or by hydrolysis of 4,5-epoxy-3-ketones followed by dehydration. However, the most general synthesis is that used by Camerino et al. to prepare Vketo-A-norandrostanes and pregnanes. Hydroxylation of 17a,20.20,21-bismethylenedioxypregn-... 

Ozonization of A -steroids usually gives complex mixtures (however, see ref. 48). Ozonolysis became a practical step in the general synthesis of B-norsteroids with the discovery that added methanol" (or formaldehyde ) improves yields significantly. Thus, Tanabe and Morisawa prepared 5/ -hydroxy-6/ -formyl-B-norsteroids (74) from cholesterol acetate, dehydroepiandrosterone acetate and pregnenolone acetate in overall yields of 64-74% by the reaction sequence represented below. 

The synthesis of 5-amino-4-carbethoxy-2-benzylthiazole 17 via the reaction of ethyl aminocyanoacetate 15 with methyl dithiophenylacetate 16 provided the first general synthesis of the previously little known 5-aminothiazoles. Similarly, the reaction between aminoacetonitrile 18 and sodium dithiophenylacetate 19 at room temperature gave 5-amino-2-benzylthiazole 20 in excellent yield. 

A general synthesis of phosphonyl thiadiazoles has been recently disclosed starting from the hydrazone 55. The hydrazones were prepared from acyl phosphonates, which in turn were made from acid chlorides 54. Thus treatment of the hydrazone 55 with thionyl chloride in the presence of DMF and sodium chloride provided the thiadiazoles in... 

In their general synthesis of quinoline-2,5,8(lf/)-triones, Avendano and coworkers use this modified protocol to access the key 2,5-dimethoxyanilide systems 11 required in their synthetic plan." For more examples, see reference 11 and references cited within. 

A new general synthesis of 3-substituted derivatives has been reported (99MC13) (Scheme 9). Thus, the nitro group of furoxan 27 underwent a facile hydride replacement on treatment with NaBH4 in EtOH to give 3-monosubstituted furoxans 23. The result of this reaction is independent of the nature of R. 

Scheme 2.3-1 General synthesis of task-specific ionic liquids from l-alkylimidazoles.

In general, isotopic exchange is both expensive and difficult. In the case of many room-temperature ionic liquids, however, the manufacture of deuterated ionic liquids is relatively easily achievable. For example, the general synthesis of l-allcyl-3-methylimidazolium salts is shown in Scheme 4.1-1 [2]. This methodology allows maximum flexibility in the deuteration on the imidazolium cation that is, it can be either ring or side chain deuteration or both. 

The method described is a general synthesis for compounds containing the —CH=CF2 moiety. There is no other simple general... 

The most successful general synthesis of corroles 13 involves the light-induced cyclization of l,19-dideoxybiladienes- c 12 under basic conditions in the presence of oxygen.1-2 6,15-16 The yields of corroles 13 arc in the range of 20-70%.17,18... 

This type of reaction however works only for methylmetallic reagents. A general synthesis of this type of substituted cyclopentenes has been developed employing /T-dimethylamino and P -trimethylammonio-o ,/i-unsaturated sulfones 21. 

Platinum (II) carbenes should be mentioned as <7-bonded organometallics. An important general synthesis by cleavage of an electron-rich alkene affords a pair of isomers, the trans-form isomerizing to the thermodynamically more stable cw-form on heating (Figure 3.61). 

The following Addnl Refs on IPN are of limited distribution 1) Anon, General Synthesis. The Ludion Question, The Ludion Sustentator , Rept No FSTC-HT-23-573-69 (1969) 2) B.H. Bonner, Ullage Requirements... 

A completely different method of synthesis of azo compounds from diazonium salts involving radical intermediates was found by Citterio et al. (1980, 1982 c), Cit-terio and Minisci (1982), and Fontana et al. (1988). It is a new general synthesis of arylazoalkanes based on the addition of an alkyl radical to an arenediazonium ion followed by reduction of the intermediate azo radical cation adduct by a metal salt (Scheme 12-80). The preferred source for the alkyl radical R in this reaction is an alkyl iodide, which gives rise to alkyl radicals cleanly in the presence of an arenediazonium salt and a Ti3+ or Fe2+ salt as in Scheme 12-81. The overall stoichiometric equation is therefore as given in Scheme 12-82. The yields vary between 36% and 79% (with respect to alkyl iodide). 

Scheme 12 General synthesis of 5-dialkylamino-3-ethoxycyclopentadienes 60 from 3-di-alkylamino-l-ethoxypropenylidenechromium complexes 57 and alkynes in a donor solvent. Conditions A pyridine, 55-80 °C, 1.5-4 equiv. of the alkyne B MeCN, 80 °C, slow addition of 2-4 equiv. of the alkyne. For further details see Table 1 [43,44,60,61]...

The preparation of l,6-oxido[10]annulene, described simultaneously by Sondheimer and Shani4 0 and by Vogel, Biskup, Pretzer, and Boll, is illustrative of the rather general synthesis of aromatic 1,6-bridged [10]annulenes starting from 1,4,5,8-tetrahydronaphthalene. Apart from the present compound, the following bridged [10]annulenes have thus far been obtained by this approach l,6-methano[10J-annulene,2-8-9 the ll,ll-dihalo-l,6-methano[10]annulenes,9 10 and 1,6-imino [ 1 OJannulene.11... 

V. A New General Synthesis for Trifluoromethyl Organometallic Compounds and Other Sigma-Bonded Metal Compounds Based on Metal Vapor as a Reagent... 

Scheme 2. Various conditions and steps involving general synthesis of polysaccharide nanoparticles...

---