Secondary from aldehydes

Besides the initiation with the vinyl ether adducts, trimethylsilyl halides in conjunction with oxolane [135] or a carbonyl compound [136-141] also provide an interesting method of end-functionalization. As discussed in Chapter 4, Section V.E.2 (also Figure 9 therein), the a-end group is (CH3)3SiO—, derived from the silyl compound, to be converted into the hydroxyl group [140,141], Depending on the structure of the carbonyl compounds, it is either secondary (from aldehyde) [136-139] or tertiary (from ketone) [137,138,140,141], both of which are difficult to obtain from the vinyl ether adducts (note that the adduct of AcOVE leads to a primary alcohol [30,31]). 

Vinyllithium [917-57-7] can be formed direcdy from vinyl chloride by means of a lithium [7439-93-2] dispersion containing 2 wt % sodium [7440-23-5] at 0—10°C. This compound is a reactive intermediate for the formation of vinyl alcohols from aldehydes, vinyl ketones from organic acids, vinyl sulfides from disulfides, and monosubstituted alkenes from organic halides. It can also be converted to vinylcopper [37616-22-1] or divinylcopper lithium [22903-99-7], which can then be used to introduce a vinyl group stereoselectively into a variety of a, P-unsaturated systems (26), or simply add a vinyl group to other a, P-unsaturated compounds to give y, 5-unsaturated compounds. Vinyllithium reagents can also be converted to secondary alcohols with trialkylb o r ane s. 

Enamines derived from aldehydes can usually be obtained by the reaction of 2 equivalents of a secondary amine with the carbonyl compound, in the presence of anhydrous potassium carbonate, followed by pyrolytic distillation of the aminal with elimination of one of the amine groups (10,15, 30-36). Ketones are directly converted to enamines under the conditions of aminal formation. The azeotropic removal of water with excess aldehyde has also been described (32,37). 

Primary and secondary halides do not perform well, mostly because N-alkylation becomes important, particularly with enamines derived from aldehydes. An alternative method, which gives good yields of alkylation with primary and secondary halides, is alkylation of enamine salts, which are prepared by treating an imine with ethylmagnesium bromide in THF ... 

The addition of Grignard reagents to aldehydes, ketones, and esters is the basis for the synthesis of a wide variety of alcohols, and several examples are given in Scheme 7.3. Primary alcohols can be made from formaldehyde (Entry 1) or, with addition of two carbons, from ethylene oxide (Entry 2). Secondary alcohols are obtained from aldehydes (Entries 3 to 6) or formate esters (Entry 7). Tertiary alcohols can be made from esters (Entries 8 and 9) or ketones (Entry 10). Lactones give diols (Entry 11). Aldehydes can be prepared from trialkyl orthoformate esters (Entries 12 and 13). Ketones can be made from nitriles (Entries 14 and 15), pyridine-2-thiol esters (Entry 16), N-methoxy-A-methyl carboxamides (Entries 17 and 18), or anhydrides (Entry 19). Carboxylic acids are available by reaction with C02 (Entries 20 to 22). Amines can be prepared from imines (Entry 23). Two-step procedures that involve formation and dehydration of alcohols provide routes to certain alkenes (Entries 24 and 25). 

As shown in Table 11 and Scheme 112, a C-H bond of terminal alkynes is activated by an Au(i) species producing gold acetylenide intermediates, which react with immonium ions generated in situ from aldehydes and secondary amines to provide propargylamines in high yields. This reaction proceeds in water with 1 mol.% of Au(i) or Au(m)... 

Secondary allylic amines 184 have been prepared from aldehydes 181 (R1 = H, Me or Ph R2 = Me, Et or H) by the following sequence treatment with an amine R3NH2 (R3 = i-Pr, t-Bu, cyclohexyl or PhCH2) yields an imine 182, which is chlorinated by N-chlorosuccinimide. Dehydrochlorination of the resulting chloro compound with potassium t-butoxide gives an allylic imine 183, which is reduced to the product by means of methanolic sodium borohydride191. 

The acyl radicals obtained by hydrogen abstraction from aldehydes easily attack protonated heteroaromatic bases. With secondary and tertiary acyl radicals decarbonylation competes with the aromatic acylation [Eq. (12)]. 

Although the CuBr/QUINAP system is an effective chiral catalyst in alkynylation of imines or iminiums, one drawback is that enantiopure QUINAP is quite expensive. An analog of QUINAP, PINAP (Figure 5.2), was readily synthesized and found as a very effective chiral ligand in the direct addition of alkynes to iminiums generated from aldehydes and secondary amines in situ (Scheme 5.8). ... 

Secondary amides have the advantage over tertiary amides that they are relatively easy to remove. It is quite difficult to stop the addition products from aldehydes, ketones, amides, epoxides and nitriles cyclizing directly to give a variety of lactone derivatives (by attack of OH on the secondary amide) or lactam derivatives (by attack of the secondary amide on the new electrophihc centre). Thioamides behave similarly . 

On the other hand, the production of desired compounds through reduction of starting material requires the electron donors to be oxidized (reductant). Alcohols are often used not only as a solvent but as the donor to produce useful compounds, e.g., anilines from nitrobenzenes,22) alcohols from aldehydes,23) and secondary amines from the corresponding Schiff bases.24) From the organic synthetic point of view, however, the separation of undesired products, aldehydes or ketones, from the alcohols is necessary unless subsequent reaction processes consume them25,26) or they are easily removed by distillation or other procedures. A recent report has shown that water acts as the electron donor and is converted into 02 in the photocatalytic regio-selective reduction of terpenes mixed with aqueous suspension of Ti02.27,28) It is notable that isolation of the desired product from the reaction mixture is simple in this type of photocatalytic reduction. 

The formation of covalent substrate-catalyst adducts might occur, e.g., by single-step Lewis-acid-Lewis-base interaction or by multi-step reactions such as the formation of enamines from aldehydes and secondary amines. The catalysis of aldol reactions by formation of the donor enamine is a striking example of common mechanisms in enzymatic catalysis and organocatalysis - in class-I aldolases lysine provides the catalytically active amine group whereas typical organocatalysts for this purpose are secondary amines, the most simple being proline (Scheme 2.2). 

Formation of secondary alcohols, RCH(OH)Ar, from aldehydes and arylboronic acids, ArB(OH)2, is catalysed by a range of palladium(O) complexes, but chloroform is required.251 Palladium-chloroform complexes are equally effective, and evidence for (Ph3P)2Pd being converted to palladium(II) intermediates, (Ph3P)2Pd(X)-CHCl2, is presented (X = Cl, then OH). 

The metal lias to a great extent replaced zinc, which was used in 1849 by Frankland in the preparation of paraffin hydrocarbons and the zinc alkyls, and subsequently by Wagner for preparing secondary alcohol from aldehydes, by Saytzeff in preparing tertiary alcohols from ketones, and by Butlerow iu the preparation of both ketones and tertiary alcohols from acid chlorides. 

Among the best enol equivalents for aldehydes are enamines.19 They are stable compounds, easily made from aldehydes 95 and secondary amines, reacting with electrophiles in the same way as enols 96 to give iminium salts 97, hydrolysed to substituted aldehydes 98. 

The reaction of aldehydes and ketones with Grignard reagents is a useful method of synthesising primary, secondary, and tertiary alcohols (Following fig.). Primary alcohols can be obtained from formaldehydes, secondary alcohols can be obtained from aldehydes, and tertiary alcohols can be obtained from ketones. The reaction involves the formation of a carbon-carbon bond and so this is an important way of building up complex organic structures from simple starting materials. 

Aldehydes and ketones when reduced yield alcohols with a hydride ion that is provided by reducing reagents like sodium borohydride or lithiumborohydride. Primary alcohols are obtained from aldehydes and secondary alcohols from ketones. 

Indium trichloride promotes catalytically the addition of alkynylstannanes to aldehydes (Table 25).42 Metallic indium also mediates the same Barbier-type coupling between alkynyl halides and aldehydes or ketones to give secondary or tertiary propargyl alcohols (Table 26). Secondary alcohols can be oxidized in situ according an Oppenauer process.395 Thus, alkynyl ketones have been prepared from aldehydes via an indium-mediated alkynylation reaction followed by an indium-mediated Oppenauer oxidation. They are also obtained via an indium-mediated alkynylation of the relevant acyl chlorides (Table 27).396... 

Such substitutions using lithium amides, secondary and in some cases tertiary amines as nucleophiles, have been introduced in early sixties as the first expedient method for this unique class of compounds. It is relevant that / ,/ -difluoro- and chlorofluorole-fins readily available through modified Wittig reaction from aldehydes constitute also good ynamine precursors. In the past decade, however, the more versatile lithium aminoacetylide method has gained more prominence. Substitution reactions are still used, among others, for phenyl, tert.-butyl, cinnamyl and cyclopropyl ynamines. 

Enamines are formed from aldehydes or ketones with secondary amines... 

Note. Aza-enolates are formed from imines, which can be made only from primary am ines. Enamines are made from aldehydes or ketones with secondary am ines. 

The first general synthesis, which has been useful for the preparation of enamines derived from aldehydes, was discovered by Mannich and Davidsen14. According to this method aldehydes and secondary amines react in the cold in the presence of potassium carbonate to give aminals 1 (equation 1). In many cases the aminal becomes the major product15,16 by the use of two equivalents of the amine. Destructive distillation of the aminal then leads to the enamine. Aminals are thermally stable up to temperatures of about 170 °C in the presence of base, and their decomposition to enamines at lower temperatures is acid-catalysed17. 

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