Methylene compounds quaternary

Michael condensations are catalyzed by alkaU alkoxides, tertiary amines, and quaternary bases and salts. Active methylene compounds and aUphatic nitro compounds add to form P-substituted propionates. These addition reactions are frequendy reversible at high temperatures. Exceptions are the tertiary nitro adducts which are converted to olefins at elevated temperatures (24). 

Early procedures used stoichiometric amounts of the quaternary ammonium catalyst to solubilize the preformed sodium or potassium salts of the active methylene compounds (prepared under anhydrous conditions) in the organic medium. Subsequently, liquidrliquid two-phase procedures using catalytic amounts of the quaternary ammonium salts were developed, and solidrliquid two-phase conditions have been used to improve yields. In some cases, only the solidrliquid two-phase procedures are effective. 

Quaternary ammonium salts of heterocyclic compounds have been used in liquid-liquid phase-transfer syntheses. When these compounds are achiral, they show a behavior very similar to that of other quaternary ammonium salts. For example, 2-dialkylamino-l-alkylpyridinium tetrafluoroborates have been used by Tanaka and Mukayama282 in the alkylation of active methylene compounds PhCH2CN, PhCH(Et)CN, and PhCH(Me)COPh. However, comparative studies of the efficiency of the catalysts show that alkylpyridinium bromides283 or N-alkyl-Af-benzyl-piperidinium chloride284 have a smaller catalytic activity compared to tetraalkylammonium halides. McIntosh285 has described the preparation of azapropellane salts 186 as potential chiral phase transfer catalysts. 

Higher Vinylogs of Cyanine Dyes. Pentamethinecyanine dyes can be obtained analogously to trimethinecyanine dyes from the methyl-substituted heterocyclic quaternary salts by condensation. Heptamethinecyanine dyes are obtained by treating the quaternary salts of 2- or 4 -m e t h y 1 - A - h c t c r o cy c 1 e s or the corresponding methylene compounds with pentamethinestreptocyanine dyes. 

Recently, the transition-metal-catalyzed addition of active methylene C-H bonds to electron-deficient olefins having a carbonyl, a nitrile, or a sulfonyl group has been extensively studied by several research groups. In particular, the asymmetric version of this type of catalytic reaction provides a new route to the enantioselective construction of quaternary carbon centers [88]. Another topic of recent interest is the catalytic addition of active methylene C-H bonds to acetylenes, allenes, conjugate ene-ynes, and nitrile C-N triple bonds. In this section, the ruthenium-catalyzed addition of C-H bonds in active methylene compounds to carbonyl groups and C-C multiple bonds is described. 

Either the tertiary amine or the quaternary ammonium salt can be stored as a stable equivalent of the exo-methylene compound. In our first example, the Mannich base with dimethylamine is first methylated with methyl iodide and then added to the conjugate addition reaction. Elimination of trimethylamine, which escapes from the refluxing ethanol as a gas, reveals the exo-methylene ketone in which the methylene group is exo to a chain. Fast conjugate addition of the stabilized enolate of diethyl malonate produces the product. 

Hesse has described an exaltolide (cyclopentadecanolide) (134 Scheme 42) synthesis starting from the readily available 2-cyanocyclododecanone (130). The latter is converted to the quaternary ammonium salt (131), which undergoes fragmentation under mild conditions to provide the lactone (133) via the lactole anion (132). The methylene compound (133) exhibits similar musk odor, as does (134). 

In the presence of NaNH2 benzylic quaternary ammonium salts generally lead to the Sommelet-Hauser rearrangement (refs. 90, 92-104). An ortho alkylation takes place via an exomethylene intermediate. If the two ortho and ortho positions are methylated, the methylene compounds can be isolated (refs. 92, 93). The first anion formed in this reaction can be trapped at a very low temperature (-80 °C) in an aldol reaction for example (ref. 103). At -30°C the isomerization and the rearrangement occur (Fig. 16). 

Usually, the aqueous salt could be too hydrophilic to allow the quaternary salt to dissolve in the organic phase, and resided exclusively in the aqueous phase anion exchange occured at or near the interface. The mechanism is applied to carbanion reactions, carbene reactions, condensation of polymerization, and C-alkylation of active methylene compounds such as activated benzylic nitriles, activated hydrocarbons, and activated ketones under PTC/OH. In most cases, the reaction involves the Q OH complex because QOH is highly hydrophilic and has extremely low solubility in the organic phase. 

Although many phenylacetamides were successfully alkylated with 2-bromo-pyridine, the corresponding thioamides were not. The pyrrolidone XI-14was employed as the active methylene compound in a condensation with 2-bromopyridines. ° Treatment of quaternary salts of halo- or alkoxy-pyridines... 

Dialkylation is sometimes useful, as in the synthesis of activated cyclopropanes (9) from 1,2-dibromoethane and various acidic methylene compounds (8) (Scheme 3), with in situ saponification of ester functions, and catalysed by another commonly used quaternary ion, benzyltriethyl ammonium. 

Catalysis of reactions between components of immiscible aqueous and organic solutions by quaternary ammonium salts was first reported in 1951 and was brought to the attention of synthetic chemists by Makosza and by Starks.Makosza investigated the alkylation of active methylene compounds such as phenylacetonitrile with benzyltriethylammonium chloride in the presence of concentrated aqueous sodium hydroxide (eq 1). Starks used more lipophilic onium... 

Aminopyridine gives, with benzoquinone, the cyclic product (72). When reactive methylene compounds are also present, further reaction can occur, as in the formation of (73) from benzoquinone, pyridine and acetylacetone 4 and of (74) from a-naphthoquinone, pyridine and aceto-acetic ester s. 1,4-Naphthoquinonedibenzenesulphonimide behaves like naphthoquinone in forming a quaternary salt with pyridine and hydrochloric acid " . 

In the presence of chiral quaternary ammonium salt catalysts, not only amino acid-derived Schiff bases but also other active methine and methylene compounds can be alkylated under biphasic conditions in an enantioselective manner as exemplified in the first report on the successful... 

Studied and to alert the reader to key problems that need to be addressed in such reactions. Three main steps are required in this process [2f] (1) deprotonation of the active methylene compound with base, which genoally occurs at the inter ce between the two layers (liquid-liquid (L/L) or solid-liquid (SifL) PTC) (2) ion-exchange of the anion (A ) with the cation of the chiral quaternary ammonium ctMnpound (quat) to form a lipt hilic ion-pair (D), which then either reacts from the interface (step 3) or is extracted into the bulk organic phase and (3) creation of the new chiral centa in product P" by all lation of the ion-pair (D) with concomitant regeneration of the catalyst. 

A relative of the latter class of compounds are the macrotricyclic quaternary ammonium salts which have been reported by Schmidtchen. The bridges may contain either methylenes or ethyleneoxy units and the nitrogens are quaternarized. The underlying principle is to provide a cavity suitable for solvating or at least trapping anions. Schmidtchen presents evidence which suggests the formation of halide inclusion complexes. The synthesis of these molecules is accomplished along more or less traditional lines Such a species is illustrated above as compound 19. 

The dialkylaminomethyl ketones formed in the Mannich reaction are useful synthetic intermediates.184 Thermal elimination of the amines or the derived quaternary salts provides a-methylene carbonyl compounds. 

Organic compounds contain four types of carbon atom methyl, methylene, methine and quaternary. And so if we simply record the spectrum as we would a proton spectrum, the result will be a series of quartets, triplets, doublets and singlets, each associated with a carbon-proton one-bond coupling constant of between 125 and 250 Hz. If we are dealing with a complex molecule, these multiplets will overlap and give us spectra which are almost impossible to analyse. In addition, coupling interactions over two or more bonds complicate the picture still further. 

The reaction of 5-[2-(iV,./V-dimethylamino)ethyl]-l,2,4-oxadiazole with methyl iodide forms the quaternary ammonium salt 170 (Scheme 22), which undergoes elimination in the presence of base (diisopropylethylamine (DIEA), TEA, l,8-diazabicyclo[4.3.0]undec-7-ene, etc.) to form an intermediate 5-vinyl-l,2,4-oxadiazole 171, which undergoes in situ Michael addition with nucleophiles to furnish the Michael adducts 172. As an example, also shown in Scheme 22, 3-hydroxy-pyrrolidine allows the synthesis of compound 172a in 97% yield. Mesylation followed by deprotonation of the 1,2,4-oxadiazole methylene at C-5 enables Sn2 displacement of the mesylate to give the 5-azabicycloheptyl derivative 173, which is a potent muscarinic agonist <1996JOC3228>. 

The second new compound linearilin (13) was an amorphous powder with [a] = -f 18.35° The HRMS of the compound m z 469.2669 and NMR with one methyl, four methoxy, six methylene, nine methine and four quaternary carbon atoms indicated the molecular formula C Hj NOg. 

C-21 methyl protons. The C-3 and C-16 melhine protons appeared at 8 3.82 and 4.99, respectively. The downfield chemical shift values of C-3 and C-6 methine protons were indicative of the presence of geminal oxygen functionahties. The C-6 resonated at 8 5.36 while the sp hybridized C-28 methylene protons resonated as two singlets, integrating for one proton each, at 8 5.56 and 6.06. A combination of H and C-NMR spectral data indicated to us that compound 11 has a steroidal skeleton. A detailed interpretation of broad C-NMR and DEPT spectra revealed the presence of three metlyl, ten methylene, eight methine and five quaternary carbon atoms in 11. The stereochemistry at various chiral centers was estabhshed with the aid of NOESY spectrum. 

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