Synthesis with unsymmetrical

The Larock indole synthesis is the internal alkyne version of the Yamanaka-Sakamoto-Sonogashira indole synthesis presented in Chapter 75. Also known as the Larock heter-oannulation, it affords 2,3-disubstituted indoles, in contrast to 2-snbstituted indoles from the Sonogashira reaction (Scheme 1, eqnations 1-3) [1-12], Like the Sonogashira, the Larock reaction has been of enormous utility in indole synthesis. With unsymmetrical alkynes, the regiochemistry is such that the more bulky group (e.g., t-butyl relative to... 

Base or (Lewis) acid catalysis leads to different products of Friedlander synthesis with unsymmetrical a-CH2 ketones, as exempHfied for the cydocondensation of (2-amino)benzophenone and methyl ethyl ketone Base catalysis (via enolate) gives rise to 2-ethyl-4-phenylquinoHne (80) as main product, while (Lewis) add catalysis (via enol)... 

Since the structures of the Gabriel-Isay condensation products of 5,6-diaminopyrimidines with unsymmetrical 1,2-dicarbonyl or a-substituted monocarbonyl compounds are always ambiguous, the synthesis of 6- and 7-substituted pteridines by an unambiguous approach was and still is a necessity and an important challenge. 

The Hinsberg thiophene synthesis has seen limited use owing to the potential for regioisomeric mixtures when unsymmetrical 1,2-dicarbonyls are condensed with unsymmetrical thiodiacetates. Thus, symmetrically substituted thiophenes are generally prepared in this manner. 

The use of diphenyl hydrazone 33 has been used in the synthesis of pyrazoles under modified conditions where the hydrazine is released in situ. Some reversal of regiochemistry is seen in the reaction with unsymmetrical dicarbonyls. With aryl hydrazine and diphenyl hydrazone, the ratio of 41 to 42 is 22 1 and 5 1, respectively. 

The original Sonogashira reaction uses copper(l) iodide as a co-catalyst, which converts the alkyne in situ into a copper acetylide. In a subsequent transmeta-lation reaction, the copper is replaced by the palladium complex. The reaction mechanism, with respect to the catalytic cycle, largely corresponds to the Heck reaction.Besides the usual aryl and vinyl halides, i.e. bromides and iodides, trifluoromethanesulfonates (triflates) may be employed. The Sonogashira reaction is well-suited for the synthesis of unsymmetrical bis-2xy ethynes, e.g. 23, which can be prepared as outlined in the following scheme, in a one-pot reaction by applying the so-called sila-Sonogashira reaction ... 

This reaction, which is named after W. Williamson, is the most important method for the synthesis of unsymmetrical ethers 3. For this purpose an alkoxide or phenoxide 1 is reacted with an alkyl halide 2 (with R = alkyl, allyl or benzyl). Symmetrical ethers can of course also be prepared by this route, but are accessible by other routes as well. 

With unsymmetrical cyclic ketones, however, mixtures due to similar migratory aptitudes of the different groups are obtained (Table 13, Nos. 2, 3). The rearrangement has also been used as key step in a d,/-muscone synthesis (Table 13, No. 4). 

Tripylborane is an interesting reagent which resembles thexylborane. One of the important uses of thexylborane lies in the synthesis of unsymmetrical thexyldialkylboranes which can then be used in the synthesis of unsymmetrical ketones. However, the reaction is only successful if the alkene used in the first hydroboration step is an internal alkene. Simple terminal alkenes such as 1-hexene react too rapidly with the initially formed thexylmonoalkylborane to allow the reaction to be stopped at that stage. Therefore, mixtures of products result (ref. 27). 

The asymmetric synthesis of unsymmetrical vicinal diamines by samarium diiodide induced reductive coupling of nitrones derived from aUphatic aldehydes with optically pure N-tert-butanesulfinyl aromatic imines has been recently reported [41]. For example, the reaction between nitrone 55 and... 

Of further particular interest was that the crystallographic results on 2,5-DSP and poly-2,5-DSP had pointed out a very important future possibility that an absolute asymmetric synthesis could be achieved if any prochiral molecule, e.g. an unsymmetrical diolefin derivative, could be crystallized into a chiral crystal and if the reaction of the chiral crystal proceeded in the same manner as the 2,5-DSP crystal with retention of the crystal lattice (Wegner, 1972, 1973). Such types of absolute asymmetric synthesis with a high enantiomeric yield have now been performed by topochemical [2+2] photoreaction of unsymmetric diolefin crystals (Addadi etal., 1982 Hasegawa et al., 1990 Chung et al., 1991a,b). 

The direct preparation of arylboronic esters from aryl halides or triflates now allows a one-pot, two-step procedure for the synthesis of unsymmetrical biaryls (Scheme 1-41) [147]. The synthesis of biaryls is readily carried out in the same flask when the first coupling of the triflate with diboron 82 is followed by the next reaction with another triflate. The synthesis of naturally occurring biflavanoids and the couphng of N-(phenylfluorenyl)amino carbonyl compounds to polymeric supports are reported [154]. 

With neutral phosphoric monoimidazolides, which are more reactive than the ionic species the reaction time for phosphorylation of an alcohol is reduced. A one-flask synthesis of unsymmetrical phosphoric diesters from N-( 1,2-dimethylethylenedioxy-phosphoryl)imidazole, prepared from di(l,2-dimethylethylene)pyrophosphate and imidazole, is presented below [103,[11]... 

Unsymmetric compartmental ligands that allow for the controlled synthesis of unsymmetric Ni2 or heterobimetallic NiM complexes have received particular attention.1876,1892 A wide range of such ligands derived particularly from 2-hydroxy-3-hydroxymethyl-5-methylbenzaldehyde and 2-hydroxy-3-hydroxymethyl-bromo-benzaldehyde has now been prepared and used for Ni com-plexation. These ligands have monopodal iminic pendent arms and either mono- or dipodal aminic pendent arms and the terminal donors of the pendent arms can be provided by pyridine, imidazole, and tertiary amino groups.1893-1897 Complexes are usually prepared by reaction of the requisite Ni11 salts with the preformed ligand. 

Unsymmetrical compartmental pyrazole ligands with different chelating side arms in the 3- and 5-positions have been developed for the controlled synthesis of unsymmetric dinickel(II)... 

The key intermediates for the synthesis of unsymmetrical, heterocyclic oxo-squaraines are the mono-squaraines (semi-squaraines) shown in Fig. 5. These intermediates can be synthesized via condensation of dialkylsquarate with an equimolar amount of methylene base [51]. The obtained alkoxy-mono-squaraines are then reacted with the second methylene base to yield unsymmetrical oxo-squaraines. These mono-squaraine intermediates display a higher reactivity compared to squaric acid or its esters they allow the synthesis of the corresponding... 

A three-component coumarin synthesis involves the Pd-catalysed coupling of o-iodophenols with alkynes and subsequent insertion of carbon monoxide. With internal alkynes, pyridine is the crucial base for successful annulation the regioselectivity with unsymmetrically substituted alkynes is only moderate (Scheme 43) . 

Prior to his work with internal alkynes, Larock found that o-thallated acetanilide undergoes Pd-catalyzed reactions with vinyl bromide and allyl chloride to give (V-acetylindole and N-acetyl-2-methylindole each in 45% yield [409]. In an extension to reactions of internal alkynes with imines of o-iodoaniline, Larock reported a concise synthesis of isoindolo[2,l-a]indoles 313 and 314 [410]. The regioselectivity was excellent with unsymmetrical alkynes. 

Synthesis. The unsymmetrical norbomadiene substituted pz (34) (Scheme 7) (34%) (36), was prepared by a mixed cyclization of benzonorbomadiene phthalonitrile (32) (93) with a sevenfold excess of dipropylmaleonitrile (33) (28) (Scheme 7). 

Miscellaneous. The reaction of the aminophosphonium salt (156) with thiols and alkoxides affords a convenient, high-yield, single-step synthesis of unsymmetrical thioethers.141 The key intermediate is the alkoxyphosphonium salt (157), which undergoes nucleophilic attack by RS- at the alkoxy carbon. 

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