J.; de Armas, P., Efficient domino process based on the catalytic generation of non-metalated, conjugated acetylides in the presence of aldehydes or activated ketones.
One-Pot Synthesis of 1,2,3-Triazoles from Benzyl and Alkyl Halides, Sodium Azide and Alkynes in Water under Transition-Metal-Catalyst Free Reaction Conditions.
The high stability of the acetylide anion makes metal acetylides relatively poor nucleophiles. Thus additions to aldehydes and ketones are usually trouble-free, but less reactive carbonyl compounds and SN2 substrates such as alkyl halides and epoxides often react sluggishly and require harsh conditions, polar cosolvents like HMPA or DMSO, and/or Lewis acid catalysts.
Acetylenes can be introduced into molecules as nucleophiles, and this the usual approach. The reaction below illustrates a common subsequent transformation of the triple bond: reduction to an alkyne, which can be done with either cis or trans stereochemistry.
Although acetylene can be deprotonated to form lithium and sodium acetylides, they are inconvenient to use, and there are some hazards in working with acetylene. Trimethylsilyacetylene or analogs are often used instead, since the silyl group can be readily cleaved under mild conditions. The acetylene "linchpin" strategy is illustrated below in a partial synthesis of Spongistatin
Aldehydes can be converted acetylenes using several methods. Most commonly used is the Corey-Fuchs reaction, followed by a Fritsch-Buttenberg-Wiechell rearrangement. The example below illustrates a very powerful follow-up transformation of the triple bond, a hydrozirconation-bromination sequence.
Lithium acetylides are readily prepared by deprotonation of acetylenes using a variety of organmetallic bases to form Li (BuLi), Mg (iPrMgCl), Zn (NR3, Zn(OTf)) or other metal acetylides.
A Click Chemistry Approach to Glycomimetics: Michael Addition of 2,3,4,6-tetra--acetyl-1-thio-β-D-glucopyranose to 4-deoxy-1,2--isopropylidene-L--pent-4-enopyranos-3-ulose - a Convenient Route to Novel 4-deoxy-(1->5)-5--thiodisaccharides.
via Grignard reagents) - suggests alternative synthesis to Friedel Crafts.In planning a synthetic strategy, apart from devising a means of constructing the carbon skeleton with the required functionality as above, there are other subtle factors, which we must address.(Good summary p169 – 172, 259 – 260, 354 – 359)We will illustrate this approach with examples, starting with synthesis of benzene derivatives. Starting point is usually fairly obvious – simple benzene derivatives or perhaps benzene itself.Reactions are usually straightforward (SEAr) and you will have met most of them before. Synthesis is simplified because the nature of the starting materials is usually clear. Thus, most reactions correspond to the following disconnection:1st decision – which bond to disconnect first!However, we can carry out monobromination on the N-acyl derivative of the amine:then we can remove the protecting group (HO-/H2O) to give the required product.So formally: Is there an alternative route? Try a different FGI!
reduction (NO2 to NH2), oxidation (CH3 to COOH), diazonium chemistry (NH2 N2+ Ar-X). In aromatic chemistry CCBFR revolve around:With aliphatic acyclic and cyclic systems – the process is not always as straightforward – need to consider a greater array of CCBFR’s and FGI’s.We shall discuss possible synthesis later, but we will concentrate on CCBFR in aliphatic systems.Review and extend CCBFR from 1C1Y, in particular:
Aldol and Claisen condensations
Alkylation of -keto esters (RCHOCH2CO2R’)
Grignard reactions And illustrate their use in synthesis. There are several ways of doing this. We shall consider the following: Note
(Not a typical substitution mechanism!) In the main we will be looking at ionic reactions.In CCBFR the carbonyl group is very importantAlso in CCBFR, organometallic compounds are important.e.g.