Amides unsaturated, metathesis

Tungsten aryloxo complexes have been shown to catalyze the intramolecular metathesis reactions of di- and tri-substituted co-unsaturated glucose and glucosamine derivatives to yield bicyclic carbohydrate-based compounds containing 12- and 14-membered rings [108,214,215]. An example is shown in Eq. 37. The tolerance for amides and esters is noteworthy, as are the yields and the size of the rings that are formed. 

It is important to note that the Ru-catalyzed RCM and the Zr-catalyzed resolution can be carried out in a single vessel, without recourse to intermediate isolation. The unsaturated medium-ring amides 5 and 8 can be subjected to 10 mol% of the chiral Zr catalyst and EtMgCl, in the same flask, to afford unsaturated 6 and 9 in 81% and 54% isolated yield, respectively. As depicted in Eq. 1, a similar tandem diene metathesis/ethylmagnesation can be carried out on ether 10, leading to the formation of unsaturated chiral alcohol 11 in 73% yield and >99% ee. 

These alkylation processes become particularly attractive when used in conjunction with powerful catalytic ring-dosing metathesis protocols [11]. The requisite starting materials can be readily prepared catalytically and in high yields. The examples shown in Scheme 6.3 demonstrate that synthesis of the heterocyclic alkene and subsequent alkylation can be carried out in a single vessel to afford unsaturated alcohols and amides in good yields and with >99% ee (GLC analysis) [12],... 

The ring-closing metathesis (RCM) approach is useful for the synthesis of indolizidinone derivatives. The procedures published are based on the use of compound 103, an amide of a pyrrolidine derivative bearing on C-l the second unsaturated branch ready for the cyclization. The reaction proceeded smoothly with high yields in both examples (Scheme 27) <2001JOC9056, 2004JOC3968>. 

Ring-closing metathesis seems particularly well suited to be combined with Passerini and Ugi reactions, due to the low reactivity of the needed additional olefin functions, which avoid any interference with the MCR reaction. However, some limitations are present. First of all, it is not easy to embed diversity into the two olefinic components, because this leads in most cases to chiral substrates whose obtainment in enantiomerically pure form may not be trivial. Second, some unsaturated substrates, such as enamines, acrolein and p,y-unsaturated aldehydes cannot be used as component for the IMCR, whereas a,p-unsaturated amides are not ideal for RCM processes. Finally, the introduction of the double bond into the isocyanide component is possible only if 9-membered or larger rings are to be synthesized (see below). The smallest ring that has been synthesized to date is the 6-membered one represented by dihydropyridones 167, obtained starting with allylamine and bute-noic acid [133] (Fig. 33). Note that, for the reasons explained earlier, compounds... 

The CM of olefins bearing electron-withdrawing functionalities, such as a,/ -unsaturated aldehydes, ketones, amides, and esters, allows for the direct installment of olefin functionality, which can either be retained or utilized as a synthetic handle for further elaboration. The poor nucleophilicity of electron-deficient olefins makes them challenging substrates for olefin CM. As a result, these substrates must generally be paired with more electron-rich crosspartners to proceed. In one of the initial reports in this area, Crowe and Goldberg found that acrylonitrile could participate in CM reactions with various terminal olefins using catalyst 1 (Equation (2))." Acrylonitrile was found not to be active in secondary metathesis isomerization, and no homodimer formation was observed, making it a type III olefin. In addition, as mentioned in Section 11.06.3.2, this reaction represents one of the few examples of Z-selectivity in CM. Subsequent to this report, ruthenium complexes 6 and 7a were also observed to function as competent catalysts for acrylonitrile... 

The palladium catalysed formation of indole derivatives has been extended by Grigg, who used carbon monoxide and unsaturated amines to trap the palladium complex formed in the insertion step. Reaction 3.10. provides an example of such a transformation. The amides were converted to the cyclic derivatives using ring closing metathesis.13... 

This cross-reaction is general for unsaturated esters, ketones, aldehydes and amides. In these cases, the dominant product is the cross-product even when the reactions are run with a 1 1 stoichiometry. In general, if one of the cross partners is slow to homodimerize but will take part in metathesis, the reaction is driven to the cross product. This observation holds for a wide variety of electron-deficient (and sterically hindered) olefins. For example, a,/3-unsaturated ketones, aldehydes and amides all undergo clean and efficient cross metathesis reactions, [41] with the dominant product in all cases being the E isomer (Eqs. 6.22 and 6.23). 

Cross-metathesis of conjugated electron-deficient alkenes such as a,ft-unsatur-ated esters, ketones, aldehydes, and amides often give high cross-product/dimer ratios due to the slow rate of dimerization of these substrates (Eq. 171). When this occurs, the cross-product is dominant even when the reactions are performed with a 1 1 stoichiometry of the reactants.330 When one of the alkene partners homodimerizes slowly, such as happens with electron-deficient and sterically hindered alkenes, the reaction is driven to the cross-product. With respect to the stereochemistry of the reaction, the E-isomer is obtained with electron-deficient alkenes (Eq. 171), and the E/Z ratio may also vary depending on the types of substituents present on the reactants. 

The first approach involved the amide formation with the 10-undecanoic acid (3) and the diamine 4 to create the monomer 5 which was then polymerized further by metathesis, as shown in Figure 14.6. A second approach to the synthesis of polyamide Nylon involved forming the polymer using the diacid 6, which was polymerized with the aliphatic diamine 4 in the presence of strong bases. Both these methods were able to use the biorenewable starting material and a metathesis step, and both led to the production of the unsaturated PAX, 20 polyamide [39]. Overall, Meier and coworkers found that the synthesis of the diacid first, followed by polymerization with TBD (1,5,7-triazabicyclo[4.4.0]dec-l-ene), was the most efficient route and had some advantages over classical methods, such as avoiding the use of an acid chloride. 

Mutlu H, Meier MAR. 2009. Unsaturated PA X,20 from Renewable Resources via Metathesis and Catalytic Amidation. Macromol Chem Phys 210 1019-1025. 

Alkaloids with polycyclic skdetal frameworks are, when it comes to their synthesis, excellent candidates for RCM. Illustrative are the indolizidines rhynchophylline (43) and its C(7)-epimer ixo-rhynchophylhne (44), both isolated from the plant Uncaria rhynchophytta (Rubiaceae) [26]. Deiters total synthesis of 43 and 44 started with the efficient construction of diallylamine 39 via amide formation between indole-3-acetic acid (38) and diallylamine (Scheme 2.10). One-pot RCM-carbomagnesation of 39 was smoothly achieved with only 1 mol% of [Ruj-I catalyst and 4 equiv. of EtMgCl to afford the 2-ethyl-3-butene-amine derivative in 71% yield. It appeared that the electron-withdrawing carbonyl moiety was critical to the success of the RCM-carbomagnesation steps. Amide reduction and subsequent treatment with acryloyl chloride dehvered the second metathesis precursor 40. Cyclization with [Ruj-I (5 mol%) then furnished the a,j8-unsaturated lactam 41 in a high yield of 91%. Continuation of the total synthesis of alkaloids 43 and 44 included a Bischler-Napieralski cychzation (42) and subsequent rearrangement into the oxindole framework. 

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