Protic additive

The a-D-glucofuranose derivative 1 was the first reported protic additive used for the chiral modification of an organometallic reagent16. 

The application of organostannanes in rhodium-catalyzed 1,4-addition reactions was first studied by Oi and co-workers.137,137a The treatment of enones or enolates with a slight excess of aryltrimethylstannane and catalytic amounts of [Rh(COD)(MeCN)2]BF4 generates the conjugate addition products in good yields. The use of protic additives enhanced the yield of the reaction (Scheme 48).138... 

More recently, Kobayashi and co-workers reported on Zr-catalyzed additions of ketene and thioketene acetals to a range of aromatic and aliphatic aldehydes (Scheme 6.25) [83], As in the Erker study, the presence of protic additives proved critical here as well. As the example in Scheme 6.25 illustrates, the addition of larger amounts of iPrOH improved the yield and ee it was reported that in the absence of the alcohol additive much lower yield and enantioselectivities" were attained. The proposed catalytic cycle, depicted in Scheme 6.25, provides a plausible rationale for the role of the additive Si transfer is facilitated by iPrOH to regenerate the chiral catalyst. Finally, it is worthy of mention... 

Yet another version of the Zr-catalyzed Mannich process developed by the Kobayashi group is summarized in Scheme 6.29 [78], In this instance, the chiral catalyst (94) is proposed to bear a single binol molecule, where the 2,2 -dibromobinol proves to be the superior choice. Once again, protic additives, particularly H20, prove to be beneficial (see Scheme 6.29). This particular class of catalytic C—C bond formations is not limited to tetrasubstituted ketene acetals as illustrated in Scheme 6.29, less substituted thioace-tals prove to be effective reaction partners as well. 

NEW APPROACH FOR FINDING OPTIMUM CRYSTALLIZATION CONDITION TAYLOR MADE CRYSTALLIZATION WITH PROTIC ADDITIVE... 

In the case of resolution of (RS j-MMT (molecular length=6) with enantiopure MA (molecular length=5), the difference in molecular lengths is one (=1). Therefore water was chosen as a protic additive to make a new hydrogen-bonding network. Thus (5)-MMT was deposited as a less-soluble diastereomeric salt with MA and water molecules (1 1 1 molar ratio).42,43... 

In benzene-, the reaction obeys first-order kinetics and has a small deuterium KIE, /mmh/Atimd =1.3. The rate constant is independent of [02], but protic additives... 

The effect of protic additives was rationalized by the formation of hydrogen-bonded adducts, such as that between benzoic acid and the carbonyl group of the coordinated benzoate, as observed by 1H NMR. Such an adduct would be expected to facilitate the formation of a polar transition state. The reaction rate also increases upon modification of the ligand with anionic groups and in polar solvents. Radical initiators have no effect. 

Studies on catalytic asymmetric aza-Baylis-Hillman reaction has shown that the reaction involves rate-limiting proton transfer in the absence of added protic species, but exhibits no autocatalysis.41 Brpnsted acidic additives lead to substantial rate enhancements through acceleration of the elimination step. Furthermore, it has been found that phosphine catalysts, either alone or in combination with protic additives, can cause racemization of the aza-Baylis-Hillman product by proton exchange at the stereogenic centre. 

Essentially all carbonyl-alkene coupling reactions are carried out in the presence of a proton source, typically an alcohol. The use of a protic additive is... 

Enol Amination. The Cu[(S,5)-t-Bu-box] (OTf)2 complex was found to be optimal for promoting the enantioselective conjugated addition of enolsilanes to azodicarboxylate derivatives (eq 13). This methodology provides an enantioselective catalytic route to differentially protected ot-hydrazino carbonyl compounds. Isomerically pure enolsilanes of aryl ketones, acylpyrroles, and thioesters add to the azo-imide in greater than 95% ee. The use of an alcohol additive was critical to achieve catalyst turnover. Amination of cyclic enolsilanes was also possible. For example, the enolsilane of 2-methylindanone provides the adduct containing a tetrasubstituted stereogenic center in 96% ee and high yield. Acyclic (Z)-enolsilanes react in the presence of a protic additive with enantioselection up to 99%. ... 

Peptide couplings with the sole use of carbodiimides and in the absence of a protic additive are usually restricted to carbamate- or Nps-protectedb l amino acids or to peptide fragments bearing a nonracemizing glycine or proline residue at the C-terminus. In these cases N,N dicyclohexylcarbodiimide (1, DCC) may be employed and is a very cheap reagent, which is also used on an industrial scale. 

The problem of epimerization has not been examined with the insoluble carbodiimides, thus addition of a protic additive noight be imperative. 

Kato, N., Suzuki, M., Kanai, M., Shibasaki, M. General and practical catalytic enantioselective Strecker reaction of keto-imines significant improvement through catalyst tuning by protic additives. Tetrahedron Lett. 2004,45, 3147-3151. 

Lautens M, Fagnou K (2001) Effects of halide ligands and protic additives on enantioselectivity and reactivity in rhodium-catalyzed asymmetric ring-opening reactions. J Am Chem Soc 123 7170-7171... 

Apart from its usefulness for some mechanistic investigations the presence of protic additives may disturb the course of a reaction and change the product distribution. It is this aspect which will be considered here. 

Tuulmels and co-workers have investigated quantitatively the extension ol the induction period by protic additives (waiter, alcohols) 1175.1761. They take as the end ol the induction period the disappearance ol the color ol a trace of added h. 

Scheme 26 Proposed nucleophilic mechanism for Pt-catalyzed hydrophosphination of Michael acceptor alkenes (X = CN or CO2R) formation of byproducts and the effect of protic additives (HY = t-BuOH or H2O)...

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