Molecular Sieves1

(electrocyclic reaction cocatalyst; mild acid catalyst; desiccant)

Form Supplied in: the most common forms are bead, pellet, and powdered solids with cavity sizes of 3, 4, 5 and 10 Å. The bead and pellet forms are adequate for drying solvents, while the powdered form is preferred for use in most reactions.

Preparative Methods: sieves are most effective if activated prior to use by drying under vacuum (<1 mmHg) at 300 °C for at least 15 h.

Handling, Storage, and Precautions: all forms of sieves readily absorb water upon exposure to air and are therefore best stored in a desiccator. Sieves can be recycled by (a) washing well with an organic solvent, (b) drying at 100 °C for several hours, and (c) reactivation at &egt;200 °C. Skin contact should be avoided as the desiccant properties of the sieves cause irritation.

General Information.

Molecular sieves are metal aluminosilicates of the general formula M2/nO.Al2O3.xSiO2.yH2O (where n is the valence of the metal, M) characterized by a regular (zeolite) structure and cavity size which is retained even with loss of hydration.2,3 Although they occur in Nature, most sieves are manufactured commercially as they can be designed with properties specific to their application. Many variations have been synthesized and the field of zeolite design is one of intense investigation.4 The Linde Division of the Union Carbide Corporation is a major supplier of molecular sieves for synthetic organic applications. Of their products, the 3, 4, and 5 Å as well as 13X sieves are the most commonly employed; these differ both in pore size (3, 4, 5, and 10 Å, respectively) and cation constitution (K, Na, Ca, and Na, respectively).5 Thus a sieve appropriate to a specific application can be selected.

Diels-Alder Catalysis.

Whether combined with a Lewis acid or used alone, molecular sieves are powerful accelerators of this concerted process. In the former case, great progress has been made toward combining this reagent with a chiral Lewis acid to induce asymmetry during reaction between two achiral molecules.6-12 This has been achieved through the use of the chiral titanate (1) and achiral auxiliary (2) which aids in coordination of the dienophile (eqs 1 and 2). Not only is this a highly successful method for the enantioselective generation of the stereocenters, but it is also catalytic. The power of this methodology is elegantly demonstrated in eq 2, taken from Narasaka's synthesis of the hydronaphthalene portions of mevinic acids, where this catalyst system is employed to introduce four contiguous chiral centers with complete diastereoselectivity and very high enantioselectivity from an achiral precursor. Although a less dramatic example, eq 3 displays the ability of sieves to function independently as cycloaddition catalysts,13 as attested to by the mild temperature and short reaction time.

Ene Reactions.

Utilization of the reagent in ene reactions parallels its use in Diels-Alder cycloadditions, although the choice of the Lewis acid cocatalyst is substrate dependent. The three most effective chiral metal complexes employed to date are either the tartrate-based titanate (1), titanium-complexed commercially available 1,1-binaphthol (see (R)-1,1-Bi-2,2-naphthotitanium Dichloride), or the more bulky binaphthol-derived system (3) (eqs 4-6).14-16 Performance of these catalytic systems is comparable to those employed in the Diels-Alder reaction in both enantioselectivity and mildness of reaction conditions.

Other Electrocyclic Reactions.

Finally, molecular sieves have been successful in facilitating asymmetric [2 + 2] cycloadditions when (1) is present, and in promoting [3 + 2] dipolar cycloadditions. Again, in the former case, the optical yields are extremely good as can be seen from eqs 7-9.17-20 In the latter case, the sieves generate the nitrile oxide in situ and this species then reacts with the acrylate acceptor to yield the isoxazole (eq 10). Although this method requires a relatively long reaction time, the mild conditions have the advantage of suppressing side reactions, including dimerization of the nitrile oxide, resulting in high yields of very pure material.21

Acid Scavenging.

In addition to their use as cocatalysts, molecular sieves also function as acid scavengers, making them especially suited to the suppression of acid-catalyzed side reactions such as polymerization. For example, they are employed in the preparation of high-purity methacrylic acid esters from methacryloyl chloride and various alcohols (primary, secondary, tertiary, and benzylic).22 This acid-scavenging ability has also proven useful in the direct acylation of acid-sensitive, unreactive tertiary hydroxyl groups and of acid- and base-sensitive amides with acyl chlorides.23,24

Sorbtion.

The reagent's sorbtion ability has been exploited in a wide range of carbonyl and carboxylate transformations. Key to their utility is the inclusion of molecules such as water and small alcohols into the sieve cavities while excluding the larger compounds, thus allowing greater control of equilibria. By this method, ketimines and enamines derived from sterically encumbered precursors are more accessible.25,26 Likewise, triphenylphosphazenes can be obtained by reaction of N-aminotriphenylphosphinime with various aldehydes and ketones.27 Reductive amination of carbonyls proceeds in better yield with molecular sieves present to absorb water.28 When coupled with tertiary amines such as 1,5-Diazabicyclo[4.3.0]non-5-ene or 1,8-Diazabicyclo[5.4.0]undec-7-ene, 3 or 4 Å sieves can effect the alkenation of d-alkoxy-a,b-unsaturated aldehydes efficiently.29,30 Amide synthesis with molecular sieves provides a general, high yielding, and chemoselective route to secondary amides free of byproducts and impurities.31 Transesterification of methyl esters with branched primary, secondary, and tertiary alcohols has been reported with the 5 Å sieve.3 Zeolites have been utilized in the preparation of an asymmetric hydrocyanating agent by reaction with titanate (1) followed by treatment with 2 equiv of Cyanotrimethylsilane at ambient temperature.32,33 Addition of this reagent to aldehydes at -78 °C in toluene provides the corresponding cyanohydrins in yields of 67-92% and optical purities ranging from 61% to 93%.

Acid Catalysis.

The Lewis acid reactivity of this reagent can be applied to Michael-type reactions as shown in eqs 11 and 12.34,35 The resulting ring systems can be further transformed into a variety of useful synthetic building blocks. Molecular sieves can also be coupled with Lewis acids to promote acetal formation and exchange. When used with p-Toluenesulfonic Acid as a cocatalyst, sieves provide a facile synthesis of acetals from carbonyls, not only when primary but also when secondary alcohols are involved.36,37 Employment with Boron Trifluoride Etherate catalyzes exchange between (tributylstannyl)methanol and Dimethoxymethane to produce the useful hydroxymethyl anion equivalent Tri-n-butyl[(methoxymethoxy)methyl]stannane in high yield.38,39

Oxidations.

Titanium silicate molecular sieves have served as catalysts in the selective oxidation of thioethers to sulfoxides.40 They effect this transformation under mild conditions (1 equiv of H2O2 in refluxing acetone) with little over-oxidation to the sulfone. When used as a promoter in Pyridinium Chlorochromate and Pyridinium Dichromate oxidations of nucleoside derivatives, sieves work remarkably well, in contrast to other additives such as Alumina, Celite, or silica gel which fail to accelerate these reactions.41 As drying agents, sieves are a crucial component of the Sharpless catalytic asymmetric epoxidation.42

Miscellaneous Reactions.

The shape selectivity of zeolites has been exploited to selectively brominate either a hindered double bond in the presence of an unhindered double bond or vice versa, depending on the reaction conditions.43 If the hindered and unhindered alkene mixture is allowed to equilibrate prior to bromine addition, bromination of the hindered alkene is greatly favored (up to a 95:5 preference). Conversely, inclusion of the bromine in the sieves followed by addition of the alkene mixture shows opposite selectivity.

Molecular sieves have been employed as acid scavengers in the transition metal-catalyzed synthesis of carboxylic acids and esters from iodides under base-free conditions, as represented in eq 13.44 Another transition metal-catalyzed reaction (eq 14) applies sieves as a cocatalyst with Iron(III) Chloride to form a nonreducing disaccharide in an alternative to the conventional Koenigs-Knorr method.45 In concert with Tin(II) Trifluoromethanesulfonate and 2,4,6-Collidine, molecular sieves promote the coupling of acetobromoglucose with various protected sugar derivatives to form exclusively trans-b-D-glucosides with glucose as the reducing unit.46 Finally, the use of zeolites as cocatalysts in palladium-catalyzed oxidative cyclizations has led to substantial improvements in the diastereoselectivity of these reactions.47,48 This is exemplified in eq 15, which shows only a 17% de in the absence of molecular sieves.


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James C. Lanter

The Ohio State University, Columbus, OH, USA



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