Professor Tsutomu Ishikawa, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
Professor Ishikawa leads a laboratory of researchers at Chiba University in the fields of drug-oriented organic chemistry, natural product chemistry, guanidine-based organic reactions, synthetic studies on aziridines, and the preparation of new polymer-supported reagents. He has published 30 papers, including “Guanidines in Organic Synthesis” – one of the top 5 most downloaded papers of 2006 in the leading organic chemistry journal Synthesis.

Superbases for Organic Synthesis

Guanidiness, Amidines, Phosphazenes and Related Organocatalysts

John Wiley & Sons

Copyright © 2009 John Wiley & Sons, Ltd
All right reserved.
ISBN: 978-0-470-51800-7

Chapter One

General Aspects of Organosuperbases

Tsutomu Ishikawa Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, Japan

In the field of organic chemistry, a base is generally defined as a reagent capable of abstracting proton to yield a carbanion species. At a basic textbook level, organobases are normally limited to amines, which are categorized as very weak bases according to the above definition. The introduction of an imine function (=NH) to the a-carbon of amines affords more basic amine species, amidines, which correspond structurally to amine equivalents of carboxylic esters (carboxylic acid imidates). Guanidines, which carry three nitrogen functions (one amine and two imines) and correspond to amine equivalents of ortho esters (carbonimidic diamides), show the strongest Brnsted basicity among these amine derivatives. Thus, basicity is proportional to the number of the substituted nitrogen functions at the same carbon atom; representative examples are shown in Figure 1.1. The basicity of guanidine is comparable to the hydroxyl ion (O[H.sup.-]). Basic amino acids, lysine and arginine, have amino and guanidine groups, respectively, at the side chains as additional functional groups and can act as base catalysts responsible for important biological actions, such as enzymatic reactions in living organisms, through hydrogen bonding networks caused by these basic characters. On the other hand, histidine belongings to an acidic amino acid in spite of carrying an imidazole ring involving an amidine function as a partial structure.

The basicity of these amine derivatives is due to the construction of highly effective conjugation system after protonation under reversible conditions; primitively, it is a reflection of the number of canonical forms, especially isoelectronic forms, in the resonance system (Figure 1.2). This is one of the reasons why guanidines are stronger bases than amidines .

Thus, a pentacyclic amidine (vinamidine) and biguanide with a vinylogous conjugation system show very strong basicity, as expected by the above account (Figure 1.3).

An alternative stabilization effect on the protonation to these two bases leading to their highly potential basicity is through bidentate-type hydrogen bond formation as shown in Figure 1.4. Alder also discussed the effects of molecular strain on the Brnsted basicity of amines.

In 1985, Schwesinger introduced phosphazenes (triaminoiminophosphorane skeletons), which contain a phosphorus atom [P(V)] bonded to four nitrogen functions of three amine and one imine substituents, as organobases containing a phosphorus atom. They are classified as [P.sub.n] bases, based on the number (n) of phosphorus atoms in the molecule.

The examples of simple P1 and P4 bases are shown in Figure 1.5. Their basicity is basically reflected by the number of the triaminoiminophosphorane units and, thus, P4 bases, the strongest phosphazene bases, show basicity comparable to organolithium compounds. Schwesinger et al. reported that the strong basicity of phosphazene bases could be caused by the efficient distribution of positive charge through conjugation system in the molecules. However, crystallographic analysis indicates a tetrahedral-like structure around the phosphorus atom in solid state. Phosphazene bases are easily soluble in common organic solvents and stable to not only hydrolysis but also attack by electrophiles owing to their steric bulk.

Verkade discovered proazaphosphatranes (cycloazaphosphines) as alternative phosphorus-containing organobases, in which a P(III) atom bonded to three amino groups is located at the bridge head. The basicity of Verkades bases is comparable to those of P2-type phosphazene bases. The corresponding phosphonium salts formed by protonation on the phosphorus atom are stabilized through effective trans-annular NP bond formation, to which the fourth nitrogen atom located at the alternative bridge head position participates; this result in propellane-type compounds with tricylo[3.3.3]dodecane skeletons, as shown in Figure 1.6.

In 1968, Alder reported the preparation of 1,8-bis(dimethylamino)naphthalene (DMAN) by N-methylation of 1,8-diaminonaphthalene. DMAN shows exceptional proton affinity through bidentate-type coordination by the two dimethylamino groups located at peri position of the naphthalene skeleton, in spite of being categorized as a weakly basic aromatic amine (Figure 1.7). Thus, DMAN is called a proton sponge.

1,8-Bis(tetramethylguanidino)naphthalene (TMGN) and guanidinophosphazenes, such as tris[bis(dimethylamino)methylene]amino-N-tert-butylaminophosphorane [[(tmg).sub.3][N.sup.t]Bu], are designed as hybrid organobases by the introduction of the guanidine function into the proton sponge and phosphazene skeletons, respectively (Figure 1.8).

Computational calculation of their protonaffinities indicates that these new generations are, as expected, stronger than the original ones.

Organic chemists often use the words strong or super as the intensive expression of basic property; however, the criteria are ambiguous and dependent upon the chemists who use the expression. Therefore, the expression such as strong or super is ambiguous and causes confusion among organic chemists. Caubre has proposed the definition of superbases as follows in his excellent review: The term superbases should only be applied to bases resulting from a mixing of two (or more) bases leading to new basic species possessing inherent new properties. The term superbase does not mean a base is thermodynamically and/or kinetically stronger than another, instead it means that a basic reagent is created by combining the characteristics of several different bases. The general equation for the definition of a superbase is illustrated in Scheme 1.1, in which the examples of unimetal superbase introduced by Caubere and a multimetal superbase by Schlosser are given. Thus, the term superbases in general applies to ionic metalcontaining bases acting under irreversible proton abstraction.

One of important and beneficial characteristics of an organic base, especially from the view point of environmental aspects, is the ability of recycling use in repeated reaction, in which reversible proton transfer occurs between the base and a substrate, an acidic counterpart. Thus, powerful organic bases that may be applicable in various organic syntheses as base catalysts have attracted much attention. According to Caubre’s definition, organic superbases should be a mixture of two or more different kinds of amine species and show a new property. In this book nonionic powerful amine derivatives of amidines, guanidines, phosphazenes and Verkades bases with comparable or higher basicity to that of DMAN are arbitrarily classified as organic superbases and discussed on their chemistry due to basic characteristics, mainly focusing on their applications to organic synthesis as potentially recyclable base catalysts. Related intelligent molecules are also discussed.

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