Some Representative Preparations

The original literature records the preparation of many hundreds of spiropyrans and is the place to look first for a specific compound. Some generalities about the best choice of intermediates and reaction conditions have been given in Section 1.2. Presented here, with an emphasis upon manipulative details, are descriptions of preparations of a typical BIPS on a large laboratory scale (in which the condensation intermediates can be observed) a Fischer s base via a Plancher rearrangement, where the reaction and purification are complex and a salicylaldehyde having a group useful for various further transformations. 

The mixture is filtered through a large (4- or 6-liter) fritted funnel (conveniently, much of the supernatant can first be siphoned off) and pressed and sucked as dry as practical. The solid is washed three times each with 2-3 L of ethanol, slurrying it well each time to remove purple streaks. The last runnings of the filtrate will be lightly colored. The solid is air dried in the dark to give 1481 g (85.6% of 1729 g theoretical) of small, dense, light tan sandy crystals, mp 175-7°C (uncorr.) (Notes 8 and 9). 

Note 1. The amount used is adjusted to correspond to the amount of freshly distilled Fischer s Base available see Note 5. 

Note 2. A high-purity material, preferably prepared from 4-nitrophenol, is necessary in order to obtain a directly pure product. Material made by nitration of salicylaldehyde usually contains small amounts of the 3-nitro isomer and gives a reddish-brown BIPS product. The 8-nitroBIPS contaminant will impart a background color to solutions and coatings made from the contaminated spiropyran. 

Note 3. The alcohol must be denatured with other alcohols or hydrocarbons, and not with ketones or aldehydes, which can react with Fischer s Base. 

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Scheme 11.11 gives some representative preparative reactions based on these methods. Entry 1 is an example of the classical procedure. Entry 2 uses crown-ether catalysis. These reactions were conducted in the aromatic reactant as the solvent. In the study cited for Entry 2, it was found that substituted aromatic reactants such as toluene, anisole, and benzonitrile tended to give more ortho substitution product than expected on a statistical basis.180 The nature of this directive effect does not seem to have been studied extensively. Entries 3 and 4 involve in situ decomposition of A-nitrosoamides. Entry 5 is a case of in situ nitrosation. 

A procedure for arylation involving in situ diazotization has also been developed.154 Scheme 11.11 gives some representative preparative methods. 

Branched P3 donor ligands such as MeC(dppm)3, MeP(dppe)2, PhP(dppe)2 and PhP(dppp)2 form distorted square-pyramidal low-spin monomeric [Co(X)2(L)] (X = Cl-, Br-) or [CoX(L)]+ (X = N03-, AcO-, acac-) complexes, e.g. (152), or dimeric trigonal-bipyramidal systems [CoX(L)]2+ (153) in which the low magnetic moment is believed to result from exchange coupling via the X bridges.509 Table 39 gives some representative preparations. Monomeric [Co(X)2(L)] is sensitive towards 02 and is inclined to dissociate to tetrahedral species in solution, whereas the dimeric systems are more stable. 

Some representative preparative reactions are given here and the major cations are listed in Table 12-3. 

Alkylidenehydrazinothiazoles (297) can be prepared either from 2-hydrazinothiazoles (549) or by direct heterocyclization (527). Their characteristic infrared bands have been reported (550). The main mass spectrometric peaks of (4-coumarinyl-2-thiazolyl)hydrazone (302) (Scheme 179) (134, 551) are situated at mle = 361. 244, 243, 118, 216, 202, 174, 117 the proposed interpretation of the fragmentation pattern should, however, be reconsidered. Scheme l80 summarizes some representative reactions of this class of compounds. 

Chemical shifts for some representatives of the less common class of A -pyrazolines are shown in Table 13. These cyclic enehydrazines are also probably puckered (69) however, no X-ray determination nor conformational study has been carried out to solve this problem. Compound (70) is representative of the rare N(l)-unsubstituted A -pyrazolines prepared by Burger et al. (79T389). 

This chapter lists some representative examples of biochemicals and their origins, a brief indication of key techniques used in their purification, and literature references where further details may be found. Simpler low molecular weight compounds, particularly those that may have been prepared by chemical syntheses, e.g. acetic acid, glycine, will be found in Chapter 4. Only a small number of enzymes and proteins are included because of space limitations. The purification of some of the ones that have been included has been described only briefly. The reader is referred to comprehensive texts such as the Methods Enzymol (Academic Press) series which currently runs to more than 344 volumes and The Enzymes (3rd Edn, Academic Press) which runs to 22 volumes for methods of preparation and purification of proteins and enzymes. Leading referenees on proteins will be found in Advances in Protein Chemistry (59 volumes. Academic Press) and on enzymes will be found in Advances in Enzymology (72 volumes, then became Advances in Enzymology and Related Area of Molecular Biology, J Wiley Sons). The Annual Review of Biochemistry (Annual Review Inc. Patio Alto California) also is an excellent source of key references to the up-to-date information on known and new natural compounds, from small molecules, e.g. enzyme cofactors to proteins and nucleic acids. 

Allylmetal reagents which hear alkyl or aryl groups at both termini are stereogenic and usually add aldehydes w ith a high degree of reagent-induced stereoselectivity (Section D.3.3.1.5.1.). Some of these reagents have been prepared in enantiomerically enriched form and used in enantioselective synthesis. Table 4 collects some representative examples. 

The first ruthenium porphyrin alkyls to be reported were prepared from the zerovalent dianion, [Ru(Por)] with iodomethane or iodocthane, giving the ruthe-nium(lV) dialkyl complexes Ru(Por)Me2 or Ru(Por)Et2 (Por = OEP, TTP). Alternatively, the Ru(lV) precursors Ru(Por)X2 react with MeLi or ArLi to produce Ru(Por)Mc2 or Ru(Por)Ar2 (Ar = / -C(,H4X where X = H, Me, OMe, F or Cl) 147-149 The osmium analogues can be prepared by both methods, and Os(Por)R2 where R = Me, Ph and CH2SiMe2 have been reported.Some representative structures are shown in Fig. 5, and the preparation and interconversion of ruthenium porphyrin alkyl and aryl complexes are shown in Scheme 10. 

Maikov et al. [37] prepared a series of C2-symmetric bipyridine-type ligands, the chiral moieties arising from the isoprenoid chiral pool (/3-pinene, 3-carene, 2-carene, or a-pinene, for example). Some representative examples are drawn in Scheme 16 (see 25, 26, 27) and were used as copper ligands of a copper(I) species obtained by an in-situ reduction of Cu(OTf )2 with phenyl-hydrazine. The use of the resulting catalysts in enantioselective cyclopropana-tion proceeded with up to 76% ee (for ligand 27) and high diastereoselectivity (up to 99 1). 

The use of chiral bis(oxazoline) copper catalysts has also been often reported as an efficient and economic way to perform asymmetric hetero-Diels-Alder reactions of carbonyl compounds and imines with conjugated dienes [81], with the main focus on the application of this methodology towards the preparation of biologically valuable synthons [82]. Only some representative examples are listed below. For example, the copper complex 54 (Scheme 26) has been successfully involved in the catalytic hetero Diels-Alder reaction of a substituted cyclohexadiene with ethyl glyoxylate [83], a key step in the total synthesis of (i )-dihydroactinidiolide (Scheme 30). 

With these catalysts, di- and even some tri-ort/io-substituted products could be formed using very low catalyst loading (50 ppm - 0.05 mol%). Some representative examples of the products prepared are shown in Scheme 6.26 [105]. 

Scheme 2.12 shows some representative Mannich reactions. Entries 1 and 2 show the preparation of typical Mannich bases from a ketone, formaldehyde, and a dialkylamine following the classical procedure. Alternatively, formaldehyde equivalents may be used, such as l>is-(di methyl ami no)methane in Entry 3. On treatment with trifluoroacetic acid, this aminal generates the iminium trifluoroacetate as a reactive electrophile. lV,A-(Dimethyl)methylene ammonium iodide is commercially available and is known as Eschenmoser s salt.192 This compound is sufficiently electrophilic to react directly with silyl enol ethers in neutral solution.183 The reagent can be added to a solution of an enolate or enolate precursor, which permits the reaction to be carried out under nonacidic conditions. Entries 4 and 5 illustrate the preparation of Mannich bases using Eschenmoser s salt in reactions with preformed enolates. 

Scheme 2.18 gives some representative olefination reactions of phosphonate anions. Entry 1 represents a typical preparative procedure. Entry 2 involves formation of a 2,4-dienoate ester using an a, 3-unsaturated aldehyde. Diethyl benzylphosphonate can be used in the Wadsworth-Emmons reaction, as illustrated by Entry 3. Entries 4 to 6 show other anion-stabilizing groups. Intramolecular reactions can be used to prepare cycloalkenes.264... 

Some representative Claisen rearrangements are shown in Scheme 6.14. Entry 1 illustrates the application of the Claisen rearrangement in the introduction of a substituent at the junction of two six-membered rings. Introduction of a substituent at this type of position is frequently necessary in the synthesis of steroids and terpenes. In Entry 2, formation and rearrangement of a 2-propenyl ether leads to formation of a methyl ketone. Entry 3 illustrates the use of 3-methoxyisoprene to form the allylic ether. The rearrangement of this type of ether leads to introduction of isoprene structural units into the reaction product. Entry 4 involves an allylic ether prepared by O-alkylation of a (3-keto enolate. Entry 5 was used in the course of synthesis of a diterpene lactone. Entry 6 is a case in which PdCl2 catalyzes both the formation and rearrangement of the reactant. 

Some representative examples. Many crown macrocycles incorporating other heteroatom types besides ether oxygens have been synthesized. In an early preparation of this type, Lehn et al. reported a synthesis for the 04N2-system (175, diaza-18-crown-6) usingthe procedure outlined by [4.5] (Dietrich, Lehn Sauvage, 1969). 

The new heterocyclic system represented by compounds of type 147 (eg. R = Cl), and containing a bis-fused [l,3,4]thiadiazepine moiety, was prepared by cyclocondensation of 1-aminobenzimidazoIe-2-thione with 6-chloropyrimidine-5-carboxaldehydes. Some representatives of the system (e.g. 147, R = NMe2> showed anti-HIV activity <00SC3719>. 

Protonation of alkenyl complexes has been used [56,534,544,545] for generating cationic, electrophilic carbene complexes similar to those obtained by a-abstraction of alkoxide or other leaving groups from alkyl complexes (Section 3.1.2). Some representative examples are sketched in Figure 3.27. Similarly, electron-rich alkynyl complexes can react with electrophiles at the P-position to yield vinylidene complexes [144,546-551]. This approach is one of the most appropriate for the preparation of vinylidene complexes [128]. Figure 3.27 shows illustrative examples of such reactions. 

In Table XVII, some representative examples prepared by the various methods are given. 

Preparatively useful procedures based on acetic anhydride,20 trifluoroacetic anhydride,21 and oxalyl chloride22 have been developed. The latter method, known as Swern oxidation, is currently the most popular and is frequently preferred to Cr(VI) oxidation. Scheme 12.3 gives some representative examples of these methods. Entry 4 is an example of the use of a water-soluble carbodiimide as the activating reagent. The modified carbodiimide facilitates product purification by providing for easy removal of the urea by-product. 

The Knoevengal reaction has been an extremely versatile method to functionalize C-5. Literally hundreds of 5-alkenyl- and 5-alkyl-2,4-oxazolidinedione analogues have been prepared in this manner. Generally, 2-thio-2,4-oxazolidine-dione, 104, is used in these reactions although 179 has been used successfully as well. Some representative examples follow. 

The aim of this chapter is not a detailed description of the technique and instrumentation but to show applications of HPLC in the preparative separation of flavonoids. Some representative examples are given in Table 1.1. In a 1982 review of isolation techniques for flavonoids, preparative HPLC had at that time not been fully exploited. However, the situation is now very different and 80% of all flavonoid isolations contain a HPLC step. Approximately 95% of reported HPLC applications are on octadecylsilyl phases. Both isocratic and gradient conditions are employed. 

Some typical examples of the preparation and properties of some representative polyesters are shown in Table 1. 

Four oxazocine rings and 15 benzoxazocine systems are possible a compilation of the literature on these compounds has been prepared (82H(19)709). Many of these ring systems have been described in patents and rather obscure journals, and in a number of cases the evidence for structural assignments is inadequate. Methods of preparation include cyclization of polyfunctional chains, and ring expansions or rearrangement of several types. Some representative examples of oxazocines and benzoxazocines that have been well characterized are compounds (305)-(310). 

The reaction of a-naphthyl isocyanate with alcohols has been reported to be a convenient analytical method for the preparation of solid derivatives [16-18]. In addition, the by-product dinaphthylurea is very insoluble in hot ligroin (b.p. 100°-120°C). The urethanes are readily soluble in hot ligroin, and on cooling the solution they recrystallize to sharp-melting solids. It is recommended that two recrystallizations be performed to obtain substances for analysis. Primary alcohols react well without the need for heating the reaction mixture. Secondary alcohols require additional heat, and the yields of urethane oft are smaller than when primary alcohols are used. Tertiary alcohols other than /-butyl [17] or /-amyl [17] were not able to react under the conditions used. Table V lists some representative alcohols and their a-naphthylurethane derivatives. 

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