Synthetic Application

The third synthetic application is demonstrated by alkenylation of 5-iodouracil and 5-iodouridine [Eq.(15)]. These iodides were allowed to couple with alkenyl(difluoro)methylsilanes to afford 5-alkenyl-substituted uracils and uridines, respectively, which are potent antitumor or antiviral agents. It is noteworthy that unprotected 5-iodo-2-deoxyuridine could be converted into the corresponding cross- 

Synthesis and applications of functionalized siloles have become ever more attractive in recent years, since these types of compounds have practical applications including Jt-conjugated organic materials of electronic and optoelectronic devices [41,42]. As well documented, substituents on siloles have a remarkable impact on the property of siloles. Therefore, it is important to realize the multi-substituted pattern of produced functional siloles. When treated with a wide variety of electrophiles such as iodine, methyl iodide, ketone, aldehyde, CO2, chlorosilane, or acid 

Due to their availability, haloarenes are frequently used for synthetic reactions, and when nucleophilic attack is rate limiting, as is usually the case, the reactivity order is F C1, Br I. Although reaction can occur in unactivated systems, this requires the use of high temperatures and/or pressures and may be aided by metal catalysts. Thus, reaction of chlorobenzene with aqueous sodium hydroxide or ammonia can yield phenol and aniline, respectively. In systems containing one or more EWGs, reaction with alkoxides or phenoxides can be used to form alkyl aryl ethers and 

The aryl ether linkage is important in many natural products and pharmaceuticals, including the antibiotic vancomycin [196]. Diaryl ethers have been efficiently prepared by the coupling of fluo-robenzonitriles with a series of phenols in DMSO using potassium carbonate as a base catalyst and with microwave irradiation [197]. A DPT study of the reaction of alkali metal phenoxides with fluo-robenzenes indicated that the role of the metal cation is to aid the binding of the aryl halide and to facilitate fluoride displacement [198]. 

Ort/io-selectivity is generally observed in the reactions of 2,4-dichloro- and 2,4-difluoro-nitrobenzene with alkoxide and thiophenoxide ions [199]. Also in less activated systems, nucleophiles generated from phenols and thiophenols with potassium fluoride-alumina and 18-crown-6-polyether will react in DMSO with cyano- or nitro-substituted fluoro- or chloro-benzenes [200]. Interestingly, the reaction of difluorobenzenes with two diffoent alcohols can occur sequentially. Introduction of the first etho function deactivates the ring, and use of more forcing conditions allows substitution of the second fluorine [201]. Consecutive displacements of fluorine and nitro groups have been observed in the reaction of ort/io-fluoronitrobenzene with chiral acyl bicyclic lactones in a highly enantioselective synthesis of spirooxindoles [202]. 

Alkyl- and aryl-thiolates are genaully more reactive than their oxygen equivalents and will readily replace halogens under mild conditions to give thioethers. Hence, the use of an alcohol solvent rather than DMSO may be possible [203]. 

It should also be noted that copper-catalyzed Ullmann-type coupling of aryl halides with amines yields substituted products [206], and reaction with diphenylamine has been used to form triaryl-amines [207], Triarylamines may also be formed in a variation of the Meyers reaction [47] by displacement by lithium amides of fluoro- or methoxy-substituents activated by an ort/io-ester function [208], The oxidation of a-adducts is discussed in Chapter 11, but it should also be mentioned that aminated products may also be produced by the oxidation of adducts formed by the addition of amide or alkylamide ions at ring carbon atoms carrying hydrogen [209]. 

Intramolecular hydrogen abstraction has been successfully utilized in a number of interesting synthetic preparations. In general the recombination of the biradical resulting from intramolecular hydrogen abstraction to form a cyclobutanol has received more attention from the point of view of photo- 

The photolysis of methylisopulegon in cyclohexane by Cookson et al. resulted in the interesting methylene cyclobutanol shown below in a 70% 

Padwa and Eisenberg used this reaction to obtain the following highly strained tricyclo compound  

The photolysis of the following steroid system resulted in two products corresponding to the Norrish type II reaction and one product due to -cleavage (Norrish type I cleavage)  

Intramolecular hydrogen transfer is also important in the photolysis of large-ring cycloalkanones such as shown below. The singlet state is thought to be the reactive species in these reactions  

Ketone 42 is readily available from fructose and is a highly effective epoxidation catalyst. Various applications of this ketone have been reported, and some of them are highlighted hereafter. 

In their two-directional synthesis of (—)-longilene peroxide, Morimoto and coworkers reported that diene 77 was epoxidized with ketone ewt-42 to give tricyclic compound 78 after cydization. Compound 78 was then transformed into (—)-long- 

As illustrated by the above examples and others [82], the epoxidation with ketone 42 has been utilized in various syntheses. The reaction can be applied to rather complex substrates with various functional groups. When more than one alkene is present, certain alkenes can often be selectively epoxidized with carefully controlled reaction 

For leading reviews on titanium-catalyzed asymmetric epoxidation of allylic alcohols, see (a) Johnson, R.A. and Sharpless, K.B. (1993) Catalytic Asymmetric Synthesis (ed. I. Ojima), VCH, New York, p. 103 (b) Katsuki, T. and Martin, V.S. (1996) Org. 

For leading references on vanadium-catalyzed asymmetric epoxidation of allylic alcohols, see (a) Murase, N., Hoshino, Y, Oishi, M and Yamamoto, H. (1999) J. Org. Chem., 64,338 (b) Hoshino, Y. and Yamamoto, H. (2000) J. Am. Chem. 

Aromatic Claisen rearrangement is an attractive means for the construction of some usefril functional groups. In this section, applications of the aromatic Claisen rearrangement to the syntheses of complex molecules are described. 

In this chapter we shall review the aqueous hydroformylation of substrates other than simple terminal alkenes. Of course, preparation of butyraldehyde or plasticizer alcohols is also a synthetic application but in the following a few examples are given for application of hydroformylation in reactions of more complex substrates and in synthesis of more elaborate molecules. Most of these chemical transformations could also be effected in one-phase reactions (organic or aqueous), however, the biphasic variants were not inferior in chemistry and offered the advantage of easy catalyst-product separation. 

Under the conditions used (150 °C, 40 bar syngas) there is a chance for reaction of [CoH(CO)3(TPPTS)J to yield [CoH(CO)4] which moves to the organic phase. In addition to some cobalt leaching (a real problem with this system) [CoH(CO)4] certainly contributes to the overall hydroformylation [157], 

Internal olefins (2-butene, 2-hexene) were also successfully hydroformylated in water with complexes prepared in situ from [PtCl2(COD)] and the tetrasulfonated diphosphines 37 at 100 °C and 80 bar syngas [148,149]. The same catalysts were suitable for the hydroformylation of 2- and 3-pentenoic acids and trans-2-pentenenitrile, too [150], The co- 

Industrial hydroformylation of allyl alcohol employs [RhH(CO)(PPh3)3] as catalyst (Kuraray see also 4.1.1.4). In an aqueous solution K[Ru(EDTA-H)C1] catalyzed both the water gas shift and hydroformylation under 10-40 bar CO at 100-130 °C. The major product was y-hydroxybutyraldehyde (35%) but large amounts of y-butyrolactone and dihydroI uran were also produced [151]. 

Taking into account the various and complex effects of solvophobic interactions, it is of interest to examine whether solvophobic properties of water and water-like solvents may be used as driving forces for synthetic purposes at high pressure. From a preparative f oint of view, it is clear that the reactants must resist the action of water and be present in high concentration. This leads to heterogeneous conditions at least for aqueous solutions. These conditions also prevail at higher pressure despite the salting-in effect of pressure. The influence of reactant concentration is shown in Fig. 10.8 (Diels-Alder reaction) and in Fig. 10.9 (Michael-like reaction) [77]. 

In Fig. 10.8 the yield increases rapidly at low reactant concentration and stabilizes at a given value depending on reaction conditions, pressure for example. This can be easily rationalized in terms of hydrophobic interactions which are highest at the saturation limit. Fig. 10.9 shows a different behavior. For diluted solutions of methacrylonitrile the medium is pseudohomogeneous. Again, the best results are obtained at the saturation limit. However, increasing the concentration of reactants beyond this limit lowers the yield of ) -aminoester. 

The biactivation method (activation by pressure and solvophobic interactions) was applied to three types of bimolecular reactions [lOOj (i) [4 + 2] cycloadditions, AV range from -30 to —40 cm mol (ii) Michael-like reactions, AV range 

As evidenced in Table 10.25, water, formamide and diols are convenient media for this cycloaddition since the reaction affords 20-30 % yield of adduct within 2 h. 

There is no reaction in acetone and methanol. This is certainly related to solvophobic interactions and hydrogen bonding which should operate between the two carbonyls of the quinone and the oxygen of water or diols. Polarity effects may also be a cause of the increased reactivity although the reaction proceeds very slowly in methanol which has a similar cohesive energy density compared to ethylene glycol. 

After having optimized the practical asymmetric phase-transfer catalysis using TaDiAS with broad substrate generality, the synthetic applications of the procedure to create complex natural products was examined, based on the easy accessibility to a variety of optically active natural and unnatural a-amino acids. 

For dihydrodiols derived from substituted benzenes, the key to their significance lies in the availability of two adjacent chiral centers with an established absolute stereochemistry. The dihydrodiol from benzene is, of conrse, the meso compound, although enantiomers produced by subsequent reaction with a chiral reagent are readily separated. There are useful reviews containing nnmerous applications (Carless 1992 Ribbons et al. 1989), many of which involve, in addition, the nse of di-flnoro-, di-chloro-, or di-bromobenzene-2,3-dihydrodiols. 

Only a few illnstrative syntheses nsing benzene and toluene di-dihydrodiols are given below  

Althongh the prodnct from the transformation of toluene by mntants of Pseudomonas putida lacking dehydrogenase activity is the cis-2R,3S dihydrodiol, the cis-2S,3R dihydrodiol has been synthesized from 4-iodotoluene by a combination of microbiological and chemical reactions. P. putida strain UV4 was used to prepare both enantiomers of the di-dihydrodiol, and iodine was chemically removed nsing H2 -Pd/C. Incubation of the mixtnre of enantiomers with P. putida NCIMB 8859 selectively degraded the 2R,3S componnd to prodnce toluene cis-2S,3R dihydrodiol (Allen et al. 1995). 

Racemic pinitol from benzene di-dihydrodiol benzoate by snccessive epoxidation and osmylation (Fignre 8.7a) (Ley et al. 1987). 

FIGURE 8.7 Examples of chemical syntheses based on cyclohexadiene cis dihydrodiols (a) pinitol, (b) condnramine A, (c) (-)-laminitol, and (d) conduritol analogs. (From Neilson, A.H. and Allard, A.-S. The Handbook of Environmental Chemistry, Springer, 1998. With permission.) 

In previous sections, ruthenium-catalyzed cycloadditions of alkynes leading to benzenes and related heterocycles were surveyed along with their underlying mechanisms. As demonstrated by the examples above, the past decade has witnessed significant development of efficient catalytic protocols and synthetic methodology, which provides chemo- and regioselective routes to polycyclic benzenes and heterocycles. In this section, applications of these methods to the constmction of unnatural functional molecules are outlined. For synthetic applications to natural products, see Chapter 7. 

A few years after the first articles of Breslow had appeared, Grieco elegantly demonstrated that the astonishing rate and selectivity enhancements of Diels-Alder reactions in water can be exploited sirccessfully in organic synthesis. He extensively studied the reactivity of dienes containing 

The extensive work of Lubineau further demonstrated the merits of water with respect to the rates and selectivities of the Diels-Alder reaction. Since 1985 he has published a large number of articles dealirig mainly with dienes that were rendered water soluble through the temporary introduction of a 

Recently the scalirg up of water-based Diels-Alder reactions has been studied.  

Apart from the thoroughly studied aqueous Diels-Alder reaction, a limited number of other transformations have been reported to benefit considerably from the use of water. These include the aldol condensation , the benzoin condensation , the Baylis-Hillman reaction (tertiary-amine catalysed coupling of aldehydes with acrylic acid derivatives) and pericyclic reactions like the 1,3-dipolar cycloaddition and the Qaisen rearrangement (see below). These reactions have one thing in common a negative volume of activation. This observation has tempted many authors to propose hydrophobic effects as primary cause of ftie observed rate enhancements. 

Mechanistic investigations have focused on the two pericyclic reactions, probably as a consequence of the close mechanistic relation to the so successful aqueous Diels-Alder reaction. A kinetic inquest into the effect of water on several 1,3-dipolar cycloadditions has been performed by Steiner , van 

Some of these syntheses of simple triflato pentaamines produce in a facile manner compounds that were previously inaccessible or obtained only by lengthy and often low-yielding routes. For example, the first synthesis of [ColNHslslurea)] employed severe conditions and extensive recrystallizations (15), which could not be extended readily to the chromium(III) analogs. Synthesis of the latter had to await the availability of the labile triflato precursor (68). From the [Cr(NH3)5(0S02CF3)] + precursor also came the first syntheses of imidazole, trimethylphosphate, methanol, dimethylacetamide, urea, acetonitrile, and formamide pentaamminechromium(III) complexes (68, 72, 84). Syntheses of ions (M = Rh or Ir) based on 

Compounds such as frans-[Co(cyclam)Cl(OS02CF3)] and trans-[Rh(en)2Cl(0S02CF3)]+ can be readily substituted to produce a series of compounds of trans geometry. This has been exemplified by syntheses of rans-[Co(cyclam)Cl(OCH-N(CH3)2)] and rans-[Rh(en)2-(NHslCl], respectively 22, 84). Recently, reaction of rans-[Co(en)2-(py)(N02)] in CF3SO3H at 0°C has produced the trans-[Co(en)2-(py)(0S02CF3)] ion, which in aqueous HCl produces the previously elusive mns-[Co(en)2(py)Cl] compound 144). Reactions of cis-[Co(en)2(OS02CF3)2] in various solvents appear to form exclusively 

Precursor Entering group Solvent Reaction (time/temp)° Yield (%) Product Reference 

The formation of binuclear compounds by reaction of a triflato complex and a complex of a potentially bridging ligand in a noncoordinating solvent has been explored in a limited way. In general, these reactions proceed by Eq. (17). 

The process has been established for a series of pentaamminemetal(III) compounds (of Co, Rh, or Ir) with bridging imidazolate (21). The (jl-pyrazine mixed decaammine diruthenium(II)/(III) dimer has also been prepared (180), in addition to a diruthenium compound with a 1,4-dicyanobicyclo[2.2.2]octane bridging ligand and a mixed ruthe-nium(III)/cobalt(III) compound with the same bridging ligand (8). Osmium(III) dimers have also been reported (192). 

Protonation does not only catalyze the isomerization, but also contributes to the nonselective background reaction by enhancing the electrophilicity of the imines (via 53). Therefore, the H+ concentration must be kept relatively low and acetic add (up to 1 equiv) was identified as an acceptable compromise. Stronger acids promote the nonenantioselective background reaction, whereas addition of bases resulted in a dramatic deceleration [12h]. 

From the rather limited data reported by Matsumura [10], Sun [11], and Zhang [17], the pipecolinic acid derived catalyst 20 and the sulfinamide 46 appear to exhibit the highest enantioselectivities, similar to those attained with Sigamide 35[12]. However, the substrate portfolio [12h[ explored with the latter catalyst is much broader (Tables 4.3 4.7) so that a rigorous comparison cannot be made at present. Further more, Sigamide has performed consistently well at the standard 5 mol% loading and in selected examples was shown to operate with the same efficiency even when as little as 1 mol% had been used. Most of the catalysts listed in Tables 4.1, 4.2 

Trichlorosilane, a nonexpensive stoichiometric reducing agent, is relatively easy to handle under anhydrous (but not necessarily anaerobic) conditions. The aqueous workup produces NaCl and SiO2, two benign inorganics, which in conjunction with the use of toluene as the optimal solvent render this method environmentally acceptable. 

Typical Procedures forthe Catalytic Hydrosilylation of Imines 

2-shift of the acetoxy group is not stabilized, yet it is electrophilic in character because of the inductive electron-withdrawing effect of the adjacent acetates. Because of matching polarity characteristics, the rate of the otherwise essentially thermoneutral hydrogen abstraction from the cyclohexane solvent becomes sufficiently rapid to sustain the chain reaction. Unstabilized secondary radicals flanked by fluorine atoms are also capable of undergoing reduction with cyclohexane [33]. 

Living polymerization is another rapidly developing area where the degenerative transfer of xanthates and related derivatives (e.g. dithioesters, dithiocarbamates, trithiocarbonates) is having a significant impact [38] (see also Volume 1, Chapter 

Finally, the principle of degeneracy may be used to replace the xanthate group with an allyl or a vinyl substituent without the need for a stannane-based reagent 

The invention or discovery of a highly efficient free-radical chain reaction in an ideal world requires that each collision between a neutral free radical and the reagent or substrate in the propagation sequence is an effective one, especially since radical-radical combination and disproportionation reactions can occur at diffusion-controlled rates. 

The introduction of 0-acyl thiohydroxamates (mixed anhydrides of carboxylic acids with thiohydroxamic acids) by the Barton group in 1983 [1] has provided one of the mildest and most convenient and versatile sources of carbon-centered radicals which fulfill the above criteria, and can hence, in Sir Derek s own words, be described as disciplined . Since their preparation from carboxylic acids is extremely straightforward, and since they have demonstrated a rapacious radicophilicity in a wide variety of very useful transformations, it is no surprise that these derivatives are commonly named either as Barton esters or by the acronym PTOC (pyridine thiocarbonyl) esters. The ongoing development of this chemistry has been summarized over the years in several useful reviews [2], and some of the tried and tested experimental procedures have also been collated [3]. 

However, when 2,6-dimethylbenzoquinone with sodium ( )-3,5-hexadienoate (generated in situ) was reacted in water in the presence of a catalytic amount of sodium hydroxide, pentacyclic adducts were formed via deprotonation of the Diels-Alder adduct followed by tandem Michael-addition reactions with another molecule of 2,6-dimethylbenzoquinone (Eq. 12.25). Similar results were obtained with sodium ( )-4,6-heptadienoate. 

Sensitive dienol ether functionality in the diene carboxylate was shown to be compatible with the conditions of the aqueous Diels-Alder reaction (Eq. 12.26). The dienes in the Diels-Alder reactions can also bear other water-solubilizing groups such as the sodium salt of phosphoric acid and dienyl ammonium chloride (Eq. 12.27). The hydrophilic acid functionality can also be located at the dienophile.  

Grieco utilized an aqueous intermolecular Diels-Alder reaction as the key step in forming the AB ring system of the potent cytotoxic sesquiterpene vernolepin. Cycloaddition of sodium ( )-3,5-hexa-dienoate with an a-substituted acrolein in water followed by direct reduction of the intermediate Diels-Alder adduct gave the desired product in 91% overall yield (Eq. 12.28). 

Similar reactions were applied to the syntheses of rf/-ep/-pyroangolen-solide, (iZ-pyroangoensoHde (Eq. 12.29) and the formal synthesis of the Inhoffen-Lythgoe diol (Eq. 12.30). The key step in the formal synthesis of the Inhoffen-Lythgoe diol is the aqueous Diels-Alder reaction between the sodium salt of the diene and methacrolein to form the cycloadduct, which then undergoes subsequent reactions to form the known hydrin-dan. Sodium ( )-4, 6, 7-octatrienoate reacted smoothly with a variety of dienophiles to give conjugated diene products. 

An intramolecular version of the Diels-Alder reaction with a diene-carboxylate was used by Williams et al. in the synthetic study of the antibiotic ilicicolin The interesting aspect of this work is that they found that under aqueous conditions, there is an observed reversal of regioselectivity (Eq. 12.31). In toluene, there is a 75 25 ratio of a/b while in degassed water the ratio of a/b is 40 60. 

Dihydroxyacetone phosphate-dependent aldolases (DHAP-aldolases) have been used widely for preparative synthesis of monosaccharides and sugar analogs (Fessner and Walter 1997 Wymer and Toone 2000 Silvestri et al. 2003). Among them, RAMA RhuA and FucA from E. coli are the most available aldolases, especially the former which was one of the first to be commercialized (Fessner and Walter 1997 Takayama et al. 1997). In many of the chemo-enzymatic strategies they are involved, the biocatalytic aldol addition to the configuration of the newly stereogenic centers is fixed by the enzyme. However, pertinent examples have been reported in which 

Azido aldehydes were also utilized for the synthesis of 6-substituted D-fructopyranoside derivatives actives against Trypanosoma brucei parasite (Azema et al. 2000). Other interesting synthetic applications of DHAP aldolases are listed below  

13 d-Fructose-6-phosphate aldolase (FSA) catalyzed aldol additions of DHA to a number of aldehyde acceptors 

An economically viable alternative to the synthesis of deoxyribonuclosides has been developed as a two stage process involving 2-deoxy-D-ribose 5-phosphate aldolase (DERA) (Fig. 6.5.14) (Tischer et al. 2001). The first step was the aldol addition of G3P to acetaldehyde catalyzed by DERA. G3P was generated in situ by a reverse action of EruA on L-fructose-1,6-diphosphate and triose phosphate isomerase which transformed the DHAP released into G3P. In a second stage, the action of pentose-phosphate mutase (PPM) and purine nucleoside phosphorylase (PNP), in the presence of adenine furnished the desired product. The released phosphate was consumed by sucrose phosphorylase (SP) that converts sucrose to fructose-1-phosphate, shifting the unfavorable equilibrium position of the later reaction. 

Site-specific mutated 2-deoxyribose-5-phosphate aldolase (DERA) was used as catalyst for the synthesis of the key intermediate useful for the preparation of the cholesterol lowering drug atorvastatin (Lipitor) (De Santis et al. 2003). 

49 Kondo, T. Murali-Krishna, C. Riesz, P. Int. /. Radiat. Biol. 1988,53, 891-899. 

50 Kimura, T. Fujita, M. Sohmiya, H. Ando, T. Chem. Letters 1995, 55-56. 

In all of these processes, however, the yields are very low and incompatible with synthetic applications. Recent studies in this domain are lacking, but the formation of nitrite and nitrate ions in aerated aqueous solutions remains a domain of current research. 

Among the recently developed synthetic methods, many reactions necessitate a preliminary sonolysis. A direct mechanism can be involved if one of the reactants penetrates into the bubble. The relative volatility with respect to the solvent should then be an important factor if this mechanism is accepted. 3 The ease of the subsequent bond cleavage should depend on the bond energies, but systematic studies have not yet been undertaken, and the bond cleaved is not necessarily the least stable one (p. 71). Examples are known in which substrates much less volatile than the solvent undergo homolysis. In these cases, an indirect process can exist, with sonolysis of the solvent acting as a relay. 

A superficial examination of the relative kinetic data gathered in Tables 3.48, 3.49, 3.51, and 3.52, along with the well-known functional group tolerance of organozinc reagents [169] and their potential in multiple processes mediated 

Selective reactions are also possible inside the same group. Wide ranges of reactivity have already been mentioned for substituted aryl bromides and iodides. In the alkyl series, selective insertion of Zn in a tertiary bromide, leaving intact a primary one, was achieved in compounds 12 and 13 with good yields (Table 3.54, entries 8-11). As we saw, the estimated selectivity for these processes is / t-aikyi/ H-aikyi = 31.8. 

In conclusion, we have established that our highly reactive zinc exhibits unusual structure-dependent reactivity that can be used to elaborate complex molecules 

Equivalents of Zn. Several additions and/or excess were used to minimize reaction times. Reaction time and temperature. l.Oequiv unless otherwise noted. 

The substitution reactions of aromatic rings and the reactions of the side chains of alkyl-and alkenylbenzenes, when taken together, offer us a powerful set of reactions for organic synthesis. By using these reactions skillfully, we shall be able to synthesize a large number of benzene derivatives. 

Let us suppose, for example, that we want to synthesize o-bromonitrobenzene. We can see very quickly that we should introduce the bromine into the ring first because it is an ortho-para director  

The ortho and para products can be separated by various methods because they have different physical properties. However, had we introduced the nitro group first, we would have obtained m-bromonitrobenzene as the major product. 

We can synthesize m-nitrobenzoic acid by reversing the order of the reactions. We oxidize the methyl group to a carboxylic acid, then use the carboxyl as an electron-withdrawing group (shown in blue) to direct nitration to the meta position. 

Starting with toluene, outline a synthesis of (a) l-biomo-2-trichloromethylbenzene, (b) l-bromo-3-trichloromethyl-benzene, and (c) l-bromo-4-trichloromethylbenzene. 

The first report of an intramolecular Diels-Alder reaction that benefited from being performed in water came from Stembach s laboratory [73]. While these workers did find that heating an aqueous solution of substrate 6.4 resulted in [4 + 2] cycloaddition, the best yield (91%) of diastereomeric cycloadducts 6.5 and 6.6 was obtained when a full equivalent of P-cyclo-dextrin was included in the reaction medium  

Unfortunately, the diastereoselectivity of this reaction was not very good ( =3/2). Two models were offered to explain the rate-accelerating effect of P-cyclodextrin on this Diels-Alder reaction. These two models illustrating possible binding of p-cyclodextrin to intramolecular cycloaddition substrate 6.4 are shown below  

One involves the simultaneous encapsulation of the diene and dienophile components within the cyclodextrin cavity, overcoming the intrinsic entropic barrier associated with bringing these two reactive centers together. This was, in fact, the same argument put forth by Breslow to explain the effect of cyclodextrins on analogous intermolecular Diels-Alder reactions. Alternatively, one could also imagine encapsulation of the dithiane moiety by the cyclodextrin. Such complexation might also accelerate the reaction by 

Hudlicky and co-workers have followed Stembach s lead and used water 

This stereoselective reaction proceeds through an exo transition state with a trans-oxazohydrindan bridge conformation. The stereocontrolled assembly of this compound in one step represents a direct route to functionalized isoquinoline derivatives, which may prove useful for alkaloid synthesis. 

---

For other examples of the synthetic application of ethyl acetoacetate, see below and pp. 293 295. 

The Mannich bases have many synthetical applications. These include —... 

Unfortunately, the number of mechanistic studies in this field stands in no proportion to its versatility" . Thermodynamic analysis revealed that the beneficial effect of Lewis-acids on the rate of the Diels-Alder reaction can be primarily ascribed to a reduction of the enthalpy of activation ( AAH = 30-50 kJ/mole) leaving the activation entropy essentially unchanged (TAAS = 0-10 kJ/mol)" . Solvent effects on Lewis-acid catalysed Diels-Alder reactions have received very little attention. A change in solvent affects mainly the coordination step rather than the actual Diels-Alder reaction. Donating solvents severely impede catalysis . This observation justifies the widespread use of inert solvents such as dichloromethane and chloroform for synthetic applications of Lewis-acid catalysed Diels-Alder reactions. 

The Diels-Alder reaction is often quoted as an example of a reaction that is little influenced by the solvent. However, this is not fully justified, since particularly water can have a pronounced effect on the rate of this reaction. This was first noticed by E elte et al." in 1973 and rediscovered in 1980 by Breslow In the years that followed this intriguing discovery, it turned out that acceleration of Diels-Alder reactions by water is a general phenomenon that can ultimately result in up to 12,800 fold accelerations". Synthetic applications followed rapidly". ... 

Higher terminal alkenes are oxidized to methyl ketones and this unique oxidation of alkenes has extensive synthetic applications[23]. The terminal alkenes can be regarded as masked methyl ketones, which are stable to acids, bases, and nucleopliiles[24]. The oxidation of terminal alkenes to methyl ketones has been extensively applied to syntheses of many natural products[77]. 

Difunctionalization with similar or different nucleophiles has wide synthetic applications. The oxidative diacetoxylation of butadiene with Pd(OAc)i affords 1,4-diacetoxy-2-butene (344) and l,2-diacetoxy-3-butene (345). The latter can be isomerized to the former. An industrial process has been developed based on this reaction. The commercial process for l,4-diacetoxy-2-butene (344) has been developed using the supported Pd catalyst containing Te in AcOH. 1,4-Butanedioi and THF are produced commercially from 1,4-diacetoxy-2-butene (344)[302]. 

This method of diene formation with definite E and Z structures has wide synthetic applications [518], particularly for the syntheses of natural products with conjugated polyene structures. Bombykol and its isomers (650 and 651) have been prepared by this method[5l9]. The synthesis of chlorothricolide is... 

There is an experimental variation in which an W-phenacylpyridinium salt is heated with an aniline[4]. This reaction can also be readily accommodated to the mechanism involving an imine intermediate. There are a few examples of use of other types of a-halokctoncs[5,6] but most of the synthetic applications have been to 2-arylindoles. 

As illustrated in Scheme 8.1, both 2-vinylpyrroles and 3-vinylpyiroles are potential precursors of 4,5,6,7-tetrahydroindolcs via Diels-Alder cyclizations. Vinylpyrroles are relatively reactive dienes. However, they are also rather sensitive compounds and this has tended to restrict their synthetic application. While l-methyl-2-vinylpyrrole gives a good yield of an indole with dimethyl acetylenedicarboxylate, ot-substitiients on the vinyl group result in direct electrophilic attack at C5 of the pyrrole ring. This has been attributed to the stenc restriction on access to the necessary cisoid conformation of the 2-vinyl substituent[l]. 

While both 2- and 3-vinylindole have been synthesized and characterized[l,2], they arc quite reactive and susceptible to polymerization. This is also true for simple l-alkyl derivatives which readily undergo acid-catalysed dimerization and polymerization[3]. For this reason, except for certain cases where in situ generation of the vinylindoles is practical, most synthetic applications of vinylindoles involve derivatives stabilized by EW-nitrogen substituents[4]. 

Pyrano[3,4-b]indol-3-ones are the most useful equivalents of the indol-2,3-quinodimethane synthon which are currently available for synthetic application. These compounds can be synthesized readily from indole-3-acetic acids and carboxylic anhydrides[5,6]. On heating with electrophilic alkenes or alkynes, adducts are formed which undergo decarboxylation to 1,2-dihydro-carbazoles or carbazoles, respectively. 

Because of the easy and versatile synthesis of thiazoles (cf. Chapter II), this reaction could have interesting synthetic applications (481). 

The large rate enhancements observed for bimolecular nucleophilic substitutions m polai aprotic solvents are used to advantage m synthetic applications An example can be seen m the preparation of alkyl cyanides (mtiiles) by the reaction of sodium cyanide with alkyl halides... 

The mam synthetic application of Grignard reagents is their reaction with certain carbonyl containing compounds to produce alcohols Carbon-carbon bond formation is rapid and exothermic when a Grignard reagent reacts with an aldehyde or ketone... 

The preparation and some synthetic applications of lithium dialkylcuprates were described earlier (Section 14 11) The most prominent feature of these reagents is then-capacity to undergo conjugate addition to a p unsaturated aldehydes and ketones... 

The principal synthetic application of lithium dialkylcuprate reagents IS their reaction with a 3 unsatu rated carbonyl compounds Al kylation of the 3 carbon occurs... 

Nucleophiles other than water can also add to the carbon-nitrogen triple bond of nitriles In the following section we will see a synthetic application of such a nude ophilic addition... 

We 11 begin by describing the preparation and properties of p keto esters proceed to a discussion of their synthetic applications continue to an examination of related species and conclude by exploring some recent developments m the active field of synthetic car banion chemistry... 

Alternative methods for its generation have made it possible to use benzyne as an intermediate m a number of synthetic applications One such method involves treating o bromofluorobenzene with magnesium usually m tetrahydrofuran as the solvent... 

Synthetic Applications. Oxazolines, which ate synthesized as indicated above, have been utilized in many different appHcations (25). When used in resin formulations, AMP, AEPD, and TRIS AMINO can incorporate the oxazoline stmeture into the polymer stmeture (26). Because they ate polyols, both AEPD and TRIS AMINO can be used in polyester resin modification. Oxazoline alkyd films ate characterized by improved performance, particularly salt-spray resistance and gloss (see Alkyd resins Coatings, special purpose, high performance). 

The transmetallation of lithio derivatives with either magnesium bromide or zinc chloride has been employed to increase further their range of synthetic application. While the reaction of l-methyl-2-pyrrolyllithium with iodobenzene in the presence of a palladium catalyst gives only a poor yield (29%) of coupled product, the yield can be dramatically improved (to 96%) by first converting the lithium compound into a magnesium or zinc derivative (Scheme 83) (81TL5319). 

The synthetic application of reactions based upon the intramolecular addition of a carbanion or its enamine equivalent to a carbonyl or nitrile group has been explored extensively. One class of such reactions, namely the Dieckman, has already been discussed in Section 3.03.2.2, since ring closure can often occur so as to form either the C(2)—C(3) or C(3)—C(4) bond of the heterocyclic ring. Some illustrative examples of the application of this type of ring closure are presented in Scheme 46. 

Oxazoles, prepared from carboxylic acids (benzoin, DCC NH4OAC, AcOH, BOSS % yield), have been used as carboxylic acid protective groups in a variety of synthetic applications. They are readily cleaved by singlet oxygen followed by hydrolysis (ROH, TsOH, benzene or K2CO3, MeOH ). 

S. Bhattacharyya, Polymer-supported reagents and catalysts Recent advances in synthetic applications. Comb Chem High Throughput Screening 3 65-92 2000. 

Synthetic applications of organosulfur reagents are expanding rapidly. Stable sulfuranes are included for the first time in BIS[2,-2,2-TRIPLUORO-l-PHENYL-l-(TRIFLUOROMETHYL)ETHOXY] diphenyl SULFURANE and DIETHYLAMINOSULFUR TRI-FLUORIDE. The latter is used to transform an alcohol to a fluoride in p-NITROBENZYL FLUORIDE. The direct homologation of a ketone to a nitrile by use of p-TOLYLSULFONYLMETHYL ISOCYANIDE is illustrated in 2-ADAMANTANECARBONITRILE. Reagents with... 

The reactivity of mercury salts is a fimction of both the solvent and the counterion in the mercury salt. Mercuric chloride, for example, is unreactive, and mercuric acetate is usually used. When higher reactivity is required, salts of electronegatively substituted carboxylic acids such as mercuric trifiuoroacetate can be used. Mercuric nitrate and mercuric perchlorate are also highly reactive. Soft anions reduce the reactivity of the Hg " son by coordination, which reduces the electrophilicity of the cation. The harder oxygen anions leave the mercuric ion in a more reactive state. Organomercury compounds have a number of valuable synthetic applications, and these will be discussed in Chapter 8 of Part B. 

The most common synthetic application of mercury-catalyzed addition to alkynes is the conversion of alkynes to ketones. This reaction is carried out under aqueous acidic conditions, where the addition intermediate undergoes protonation to regenerate Hg. ... 

The conjugate base of 1,3-dithiane has proven valuable in synthetic applications as a nucleophile (Part B, Chapter 13). The anion is generated by deprotonation using n-butyllithium ... 

In most cases, the product ratio can be controlled by choice of reaction conditions. Ketones are isolated under conditions where the tetrahedral intermediate is stable until hydrolyzed, whereas tertiary alcohols are formed when the/Tetrahedral intermediate decomposes while unreacted organometallic reagent remains. Bxamples of synthetic application of these reactions will be discussed in Chapter 7 of Bart B. 

Enolates of aldehydes, ketones, and esters and the carbanions of nitriles and nitro compounds, as well as phosphorus- and sulfur-stabilized carbanions and ylides, undergo the reaction. The synthetic applications of this group of reactions will be discussed in detail in Chapter 2 of Part B. In this section, we will discuss the fundamental mechanistic aspects of the reaction of ketone enolates with aldehydes md ketones. 

The conversion of alcohols to esters by O-acylation and of amines to amides by N-acylation are fundamental organic reactions. These reactions are the reverse of the hydrolytic procedures discussed in the preceding sections. Section 3.4 in Part B discusses these reactions from the point of view of synthetic applications and methods. 

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