Unusual Reactions

The purpose of this chapter is to introduce a number of useful synthetic reactions. Admittedly, all of these reactions are not unusual in the sense of organic chemistry and a few would have been predicted. However, some are unusual in the sense that they involve both the functional groups of MA. In some cases the ring system is unique for the reaction, for example, in the oxauracil synthesis. Also included in this chapter are 1,3-dipolar cycloadditions. Here too, some cases are given where more than one molecule of MA participates to arrive at quite unusual products. Some of these reactions are very high yielding and they are too useful synthetically to be regarded as extraneous. We believe Sec. 7.2 will justify these comments. 

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The coupling of 1,8-diiodonaphthalene (25) with acenaphthylene (26) affords acenaphth[l,2-a]acenaphthylene (27). It should be noted that the reaction involves unusual trans elimination of H—Pd—1[32], This tetrasubstituted double bond in 11 reacts further with iodobenzene to give the [4, 3, 3]propellane 28 in 72%. This unusual reaction may be accelerated by strain activation, although it took 14 days[33]. 

Low yield in pentamethine thiazolocyanine results also from the fission of the pyridine ring in the presence of 2-chloro-3.3-dimethylindolenine (544). Explanations of this unusual reaction have been given (Scheme 44) (67). 

An unusual reaction was reported in which 2-(4-pyridyl)-4-carboxyethylthiazole (50) prepared from thioisonicotinamide (49) and ethylbromopyruvate (48) was converted to 51, which upon treatment with KNCS in the presence of NaHCOj gave 52 (618). This was again cyclized with 48 to yield 2-(4-pyridyI)-4-(4-ethoxycarbonyl-2-thiazolyl hydrazino-carbonyl)thiazole (S3) (Scheme 24). 

An unusual reaction has been reported by Reynaud et al. (515) in which all the atoms are in the starting molecule. 

Under acidic conditions, furfuryl alcohol polymerizes to black polymers, which eventually become crosslinked and insoluble in the reaction medium. The reaction can be very violent and extreme care must be taken when furfuryl alcohol is mixed with any strong Lewis acid or Brn nstad acid. Copolymer resins are formed with phenoHc compounds, formaldehyde and/or other aldehydes. In dilute aqueous acid, the predominant reaction is a ring opening hydrolysis to form levulinic acid [123-76-2] (52). In acidic alcohoHc media, levulinic esters are formed. The mechanism for this unusual reaction in which the hydroxymethyl group of furfuryl alcohol is converted to the terminal methyl group of levulinic acid has recendy been elucidated (53). 

Ring closure of o-benzoylbenzoic acid to anthraquinone is an unusual reaction in that normally it is not predicted to occur ortho to a keto group. Several theories have been proposed to explain the mechanism whereby this could possibly occur. One involves a complex ionization of o-benzoylbenzoic acid (41), the other favors the intermediate formation of 3-hydroxy-3-phenyl-l(3JT)isobenzofuranone (9) [64693-03-4] and 3-phenylphthaHdyl sulfate (10) (42) ... 

An unusual reaction leading to a Ti—C bond is unrelated to those just discussed. Diphenylketene adds Ti(OR)4 (199) as follows ... 

An unusual reaction, probably involving the mechanism shown, results in the partial conversion of halonaphthyridines such as (144) to pyrido-[3,2- f]- or -[4,3- f]-pyrimidines (e.g. 145) with KNH2 in liquid ammonia (78MI21500, 73MI21500). 

The use of guanidine for cyclization gives amino substituted derivatives (e.g. 212) (52CB1012), and in this case o-aminonitriles may be used to furnish diamines (e.g. 8UOC1394). An unusual reaction involving nitriles occurred during the preparation of nicotinonitrile from the amide and ammonium sulfamate, when a 60% yield of the dimeric by-product (213) was formed via the nitrile (69BSB289). Similar products have been obtained from... 

Amongst the more unusual reactions, 2,3-thiazolo fused pyrido[3,2-d]pyrimidines have been prepared from 3-aminopicolinic acid and 2-bromothiazoles, whilst a similar derivative resulted with allyl isothiocyanate (221 222) <72IJC602). Similar products are also produced in [3 + 3] reactions of 2-aminothiazoles (Section 2.15.5.7.1). 

An unusual reaction involving s-triazine (247) and ethyl acetoacetate with sodium ethoxide leads eventually to the pyrido[4,3-ring opening and Dimroth-type rearrangement of the intermediate (248) (80JHC389>. 

Some rather unusual reactions to ultraviolet light. 

The extended ylides 270 react with electrophiles at the end of the side chain, as shown in Scheme 9 (92H(34)1005). The most unusual reaction is the nitration which requires a decarbalkoxylation, but the structure 271 is confirmed by X-ray diffraction. 

Unusual reactions occur between diazomethane and heterocyclic thiocarbonyl compounds. For example, pyran-4-thiones give methylene ethers of 1,2-dimercaptans formed by dimerization (cf. 115 —>116). 4-Thioflavones and 4-thiochromones react similarly. 

Hydrazobenzene 1 (1,2-diphenyl hydrazine) is converted to benzidine 2 (4,4 -diaminobiphenyl) under acidic conditions.This unusual reaction is called the benzidine rearrangement, and can be observed with substituted diphenyl hydrazines as well. 

The initial series of major tranquilizers consists of alkylated derivatives of 4-aryl-4-hydroxypiperidines. Construction of this ring system is accomplished by a set of rather unusual reactions. Condensation of methylstyrenes with formaldehyde and ammonium chloride afford the corresponding hexahydro-1,3-oxazines (119). Heating these oxazines in the presence of acid leads to rearrangement with loss of water to the tetrahydropyridines. Scheme 1 shows a possible reaction pathway for these transformations. Addition of hydrogen bromide affords the expected 4-bromo compound (121). This last is easily displaced by water to lead to the desired alcohol (122) The side chain (123) is obtained by Friedel-Crafts acylation of p-fluorobenzene with 4-chloro-butyryl chloride. Alkylation of the appropriate arylpiperidinol with 123 affords the desired butyrophenone derivative. Thus,... 

A rather unusual reaction forms the key step in the preparation of a benzomorphan bearing a fatty side chain, The scheme used to form the benzomorphan nucleus, which is patterned after the Grewe synthesis originally developed for... 

In the fifty or so years since the discovery of a-metalated epoxides, our understanding of their reactivity has advanced to such a level that their use in routine organic synthesis is now possible. Many research groups continue to examine their unusual reaction pathways and to develop these into synthetically useful processes. In contrast, the chemistry of a-metalated aziridines is still in its infancy and there are undoubtedly many interesting facets of their nature still to be explored and applied in organic synthesis. 

The [3S+1C] cycloaddition reaction with Fischer carbene complexes is a very unusual reaction pathway. In fact, only one example has been reported. This process involves the insertion of alkyl-derived chromium carbene complexes into the carbon-carbon a-bond of diphenylcyclopropenone to generate cyclobutenone derivatives [41] (Scheme 13). The mechanism of this transformation involves a CO dissociation followed by oxidative addition into the cyclopropenone carbon-carbon a-bond, affording a metalacyclopentenone derivative which undergoes reductive elimination to produce the final cyclobutenone derivatives. 

Coupling of alkenylcarbene complexes and siloxy-substituted 1,3-dienes affords vinylcyclopentene derivatives through a formal [3C+2S] cycloaddition process. This unusual reaction is explained by an initial [4C+2S] cycloaddition of the electron-poor chromadiene system as the 471 component and the terminal double bond of the siloxydiene as the dienophile. The chromacyclohexene intermediate evolves by a reductive elimination of the metal fragment to generate the [3C+2S] cyclopentene derivatives [73] (Scheme 26). 

Ideally, it would be desirable to determine many parameters in order to characterize and mechanistically define these unusual reactions. This has been an important objective that has often been considered in the course of these studies. It would be helpful to know, as a function of such parameters of the plasma as the radio-frequency power, pressure, and rate of admission of reactants, (2) the identity and concentrations of all species, including trifluoromethyl radicals, (2) the electronic states of each species, (3) the vibrational states of each species, and (4) both the rotational states of each species and the average, translational energies of, at least, the trifluoromethyl radicals. 

An unusual reaction of carbenes is that of insertion into C—H bonds (12-19). Thus. CH2 reacts with... 

An unusual reaction is used to form a KRe 4 HjO. The reduction of potassium perrhenate in en-H20 solutions by potassium metal yields a white solid containing the Rh ion mixed with KOH. Extraction with isopropyl alcohol gives a colloidal brown liquid containing a mixture of KOH, isopropyl alcohol and the rhenidc. Fractional extraction of the liquid gives a gray solid that contains 5.5-60% KRe 4 HjO... 

Treatment of N-benzoyl-L-alanine with oxalyl chloride, followed by methanolic triethylamine, yields methyl 4-methyl-2-phenyloxazole-5-carboxylate 32 <95CC2335>. a-Keto imidoyl chlorides, obtained from acyl chlorides and ethyl isocyanoacetate, cyclise to 5-ethoxyoxazoles by the action of triethylamine (e.g.. Scheme 8) <96SC1149>. The azetidinone 33 is converted into the oxazole 34 when heated with sodium azide and titanium chloride in acetonitrile <95JHC1409>. Another unusual reaction is the cyclisation of compound 35 to the oxazole 36 on sequential treatment with trifluoroacetic anhydride and methanol <95JFC(75)221>. 

A. Nucleophilic Reactions of the P=0 Group.—Tris(trifluoromethyl)-phosphine oxide (33) reacts with hexamethyldisiloxane to give a phos-phorane, whose n.m.r. spectrum at — 140 °C shows non-equivalent trifluoromethyl groups. Although this unusual reaction clearly involves nucleophilic attack of the phosphoryl oxygen on silicon at some stage of the reaction, a full study of the mechanism has not been published. Tertiary phosphine oxides can be converted cleanly into dichlorophos-phoranes (34) by treatment with two moles of phosphorus pentachloride. Alkylation of the sodium salt of tetraphenylmethylenediphosphine dioxide (35) with alkyl halides, in dimethyl sulphoxide, has been reported to... 

An unusual reaction was been observed in the reaction of old yellow enzyme with a,(3-unsat-urated ketones. A dismutation took place under aerobic or anaerobic conditions, with the formation from cyclohex-l-keto-2-ene of the corresponding phenol and cyclohexanone, and an analogous reaction from representative cyclodec-3-keto-4-enes—putatively by hydride-ion transfer (Vaz et al. 1995). Reduction of the double bond in a,p-unsaturated ketones has been observed, and the enone reductases from Saccharomyces cerevisiae have been purified and characterized. They are able to carry out reduction of the C=C bonds in aliphatic aldehydes and ketones, and ring double bonds in cyclohexenones (Wanner and Tressel 1998). Reductions of steroid l,4-diene-3-ones can be mediated by the related old yellow enzyme and pentaerythritol tetranitrate reductase, for example, androsta-A -3,17-dione to androsta-A -3,17-dione (Vaz etal. 1995) and prednisone to pregna-A -17a, 20-diol-3,ll,20-trione (Barna et al. 2001) respectively. 

Unusual reactions have been encountered in the aerobic degradations carried out by Azoarcus evan-sii and Geobacillus stearothermophilus (Zaar et al. 2001). The anaerobic degradation of benzoate by Azoarcus evansii (Ebenau-Jehle et al. 2003) and Thauera aromatica (Domer and Boll 2002), and of 3-hydroxybenzoate by Th. aromatica (Laempe et al. 2001) is discussed later. 

A formally comparable pathway is used by a strain of Alcaligenes sp. that degrades 4-hydroxyacetophenone to 4-hydroxybenzoyl methanol, which is oxidized in an unusual reaction to 4-hydroxybenzoate and formate. The 4-hydroxybenzoate is then metabolized to 3-ketoadipate via 3,4-dihydroxybenzoate (Figure 8.35b) (Hopper et al. 1985). 

Some unusual reactions have emerged in the degradation of phenylacetate and 3-phenyl... 

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