1,2-/1,3-Oxazoles alkylation

The synthesis of phorboxazole B has been accomplished in 27 linear steps [11] in an overall yield of 12.6%. The key fragment couplings include a metalated oxazole alkylation and an oxazole-stabilized Wittig olefination. 

Pyrazoles and imidazoles carrying a substituent on nitrogen, as well as oxazoles, thiazoles, etc., are converted by alkyl halides into quaternary salts. This is Illustrated by the preparation of thiamine (89) from components (87) and (88). 

In addition to the reactions described in the preceding section, alkyl groups in the 2-positions of imidazole, oxazole and thiazole rings show reactions which result from the easy loss of a proton from the carbon atom of the alkyl group which is adjacent to the ring (see Section 4.02.3.1.2). 

Similar alkylations may be effected on oxygen. l-(2-Chloroethyl)imidazolidin-2-one (312) when treated with potassium hydroxide or sodium hydride underwent ring closure to the tetrahydroimidazo[2,l-6]oxazole (313) (57JA5276). This approach can be used for the preparation of bicyclic hydantoins and the corresponding dihydro derivatives of (313) using the mesylate of (312) and NaH (77JHC5U, 79JMC1030). 

Naphth[2,l-d]oxazole, 2-methyl-oxidation, 6, 188 reactions, 6, 216 Naphthoxazoles, anilino-alkylation, 6, 189... 

Dewar and Turchi carried out similar rearrangements of secondary and tertiary alkyl and aryl oxazole-4-carboxamides (5a-e) to the corresponding secondary and tertiary 5-aminooxazoles (6a-e). For example, they realized yields > 90% when the amide nitrogen is part of a heterocyclic ring system. 

In 1909, Robinson demonstrated the utility of acylamidoketones as intermediates to aryl-and benzyl-substituted 1,3-oxazoles through cyclization with sulfuric acid. Extension of sulfuric acid cyclization conditions to alkyl-substituted oxazoles can give low yields, for example 10-15% for 2,5-dimethyl-l,3-oxazole. Wiegand and Rathbum found that polyphosphoric acid can provide alkyl-substituted oxazoles 4 in yields equal to or greater than those obtained with sulfuric acid. Significantly better yields are seen in the preparation of aryl- and heteroaryl-substituted oxazoles. For example, reaction of ketoamides 5 with 98% phosphoric acid in acetic anhydride gives oxazoles 6 in 90-95% yield. ... 

Van Leusen and Possel described the use of mono-substituted tosylmethyl isocyanides (TosCHRN=C R = alkyl, benzyl, allyl) in the synthesis of 4,5-substituted oxazoles. For example, 4-ethyl-5-phenyloxazole (8) was prepared in 82% yield by refluxing a-tosylpropyl isocyanide (7) and benzaldehyde for 1 hr with 1.5 equivalent of K2CO3 in MeOH. 

The hetero ring in 4-(l -hydroxyalkylidene)-5-oxazolones is cleaved by alcoholic HCl to form alkyl a-acylaminoacylacetates, which cyclize to oxazole-4-carboxylates [Eq. (25)]. This rearrangement occurs directly in alkali, and a carbon-14 tracer study has substantiated a mechanism involving ring opening followed by the alternative ring closure. ... 

Treatment of a 3-aminotriazolopyridine with acid gave the imidazopyridine 242 (81T1787), also obtained from the 3-nitro derivative by catalytic reduction (83AHC79). Quaternary salts derived from compound 2, when treated with tri-ethylamine and subsequently heated give 2-pyridylcyanamides 243 or 2-(oxazol-l-yl)pyridines 244 depending on the alkyl group (86H(24)2563) the ylides are presumably intermediates (see also Section IV.I). 

The oxazole ring can be constructed on a quinoline ring such as 589 by alkylation to give 590 which upon treatment with halogen in CHCI3 gave the corresponding oxazoloquinolinium derivative 591 that upon treatment with... 

Hetero-benzylic anionic reagents, derived from 2-alkyl-l,3-oxazoles, -1,3-thiazoles and -imidazoles and related compounds, are not covered in this section because these resemble metallo 1-azaenolates in their reactivity (Section D.l.3.5.). 

Fig. 13 Synthesis of oxazoles on JandaJel. Reagents and conditions a toluene, alkyl acetoacetate (R0(C0)CH2C0R R =t-Bu), reflux, 6h or alkyl acetoacetate (R = Me, Et), toluene, LiC104, reflux, 6h fc dodecylbenzenesulfonyl azide, EtsN, toluene, rt, 16 h c benzamide, Rh2(oct)4, toluene, 65 °C, Ih rf Burgess reagent, pyridine, chlorobenzene, MW 100 °C, 15 min (or 80 °C, 4 h with conventional heating) e AICI3, piperidine, CH2CI2, rt, 16 h...

Much of the early work into the rhodium(II)-catalysed formation of oxazoles from diazocarbonyl compounds was pioneered by the group of Helquist. They first reported, in 1986, the rhodium(II) acetate catalysed reaction of dimethyl diazomalonate with nitriles.<86TL5559, 93T5445, 960S(74)229> A range of nitriles was screened, including aromatic, alkyl and vinyl derivatives with unsaturated nitriles, cyclopropanation was found to be a competing reaction (Table 3). 

To date most of the nitriles studied have been simple alkyl or aromatic derivatives with little other functionality. We recently attempted to extend the reaction to iV-protected a-aminonitriles, derived by dehydration of a-aminoacid amides (Path A, Scheme 25), but this proved unsatisfactory, and therefore we investigated an alternative diazocarbonyl based route in which the order of steps was reversed, i.e. a rhodium catalysed N-H insertion reaction on the amide followed by cyclodehydration to the oxazole (Path B, Scheme 25). 

Hayashi et al. [18] have synthesized two diastereoisomers of 2,2 -bis[4-(alkyl)oxazol-2-yI]-l,T-binaphthyl,bis(oxazoline) derivatives possessing both binaphthyl axial chirality and carbon centered chirality (structures 9 and 10, Scheme 5). 

The Michael type reaction of (3R)-5-t-butyldimethysiloxy-3-phenyl-17/-pyrrolo[ 1,2-c]oxazole with nitroethylene proceeds in the presence of Lewis acid to give the alkylated product in good chemical yield and diastereoselectivity. In the case of nitroethylene, the Diels-Alder type transition state is favored to give the yy/i-adduct selectively (Eq. 4.72).91... 

Imidazolines are also formed in silver cyanide-catalyzed cyclization of alkyl isocyanides with aliphatic diamines (Scheme 103).169 This simple synthesis can be applied in a general way with difunctional nucleophiles and has been used to prepare benzimidazoles, oxazoles, thiazoles, and oxazines.169 It is suggested that transient carbene complexes are formed in these reactions (cf. 87 in Scheme 103) but further work is required to ascertain the mechanism and scope of these processes. 

Application of the Ritter reaction conditions on y-hydroxy-a,P-alkynoic esters, 102, produced ethyl 5-oxazoleacetates 103 or y-A-acylamino-P-keto ester 104 by reaction with aryl or alkyl nitriles respectively. The y-A-acylamino-P-keto ester 104 can also be transformed into oxazole derivatives using an additional step involving POCI3 <06TL4385>. 

Vedejs developed an enantiocontrolled synthesis of aziridinomitosenes involving internal alkylation of the oxazole 132 to produce an oxazolium salt 133 followed by nucleophilic addition of cyanide providing the adduct 134 <00JA5401>. Electrocyclic ring opening of 134 to the azomethine ylide 135 with internal [2+3] trapping produces the tetracyclic product 137 via the pyrroline 136. 

Lithiated 2-alkyl-4,5-dihydro-l,3-oxazoles (363) react with nitrones in high stereoselectivity to give initially 1,6-dioxa -2,9-diazaspiro [4.4] nonane (364). Upon further treatment with oxalic acid it is quantitatively converted to 4,4-dimethyl-2-( 1 -methyl-2-phenylvinyl)-4,5-dihydro-1,3-oxazole (365) (diastereo-meric mixture E/Z = 9 1) with elimination of tert-buthylhydroxylamine (Scheme 2.157) (598, 599). 

The alkylation of the G-H bonds occurs even in the CH=N moiety of five-membered heteroaromatic compounds such as thiazoles, benzimidazoles, and oxazoles (Equation (25)).26,26a This intermolecular alkylation without chelation assistance is very interesting. 

When the diazoimides 253 are subjected to Rh2(OAc)4 at 80 °C in presence of an alkyl alcohol, pcrhydropyrrolo[2,1 -b -oxazol-4-ones 254 were isolated in good yields as a diastereomeric mixture. If the alcohol is replaced by terminal alkyl diols, the corresponding bis(2,3-fused perhydropyrrolo[2,l- ]oxazol-4-one) systems 255 were obtained (Scheme 37) <2003CC440>. 

Lewis acid SnCLj-assisted reaction between the l,3-thiazole-5-thione 434 and /ra r-2,3-dimethyloxirane led to the m 4,5-dimethyl-l,3-oxathiolane 435 The same Lewis acid enabled a second addition of /ra/ -2,3-dimcthyloxirane onto the C—N bond of the 1,3-thiazole ting of 434, leading to the formation of the tetrahydro-2//-thiazolo[2,3- ]-oxazole adduct 436 (Equation 200) <2000HCA3163>. Condensation of 2,4-dinitroimidazole, 8-bromotheophylline, and 8-bromoadenine with substituted methyloxiranes involved sequential A -alkylation-r/wo-substitution and furnished a series of 2,3-dihydro-imidazo[2,l- ]oxazole derivatives 437, 438, and 439 (Equations 201-203) <2000CCC1126, 2000EJ03489, 2005TL3561, 2004JHC51>. 

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