5- Bromo-2- benzaldehyde, reaction with

Unsymmetric compartmental ligands that allow for the controlled synthesis of unsymmetric Ni2 or heterobimetallic NiM complexes have received particular attention.1876,1892 A wide range of such ligands derived particularly from 2-hydroxy-3-hydroxymethyl-5-methylbenzaldehyde and 2-hydroxy-3-hydroxymethyl-bromo-benzaldehyde has now been prepared and used for Ni com-plexation. These ligands have monopodal iminic pendent arms and either mono- or dipodal aminic pendent arms and the terminal donors of the pendent arms can be provided by pyridine, imidazole, and tertiary amino groups.1893-1897 Complexes are usually prepared by reaction of the requisite Ni11 salts with the preformed ligand. 

In the first reports on the use of esters of 4-bromo-2-butenoic acid (191a and b, crotonic acid) and of 4-bromo-3-methyl-2-butenoic acid (191c, senecioic acid), the corresponding Reformatsky reactions with benzaldehyde were performed with the old-fashioned procedure, which required heating the haloester, the aldehyde and granulated zinc in benzene/ether mixtures at reflux temperature. 

The aldehydes 3 were synthesized either by Vilsmeyer formyladon of 2 or by reaction of 4-fluorobenzaldehyde with a secondary amine (20). The stilbenes 4 were formed from the corresponding 4-dialkylamino-benzaldehydes either by the Homer-Emmons reaction with 4-nitrobenzyl-(diethyl)phosphonate (prepared by the Arbuzov reaction of a-bromo-4-nitrotoluene) or with 4-methylsulfonylbenzyl(diethyl)phosphonate (prepared in three steps from 4-methylthiobenzylaicohol) (21). A few nitrostilbene compounds were synthesized by heating aldehyde 3 with 4-nitrophenylacetic acid in the presence of piperidine. 

Reductive dehalogenation of fi-halo ketones.1 a-Bromo or a-chloro ketones undergo reductive dehalogenation on reaction with freshly prepared A1I3 in refluxing CH3CN (80-95% yield). The reaction probably involves an aluminum enolate since addition of benzaldehyde results in an aldol condensation. 

Yamamoto et al. have reported that reaction of internal alkynes with o-bromo-benzaldehydes [5] or analogous ketones [6] under different reaction conditions affords indenols (Scheme 4). It is believed the mechanism is similar to that of Scheme 3, but using path A, except that the protonolysis of intermediate 9 in Scheme 3 occurs, rather than /3-hydride elimination, to form indenols. Therefore, no C-H bond transformation is involved in this indenol process. 

The halogen metal exchange reaction between 7-bromo or 7-iodo-3-phenyltriazolopyrimidine 165 and butyllithium in iV,N,N, N -tetra-methylethylenediamine afforded the 7-lithio compound 166, whereas a similar reaction with the 7-chloro derivative 165 (R = H) gave the ring-fission product, 5-amino-l-phenyl-l//-l,2,3-triazole-4-carbonitrile 169 (91 CPB2793). Reaction of 166 with electrophiles such as benzaldehyde and ketones gave 170 and 167 respectively, together with 7,7 -bis[3-phenyl-3//-1,2,3-triazolo[4,5-d]pyrimidine] 168 (Scheme 34). 

Trimethyl(4-phenyl-1,3-butadienyl)silane can be prepared by the reaction of bis(trimethylsilyl)methyHithium with cinnamaldehyde or 1,3-bis(trimethylsilyl)pro-penyllithium with benzaldehyde." - The reaction of 1-bromo-2-phenylthioethene with (E)-2-trimethylsilylethenyimagnesium bromide in the presence of a palladium catalyst gives the corresponding dienyl sulfide which serves as a precursor for the preparation of butadienylsilanes.s However, the starting materials in most of these syntheses are not readily available. 

Analogous to amino acids, a-hydroxy acids form cyclic anhydrides when treated with phosgene. However, a much more efficient reagent for this transformation with lactic acid is trichloromethyl chloroformate. By this method, L-lactic acid O-carboxyanhydride (3) is prepared as a crystalline solid in 46% yield [2]. Although 3 has found application in polymer chemistry, its use in asymmetric synthesis has been limited. Reaction of 3 with 4-bromo-benzaldehyde methylthio(thiocarbonyl)hydrazone in the presence of TFA gives a mixture of 4 (25%) and 5 (56%), which is separable by column chromatography [3]. 

The reaction of 148 with 10% HCl-MeOH afforded selective hydrolysis of the amide to form the 3-aminopyridine 149, in which the ring was subsequently closed after treatment with palladium(O) to give the /3-carboline 150. Friedlander condensation of 150 with 2-amino-3-benzyloxy-4-bromo-benzaldehyde (151), which was synthesized in four steps (5S), gave the 2-/3-carbolinequinoline 152. Hydrogen bromide gas debenzoylation of 152 was followed by oxidation with potassium nitrosodisulfonate (Fremy s salt) to obtain Kende s intermediate 131. 

A similar methodology was used by Hombrecher to synthesize the derivative 59b. This was carried out by reaction of di-O-isopropylidene-a-D-galactopyranosyl substituted benzaldehyde 109 with pyrrole (Scheme 21). The aldehyde 109 was synthesized by a F-catalyzed condensation reaction of 6-bromo-6-desoxy-l,2 3,4-di-0-isopropylidene-a-D-galactopyranose with 4-formylbenzoic acid. 

Table 2.23 shows the results of reactions with bromo- and iodoethane, magnesium and benzaldehyde in diethyl ether and in THF. 

Indeed the formation of more than 20% benzyl alcohol was reported in the reaction of bromo- or iodoethane with magnesium and benzaldehyde (Table 2.23) and 30% in the uncontrolled reaction of bromobenzene with magnesium and benzaldehyde (Table 2.24). 

Acetals of 3-bromo-4-fluoro benzaldehydes have been successfully subjected to the Ullmann reaction with several phenolates and anilines, leaving the fluorine untouched, producing the following intermediates ... 

Also the bromine-lithium exchange in 4-bromo-2-trifluoromethylquinazoline 1263 was described using butyl lithium. The corresponding litho-derivative 1264 was entered into reaction with benzaldehyde to give alcohol 1265 (Scheme 280) [742]... 

In the chromium-mediated reaction of 1-fluoro-l-bromo-l-alkene with an aldehyde, the ( )-isomer reacts more quickly than the (Z)-isomer. Therefore, when a mixture of stereoisomer 42a was subjected to the reaction with benzaldehyde in the presence of CrCl2 and Ni catalyst, a (Z)-isomer of allylic alcohol 51 was selectively formed [77, 78] (Scheme 21). The reaction proceeds through an alkenylchromium species 52, and the formation of the ( )-alkenylchromium species is much faster than that of the (Z)-isomer. Actually, the reactimi of a pure (Z)-isomer of 1 -fluoro-1 -bromo-1-alkene with aldehyde is sluggish, and the corresponding ( )-isomer of the product was obtained in low yield or not obtained at all. Therefore, a good method for the synthesis of ( )-51 has not yet been reported. 

In a separate report, the Darzens reaction was recently used by Barluenga, Concellon, and coworkers for the preparation of enantiopure a"-amino a,P-epoxy ketones. Accordingly, the Z enolate of a"-amino a-bromo ketone 41 was generated with KHMDS at -100°C. Benzaldehyde was added, and trans epoxyketone 42 was isolated in 87% yield and >95% de. ... 

Kitazume and Kasai [55] have investigated the Reformatsky reaction in three ionic liquids. This reaction involves treatment of an a-bromo ester with zinc to give an a-zinc bromide ester, which in turn reacts with an aldehyde to give an addition product. An example is given in Scheme 5.1-26. Moderate to good yields (45-95 %) were obtained in ionic liquids such as [EDBU][OTf] for the reactions between ethyl bro-moacetate or ethyl bromodifluoroacetate and benzaldehyde [55]. 

Other electrophilic substitution reactions on aromatic and heteroaromatic systems are summarized in Scheme 6.143. Friedel-Crafts alkylation of N,N-dimethyl-aniline with squaric acid dichloride was accomplished by heating the two components in dichloromethane at 120 °C in the absence of a Lewis acid catalyst to provide a 23% yield of the 2-aryl-l-chlorocydobut-l-ene-3,4-dione product (Scheme 6.143 a) [281]. Hydrolysis of the monochloride provided a 2-aryl-l-hydroxycyclobut-l-ene-3,4-dione, an inhibitor of protein tyrosine phosphatases [281], Formylation of 4-chloro-3-nitrophenol with hexamethylenetetramine and trifluoroacetic acid (TFA) at 115 °C for 5 h furnished the corresponding benzaldehyde in 43% yield, which was further manipulated into a benzofuran derivative (Scheme 6.143b) [282]. 4-Chloro-5-bromo-pyrazolopyrimidine is an important intermediate in the synthesis of pyrazolopyrimi-dine derivatives showing activity against multiple kinase subfamilies (see also Scheme 6.20) and can be rapidly prepared from 4-chloropyrazolopyrimidine and N-bromosuccinimide (NBS) by microwave irradiation in acetonitrile (Scheme... 

Fluorine-containing compounds can also be synthesized via enantioselective Reformatsky reaction using bromo-difluoroacetate as the nucleophile and chiral amino alcohol as the chiral-inducing agent.86 As shown in Scheme 8-41, 1 equivalent of benzaldehyde is treated with 3 equivalents of 111 in the presence of 2 equivalents of 113, providing a,a-difluoro-/ -hydroxy ester 112 at 61% yield with 84% ee. Poor results are observed for aliphatic aldehyde substrates. For example, product 116 is obtained in only 46% ee. 

Benzene-l,4-diols are oxidized to quinones by benzyltrimethylammonium tribromide under mild conditions in almost quantitative yields [6]. With an excess of the tribromide further reaction produces the 2-bromo-l, 4-quinones. This oxidation is in contrast to the analogous reaction of phenols, which produces bromophenols (see Section 2.3). Hindered 4-methyl-phenols are oxidized to the corresponding benzyl alcohols, benzaldehydes, bromomethyl derivatives and 4-bromo-4-methylcyclo-hexa-2,5-dien-l-ones [7]. Benzylic alcohols are oxidized under neutral or basic conditions to yield the corresponding aldehydes (>70%) oxidation with an excess of the reagent produces the benzoic acids (>90%) [8],... 

Asymmetric induction using catalytic amounts of quininium or A-methyl-ephedrinium salts for the Darzen s reaction of aldehydes and ketones with phenacyl halides and chloromethylsulphones produces oxiranes of low optical purity [3, 24, 25]. The chiral catalyst appears to have little more effect than non-chiral catalysts (Section 12.1). Similarly, the catalysed reaction of sodium cyanide with a-bromo-ketones produces epoxynitriles of only low optical purity [3]. The claimed 67% ee for the phenyloxirane derived from the reaction of benzaldehyde with trimethylsul-phonium iodide under basic conditions [26] in the presence of A,A-dimethyle-phedrinium chloride was later retracted [27] the product was contaminated with the 2-methyl-3-phenyloxirane from the degradation of the catalyst. 

Condensation of 2-hydrazinopyrimidine (384) with an aromatic aldehyde formed the Schiff bases (386), which then cyclized with bromine to 6-bromo-l,2,4-triazolo[4,3-a]pyrimidine (383) and with carbon disulfide to 387 (92PS145). A similar cyclization was effected also on 384 to give 388 (68T2839 85FRP2549834), but the cyclization of 384 or 385 with carbon disulfide afforded 3-thiolo-l,2,4-triazolo[4,3-a]pyrimidin-7-ones 389 and 390, respectively. A small amount of the isomeric 3-thiolo-l, 2,4-triazolo[4,3-a]pyrimidin-5-one was isolated in the former case (68T2839). Reaction of 385 with benzaldehyde [67JCS(C)498] or p-chlorobenzaldehyde (90MI3) followed by oxidation with LTA in benzene afforded 391 (Scheme 73). 

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