Benzaldehyde, alkylation with

Scheme 10 Benzaldehyde alkylation with dialkylzinc catalysed by grafted /3-aminoalcohol.

Further substitution of benzoic acid leads to a drug with antiemetic activity. Alkylation of the sodium salt of p-hydroxy-benzaldehyde (8) with 2-dimethylaminoethyl chloride affords the so-called basic ether (9). Reductive amination of the aldehyde in the presence of ammonia gives diamine, 10. Acylation of that product with 3,4,5-trimethoxybenzoyl chloride affords trimetho-benzamide (11). ... 

Activity is apparently retained when the ring nitrogen is alkylated as in flordipine (42). Aldol condensation of the benzaldehyde 39 with ethyl acetoacetate gives the unsaturated ester 40. The nitrogen containing reaction partner 41 is obtained by condensation of 32 with 2- morpholi-noethylamine. Reaction of 40 with 41 leads to flordipine (42) [12]. 

Benzaldehyde cyanohydrin is reacted with urea to displace the hydroxyl group of the cyanohydrin. That intermediate is treated with HCI to convert the urea nitrogen to a nitrile. The resultant imine is hydrolyzed to the phenylhydantoin. Alkylation with ethyl iodide gives ethotoin, as described by A. Pinner in Chem. Ber. 21, 2325 (1888). 

Chiral (2 )-(Z)-l-methyl-2-butenylboronate 13 was synthesized by way of a-chloroethylboronate 12,0. This route, in which the dichloromethyl starting material is first alkylated with methyllithi-um and then 12 is treated with (Z)-2-propenyllithium, was developed since a-chloro-2-butenyl-boronates such as 7 and 15 are sensitive to racemization, owing to the presence of nucleophilic chloride ions, during the reactions of (4f ,5/ )-2-(dichloromethyl)-4,5-dimethyl-l,3,2-dioxa-borolane and (Z)- or ( )-2-propenyllithium. The route to 13 may be performed as a one-pol operation with an overall yield of >90%. The diastereomeric purity of 13 was estimated to be >98% based on a subsequent reaction with benzaldehyde. 

The reaction has been applied to nonheterocyclic aromatic compounds Benzene, naphthalene, and phenanthrene have been alkylated with alkyllithium reagents, though the usual reaction with these reagents is 12-20, and Grignard reagents have been used to alkylate naphthalene. The addition-elimination mechanism apparently applies in these cases too. A protected form of benzaldehyde (protected as the benzyl imine) has been similarly alkylated at the ortho position with butyl-lithium. ... 

The oxime 299 is silylated in the presence of catalytic amounts of TMSOTf 20 to 300, which affords, via the Beckmann fragmentation intermediate 301 and alkylation with allyltrimethylsilane 82, 66% of the seco nitrile 302 [101, 102] (Scheme 4.39). Tris(trimethylsilyl) ketenimine 303 reacts with aldehydes such as benzaldehyde in the presence of Bp3-OEt2, via the aldol adduct 304, to give the unsaturated nitriles 305, in 99% yield, and HMDSO 7 [103]. 

Silylation of hydroxylamine or N-alkyl or N-ethoxycarbonyUiydroxylamines is usually accomphshed, in 52-84% yield, by silylation with TCS 14/NEt3 [63, 161, 162]. Whereas the reaction of N,0-bis(trimethylsilyl)methylhydroxylamine 952 with aldehydes such as benzaldehyde, or with ketones, with to adducts such as 953, has already been mentioned at the beginning of Section 7.3 thermal and other reactions of N,0-bis(trimethylsilyl)hydroxylamine 1141 or N-substituted N,0-bis(trimethylsi-lyl)hydroxylamines 1121, 1128, 1131 are discussed in this section. 

Acetal handle 78 synthesized from Merrifield resin and 4-hydroxy-benzaldehyde was applied to the solid-phase synthesis of carbohydrates and 1-oxacephams (Scheme 41) [90]. For the latter, a 1,3-diol was initially anchored to the support to form a cyclic acetal. A ring opening reaction with DIBAL generated a resin-bound alcohol which was converted to the corresponding triflate for A-alkylation with 4-vinyl-oxyazetidin-2-one. A Lewis acid catalyzed ring closure released 1-oxa-cephams from the support. 

Diiodosilane reduces acetals to alkyl iodides in a reductive iodination reaction (Eq. 312).358,505 Alkyl bromides are formed from the reductive bromination of benzaldehyde acetals with the combination Et3SiH/SnBr2.506... 

Comparison of the configuration of the stannane with the prodncts of reaction reveals that primary alkyl halides that are not benzyhc or a to a carbonyl react with inversion at the lithium-bearing carbon atom. In the piperidine series, the best data are for the 3-phenylpropyl compound, which was shown to be >99 1 er. In the pyrrolidine series, the er of the analogous compound indicates 21-22% retention and 78-79% inversion of configuration. Activated alkyl halides such as benzyl bromide and teri-butyl bromoacetate afford racemic adducts. In both the pyrrolidine and piperidine series, most carbonyl electrophiles (i.e. carbon dioxide, dimethyl carbonate, methyl chloroformate, pivaloyl chloride, cyclohexanone, acetone and benzaldehyde) react with virtually complete retention of configuration at the lithium-bearing carbon atom. The only exceptions are benzophenone, which affords racemic adduct, and pivaloyl chloride, which shows some inversion. The inversion observed with pivaloyl chloride may be due to partial racemization of the ketone product during work-up. 

Other important compounds include oxindole, which is the lactam of 2-aminophenylacetic acid. This compound has an active methylene group, which can be deprotonated with a base such as sodium ethoxide, and the anion that is formed can be alkylated with- a variety of electrophiles (Scheme 7.20). In the case of benzaldehydes, the initially formed aldols are unstable and these dehydrate readily to the corresponding (E)- and (Z)-(benzy lidene)oxindoles. 

Thiazolium ion based ionic liquids (OIL) have been used to promote the benzoin condensation of benzaldehyde. 4- And 5-methylthiazoles are readily alkylated with n-butyl bromide to give the corresponding bromide salt. Anion exchange with sodium tetrafluoroborate gave the tetrafluoroborate salt 53 as a stable yellow orange oil. When activated with a small quantity of triethylamine (5 mol%) the oil promotes the coupling of benzaldehyde to benzoin <99TL1621>. 

More recent patents describe the following preparation from a-methylcinnam-aldehyde. a-Methylcinnamaldehyde (from benzaldehyde and propionaldehyde) is hydrogenated to a-methyldihydrocinnamic alcohol. The alcohol is alkylated with tert-butyl chloride or isobutene to 4-tert-butyl-o -methyldihydrocinnamic alcohol, which is subsequently dehydrogenated to the desired aldehyde [152, 153]. 

Isoniazide, the hydrazide of pyridine-4-carboxylic acid, is still, well over half a century after its discovery, one of the mainstays for the treatment of tuberculosis. Widespread use led to the serendipitous discovery of its antidepressant activity. This latter activity is retained when pyridine is replaced by isoxazole. The requisite ester (45-4) is obtained in a single step by condensation of the diketo ester (45-1), obtained by aldol condensation of acetone with diethyl oxalate, with hydroxylamine. One explanation of the outcome of the reaction assumes the hrst step to consist of conjugate addition-elimination of hydroxylamine to the enolized diketone to afford (45-2) an intermediate probably in equilibrium with the enol form (45-3). An ester-amide interchange of the product with hydrazine then affords the corresponding hydrazide (45-5) reductive alkylation with benzaldehyde completes the synthesis of isocarboxazid (45-6) [47]. 

Alkylation of 3-methyl-1,2,4,5-tetrahydro-3//-3-benzazepin-2-one in THF-DMF solution containing sodium hydride, with primary and secondary alkyl halides and with a-bromoesters, results predominantly in 1-monoalkyl derivatives, whereas with w,w-dibromoalkanes, 1,1-spiro derivatives are formed (80T1017). Apparently, 6,7-dihydro-5//-dibenz[6,rf]azepin-6-one does not condense with benzaldehyde or with nitrosobenzene at the active methylene group (55JA3393). 

Reductive amination of benzaldehyde with (R)-81 provided the corresponding benzyl amine, which was reductively alkylated with formaldehyde to give 82 (Scheme H) " Compound 82 was debenzylated by hydrogenation in the presence of Pearlman s catalyst to afford frovatriptan ((/J)-6). Alternatively, monomethylation of amine (/ )-81 was affected by treatment with carbon disulfide and dicyclohexylcarbodiimide in pyridine to provide isothiocyanate 83, which was reduced with sodium borohydride to give (l )-6. 

Alkylation and deprotection of N-protected aminomethylphosphonate esters 6 are shown in Scheme 6. The nitrogen is protected as the imine derived from benzophenone or a benz-aldehyde, and a variety of conditions are used for deprotonation and alkylation (Table 2). The benzaldehyde imine of aminomethylphosphonate can be deprotonated with LDA and alkylated with electrophilic halides (entries 1 and 2). For the best yields, saturated alkyl bromides require an equivalent of HMPA as an additive. 36 Allylic esters can be added to the carbanion with palladium catalysis (entries 3-7). 37,38 For large-scale production, phase-transfer catalysis appears to be effective and inexpensive (entries 8-12). 39,40 ... 

Aliphatic primary and secondary amines can be linked to insoluble supports as ben-zylamines by reductive alkylation with support-bound benzaldehydes or by N-alkyla-tion with support-bound benzyl halides or sulfonates (Figure 3.25 see also Section 10.1). Benzhydrylamines and tritylamines are usually prepared by N-alkylation with the corresponding halides. 

Under similar conditions reaction with alkyl bromides and benzyl chloride led exclusively to ring alkylation. With benzaldehyde, alkylation occurred solely at the exo-methylene position, while acetone gave approximately a 1 1 mixture of the isomeric ring- and... 

Aldol condensation.3 Benzaldehydes condense with alkyl aryl ketones in the presence of basic alumina to form chalcones in 70-85% yield. Benzaldehydes... 

The aminodiol 745, obtained from 2-amino-1,3-propanediol by two sequential reductive alkylations with 2,4-dimethoxybenzaldehyde and benzaldehyde, reacted with 3-chloro-2-(chloromethyl)prop-l-ene to give dioxocin 683 in 46% yield <2006JOC413>. Similar formation of dioxocins was observed when 3-chloro-2-(chloromethyl)prop-l-ene... 

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