Catalytic reductive alkylation

Aminonitrile formation on 125 with potassium cyanide and piperidine hydrochloride affords the derivative, 135. Hydrolysis as above gives the corresponding amide (136). Debenzylation is accomplished by catalytic reduction. Alkylation of the secondary amine with the side chain (96) used in the preparation of diphenoxylate affords pirintramide (138) This compound, interest-... 

Catalytic Reductive Alkylation of Aromatic and Alkyl Amines and Diamines over Sulfided and Unsulfided Platinum Group Metals... 

Secondary amines synthesized by catalytic reductive alkylation of primary amines are used in a variety of fine and specialty chemical indnstries. For example, derivatives of cyclohexylamine are used as corrosion inhibitors, N-(l,3-dimethylbntyl)-N -phenyl-p-phenylenediamine (6-PPD) is nsed as an anti-oxidant in rabber indnstiy, several dialkylated diamines are used in the coatings indnstiy, while they are nsed in the pharmacentical industry as pharmacophores (1-7). Harold Greenfield and co-workers have examined the ability of platinum group metals (PGM), base metals, and their snlfides to catalyze rednctive alkylation of primary and secotrdary amines (8-11). They found that different catalysts are optimal for the... 

The UV-Vis spectral detection of an intermediate in the catalytic reductive alkylation reaction provides only circumstantial evidence of the quinone methide species. If the bioreductive alkylating agent has a 13C label at the methide center, then a 13C-NMR could provide chemical shift evidence of the methide intermediate. Although this concept is simple, the synthesis of such 13C-labeled materials may not be trivial. We carried out the synthesis of the 13C-labeled prekinamycin shown in Scheme 7.5 and prepared its quinone methide by catalytic reduction in an N2 glove box. An enriched 13C-NMR spectrum of this reaction mixture was obtained within 100 min of the catalytic reduction (the time of the peak intermediate concentration in Fig. 7.2). This spectrum clearly shows the chemical shift associated with the quinone methide along with those of decomposition products (Fig. 7.3). 

SCHEME 7.6 Catalytic reductive alkylation of guanosine with 13C at the C-10 position of WV-15. The inset shows generation of the iminium methide upon reduction. 

The ferrocenylmethy1 group, which can be introduced by catalytic reductive alkylation of amino acids or amino acid esters... 

Contaminants and by-products which are usually present in 2- and 4-aminophenol made by catalytic reduction can be reduced or even removed completely by a variety of procedures. These include treatment with 2-propanol (74), with aUphatic, cycloaUphatic, or aromatic ketones (75), with aromatic amines (76), with toluene or low mass alkyl acetates (77), or with phosphoric acid, hydroxyacetic acid, hydroxypropionic acid, or citric acid (78). In addition, purity may be enhanced by extraction with methylene chloride, chloroform (79), or nitrobenzene (80). 

Reduction. Quinoline may be reduced rather selectively, depending on the reaction conditions. Raney nickel at 70—100°C and 6—7 MPa (60—70 atm) results in a 70% yield of 1,2,3,4-tetrahydroquinoline (32). Temperatures of 210—270°C produce only a slightly lower yield of decahydroquinoline [2051-28-7]. Catalytic reduction with platinum oxide in strongly acidic solution at ambient temperature and moderate pressure also gives a 70% yield of 5,6,7,8-tetrahydroquinoline [10500-57-9] (33). Further reduction of this material with sodium—ethanol produces 90% of /ra/ j -decahydroquinoline [767-92-0] (34). Reductions of the quinoline heterocycHc ring accompanied by alkylation have been reported (35). Yields vary widely sodium borohydride—acetic acid gives 17% of l,2,3,4-tetrahydro-l-(trifluoromethyl)quinoline [57928-03-7] and 79% of 1,2,3,4-tetrahydro-l-isopropylquinoline [21863-25-2]. This latter compound is obtained in the presence of acetone the use of cyanoborohydride reduces the pyridine ring without alkylation. 

The yield of the more active RRR-a-tocopherol can be improved by selective methylation of the other tocopherol isomers or by hydrogenation of a-tocotrienol (25,26). Methylation can be accompHshed by several processes, such as simultaneous halo alkylation and reduction with an aldehyde and a hydrogen haUde in the presence of staimous chloride (27), amino alkylation with ammonia or amines and an aldehyde such as paraformaldehyde followed by catalytic reduction (28), or via formylation with formaldehyde followed by catalytic reduction (29). 

The N,]S -dialkyl-/)-PDAs are manufactured by reductively alkylating -PDA with ketones. Alternatively, these compounds can be prepared from the ketone and -lutroaruline with catalytic hydrogenation. The /V-alkyl-/V-aryl- -PDAs are made by reductively alkylating -nitro-, -nitroso-, or /)-aminodipheny1 amine with ketones. The AijAT-dialkyl- PDAs are made by condensing various anilines with hydroquinone in the presence of an acid catalyst (see Amines-aromatic,phenylenediamines). 

Sulfonamides (R2NSO2R ) are prepared from an amine and sulfonyl chloride in the presence of pyridine or aqueous base. The sulfonamide is one of the most stable nitrogen protective groups. Arylsulfonamides are stable to alkaline hydrolysis, and to catalytic reduction they are cleaved by Na/NH3, Na/butanol, sodium naphthalenide, or sodium anthracenide, and by refluxing in acid (48% HBr/cat. phenol). Sulfonamides of less basic amines such as pyrroles and indoles are much easier to cleave than are those of the more basic alkyl amines. In fact, sulfonamides of the less basic amines (pyrroles, indoles, and imidazoles) can be cleaved by basic hydrolysis, which is almost impossible for the alkyl amines. Because of the inherent differences between the aromatic — NH group and simple aliphatic amines, the protection of these compounds (pyrroles, indoles, and imidazoles) will be described in a separate section. One appealing proj>erty of sulfonamides is that the derivatives are more crystalline than amides or carbamates. 

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). 

A further simplification of the requirements for activity came from the preparation of two spasmolytic agents that completely lack the aromatic ring. Thus, double alkylation of phenylace-tonitrile (54) with 1,5-dibromopentane leads to the corresponding cyclohexane (55). This intermediate is then saponified and the resulting acid (56) esterified with w,w-diethylethanolamine. Catalytic reduction of the aromatic ring affords dicyclonine (51). ... 

Condensation of the anion obtained on reaction of acetonitrile with sodium amide, with o-chlorobenzophenone (36), affords the hydroxynitrile, 37. Catalytic reduction leads to the corresponding amino alcohol (note that the benzhydryl alcohol is not hydrogenolyzed). Reductive alkylation with formaldehyde and hydrogen in the presence of Raney nickel gives the antitussive a-gent, chlorphedianol (39). °... 

The p-chloro analog of phentermine has much the same activity as the parent compound, with perhaps a somewhat decreased activity on the central nervous system. Alkylation of p-chloro-benzyl chloride with the carbanion obtained from treatment of 2-nitropropane with strong base affords the compound containing the required carbon skeleton (74). Catalytic reduction of the nitro group yields chlorphentermine (75). ... 

The synthesis of enalapril follows the normal course tor such compounds in that L alanyl-L prolme (27) was reductively alkylated with ethyl 2-oxo 4 phenylbutyiate (26) using sodium cyanoborohydnde as the reducing agent (catalytic reduction may also be used) The product is... 

Spirapril (37) is a clinically active antihypertensive agent closely related structurally and mechanistically to enalapril. Various syntheses are reported with the synthesis of the substituted proline portion being the key to the methods. This is prepared fkim l-carbobenzyloxy-4-oxopro-line methyl ester (33) by reaction with ethanedithiol and catalytic tosic acid. The product (34) is deprotected with 20% HBr to methyl l,4-dithia-7-azospiro[4.4 nonane-8-carboxylate (35), Condensation of this with N-carbobenzyloxy-L-alanyl-N-hydroxysuccinate leads to the dipeptide ester which is deblocked to 36 by hydrolysis with NaOH and then treatment with 20% HBr. The conclusion of the synthesis of spirapril (37) follows with the standard reductive alkylation [11]. 

Most of the widely used antidepressants are tricyclics related to imipramine. A 1-phenyltetrahy-droisoquinoline analogue, nomifensine (60), departs from this structural pattern. Hiarmacologi-cally it inhibits the reuptake of catecholamines such as dopamine at neurons. It can be synthesized by alkylation of 2-nitrobenzyl-methylamine with phenacyl bromide followed by catalytic reduction of the nitro group (Pd-C) and then hydride reduction of the keto moiety to give 59. Strong acid treatment leads to cyclodehydration to nomifensine (60) [17]. 

Amides are very weak nucleophiles, far too weak to attack alkyl halides, so they must first be converted to their conjugate bases. By this method, unsubstituted amides can be converted to N-substituted, or N-substituted to N,N-disubstituted, amides. Esters of sulfuric or sulfonic acids can also be substrates. Tertiary substrates give elimination. O-Alkylation is at times a side reaction. Both amides and sulfonamides have been alkylated under phase-transfer conditions. Lactams can be alkylated using similar procedures. Ethyl pyroglutamate (5-carboethoxy 2-pyrrolidinone) and related lactams were converted to N-alkyl derivatives via treatment with NaH (short contact time) followed by addition of the halide. 2-Pyrrolidinone derivatives can be alkylated using a similar procedure. Lactams can be reductively alkylated using aldehydes under catalytic hydrogenation... 

Abstract Significant advances have been made in the study of catalytic reductive coupling of alkenes and alkynes over the past 10 years. This work will discuss the progress made in early transition metal and lanthanide series catalytic processes using alkyl metals or silanes as the stoichiometric reductants and the progress made in the use of late transition metals for the same reactions using silanes, stannanes and borohydrides as the reductant. The mechanisms for the reactions are discussed along with stereoselective variants of the reactions. 

Inclusion of basic nitrogen in the p-position is also compatible with antiinflammatory activity in this series. Nitration of phenylacetic acid (27) affords 28. Methyl iodide alkylation of the enolate prepared from 28 using two equivalents of sodium hydride gives 29. This appears to involve an Ivanov intermediate (28a). Catalytic reduction of the... 

The antibiotic 2-methylfervenulone (310) was synthesized most conveniently by treatment of 338 with dimethyiformamide-phosphorus oxychloride to afford 339, followed by acid hydrolysis to give fervenulone 340. Subsequent alkylation with methyl iodide in dimethylformamide gave 310 (78JOC469). Reaction of 339 with sodium benzyloxide gave the benzyloxy derivative 344, which on catalytic reduction with palladium-charcoal provided 340. 

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