Phenethyl amide

The Bischler-Napieralski reaction involves the cyclization of phenethyl amides 1 in the presence of dehydrating agents such as P2O5 or POCI3 to afford 3,4-dihydroisoquinoline products 2. This reaction is one of the most commonly employed and versatile methods for the synthesis of the isoquinoline ring system, which is found in a large number of alkaloid natural products. The Bischler-Napieralski reaction is also frequently used for the conversion of N-acyl tryptamine derivatives 3 into p-carbolines 4 (eq 2). 

The synthesis of 3,4-dihydroisoquinolines via intramolecular reactions of phenethyl amides was first reported by August Bischler and Bernard Napieralski in 1893. The authors described the conversion of A-acyl phenethylamide (1, R = Me) and A-benzoyl phenethylamide (1, R = Ph) to 1-methyl-3,4-dihydroisoquinoline (2, R = Me) and 1-phenyl-3,4-dihydroisoquinoline (2, R = Ph), respectively, in the presence of P2O5. This reaction has subsequently proven to be one of the most general methods ever developed for the synthesis of dihydroisoquinolines. 

In some instances the attack of the arene on the nitrilium salt occurs at the ipso carbon rather than the ortho carbon. For example, the Bischler-Napieralski cyclization of phenethyl amide 10 affords a 2 1 mixture of regioisomeric products 11 and 12. The formation of 12 presumably results from attack of the ipso aromatic carbon on the nitrilium salt 13 followed by rearrangement of the spirocyclic carbocation 14 to afford 15, which upon loss of a proton vields product 12. ... 

F. Cularine.—New syntheses of ( )-cularine (ISO) and its derivatives using intramolecular Ullmann186 and phenolic oxidative coupling187,188 reactions as key steps have been reported. It is well known that 7,8-disubstituted isoquinolines cannot be prepared by the Bischler Napieralski reaction. This problem was circumvented (Scheme 14) by using an ethoxycarbonylamino-/ -phenethyl-amide (177) in order to activate the para-position and thus to effect the required cyclization reaction (177) — (178).186 Conventional steps then led to the phenol (179) which under Ullmann reaction conditions gave (+)-cularine (180). 

Complexation of Rh or Ru center to A-a-phenethyl amides of A-Boc-a-thioamino acids (but not the amino acid derivatives) forms highly effective catalysts for asymmetric hydrogenation of aryl ketones. ... 

Heterocyclic analogues of BINAP, such a< 2,2, 5,5 -tetramethyl-4,4 -bis(dipheny Iphosph and tested in the Heck reaction. Incorporaut sulfinyl group to a double bond elicits enj intramolecular Heck reaction. Optically ai ides are produced from (/ )-l-f-butylsulfinylcy Palladacycle (109) and its analogues ind rearrangement of allylic imidates. - For a thioamides, it is convenient to allylate thi dine. This process involves a thio-Claisen n Enantioselective deprotonation of ketones slum bis[yV-benzyl-N-(a-phenethyl)]amide.-- tonation of enolates. ... 

Enantioselective deprotonation of ketones is achieved by using a homochiral magnesium bis[Af-benzyl-A -(a-phenethyl)]amide. On the other hand, 110 is excellent for protonation of enolates. ... 

Cyclization of Tertiary Cyclohexyl-ethyl-phenethyl-amide Derivatives... 

In contrast to formamide 21.33, sulfonamide-derived catalysts 21.34, and 21.35 worked efficiently in catalytic quantities (<15 mol%, 0°C, 24 h) producing good yields and high enantioselectivities (<98% ee) over a wide range of aromatic and a,(3-unsaturated aldehydes." It was shown that the configuration of the phenethyl amide fragment in 21.34 did not affect enantioselectivily of the reaction. ... 

Substitution on the phenethyl side chain of the substrate is usually well tolerated. For example, reaction of carbamate 44 with POCI3 afforded a 75% yield of the corresponding lactam 45. However, in some instances substituents on the chain lead to low yields, such as in the reaction of amide 46, which provided only a 29% yield of the desired product 47 (albeit with 9 1 diastereoselectivity). ... 

A number of novel structures containing a quaternary diphenyl carbon centre, as in methadone, have been described. Certain basic amides (XXXV) of O-ethylbenzilic acid are active by mouth in mice and rats. The most active members are somewhat more potent than pethidine and carry [3-arylethylamino V-substituents such as phenethyl and 2- (or 4-) pyridylethyl. Detailed pharmaco-... 

Alkylation, of 2-acetamidothiazoles, 35, 37 with alkali amides, 34, 35 of alkylaminothiazole, 34 with alcohols, 47, 80, 90 of aminothiazoles, with alcohols, 38 with benzyl chloride. 33 with chloracetic acid, 33 with chloracetic esters, 33 with 3-chloropropionic acid, 33 with dimethylaminoethylchloride, 35 with ethylene oxide, 34, 38 with ethyl iodide, 33 with phenethyl chloride, 35 with 2-propynyl bromide. 32 in aprotic solvents, 35 of azothiazoles, 105... 

Tetrahydrocarbazoles and related fused systems have been accessed by a route relying on palladium-catalyzed tandem formation of alkenyl and aryl C-N bonds. For instance, the starting triflate 477 could be efficiently transformed into the target system 478 by amination with aniline (Equation 133) <2005AGE403>. Annulation of (2-triflyloxy)phenethyl carbonates with amides in the presence of a palladium catalyst has been used as a route to various N-substituted indoline derivatives <2005OL4777>. 

Boyer D, Bauman JN, Walker DP, et al. Utility of MetaSite in improving metabolic stability of the neutral indomethacin amide derivative and selective cyclooxygenase-2 (COX-2) inhibitor 2-(l-(4-chlorobenzoyl)-5-methoxy-2-methyl-lf/-indol-3-yl]-N-phenethyl-acetamide. Drug Metab Dispos. 2009 37(5) 999-1008. 

The same methodology has been extensively developed for the synthesis of optically active p-ketophosphonates from (3/ ,l 7 )-methyl T-phcnylethyl 3-hydroxypentanedioate. Low-temperature condensation of this unprotected hydroxy diester with dimethyl 1-lithiomethylphosphonate in excess in THF gives the desired optically active functionalized P-ketophosphonate in fair yield (43%). It has been observed that the methyl ester reacts faster than the I -phenethyl ester, and it is necessary to operate without the silyl protecting group to avoid a P-elimination reac-tion. - 2< By an analogous route, the reaction of dimethyl 1-lithiomethylphosphonate (1.3 eq) with the corresponding protected hydroxy ester-amide (Nahm-Weinreb amide) provides the... 

Amides 113-115 are especially attractive, since the unsaturated chain, cyclic enone, and removable chiral auxiliary such as an a-phenethyl substituent are simultaneously attached to the nitrogen atom. However, the allylic or benzylic hydrogen atoms present in the starting molecule allow competitive hydrogen abstraction processes. In the presence of an a-phenethyl group, cycloadducts were indeed isolated but in low yields and poor diastereomeric excess, besides rearranged products [75]. 

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