Butyrolactams

The acylpalladium complex formed from acyl halides undergoes intramolecular alkene insertion. 2,5-Hexadienoyl chloride (894) is converted into phenol in its attempted Rosenmund reduction[759]. The reaction is explained by the oxidative addition, intramolecular alkene insertion to generate 895, and / -elimination. Chloroformate will be a useful compound for the preparation of a, /3-unsaturated esters if its oxidative addition and alkene insertion are possible. An intramolecular version is known, namely homoallylic chloroformates are converted into a-methylene-7-butyrolactones in moderate yields[760]. As another example, the homoallylic chloroformamide 896 is converted into the q-methylene- -butyrolactams 897 and 898[761]. An intermolecular version of alkene insertion into acyl chlorides is known only with bridgehead acid chlorides. Adamantanecarbonyl chloride (899) reacts with acrylonitrile to give the unsaturated ketone 900[762],... 

Pyrrohdinone (2-pyrrohdone, butyrolactam or 2-Pyrol) (27) was first reported in 1889 as a product of the dehydration of 4-aminobutanoic acid (49). The synthesis used for commercial manufacture, ie, condensation of butyrolactone with ammonia at high temperatures, was first described in 1936 (50). Other synthetic routes include carbon monoxide insertion into allylamine (51,52), hydrolytic hydrogenation of succinonitnle (53,54), and hydrogenation of ammoniacal solutions of maleic or succinic acids (55—57). Properties of 2-pyrrohdinone are Hsted in Table 2. 2-Pyrrohdinone is completely miscible with water, lower alcohols, lower ketones, ether, ethyl acetate, chloroform, and benzene. It is soluble to ca 1 wt % in aUphatic hydrocarbons. 

Additions of aryl- or alkyllithium reagents to N-silylated formamides 508 give the imines 509 in 55-80% yield [90, 91] some of these imines can subsequently be converted into the corresponding //-lactams by reaction with enolates of alkyl butyrates [92]. Conversion of N-silylated butyrolactam 388 into cyclic Schiff bases such as 390, by reaction with methyl- or butyllithium, via O-silylated butyrolactam 389, is discussed in Section 4.8 (Scheme 5.28). 

Bode and co-workers have used NHCs to form y-butyrolactams 34 from enals 27 and saccharin-derived cyclic sulfonylimines 32. A range of [3-alkyl and [3-aryl substituted enals, and a variety of substituted imines, are tolerated in this reaction,... 

Bode and co-workers have extended the synthetic ntility of homoenolates to the formation of enantiomerically enriched IV-protected y-butyrolactams 169 from saccharin-derived cyclic sulfonylimines 167. While racemic products have been prepared from a range of P-alkyl and P-aryl substitnted enals and substitnted imi-nes, only a single example of an asymmetric variant has been shown, affording the lactam prodnct 169 with good levels of enantioselectivity and diastereoselectivity (Scheme 12.36) [71], As noted in the racemic series (see Section 12.2.2), two mechanisms have been proposed for this type of transformation, either by addition of a homoenolate to the imine or via an ene-type mechanism. 

Similarly, the N-Boc-protected 3,4-methano-y-aminobutyric acid 141 and the 4-spiro-cyclopropane-y-butyrolactam 145 have been obtained in overall yields of 55% and 44%, respectively (Scheme 11.36) [109,110,119b]. 

Beckmann like rearrangements have not been extensively explored but should translate this spiroannulation into a y-butyrolactam synthesis108). 

Complexes of the lanthanides with a few cyclic amides are known. Miller and Madan have reported the complexes of 7-butyrolactam with lanthanide nitrates (60) and perchlorates (61). Complexes of lanthanide perchlorates and lighter lanthanide nitrates with BuL have a L M of 8 1. However, complexes of heavier lanthanide nitrates have a L M of only 3 1. By changing the solvent used for the crystallization of the abovementioned complexes, complexes of the formula [La(BuL)4(N03)3] and [Gd(BuL)3(N03)3] could be prepared (60). Complexes of NMBuL (61, 62) and CLM (63-66) have also been reported. 

W. Zimmermann, A. Donhardt, W. Braun, Uber den Nachweis von 2-Brom-2-Athyl-4-Hydroxybutyramid und 2-Brom-2-Athyl-4-Butyrolactam nach Carbromalgabe , Arch. Toxicol. 1978, 40, 119-124. 

Mahboobi et al. described a novel synthesis of staurosporinone (293) (791). The intermolecular Michael addition of l-(indol-3-yl)-2-nitroethene (1472) to methyl indol-3-ylacetate (1313) provided with high diastereoselectivity methyl 2,3-bis(indol-3-yl)-4-nitrobutanoate (1473). Catalytic hydrogenation and lactamization afforded 2,3-bis(indol-3-yl)-y-butyrolactam (1474) in 87% yield. Oxidative cyclization of the ds-lactam 1474 with DDQ in the presence of catalytic amounts of p-TsOH led to staurosporinone (293) (791) (Scheme 5.249). 

Lactams are named in several ways. They are named as alkanolactams by the IUPAC substitutive system, such as 3-propanolactam, 4-butanolactam, 5-pentanolactam, and 6-hexano-lactam, respectively, for the 4-, 5-, 6-, and 7-membered rings, respectively. An alternate IUPAC method, the specialist heterocyclic nomenclature system, names these lactams as 2-azetidinone, 2-pyrrolidinone, 2-piperidinone, and hexahydro-2f/-azepi n-2-one, respectively. These lactams are also known by the trivial names fl-propiolactam, a-pyrrolidone (y-butyrolactam), a-piperidone (8-valerolactam), and e-caprolactam, respectively. 

The first oxidation by a Ru complex of an amide was carried out by Berkowitz and Rylander in 1958, using stoich. RuOyCCl to convert y-butyrolactam to suc-cinimide [52]. 

Thus, the 1,4-addition of the lactams 72 to nitroolefins provided access to the Michael adducts 73 with good stereoselectivities, which could be improved by recrystallization or chromatography. After reduction and protection of the amino group the y-butyrolactams 74 were converted to the corresponding a-substituted lactams 75 in good overall yields (37-65%) and excellent diastereo- and enantio-... 

There are also a number of species for which a tetrahedral intermediate-like structure has been claimed but which require substantiation before the claims can be fully accepted. Thus, on the basis of infrared spectroscopic evidence it was claimed that y-butyrolactam, on treatment with concentrated (23%) potassium hydroxide solution, is converted into the ionized tetrahedral intermediate [52] characterized by a band at 1555 cm-1 (Vinnik and Moiseyev, 1963). However, this interpretation has been criticized (Robinson,... 

The first-generation synthesis of levetiracetam (3), as shown in Scheme 14.9 [29], starts with benzoyl protection and oxidation of (S)-aminobutanol (32), which gives rise to the corresponding N-benzoyl protected (S)-aminobutyric acid (33). After N-benzoyl amidation and deprotection, (S)-aminobutyramide (34) is obtained. Chemoselective butyrolactam ring formation using the intermediate 34 and 4-chlorobutyryl chloride finally affords levetiracetam (3). 

Butyl sulfides, dl32, dl33 Butyl sulfite, dl34 Butyl sulfone, dl35 Butyrolactam, p275... 

When /V-(2-hydroxyacetyl)-2-pyrrolidone (83) (Scheme 23) was dissolved in water at pH > 8, irreversible cleavage of the exocyclic and endocyclic amide C-N bond occurs. The former led to y-butyrolactam (87) and glycollic acid (88). The latter, a... 

Prednisone (Potency x 30) Note. No E isomer is possible in this example. 3-(3,4-Dimethoxy phenyl)-butyrolactam (Antidepressant)... 

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