Piperazine N-alkylation

Piperazine, N-alkylation with benzyl chloride, 42, 19 Piperazine, 1-benzyl-, 42,19 Piperidine, addition to ethylene, 43, 45 as catalyst for Claisen-Schmidt condensation, 41, 40 Piperidine, 1-ethyl-, 43, 45 Piperidine, 1-(2-naphthyl)-, 40,74 Pivalic acid, oxidative coupling to a,a,-a, a -tetramethyladipic add, 40, 92... 

N-alkylation and N-acylation of piperazine-2,5-diones are quite common and have been routinely employed in several synthetic sequences (see Section IV,C). Such operations have also been performed as measures for the temporary protection of the nitrogen during further synthetic maneuvers in other parts of the molecule. Three different alkyl groups have been employed as such protecting groups. Kishi has used the methoxymethyl group for N-protection (potassium r-butoxide, chloro-methyl methyl ether 0°C, 75% yield). Deprotection was achieved by cone. HCl-ethanol at reflux temperature (81T2045). 

Yoshimura has introduced the p-methoxybenzyl group for N-protection in piperazine-2,5-diones (83CL1001 85BCJ1413). The N-alkylation is carried out with sodium hydride and p-methoxybenzyl bromide in DMF at room temperature. Deprotection is achieved by ceric ammonium nitrate (CAN) in acetonitrile-water. 

Cyclic dipeptides, especially when N-alkylated, undergo extremely fast epimerization (79JA1885). For example, cyclo(L-Pro-L-Phe) is rapidly converted to its diastereomer, cyclo(D-Pro-L-Phe) (80% conversion), by treatment with 0.5 N NaOH at 25°C for 15 min. This diastereomer is the one in which the proline residue has epimerized and not the more activated phenylalanine. CNDO/2 calculations seem to provide a rationale for this. It is not yet completely clear why such base-catalyzed epimerizations of piperazinediones are so easy the conformation of the molecule may play a role in this (79MI1). It is also worth noting that even in linear peptides, rm-amides of N-alkyl-amino acids, which consist of s-trans and s-cis rotamers of almost equal energy, are more prone to racemization than the sec-amides, which exist only in the s-trans configuration. Of course, the amide functions of piperazine-2,5-diones are obliged to assume the s-cis conformation. 

The entire gamut of N-alkylation protection, deprotection, aldol condensation, etc., is nicely brought out in the synthesis of isomeric 1- (or 4)methyl-3-arylmethyl-piperazine-2,5-diones from the same starting material (88CPB2607) (Scheme 29). 

Formation of piperazine-2,5-diones from dipeptide esters containing Pro or other N-alkyl amino acids has also been observed during SPPS. The dipeptides most prone to cyclization are those that contain a C-terminal Pro or other IV-alkyl amino acids connected via an ester bond to a sterically unhindered handle.1171-1781 Scheme 33 depicts the formation of piperazine-2,5-diones 81 from dipeptides 80 in which the IV-alkyl amino acid is connected via a benzyl ester to the solid support. 

The lability of peptides and proteins to acidic conditions was first reported in 1920 by Dakin,12031 who found that acid hydrolysis of peptides or proteins that contain consecutive N-alkyl amino acids leads to the formation of piperazine-2,5-diones (DKP) this side reaction lowered their yield during amino acid analysis. For example, the piperazine-2,5-dione c[-Hyp-Pro-] was isolated from the hydrolyzate of gelatine. 

The N-alkylation, N-arylation, and in particular N-heteroarylation of piperazines is an important process because of the common propensity (justified or not) for introducing a piperazino grouping into structures perceived as potentially bioactive in a variety of drug-related areas. The various routes to such N-alkylated piperazines are outlined in this section, which also includes examples of the N-alkylation of di- or tetrahydropyrazines the N-alkylation of (tautomeric) pyrazinones and the like is covered in Section 5.1.2.2. 

Note The Rh-catalyzed C-acylation of reduced pyrazines with carbon monoxide and ethylene appears to offer considerable potential for further development. l-Methyl-4-(pyridin-2-yl)piperazine (292) gave l-methyl-3-propionyl-4-(pyridin-2-yl)-l,4,5,6-tetrahydropyrazine (293) [Rh4(CO)12, PhMe, H2C=CH2 J, to 10 atm, CO l to 15 atm, 25°C, autoclave then 160°C, 20 h 85%] several N-alkyl/aryl homologues were made similarly.1404... 

Another type of N-alkylation is provided by the Mannich reaction. 1,3-Dimethyl-8-azapurin-2,6-dione, formaldehyde, and morpholine, stirred in cold ethanol, gave l,3-dimethyl-7-(JV-morpholinylmethyl)-8-azapurine-2,6-dione in 70% yield. Lower yields were obtained from piperidine and some piperazines. 

Polyalkylene polyamines are typical by-products in the amination of dihydroxy compounds. Some of these oligomers, e. g. diethylenetriamine and triethylene-tetramine, are valuable compounds they are produced industrially from ethanol-amine (sometimes directly from ethylene oxide) and ammonia or a mixture of ammonia and ethylenediamine. Over a Ni-Re boride catalyst the selectivity for diethylenetriamine was ca 25 %, almost independent of the conversion [27]. Higher temperatures favored the formation of worthless cyclic products, mainly piperazine and its N-alkylated derivatives (Scheme 9). Recycling the cyclic byproducts can minimize their formation and the higher oligomers can be decomposed to useful dimers and trimers [26]. 

Chloro-4-substituted-4/7-benzo-l-thia-2,4-diazine 1,1-dioxides 154 (R = alkyl, Ph R = H, Cl) undergo substitution of the chloride in the presence of amines to provide the 3-(aminoalkyl) derivatives 155 (R = COAr, NH2, NHCOAr) (Equation 26) <2006BMC650>. Compounds related to 154 react similarly with aryl carboxamides in the presence of base to provide the C-3 A-amido analogs of 155 <2006BMC650>. The 3-(bromomethyl)-3,4-dihydro-277-benzo-l-thia-2,4-diazine 1,1-dioxides 156 (R=H, Me, Cl) react with piperidines to afford the substitution products 157 (Equation 27) as do the related 3-(bromomethyl)-277-benzo-l-thia-2,4-diazine 1,1-dioxides <2005BML1185>. Similar displacements with piperazine nucleophiles on N-alkylated 277-thieno[3,4-( ]-l-thia-2,4-diazine-3(477)-one 1,1-dioxides have been reported <2000EJM751>. 

In general piperazine-2,5-diones (155) are not difficult to prepare indeed their ease of formation can sometimes be irritating. Mono-N-alkyl derivatives, however, are more of a challenge. An improved synthesis of 1-methyl-2,5-piperazinedione has been achieved and this is outlined in Scheme 10. 

The structure of piperazine is similar to that of piperidine. Electron diffraction studies show that it prefers a chair conformation with bond lengths C-C 154.0 and C-N 146.7 pm, and bond angles C-C-N 110 and C-N-C 109°. The N-H bonds favor the equatorial position and the same applies to N-substituents in N-alkyl and N,N-diaIkylpiperazines. 

Articles from two companies have reviewed their approaches to solution phase libraries. Merritt et al. [1] described the evolution of approaches at Glaxo Wellcome. The initial approach to pooled libraries was successful in identifying leads for medicinal chemistry programmes but also identified problems and prompted future efforts to be directed to discrete libraries. Garr et al. [2] reviewed the methods used at Panlabs for preparation and analysis of three classes of compounds for the Optiverse Screening Library. A series of solution phase libraries based on 4-aminopiperidine, piperazine and 4-aminobenzylamine were synthesised by acylation, sulphonylation and N-alkylation. 

Azetidones (p-lactams) are generally obtained in high yield from (3-halopropion-amides (Table 5.18) and the low yield from the reaction of N-phenyl (3-chloropropi-onamide can be reconciled with the isolation of A-phenyl acrylamide in 58% yield [34]. The unwanted elimination reaction can be obviated by conducting the cyclization in a soliddiquid system under high dilution [35, 36]. Azetidones are also formed by a predominant intramolecular cyclization of intermolecular dimerization to yield piperazine-2,5-diones, or intramolecular alkylation to yield aziridones. Aone-pot formation of azetidones in 45-58% yield from the amine and P-bromocarboxylic acid chloride has also been reported [38]. 

The spontaneous formation of piperazine-2,5-diones occurs mainly during N-deprotection or the acylation step to dipeptide esters (usually unhindered esters such as Me, Et, Bzl, and Pac esters) that contain an TV-alkyl amino acid especially at the C-terminusJ152 In some cases the formation of piperazine-2,5-diones becomes the major reaction product and thus prevents peptide elongation by the [1+2] or [1+3] segment condensation strategy in solution synthesis or elongation of the peptide from the C-terminus in SPPS. Piperazine-2,5-dione formation... 

Piperazine-2,5-dione formation can occur not only in the case of dipeptides esters or amides containing a free amino group, but also during the activation of N-blocked or protected IV-alkyl amino acids containing dipeptides or even tripeptides. Thus, the activated dipeptide Z-Gly-Pro-ONp (76) afforded the Z-protected piperazine-2,5-dione 77 when subjected to buffered dioxane solution at pH 8 (Scheme 29)J159 ... 

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