2.2.6.6- Tetramethylpiperidine 4-substituted

Allen, N.S., Edge, M., He, J., Chen, W., Kikkawa, K., Minagawa, M. Thermal and photooxidative behaviour of 2-hydroxybenzophenone stabilisers in polyolefin films Effeet of 4-butoxy-4-amino-tetramethylpiperidine substitution. Polym. Degrad. Stab. 42, 293-306 (1993)... 

Primary and secondary aliphatic amines, morpholine and 2-methylaziridine and aniline and even the sterically hindered 2.2,6,6-tetramethylpiperidine readily react with 6-bromo-trithiadiazepine 7, in certain cases in the presence of /V./V-diisopropylethylamine, at room temperature by substitution of the bromine atom ammonia, for example, yields trithiadiazepin-6-amine 22 (R1 = R2 = H). There is compelling evidence that these reactions proceed by an elimination-addition mechanism via the heteroaryne, trithiadiazepyne 21.391... 

Most radicals are transient species. They (e.%. 1-10) decay by self-reaction with rates at or close to the diffusion-controlled limit (Section 1.4). This situation also pertains in conventional radical polymerization. Certain radicals, however, have thermodynamic stability, kinetic stability (persistence) or both that is conferred by appropriate substitution. Some well-known examples of stable radicals are diphenylpicrylhydrazyl (DPPH), nitroxides such as 2,2,6,6-tetramethylpiperidin-A -oxyl (TEMPO), triphenylniethyl radical (13) and galvinoxyl (14). Some examples of carbon-centered radicals which are persistent but which do not have intrinsic thermodynamic stability are shown in Section 1.4.3.2. These radicals (DPPH, TEMPO, 13, 14) are comparatively stable in isolation as solids or in solution and either do not react or react very slowly with compounds usually thought of as substrates for radical reactions. They may, nonetheless, react with less stable radicals at close to diffusion controlled rates. In polymer synthesis these species find use as inhibitors (to stabilize monomers against polymerization or to quench radical reactions - Section 5,3.1) and as reversible termination agents (in living radical polymerization - Section 9.3). 

The hindered secondary amines can be highly effective photostabilizers for various polymers (]+.,5.,.6) Various hindered amines have been shown to retard oxidation, but most share the common feature of being secondary or tertiary amines with the a-carbons fully substituted. The most widely exploited representatives of this class are based on 2,2,6,6-tetramethylpiperidine either in the form of relatively simple low molecular weight compounds, or more recently as backbone or pendant groups on quite high molecular weight additives ( i.,5.,6). The more successful commercial hindered amines contain two or more piperidine groups per molecule. Photo-protection by tetra-methylpiperidines (near UV transparent) must result from the interruption of one or more of the reactions 1 to 3. Relatively recent results from our own laboratories, and in the open literature will be outlined in this context. 

Substituted tetramethylpiperidines and their oxidation products appear to act as UV stabilizers for polypropylene by weakly scavenging PP, PPO2 and possibly other radicals involved in the photo-oxidation. Their weak scavenging ability is off-set by the... 

The polymer degradation scheme discussed above and shown in Figure 1 is valid in polymers without any additives. However, most commercially available materials are doped with UV absorbers and with light and thermal stabilizers in order to extend their lifetime. The HAS rank among the most important additives used for light and heat stabilization of polymers [9,15,16]. Most commercially available HAS stabilizers are 4-substituted 2,2,6,6-tetramethylpiperidines, as shown below [17],... 

GABA HMG-CoA HMPA HT LDA LHMDS LTMP NADH NBH NBS NCS NIS NK NMP PMB PPA RaNi Red-Al RNA SEM SnAt TBAF TBDMS TBS Tf TFA TFP THF TIPS TMEDA TMG TMP TMS Tol-BINAP TTF y-aminobutyric acid hydroxymethylglutaryl coenzyme A hexamethylphosphoric triamide hydroxytryptamine (serotonin) lithium diisopropylamide lithium hexamethyldisilazane lithium 2,2,6,6-tetramethylpiperidine reduced nicotinamide adenine dinucleotide l,3-dibromo-5,5-dimethylhydantoin A-bromosuccinimide A-chlorosuccinimide A-iodosuccinimide neurokinin 1 -methyl-2-pyrrolidinone para-methoxybenzyl polyphosphoric acid Raney Nickel sodium bis(2-methoxyethoxy)aluminum hydride ribonucleic acid 2-(trimethylsilyl)ethoxymethyl nucleophilic substitution on an aromatic ring tetrabutylammonium fluoride tert-butyldimcthyisilyl fert-butyldimethylsilyl trifluoromethanesulfonyl (triflyl) trifluoroacetic acid tri-o-furylphosphine tetrahydrofuran triisopropylsilyl A, N,N ,N -tetramethy lethylenediamine tetramethyl guanidine tetramethylpiperidine trimethylsilyl 2,2 -bis(di-p-tolylphosphino)-l,r-binaphthyl tetrathiafulvalene... 

Barriers to rotation of nitrosamines in which the amino part is embedded in a cyclic system seem generally to be smaller. However, Harris and associates (82) reported that the barrier of /V-nitroso-2,2,5,5-tetramethylpyrrolidine (43) was over 22.6 kcal/mol. This must be higher than the barrier required for isolation of rotamers at room temperature, and is even higher than that in /V-nitroso-2,2,6,6-tetramethylpiperidine (44). Harris and Pryce-Jones attribute the high barrier of 43 relative to 44 to the more stable ground state of the former. If the pyrrolidine derivative is properly substituted, the atropisomers are expected to be isolable at room temperature. 

TEMPO (2,2,6,6-tetramethylpiperidine-Af-oxyl) and its cognates (4-OH, 4-oxo, 4-OMe substituted derivatives TMIO etc.) belong to a group of stericaUy hindered aminoxyl radicals (Chart 1) and, in view of the long hfetimes, are said to be persistent and... 

Hindered amines have attracted considerable interest recently as UV stabilizers for a number of polymers, especially polyenes (B-81MI11503, B-78MI11508). Among the compounds available commercially, those based on substituted 2,2,6,6-tetramethylpiperidine (8) and (9) have become the most important (72USP3640928). The high molecular weights of these... 

The stereodynamics of N-substituted 2,2,6,6-tetramethylpiperidines 99 (cf. Scheme 37a) were studied by Abraham and Lunazzi et al. (93JCS(P2)1299). The temperature dependence of the NMR spectra showed that a conformational interconversion takes place this could be ring inversion, N-inversion, rotation about the exocyclic bond or a complex combination of these processes. Barriers to this process are shown in Table XII. The rate-determining process changes as the nitrogen... 

Table XII. Barriers (AG /kcal mol ) to the Interconversion Process in N-Substituted 2,2,6,6-Tetramethylpiperidines 99...

Allylic azides, e.g., 1, were produced by treatment of the triisopropylsilyl enol ethers of cyclic ketones with azidotrimethylsilane and iodosobenzene78, but by lowering the temperature and in the presence of the stable radical 2,2,6,6-tetramethylpiperidine-/V-oxyl (TEMPO), 1-triso-propylsilyloxy-l,2-diazides, e.g., 2, became the predominant product79. The radical mechanism of the reaction was demonstrated. A number of 1,2-diazides (Table 4) were produced in the determined optimum conditions (Method B 16h). The simple diastereoselectivity (trans addition) was complete only with the enol ethers of unsubstituted cycloalkanones or 4-tert-butylcy-clohexanone. This 1,2-bis-azidonation procedure has not been exploited to prepare a-azide ketones, which should be available by simple hydrolysis of the adducts. Instead, the cis-l-triiso-propylsilyloxy-1,2-diazides were applied to the preparation of cw-2-azido tertiary cyclohexanols by selective substitution of the C-l azide group by nucleophiles in the presence of Lewis acids. 

In all the examples given so far, the substrate carries at least one V-o -hydrogen atom. The anodic oxidation of fully substituted amides, like N, V-di-/cr/-butylformamide and V-formyl-2,2,6,6-tetramethylpiperidine, in MeOH would be expected to follow a different pathway. The products isolated after 12-14 F, methyl V-/cr/-butylcarbamate and V-methoxycarbonyl-2,2,6,6-tetramethylpiperidine, respectively [Eq. (37)] [102], indicated that the primarily formed substrate radical cation looses the formyl proton. Further oxidation of the neutral radical leads to the cation, which may either undergo cleavage, as in Eq. (38), or nucleophilic attack by the solvent, as in Eq. (39). 

The solvent MeCN may be incorporated in the product in an altogether different type of process, which leads to formation of substituted acetonitriles. For instance, the oxidation of 2,2,6,6-tetramethylpiperidine, or the corresponding morpholine, in MeCN-NaC104 under oxygen-free conditions leads to the formation of an aminoace-tonitrile derivative [187]. The reaction was suggested to follow the mechanism given in Eq. (56). 

In other studies the influence of N substitution on the effectivity of 4-benzoyloxy-2,2,6,6-tetramethylpiperidine was studied [116-118]. In this case the effectivity decreased in the order O > O-butyl > butyl > hydrogen > acetyl. It was shown that the tertiary hindered amines were oxidized and converted to the parent secondary amine. 

The photostabilizing efficiency of A-methyl HAS pNCH3, e.g. 28,29,31, R = CH3,32) is within experimental error comparable to that of secondary HAS I NH [43,111,173,174], The simplest and most logical explanation includes a transformation of NCH3 into NH. Some studies contributed to the mechanism of this conversion. Model A-substituted tetramethylpiperidines having an H-atom on the a-carbon in the A-substituent were found to be photo-oxidized more easily than the corresponding secondary HAS [173]. Besides, the tertiary HAS decomposed /ert-butylhydroperoxide more rapidly than did NH. The reaction rates with terf-butylhydroperoxide at 132 °C were as follows ... 

Great attention has been paid to HAS and their safety application in plastics and coatings. The 4-unsubstituted 2,2,6,6-tetramethylpiperidine is considered as relatively toxic, the acute oral toxicity being about 1 g/kg. The substitution in position 4 (i.e. the general mode in the synthesis of HAS for polymer purposes) dramatically improves the situation. Therefore, commercial HAS like 28 (R = H), 34,35a or 35b were approved for stabilization of packaging materials in contact with food [307]. Some data are available on properties of TEMPO (2,2,6,6-tetramethylpiperidinyl-l-oxyl) and its 4-amino or 4-hydroxy derivatives. They were found to act as weak intrinsic direct mutagens in Salmonella typhimurium. TEMPO increases intracellular hydroperoxide concentration. This may indicate its pro-oxidative effect which does not result, however, in cellular toxicity [314]. 

Similar results have been reported by Felder and Schumacher (3, Bellus, Lind, and Wyatt (9). The results indicate that among the tested compounds, the most efficient quencher of singlet oxygen is the N-methyl-substituted piperidine derivative, followed by nickel chelates and nitroxyl compounds of the hindered amines. The 2,2,6,6-tetramethylpiperidines themselves were of relatively low efficiency. 

The Ru-catalyzed epoxidation of tran -stilbene in the presence of NaI04 was carried out using a bipyridyl ligand with a fluorous ponytail at the 4 and 4 positions. As illustrated by the first equation in Scheme 8, a triphasic system comprising water, dichloromethane and perfluorooctane was employed in the reaction. The reaction was complete in 15 min at 0°C and tran -stilbene oxide 5 was obtained from the dichloromethane layer in a 92% yield. The fluorous layer, containing the catalyst, could be recycled for four further runs without any addition of RuCls. The same perfluoroalkyl-substituted bipyridyl ligand was used successfully in the copper(i)-catalyzed TEMPO (2,2, 6,6 -tetramethylpiperidine (V-oxyl)-oxidation of primary and secondary alcohols under aerobic conditions (Scheme 8, second equation). ... 

The selection of the lithiation reagent also has a strong influence over the regioselectivity of the electrophilic substitution the bulkier the base, the more favorable the reaction at the C5 position. For example, lithium 2,2,6,6-tetramethylpiperidine (LiTMP) directs the formation of the C5-substituted product at a 79 1 ratio to the C2-substituted thiophene. A variety of electrophiles can be substituted after lithiation by LiTMP. ... 

The modifications of the Gilman-Speeter reaction include the activation of zinc by tri-methylsilyl chloride (TMSCl) and the application of lithium ester enolate" or lithium thioester enolate as the substitute for the traditional Reformatsky reagent. In these modifications, it was found that TMSCl-activated zinc is much more effective in promoting the reaction between ethyl bromoacetate and Schiff bases. In addition, in the presence of a chiral ether ligand, the reaction between lithium ester enolate and imines affords 0-lactams of high enantiomeric excess, probably due to the formation of a ternary complex reagent. " The enantioselectivity and reactivity of the ternary complex depend on the size and nature of the lithium amide used. For example, the lithium amide from 2,2,6,6-tetramethylpiperidine (LTMP) is unfavorable for this reaction." ... 

At this juncture, the stereochemistry of the amine-substituted carbon required inversion to the correct configuration of the natural product. Toward this end, lactone 354 was treated with tetramethylguanidine and 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) under an air atmosphere in THE. These conditions led to oxidation to yield enamine 355, which was subsequendy reduced with sodium cyanoborohydride to complete the epimerization process. These conditions were also sufficiently hydridic to reduce the ketone carbonyl. Heating in ethyl acetate then led to cycHza-tion to yield lactam 356. Oxidation using IBX next provided ketone 357, which was employed as a coupling partner for 2-iodoanihne in the key indolization step (Scheme 51). 

Highly efficient rhodium-catalyzed direct arylations were accomplished through the use of 2,2, 6,6 -tetramethylpiperidine-N-oxyl (TEMPO) as terminal oxidant [17]. Thereby, a variety of pyridine-substituted arenes was regioselectively functionalized with aromatic boronic acids (Scheme 9.5). However, in order for efficient catalysis to proceed, 4equiv. of TEMPO were required. The use of molecular oxygen as terminal oxidant yielded, unfortunately, only unsatisfactory results under otherwise identical reaction conditions. However, a variety of easily available boronic acids could be employed as arylating reagents. 

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