N - Hydroxyphthalimide

N-Hydroxyphthalimide A-Hydroxyphth-alimide (NHPI) was shown to be a mediator for the electrochemical oxidation of (1) to (2) (Eq. 6) [57, 58], although the yields of (2) were not always satisfactory. A large deuterium isotope effect ( h/ d = 10.6) was observed in the oxidation of benzhydrol [59]. Recently, tetrafluoro-NHPI was found to be efficient for the oxidation of borneol [60]. 

Scheme 32 Oxidation of alcohols with N-hydroxyphthalimides as mediator.

Ishii and coworkers, in the course of their studies on the N-hydroxyphthalimide (NHPI)-catalyzed functionalization of cyclohexane, have observed that the nitrosation of cyclohexane 52 by fert-butyl nitrite 53 can be successfully achieved without photoirradiation and under halogen-free conditions by using NHPI as a catalyst (Scheme 31). 

Benzyl -o-xylopyranoside was converted into the alcohol 54 (a somewhat capricious isopropylidenation) [39] and a Mitsunobu inversion with N-hydroxyphthalimide, followed by protecting group removal, gave the hydro-xylamine 55. Transfer-hydrogenation (ammonium formate and palladium-on-charcoal in refluxing methanol) [40] then gave, on a small scale and in almost a quantitative yield, the enantiomer of the desired tetrahydro-l,2-oxazine 52. We have never been able to repeat this result since Figure 4 shows the NMR spectra acquired at the time [41]. 

Efficient oxidation of alkanes with molecular oxygen can be attained using N-hydroxyphthalimide combined with Co(acac) (n = 2,3).1121 According to a new concept, photocatalyzed selective oxidation of small hydrocarbons at room temperature is carried out over alkali or alkaline-earth ion-exchanged zeolites.1122... 

Efficient catalytic alkane nitrations can be performed with the assistance of N-hydroxyphthalimide (NHPI) with N02 in air [Eq. (10.57)]298 or with HNO3.299 NHPI may also be used to form alkanesulfonic acids by reacting alkanes with S02 300... 

Recently, N-hydroxyphthalimide (NHPI) catalysis has been applied to a variety of aerobic oxidations of organic compounds [12], We have reported how NHPI, in the presence of Co(II) salts, is able to generate the phthalimido N-oxyl (PINO) radical, which rapidly abstracts hydrogen from aromatic and aliphatic aldehydes, in a free-radical chain mechanism under aerobic conditions (Scheme 14.2) [13]. The role of oxygen is to oxidize Co(II) to Co(III), which is also involved in the oxidation of the intermediate (Equation 14.8). 

Catalysis by TEMPO has the advantage of being general for oxidation of both benzylic or non benzylic alcohols to aldehydes, whereas catalysis by PINO, although limited to the synthesis of aromatic aldehydes, has the advantage that the radical is generated in situ from the less expensive N-hydroxyphthalimide, which can be more easily recovered and recycled. 

A solution of 3 mmol 3-cyanobenzyl alcohol, 0.3 mmol N-hydroxyphthalimide, 0.015 mmol Co(OAc)2, and 0.15 mmol m-chlorobenzoic acid in 15 mL acetonitrile was stirred at r.t. for 4h under 02 at atmospheric pressure. GC analysis (3-chloro-benzaldehyde as internal standard) revealed 3-cyanobenzaldehyde in 98% yield. Flash column chromatography on silica gel yielded 2.8 mmol of pure 3-cyanobenz-aldehyde (m.p. 77-78 °C 93 % yield). 

To a stirred mixture of anhydrous potassium carbonate (7 g, 50.7 mmol) and N-hydroxyphthalimide (14 g, 95 mmol) in DMSO (250 ml) was added, over 5 min, diphenyliodonium chloride (38 g, 120 mmol). After 15 h of stirring at room temperature the reaction mixture was added to ice (600 g). Colourless crystals of (V-phenyloxyphthalimide separated after 1 h. They were collected, washed with water and dried to give 20 g (90%) of crude product upon recrystallization from ethanol pure A-phenyloxyphthalimide (13.5 g, 66%) was obtained, m.p. 143.5-145°C. 

Recently the Co/Mn/N-hydroxyphthalimide (NHPI) systems of Ishii have been added to the list of aerobic oxidations of hydrocarbons, including both aromatic side chains and alkanes. For example, toluene was oxidized to benzoic acid at 25°C [125] and cyclohexane afforded adipic acid in 73% selectivity at 73% conversion [126], see Fig. 4.46. A related system, employing N-hydroxysac-charine, instead of NHPI was reported for the selective oxidation of large ring cycloalkanes [127]. 

Co(acac)3 in combination with N-hydroxyphthalimide (NHPI) as cocatalyst mediates the aerobic oxidation of primary and secondary alcohols, to the corresponding carboxylic acids and ketones, respectively, e.g. Fig. 4.71 [205]. By analogy with other oxidations mediated by the Co/NHPI catalyst studied by Ishii and coworkers [206, 207], Fig. 4.71 probably involves a free radical mechanism. We attribute the promoting effect of NHPI to its ability to efficiently scavenge alkylperoxy radicals, suppressing the rate of termination by combination of al-kylperoxy radicals (see above for alkane oxidation). 

N-Hydroxyphthalimide (8.7 mmol), iodoacetic acid (8.7 mmol) and 1,3-dicyclohexylcarbodiimide (8.7 mmol) were dissolved in 250ml EtOAc and stirred 5 hours at room temperature. The mixture was filtered, dried, the residue crystallized in ethanol, and the product isolated in 75% yield, mp = 120 °C. 

N-Tritioacetoxysuccinimide has also been prepared by the esterification of N-hydroxyphthalimide with H3-acetic acid and is described (3). 

At higher temperatures, compounds 56 condense with another molecule of J 103-113-120-200-201 Qr with potassium phthalimide120,202 to form 58a or 58b, respectively, and with N-hydroxyphthalimide.202... 

DCC can be used to prepare 5-alkyl and 5-aryl thiocarboxylates (1) from carboxylic acids and thiols according to equation (5). This method has been successfully applied to the synAesis of thiol esters with sensitive substituents, e.g. 5-methyl thioacrylate, a natural product. In particular, N-protected amino acid and peptide 5-phenyl esters, which are useful building blocks in peptide synthesis, are obtained in excellent yields without racemization. N-Hydroxyphthalimide and DMAP have been used as cocatalysts to facilitate the reaction. The preparation of the Wittig reagent (5) by this route is shown in equation (6). 

Sakaguchi, S., Hirabayashi, T., Ishii, Y. First Ritter-type reaction of alkylbenzenes using N-hydroxyphthalimide as a key catalyst. Chem. Commun. 2002, 516-517. 

Petrassi, H. M., Sharpless, K. B., Kelly, J. W. The copper-mediated cross-coupling of phenylboronic acids and N-hydroxyphthalimide at room temperature synthesis of aryloxyamines. Org. Lett. 2001,3,139-142. 

The synthesis of N-hydroxyphthalimide by Nefkens (1—>4) is indirect. A direct synthesis worked out later by Mazur and Plume is shorter and the yield is higher (91%). A solution of 1.1 moles of hydroxylamine hydrochloride in 1.5 1. of pyridine in a 1-1. one-necked round-bottomed flask was cooled to 30°, 1.0 mole of phthalic anhydride was added in one portion, and the flask was swirled until a clear solution resulted (42°). The solution was heated at an internal temperature of 90° for 15 min. and the pyridine was distilled on a rotating evaporator at water-pump pressure. The hot viscous residue was added rapidly to 1 1. of 1 A acetic acid and the resulting precipitate was collected and washed thoroughly with 0.01 A acetic acid. 

The preparation of the reagent in 70% yield by reaction of N-carboethoxy-phthalimide (1) with hydroxylamine and triethylamine in boiling absolute ethanol appears to involve cleavage of the heterocyclic ring (2) and its re-formation (3) with elimination of urethane the solution turns red with formation of the triethylara-monium salt of N-hydroxyphthalimide (4), and after acidification and dilution with water this separates in nearly colorless needles. The reagent is used in peptide... 

Coupung, dehydrative Bis-o-phenylene pyrophosphite. N,N -Carbonyldiimidazole. N,N -Carbonyl-J-triazine. l-Cyclohexyl-3-(2-morpholinomethyl)-carbodiimide. 1,1-Di-chlorodiethyl ether. Dicyclohexylcarbodiimide. Diethyl chlorophosphonate. Diethyl-cyanamide. Diethyl ethylenepyrophosphite. N-(3-Dimethylaminopropyl)-N -ethylcarbo-diimide hydrochloride. Diphenylketene p-tolylamine. Ethoxyacetylene. l-Ethyl-3(3 -di-methylaminopropyllcarbodiimide hydrochloride. Ethylene chlorophosphite. N-Ethyl-S-phenyliioxazolium-3 -sulfonate. N-Hydropyridine. N-Hydroxyphthalimide. N-Hydroxy-piperidine, N-Hydroxysuccinimide. Phenylphosphorodi-d-imidazolate). 

Figure 17. N-Hydroxyphthalimide/Co(II)-catalysed chemoselective oxidation of a secondary alcohol.

One notable achievement is the process that makes use of N-hydroxyphthalimide (NHPI) as the catalyst for the aerial oxidation of cyclohexane [30]. NHPI is a cheap, nontoxic catalyst easily prepared by the reaction of phthalic anhydride and hydrox-ylamine. It acts as a precursor of the phthalimido-N-oxyl (PINO) radical, which is the effective abstracting species in the free radical process (Scheme 7.7). 

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