A-methyl morpholine

FIGURE 8.15 Alkylamines encountered in peptide synthesis. 1, pyridine 2, 2,4,6-trimethylpy-ridine 3, 2,6-di-ferf-butyl-4-methylpyridine 4, 4-dimethylaminopyridine 5, A-methyl-morpholine, 6, fV-methylpiperidine 7, triethylamine 8, diisopropylethylamine 9, l-diethylaminopropane-2-ol 10, dicyclohexylamine 11, diethylamine 12, piperidine 13, piperazine 14, morpholine 15, l,8-diazabicyclo[5.4.0]undec-7-ene 16, 4-(aminoethyl)piperidine 17, frw(2-aminoethyl)amine 18, 3-dimethylaminopropylamine 19, methylamine 20, dimethy-laminoethane-2-ol 21, 1,2,2,6,6-pentamethylpiperidine 22, l,4-diazabicyclo[2,2,2]octane 23, 7-methyl-1,5,7-triazabicyclo[4,4,0]dec-5 -ene. 

TPA-Ru04 (4.5 mg, 0.013 mmol) is added to the nitro compound (0.13 mmol), A-methyl-morpholine-iV-oxide (22.7 mg, 0.194 mmol), AgOAc (43 mg, 0.258 mmol), K2CO, (90 mg, 0.65 mmol) and powdered 4A molecular sieves (0.1 g) in MeCN (2 ml). The mixture is stirred for 10 h at 40° C and Et20 (5 ml) is then added. Filtration through Celite and evaporation of the filtrate yields the ketone. 

Fig. 4. Danishefsky s total synthesis formation of cyclobutanone, sulfenylation, and successive oxidation reactions. DME = 1,2-dimeth-oxyethane, TBAF = tetra-n-butylammonium fluoride, NMO = A/-methyl-morpholine-N-oxide.

A one-sided binding of the complex to the support resulted in further improvements (92). This requires synthesis of nonsymmetric salen-type ligands, which is complicated by the tendency of such ligands to equilibrate to give mixtures containing symmetric Schiff bases. Excellent results were obtained with monomer 7d, diluted in a methacrylate polymer, by using a combination of meta-chloroperbenzoic acid (mCPBA) and A-methyl-morpholine-A-oxide (NMO) as the oxidants ... 

A solution of IV-acetyl-S-trityl-L-cysteine (0.71 mmol) and 80 jxl A-methylmorpholine dissolved in 5 ml of EtOAc was stirred at -15°C, then treated with 93 jxl isobutyl chloroformate. After 15 minutes, S-acetylcysteaminehydrochloride (0.71 mmol) and an additional 80 xl A-methyl-morpholine were added and the mixture stirred for 15 minutes at — 15°C and then 3 hours at ambient temperature. A-Methylmorpholine hydrochloride was then filtered off and the mixture was washed twice with 2.5 ml of EtOAc and concentrated. The gummy residue was purified by flash chromatography with silica gel using EtOAc/30% petroleum ether and the product isolated in 55% yield as a colorless powder, mp = 111-113°C. 

A very broad class of primary oxidants act as oxygen atom transfer agents, the most widely nsed oxidants in oxidation catalysis. These inclnde peracids or their anion forms, snch as MCPBA or oxone (O-OSOs ) as well as A-oxides snch as A-methyl morpholine A-oxide or hypochlorite ion. They all have general structure XO, where X is a good leaving gronp. 

Add DIPEA to the vessel (usually slight excess, 3.5-4 eq) and stir with a PTFE stick until complete dissolution of the A-protected amino acid occurs. Other tertiary amines can be used such as A-methyl morpholine or triethylamine. 

Zong eta/, reported a new method for preparing A -acyloxaziridines 359 via the tandem 0,N-addition of hydroxamic acids 357 to methyl propiolate 358 (Equation 14) <1998TL6227>. The reaction was carried out in the presence of a catalytic amount of A -methyl morpholine. The desired A -acyl oxaziridines were obtained in good to excellent yields (Table 32). 

Recently, DMTMM 75 has been described as an efficient, one-pot coupling reagent for ester and amide bond formation (102). This reagent first undergoes an SNAr reaction as in the case of cyanuric fluoride 9. The activated ester then undergoes aminolysis. The in situ liberation of A-methyl morpholine avoids the use of an additional base conveniently. The triazi-none 76 by-product is eliminated easily by an aqueous wash (see Fig. 16). 

The primary alcohol Z-13 is oxidized to aldehyde 14 (Segment BC) using the Swern protocol. Typically, Swern oxidation is performed in CH2CI2 using oxalylchloride, dimethyl sulfoxide and triethylamine at -78 °C. In transformations of chiral, enolizable alcohols, milder bases such as A-methyl morpholine or sterically hindered bases such as diisopropylethylamine Hunig s base) are widely used. Swern oxidation is an inexpensive, fast (typically several minutes), mild and selective oxidation method for primary and secondary alcohols. For the detailed mechanism, see Chapter 5, p. 86. 

Discovered in 1987, the tetra-n-propylammonium perruthenate (TPAP) oxidation is straightforward to run. The reagent is expensive and thus it is used in catalytic amounts and becomes re-oxidized by A-methyl morpholine-A-oxide. For a review see Ley, S. V. Norman, J. Griffith, W. P Marsden, S. P. Synthesis 1994, 639-666. 

Tetrapropylammonium perruthenate (TPAP 63 mg) was added in 1 portion to a stirred mixture of A -Boc-4-fra .y-hydroxy-L-proline (1 g, 3.47 mmol), A-methyl-morpholine A-oxide (0.62 g, 15.6 mmol), and powdered molecular sieves (4 A, 1.78 g) in CH2CI2 (7 mL) at room temperature under argon. The mixture was stirred for 3 h, filtered, and evaporated in vacuo to give a black residue. The product was purified by... 

In dihenzyl phosphates or phosphonates treatment with refluxing A/-methyl-morpholine results in monodebenzylation (60-100% yield). ... 

To a solution of 7 (458 mg, 1.7 mmol) and A-methyl morpholine A-oxide (244 mg) in r-butanol (1 mL), a few crystals of osmium tetraoxide dissolved in THF (1.5 mL) were added. After 3 days 40% aqueous solution of NaHSOj (3 mL) was added, the mixture was stirred for additional 30 min, and extracted with ethyl acetate (3 x 20 mL). The extracts were dried (MgS04) and concentrated to dryness. The residue was purified by chromatography on a silica gel column with light petroleum-ether-methanol (4 5 0.5) to yield 9 (371 mg, 72%) mp 89.5° (from a mixture of hexane and ethyl acetate), [a] 4- 52° (c 1.0, CHCI3). 

Numerous syntheses have been reported of the AT i receptor antagonist telmisartan, which contains two benzimidazoles/ Although typical reductive cyclization conditions are used in most of the reported syntheses, one patent describes unique cyclization conditions for formation of the second benzimidazole ring system/ In this one-pot protocol, the 2-propyl-4-methyl-l//-benzimidazole-6-carboxylic acid is first activated with 2-chloro-4,6-dimethoxy-l,3,5-triazine in A-methyl morpholine (NMM) and methanol, then treated with A-methyl-o-phenylenediamine and heated to reflux to provide the cyclized product. This protocol allow for synthesis of the benzimidazole system under nonacidic conditions and moderate temperatures. 

Catalytic amounts of camphor-10-sulfonic acid (CSA) in methanol and dichloro-methane smoothly cleave the orthoester function in 23, giving the intermediate y-lactone-l,3-diol. Subsequent protection of the primary alcohol function with di-methylphenylchlorosilane (TPSCl) in dimethylformamide with imidazole as the base and of the secondary alcohol function via alcoholate with benzylbromide (BnBr) following WiLLlAMSON s ether synthesis yields the y-lactone 24. Its reduction with lithiumaluminumhydride leads to two vicinal primary alcohol groups. Thereafter, camphor-10-sulfonic acid (CSA) in dichloromethane selectively cleaves the TBS ether and catalyzes the transketalization with acetone dimethyUcetal to the precursor 25 of the aldehyde 8. Smooth oxidation of the primary alcohol function in 25 is achieved with tetrapropylammoniumperruthenate (TPAP) and A-methyl-morpholine-A-oxide (NMO) in acetonitrile. 

This procedure has been modified to become an effective catalytic procedure in which A methyl-morpholine A(-oxide is used as the secondary oxidant. In this manner, (JE -sdlbene has been conver d into (+)-(/jreo-hydrobenzoin (55% yield after two recrystallizations, >99% ee) on a one molar scale, by treatment with osmium tetroxide (0.002 mol equiv.) and IV-methylmorpholine IV-oxide (1.2 mol equiv.) in aqueous acetone in the presence of dihydroquinidine p-chlorobenzoate (0.134 mol equiv.). The latter compound can be recovered in 91% yield. 

The problem is apparently due to some residual aluminum that is hard to remove. If, however, the reduction is carried out in a iV-methylmorpholine solution, followed by addition of potassium tartrate, a pure product can be isolated. A -Methylmorpholine is a good solvent for reductions of various macromolecules with metal hydrides.In addition, the solvent permits the use of strong NaOH solutions to hydrolyze the addition complexes that form. Other polymers that can be reduced in it are those bearing nitrile, amide, imide, lactam, and oxime pendant groups. Reduction of polymethacrylonitrile, however, yields a product with only 70% of primary amine groups. Complete reductions of pendant carbonyl groups with LiAlH4 in solvents other than A -methyl-morpholine, however, were reported. Thus, a copolymer of methyl vinyl ketone with styrene was fully reduced in tetrahydrofuran. ... 

Commercially available enantiopure acetate 30 was aminated with sodium di-tert-butyloxy diimide by palladium catalyst to give bis-Boc amide 31, which was quantitatively dihydroxylated by using catalytic osmium tetraoxide and A -methyl morpholine A -oxide (NMO) in THF/water resulting in the cw-diol 32. The free base 33 was liberated from 32 by concentrated... 

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