A -Methylmorpholine

Similar hydroxylation-oxidations can be carried out using a catalytic amount of osmium tetroxide with A-methylmorpholine oxide-hydrogen peroxide or phenyliodosoacetate." A recent patent describes the use of triethylamine oxide peroxide and osmium tetroxide for the same sequence. Since these reactions are of great importance for the preparation of the di-hydroxyacetone side-chain of corticoids, they will be discussed in a later section. 

N-Methylmorpholine Oxide-Hydrogen Peroxide Oxidation. The preparation of A-methylmorpholine oxide-hydrogen peroxide is described in Reagents for Organic Synthesis by L. Fieser and M. Fieser. 

With dibenzyl phosphates or phosphonates, treatment with refluxing A-methylmorpholine results in monodebenzylation (60-100% yield). 

Unfortunately, a serious problem with the osmium tetroxide reaction is that Os04 is both very expensive and very toxic. As a result, the reaction is usually carried out using only a small, catalytic amount of OsO, in the presence of a stoichiometric amount of a safe and inexpensive co-oxidant such as A -methylmorpholine N-oxide, abbreviated NMO. The initially formed osmate intermediate reacts rapidly with NMO to yield the product diol plus... 

In a similar reaction, 2,3,6-trimethoxydibenz[6,/]oxepin gives 10,11-dihydro-2,3,6-trimeth-oxydibenz[/>,/]oxepin-cw-10,l 1-diol upon treatment with osmium(VIII) oxide in the presence of A-methylmorpholine A -oxide.262 When treated with acid the diol undergoes a pinacol rearrangement to the corresponding xanthene-9-carbaldehyde. 

A very mild oxidative transformation of nitro compounds into ketones using tetrapropylam-monium perruthenate (TPAP) has been developed. A stoichiometric amount of TPAP in the presence of A-methylmorpholine A-oxide (NMO) and 4 A molecular sieves (MS).18a As the reaction conditions are neutral and mild, this method is compatible with the presence of other sensitive functionalities (Eq. 6.11). This transformation can be carried out with 10 mol% of TPAP and 1.5 equiv of NMO in the presence of potassium carbonate, 4 A MS, and silver acetate (Eq. 6.12).18b... 

A high performance capillary electrophoresis (HPCE) was described for the separation and simultaneous determination of OTC, TC, CTC, DC, and chloramphenicol in honey. The use of buffer pH 3.2 containing 0.02 mol/L Na2HP04 and 0.01 mol/L citric acid with addition of 4% (v/v) A-methylmorpholine and 12% (v/v) acetonitrile demonstrated a good separation of these five antibiotics within 20 min. The proposed method gave detection limit (signal to noise ratio > 5) of 20 pg/L for OTC [26],... 

In summary, the reaction of osmium tetroxide with alkenes is a reliable and selective transformation. Chiral diamines and cinchona alkakoid are most frequently used as chiral auxiliaries. Complexes derived from osmium tetroxide with diamines do not undergo catalytic turnover, whereas dihydroquinidine and dihydroquinine derivatives have been found to be very effective catalysts for the oxidation of a variety of alkenes. OsC>4 can be used catalytically in the presence of a secondary oxygen donor (e.g., H202, TBHP, A -methylmorpholine-/V-oxide, sodium periodate, 02, sodium hypochlorite, potassium ferricyanide). Furthermore, a remarkable rate enhancement occurs with the addition of a nucleophilic ligand such as pyridine or a tertiary amine. Table 4-11 lists the preferred chiral ligands for the dihydroxylation of a variety of olefins.61 Table 4-12 lists the recommended ligands for each class of olefins. 

FIGURE 4.15 Enantiomerization during aminolysis of 2-alkoxy-5(4A)-oxazolones in the presence of Et3N.24 Percentage -d-l- Epimer formed in reaction with H-Lys(Z)-OBzl.HCl/A-methylmorpholine in CH2C12. 

FIGURE 7.5 Preparation of a protected dipeptide by the mixed-anhydride method, employing a chloroformate that generates a cleavable urethane.13 The urethane impurity is destroyed by a P-elimination reaction. NMM = A-methylmorpholine, Msc = methane-sulfonylethoxycarbonyl. 

FIGURE 7.12 Preparation of activated esters of A-alkoxycarbonylamino acids by reaction of the hydroxy compound with a mixed anhydride (path A), obtained by leaving the three reagents (NMM = A-methylmorpholine) in CH2C12 at 23°C for 2 minutes.35 Mixed carbonate that is formed (path B) is readily eliminated by crystallization of the ester. 

FIGURE 8.5 Synthesis of p-nitroanilides by aminolysis (A) of the mixed anhydride obtained with M = A-methylmorpholine as base,14 (B) of the dichlorophosphoric anhydride obtained with P = pyridine as base and solvent, [Rijkers et al., 1991] and (C) by reaction with p-nitrophenylisocyanate. (Nishi Noguchi, 1973). 

In the stoichiometric ADH of ( )-3-hexene the highest ee was achieved using the ligand 4b (88% ee). On the other hand, the catalytic process (Table 10.4, entries 1-3) was carried out by slow addition of ( )-3-hexene (1 equiv.) to a mixture of 4a (0.25 equiv.), A-methylmorpholine A-oxide (NMO, 1.5 equiv.) and OSO4 (0.004 equiv.) in acetone-water (10/1, v/v) at 0 °C, followed by working-up with Na2S205. Although the catalytic reaction was slow and required a slower addition... 

Reductive y-lactone ring opening, with concomitant desilylation at the tertiary position by LiAlH4, gave triol 17 in 80% yield. Finally, acetonide formation followed by oxidation with tetra-n-propylammonium perruthenate/A-methylmorpholine / /-oxide oxidation, led to the target aldehyde 19 in 80% overall yield. 

There has been a study of the mechanism of the activation of carboxylic acids to peptide formation by chloro-s -triazines in combination with tertiary amines. The first step, exemplified in Scheme 2 by the reaction of 2-chloro-4,6-disubstituted-l,3,5-triazines (18) with A -methylmorpholine, is formation of a quaternary triazinylammonium salt (20). Here there is NMR evidence for the formation at —50°C of the intermediate (19), showing that the substitution involves the two-step SnAt mechanism rather than a synchronous pathway. The subsequent reaction of (20) with a carboxylic acid yields the 2-acyloxy derivative (21), which carries an excellent leaving group for the amide-forming step. ... 

Substituted phenyl azides react with acrolein and morpholine to give A -l,2,3-triazolines (743) (Scheme 149). Hoffmann elimination of A -methylmorpholine from the quaternized intermediates (744) by treatment with Ag20 affords 4-methylene triazoles (745) <86JCR(S)132>. 

Scheme 38. Reagents and conditions (a) 4 equiv. LDA, 8 equiv. TMSCI then saturated tartaric acid (92%) (b) LDA (65%, 4 1 /Z) (c) diisobutylaluminium hydride (DiBAIH) (97%) (d) CrOs, pyridine (78%) (e) LHMDS (f) DiBAIH (g) BF3-Et20(89%) (h) CrOs, H2SO4 (59%) (i) HOBt, DCC, -AZ-methylmorpholine (77%) (j) CH3NHNH2) (k) Boc-(L)-Ala, HOBt, DCC, A/-methylmorpholine (I) TFA (overall yield last four steps 22%).

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