DMAPS

Formation - "activated acid", base, solvent, (DMAP)... 

As a catalyst for ester and amide formation from acyl chlorides or anhydrides, 4-(di-methylamino)pyridine has been recommended (DMAP G. Hdfle, 1978). In the presence of this agent highly hindered hydroxyl groups, e.g. of steroids and carbohydrates, are acylated under mild conditions, which is difficult to achieve with other catalysts. 

We shall describe a specific synthetic example for each protective group given above. Regiosdective proteaion is generally only possible if there are hydroxyl groups of different sterical hindrance (prim < sec < tert equatorial < axial). Acetylation has usually been effected with acetic anhydride. The acetylation of less reactive hydroxyl groups is catalyzed by DMAP (see p.l44f.). Acetates are stable toward oxidation with chromium trioxide in pyridine and have been used, for example, for protection of steroids (H.J.E. Loewenthal, 1959), carbohydrates (M.L. Wolfrom, 1963 J.M. Williams, 1967), and nucleosides (A.M. Micbelson, 1963). The most common deacetylation procedures are ammonolysis with NH in CH OH and methanolysis with KjCO, or sodium methoxide. 

Because coupling is not always quantitative, the non-reacted terminal deoxynucteoside must be excluded from the following synthesis cycles. Otherwise deletion sequences will render the isolation of the pure final product difficult. Therefore a capping step (step 3) follows, e.g., acetylation with acetic anhydride and N,N-dimethyl-4-pyridinamine (DMAP) in dioxane. Capping times should be as short as possible, especially with 2-cyanoethyl phosphite triesters, which are sensitive to bases such as DMAP. 

Indole (10mmol) was added to dry CH3CN (20 ml) and the mixture stirred while DMAP (122 mg, 1,00 mmol) and di-tert-butyl dicarbonate (2.62 g. 12 mmol) were added. Evolution of gas was noted and stirring was continued... 

Vinylpyridine (23) came into prominence around 1950 as a component of latex. Butadiene and styrene monomers were used with (23) to make a terpolymer that bonded fabric cords to the mbber matrix of automobile tires (25). More recendy, the abiUty of (23) to act as a Michael acceptor has been exploited in a synthesis of 4-dimethylaminopyridine (DMAP) (24) (26). The sequence consists of a Michael addition of (23) to 4-cyanopyridine (15), replacement of the 4-cyano substituent by dimethylamine (taking advantage of the activation of the cyano group by quatemization of the pyridine ring), and base-cataly2ed dequatemization (retro Michael addition). 4-r)imethyl aminopyri dine is one of the most effective acylation catalysts known (27). 

Most of them are generally classified as poisons. Exceptions to this rule are known. A notable one is 4-dimethyl aminopyridine (DMAP) (24), which is widely used in industry as a superior acylation catalyst (27). Quaternary salts of pyridines are usually toxic, and in particular paraquat (20) exposure can have fatal consequences. Some chloropyridines, especially polychlorinated ones, should be handled with extra care because of their potential mutagenic effects. Vinylpyridines are corrosive to the skin, and can act as a sensitizer for some susceptible individuals. Niacin (27), niacinamide (26), and some pyridinecarbaldehydes can cause skin flushing. 

Dimethylaminopyridine [1122-58-3] (DMAP) (24) has emerged as the preferred catalyst for a variety of synthetic transformations under mild conditions, particularly acylations, alkylations, silylations, esterifications, polymeri2ations, and rearrangements (100). POLYDMAP resin [1122-58-3], a polymeric version of DMAP, is available, and is as effective as DMAP as a catalyst for acylation reactions. Furthermore, it can be recycled without regeneration more than 20 times with very Htde loss in activity. POLYDMAP is a trademark of Reilly Industries, Inc. 

TBDMSCl, DMAP, Et3N, DMF, 25°, 12 h. " These conditions were used to silylate selectively a primaiy over a secondary alcohol. Besides DMAP, other catalysts such as 1,1,3,3-tetramethylguanidine, 1,8-diazabicy-clo[5.4.0]undec-7-ene(83-99%), l,5-diazabicyclo[4.3.0]non-5-ene, and ethyldiisopropylamine have been used. ... 

TBDPSCl, DMAP, Pyr. Selective silylation of a primary hydroxyl was achieved under these conditions. 

TBDPSCl, DMAP, triethylamine, CH2Cl2. This combination of reagents was shown to )e very selective for the silylation of a primary hydroxyl in the presence of a secondary hydroxyl. 

AC2O, AcCl, Pyr, DMAP, 24-80°, 1-40 h, 72-95% yield. The use of DMAP increases the rate of acylation by a factor of 10. These conditions will acylate most alcohols, including tertiary alcohols. The use of DMAP (4-N,N-dimethylaminopyridine) as a catalyst to improve the rate of esterification is quite general and works for other esters as well. 

The nitrobenzyl caibonates were prepared to protect a secondary hydroxyl group in a thienamycin precursor. The o-nitrobenzyl carbonate was prepared from the chloroformate (DMAP, CH2CI2, 0° - 20°, 3 h) and cleaved by irradiation, pH 7. The p-nitrobenzyl carbonate was prepared from the chloroformate (—78°, n-BuLi, THE, 85% yield) and cleaved by hydrogenolysis (H2/Pd-C, dioxane, H2O, EtOH, K2HP04). It is also cleaved by electrolytic reduction. ... 

The 2-iodobenzoate is introduced by acylation of the alcohol with the acid (DCC, DMAP, CH2CI2, 25°, 96% yield) it is removed by oxidation with CI2 (MeOH, H2O, Na2C03, pH > 7.5). ... 

SEMCl, DMAP, Et3N, benzene, reflux, 3 h, 98% yield. ... 

DMAP = 4-dimethylaminopyridine (lO" times more effective than pyri- dine) ... 

RCO.H, R OH, DCC/DMAP, Et20, 25°, 1-24 h, 70-95% yield. This method is suitable for a large variety of hindered and unhindered acids and alcohols. ... 

The reaction is not suitable for hindered carboxylic acids, since considerable symmetrical anhydride formation (52% with pivalic acid) results. Symmetrical anhydride formation can sometimes be suppressed by the use of stoichiometric quantities of DMAP. 

Fluorenylmethyl esters of A -protected amino acids were prepared using the DCC/ DMAP method (50-89% yield) or by imidazole-catalyzed transesterification of... 

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