Pyridine acylation catalyst

In order to understand the effect of these catalysts, it is important to observe that they do not act themselves as enhancers (no effect on light output is observed, when used alone). An explanation is proposed by considering in more detail the reaction steps from diazaquinone (L) to the luminol peroxide intermediate. This reaction involves nucleophilic attack on one of the diazaquinone carbonyls by hydrogen peroxide monoanion. A hydroperoxide species is formed, which can rearrange to the endoperoxide. Either compound is very unstable and collapses to 3-amino-phthalate in its excited state. Perhaps pyridine acylation catalysts could facilitate hydrogen peroxide attack by converting L into a more reactive intermediate. 

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. 

Pyridine, 6-cyano-l,2-dihydro-thermal dimerization, 2, 370 Pyridine, 2-cyanomethyl-tautomerism, 2, 159 Pyridine, 4-cyanomethyl-tautomerism, 2, 159 Pyridine, 2-cyano-2,3,4,5-tetrahydro-metallation, 2, 387 Pyridine, 2,5-diacetyl-ipso substitution, 2, 301 Pyridine, 3,5-diacetyl-l,4-dihydro-Hantzsch synthesis, 2, 482 Pyridine, 4-dialkylamino-as acylation catalysts, 2, 34 Pyridine, 2,2-dialkyl-l,2-dihydro-... 

In 1967, (3) it was discovered that DMAP catalyzes the benzoylation of m-chloroaniline 10 times faster than pyridine. This enormous increase in reaction rate is unmatched by any other nucleophilic acylation catalyst (3. It was shown that the catalytic action of DMAP and PPY is not primarily due to their larger pKa s with respect to pyridine, but is a result of enhanced nucleophilic catalysis. 

In 2004, Birman and coworkers set out to develop an easily accessible and highly effective acylation catalyst based on the 2,3-dihydroimidazo[l,2-a]-pyridine (DHIP) core. The first chiral derivative to be prepared and tested was (R)-2-phenyl-2,3-dihydroimidazo[l,2-fl]-pyridine 44 (H-PIP) [152]. Derived from R)-2-phenylglycinol, this catalyst afforded the KR of ( )-phenylethylcarbinol in 49% ee at 21% conversion s = 3.3). In order to improve the reactivity of the catalyst, the authors decided to introduce an electron-withdrawing substituent on the pyridine ring that would increase the electrophilicity of the acylated intermediate. Hence, three new derivatives (Br-PIP, NO -PIP and CF3-PIP) were synthesised and tested under rigorously identical conditions [152]. One of these easily accessible compounds, 2-phenyl-6-trifluoromethyl-dihydroimidazo[l,2-a]pyridine (45, abbreviated as CF3-PIP), proved to be particularly effective as, when combined with (EtC0)20 and iPr NEt, it resolved a variety of aryl alkyl iec-alcohols with good to excellent selectivities s = 26-85) (Table 7) [152]. 

Marquardt and Liining 28) immobilized concave pyridines on two types of dendrimers (9 and 10) to obtain a recoverable acylation catalyst. For comparison... 

Dialkylaminopyridines, which are active acylation catalysts, have been prepared by Patell and Sparrow,226 using secondary amines and 4-bromo-pyridine hydrochloride under liquid-liquid PT conditions. 

The organic acylation catalysts currently known are tertiary amines, N-heteroar-omatic compounds (for example pyridine derivatives), or phosphines they can be of central, planar, and axial chirality. Finally, small peptides carrying N-methylhis-tidine as the catalytically active subunit have also been employed they also will be discussed in this chapter. 

In addition to phosphines and pyridines, N-alkylated imidazoles are also known to act as a nucleophilic catalysts in acylation reactions [1], In the approach by Miller et al. short oligopeptides incorporating N-alkylhistidine derivatives were used as enantioselective acylation catalysts [27]. The design of, e.g., the tripeptide... 

One particular amino-pyridine has a special role as a more effective acylation catalyst than pyridine itself. This is DMAP (DiMethylAminoPyridine) in which the amino group is placed to reinforce the nucleophilic nature of the... 

The synthesis of DMAP, the useful acylation catalyst mentioned in Chapters 8 and 12, is carried out by initial attack of thionyl chloride (SOCI2) on pyridine. Suggest how the reactions might proceed. 

These two compounds are superior to pyridine as catalysts for acylation of alcohols, particularly for tertiary and sterically hindered alcohols. Even axial lljS-hydroxyl groups of steroids can be acetylated in yields as high as 80%. Several useful C-acylations have been reported. The reagents catalyze the transformation of amino acids into or-acylamino ketones (equation II). They are superior to pyridine for reaction of isocyanates and carboxylic acids to form amides (equation III). 

Related catalysts. Hassner et al. have prepared a number of substituted derivatives of pyridine, pyridazine, and quinoline, but only a few are useful acylation catalysts. Of these, 4-pyrrolidinopyridine (2) and l,l,3,3-tetramethyl-4-(4-pyri-dyl)guanidine (3) are most effective. 

The usual reagents for acylation of steroid alcohols are acyl chlorides or acid anhydrides, in pyridine as catalyst and solvent, or acid anhydrides with mineral acids as catalyst. All secondary hydroxyl groups (except [12]) can be esterified in pyridine,... 

When primary amines react with a-acylaminoketones the resulting Schiff bases can be cyclized in the presence of phosphoryl chloride, phosphorus pentachloride, or triphenylphosphine and triethylamine in hexachloroethane to give 1-substituted imidazoles (11) (Scheme 2.1.4). The starting a-acyl-aminocarbonyls are readily prepared from a-amino acids by reduction with sodium amalgam [31, 32] or by the Dakin-West reaction [33, 34], which is most conveniently conducted in the presence of 4-(AUV-dimethylamino)pyridine (DMAP) as an acylation catalyst [35 37]. 

Acylation catalyst.2 4-Pyrrolidinopyridine (1), like N,N-dimethyl-4-pyridinamine (3, 118-119), is a very effective catalyst for acylation of sterically hindered alcohols. In a typical procedure, the alcohol is treated with a carboxylic acid anhydride and an equimolar amount of the dialkylaminopyridine at room temperature. In preparations on a larger scale, 1 eq. of triethylamine is added to bind the acid formed in the acylation. For example, methyl cholate is converted into the triacetate at room temperature within 2 hr. using 4-pyrrolidinopyridine as catalyst. Acetylation with Ac20/pyridine at room temperature affords only the 3,7-diaeetate (the 12a-hydroxyl group is axial).3 4-Dialkylaminopyridines are particularly useful catalysts for acylation of add-sensitive tertiary alcohols such as linalool (2), which can be acetylated in 80% yield by this new procedure. 

Acylation catalyst. This base is superior to pyridine as a catalyst for O-acyla-tions. Even tertiary alcohols are readily acylated. Thus 1-methyl-1-cyclohexanol is converted into the acetate by treatment with acetic anhydride, trimethylamine (to combine with the acid formed), and a catalytic amount of this base in 86% yield at room temperature (14 hours). The yield of acetate was less than 5% when pyridine and/or triethylamine was used.2... 

Pyridines, and especially 4-dialkylaminopyrines, are well-known nucleophilic acylation catalysts and are widely used in organic synthesis.7 When they are added to the SPTZ substrate the reported7 overall reactivity is observed ... 

With pyridine, acid chlorides and acid anhydrides yield A-acyl pyridinium salts 6 which are very reactive and sensitive to hydrolysis, unlike the quaternary salts 2-5 they are involved in the acylation of alcohols and amines in pyridine as solvent (Einhorn variant of the Schotten-Baumann reaction). However, 4-dimethylaminopyridine 12 (Steglich reagent) and 4-(pyrrolidin-l-yl)pyridine 13 are better acylation catalysts by a factor of 10 [46a]. Reactions with sulfonyl chlorides in pyridine proceed via A-sulfonylpyridinium salts 14. 

Esterification. DCC has seen little use for esterification because of variable yields, which are satisfactory only in the case of phenols and thiophenols. Pyridine exerts a favorable effect the more effective acylation catalyst DMAP is more useful. With this catalyst, esters and thioesters can be obtained generally in yields of 60-95 7 . Even the hindered 2,4,6-trimethylbenzoic acid can be converted in this way into the methyl ester in yield. However, the method is subject to steric effects for example, adamantqnecarboxylic acid does not react with r-butyl alcohol under these conditions. 

Figure 7.24 Using diphenylketene as acylating agent and a concave pyridine as catalyst, the 2-position of a glucose derivative can be acylated exclusively "...

---