Collidine, derivatives

Whereas thousands of tons of pyridine and picolines are required for agrochemical, vitamin B3, and consumer product markets, lutidine and collidine derivatives are made on the 10-100 ton scale only, primarily for use as solvents and intermediates in the pharmaceutical industry. Acetone, CH2O, and ammonia are used commercially to produce 2,6-lutidine (21) over metal-promoted catalysts. Zeolites MFI [45] and BEA [26] have featured in the most recent literature. 

This reaction has been used for the syntheses of pyridine and collidine derivatives. 

This reaction consists of the condensation of two molecular equivalents of a 1,3 diketone (or a J3-keto-ester) with one equivalent of an aldehyde and one of ammonia. Thus the interaction of ethyl acetoacetate and acetaldehyde and ammonia affords the 1,4-dihy dro-pyridine derivative (1), which when boiled with dilute nitric acid readily undergoes dehydrogenation and aromatisation" to gb e the diethyl ester of collidine (or 2,4,6-trimethyl-pyridine-3,5 dicarboxylic acid (II)). For the initial condensation the solid aldehyde-ammonia can conveniently be used in place of the separate reagents. 

Present-day nomenclature is partly the result of the conflict and interplay of two functions the need to communicate in speech and on the printed page on the one hand, and the need for archival storage of information and its efficient, reliable retrieval. The former function came first, and laid the basis for the nomenclature most commonly used even today, and gave birth to a wealth of trivial names (i.e. names that give little or no information on structure). These were often coined on the basis of the origin of the substance, as in the case of collidine, obtained from distillation of bones in glue factories, or were derived from a special characteristic, as in the case of skatole, which has a fecal odor. Such names are short and generally euphonious, but they must be memorized they cannot be deduced from the structure. 

Hg(C104)2, 2,4,6-collidine, acetone, H2O (9 1), 5 h NH3, dioxane, H2O (1 1). In this case Hg(II) is used to cleave the MTM group, liberating a hydroxyl group, which assists in the cleavage of the carbonate on treatment with ammonia. Cleavage by ammonia is 500 times faster for this hydroxy derivative than for the initial MTM derivative. 

Meroquinenine, CgHjjOaN (meroquinene), formed by the oxidation of all four alkaloids and of cinchoninone or quininone and by the hydrolysis of quinenine or cinchenine (p. 489), crystallises from methyl alcohol in needles, m.p. 223-4° (dee.), [ajp -f- 27-5° (H2O). It gives a nitrosoamine, m.p. 67°, and a monoacetyl derivative, m.p. 110°, and can be esterified the ethyl ester hydrochloride has m.p. 165°. When oxidised by chromic acid it yields formic and cincboloiponic acids. On reduction with zinc dust and hydriodic acid, it adds on two atoms of hydrogen forming cincholoipon, CgH jOaN, and when heated with hydrochloric acid at 250-60° gives 3-ethyl-4-methylpyridine ()3-collidine). 

Mono-substitution occurs most readily in the stepwise replacement of the halogen substituents of 2,4,6-trichloro-s-triazine with aqueous methanol and sodium bicarbonate (30°, 30 min), the monomethoxy derivative (324) is obtained on heating (65°, 30 min), the disubstitu-ted derivative is formed and on brief heating (65°) with the more basic sodium carbonate or methanolic sodium hydroxide (25°, 3 hr) complete methoxylation (320) occurs. Ethanolic ethoxide (25°, 1 hr) or sodium carbonate (35°) is sufficient to give complete ethoxy-dechlorination. The corresponding phenoxy derivatives are obtained on treatment with one (0°), two (15°, 1 hr), or three equivalents (25-70°, 3 hr) of various sodium phenoxides in aqueous acetone. The stepwise reaction with phenols, alcohols, or thiols proceeds in better yield in organic solvents (acetone or chloroform) with collidine or 2,6-lutidine as acid acceptors than in aqueous sodium bicarbonate. ... 

The above-mentioned results indicate the additive effect of protons. Actually, a catalytic process is formed by protonation of the metal-oxygen bond instead of silylation. 2,6-Lutidine hydrochloride or 2,4,6-collidine hydrochloride serves as a proton source in the Cp2TiCl2-catalyzed pinacol coupling of aromatic aldehydes in the presence of Mn as the stoichiometric reduc-tant [30]. Considering the pKa values, pyridinium hydrochlorides are likely to be an appropriate proton source. Protonation of the titanium-bound oxygen atom permits regeneration of the active catalyst. High diastereoselectivity is attained by this fast protonation. Furthermore, pyridine derivatives can be recovered simply by acid-base extraction or distillation. 

An elecrophilic Br+ or I+ can be successfully transferred to hydroquinidine (13) and two of its commercially available derivatives (4-chlorobenzoate and 9-phenanthryl ether hydroquinidines) simply by mixing two equivalents of the hydroquinidine with one equivalent of sym(co d ne)2-X+ perchlorate in methylene chloride or acetonitrile. H NMR studies (31) showed that the iodonium ion was associated with the nitrogen at the quinuclidine portion of the hydroquinidine instead of the aromatic nitrogen and also that all of the sym-collidines were removed from the X+ since only free collidine and no collidine-I+ peaks were observed. The (hydroquinidine)2-halonium ion is stable in solution for more than 30 minutes at room temperature these ions (and their parent amines) are more soluble in methylene chloride than in acetonitrile, and having R group other than hydrogen also improves the solubility. 

Fig. 1 Lewis and Funderburk found that the H/D primary kinetic isotope effects (25 °C in aqueous t-butyl alcohol) for proton abstraction from 2-nitropropane by pyridine derivatives all exceed the maximum isotope effect that could have been derived from the isotopic difference in reactant-state zero-point energies alone (a value around 7). The magnitude of the isotope effect increases with the degree of steric hindrance to reaction presented by the pyridine derivative, the identical results for 2,6-lutidine and 2,4,6-collidine ruling out any role for electronic effects of the substituents. The temperature dependence shown for 2,4,6-collidine is exceedingly anomalous the pre-exponential factor Ahis expected to be near unity but is instead about 1/7, while the value of AH — AH = 3030 cal/mol would have generated an isotope effect at 25 °C of 165 if the pre-exponential factor had indeed been unity.

Fuji and Kawabata further demonstrated the utility of their catalyst by successfully achieving the KR of iV-protected cyclic cw-amino alcohols [113], Hence, by using 5 mol% of 4-PPY 29 in the presence of a stoichiometric amount of collidine in CHCI3 at room temperature, a variety of cyclic cw-amino alcohol derivatives were resolved with moderate to good selectivities = 10-21) (Table 6) [113],... 

Electrophilic iodine reagents have also been employed in iodocyclization. Several salts of pyridine complexes with I+ such as bis(pyiidinium)iodonium tetrafluoroborate and bis(collidine)iodonium hexafluorophosphate have proven especially effective.61 y-Hydroxy- and d-hydroxyalkcncs can be cyclized to tetrahydrofuran and tetrahydropyran derivatives, respectively, by positive halogen reagents.62 (see entries 6 and 8 in Scheme... 

Products with a [5]metacyclophane skeleton are obtained when dihalocarbene adducts of certain cycloheptene derivatives are treated with silver(I)perchlorate in the presence of 2,4,6-collidine in tetrahydrofuran [177, 178]. 

Several attempts have been made, especially in recent years, to oxidize saturated to unsaturated azlactones. 64 The oxidation of saturated azlactone 13 with DDQ or o-chloranil in the presence of collidine as a weak base affords the unsaturated azlactone 14 in 40-50% yield (Scheme 5). Breitholle and Stammer 65 reported the preparation of unsaturated azlactone 16 by dehydrobromination of the bromopseudoazlactone 15 (Scheme 5). The pseudoazlactones derived from Ala and Abu tend to dibrominate, but careful reaction conditions allowed their isolation in acceptable yields. 65 This procedure is applicable to the preparation of derivatives of AAla, AAbu, AVal, and ALeu. 66 ... 

The clean conversion of support-bound, primary amines into sulfonamides by treatment with sulfonyl chlorides is more difficult to perform than the acylation of amines with carboxylic acid derivatives, probably because of the oxidizing properties of sulfonyl chlorides and because primary amines can be doubly sulfonylated. Weak bases (pyridine, 2,6-lutidine, NMM, collidine), short reaction times, and only a slight excess of sulfonyl chloride should therefore be used to convert primary amines into sulfonamides (Table 8.7). 

The reaction was also carried out on the laboratory scale by Bayer 182) (use of special electrolytes and collidine as an auxiliary base), Fuso 183> (use of phosphorus compounds as conductive salts) and UOPl84) (use of alcoholates as electrolytes). Under comparable conditions, p-cresol cannot be oxidized to the corresponding p-hydroxy-benzaldehyde derivatives. If the phenolic hydroxyl group is protected, it is also possible to obtain p-hydroxybenzaldehyde derivatives. 

The assigned structures are confirmed by relating them chemically to GAs or GA-derivatives of known structure. For example, GAl o methyl ester was converted to the known compound, deoxy GA methyl ester (j+3), by formation of the toluene-p-sulfonate and treatment of this with boiling collidine (1-2). 

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