Pyridines 4-isopropyl

The nucleophilic equivalent of the Friedel-Crafts reaction of pentafiuoropyridine with hexafiuoropropene—potassium fiuoride ia sulfolane gave perfiuoro-(4-isopropyl)pyridine ia 94% yield (426). 

Phosphite esters are formed readily by the reaction of phosphoms haUdes and isopropyl alcohol. Eor example, triisopropyl phosphite [116-17-6] is prepared from phosphoms trichloride [7719-12-2] and isopropyl alcohol at low temperatures ia the presence of an acid scavenger, eg, pyridine [110-86-1]. 

When exposed to ait, the sodium salts tend to take up moisture and form dihydrates. The alkah metal xanthates are soluble ia water, alcohols, the lower ketones, pyridine, and acetonitrile. They are not particularly soluble ia nonpolar solvents, eg, ether or ligroin. The solubiUties of a number of these salts are Hsted ia Table 4. Potassium isopropyl xanthate is soluble ia acetone to ca 6 wt %, whereas the corresponding methyl, ethyl, / -propyl, n-huty isobutyl, isoamyl, and benzyl [2720-79-8] xanthates are soluble to more than 10 wt % (12). The solubiUties of the commercially available xanthates ia water are plotted versus temperature ia Figure 1 (14). 

Benzoyl chloride and sodium isopropyl xanthate gave a mixed anhydride that was stable to pyridine catalyst, but a 2-year-old sample had turned to isopropyl ben2oate (16). 

Ethyl isopropyl ether 110 CsHi O Pyridine 172 C5H5N... 

The phosphorodithioate is stable to heating at 100°, 80% acetic acid (1 h), dry or aqueous pyridine (days) and refluxing methanol, ethanol or isopropyl alcohol for Ih. 

The most thoroughly investigated compounds are the alkyl-pyridines. Coleman and Fuoss compared the reactions of pyridine, 4-picoline, and 4-isopropylpyridine with n-butyl bromide and found a steady increase in the rate in the order given the activation energies are 16.0,15.95, and 15.6 kcal per mole, respectively. Brown and Cahn carried out a detailed study of the reactions of 2-, 3-, and 4-alkyl-pyridines with methyl, ethyl, and isopropyl iodides in nitrobenzene the results are given in Table II. These data show the higher activation... 

Random incorporation of two different acetoacetates can also be avoided by converting one of the acetoacetates to a derivative which carries the future pyridine nitrogen. For example, treatment of ethyl acetoacetate with ammonia gives the corresponding P-aminocrotonate 32. The aldehyde (34) required for preparation of such an unsymmetrical compound is prepared by reaction of the product from direct metallation of 33 with dimethylformamide. Condensation of that aldehyde with methyl acetoacetate and the p-aminocrotonate from isopropyl acetoacetate leads to isradipine (35) [9]. The same aldehyde with ethyl acetoacetate and the P-aminocrotonate from ethyl acetoacetate gives darodipine (36) [10]. In much the same vein, condensation of the ben-zaldehyde 37 with methyl acetoacetate and its P-aminocrotonate derivative affords riodipine (38) [11]. 

The methyl groups adjacent to the pyridine nitrogens can also be modified without changing calcium channel blocking activity. The most significant change involves replacement of methyl by a nitrile group. Hantsch type condensation of the nitrobenzaldehyde 43 with methyl acetoacetate and the vinyl amine 44 from isopropyl 3-cyano-3-ketopropionate leads directly to nilvadipine (45) [13]. 

This residue is dissolved in isopropyl alcohol and 1 gram N-bis-chloroethyl-aniline is added to it. The mixture is refluxed for 3 hours. The solvent is removed at a reduced pressure, the residue is treated with 50% potassium carbonate, and extracted with ether. By treating with ethereal hydrochloric acid, 2-N -m-chlorophenylpiperazino-propyl-s-triazole-[4,3-al-pyridine-3-one hydrochloride is precipitated MP 223°C. 

In the course of this study, the authors determined /Lvalues for dibenzyl, methyl phenyl, methyl p-nitrophenyl, di-p-tolyl, di-isopropyl and tetramethylene sulphoxides and for diethyl, dipropyl and dibutyl sulphites. The /Lscales are applied to the various reactions or the spectral measurements. The /Lscales have been divided into either family-dependent (FD) types, which means two or more compounds can share the same /Lscale, family-independent (FI) types. Consequently, a variety of /Lscales are now available for various families of the bases, including 29 aldehydes and ketones, 17 carboxylic amides and ureas, 14 carboxylic acids esters, 4 acyl halides, 5 nitriles, 10 ethers, 16 phosphine oxides, 12 sulphinyl compounds, 15 pyridines and pyrimidines, 16 sp3 hybridized amines and 10 alcohols. The enthalpies of formation of the hydrogen bond of 4-fluorophenol with both sulphoxides and phosphine oxides and related derivatives fit the empirical equation 18, where the standard deviation is y = 0.983. Several averaged scales are shown in Table 1588. 

The reactions of the isopropyl-substituted 3-dimethylaminopropenyli-denechromium complex 109 with terminal alkynes 90 bearing a bulky substituent (e.g., R=ter -butyl, mesityl, adamantyl etc.), in the presence of moist pyridine, yield 2-(acylmethylene)pyrrolidines 110 (Scheme 23) [84]. The dihydroazepinetricarbonylchromium complexes 111 were found to be the key... 

Brown and McDonald (1966) provided another type of kinetic evidence for these size relationships by determining secondary kinetic isotope effects in reactions of pyridine-4-pyridines with alkyl iodides. For example, the isotopic rate ratio in the reaction between 4-(methyl-d3)-pyridine and methyl iodide at 25-0 C in nitrobenzene solution was determined to be kjyfk = l-OOl, while that in the corresponding reaction with 2,6-(dimethyl-d6)-pyridine was 1-095. (Brown and McDonald (1966) estimate an uncertainty of 1% in the k jk values.) Furthermore, the isotopic rate ratio in the case of the 2-(methyl-d3)-compound increased from 1 030 to 1-073 as the alkyl group in the alkyl iodide was changed from methyl to isopropyl, i.e. the isotope effect increased with increasing steric requirements of the alkyl iodide. 

In 2004, ruthenium-catalysed asymmetric cyclopropanations of styrene derivatives with diazoesters were also performed by Masson et al., using chiral 2,6-bis(thiazolines)pyridines. These ligands were prepared from dithioesters and commercially available enantiopure 2-aminoalcohols. When the cyclopropanation of styrene with diazoethylacetate was performed with these ligands in the presence of ruthenium, enantioselectivities of up to 85% ee were obtained (Scheme 6.6). The scope of this methodology was extended to various styrene derivatives and to isopropyl diazomethylphosphonate with good yields and enantioselectivities. The comparative evaluation of enantiocontrol for cyclopropanation of styrene with chiral ruthenium-bis(oxazolines), Ru-Pybox, and chiral ruthenium-bis(thiazolines), Ru-thia-Pybox, have shown many similarities with, in some cases, good enantiomeric excesses. The modification... 

Fig. 4.18. First-order reaction plots of decomposition of tetraethylammonium titrant in (A) isopropyl alcohol, (B) isopropyl alcohol-toluene (1 1), (C) benzene and (D) pyridine.

In recent years, a variety of aryl boronic acids are commercially available, albeit in some cases they may be expensive for large scale purposes. During our work in the mid-1990 s boronic acid (II) was not commercially available and so two different protocols were used to prepare this acid. The first approach involved the transmetallation with n-butyl lithium of aryl bromide (I) and trapping the lithio species generated with trialkyl borate followed by an acid quench. Aryl bromide (I) is easily prepared by reaction of o-bromobenzenesulfonyl chloride with 2-propanol in the presence of pyridine as a base. The second approach was a directed metallation of isopropyl ester of benzene sulfonic acid (VII), to generate the same lithio species and reaction with trialkyl borate. The sulfonyl ester is prepared by reaction of 2-propanol with benzenesulfonyl chloride. From a long-term strategy the latter approach is... 

The acyclic version of Larock s heteroannulation was successfully applied to the synthesis of highly substituted pyridines [166]. The annulation of rert-butylimine 210 with phenyl propargyl alcohol produced pyridine 211 regioselectively in excellent yield. The regiochemistry obtained was governed by steric effects. Furthermore, the choice of imines was crucial to the success of the heteroannulations. terr-Butylimine was the substrate of choice, since all other imines including methyl, isopropyl, allyl and benzyl imines failed completely to produce the desired heterocyclic products. 

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