Internal alkylation

Much interesting work has been done in the last ten years on the bridging of pyrrole and piperidine rings. Early in their work on this subject Clemo and Metcalfe (1937) prepared quinuclidine (V) by the reduction of 3-ketoquinuclidine (IV), the latter resulting from the hydrolysis and decarboxylation of the product (III) of a Dieckmann internal alkylation, applied to ethyl piperidine-l-acetate-4-carboxylate (II), itself made by condensing ethyl piperidine-4-carboxylate (I) with ethyl chloroacetate. 

Methyldihydrostrychnidinium-A acetate is produced in much small amount in the hydrogenation ( internal alkylation) reaction and w isolated as the iodide, m.p. 345-350°, and converted to the chloric which on treatment with sodium methoxide gave methoxymethyltetr hydrostrychnidine (c in the above list) with some des-base-D, and < thermal decomposition yielded dihydrostrychnidine-A. These and oth reactions of des-base-D are regarded as best accounted for by formu (XVIII). ... 

For dirnethyldesweostrychnidine the Achmatowicz formula has been slightly modified to (XIX) by Holmes and Robinson. The third substance, dimethyWesstrychnidine-D yields both a dihydro- and a tetrahydro-derivative and, unlike des-base-D, from which it is derived, does not undergo internal alkylation when subjected to the hydrogenation process in acid solution it is represented by (XX). 

A. l-(l-Cyclopenten-l-yl)piperidine (148) reaeted with N-methyl-3-bromopropylamine hydrobromide to yield 74% of a mixture of enamines (149) 112). The proposed mechanism involved an amine exchange to give the enamine 150 which underwent internal alkylation. 

In the reaction of 2-chlorocyclohexanone with a secondary amine (632) one encounters an intramolecular enamine alkylation analogous to the internal alkylations which constitute the critical step of some Favorskii rearrangements. 

Cyclization of the two pendant alkyl side chains on barbiturates to form a spiran is consistent with sedative-hypnotic activity. The synthesis of this most complex barbiturate starts by alkylation of ethyl acetoacetate with 2-chloropentan-3-one to give 152. Hydrolysis and decarboxylation under acidic conditions gives the diketone, 153. This intermediate is then reduced to the diol (154), and that is converted to the dibromide (155) by means of hydrogen bromide. Double Internal alkylation of ethyl... 

MISCELLANEOUS FUSED HETEROCYCLES with mild base causes internal alkylation and consequent... 

This method has been used to close rings of from three n = 0) to seven members, although five-membered ring closures proceed in highest yields. Another ringclosing method involves internal alkylation. ... 

Pd(PPh )2 12 catalyses the internal alkylation of the phosphonate esters (96) and the formation of the 3-methyiene-l-oxa-2-phosphacycl.oalkane 2-oxides (97 ) phosphorus-containing analogues of a-methylenelactones. Further examples of the... 

Preparation of nefopam starts with the acylation of aminobenzhydrol 1 (obtainable by reduction of the corresponding benzoylbenzamide) with chloroacetyl chloride treatment of the chloroamide (2) with potassium tertiary butoxide results in internal alkylation to give the eight-membered ring (3). Reduction of the lactam function with lithium aluminum hydride gives the amine and, thus, nefopam (4). ... 

Vedejs developed an enantiocontrolled synthesis of aziridinomitosenes involving internal alkylation of the oxazole 132 to produce an oxazolium salt 133 followed by nucleophilic addition of cyanide providing the adduct 134 <00JA5401>. Electrocyclic ring opening of 134 to the azomethine ylide 135 with internal [2+3] trapping produces the tetracyclic product 137 via the pyrroline 136. 

An internal alkylation via a nitrogen ylide has also been reported7. Thus, the bromide salt of methyl 6-[dimethyl(2-propenyl)ammonio]penicillanate gives a 75% yield of methyl 6/J-dimeth-ylamino-6oi-(2-propenyl)peniciHanate (see Table 2). 

Catalytic hydrogenation of (23-12) over palladium on charcoal results in the scission of the weak N—O bond and the formation of amino alcohol (24-1). This is converted to a pyrrolidine by an internal alkylation reaction. Thus, reaction of the intermediate with carbon tetrabromide and triphenyl phosphine presumably converts the alcohol to a bromide internal displacement by the primary amine forms the five-membered ring (24-2). Alkylation of that amine with the complex bromo amide (24-3) then affords the endothehn antagonist atrasentan (24-4) [25]. 

Regioselective alkylation of a methyl ketone Even though the kinetic enolate of 2-heptanone consists of a mixture of terminal and internal enolates in the ratio 87 13, benzylation in DME results in preferential internal alkylation. Regioselective benzylation at the terminal position can be enhanced by addition of various ligands such as benzo-14-crown-4 and DMF, but HMPT is the most effective ligand, resulting in a ratio of terminal to internal benzylation of 11 1. The three ligands also increase the rate of alkylation. The same effect, but less marked, is observed in alkylation with the less reactive electrophile butyl iodide. 

Kim H, Choi WJ, Jung J, Kim S, Kim D (2003) Construction of Eight-Membered Ether Rings by Olefin Geometry-Dependent Internal Alkylation First Asymmetric Total Syntheses of (+)-3-( ) and (+)-3-(Z)-Pinnatifidenyne. J Am Chem Soc 125 10238... 

Fixation of aromaticity pathways in porphyrins can also be achieved through internal substitution. In the X-ray structure of A-methylporphyrin 14 (Fig. 11), the NH proton was localized on the nitrogen opposite the internal alkyl group, leading to an appropriate adjustment of the conjugation pathway [83], A complementary example is provided by octaethylporphyrin A-oxide 15, which exists as the 22H,24H tautomer both in solution and in the solid state [84],... 

Cyano-stabilized anions have been internally alkylated to generate 10-581, 14-582 and 16-membered583-586 rings. The ring-closure step in a synthesis of zearalenone has been performed in this way (equation 89)582. 

This carbocation undergoes internal alkylation to yield the observed product. 

Catalytic hydrogenation of 29 over palladium on charcoal results in scission of the weak N—O bond and formation of aminoalcohol 30. This compound is converted to a pyrrolidine by an internal alkylation... 

The energetics of the dissociation processes are summarized in table 2. The next-to-last column shows the fraction of the effective available energy. Eavi, which appears as the alkyl fragment internal excitation. The final column shows the alkyl internal energy as a fraction of the total (translational plus internal) alkyl energy. Two conclusions are clear (i) the fraction of the effective available energy which appears as alkyl internal excitation does not depend drastically on whether I or I is produced, and (ii) this fraction rises dramatically from a very low value for methyl to approximately one half for n-propyl. 

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