N-alkylation reactions

A recent formal synthesis of the alkaloid (—)-mitralactonine relied on a reaction that allowed the simultaneous creation of three new bonds, two of them a and one ft with respect to the quinolizine nitrogen. As shown in Scheme 112, treatment of triptamine with chiral aldehyde 480 in the presence of acid directly gave a mixture of diastereo-meric indoloquinolizidines 481 and 482 through a mechanism involving a Pictet-Spengler cyclization and a N-alkylation reaction <2007SL79>. 

Scheme 6.115 Synthesis of primary and tertiary amines by N-alkylation reactions.

Besides N-alkylation reactions, there are also reports in the literature concerning microwave-promoted O-alkylations. A mild method for the O-alkylation of phenols with alkyl bromides and chlorides has been developed by Wagner and coworkers (Scheme 6.117 a) [235], The protocol is applicable to substrates that are sensitive to strong bases or to hydrolysis, or are difficult to extract from an aqueous phase. The procedure uses methanol as a solvent and a stoichiometric amount of potassium carbonate as a weak base. Optimum yields were obtained by heating the phenol with 1.2 equivalents of the alkyl bromide (or 3 equivalents of the less reactive chloride) at 100-140 °C for 15-30 min. 

Several solvent-free N-alkylation reactions have been reported which involve the use of phase transfer agent, tetrabutylammonium bromide (TBAB), under microwave irradiation conditions, an approach that is described in Chapt. 5 [34],... 

Nalidixic acid, 3 29 21 104, 123, 215 year of disclosure or market introduction, 3 6t N-alkylation reactions of aniline, 2 785-786 microwaves in, 16 557-558 Naltrexone drug delivery, 9 65—66 Nameplate capacities, 23 547-548 Nametre viscometer, 21 739 NAND arrays, 22 258 Nanoaluminum composites, 10 19, 20 Nanoassemblies, shell and core cross-linked, 20 489-490 Nanocar, 24 62 Nanocarbon materials, 1 718-722 Nanoceramics, 1 705-708 Nanoclays, 11 313-314... 

Niridazole Niridazole, l-(5-nitro-2-thiazolyl)-2-imidazolidinone (38.1.11), is made by reacting 2-amino-5-nitrothiazol with 2-chloroethylisocyanate to make the disubstituted urea (38.1.10). Heating this compound results in an intramolecular N-alkylation reaction to form the desired imidazolidine derivative, niridazole [7-11]. 

The naphthyridines undergo N-alkylation reactions as expected. Thus, N-6 and N-7 are methylated first in 1,6- and in 1,7-naphthyridine, respectively. The quaternary iV-methyl salts are oxidized by potassium ferricyanide to afford the JV-methyl-a-one derivatives (95-98).54-56 The kinetics of... 

A less common approach to 2,5-diketopiperazine was reported by Marcaccini et al. [79] who used a Ugi-4CR between amines, aldehydes, isocyanides, and chloroacetic acid to get adducts 140. Treatment of 140 with ethanolic potassium hydroxide led to an intramolecular amide N-alkylation reaction, giving 2,5-diketopiperazines 141... 

The synthesis of N-alkylated dihydropteridinones 34 started with a displacement reaction of 4,6-dichloro-5-nitropyrimidine with a fluorous amino-ester (Scheme 23) [53]. The compounds formed 35 were then reacted with secondary amines to yield 36. The reduction of the nitro group of 36 was conducted by hydrogenation using Pd on charcoal as a catalyst. The cyclization reactions of 37 were promoted by microwave irradiation. The N-alkylation reaction of the cyclized products 38 with benzyl halides gave monobenzylated... 

The same experimental procedure was used for further N-alkylation reactions of 2,4-bis(trimethylsilyloxo)thieno[3,2-d]pyrimidine-2,4-diones 271. Thus, reaction of 271 with 2-acetoxyethyl acetoxymethyl ether, 2-(acetoxymethoxy)propane-l,3-dibenzoate, and benzyloxymethyl acetate gave the respective 1- and 3-alkylated derivatives 274 and 275, 276 and 277, and 278 and 279 (90MI1 94JHC305 94MI2, 94MI3). ... 

Synthesis, structure and conformational behavior of cyclophanes are of interest. Synthesis of a novel chiral cyclophane consisting of indole as one of the core units was achieved [198]. The first bridge of the cyclophane 273 is formed by a conjugate addition of indole (2) to the unsaturated ketone 269. An intramolecular N-alkylation reaction of 271 resulted in the formation of... 

N-substituted iron porphyrins form upon treatment of heme enzymes with many xenobiotics. The formation of these modified hemes is directly related to the mechanism of their enzymatic reactivity. N-alkyl porphyrins may be formed from organometallic iron porphyrin complexes, PFe-R (a-alkyl, o-aryl) or PFe = CR2 (carbene). They are also formed via a branching in the reaction path used in the epoxidation of alkenes. Biomimetic N-alkyl porphyrins are competent catalysts for the epoxidation of olefins, and it has been shown that iron N-alkylporphyrins can form highly oxidized species such as an iron(IV) ferryl, (N-R P)Fe v=0, and porphyrin ir-radicals at the iron(III) or iron(IV) level of metal oxidation. The N-alkylation reaction has been used as a low resolution probe of heme protein active site structure. Modified porphyrins may be used as synthetic catalysts and as models for nonheme and noniron metalloenzymes. 

The N-alkylation reaction represents a bifurcation of the normal alkene epoxidation reaction cycle and, therefore, N-alkylation is a suicide event that leads to catalytic inhibition in the native system. With synthetic tetraarylporphyrins that mimic the N-alkylation reaction, the use of halogen-substituted catalysts that are stable toward oxidative degradation (26, 27) provide the most useful model systems because the heme model remains intact for a significantly greater number of turnovers than the partition number. The partition number is the ratio of epoxidation cycles to N-alkylation cycles, i.e., N-alkyl porphyrins are formed before the heme is oxidatively destroyed. 

Traylor (38) has also shown that biomimetic iron N-alkylporphyrins themselves are competent catalysts for epoxidation of alkenes with a rate constant of about 104 M-1 s-1. On the basis of these observations and rearrangement reactions of specific alkenes, Traylor has proposed the reaction sequence outlined in Scheme 3 as representative of the oxidation and N-alkylation reactions of the P-450 model systems. In this scheme, the epoxide and the N-alkylated heme are derived from a common, electron-transfer intermediate (caged ferrylporphyrin-alkene cation radical). Collman and co-workers (28, 29) prefer a concerted mechanism (or a short-lived, acyclic intermediate) for epoxidation and N-alkylation reactions. Both authors note that the reactions catalyzed by cytochrome P-450 (and biomimetic reactions) probably can not be ascribed to any single mechanism. 

Synthesis of 11C-labelled radiopharmaceuticals in N-alkylation reaction with 11C-methyl iodide... 

Several 1 -labelled radiopharmaceuticals have been prepared281 by Langstrom and coworkers by N-alkylation reactions with 1 -methyl iodide, carried out in DMF as demonstrated in equation 118. 

A stereoselective synthesis of (+)-pilocarpine (7) starting from L-histidine (2) has been worked out by Noordam et al. (88 - 90). Use was made of the S configuration of the amino acid, which is the same as that of C-3 of the lactone ring in both (+)-pilocarpine and (+)-isopilocarpine. Furthermore, regioselective N-alkylation reactions of the imidazole nucleus of histidine had been developed by Beyerman et al. (29,91). Schemes 3 and 4 depict the different ways of the regioselective alkylations. For the synthesis of pilocarpine, the N7I-methylation has been performed via Nb-protection with the 4-nitrobenzenesulfonyl group, instead of the benzoyl group (29). 

C-alkylation reactions 0-alkylation reactions N-alkylation reactions... 

Terminal alkynes are weakly acidic. The alkyne hydrogen can he removed by s strong base 9uch ae Na NH.. to yield nn a<%tylide anipn An acetylide anion ads as a nucleophile and can displace a halide ion from a primary alkyl halide in a n alkylation reaction. Acetylide anions are more stable iJian either alkyl anions or vinylic anions because their m ative charge is in a hybrid orbital with 50% s character, allowing the charge to be doser to the nucleus. 

The occurrence of a maximum in Fig. 7 is in agreement with Rideal mechanism. Thus, the 2MN yield is a function of the partial pressure of N and methanol, and the fraction of sites covered by methanol. According to the proposed Rideal type mechanism, the N alkylation reaction with MeOH produces methyl derivative and a few di-,tri-, and tetra-... 

Venuto, P.B., L.A. Hamilton and P. S. Landis. Organic Reactions Catalyzed by Crystalline Aluminosilicates, n. Alkylation Reactions Mechanistic and Aging Considerations. J. Catal., 1966, 4, 484-493. 

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