N-acyliminium-ion

Even more reactive C=N bonds are present in N-acyliminium ions.202... 

Veerman JJN, Rutjes FPJT, Van Maarseveen JH, Hiemstra H. A novel acid stable/base labile carbamate linker for N-acyliminium ion reactions on solid support. Tetrahedron Lett 1999 40 6079-6082. 

For the synthesis of 2-519, the amines 2-516 were first treated with AlMe3 in benzene at r.t. and after addition of the enol acetates 2-515, easily accessible from 2-513 and 2-514, heated under reflux. Mechanistic investigations using on-line NMR spectroscopy, reveal that a metalated amide 2-517 is formed first. This then leads to a N-acyliminium ion 2-518 which undergoes an electrophilic substitution. Overall, three new bonds are formed selectively in the domino process, and the alkaloid scaffolds 2-519 are provided in very good yields of 79-89%. Interestingly, use of the keto esters 2-513 instead of 2-515 did not lead to the desired products 2-519. 

Padwa s group has not only developed highly efficient domino reactions using transition metal catalysis, but they are also well known for their unique combinations of a cycloaddition and a N-acyliminium ion cyclization. An example of this strategy, which is very suitable for the synthesis of heterocycles and alkaloids, is the reaction of 4-98 to give 4-101 via the intermediates 4-99 and 4-100 (Scheme 4.22). Furthermore, 4-101 was transformed into the alkaloid (+)-y-lycorane 4-102 [32]. 

In 1997, the controversial mechanism of the Biginelli reaction was reinveshgated by Kappe using NMR spectroscopy and trapping experiments [94], and the current generally accepted process was elucidated (see Scheme 9.23). The N-acyliminium ion 9-112 is proposed as key intermediate this is formed by an acid-catalyzed reaction of an aldehyde with urea or thiourea via the semiaminal 9-111. Intercephon of 9-112 by the enol form of the 1,3-dicarbonyl compound 9-113 produces the open-chain ureide 9-114, which cyclizes to the hexahydropyrimidine 9-115. There follows an elimination to give the final product 9-116. 

Other types of N-acyliminium ion-based cyclizations that are assisted by micro-wave irradiation are highlighted in Scheme 6.235 [418],... 

It is well known that oxidation of carbamates leads to the formation of N-acyliminium ions via dissociation of the C-H bond a. to nitrogen. The electrochemical,4 metal-catalyzed,5 and chemical methods6 have been reported in the literature to accomplish this transformation. The transformation serves as a useful tool for organic synthesis, although only compounds of high oxidation potentials such as methanol and cyanide ion can be used as nucleophile. It... 

Radical addition to an Af-acyliminium ion is also an interesting feature of the cation pool chemistry. We found that an alkyl iodide reacted with an N-acyliminium ion pool in the presence of hexabutyldistannane to give coupling product 19.24 A chain mechanism shown in Scheme 10, which involves the addition of the alkyl radical to the N-acyliminium ion to form the corresponding radical cation, seems to be reasonable. The present reaction opens a new possibility for radical-cation crossover mediated carbon-carbon bond formation. 

A schematic diagram of the cation flow method for generating N-acyliminium ion 2 is shown in Fig. 5. A solution of carbamate 1 is introduced into the anodic compartment of electrochemical microflow cell, where oxidation takes place on the surface of a carbon fiber electrode. A solution of trifluoromethanesulfonic acid (TfOH) was introduced in the cathodic compartment, where protons are reduced to generate dihydrogen on the surface of a platinum electrode. A-Acyliminium ion 2 thus generated can be analyzed by an in-line FT-IR analyzer to evaluate the concentration of the cation. The solution of the cation is then allowed to react with a nucleophile such as allyltrimethylsilane in the flow system to obtain the desired product 3. 

In addition to electron-deficient alkenes, under the catalysis of TiCLt, 1,2-allenylsi-lanes can react with aldehydes or N-acyliminium ion to afford five-membered vinylic silanes 71 and 72. Here the carbocations generated by a Lewis acid regiospecifically attack the C3 of the 1,2-allenylsilanes to produce a vinyl cation stabilized by hyper-... 

Hiemstra and co-workers reported the first example of an iodine-promoted allenyl N-acyliminium ion cyclization for the total synthesis of (+)-gelsedine, the enantiomer of the naturally occurring (-)-gelsedine [72], Compound 341 was prepared from (S)-malic acid. When 341 was dissolved in formic acid with a large excess of Nal and heated at 85 °C for 18 h, 343 was found to be the major product isolated in 42% yield. The latter was then successfully converted to (+)-gelsedine in a multi-step manner. Other routes without the allene moiety failed to provide the desired stereoisomer. The successful one-step transformation of 341 to 343 was key to the success of this synthesis. 

This idea is perhaps easiest to illustrate for the oxidation of an amide (Scheme 1). Amide oxidation reactions are of tremendous synthetic interest because they can provide an oxidative alternative to the synthesis of reactive N-acyliminium ion intermediates (3). Such a route would complement well the existing reductive and condensation-based approaches [1-3]. However, because amides... 

Scheme 17 Generation of N-acyliminium ions by anodic decarboxylation.

Scheme 19 Anodic conversion of amides to N-acyliminium ions.

H, Aik), ions 51 are able to add the weakly nucleophilic nitriles to give N-acyliminium ions 14 and 52 (Section II,A,l)(89ZOR2416 91MI1). This catalysis was used in the development of new methods for the synthesis of 3-azapyrylium salts from ketones 53 and 54 (Scheme 7). 

As mentioned above, the polar 1,4-cycloaddition of N-acyliminium ions 14 and 18 to olefins gives 5,6-dihydro-4H-l,3-oxazinium salts 16 (Section fI,A,l), or forms the 1,3-oxazinium salts with acetylenes (Section III, A). The same ions 89 and 91 add nitriles to furnish 1,3,5-oxadiazinium salts 90 and 92, little investigated until now (65CB334 88ZOR230). Salts 92 are unstable and can dissociate at elevated temperatures with nitrile liberation. Therefore, they may serve as original reservoirs for active jV-acyliminium cations. 

N-Acyliminium ions as intermediates in alkaloid synthesis, 32, 271 (1988) Ajmaline-Sarpagine alkaloids, 8, 789 (1965), 11, 41 (1968)... 

The Pictet-Spengler reaction is the method of choice for the preparation of tetrahydro-P-carbolines, which represent structural elements of several natural products such as biologically active alkaloids. It proceeds via a condensation of a carbonyl compound with a tryptamine followed by a Friedel-Crafts-type cyclization. In 2004, Jacobsen et al. reported the first catalytic asymmetric variant [25]. This acyl-Pictet-Spengler reaction involves an N-acyliminium ion as intermediate and is promoted by a chiral thiourea (general Brpnsted acid catalysis). 

Cheng JF, Chen M, Arrhenius T, Nadzan A (2002) A convenient solution and solid-phase synthesis of delta(5)-2-oxopiperazines via N-acyliminium ions cyclization. Tetrahedron Lett 43(36) 6293-6295... 

Tetracyclic benzo[/]-4-oxopyrrolo[l,2-fl]thieno[3,2-c]azepine 103a, as well as its piperidone homolog 103b, can be prepared through intramolecular N-acyliminium ion cyclization of hydroxylactams 102 (Scheme 20 (2001 HI 519)). 

N-Alkyl isoindolo[2,l-fc][2,4]benzodiazepines 190 (R = alkyl. Scheme 38, Section 3.1.1.2) are synthesized by an intramolecular N-acyliminium ion-amide reaction (1997TL2985, 1998T1497). Isothiocyanates 23 undergo under basic conditions in DMF ring closure by an intramolecular substitution between N1 of the pyrrole ring and isothiocyanate group to afford benzo[/]pyrrolo[l,2-c] [l,3]diazepine-5-thiones 25 (Scheme 2, Section 2.1.1.1 (2005BMCL3220)). 

The N-acyliminium ion cyclization of glutarimide 78c with terminal alkene does not show the usual selectivity in favor of ring contraction pyridobenzazepine 78d and the isomeric chloromethylquinolizidine are isolated in nearly equal amounts (10OL1696). 

Tetracyclic lactam 134 was similarly obtained from the hydroxylactam by N-acyliminium ion cyclization (01H(55)1519, 02BKC1623). 

V-Acyliminium ions are even more reactive toward alkenyl and allylic silanes. N-Acyliminium ions are usually obtained from imides by partial reduction. The partially reduced /V-acylcarbinolamincs can then generate acyliminium ions. Intramolecular examples of such reactions have been observed. 

In 2004, Taylor and Jacobsen suggested a procedure for the enantioselective acetyl-Pictet-Spengler reaction, that is the cyclization of electron-rich aryl or heteroaryl groups onto N-acyliminium ion enabling access to substituted tetrahydro-P-carbolines and tetrahydroisoquinolines that are core structure elements in natural and synthetic organic compounds [202, 203]. Screening various thiourea catalyst candidates such as 47 in the formation of model product Np-acetyl-... 

Pyrrole-containing thiourea derivatives 52 and 53 were developed and optimized for hydrogen-bonding activation of N-acyliminium ions [76] in the acyl-Pictet-Spengler [202, 205] (Schemes 6.50 and 52) and acyl-Mannich reaction [204] (Scheme 6.51). List et al. extended the applicability of this thiourea type to... 

Kano and co-workers.Once the 2,4-oxazolidinedione moiety has been incorporated, amide reduction then affords an a-hydroxy lactam, the key N-acyliminium ion precursor. Representative examples of 2,4-oxazolidinediones and the products derived from A -acyliminium ion cyclization are shown in Schemes 6.61-6.63, pp. 110-112. 

Fuji and co-workers have demonstrated the use of a PPY derivative that utilizes remote stereochemistry and an interesting induced fit process to control selectivity [21]. Upon acylation of catalyst 20, a conformational change occurs, stabilizing the intermediate N-acyliminium ion 21 (Fig. 2a,b). Chemical shifts in the XH NMR and nOes observed support a Jt-Jt interaction between the electron-rich naphthyl ring and the electron-deficient pyridinium ring. This blocks the top face of the catalyst and directs attack of the alcohol from the bottom face. Catalyst 20 effects resolutions of diol-monoesters and amino alcohol derivatives such as 22 and 23 with moderate to good selectivity factors (fcrei=4.7-21, see Fig. 2c) [22]. 

Fig. 2. Fuji s chiral PPY catalyst 20. (a) Preferred conformation of 20. (b) Preferred conformation of N-acyliminium ion 21. (c) Substrates 22 and 23...

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