N-acyliminium ions reactions

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. 

N-Acyliminium ion reactions and cleavage (II) (Scheme 107) [393] This method was identical to the aforementioned general procedure except that, after cleavage, 1 m HCl in MeOH (4 mL) was added to the filtrate and the solvents were evaporated. The residue was extracted with iPrOH (2 mL), and the extract was filtered and concentrated to afford the products as their HCl salts. 

For synthetic applications the N-acyliminium species (1) is nearly always generated in situ because of its high reactivity. Heterolysis of an acetal-like structure of type (2) is a very popular method to effect N-acyliminium ion reactions. In most cases X is a hydroxy, alkoxy or acyloxy function and an acidic catalyst is used to generate (1). If X is methanesulfonyloxy, no catalyst is required, as thermal conditions suffice to produce the intermediate. If X is methoxy or ethoxy, precursor (2) is usually a stable molecule, which allows the execution of diverse reactions under neutral or basic conditions elsewhere in the molecule before the (V-acyliminium intermediate is employed. 

Mooiweer, H.H., Hiemstra, H., and Speckamp, W. (1991) Total synthesis of ( )-a-allokainic acid via two allylsilane N-acyliminium ion reactions. Tetrahedron, 47, 3451-3462. 

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. 

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. 

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... 

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). 

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)). 

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... 

The synthesis of l-azabicyclo[4.n.O] systems 31 has also been carried out by using a similar substitution between heteroaromatic rings such as furan and the N-acyliminium ion as the key reaction 20). 

Yoshida and coworkers also developed a microreaction system for cation pool-initiated polymerization [62]. Significant control of the molecular weight distribution (Mw/Mn) was achieved when N-acyliminium ion-initiated polymerization of butyl vinyl ether was carried out in a microflow system (an IMM micromixer and a microtube reactor). Initiator and monomer were mixed using a micromixer, which was connected to a microtube reactor for the propagation step. The polymerization reaction was quenched by an amine in a second micromixer. The tighter molecular weight distribution (Mw/M = 1.14) in the microflow system compared with that of the batch system (Mw/M > 2) was attributed to the very rapid mixing and precise control of the polymerization temperature in the microflow system. 

The reactions of sterically encumbered allenylsilanes of structure type (66) with N-acyliminium ions generated by the dtanium tetrachloride promot reacdon of ethoxypyirolidinone produced the nitrogen heterocycle (70), as depicted in Figure 13. In this reacdon it is likely the lactam product is generated by a pathway similar to that involved in the [3 -) 2] cyclopentene anneladon. Thus, a regiospecific electro-... 

R.A. Batey and co-workers developed a modification of the Petasis-boronic acid-Mannich reaction that occurs via N-acyliminium ions derived from A/-protected-2,3-dihydroxypyrrolidine and 2,3-dihydroxypiperidine derivatives. This method was utilized in the total synthesis of (+)-deoxycastanospermine. The formation of the A/-acyliminium ion was achieved by treating A/-Cbz-2,3-pyrrolidine with BF3-OEt2. ° Subsequent vinyl transfer from the alkenylboronic ester provided the product with excellent yield and diastereoselectivity. 

Scheme 5.2.69 Reactions of allenylstannanes with N-acyliminium ions...

---