A-Acyliminium ions generation

Acryloyl isocyanates, reaction with amino-sugars, uridine analogs from, 55, 139 A-Acyldehydroaminoacids, addition of nucleophiles, 57, 230 Acylhydrazones, a/3-unsaturated, cycloadditions, 57, 14 A-Acyliminium (ions), generation from alkylidenepiperazine-2,5-diones, 57, 230... 

The reactions of steiically encumbered allenylsilanes of structure type (66) with A -acyliminium ions generated by the titanium tetrachloride promot reaction of ethoxypyirolidinone product the nitrogen heterocycle (70), as depicted in Figure 13. In this reaction it is likely the lactam prc uct is generated by a pathway similar to that involved in the [3 + 2] cyclopentene aimelation. Thus, a regiospecific electro-... 

Acid-induced reactions of silicon-containing unsaturated compounds with A -acyliminium intermediates have proven particularly useful. Allylsilanes lead to the corresponding allyl-substituted products. This reaction proceeds well even for -lactams (equation 49). 5.86 j, g penicillin-derived 4-acetoxyazet-idinone (91) reacts with excess allylsilane in refluxing dichloroethane, catalyzed by TMSOTf, to produce as the sole product trans compound (92). A -Acyliminium ions generated from cyclic ureas and carbamates (93) likewise yield allylated products with virtually complete trans stereoselectivity (equation SO). Allylstannanes react under somewhat milder conditions than allylsilanes, requiring only a catalytic amount of BFsZ EtjO at room temperature for a 3-lactam system (equation 51). This allylstannane procedure was applied to cyclic carbamate systems for the stereoselective synthesis of several isomers of statine. Thus, ethoxycarbamate (94) reacts with methallyltributylstannane in excellent yield and dia-stereoselectivity (equation 52). ... 

Intramolecular additions to A-acyliminium ions (generated by Pummerer reaction) were used to prepare highly functionalized tricyclic intermediates for the synthesis of the putative alkaloid jamtine (286). Synthesis of cherylline (88) in both of its enantiopure forms was achieved using a chiral auxiliary through a sequence involving reductive amination-acid-promoted cyclization (287). 

F. 2.1 An example of inline flow ATR analysis of an A-acyliminium ion generated by flow eleetrolysis [1]... 

Generation of A-Acyliminium Ions and Synthesis of Their Precursors... 

For synthetic applications, A-acyliminium ions are nearly always generated in situ in view of their limited stability and high reactivity. Although a large variety of methods leading to A-acyliminium ions are known, only the synthetically more useful procedures, as well as the synthesis of the precursors, will be discussed in this section. 

The A-(l-alkoxyalkyl)amides and -carbamates are stable compounds, thus allowing reactions under neutral or basic conditions to be carried out elsewhere in the molecule before generation of the A-acyliminium ion with an acidic catalyst. 

Optically active five- or six-membered cyclic A -acyliminium ions of this type are generated from the a-inethoxy derivatives, easily obtainable through anodic methoxylation of intermediates that are prepared via ex-chiral-pool syntheses from certain natural amino acids. Reaction of 5-substituted five-membered cyclic A -acyliminium ions with various nucleophiles leads to the predominant formation of cw-products with moderate selectivity. The trans-selective reaction with alkyl copper reagents appears to be an exception. 

A-Acyliminium ions are usually prepared in situ in the presence of a potential nucleophile. There are several ways of generating acyliminium ions. Cyclic examples can be generated by partial reduction of imides.204... 

A-Acyliminium ions, which are even more reactive toward allylic and alkenyl-silanes, are usually obtained from imides by partial reduction (see Section 2.2.2). The partially reduced A-acylcarbinolamines can then generate acyliminium ions. Such reactions have been employed in intramolecular situations with both allylic and vinyl silanes. 

Another example of the addition of terminal alkynes to C=N in water is the coupling of alkynes with in-situ-generated A-acylimines (Eq. 4.32) and A-acyliminium ions (Eq. 4.33). In 2002, Li et al. developed a coupling reaction of alkynes with A-acylimines and A-acyliminium ions mediated by Cu(I) in water to generate propargyl amide derivatives.57 Either an activated imine derivative or imininum derivative was proposed as the intermediate, respectively. 

Af-Acyliminium ions are known to serve as electron-deficient 4n components and undergo [4+2] cycloaddition with alkenes and alkynes.15 The reaction has been utilized as a useftil method for the construction of heterocycles and acyclic amino alcohols. The reaction can be explained in terms of an inverse electron demand Diels-Alder type process that involves an electron-deficient hetero-diene with an electron-rich dienophile. Af-Acyliminium ions generated by the cation pool method were also found to undergo [4+2] cycloaddition reaction to give adduct 7 as shown in Scheme 7.16 The reaction with an aliphatic olefin seems to proceed by a concerted mechanism, whereas the reaction with styrene derivatives seems to proceed by a stepwise mechanism. In the latter case, significant amounts of polymeric products were obtained as byproducts. The formation of polymeric byproducts can be suppressed by micromixing. 

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 an another analogous set of reactions, Matsumura and coworkers have shown that electrochemically derived A -acyliminium ions can serve as electrophiles in asymmetric alkylation reactions (Scheme 25) [57]. In this case, the methoxycarbamate of a series of cyclic amines was oxidized in order to generate the AZ-a-methoxy carbamates. 

Padwa et al. (187,188) concisely summarized his domino cycloaddition/ A -acyliminium ion cyclization cascade process, which involves sequentially the generation of an isomiinchnone 1,3-dipole, intramolecular 1,3-dipolar cycloaddition reaction, 77-acyliminium ion formation, and, hnally, Mannich cyclization. Kappe and co-workers (189) utilized Padwa s cyclization-cycloaddition cascade methodology to construct several rigid compounds that mimic the putative receptor-bound conformation of dihydropyridine-type calcium channel modulators. 

A-Acyliminium ions are more reactive partners for condensation reactions than the standard Strecker intermediate 24 they are not generally isolable, but must be generated in situ and trapped to give the stable product. However, with proper choice of acyl group, they provide a-amidophosphorus analogues that are appropriately protected for peptide synthesis. 

The reaction of 2,4-pentadienyltrimethylsilane with IV-acyliminium ion generated in situ at —78°C results in the formation of pentadienyl-substituted lactams 87 in good yield (equation 59). It is noted that the reaction temperature is an important factor for controlling the e-regioselectivity. A mixture of e- and /-substitution products at the dienyl system is obtained when the reaction is carried out at 0 °C127. 

The high reactivity of the A-acyliminium ion intermediate 149 (generated from 147 via 148) was used to access the 2-benzazepine-3-ones 150 (e.g., R1 = H, R2 = Ph, 31%) in moderate yields <2005SL2791>. The N-substituted analogues 153 (e.g., R1 II. IT = Ph, R4 = Bn) could be realized via the analogous reactive intermediate 152 but produced in this latter case by SbCls-mediated addition of the acid chlorides 151 to the imines 153 (Scheme 20) <2005SL2791>. 

The iV-acyliminium ion can be characterized by FTIR spectroscopy as well. The starting carbamate 1 exhibited an absorption at 1694 cm due to the carbonyl stretching, while the A -acyliminium ion 2 generated by the cation pool method exhibited an absorption at 1814 cm". The higher wave number observed for the cation is consistent with the existence of a positive charge at the nitrogen atom adjacent to the carbonyl carbon. The shift to higher wave number is also supported by DFT (density functional theory) calculations. 

Thus, an A -acyliminium ion pool 4 was allowed to react with an enamine derivative 8 (Scheme 8). The addition of the cation to the carbon-carbon double bond generated the second cation 9, which seemed to exist either as the open form or the cyclic form. In the next step, cation 9 was treated with allyltrimethylsilane to give the final three component coupling product 10. 

Various A/-acyliminium ions like C29 can be generated under mild reaction conditions from V-(l-stannylalkyl) amides or carbamates 29 (Table 5), 32-34 (Table 6), 38, and 40 (Scheme 14) by oxidation with... 

With the stannyl group as electroauxiliary, oxonium or A-acyliminium ions can be generated, which react in an electrophilic intramolecular addition or aromatic substitution to afford cyclic six-membered ethers or amines or their benzo analogues [Table 7, numbers 20 and 21] [172b]. Swenton has explored the dependence of yield... 

The first step in the mechanism of the Biginelli reaction is the acid-catalyzed condensation of the urea with the aldehyde affording an aminal, which dehydrates to an A/-acyliminium ion intermediate. Subsequently, the end form of the 3-keto ester attacks the A/-acyliminium ion to generate an open chain ureide, which readily cyclizes to a hexahydropyrimidine derivative. 

In spite of the success of the intra-molecular cyclization, the generation of the reactive A-acyliminium ion under aprotic conditions is desirable, to avoid competing protodestannylation. Yoshida and coworkers have demonstrated a three-component coupling in which the enamide 160 reacts with the A-acyliminium ion 161 yielding a stabilized A-acyliminium species 162, which is captured by allyl-tri-n-butylstannane to give 163 (Scheme 5.2.34).5o... 

Acylation of quinoline with methylchloroformate (Scheme 5.2.69) generates the A-acyliminium ion in situ, which is efficiently trapped by allenyltri-n-butylstannane to give the 1,2-dihydroquinoline 322 in excellent yield. A potentially important Se substitution is illustrated by the reaction of 4-acetoxy-2-azetidinone 323 with the mixture of diastereomers 324 (Scheme 5.2.69) in the presence of BFj OEt2. Generation of the reactive A-acyliminium species leads to formation of jS-lactam 325 with moderate diastereoselection.ioo... 

Treatment of the solid-supported amino acetals (529) with catalytic PTSA, followed by addition of IH-benzotriazole, resulted in the 2-benzotriazole-substituted piperidines (530) as stable N-acyliminium ion precursors, according to Katritzky [392]. A number of different carbon nucleophiles were then added to the N-acyliminium ions, generated under acid catalysis by either boron trifluoride etherate or camphorsulfonic acid (Scheme 107). 

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