A-Acyliminium ions reactions

Recently the total synthesis of natural (-)-sedacryptine (228) was accomplished in an organocatalyzed Mannich/ aza-Achmatowicz/A-acyliminium ion reaction sequence in 0.6% overall yield over 14 steps (Scheme 11.50) [155], Retrosynthetic analysis revealed piperidinone 223, which was accessible from sulfone 221 via asymmetric Mannich reaction, protection of the carbonyl group, and aza-Achmatowicz reaction, to be a promising intermediate toward (-)-sedacryptine (228). Then, addition of allyltri-methylsilane to the in situ formed A-acyliminium ion afforded the c -substituted piperidinone 224 as single diaste-reomer. Compound 225, which was subjected to ozonolysis. 

The reaction of A-acyliminium ions with nucleophilic carbon atoms (also called cationic x-amidoalkylation) is a highly useful method for the synthesis of both nitrogen heterocycles and open-chain nitrogen compounds. A variety of carbon nucleophiles can be used, such as aromatic compounds, alkcncs, alkyncs, carbcnoids, and carbanions derived from active methylene compounds and organometallics. 

A number of comprehensive reviews1 6on the reaction of A-acyliminium ions, including detailed accounts of their application in alkaloid synthesis7- 8, have appeared. This section does not deal with [4 + 2] cycloaddition reactions of A -acyliminium ions these will be discussed in Section D.1.6.1.1. 

For reactions of A-acyliminium ions with alkenes and alkynes one has to distinguish between A-acyliminium ions locked in an s-trans conformation and those which (can) adopt an s-cis conformation. The former type reacts as a (nitrogen stabilized) carbocation with a C —C multiple bond. Although there are some exceptions, the intramolecular reaction of this type is regarded as an anti addition to the 7t-nucleophile, with (nearly) synchronous bond formation, the conformation of the transition state determining the product configuration. 

General Aspects Reaction Behavior of A-Acyliminium Ions... 

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. 

Bisamides (or biscarbamates), which are easily obtainable from the reaction of an aldehyde with two equivalents of a primary amide (carbamate), are converted into the corresponding A-acyliminium ions on heating, often in the presence of strong (Lewis) acids or acylating compounds1 3. 

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. 

Predominant formation of s-products on reaction of A -acyliminium ions, containing an additional conjugated double bond, with propylzinc iodide likewise arises from A(1 3) strain as discussed133. 

With certain substituents, such as methoxy150 or (substituted) phenyl53 functions, in the allylie position the reaction outcome completely changes, giving rise to predominant or exclusive formation of five-membered ring products via a preceding 2-aza-Cope rearrangement of the initially formed A -acyliminium ion. These substituents clearly stabilize the intermediary carbo-cation 3. 

So far, only reactions in which the internal nucleophile is tethered to the nitrogen atom of the A -acyliminium ion have been discussed, however, cyclizations with nucleophiles attached to other positions are also possible. If the nucleophile is connected to the carbon atom adjacent to the carbonyl group, bridged azabicycloalkane derivatives are obtained in high yield by using the more reactive allyl- or propargylsilanes. 

The mode of the diastcrcofacial selectivity is completely reversed in the case of reactions with A -methyl A-acyliminium precursors 4176. Now the nitrogen atom of the A-acyliminium ion is not able to chelate with the tin atom and the lower diastereoselectivity is explained by the less rigid nonchelation-controlled transition state 5. An electronic effect, such as n-iz attraction between the electron-deficient carbonyl group of the acyliminium ion and the electron-rich phenyl group of the phcnylthio substituent R, may account for the somewhat higher diastereoselectivity in the case of arylthio substituents R. 

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. 

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. 

Enantiospecific syntheses of amino derivatives of benzo[ ]quinolizidine and indolo[2,3- ]quinolizidine compounds have also been achieved via A-acyliminium ion cyclization reactions, as an alternative to the more traditional Bischler-Napieralski chemistry (see Section 12.01.9.2.2). One interesting example involves the use of L-pyroglutamic acid as a chiral starting material to construct intermediates 240 via reaction with arylethylamine derivatives. Diisobutylaluminium hydride (DIBAL-H) reduction of the amide function in 240 and subsequent cyclization and further reduction afforded piperidine derivatives 241, which stereoselectively cyclized to benzo[ ]quinolizidine 242 upon treatment with boron trifluoride (Scheme 47) <1999JOC9729>. 

Kise and coworkers have shown that organozinc reagents can be added to electrochemically derived A -acyliminium ions. These reactions have been used to synthesize /J-amino acid derivatives (Scheme 24) [56]. 

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. 

Both anodic oxidation reactions proceeded well. As illustrated in Scheme 44, an anodic methoxylation of menthyl pyroglutamate followed by the trapping of an incipient A-acyliminium ion with allyl-silane in the presence of Lewis acid led to (138) [86]. While the stereoselectivity of this reaction was not high, the major product from the reaction could be fractionally crystallized from hexane and the route used to conveniently prepare (138) on a scale of 10 g. In this case, a platinum wire anode was used in order to keep the current density high. This was required because of the high oxidation potential of the secondary amide relative to the methanol solvent used in the reaction. 

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. 

An alternative method for the synthesis of proline-related phosphonates is attractive because peptides with a C-terminal Prop(OPh)2 22 can be obtained directly (Scheme 15) J43l The real intermediate reacting with triphenyl phosphite remains unknown but it is very likely that it is a cyclic A-acyliminium ion. Thus, the reaction could be similar to the amidoal-kylation of triphenyl phosphite with carbamates and aldehydes. 

Upon addition of boron trifluoride etherate, acetoxylactam 8 eliminates an acetoxy group to produce A-acyliminium ion 9. The indo-lizidinone 10 is formed diastereomerically pure in an iminium-ion-ini bated cyclization reaction of the Overman type ending in a vinyl-silane.14... 

The bromination of the tetracyclic compound (30) affords71 the novel compound (31) formed by capture of the Wheland intermediate by die neighbouring carboxylate ion. The intramolecular reaction of some activated pyridines witii A -acyliminium ions led to some novel heterocycles [e.g. (33) from (32) in the presence of p-toluenesulfonic acid in benzene] by cyclization para to an electron-donating substituent.72... 

Cyclization reactions of a-acyliminium ions with allyl- and propargyl-silanes constitute a useful method for the preparation of various N-bridgehead bicyclic systems. Thus, from a reaction of hydroxylactams 107 and 108, the azaazulenes 109 and 110 were obtained in excellent yields (83TL1407). Similarly, the keto amide 112 was obtained from the imide 111 by reduction to the corresponding hydroxylactam and acid-catalyzed cyclization (84JCS(P1)2477). 

Activated A-acyliminium ion precursors were alkylated with 1-alkenyl or aryl boronates in the presence of a Lewis acid catalyst, presumably by an analogous process to that of the boron-Mannich reaction (Equations (134) and (135)).596,597... 

On the other hand, our own group and Jochims and coworkers in Germany found recently and independently another pathway for formation of the A -acyliminium ions from aldehydes and nitriles in which the order of activation of the reagents differs from that in the Ritter reaction. The method involves an initial electrophilic activation of the... 

In these reactions attention should be paid to the 118 -> 121 as well as the 126 -> 127 rearrangements, which were unknown until recently for A -acyliminium ions. It is possible, however, that in this situation an alternative mechanism involving an isomeriza-the stage of the (9-protonated intermediate, i.e. a 1,2-shift in the hydroxycarbenium ion 13386 formed from 132 (equation 45), may take place. 

Starting with the knowledge of carbenium ion stability and the understanding that it is necessary to decrease this stability enabling the reaction of these ions with nitriles102 (Section III.B.l), it should be assumed that acetals 209, oc-haloethers 211, enols 217 and vinyl ethers 218 are ineffective precursors since they are the sources of the highly stable hydroxy- (223) and alkoxycarbenium ions 224. In contrast, the carbonyl compound derivatives, which can produce destabilized ions (in comparison to ions 223 and 224) are the most interesting for reactions with nitriles. This includes acyloxycarbocations 225 (see Section III.B.3), halocarbocations 226, A-acyliminium ions 228 and vinyl cations 229. 

The quite general character of this classification may be illustrated by another reaction, the formation of the heteroanalogs of A-acyliminium ions 362153 (equation 102). 

The reaction differs from the Ritter reaction by the two types of electrophilic activation of the reagents and by the two types of rearrangement of nitrilium 285 and carboxonium ions 288 (equation 94). Besides, this interaction proceeds at an oxidation level of two, while the Ritter reaction occurs at an oxidation level of one17. While it may be shown that A-acyliminium ions 365 can be obtained from a carbonyl compound and a nitrile via the Ritter reaction, then it is only the second step b) in a three-step process where the first step (a) is the reduction of carbonyl compound 364 to alcohol 366 and the third step (c) is an oxidative dehydrogenation of amide 369 obtained3 (equation 105). 

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... 

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