Reissert-type intermediates

The formation of a Reissert anion (intermediate of type 16) is usually the introductory step in a great number of synthetic routes leading to isoquinoline as well as indole alkaloids and related compounds. On the one hand, the alkylation of a Reissert anion with alkyl halide followed by alkaline hydrolysis is the most frequently used method for the synthesis of 1-alkyl- or 1-arylalkylisoquinolines (20) (Scheme 4). On the other hand, Reissert anions react with aldehydes to form... 

Note 1,6-Naphthyridine appears to undergo Reissert-type additions only at its 5-and 6-positions the products are useful intermediates for further elaboration. 

Acid chlorides 21 and chloroformates 23 are the most commonly used activating agents and the preferred reagents for evaluating the reactivity of other components in new Reissert-type processes. For example, in studies on the total synthesis of the indolopyridine alkaloids 42, acetyl chloride was used in the key step to prepare the common synthetic intermediate 41. In this case, an enamide moiety intramole-cularly attacks the in situ generated Ai-acylazinium salt, and the Reissert adduct is spontaneously oxidized and hydrolyzed to regain aromaticity in the last step (Scheme 7) [44, 45]. 

Sequential reaction of azines with alkyl hthium compounds and chloroformates usually affords the expected Reissert-type products 136, together with minor amounts of doubly acylated compounds 135 (Scheme 18b). Isoquinoline is likely to react directly with the alkyl-lithium compound to generate the alkylated lithio-enamine intermediate E, and this species may account for the formation of dihydroisoquinolines 135 and 136, through interaction with the electrophihc partner. Mamane recently expanded this concept by replacing the acylating agent with different electrophiles. These combinations lead exclusively to isomers 134 (Scheme 18) [118-120]. 

Zhu and coworkers implemented a family of Ugi-type MCRs, based on intramolecular trapping of the intermediate nitrilium ion by a carboxamido group, to prepare diversely substituted oxazoles as versatile synthetic intermediates [192-194], They later reported an interesting example of the Ugi-Reissert process using this feature (237, Scheme 34a) [195], This strategy enabled the direct addition of isocyanides to the Ai-alkyl nicotinamide salts 239. However, the different substitution pattern of the carboxamido group, led to a different outcome isomerization of the putative bis-iminofurane intermediate to the cyano-carbamoyl derivative 240. Remarkably, the process is also efficient in a Reissert-type reaction (Scheme 34b, c) [196]. 

The Reissert-type reaction is considered to proceed via two steps (i) the generation of an acyl quinolinium intermediate by a nucleophilic attack of quinoline to an acid chloride and (ii) the addition of cyanide [150]. Shibasaki has developed an... 

Pyrimidine reacts with trimethylsilyl cyanide and benzoyl chloride with aluminum chloride as catalyst, to give the Reissert-type compound (366) <81JHC443>. The intermediate acylpyrimidinium cation (367) adds a soft nucleophile such as the silyl ether of acetophenone, and the adduct rapidly undergoes a second A-quaternization to (368) with a subsequent nucleophilic attack to form (369) (Scheme 61). The reactive intermediate can also be trapped by reactions with heteronucleophiles <88JCS(P1)725>. Intramolecular nucleophilic addition is shown in the formation of the spiran derivative (370) <92JOC2526>. 

The synthesis of porphobilinogen from 2-methoxy-4-methyl-5-nitropyridine (section 5.15.2.3) is an example of a Reissert-type synthesis (section 17.16.1.2) affording in this case a 6-azaindole as an intermediate. 

Addition to Carbonyls, Imines (Strecker-type Reactions), and Heteroaromatic Rings (Reissert-type Reactions). Cyanohydrin trimethylsilyl ethers are of significant synthetic interest as they can be transformed into a variety of multifunctional intermediates. Aldehydes and ketones can be enantioselectively converted to cyanohydrin trimethylsilyl ethers when treated with cyanotrimethylsilane in the presence of a Lewis acid and a chiral ligand. Enantioselective and/or diastereoselective formation of cyanohydrins and their derivatives has been reported and most of these reactions involve chiral ligands and metal catalysts containing Ti (eq 24), Sm (eq 25), and A1 (eq 26). ... 

Cyclic Reissert equivalent compound 265 yields, by transformation into intermediate 266 followed by sulfuryl chloride-mediated ring-opening rearrangement, L-type homoberbine enamide 267 (05T5037). 

A reinvestigation of the experiments on the UV irradiation of l-acetyl-l,2-dihydroquinoline-2-carbonitriles (Reissert compounds) 561 unequivocally demonstrated that the rearrangement via the diradical intermediate 562 gave 4//-3,l-benzoxazines 563 and 565 rather than the benzazete derivatives described earlier. The yields and the type of products were strongly influenced by the substituent R at position 4 while irradiation of the unsubstituted quinoline 561 (R=H) gave 3,1-benzoxazine 563 in nearly quantitative yield, the amount of the corresponding methyl-substituted analog 565 that could be isolated was considerable lower, due to its irreversible isomerization via 562 to the stable cycloprop[/ ]indole derivative 564 (Scheme 107) <199811(49)121 >. 

Different types of activating agents have been employed in Reissert-related reactions (Scheme 6). In many cases, it is mandatory to generate, or even isolate, the corresponding azinium salt intermediate, and sequentially proceed with the nucleophilic addition. Moreover, since the former step often takes place selectively and at a fast rate, the transformation can be performed in a multicomponent manner without any functional group interference. 

The unusual coimectivity pattern of the dipoles 247 and 248, whereby the isocyanide nitrogen is linked to the a-carbon of the azine, suggests a markedly distinct reaction mechanism (Scheme 37) to that of the Ugi-Reissert reaction. A reasonable mechanistic proposal may involve the formation of the A-acylazinium salt I, which would then be attacked at its a-position by the isocyanide, then leading to the Amdtsen-type dipoles 249 (which have been isolated in some cases). Alternatively, the isocyanide can attack the activated carbonyl group in I, triggering a cascade leading to the generation and subsequent transformation of intermediate... 

High yields of a-cyanoazines are obtained from pyridine, quinoline or isoquinoline (V-oxides and TMS-CN in acetonitrile/triethylamine or in DMF, and so in THF in the presence of tetrabutylammoni-um fluoride. In another variation TMS-CN together with dimethylcarbamoyl chloride is used. Mechanistically these transformations should be similar to the Reissert reaction and may run through intermediates of type (18) and (19 Scheme 22) ... 

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