Intermediate ketene iminium

The stereochemical course of the annulation process has been determined by reaction of acryloyl chloride with the morpholine enamine of 4-f-butyl-2-methylcyclohexanone. The bicyclic dione was obtained in 76% yield as a 4 1 mixture of two isomers (Scheme 150). X-ray analysis of the main isomer showed that reaction had occurred by axial attack from the same side as the C-2 methyl group. In order for regeneration of the enamine system to occur under conditions of stereoelectronic control, the intermediate ketene-iminium salt presumably adopts a twist conformation. Cyclization of the ketene... 

Unlike ketcnc cycloadditions, very few mechanistic studies have been carried out with ketene iminium salt cycloadditions. Differences in regiochemistry in the latter examples suggest that these reactions are not concerted and that a carbcne-type addition to the alkene leading to an intermediate such as 6 is responsible for these reactions.8... 

The ketene iminium salt cycloaddition route has been used to prepare a key intermediate 7 for the synthesis of grandisol.10... 

The intramolecular ketene iminium salt route has been used in the preparation of a key intermediate 16 for the synthesis of prostaglandins,16... 

Amino-substituted naphthalenes can be obtained by reacting phenyl vinyl acetamides with triflic anhydride in the presence of a base via the ketene-iminium intermediate (100). ... 

Scheme 7.23 illustrates the diastereoselectivities observed under various conditions in the synthesis of 2,3-dimethyl pent-5-enamides from ( )-2-buten-l-ol [11, 14, 25, 26, 47]. The anti isomer usually predominates with the exception of the thermal Ficini-Claisen variant (Scheme 7.23, Eq. 2) [18]. In this case, slow addition of the allylic alcohol to the ynamine at elevated temperatures resulted in a 1 2 mixture of aniv.syn products. This result can be explained by assuming that addition of the alcohol to the ketene iminium intermediate (cf 16, Scheme 7.9) occurs from the less hindered side and results in the preferential formation of the (E)-ketene N,0-acetal. This kinetic intermediate then undergoes rearrangement...

The previous sections have dealt with stable C=N-I- functionality in aromatic rings as simple salts. Another class of iminium salt reactions can be found where the iminium salt is only an intermediate. The purpose of this section is to point out these reactions even though they do not show any striking differences in their reactivity from stable iminium salts. Such intermediates arise from a-chloroamines (133-135), isomerization of oxazolidines (136), reduction of a-aminoketones by the Clemmensen method (137-139), reductive alkylation by the Leuckart-Wallach (140-141) or Clarke-Eschweiler reaction (142), mercuric acetate oxidation of amines (46,93), and in reactions such as ketene with enamines (143). 

The reaction of enamines with ketene (146) and sulfene (147) are presumed to proceed by a two-step process involving an iminium intermediate such as 99. In fact, reaction with all electrophilic olefins such as acrylonitrile and related reagents could be thought of as going through an iminium intermediate similar to 99. Another example is given by addition to an enamine... 

Hepatite Virus NS3/4A having the pyrrolidine-5,5-trans-lactam skeleton [83], starting from (R)- and (S)-methionine, respectively. The key step is the addition of the proper silyl ketene acetal to an iminium ion, e.g., that generated by treatment of the intermediate 177 with boron trifluoride, which provided the adduct 178 with better diastereoselectivity than other Lewis acids. Inhibitors of hepatitis C virus NS3/4A were efficiently prepared by a similar route from (S)-methionine [83]. The addition of indole to a chiral (z-amino iminium ion was a completely diastereoselective step in a reported synthesis of tilivalline, a natural molecule which displays strong cytotoxicity towards mouse leukemia L 1210 [84]. 

With trimethylsilyl iodide 17 the 0,N-acetal 457 gives the iminium iodide as reactive intermediate this converts the enol silyl ether 107 a in situ into the Man-nich-base 669, in 81% yield, and hexamethyldisiloxane 7 [195]. On treatment of the 0,N-acetal 473 (or the N-silylated Schiff base 489) with TMSOTf 20 (or Zny, the intermediate iminium triflate adds to the ketene acetal 663 to give mefhoxytri-methylsilane 13 a and silylated / -amino esters such as 670, which are readily transsilylated by methanol to give the free / -aminoester [70, 196] (Scheme 5.61). 

Warming the above a-thioiminium salt in the presence of the thiophile and base was critical in order to accomplish the sulfide-contraction process. At ambient temperature, work-up of the same reaction mixture produced the oxolactam analog of (102) as the major product (74%) along with a small amount (12%) of vinylogous carbamate (103). In order to better understand the underlying mechanism that prevailed under ambient versus elevated temperatures, NMR studies were conducted on the a-thioiminium salt (107). This intermediate, when dissolved in deuterated chloroform at ambient temperature in the presence of DBU, was converted immediately to a proposed S,N-ketene acetal (108 Scheme 23). Triphenylphosphine had no effect on the iminium salt. Aqueous work-up yielded the lactam (109), which is consistent with formation of the S,N-ketene acetal. However, wanning the intermediate (107) in the presence of the base and thiophile allowed the reaction to eventually proceed via the sulfur-extrusion pathway, due to the reversibility of the S,N-ketene acetal formation. 

Silyloxycyclopropanecarboxylates are masked homoenolate equivalents which can also add to dimethyl(methylene)iminium salts. In one of several examples reported by Reissig and Lorey, methyl 2-f-butyl-2-(trimethylsilyloxy)cyclopropanecarboxylate and triflate salt (33) react to produce methylaminomethyl-y-oxo ester (64 Scheme 14). The reactive intermediate has not been precisely determined but is most likely a ring-opened enolate (63) or its silyl ketene acetal derivative. The reaction can also be performed using the chloride iminium salt (31) in the presence of TiCU, but the reproducibility is poor due to reduced solubility. The products of these reactions are convenient precursors to a-methylene-8-lactones and acrylic acid derivatives. 

The Polonovski-type reaction of the tetrahydroisoquinoline Al-oxide 51 with an O-TBDPS ketene acetal, which activates the iV-oxide, produces an intermediate iminium ion that reacts with 0-TMS ketene acetal resulting in alkylation at the 1-position <97JOC8268>. 

Martin et developed a biogenetic entry into Ala-methylvellosimine (168) which employed an iminium ion-mediated cyclization similar to van Tamelen s original proposal. As shown in Scheme 4, dihydrocar-boline 169, which was readily obtained from commercially available D-tryptophan, was allowed to react with the vinyl ketene acetal 170 to afford a single product which was directly converted into the i-butyl ester 171. The Nb acylation of amine 171 with diketene furnished an intermediate P-keto amide that underwent facile cyclization via an intramolecular... 

For example, consider a recent communication on the synthesis of P-amino acids.Hemi-aminal 31, under the influence of boron trifluoride, could be converted to acyl iminium ion 33. Capture of the electrophilic species 33 with the ketene acetal 32 provided ready access to 34. These advanced intermediates could be transformed into the desired P-amino acids 35. 

The class of 1,2,3-oxathiazinane-2,2-dioxide heterocycles are accessible through sulfamate ester insertion into ethereal C -H centers under [Rh2(OAc)4] catalysis. These N,0-acetals, as iminium ion equivalents, coupled smoothly with silyl enol ethers, ketene silyl acetals, and thioacetals in the presence of a catalytic amount of Sc(OTf)3 (10mol%) to give the corresponding adducts with moderate to high diastereoinduction (Scheme 12.43) [107]. It is noted that the procedure does not require purification of the intermediate oxathiazinane. 

This facile and efficient thiophene formation can be rationahzed by primary S-alkylation of 33 to give the iminium cation 35 followed by deprotonation (HBr ehmination) to the ketene-S,N-acetal 36, which cyclizes by intramolecular enamine addition to the carbonyl group (36->-37) intermediate 37 aromatizes to the products 34 by H2O elimination. Thiomorpholides (33) are easily obtained by Willgerodt-Kindler reaction of acetophenones with sulfur/morphoHne [81]. 

In the absence of EIbN, the intermediate iminium cation can be captured with nucleophiles such as silyl ketene acetals, silyl enol ethers, enamines, and aUyl stannanes (eq 40). ... 

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