Hydroformylation-amination intramolecular

Because of the chelate control of the process, allylamides such as 129 react under hydroformylation conditions to give mainly the branched aldehyde 131, together with cyclic derivatives 132 and 133 (Table 5) [82, 83]. Products 132 and 133 are formed from the linear aldehyde through a sequence of reactions involving cyclization to give the enamide 134, followed by hydrogenation or hydroformylation, respectively [84]. 

Hydroformylation of substrate 130 does not show a similar directing effect and, depending on the catalyst used, gives the terminal aldehyde from which 131 or 132 are formed. 

The reaction also works with cyclic amides to afford bicyclic heterocycles [84]. The 3-butenamide 135 (n=l, R=H) also undergoes a consecutive process which affords compounds 136 or the dimer 138 depending on the ligand used (Table 6) [84, 85], Large excess ofPPhs affords almost exclusively the linear aldehyde and further to the pyrrolidone 136 by cyclization, water elimination to give 140, and double bond isomerization. 

Cross-coupling reaction between pyrrohdone 137 and the intermediate 140 would give the dimer 138. In the 4-pentenamide 135 (n=2) the regioselectivity which gives the branched aldehyde is also very high and apparently is controlled by the formation of a chelate. Then the branched aldehyde cychzes and eliminates water to give the lactam 139. 

The buUdness of the substituent on the amide nitrogen virtually does not have any effect on the regioselectivity, but it exerts a marked effect on the cyclic/acychc ratio of the products. The effect of the bulky N-substituents is particularly pronounced in the trityl derivative (R=Tr, n=l), since no formation of pyridone 136 was observed. A mixture of open chain linear aldehyde and pyrrolin-2-one 137 was obtained. 

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A quinazoline alkaloid skeleton has been synthesized by means of the Rh-catalyzed cyclohydrocarbonylation of diaminoalkenes. The reaction of 2-(A -allylaminomethyl)aniline 55 gave quinazoline 59 in excellent yield through the highly linear-selective hydroformylation of 55 to aldehyde 56, followed by the sequential formations of hemiaminal 57 and iminium ion 58 as intermediates and then the subsequent intramolecular amine addition (Scheme In the same manner, the reaction of A -allyl-2-aminomethylaniline 60 afforded 61 in 96% yield. ... 

It seemed interesting to trap the iminium ion intermediate by performing an intramolecular aSH, so we plarmed a CHC/aSH/hydroformylation domino reaction (Scheme 10). This reaction involves an allylsilane present on the amine moiety which, in an acidic medium, reacts with an acyliminium ion derived from the CHC to form a vinyl group. The resulting vinyl double bond must be hydroformylated regioselectively by the rhodium complex present in the reaction medium to lead to a functionalized polycyclic structure. 

There are numerous reports of hydrofonnylation reactions where an amine substituent in the substrate condenses with the aldehyde product to form a heterocyclic ring (Fig. 6). Intramolecular hydroaminomethylation reactions are often referred to as cyclohydrocarbonylation reactimis. A Cbz-protected homoallylic amine underwent cyclohydrocarbonylatiOTi with Rh-biphephos to form the natural product, ( )-coniine (Fig. 6, 13) [25]. Alper recently reported the formation the seven-membered ring of 2-benzazepines (Fig. 6, 14) by hydroformylation of 2-isopropenylbenzaldehydes in the presence of anilines [26]. Intramolecular hydroaminomethylation of 2-isopropenylanilines produces 1,2,3,4-tetrahydroquinolines (Fig. 6, 15) [27]. In some instances, the enamine derived from intramolecular condensation of the resulting aldehyde is desired. For example, the synthesis of a key intermediate (Fig. 6,16) in the synthesis of a series of ACE inhibitors was... 

Alkene or alkyne hydroformylations followed by intramolecular amine condensations are... 

In the presence of alcohols or amines, the aldehydes generated in the hydroformylaton reaction give acetals or imines. Depending on the hydroformylation catalyst used an additional acid catalyst is required. When the process is intramolecular, (i.e. when alcohols, amines or amides are present in the starting material), it is spontaneous and gives hemiacetals or imines, especially if five or six member rings can be formed [4b]. Moreover the presence... 

As a special case, the formation of hemiacetals 2 (lactolization) during the hydroformylation of hydroxy-functionalized olefins, such as allyl or homoallyl alcohols, has to be mentioned (1, Y= O, Scheme 5.70). With these substrates, the reaction occurs in an intramolecular manner. In the presence of an external alcohol, the cyclic hemiacetal can further react to give a nonsymmetric cyclic acetal 3. Hemiacetals can be subjected to hydrogenation to afford diols 4. Under reducing conditions and in the presence of amines, amino alcohols 5 are formed both are valuable building blocks in fine chemistry. Alternatively, oxidation gives lactones 6 [5]. By dehydration of hemiacetals, cychc vinyl ethers 7 are formed. The same transformation with allylamines (Y=NR) gives cyclic hemiaminals, A/ ,0-acetals, lactames, or vinyl amines. 

Intermolecular and intramolecular HAMs are known. The transformation can be considered as a tandem reaction [2,3] consisting of three consecutive steps (i) hydroformylation, (ii) formation of an imine or an enamine, and (iii) reduction. Finally, the Af-alkylated amine is produced [4]. Clearly, these reactions can also be carried out in separate steps, but the application of uniform reaction conditions offers considerable advantages, such as the use of a single catalyst for the hydroformylation and the hydrogenation steps. Moreover, the equihbrium of the formation of the intermediate imine or enamine can be advantageously shifted by the irreversible hydrogenation in the last step [5]. 

Hydroformylation of substrates incorporating O- or N-nudeophilic moieties leads to cyclic hemiacetals, acetals, 0,N-acetals, or enamines depending on the reaction conditions and the functional groups of the substrates. In the total synthesis of the anticancer agent, natural product leucascandroUde A (24), three different carbonyla-tion steps were incorporated (Scheme 12.1). Alkene 20 underwent a cyclohydrocar-bonylation reaction under hydroformylation conditions, resulting in the formation of hemiacetal 21. The other two carbonylation steps involved formylation of 18 and intramolecular alkoxycarbonylation of alkene 22 [28]. Various tryptamine derivatives [29] and the framework of piperidine alkaloids [30] were also synthesized via cyclohydrocarbonylation starting from functionalized homoallylic amines or aniline derivatives, respectively. 

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