Reaction tandem double addition-cyclization

Ma et al. described the palladium(0)-eatalyzed three-component tandem double-addition-cyclization reaction of 2-(2,3-allenyl)malonate 218, Phi, and A-Ts-imine 219 for the stereoselective synthesis of 2,5-m-pyrrolidine 220... 

Pd(0)-catalyzed three-component tandem double addition-cyclization reaction four cationic palladium intermediates were characterized by high-resolution ESI-ETMS... 

Three-Component Pd(0)-Catalyzed Tandem Double Addition-Cyclization Reaction... 

In another study of palladiumotalyzed reactions involving allenes [38], Guo et al. described a three-component tandem double addition-cyclization reaction of allenyl malonates, aryl halides and imines to give pyrroUdine derivatives [42] (Scheme 7.22). Apart from the methodological synthetic study, the authors conducted a mechanistic study of the process using the ESI-MS technique [43]. The particular reaction studied is shown in Scheme 7.22. 

Scheme 7.22 Tandem double addition-cyclization reaction studied by ESI-MS.

Scheme7.23 Proposed mechanism forthe Pd(0)-catalyzedthree-component tandem double addition-cyclization reaction based on ESI-MS studies.

The Re(III) complex Re(PPh3)2(MeCN)Cl3 (2 mol%) catalyzes the ATRA of tetrachloromethane or bromotrichloromethane to terminal alkenes in 39-76% yield [303]. p-Pinene suffered a cyclobutylcarbinyl radical ring opening, thus supporting the free radical mechanism. With l, -dienes double addition was found, while 1,3-dienes gave the 1,4-addition product. Internal alkenes were almost inert under the reaction conditions. 1,6-Dienes 158 underwent a tandem radical addition/ cyclization reaction to cycles 159 in 64—87% yield with 3-6 1 c/s-diastereos-electivity (cf. Fig 43). This compares well to the results obtained with the most frequently used catalyst Ru(PPh3)3Cl2 (see Part 2, Sects. 3.3.1 and 3.3.2). 

Similarly, cyclizative tandem double-carbonylation reactions of 4-pentenyl iodide under irradiation conditions, is boosted by the addition of a catalytic amount of palladium complexes [72]. When performed in the presence of diethylamine, the carbonylation provided a triply carbonylated a,<5-diketo amide as the major product along with the doubly carbonylated y-keto amide (Scheme 6.48). Experimental evidence supports the interplay of two reactive species, radicals and organopalladium... 

Yang and Burton studied reductive radical additions of iododifluoroacetate 37 to olefins 38 and dienes catalyzed by 6-17 mol% of a catalyst generated from NiCl2 and stoichiometric amounts of zinc in the presence of water (Fig. 8) [90, 91]. Olefins gave the reductive addition products 40a in 60-83% yield, while 1,5-hexadiene or 1,8-nonadiene provided double addition products exclusively in 55% and 73% yield. 1,7-Hexadiene gave an inseparable mixture of the expected acyclic double addition product and a tandem addition/cyclization product, in which the former dominated. The radical nature of the addition is supported by inhibition of the reaction by para-dinitrobenzene. The reaction proceeds probably via initially formed atom transfer product 39, which is subsequently reduced by nickel(0) and zinc. This is supported by deuterium incorporation, when D20 was used instead of water. No deuterium incorporation was observed with THF-dg, thus ruling out hydrogen transfer from the solvent. 

Intramolecular reaction of an allylsilane and an aldehyde was performed to prepare cyclic compounds as illustrated in Eq. (90) [233], which shows a high diastereoselec-tivity. The cyclization of optically active allylsilane proceeds stereoselectively in a manner consistent with the antiS l mechanism (Eq. 91) [234]. Development of a new reagent with a bis-allylsilane moiety effected tandem inter- and intramolecular cyclizations to give cyclic compounds as exemplified in Eqs (92) [235] and (93) [236-238]. In Eq. (92), the double addition product initially formed underwent a pinacol-type rearrangement under the influence of TiCU to give, eventually, the methyl cyclopentyl ketone. Further examples of intramolecular cyclization of allylsilanes are summarized in Table 8. 

Gas-phase synthesis of 3,4-dihydro-2,4-dioxo-277-l,3,5-oxadiazinium ions (16 X = Y = O) via cyclization of acylium (17 X = O) and thioacylium ions (17 X = S) with isocyanates (18 Y = O) and isothiocyanates (18 Y = S) has been investigated using tandem-in-space pentaquadrupole mass spectrometry (MS) <2005JAM1602>. The formation of single (19) and double (20) addition products in these reactions was observed to occur concurrently with proton transfer. The products of double addition have been observed to be favored in reactions with ethyl isocyanate, whereas the reactions with ethyl isothiocyanate formed preferentially either the single-addition product or proton-transfer products, or both. Furthermore, ab initio calculations at the Becke3LYP//6-311- -G(dp) level indicate that cyclization of the double addition products is favored and 3,4-dihydro-2,4-dioxo-277-l,3,5-oxadiazinium ions (16 X = Y = 0) are formed (Scheme 2) <2005JAM1602>. 

A interesting and useful reaetion is the intramolecular polycyclization reaction of polyalkenes by tandem or domino insertions of alkenes to give polycyclic compounds[l 38]. In the tandem cyclization. an intermediate in many cases is a neopentylpalladium formed by the insertion of 1,1-disubstituted alkenes, which has no possibility of /3-elimination. The key step in the total synthesis of scopadulcic acid is the Pd-catalyzed construction of the tricyclic system 202 containing the bicyclo[3.2. Ijoctane substructure. The single tricyclic product 202 was obtained in 82% yield from 201 [20,164). The benzyl chloride 203 undergoes oxidative addition and alkene insertion. Formation of the spiro compound 204 by the intramolecular double insertion of alkenes is an exam-ple[165]. 

The cyclization of the enediynes 110 in AcOH gives the cyclohexadiene derivative 114. The reaction starts by the insertion of the triple bond into Pd—H to give 111, followed by tandem insertion of the triple bond and two double bonds to yield the triene system 113, which is cyclized to give the cyclohexadiene system 114. Another possibility is the direct formation of 114 from 112 by endo-rype. insertion of an exo-methylene double bond[53]. The appropriately structured triyne 115 undergoes Pd-catalyzed cyclization to form an aromatic ring 116 in boiling MeCN, by repeating the intramolecular insertion three times. In this cyclization too, addition of AcOH (5 mol%) is essential to start the reaction[54]. 

A cyclization reaction by the SN1 mechanism is also possible either by the intramolecular addition of the aryl cation onto a tethered double bond, or by an intermolecular tandem formation of an Ar—C and a C—O bond with the concomitant formation of cyclic products. 

Two other Ni(CO)4 substitutes, Ni(CO)3PPh3 and Ni(COD)2/dppe, prove to be appropriate for the catalysis of tandem metallo-ene/carbonylation reactions of allylic iodides (Scheme 7)399. This process features initial oxidative addition to the alkyl iodide, followed by a metallo-ene reaction with an appropriately substituted double or triple bond, affording an alkyl or vinyl nickel species. This organonickel species may then either alkoxycar-bonylate or carbonylate and undergo a second cyclization on the pendant alkene to give 51, which then alkoxycarbonylates. The choice of nickel catalyst and use of diene versus enyne influences whether mono- or biscyclization predominates (equations 200 and 201). 

Another significant example of tandem reaction is given by the synthesis of substituted (alkylthio)pyrrolines or pyroglutamates as shown in Scheme 9 starting from a y -substituted alkenoyl ester [49]. It consists of the addition of thiyl radicals to the isocyanide function, followed by a 5-exo-trig cyclization of the imidoyl radical to the double bond. 

---