Alkenyl C−H Insertion of Iodonium Ylides into Pyrroles:  Studies toward the Total Syntheses of Tolmetin and Amtolmetin Guacil

Abstract

The thermal-catalyzed or photochemical reaction of iodonium ylides with pyrroles yields exclusively alpha-substituted pyrroles in moderate to good yields. [reaction: see text]

Chemistry of Polyvalent Iodine

“…The product composition in the rhodium(II) catalyzed reactions of iodonium ylides was found to be identical to that of the corresponding diazo compounds, which indicates that the mechanism of both processes is similar and involves metallocarbenes as key intermediates as it has been unequivocally established for the diazo decomposition 849. Recent examples of the transition metal catalyzed carbenoid reactions of iodonium ylides are represented by the following publications: Rh(II)- or Cu(I)-catalyzed cyclopropanation reactions using the unstable ylides PhIC(H)NO 2 863 and PhIC(CO 2 Me)NO 2 865,866 generated in situ from nitromethane and methyl nitroacetate; Rh(II)-catalyzed three-component coupling of an ether with a nitromethane-derived carbenoid generated from PhIC(H)NO 2 ;864 Rh(II)- or Cu(II)-catalyzed insertion of carbene into alkenyl C-H bond in pyrroles,880 flavones,881 and highly phenylated ethylenes;882 Rh(II)-catalyzed reaction of iodonium ylides with conjugated compounds leading to efficient synthesis of dihydrofurans, oxazoles, and dihydrooxepines;883 synthesis of various heterocycles by Rh(II)-catalyzed reactions of iodonium ylides with vinyl ethers, carbon disulfide, alkynes, and nitriles;884 Rh(II)-catalyzed reaction of iodonium ylides with electron-deficient and conjugated alkynes leading to substituted furans;885 efficient synthesis of β-substituted α-haloenones by Rh(II)-catalyzed reactions of iodonium ylides with benzyl halides and acid halides;886 Rh(II)- or Cu(II)-catalyzed generation/rearrangement of onium ylides of allyl and benzyl ethers via iodonium ylides;887 and Rh(II)- or Cu(II)-catalyzed stereoselective cycloaddition of disulfonyl iodonium ylides with alkenes leading to 1,2,3-trisubstituted benzocyclopentenes888 or functionalized indanes 889–891…”

Carbene Complexes of Nonmetals

“…[19] The high-yielding reaction of 49 with the α-position of N-methylpyrrole, 49 Ǟ 50, was employed in a synthesis of the anti-inflammatory agent tolmetin. [72] Thermolysis of 49 in the presence of (Z)-and (E)-3-heptene afforded the cyclopropanes 48 and 51, respectively, in a stereospecific reaction (less than 2% of the ''wrong'' isomer was formed). [19] CϪH insertion and stereospecific cyclopropanation, proceeding under the same conditions, strongly suggest the intermediacy of a singlet carbene.…”

“…As indicated in 70b, the methyl group points to the center of the benzene ring. Stationary points were also located for 1:2 carbene-benzene complexes (72), which show about twice the stabilization energy of 70. [94] To summarize, both experimental and computational evidence of carbene-benzene π-complexes has been obtained, in contrast to carbene-alkene complexes.…”

Iodonium ylides in organic synthesis

“…A detailed discussion of the reaction mechanisms and synthetic applications of iodonium ylides as carbene precursors can be found in the earlier reviews. [14][15][16][17][18] Bis(methoxycarbonyl)(phenyliodinio)methanide 4, the most common iodonium ylide derived from malonate methyl ester, has found synthetic applications in the C-H insertion reactions, [57][58][59][60][61] and in the cyclopropanation of alkenes, 22,28,[62][63][64][65][66] including enantioselective cyclopropanations in the presence of chiral rhodium complexes. 15,67,68 Representative examples of these reactions are shown in Scheme 12 and include the BF 3 -catalyzed bis(carbonyl)alkylation of 2-alkylthiophenes 43, 58 and the optimized procedure for rhodiumcatalyzed cyclopropanation of styrene 44.…”