Dimethyl indole-6,7-dicarboxylate

Beccalli et al. reported a synthesis of carbazomycin B (261) by a Diels-Alder cycloaddition using the 3-vinylindole 831 as diene, analogous to Pindur s synthesis of 4-deoxycarbazomycin B (619). The required 3-vinylindole, (Z)-ethyl 3-[(l-ethoxy-carbonyloxy-2-methoxy)ethenyl]-2-(ethoxy-carbonyloxy)indole-l-carboxylate (831), was synthesized starting from indol-2(3H)one (830) (620). The Diels-Alder reaction of the diene 831 with dimethyl acetylene dicarboxylate (DMAD) (535) gave the tetrasubstituted carbazole 832. Compound 832 was transformed to the acid 833 by alkaline hydrolysis. Finally, reduction of 833 with Red-Al afforded carbazomycin B (261) (621) (Scheme 5.99). 

Miki and Hachiken reported a total synthesis of murrayaquinone A (107) using 4-benzyl-l-ferf-butyldimethylsiloxy-4fT-furo[3,4-f>]indole (854) as an indolo-2,3-quinodimethane equivalent for the Diels-Alder reaction with methyl acrylate (624). 4-Benzyl-3,4-dihydro-lfT-furo[3,4-f>]indol-l-one (853), the precursor for the 4H-furo[3,4-f>]indole (854), was prepared in five steps and 30% overall yield starting from dimethyl indole-2,3-dicarboxylate (851). Alkaline hydrolysis of 851 followed by N-benzylation of the dicarboxylic acid with benzyl bromide and sodium hydride in DMF, and treatment of the corresponding l-benzylindole-2,3-dicarboxylic acid with trifluoroacetic anhydride (TFAA) gave the anhydride 852. Reduction of 852 with sodium borohydride, followed by lactonization of the intermediate 2-hydroxy-methylindole-3-carboxylic acid with l-methyl-2-chloropyridinium iodide, led to the lactone 853. The lactone 853 was transformed to 4-benzyl-l-ferf-butyldimethylsiloxy-4H-furo[3,4- 7]indole 854 by a base-induced silylation. Without isolation, the... 

Several 2-(2-thienyl) and 2-(3-thienyl)pyrrole-3-carboxylates were made by reaction of acetylthiophene oximes with methyl propiolate or dimethyl acetylene-dicarboxylate. <93JCR(S)210> This reaction is related to other sigmatropic rearrangements which have been used in pyrrole and indole synthesis. 

The photocycloaddition chemistry of pyridines substituted with electron-donor and electron-acceptor groups at the 2- and 3- positions continues to be exploited. The results of irradiation of such pyridines in the presence of 2-cyanofuran have now been described. The yields of the (47r+47r) cycloadducts (29) and (30), the pyridine dimer (31) and the transposition isomer (32) are dependent on the level of methyl substitution on the heteroarene and are given in Scheme 2. Other photocycloadditions to heteroarenes reported within the year include the reactions of benzodithiophene (33) with butadiyne derivatives and dimethyl acetylene dicarboxylate, giving low yields of (34) and (35) respectively, the latter from photorearrangement of the primary adduct (36). The (271+471) photocycloaddition of indoles (37) to cyclohexa-1,3-dienes (38) is sensitized by the aromatic ketones (39), and yields (14-46%) of the exo and endo isomers of the adduct (40) in ratios which are dependent on the substituents on the addends. 

This reaction was initially reported by Diels and Reese in 1934. It is the conjugate addition between hydroazobenzene and dimethyl acetylene-dicarboxylate. The resulting adduct can be transformed into three different heterocyclic compounds under various experimental conditions (i.e pyrazolones with acid, indoles upon heating in xylene, and quinolones with base ). For example, l,2-diphenyl-3-carbomethoxy-5-pyrazolone will be generated from the adduct in acetic acid (acidic condition), whereas dimethyl indole-2,3-dicarboxylate is produced in xylene (neutral condition) and 2-hydroxy-3-anilino-4-carbomethoxy-quinoline is yielded in pyridine (basic condition). The latter can be further converted into 2,3-dihydroquinoline upon decarboxylation and hydrolysis." This reaction has been extended to heat the 1 1 adduct in picoline. ... 

Thieno[2,3-6]indoles (532) have been prepared through the reaction of (533) with phosphorus pentasulphide. The system (532) underwent an interesting Diels-Alder reaction, i.e. to (534), with dimethyl acetylene-dicarboxylate. ... 

Finally, rhodium was aesthetically used in a three-component reaction toward the synthesis of spiroxindole derivatives 85 with dimethyl acetylene dicarboxylate (DMAD), aryl aldehydes 86, and cyclic diazoamides 87 (Scheme 9.23) [41]. The authors also demonstrated that the reaction was efficient with heteroaryl reactant (2-fiiraldehyde, indole-3-carbaldehyde) and electron-deficient alkenes (maleic anhydride) instead of DMAD. 

For example. 2-ethoxyindole (1 a) with the alkyne diester in refluxing dioxane yields dimethyl 2-ethoxy-3//-l-benzazepine-3,4-dicarboxylate (2) as a minor product along with a 50 % yield of a mixture of the cis- and tran.v-indol-3-ylacrylates 3.20 However, with 2-ethoxy-l-methylindole (1 b) the l//-l-benzazepine 4 becomes the major product. An analogous reaction with l,2-bis(trifluoromethyl)acetylene to yield 2-ethoxy-l -methyl-3,4-bis(trifluoroiriethyl)-1 //-1-benzazepine has been performed however, the yield was not reported.142... 

In the presence of hydrochloric acid, dimethyl l-methyl-l//-l-benzazepine-3,4-dicarboxylate (1) adds methanol at the C2 —C3 bond to give the 2,3-dihydro-l//-l-benzazepine-3,4-dicar-boxylate 2.21 Addition of indole takes place in a like manner under similar conditions (see Section 3.2.2.5.2.). 

In the presence of a catalytic amount of concentrated hydrochloric acid, dimethyl 1 -methyl-1 H-l-benzazepine-3,4-dicarboxylate (1) undergoes addition of 1-methylindole, probably via initial protonation of the enaminic 3-position of the benzazepine ring, to give the indolyldihydrobenz-azepine 2.21 In fact, adduct 2 is the major product from the reaction of 1-mcthylindole with dimethyl acetylenedicarboxylate in acetonitrile. Similar adducts are obtained with indole. 

Indole reacts with dimethylacetylene dicarboxylate giving tetramethylcar-bazol-l,2,3,4-tetracarboxylate as a major product,formed via 384 (R = H, and/or geometric isomer) and then Diels-Alder addition and dehydrogenation. /V-Acetylindole undergoes an extraordinary double condensation and cyclization with methyl acrylate in the presence of palladium(II) acetate in acetic acid giving 9% of the dimethyl 9-acetylcarbazole-2,3-dicar-boxylate 393 as well as 394 and 395, the products of monosubstitution at the indole a and S-positions. ... 

Pyrroles, indoles and benzo[ft]thiophene act as good dienophiles in inverse electron demand Diels-Alder reactions with 1,2-diazines, 1,2,4-triazines and sy/n/n-tetrazines. This is examplified by the formation of compounds (189) in excellent yields on interaction of indoles and benzo[c]thiophene with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate (87JOC4610 90JOC3257). There are also many examples of such intramolecular reactions, e.g. (190 — 191). 

Nonpeptidic scaffolds may also be used to position carbonyl groups for the nucleation of helices. In the present case, three successive carbonyl groups are positioned in 3,6-dimethyl-4-oxo-2,3,4,5,6,7-hexahydro-l//-indole-3,6-dicarboxylic acid (11) (Scheme 5) to mimic those in the first turn of an a-helix.112" Peptide H-Glu-Ala-Leu-Ala-Lys-Ala-NH2 was attached to 11 through a linking residue and helix induction was examined by CD and NMR. 

A facile preparation of pyrrolo 3,4-/ indoles 143 from pyridazino[4,5-fc]indoles 142 using a Zn/AcOH reductive ring contraction has been described [38], Since compounds 142 are easily prepared from the inverse electron demand cycloaddition of indoles 141 with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate, this represents a simple, two-step sequence to prepare the pyrroloindoles 143 (Scheme 26). 

The reaction of 3-phenyl-4-benzoylselenolo[3,4-6]indole (135) and DMAD afforded dimethyl 9-benzoyl-l-phenylcarbazole-2,3-dicarboxylate (136) <82JHC227>. 

The inverse electron demand Diels-Alder (IDA) reactions of 3-substituted indoles as 2rt-components with 1,2,4-triazines and 1,2,4,5-tetrazines proceeded in excellent yields both inter- and intramolecularly <1996TL5061>. The reaction of iT-BOC-tryptamine (1110, R = BOCNH(CH2)2) and indole 1110 (R =Me) with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate 1111 in refluxing dioxane (3h) provided cycloadducts 1112 (R2 = B0C) and 1113, respectively, in excellent yields (80% and 82%, Scheme 217). Deprotection of compound 1112 produced derivative 1112 (R = H, >99%). 

X-Ray studies of the system, using dimethyl 4-formyl-2,3-dihydro-1,4-benzothiazine-2,3-dicarboxylate,17 41/-1,4-benzothiazine 1,1-dioxide,18 and the 3-methyl derivative,19 showed these molecules to be essentially planar with only small distortions associated mainly with the heteroatoms in the thiazine ring. The various bond lengths and angles were related to those of indole in an attempt to rationalize their reactivity toward electrophiles, which has been reported20 to be similar to that of indole. Molecular mechanics calculations similarly indicated essentially planar rings for trans-2-dimethyl-4-acetyldihydrobenzo thiazine.21... 

Tetramethyl pyridazine-3,4,5,6-tetracarboxylate, but not 3,6-dichloropyridazine or dimethyl phthalazine-l, 4-dicarboxylate, takes part in a Diels-Alder reaction with indole under very concentrated conditions (Scheme 31). The adduct produced after elimination of nitrogen aromatizes by ring opening and the resultant aniline attacks the adjacent ester group to give the phenanthridone... 

Snyder and co-workers tried to utilize cycloadditions of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate 150 to N-substituted indoles 325 as the key step in the attempted preparation of carbazoles <1997TL8611>. However, unlike previous examples reported by Haider and Wanko with 3,6-bis(trifluoromethyl)-l,2,4,5-tetrazine 147 <1994ACO205, 1994H(38)1805>, the initially formed dimethyl 5//-pyridazino[4,5-3]indole-l,4-dicarboxylates 326 did not react further with any dienophile. On the other hand, they underwent reductive ring contraction readily with zinc in acetic acid to furnish dimethyl 5//-pyridazino[4,5-3]indole-l,4-dicarboxylates 327 (Scheme 78) <1997TL8611>. 

Bennasar extended his research on 2- and 3-indolylacyl radicals to intramolecular cyclizations to yield 2,3-fused indoles [112], Under nomeductive conditions (n-Bu6Sn2, hv), radical 201 underwent a cascade addition-oxidative cyclization sequence with a number of alkene acceptors including dimethyl fumarate (45%), methyl 1-cyclohexenecarboxylate (53%), methyl crotonate (71%), vinyl sulfone (22%), and the a,p-unsaturated lactam ester, 2-oxo-5,6-dihydro-2H-pyridine-l,3-dicarboxylic acid dibenzyl ester (41%) to form cyclopenta[h]indol-3-ones 202. Reaction of 201 with acrylonitrile and methyl acrylate, however, generated cyclo-hepta[h]indoles, the products of bis-addition-cyclization sequences. 

Kreher improved upon Welch s lactam reduction by using diisobutylaluminum hydride (DIBAL) to reduce either lactam (Scheme 14, equation 1) [80]. Srinivasan and Jeevanandam employed a route similar to Sha s [78] to prepare a series of 2,4-dihydropyrrolo[3,4- ]indoles 43 (equation 2) [81]. A Diels-Alder reaction of 43 (R=Me, R =Bn) with DMAD gave the cycloadduct in 70% yield, which on exposure to tosic acid yielded dimethyl 4-benzylamino-l-methyl-5-(phenylsulfonyl)carbazole-2,3-dicarboxylate (68% yield). Snyder and coworkers described a novel pyri-dazine reductive ring contraction, as explored by Boger... 

The starting pyridazino[4,5-fc]indoles were prepared from the TV-protected indole and dimethyl 1,2,4,5-tetra-zine-3,6-dicarboxylate in 70% to 95% yield. 

Another pioneer in the Diels-Alder reactions of vinylpyrroles was Noland, who also developed the reactions of vinylindoles to yield carbazoles. Some examples of the former are shown in Scheme 2 (equations 1 and 2) [4-7], Jones and his colleagues were equally active in this cycloaddition chemistry of vinylpyrroles (equations 3 and 4) [8-12], These workers measured the rates of the reaction between 1-methyl-2-vinylpyrrole and seven dienophiles, with maleic anhydride being 4800 to 50,000 times more reactive than the other dienophiles (DMAD, maleonitrile, fumaronitrile, dimethyl maleate, methyl acrylate, and acrylonitrile) [8], In a clever tactic to thwart the formation of dihydroindoles, Jones used an excess of methyl propio-late to convert the initial adduct to a second Diels-Alder cycloadduct that subsequently loses ethene by a retro-Diels-Alder reaction to afford the dimethyl 1-methyl (phenyl)-4,7-dicarboxylates (equation 4). The reactions are concerted and were consistent with FMO calculations (HOMO[vinylpyrrole]-LUMO[alkene]). The yields are 54% to 81%, but attempts to dehydrogenate the tetrahydroindole products to indoles were unsuccessful. 2-Vinylpyrrole itself undergoes Michael additions and polymerization with these dienophiles. Domingo, Jones, and coworkers subsequently... 

A stirred mixture of 1,2,3,4-tetrahydro- -carboline-l-carboxylic acid, acetic anhydride, and dimethyl acetylenedicarboxylate heated 45 min. at 115° -> methyl 3-methyl-5,6-dihydro-llH-indolizino[8,7-b]indole-l,2-dicarboxylate. Y 75%. F. e. s. F. M. Hershenson, J. Org. Chem. 57, 3111 (1972) cf. Synth. Meth. 19, 911. 

Analogous method was utilized by authors [20] also in synthesis of new 5-alkyl-l,4-dioxo-2H,3H,5H-pyridazino[4,5-b]indoles(35-40) (scheme 3). These substances are produced by simultaneous N-alkylation and esterification of indole-2,3-dicarboxylic acid [24], with subsequent hydrazinolysis of diethers (29-34). The authors managed to prepare dimethyl ethers in a pure state so that they were able to increase yield of corresponding 1,4-dioxo pyridazinoindoles (35-40) up to 62-85%. 

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