4,7-Dihydroindole

Indoles are usually constructed from aromatic nitrogen compounds by formation of the pyrrole ring as has been the case for all of the synthetic methods discussed in the preceding chapters. Recently, methods for construction of the carbocyclic ring from pyrrole derivatives have received more attention. Scheme 8.1 illustrates some of the potential disconnections. In paths a and b, the syntheses involve construction of a mono-substituted pyrrole with a substituent at C2 or C3 which is capable of cyclization, usually by electrophilic substitution. Paths c and d involve Diels-Alder reactions of 2- or 3-vinyl-pyrroles. While such reactions lead to tetrahydro or dihydroindoles (the latter from acetylenic dienophiles) the adducts can be readily aromatized. Path e represents a category Iley cyclization based on 2 -I- 4 cycloadditions of pyrrole-2,3-quinodimcthane intermediates. 

A traditional method for such reductions involves the use of a reducing metal such as zinc or tin in acidic solution. Examples are the procedures for preparing l,2,3,4-tetrahydrocarbazole[l] or ethyl 2,3-dihydroindole-2-carbox-ylate[2] (Entry 3, Table 15.1), Reduction can also be carried out with acid-stable hydride donors such as acetoxyborane[4] or NaBHjCN in TFA[5] or HOAc[6]. Borane is an effective reductant of the indole ring when it can complex with a dialkylamino substituent in such a way that it can be delivered intramolecularly[7]. Both NaBH -HOAc and NaBHjCN-HOAc can lead to N-ethylation as well as reduction[8]. This reaction can be prevented by the use of NaBHjCN with temperature control. At 20"C only reduction occurs, but if the temperature is raised to 50°C N-ethylation occurs[9]. Silanes cun also be used as hydride donors under acidic conditions[10]. Even indoles with EW substituents, such as ethyl indole-2-carboxylate, can be reduced[ll,l2]. 

The reactions of pyrroles with dimethyl acetylenedicarboxylate (DMAD) have been extensively investigated. In the presence of a proton donor the Michael adducts (125) and (126) are formed. However, under aprotic conditions the reversible formation of the 1 1 Diels-Alder adduct (127) is an important reaction. In the case of the adduct from 1-methylpyrrole, reaction with a further molecule of DMAD can occur to give a dihydroindole (Scheme 48) (82H(19)1915). 

The photocyclization of N-aryl enamines derived from cyclic or acyclic ketones proceeds under mild conditions to produce 2,3-dihydroindole derivatives (178b). The stereochemistry of the products is predominantly trans, which follows from a photochemical electrocyclic process which should take place in a conrotatory manner (178c,I78d). However, the presence of some cis products is not as easily explained. 

When the original reaction between the 1-methylpyrrole and dimethyl acetylenedicarboxylate was carried out on a larger scale with inadequate cooling, an exothermic reaction took place and none of the dihydroindole (48) could be detected among the products. However these included the mellitic ester (49) and the pyrrole (50), indicating that some of the dihydroindole (48) had formed and had combined with more of the acetylenic ester as already described. A decomposition product of the dihydroindole as yet unidentified, tetramethyl l-methylindole-2,3,6,7-tetracarboxylate (52), and tetramethyl prehnit-... 

For the preparation of 2,3-dihydroindoles (8) from indoles (7), two reduction methods are known. In the column Reduction Method in the table, the one indicated A represents use of EtsSiH in TFA (79JOC4809) and the other, indicated B, employs NaBHsCN in AcOH (77S859, 88JMC1746). Although both methods are applicable, the former is generally superior to the latter. In some cases, depending on the substrates structures, the reverse cases are also observed. Examples are the reactions marked B in the column. 

Larock has developed a new catalyst system for the Pd-catalyzed cyclization of olefinic tosylamides. Whereas typical conditions require either stoichiometric amounts of Pd(II) salts or catalytic amounts of Pd(II) in the presence of benzoquinone as a reoxidant, the new catalyst system utilizes catalytic Pd(OAc)2 under an atmosphere of O2 in DMSO with no additional reoxidant <96JOC3584>. Although o-vinylic tosylamides 76 can be cyclized to Af-tosylindoles 77 using this catalyst system, PdCla/benzoquinone is more effective for such cyclizations. Interestingly, in the case of o-allylic tosylanilides, the cyclization can be modulated to afford either dihydroindole or dihydroquinoline products. In a related approach involving a common 7i-aUyl Pd-intermediate, 2-iodoanilines were coupled with vinylic cyclopropanes or cyclobutanes in the presence of a Pd catalyst to afford dihydroindoles <96T2743>. 

Researchers at Lilly have prepared a series of alkylamine H3 antagonists. Examples include the amide (57), which has a of 1.05 nM and the tetra-hydroisoquinoline (58), which has a A) of 0.37 nM [132]. Both compounds are inactive at the Hi, H2, and H4 receptors. This same group also disclosed a series of azepines, represented by (59) (H3 A j = 0.85 nM) and (60) [133]. Compound (60) is reported to have 100% bioavailability and a 12.4 h half-life in rat. Related dihydroindoles such as (61) (A j = 0.5nM) and tetra-hydroquinolines were also shown to be H3 antagonists [134]. 

Although geneologically related to indoles, the dihydroindoles behave chemically rather like alkyl anilines. When diphenylamine reacts with chloro-propionyl chloride, amide 40 results this in turn readily cyclizes to oxindole 41. Sodium hydride followed by 2-chloroethyldimethylamine alkylates the 3-position (possibly through an intermediate aziridinium ion) partial demethylation is accomplished by refluxing with ethylchiorocarbonate, followed by hydrolysis of the intermediate carbamate to give indolinone 42, the antidepressant amedalin Repetition of this sequence on the chloropropyl homologue, followed by reduction of the appropriate indolinone produces dihydroindole 43, daledalin, which also has antidepressant activity. ... 

Dialkenyl)-4-nitropyrroles are prepared by the reaction of nitrodienes with 1-isocyano-l-tosyl-l-alkenes. 3-Nitroindoles are prepared in good yields via a thermal 6Jt-electrocycliza-tion of 2,3-(dialkenyl)-4-nitropyrroles in nitrobenzene. Nitrobenzene causes aromatization of the initially formed dihydroindoles (Eq. 10.17).21... 

Dimethyl 2-(17/-indol-2-yl)but-2-enedioate, easily available by reaction of 4,7-dihydroindole with dimethyl acet-ylenedicarboxylate followed by oxidation with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ), treated with PTAD provided compound 703, which was thermaly isomerized to 704 (Scheme 111) <2006JOC7793>. 

The a-oxoketene dithioacetal 6.40 is derived from indoxyl (l,2-dihydroindol-3-one), a heterocyclic carbonyl precursor, and its reaction with simple allyl anions will also yield the corresponding Jl-annulation product. Thus when 6.40 was reacted with allyl anions 65 the corresponding carbinol acetals 66 formed insitu underwent smooth BF3.Et20 assisted cyclization to afford the corresponding carbazoles 67 in high yields <99T11563>. 

Intramolecular process with rhodium catalyst has been described for the syntheses of indane, dihydroindoles, dihydrofurans, tetralins, and other polycyclic compounds. Wilkinson catalyst is efficient for the cyclization of aromatic ketimines and aldimines containing alkenyl groups tethered to the K z-position of the imine-directing group. 

Ervafoline Series. Ervafoline (246, C40H44N4O4 (high resolution mass spectrometry), MP 285°C, [a]D +279°) showed UV maxima at 252, 306, and 326 nm owing to the presence of (3-anilinoacrylic and dihydroindole chromphores. In the... 

The structure of the 3-oxo derivative 65 was determined by high resolution mass spectrometry, which demonstrated that a single oxygen atom had been incorporated into the alkaloid skeleton. Peaks in the mass spectrum at mte 174 and 188 provided evidence that the additional oxygen atom was not in the dihydroindole portion of the molecule, while a peak at mte 138 supported the presence of an oxygenated piperdine ring. This metabolite was also chemically compared with authentic oxodihydrovindoline derivatives previously prepared and provided for comparison by J. P. Kutney. 

Doi and Mori made excellent use of dihydroindole triflate 189 in Pd-catalyzed cross-coupling reactions. This compound was discussed earlier in the Suzuki section, and it also undergoes Stille couplings as illustrated below [140]. A final dehydrogenation completes the sequence to indoles. 

DihydroindolesA novel synthesis of fused dihydroindoles involves [2 + 2 + 2]cycloaddition of alkynes with the 2,3-double bond of N-alkynoylated pyrroles. The reaction of 1 with bis(trimethylsilyl)ethyne results in two diaster-... 

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