4.5.6.7- Tetrahydroindole

Intramolecular nucleophilic additions by nitrogen functional groups onto pendant alkynes and allenes represent an important class of type la approaches to functionalized pyrroles. A platinum-catalyzed (PtCl4) cyclization of homopropargyl azides provided an entry to 2,5-disubstituted pyrroles and 4,5,6,7-tetrahydroindoles (fused pyrroles) <06OL5349>. 

The reported reaction times of 20 h could be excessive and good yields could probably be obtained after ca, 5 h. 4,5,6,7-tetrahydroindole. 

Molindone Molindone, 3-ethyl-6,7-dihydro-2-methyl-5-(morpholinomethyl)indol-4(5F0-one (6.4.3), is synthesized by the nitrozation of diethylketone using nitric acid or methyl-nitrite into nitrozodiethylketone (6.4.1). Reduction of this product with zinc in acetic acid into 2-aminodiethylketone in the presence of cyclohexandion-1,3 gives 3-ethyl-2-methyl-4,5,6,7-tetrahydroindol-4-one (6.4.2). Aminomethylation of this product using morpholine and formaldehyde gives molindone (6.4.3) [51-52]. 

Reaction of cyclohexanone oxime (59) with phenylacetylene in the presence of KOH/ DMSO afforded Z-[l-(2-phenylvinyl)]-3-phenyl-4,5,6,7-tetrahydroindole (60) (equation 25) °. Transformation of 0-vinylacetophenone oxime (61) in the system f-BuOK/THF has been studied. The reaction at 60-65 °C afforded 2,4-diphenylpyrrole (62) and oligomeric products instead of the desired 2-phenylpyrrole (equation 26) . ... 

Michael addition reaction at the 5-position <8lUP30500). The dihydroindoles are readily dehydrogenated with DDQ to give the indoles, but the 4,5,6,7-tetrahydroindoles have resisted all attempts to convert them into the fully aromatic systems (81JOC4515, cf. 81ACS(B)77>. 

Dependence of the Yield of 4,5,6,7-Tetrahydroindole 1 and Its N-Vinyl Derivative (2) on the Composition of DMSO/Dioxane Mixture"... 

It can be seen that the reaction takes place when DMSO is added to the dioxane solution in as small amounts as 5-10%. Varying the DMSO concentration makes it possible to carry out the reaction selectively, which means that either 4,5,6,7-tetrahydroindole (1) (with a small DMSO content) or l-vinyl-4,5,6,7-tetrahydroindole (2) (in pure DMSO) can be obtained. 

Although true for many oximes of aliphatic and alicyclic ketones, the previous sequence is not absolute and can change depending on the reaction conditions and ketoxime type. Tetrabutylammonium hydroxide, for instance, which catalyzes fairly actively in the synthesis of 4,5,6,7-tetrahydroindole from cyclohexanon oxime and acetylene (79KGS197), turned out to be nearly inert with alkyl aryl ketoximes (78ZOR1733). 

A much more efficient means of promoting the reaction is variation of the KOH content of the reaction mixture. This was convincingly shown for the conversion of cyclohexanone oxime to 4,5,6,7-tetrahydroindole (1) and its N-vinyl derivative in the reaction with acetylene in KOH/DMSO (Scheme 1) (81ZOR 1977). At a moderate temperature (100°C), an increase in the KOH content (up to an equimolar ratio to the oxime) enhances the yield of l-vinyl-4,5,6,7-tetrahydroindole (Table VI). Under more severe conditions (120°C) the alkali starts to accelerate side processes as a consequence of which an inverse dependence of the yield of l-vinyl-4,5,6,7-tetrahydroindole upon the content of base is observed (cf. Table VI). 

Experiments on the synthesis of 4,5,6,7-tetrahydroindole and 1 -vinyl-4, 5,6,7-tetrahydroindole from cyclohexanone oxime and acetylene on bench reactors of 5 and 25 L performed under a 1.5 atm pressure give positive answers to these questions. Thus, at 100°C and KOH concentration of 0.4 mol/L, the output of 1 L of catalyst solution can amount to 50-100 g of pyrroles per hour. This means that in a small 1 m3 reactor, it is possible to produce up to 400 tons of 4,5,6,7-tetrahydroindoles (1 and/or 2) per year, which is quite acceptable to meet an initial demand for these products. It can initiate, for instance, a cheap indole manufacture by catalytic dehydrogenation of tetrahydroindoles 1 and 2. 

Operation of the plant on a large scale has shown that when the reaction is carried out in DMSO using KOH in an amount of 1 mol per 1 mol of cyclohexanone oxime, it is possible to obtain l-vinyl-4,5,6,7-tetrahydroindole in a yield higher than 80% and purity of up to 99% under an acetylene pressure from 0.3 to 1.5 atm without heat supply, at the expense of the exothermic character of the process. 

When the reaction is carried out under pressure, the yields of pyrroles 1 and 2 are 74-81 and 93%, respectively (Table XIX). Under atmospheric or slightly excess pressure (1.2-1.5 atm), they are 50 and 90%, respectively (78MIP1, 79KGS197). The synthesis of 4,5,6,7-tetrahydroindole (1) from cyclohexanone oxime and acetylene at atmospheric pressure (the yield is 45% when based on the initial oxime and 56% on the oxime reacted) has already been included in the manual (88MI1). Principle features and experimental details of this synthesis have been discussed (79KGS197). 

Methylcyclohexanone and suberone (cycloheptanone) oximes correspondingly give 7-methyl-4,5,6,7-tetrahydroindole (33, yield 70%), its N-vinyl derivative [34, yield 80% (75MI1)], and 4,5,6,7,8-pentahydro-l//-cyclohepta[6]-pyrrole [35, yield 79% (76MIP1 80KGS1299)] (Table XIX). 

Fig. 6. Typical kinetics of the reaction of cyclohexanone oxime with acetylene I. cyclohexanone oxime 2, 4,5,6.7-tetrahydroindole 3, l-vinyl-4,5,6,7-tetrahydroindolc 4. an intermediate. Reaction conditions DMSO, 86°C, PC2h2 720 mm Hg, concentration of KOH and cyclohexanone oxime 0.47 mol/L C = C,/C0. where C0and C,are the initial and present concentration of components, respectively.

Tetrahydroindoles (1, 2) are prepared by the condensation of cyclohexanone oxime (116) with vinyl chloride in the presence of KOH in a DMSO medium at 90-140°C under atmospheric pressure (Scheme 56) (81MIP1 86ZOR489). 

Effect of Reaction Conditions between Cyclohexanone Oxime (116) and Vinyl Halides on the Yield of 4,5,6,7-Tetrahydroindole (1) and I-Vinyl-4,5,6,7-Tetrahydroindole (2)... 

For a preparative synthesis of 4,5,6,7-tetrahydroindole (1), the following conditions have been recommended (86ZOR489) 110°C, 3 hr, the oxime 116/KOH/vinyl chloride molar ratio 1 6 5, yield 46% based on the oxime consumed with oxime conversion of 75%. 

Tetrahydroindole (1) was isolated by extraction of the reaction mixture with organic solvents (Et20, benzene) and purified by distillation or recrystallization. This process for preparing 4,5,6,7-tetrahydroindole is simple enough, industrially feasible, safe, and based on the cheap and accessible raw materials. Cyclohexanone oxime is an inexpensive large-scale commercial product (caprolactam synthesis intermediate), vinyl chloride being one of the cheapest commercial vinyl compounds. 

A synthesis of 4,5,6,7-tetrahydroindole (1) and its N-vinyl derivatives (2) using 1,2-dihaloethanes (Scheme 61) has been described in detail (82KGS1202). In spite of lower yields of pyrroles, this version of the reaction may prove to be the most suitable for laboratories that have no acetylene or experience working with this gas. 

The uncoordinated portion of the 3-vinylpyrrole complexes described above resembles an electron-rich diene, and undergoes a Diels-Alder reaction under mild conditions with electron-deficient alkenes and al-kynes to give functionalized 5,6,7,7a-tetrahydroindole complexes 122 and 149-164 in moderate to excellent yields (Table 10). In most cases, only one stereoisomer is observed even though up to four new stereocenters are formed. For tetrahydroindole complexes 122 and 150, relative stereochemistry has been assigned and is consistent with cycloaddition occurring through an endo-transition state as well as dienophile attack occurring anti to metal coordination. Furthermore, no isomerization occurs to the 4,5,6,7-tetrahydroindole system, which predominates for uncoordinated tetrahydroindoles.23... 

Reaction of 4,7-dihydroindoles with DMAD led to Michael product 644 (ratio of (E) (Z) = 1 2.5). Aromatization of the cyclohexadiene ring by DDQ gave the not easily accessible 2-vinylindole 645 (Scheme 129) <2006JOC7793>. 4,5,6,7-Tetrahydroindole with DMAD (CH2CI2, 20°C, 36h) gives addition product in a yield of 50% (ratio of (E) (Z) = 1 3.3). 

Electrophilic alkynes are also very active acceptors of pyrrole-2-carbodithioate-anions. Thus, the addition of 4,5,6,7-tetrahydroindole-2-carbodithioate 772b to acylalkynes occurs to furnish stereoselectively the (Z)-adducts 774 (Scheme 152). The sterically overcrowded double bond of adducts 774 still remains active enough to participate... 

The kinetics of the reaction of cyclohexanone oxime (1) with acetylene (Equation (1)) in MOH-DMSO under atmospheric pressure was studied and quantitative data on the effect of alkaline cations on the yields of 4,5,6,7-tetrahydroindole (2) and its N-vinyl derivative 3 as well as on the reaction selectivity were obtained (08DOC(423)66). 

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