2.5- Dimethoxytetrahydrofuran, reaction

The parent indolo[2,3-fl]carbazole (1) has also been the subject of a study probing its reactivity toward oxidizing agents. One of the substrates involved, namely 85 (prepared from 1 and 2,5-dimethoxytetrahydrofuran in the presence of acid), was subjected to treatment with m-chloroperbenzoic acid, to give the dione 86 as the major product and a sensitive compound assigned the hydroxy structure 87. A cleaner reaction took place when 85 underwent oxidation with tert-butyl hydroperoxide assisted by VO(acac)2, to produce 86 exclusively in 86% yield. Likewise, A,N -dimethylindolo[2,3-fl]carbazole furnished the dione 88 on treatment with this combination of reagents (96J(X 413). 

Later, Schopf et al. (67,68) found that the yield could be raised to 83% by using, at 25°C, dilute solutions buffered at pH 5 (physiological conditions). Despite this relatively high yield the reaction was not very suitable for the production of tropinone (124), especially in large scale, because of the lack of a convenient method to obtain succinaldehyde (140). This obstacle was later circumvented when it was found that succinaldehyde (140) could be replaced by its synthetic equivalent, 2,5-dimethoxytetrahydrofuran (143) (Scheme 3). 

A one-pot reaction between a tryptophan ester, benzotriazole, and 2,5-dimethoxytetrahydrofuran in acetic acid gives the diastereomeric benzotriazolyl tetracycles, 349, in good yield. Substitution of the benzotriazole by reaction with silyl enol ethers and boron trifluoride etherate gives the corresponding ketones 350 and 351, and reaction with allylsilanes gives the corresponding alkenes 352 and 353. If the boron trifluoride etherate is added to the mixture before the silane, elimination of benzotriazole from 349 is also observed (Scheme 83) <1999T3489>. 

A milder Clauson-Kaas pyrrole synthesis was reported that alleviated the need for acid or heat <06TL799>. The innovation involved the hydrolysis of 2,5-dimethoxytetrahydrofuran giving 2,5-dihydroxytetrahydrofuran. The latter was converted into pyrroles by treatment with primary amines in an acetate buffer. The Clauson-Kaas pyrrole synthesis was studied utilizing a K-10 montmorillonite acid catalyst and microwave irradiation <06OPP495>. Mild reaction conditions (cat. p-TsOH) allowed for the preparation of pyrrole-3-carboxaldehydes from 2,5-dimethoxytetrahydrofuran-3-carboxaldehydes <06S1494>. 

Reactions with dialdehydes allow the introduction of two additional rings in one step. Thus, condensation of 1 -(2-aminoethyl)pyrrole with glutaraldehyde and benzotriazole gives tricyclic intermediate 627 in which the benzotriazolyl moiety can be readily substituted with nucleophiles to give products 628 (Scheme 97) <2002JOC8220>. Condensation of ethyl ester of L-tryptophan with 2,5-dimethoxytetrahydrofuran and benzotriazole in acetic acid gives tetracyclic intermediate 629 which upon treatment with nucleophiles (silyl derivatives) is converted to products 630 <1999T3489>. 

A new synthesis of arylmethylene- and arylmethine-pyrroles [25 R = CH2C6H4X and CH(C02H)CH2Y] uses 2,5-dimethoxytetrahydrofuran (26). The reaction is subject to acid-base catalysis, and is typically successful only in solvent mixtures of such character, e.g. acetic acid-pyridine. A mechanistic investigation has identified a number of iminium ion intermediates [e.g. tautomerism (27a) (27b)] to explain by-products in particular cases. 

After reduction and reaction with 2,5-dimethoxytetrahydrofuran, l-Asparagine was converted into a pyrrole derivative which was cyclized with trifluorosulfonyl anhydride into 67 [90H(31)9],... 

Examples of the simple reactions include the conversion of the ester group of 27 into hydrazides (Equation 10), such as 28 <2004JCCS1325>, and replacement of the amino moiety of 27 with the pyrrole ring via reaction with 2,5-dimethoxytetrahydrofuran to produce 29 (Scheme 3) <2004JCCS1325>. Identical chemistry has been conducted on the corresponding diphenyl derivative <1994PS(89)193>. 

Torok and co-workers312 have reported the one-pot synthesis of /V-arylsulfonyl heterocycles through the reaction of primary aromatic sulfonamides with 2,5-dimethoxytetrahydrofuran. When triflic acid is used in catalytic amount, IV-arylsulfonylpyrroles are formed (Scheme 5.34). Equimolar amount of triflic acid results in the formation of N- ary I s u I fo n y I i n do I e s, whereas /V-arylsu Ifonylcar-bazoles are isolated in excess acid (Scheme 5.34). In the reaction sequence 1,4-butanedial formed in situ from 2,5-dimethoxytetrahydrofurane reacts with the sulfonamide to give the pyrrole derivative (Paal-Knorr synthesis). Subsequently, one of the formyl groups of 1,4-butanal alkylates the pyrrole ring followed by a second, intramolecular alkylation (cyclialkylation) step. 

The reaction of nitro compound 337 with /-butyloxycarbonic anhydride in the presence of DMAP resulted in 2-nitro-benzenesulfonamide 338, which upon reduction with iron in AcOH gave 339 (Scheme 70). The latter when refluxed with 2,5-dimethoxytetrahydrofuran in AcOH afforded pyrrole sulfonamide 340 in good yield along with the fused 1,2,5-thiadiazepines 103 and 104, as a side product. Subsequently, 340 upon reaction with triphosgene afforded 103 and 104. 

The Clauson-Kaas reaction between 2,5-dimethoxytetrahydrofuran 19 and phenylsulfonamide performed in the presence of triflic acid (TfOH) led to either pyrrole 20, indole 21, or carbazole 22 depending on the amount of triflic acid used <07TL4047>. The latter two compounds were formed by the annulation of pyrrole or indole by butanedial (generated by the acid-mediated hydrolysis of 19). A double Clauson-Kaas sequence starting with hydrazine allowed for the preparation of 1,1 -bipyrrole <07JOC93 95>. 

In an application of the Paal-Knorr pyrrole synthesis, the synthetic equivalents 3 of 1,4-ketoaldehydes were prepared by the radical addition of ketones 4 to vinyl pivalate. Treatment of the intermediates 3 with amines gave pyrroles 5 <03SL75>. Other new extensions of this popular pyrrole synthesis include the preparation of a number of pyrroles from hexane-2,5-dione and amines under solvent-free conditions in the presence of layered zirconium phosphate or phosphonate catalysts <03TL3923>, and the development of a solid-phase variant of this reaction <03SL711>. Likewise, the preparation of iV-acylpyrroles from primary amides and 2,5-dimethoxytetrahydrofuran in the presence of one equivalent of thionyl chloride has also been reported <03S1959>. 

Reaction of the derivative 149 (R1 = R2 = 2,5-dimethyl-3-thienyl) with DMF acetal gives the amidine 150 (85%) (Scheme 28) (01MI2424). Condensation of the derivatives 149 (R1, R2 = alkyl or aryl) with 2,5-dimethoxytetrahydrofuran, in the presence of 4-chloropyridinium chloride, gives the pyrrole derivatives 151 (25-86%) (Scheme 28) (96JHC2007, 98JHC1313). 

Quite interestingly, the hydrazido(2-) Hgands derived from the ligating N2 in complexes 1 and 2 are transformed into N-hetero cyclic compounds by application of the condensation and related methods (Scheme 6). Thus, their reactions with 2,5-dimethoxytetrahydrofuran, pyrylium salts, and phthalaldehyde, followed by workup of the complexes containing N-heterocyclic ligands with LiAlH4 or KOH/alcohol, result in the formation of pyrroles [29], pyridines [30], and phthalimidines [31], respectively. 

Fluorobenzo[h]thiophen-2(3//)-one has been prepared via diazotization of sodium (2-amino-4-fluorophenyl)acetate followed by reaction with sodium sulphide and ring-closure. The reaction of 3-amino-2-ethoxycarbonyl-benzo [ft] thiophen with 2,5-dimethoxytetrahydrofuran gave 3-(l-pyrrolyl)-2-ethoxycarbonylbenzo [ft] thiophen, which through Curtius reaction was... 

Electrophilic annelation has also been used to convert indoles to carbazoles. The condensation of amines with 2,5-dimethoxytetrahydrofuran, which is a very useful method of synthesis of pyrroles (see Section 2.03.2.7), if carried out for an extended period, gives JV-substituted carbazoles. This reaction occurs by two successive annelations (Scheme 139) <86T2l3l>. 

Surprisingly, 2,5-dimethoxy-2,5-dihydrofuran did not form the expected aldehydes under CO/H2 pressure (3 MPa) in the presence of the Rh/TPPTS system. Instead of hydroformylation, hydrogenation was the main reaction path in water, where 2,5-dimethoxytetrahydrofuran and its hydrolysis product were obtained. However, hydroformylation occurred when the surface-active phosphine Ph2P(CH2)ioP03Na2 was used [15]. 

Ekkati and Bates reacted more functionalized amides using 2,5-dimethoxytetrahydrofuran as the solvent and thionyl chloride as the acid source to generate a variety of iV-acyl pyrroles similar to 5 with good yields. Under these conditions the reaction times and temperatures were greatly reduced. 

Sulfonamides have also seen great success as partners in the Clauson-Kaas reaction. Similar to amides the pyrroles generated are protected by the starting sulfonamides. Karousis and co-workers reported a successful example of this procedure with 3-formyl-2,5-dimethoxytetrahydrofuran 7 to generate tosyl-protected pyrrole carbaldehyde 8. The tosyl-protecting group was later removed under mildly basic conditions (K2CO3, MeOH at room temperature). 

Abid and co-workers reported that using reaction conditions that vary only in the amount of trifluoroacetic acid protected pyrroles, indoles and carbazoles are generated." The reaction conditions involved reacting an aryl sulfonamide with 5 equiv of 2,5-dimethoxytetrahydrofuran in the dichloromethane and different amounts of TFA. When a catalytic amount of TFA was added the expected pyrrole (10) resulted. When a full equivalent of TFA was used the protected indole was produced (11) and finally when 3.5 equiv of TFA was used the protected carbazole (12) resulted. 

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