Fischer ring closure

The reduction of 2-methyl-1,2,3,4-tetrahydro-y-carboline (92) with zinc and hydrochloric acid in the presence of mercuric chloride gives the indolenine derivative, 2-methyl-l,2,3,4,4a,9b-hexahydro-y-carbo-line (93). A related compound, 4,9b-diethyl-2-methyl-l,2,3,4,4a,9b-hexahydro-y-carboline (96), was obtained by catalytic hydrogenation of 95, which was prepared by Fischer ring closure of the phenyl-hydrazone 94. The stereochemistry of the B/C ring junction in these... 

It is interesting to note that the nitrogen of the amide was sufficiently nucleophilic to be added to the indolenine in XXXII or XXXII( H+), so that the product of the Fischer ring closure was the eseroline XXXIII and not the intermediate indolenine XXXII. 

Sulfuric acid Indolenines and indoles by Fischer ring closure... 

A number of instances in which application of the Fischer synthesis led to extended 3,4-dihydro-j8-carbolinium derivatives have been recorded. Typical for this approach is the ring closure of the phenyl-hydrazone 123 to the expected tetracyclic product... 

A synthetic approach to the same tetracyclic y-carboline nucleus (235) is the consecutive Fischer indole and Bischler-Napieralski ring closure of o-acetamidoacetophenone methylphenyUiydrazone (234). The Bischler-Napieralski reaction has also been used in the synthesis of 3,4-benz-j8-carbolines (236) and 3,4-benz-3-carbolines, e.g. 237... 

Fischer s original method for conversion of the nitrile into an aldehyde involved hydrolysis to a carboxylic acid, ring closure to a cyclic ester (lactone), and subsequent reduction. A modern improvement is to reduce the nitrile over a palladium catalyst, yielding an imine intermediate that is hydrolyzed to an aldehyde. Note that the cyanohydrin is formed as a mixture of stereoisomers at the new chirality center, so two new aldoses, differing only in their stereochemistry at C2, Tesult from Kiliani-Fischer synthesis. Chain extension of D-arabinose, for example, yields a mixture of D-glucose and o-mannose. 

Shortly before this work by Pschorr, similar ring closures had been described for other compounds in which two benzene rings are already linked. Thus Graebe and Ullmann (1894) found that 2-diazobenzophenone can be converted into fluorenone in the analogous manner (Scheme 10-74). Similarly, when Staedel (1894) added nitrous acid to 2,2 -diaminobenzophenone he obtained some 1-hydroxyfluorenone. The ring closure of 2-benzylbenzenediazonium ion to give fluorene (Scheme 10-75) was described by Fischer and Schmidt (1894). 

The following schematic representation of pyranose ring closure in D-glucose shows the reorientation at C-5 necessary to allow ring formation this process corresponds to the change from Fischer to modified Fischer projection. 

The spiroindolinobenzopyran 2 is a classical example of spiropyran and is easily prepared by the condensation of l,3,3-trimethyl-2-methyleneindo-line (Fischer s base) and salicylaldehyde in anhydrous ethanol or benzene (Scheme 2).ia The nucleophilic attack of Fischer s base on the carbonyl group (like an enamine) gives an aldol product, which undergoes ring closure followed by dehydration. This condensation is reversible therefore, an exchange of the salicylaldehyde component of spiropyran with a different salicylaldehyde is possible. For example, when a solution of spiropyran 2 (Scheme 2) was refluxed with 3,5-dinitro-substituted salicylaldehyde, the open form of 6,8-dinitro-BIPS was obtained.2... 

On the other hand, the nonbiogenetic approach usually adopts a convergent process such as shown in Scheme 15. When 18 is cleaved through C-6—C-7 (as 18 - 60), phenylhydrazine and a tricyclic moiety (61) which contains six chiral centers result. The synthetic problem then becomes synthesis of 61 followed by a Fischer indole synthesis and a final ring closure between C-6 and C-7 (61 -> 60 - 18). 

Alkenyl Fischer carbene complexes can serve as three-carbon components in the [6 + 3]-reactions of vinylchro-mium carbenes and fulvenes (Equations (23)—(25)), providing rapid access to indanone and indene structures.132 This reaction tolerates substitution of the fulvene, but the carbene complex requires extended conjugation to a carbonyl or aromatic ring. This reaction is proposed to be initiated by 1,2-addition of the electron-rich fulvene to the chromium carbene followed by a 1,2-shift of the chromium with simultaneous ring closure. Reductive elimination of the chromium metal and elimination/isomerization gives the products (Scheme 41). 

Among the synthetically useful reactions of Fischer carbenes, the benzannulations are certainly the most prominent. In particular, the so-called Dotz reaction, first reported by Dotz in 1975 [3], is an efficient synthetic method that starting from aryl- or alkenyl-substituted alkoxycarbene complexes of chromium affords p-alkoxyphcnol derivatives by successive insertion of the alkyne and one CO ligand in an a,/Tunsaturated carbene, and subsequent electrocyclic ring closure (see Figure 1). 

Calculations [28] on the formation of cyclopropanes from electrophilic Fischer-type carbene complexes and alkenes suggest that this reaction does not generally proceed via metallacyclobutane intermediates. The least-energy pathway for this process starts with electrophilic addition of the carbene carbon atom to the alkene (Figure 1.9). Ring closure occurs by electrophilic attack of the second carbon atom... 

Calculations performed for cyclopropanation with Fischer-type carbene complexes [28] indicate that the electrophilic attack of the carbene complex at the alkene and the final ring closure are concerted. Extrapolation from this result to the C-H insertion reaction (in which a a-bond instead of a 7i-bond is cleaved) suggests that C-H bond cleavage and the formation of the new C-C and C-H bonds might also be concerted (Figure 3.38). 

The most useful route to indoles is the Fischer indole synthesis, in which an aromatic phenylhydrazone is heated in acid. The phenylhydrazone is the condensation product from a phenylhydrazine and an aldehyde or ketone. Ring closure involves a cyclic rearrangement process. 

Most indoles are synthesized by the Fischer indolization reaction. Here a phenylhydrazine is first reacted with an aldehyde, or ketone, carrying an a-methylene group (not acetaldehyde). The corresponding hydrazone is then treated with an acid, often hydrochloric acid. Ring closure occurs, through a [3,3]-sigmatropic change, and ammonia (as the ammonium cation) is lost (Scheme 7.14). 

Comparatively few examples exist of ring closure on to a phenyl ring, but where this is available normal Fischer indolization conditions can be used. Of particular interest are the synthesis of /3-carboline (5 Scheme 59) (72JCS(Pl)53l) and the pyrrolothiapyran (190 ... 

The isomeric oxiranes prepared by ring closure of l-bromo-l-phenyl-2-propan-ol (ref. 9) were separated on a Fischer concentric tube column (theoretical plate number 90) (b.p. cis (1) 355 K/13 mm Hg, trans (2) 361 K/13 mm Hg, ac-... 

Fischer carbene complexes 639 can be coupled with 3-alkynyl-2-heteroaromatic carbaldehydes to form initially the alkenylcarbene complexes 640, which undergo CO insertion to give the ketene intermediates 641, which upon ring closure affords heteroaryl-fused 277-pyran-2-ones (Scheme 147) <2001TL777, 2002JOC4177>. 

Thieno[2,3-Z>]pyrroles have been prepared from 2-thienylhydrazines and carbonyl compounds under the conditions of Fischer indolization (77S487). The Bu OCO group is eliminated, and the intermediate hydrazone can undergo ring closure (equation 15). Thieno[3,2-Z>]pyrroles were prepared similarly from acylated 3-hydrazinothiophenes (75CHE1133). 

The synthesis of azaindoles by the Fischer indole synthesis has been tried more often than by any other method. It has given varied results, with over thirty successful ring closures of pyridyl- or quinolyl-hydrazones reported. Most of these have led to carboline deriva-... 

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