Pyrroles electrocyclization

The insertion of alkynes into a chromium-carbon double bond is not restricted to Fischer alkenylcarbene complexes. Numerous transformations of this kind have been performed with simple alkylcarbene complexes, from which unstable a,/J-unsaturated carbene complexes were formed in situ, and in turn underwent further reactions in several different ways. For example, reaction of the 1-me-thoxyethylidene complex 6a with the conjugated enyne-ketimines and -ketones 131 afforded pyrrole [92] and furan 134 derivatives [93], respectively. The alkyne-inserted intermediate 132 apparently undergoes 671-electrocyclization and reductive elimination to afford enol ether 133, which yields the cycloaddition product 134 via a subsequent hydrolysis (Scheme 28). This transformation also demonstrates that Fischer carbene complexes are highly selective in their reactivity toward alkynes in the presence of other multiple bonds (Table 6). 

Pyrrolizin-3-ones may also be obtained by FVP of 3-(pyrrol-2-yl)propenoate esters such as 62, 69, and 74. Also, benzo-annulated pyrrolizinone 17 was obtained by FVP of 2-(tf-methoxycarbonyl phenyl (pyrrole <1999J(P1)2047>. FVP of alcohols 77, 78, and 79 led to 3//-pyrrolyzine derivatives 1, 192, and 193, respectively, in good yields (66-95%). These transformations proceed by elimination of water and subsequent electrocyclization of the in situ-generated cumulene (Scheme 44) <1999J(P1)2049>. 

Upon reaction of A -vinyliminophosphoranes (109) with aromatic isocyanates, vinylcarbodiimides (110) are formed, as shown in Scheme 47. Divi-nylcarbodiimides (111) can be obtained as side products (88CB271). With isonitriles the vinylcarbodiimides also afford pyrroles (112) via [4 + 1]-cycloaddition. Divinylcarbodiimide can also react via [4 -l- l]-cycloaddition with an isonitrile, whereupon an electrocyclic step of the initial diaza-1,3,5-trienes (113) follows. Finally, the pyrrolo[2,3-e]pyrazine 114 is obtained (88CB271). 

Fluoro-substituted dihydrofuro[3,2-r ]pyridinones are obtained from the thermolysis reaction of cyclopropa[3]-furo[2,3-f]pyrroles, 134, along with the loss of HF (Equation 67) <2005SL1006>. Compound 134 is generated from pyrroles via reaction with a carbene to give an azomethine ylide which undergoes an electrocyclization reaction. 

The product distribution depends upon the substituents on the dipolar system. The details of the complex mechanistic pathway were demonstrated on the most simple first example as early as 1987 (Scheme 36) (87TL2689). In all cases the first step is postulated as a 1,7-electrocyclization. The formation of pyrrole 123 may proceed through the key intermediate 119 (a conjugated keto-carbene) which is formed either directly from 114, or from 116, or possibly from the N/O Cope product 115. 

Aromatic and heteroaromatic rings can participate effectively in the 8ir electrocyclization of nitrones. Upon thermal activation, the benzo derivative 130a did not produce the expected products (92TL61).The conversion of the other derivatives 130b-f at 420°C did, however, give the annulated pyrrole 132 and pyridone 133 derivatives, via the intermediates 131, along with some minor by-products (Scheme 38) (94CB247). 

The reaction of ketocarbenoids with pyrroles leads to either substitution or cyclopropanation products, depending on the functionality on nitrogen. With N-acylated pyrrole (209) reaction of ethyl diazoacetate in the presence of copper(I) bromide generated the 2-azabicyclo[3.1.0]hex-3-ene system (210) and some of the diadduct (211 Scheme 44).162163 On attempted distillation of (210) in the presence of copper(I) bromide rearrangement to the 2-pyrrolylacetate (212) occurred, which was considered to proceed through the dipolar intermediate (213). In contrast, on flash vacuum pyrolysis (210) was transformed to the dihydropyridine (214). A plausible mechanism for the formation of (214) involved rearrangement of (210) to the acyclic imine (215), which then underwent a 6ir-electrocyclization. 

A number of electrocyclic reactions under PET conditions have been reported. In this way, A-benzyl-2.3-diphcnylaziridinc (40) underwent a 3 + 2-cycloaddition with alkene and alkyne dipolarophiles to afford substituted pyrrole cycloadducts (41) via the radical cation intermediate (42) see Scheme 7.80 Elsewhere, novel arylallenes have been used as dienophiles in a radical cation-catalysed Diels-Alder cycloaddition reaction with 1,2,3,4,5-pentafluromethylcyclopentadiene, which often occurred with peri-, chemo-, facial- and stereo-selectivity.81... 

Pyrroles, H.M.L. Davies. Synthesis of Porphyrins with Exocy-clic Rings from Cycloalkenopyrroles, T.D. Lash. Palladium-Catalyzed Coupling Reactions of Indoles, A.R. Martin and Q. Zheng. Cycloaddition Reactions of Indole Derivatives, U. Pindur. Transition-Metal Mediated Synthesis of Carbazole Derivatives, H. J. Knoiker. Synthesis of [b]-Annelated Indoles by Thermal Electrocyclic Reactions, S. Hibino and E. Sugi-no. Total Synthesis of (-) and ent (-) Duocarmycin SA, D.L. Boger. Index. I... 

The actual cyclisation stage is not as imponderable as it appears. The first step is the acid-catalysed equilibration between hydrazone 7.8 and ene hydrazine 7.10. The next step, which is irreversible, is a concerted electrocyclic reaction, forming a strong carbon-carbon bond, and breaking a weak nitrogen-nitrogen bond. The resulting imine 7.11 immediately re-aromatises by tautomerisation to aniline 7.12. Finally, acid-catalysed elimination of ammonia forms indole 7.9, reminiscent of the last step of the Knorr pyrrole synthesis (Chapter 2). 

In the three different approaches envisaged for the total syntheses of rhazinilam, the construction of the pyrrole ring was operated in two different manners a Knorr-type reaction in the Smith synthesis and a 1,5-electrocyclization of an allyl-iminium compound in the Sames and Magnus syntheses. 

Electrocyclization of a suitable carbanion (e.g., 164) can also occur as illustrated in Scheme 92 <1978AGE676>. Likewise, the electrocyclization of the precursor 165, which can be prepared by condensation of a chromiumaminocarbene complex with a suitable amide, provides the pyrrole 166 (Scheme 93) <20020M1819>. 

The thermal rearrangement of 1-substituted pyrroles to 2- (and 3-) substituted isomers by sequential [l,5]-shifts has been known and studied extensively <1966JA3671, 1976S0281, 1988J(P1)339>. It was also shown that pyrrol-2-yl)acrylate 16 and related compounds undergo concerted elimination of alcohols under flash vacuum pyrolysis (FVP) conditions to give pyrrolizin-3-one 18 by electrocyclization of an intermediate 17 (Scheme 7) <1997J(P1)2195>. 

Electrocyclization of the precursor 148, which was prepared by condensation of a chromium aminocarbene complex with a suitable amide, provided the pyrrole 149 (Equation 44) <20020M1819>. 

The synthesis of a number of pyrrole derivatives has been effected by the thermal conversion of 3-vinyl-2H-aziiines to butadienylnitrenes followed by 1,5-electrocyclization (75JA4682). For example, the thermal transformations observed on thermolysis of 2H-azirine 28 were rationalized in terms of an equilibration of the 2H-azirine with a butadienylnitrene, which subsequently rearranged to the final products. The rearrangement of 28 to pyrrole 30 was envisaged as occurring by an electrocyclic reaction followed by a 1,5-sigma tropic ethoxycarbonyl shift and subsequent tautomerization... 

Of the 5-membered heteroaromatic systems, pyrrole reacts most like benzene in alkyne photocycloaddition, giving a 3,4-disubstituted azepine by 2,3-cycloaddition followed by electrocyclic ring-opening fequation 73) . Azepines with a different substitution pattern have been made by therpial 2,5-addition of an alkyne to a pyrrole, followed by photochemical ring-closure and thermal ring-opening of the tetracyclic photoproduct (equation 74) . 

The azide (95), for example, is converted on irradiation in acetonitrile into the pyrrole (96) the proposed mechanism, which involves initial formation of a nitrene, 1,5-electrocyclization to the fused 2H-pyrrole, and sigmatropic migration of the 2-substituent, is shown in Scheme 7. 2-Azidostyrenes have similarly been... 

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