Pyrroles 1,3-diynes

The synthesis can be conducted both in solution and without solvents. The reaction in solvent (e.g., methanol, ethanol, dioxane, dimethylformamide) is recommended for volatile 1,3-diynes and amines in this case the pyrroles are purer and the yield is higher. With disubstituted diacetylenes, ammonia and primary alkyl- and arylamines produce 1,2,3-trisubstituted pyrroles under the same conditions (65CB98 71MI1). Since disubstituted diacetylenes are readily obtained by oxidative coupling of acetylenes (98MI2), this reaction provides a preparative route to a wide range of pyrroles. 

The condensed isobenzofuran derivative l,3-dimethyl-2,5,7-triphenyl-2/f-furo[3,4-/]isoindoloquinone (64), has been prepared in four steps from a pyrrole derivative143 (Scheme 79) a thiophene analog of64 has been obtained in a similar manner.144 Key intermediates in both types of reactions are condensed rhodacyclopentadienes (cf. 63) which are obtained from appropriate diynes. 

The methodology is useful for a variety of synthetic purposes. The cycloadditions are not subject to steric hindrance. Thus diyne cycloadditions to 2,5-disubstituted furans or pyrroles, followed by elimination of the oxygen or nitrogen bridges, provides an excellent, short route to peri-substituted arenes, as in the following examples 4 6 8... 

Ojima has reported a rhodium-catalyzed protocol for the disilylative cyclization of diynes with hydrosilanes to form alkylidene cyclopentanes and/or cyclopentenes. As an example, reaction of dipropargylhexylamine with triethyl-silane catalyzed by Rh(acac)(GO)2 under an atmosphere of CO at 65 °G for 10 h gave an 83 17 mixture of the disilylated alkylidene pyrrolidine derivative 92b (X = N-//-hexyl) and the disilylated dihydro-1/ -pyrrole 92c (X = N-//-hexyl) in 76% combined yield (Equation (60)). Compounds 92b and 92c were presumably formed via hydrosilyla-tion and hydrosilylation/isomerization, respectively, of the initially formed silylated dialkylidene cyclopentane 92a (Equation (60)). The 92b 92c ratio was substrate dependent. Rhodium-catalyzed disilylative cyclization of dipro-pargyl ether formed the disilylated alkylidene tetrahydrofuran 92b (X = O) as the exclusive product in low yield, whereas the reaction of dimethyl dipropargylmalonate formed cyclopentene 92c [X = C(C02Et)2] as the exclusive product in 74% isolated yield (Equation (60)). 

Aaron L. Odom of Michigan State University has described (Org. Lett. 2004, 6, 2957) a new approach to dialkyl pyrroles. Ti-catalyzed hydroamination of a 1,4-diyne such as 1 leads smoothly to 2. Similarly, Ti-catalyzed hydroamination of a 1,5-diyne such as 3 delivers 4. An inherent limitation of this approach is that it only allows substitution at the 2 and the 5 positions of the pyrrole. 

There have also been several reports of the cyclization of diynes with amines under the influence of copper(I) chloride (equation 73) (65CB98, 70KGS125, 72TL3487). This is a potentially useful reaction for symmetrically substituted pyrroles, since symmetrical diynes can be obtained by oxidative coupling of alkynes. 

The Rh4(CO)i2-catalyzed reactions of 1,6-diynes at 95 °C and 20 atm of CO in benzene or acetonitrile are less selective than those catalyzed by Rh2Co2(CO)i2 or Rh(acac)(CO)2, and a different type of silylcarbobicyclization product, azabicyclo[3.3.0]octadienone (351), is formed in addition to 349-type product (352) when benzyldipropargylamines (350) are used (equation 142)339. The formation of a small amount (5%) of the bicyclic pyrrole of 351-type with 7V-tosyl group is also observed besides 348-type (18%) and 349-type (51%) products in the reaction of IV-tosyldipropargylamine339. 

Titanium-catalyzed hydroamination of the diyne 470 has been demonstrated to proceed via a 5-r r/o- /g-cyclization affording the pyrrole 471 (Equation 130). Pyrroles have also been isolated as products from similar reactions involving related 1,5-diynes, which resulted from S-exo-dig-annuhitiom <2004OL2957>. 

A titanium-catalyzed hydroamination of 1,4-diynes and 1,5-diynes produces 1,2,5-trisubstituted pyrrroles in one synthetic step <04OL2957>. Treatment of 1,4-diyne 33 with titanium complex 34 led to the formation of pyrrole 35 via a hydroamination to an imino alkyne followed by an intramolecular 5-endo dig cyclization. Another transition metal-mediated pyrrole... 

Construction of the phosphole ring, with one useful exception, is accomplished by methods that are quite different from those employed for the N, S, O ring systems. Because of fundamental differences in the chemistry of phosphines versus amines, none of the familiar carbonyl condensation processes are known to be applicable to phosphole synthesis. Thus an attempt to use the Paal-Knorr condensation of 1,4-dicarbonyl compounds with PhPH2 <65JCS2184> and with PH3 <88ZOB783> failed to give phospholes. The only successful method known to the present that is common to both the phosphole and pyrrole ring systems is the condensation of 1,3-diynes with primary phosphines... 

Furan also undergoes a primary [4+2] cycloaddition with 3, but this is followed by a [2+1] addition of 2 to the newly formed double bond to furnish the isolated tricyclic compound 5. Thiophene behaves differently its reaction with 3 furnishes the disilathiirane 6 as a formal sulfur-abstraction product [3]. This strongly divergent behavior of five-membered ring systems prompted us to investigate the photolyses of 1 also in the presence of a selenophene, a tellurophene, and a pyrrole. We report here on the photolysis of 1 in the presence of these cyclic dienes as well as similar reactions with acyclic diynes. 

A domino Mannich/aza-Michael reaction was applied to the synthesis of 2,5-cis-configured polysubstituted pyrrolidines from y-malonate-substituted a,P-unsaturated esters with N-protected arylaldimines [117]. In this report, bifunctional thioureas were trialed with the Takemoto catalyst, being the most efficient with respect to yield as well as enantiomeric and diastereomeric excess. In a separate approach, the Garcia-Tellado group approached the pyrrole ring system 234, beginning with a tertiary skipped diyne 233 and a primary amine (Scheme 7.50). 

A gold(I)-catalysed cycloisomerization of 1,6-diynes containing propargylic esters and arenynes is reported for the synthesis of 3-pyrrolines or pyrroles (Scheme 111). ... 

Schulte [285, 286] and later Chalk [287] described the Cu(I)-catalyzed synthesis of symmetrical 2,5-diarylpyrroles 261 from conjugated diynes 257 and primary amines 258. The reaction is believed to proceed via the transition metal-catalyzed hydroamination [33, 288-291] leading to tautomeric aminoenyne 259 or homopro-pargylic imine 260 intermediates, which further undergo 5-endo-dig cyclization to furnish pyrrole product 261 (Scheme 8.95). 

Expanding upon these early results, the Odom group [322] showed that using a preformed diyne is not required but rather a four-component coupling reaction could be exploited to generate pentasubstituted pyrroles in up to 82% isolated yield (Table 15.27). In this case, the Ti(indolyl) complexes have been used to advantage to reahze this efficient synthesis. 

Alternatively, 1,3-diynes can also be used for the assembly of pyrroles, as has been shown by Bertrand [179], Odom [321], and Ackermann [324]. Skrydstrup showed that these easily accessed diyne starting materials can undergo efficient Au(I)-catalyzed hydroamination reactions with aniline derivatives to give trisubstituted... 

Scheme 15.99 Au-catalyzed hydroamination of 1,3-diynes for the synthesis of pyrroles.

Addition of primary amine to a 1,4- or 1,5-diyne could be accomplished using titanium complex Ti(NMe2)2(dpma), resulting in an imine-yne that can undergo cyclization to the pyrrole derivatives. The Markovnikov hydroamina-tion products of 1,4-pentadiyne could undergo 5-endo-dig cyclization to yield a 2-methylpyrrole. Meanwhile, Markovnikov hydroamination of 1,5-hexandiyne would yield an imine-yne that could undergo 5-exo-dig cyclization to a 2,5-dimethylpyrrole [314] (Scheme 14.135). 

The [Ni(cod)2]-catalysed 3 + 2-cycloaddition of methyleneaziridines (32) with diynes (33) yielded substituted pyrroles (34), via azomethine ylides, with excellent regios-electivity (Scheme 10)." ° Aromatic heterocycles and carbocycles, including benzene and pyridine derivatives, have been shown to behave as 2a -electron components in the 3 + 2-cycloaddition reactions of non-stabilized azomethine ylides. Highly functionalized polyheterocyclic adducts are produced by this cycloaddition process." ... 

Reductive cyclization of diynes or enynes was catalyzed by NHC-Pt complexes in the presence of H2 and SnCl2 as activator (Equation (10.33)) to afford an interesting pathway to 2,5-dihydrofurans, pyrroles or cyclopentenes in moderate to good yields (50-88%). ° ... 

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