1.2- dihydropyrroles

The pyrrolines or dihydropyrroles can exist in three isomeric forms 1-pyrroline (3,4-dihyro-2JT-pyrrole [5724-81-2]) (16) is an unstable material that resiniftes upon exposure to air 2-pyrroline (2,3-dihydro-lJT-pyrrole [638-31-3]) (17) is even more unstable only 3-pyrroline (2,5-dihydro-lJT-pyrrole [109-96-6]) (18) is reasonably stable. 3-Pyrroline bods at 91°C and has a density of 0.9097 g/cm and a refractive index of 1.4664. 

Dihydropyrroles (2-pyrrolines 231) are in tautomeric equilibrium with the corresponding 1-pyrrolines (232) the latter readily form trimers of type (233). The trimer dissociates in boiling THF to 1-pyrroline (232) trimerization is relatively slow at -78 °C and the monomer can be trapped by reaction with acylating reagents to give (V-acyl-2-pyrrolines (81JOC4791). 

A/ -Methoxycarbonyl-2-pyrroline undergoes Vilsmeier formylation and Friedel-Crafts acylation in the 3-position (82TL1201). In an attempt to prepare a chloropyrroline by chlorination of 2-pyrrolidone, the product (234) was obtained in 62% yield (8UOC4076). At pH 7, two molecules of 2,3-dihydropyrrole add together to give (235), thus exemplifying the dual characteristics of 2,3-dihydropyrroles as imines and enamines. The ability of pyrrolines to react with nucleophiles is central to their biosynthetic role. For example, addition of acetoacetic acid (possibly as its coenzyme A ester) to pyrroline is a key step in the biosynthesis of the alkaloid hygrine (236). 

R H) then the palladium intermediate can be induced to undergo a variety of other reactions 80JA3583). The catalytic cyclization of 5-tosylamidoalkenes to dihydropyrroles has been achieved similarly (Scheme 7b) 82JA2444). 

CLOKE - WILSON Cyclopropylkelone Rearrangement Rearrangement o( cyclopropyl ketones or imines to dihydnofurans or dihydropyrroles, thermally, photochemically, or by Lewis adds... 

Pyrrole is known to slowly undergo hydrogenation to 2,5-dihydropyrrole, which is then easily hydrogenated to pyrrolidine. 

Work out the energy of both hydrogenations (data for 2,5-dihydropyrrole and pyrrolidine are available the energy of H2 is given at right). Are both reactions equally exothermic If not, why not Why is the first hydrogenation step slower than the second step ... 

By means of and NMR spectroscopy it was found that 2-(meth-ylamino)-l-pyrroline (R = Me) is present in solution mainly in the amino form. For the corresponding A -phenyl derivative an equilibrium between 2-aminopyrroline, imino, and 2-amino-4,5-dihydropyrrole tautomers is found (Scheme 20) (87MI5). 

Rolgamidine (14) is a dihydropyrrole derivative which has antidiarrheal activity It can be synthesized by alkylation of trans 2,5-dimethyl-3 pyrroline (12) with methyl bromoacefate to give 13 An amide-ester exchange reaction with guanidine hydrochloride completes the synthesis of rolgamidine (14) [3]... 

Non-enolizable imines such as 9-fluorene imines react with alkynylcarbene complexes to afford mixtures of mesoionic pyrrolium carbonyltungstates and dihydropyrrole derivatives [68] (Scheme 23). Although both compounds can be considered as [3C+2S] cycloadducts, formation of each of them follows a very different pathway. However, the first intermediate of the reaction is common for both compounds and supposes the conjugated addition of the imine to the alkynylcarbene complex to form a zwitterionic intermediate. A cyclisation... 

The same principle of sequential cyclopentene-opening RCM resulting in the formation of a dihydropyrrole ring was the key step in Blechert s novel approach to the polyhydroxylated indolizine alkaloid (-)-swainsonine (378) via RRM of 375 (Scheme 73) [157]. 

Starting from the appropriate diallyl amines or ethers, 4,5-dihydropyrroles and 4,5-dihydrofurans could be obtained in good yields in a matter of minutes. 

Feldman reported a route to dihydropyrroles, pyrroles, and indoles via the reaction of sulfonamide anions with alkynyliodonium triflates <96JOC5440>. Thus, upon nucleophilic addition of the anion of 91 to the p-carbon of the alkynyliodonium salt, the alkylidene carbene 92 is generated which can the undergo C-H insertion to the desired product 93. 

IH of aminoalkynes can be performed under mild conditions using CpTiCb or CpTi(Me)2Cl as catalyst precursors to give dihydropyrrole and tetrahydropyridine derivatives (regioselective Exo-Dig processes) in high yield with TOE near 10 h (e.g., Eq. 4.79) [297]. 

Coupled intermolecular hydroaminations and intramolecular cycUzations give pyrroles resulting from isomerization of the initially formed exomethylene dihydropyrrole derivatives (Eq. 4.85) [137]. 

The effieiency of eatalyst Ic was examined in the ring closing metathesis of challenging substrate 3c. Full eonversion of dimethallylamide (3c) was achieved after heating to 80°C for 2.5 h with a catalyst loading of 2.5 mol%. The larger scale run furnished 80% isolated yield of the desired dihydropyrrole 4c. 

Dihydropyrrole a-ketoester 423 when reacted with 2,2,2-trichloroethyl carbazate in refluxing xylene underwent smooth cycloaddition to afford cycloadduct 48 in 86% yield. Reaction of 423 with thiosemicarbazide in acetic acid yielded a product mixture to give the tetracycle 48. Its benzyloxycarbonyl group was cleaved by reaction with HBr to give crystalline 424 <2002JOG7880> (Scheme 94). 

The tricyclic core of spirotryprostatin B can be formed via formation of the dihydropyrrole 325 <2000AGE4596>. Removal of the silyl protecting group of 322, followed by Dess-Martin oxidation, and reaction of the resultant aldehyde with the potassium salt of the diketopiperazine phosphonate 323 led to formation of the enamide 324. 

Scheme 11.33. Aminocyclopropanation of N-protected 2,5-dihydropyrroles 126 and debenzylation of the exo-6-amino-3-azabicyclo[3.1. OJhexane 129 [105b, 113].

Two laboratories have independently disclosed an interesting series of mechanism-based inhibitors. The dihydropyrrole 31, which appeared in a patent application [61], was reported to inhibit rat lung SSAO/VAP-1 with an IC50 = 500 nM. Recently, the Sayre team extended earlier work [74] and showed that these inhibitors, exemplified by 32, covalently bound to the enzyme with the cofactor in the reduced form [75]. Presumably, aromatization of the dihydropyrrole moiety accounts for the observed potencies. 

Dihydropyrrole triflate 55 is smoothly converted to the 2-phenyl derivative 56 under Negishi conditions [53]. This sequence represents a useful alternative to conventional pyrrole Negishi couplings. 

Dihydropyrrole triflate 55, which was mentioned in Section 2.3.2, undergoes facile Stille couplings to yield, for example, 2-acylpyrrole derivative 116 after hydrolysis. Also prepared in these studies were the corresponding 2-vinyl (77%) and 2-phenyl (56%) derivatives [53, 81]. 

Pyrrole fails to undergo a Heck reaction with 1-bromoadamantane [90], However, dihydropyrroles such as 131 and 132 undergo Heck reactions with ease, although the yields are variable [91-93]. Some examples are illustrated below. Since dihydropyrroles can be oxidized to pyrroles with a variety of reagents [94, 95], these Heck reactions of dihydropyrroles should constitute viable routes to pyrroles. 

In these Heck reactions some degree of enantioselectivity (up to 83% ee) is achieved in the presence of (/ )-BINAP, although the yields of Heck products are often very low in the highest degree of enantioselectivity (e.g., 19% isolated yield at 83% ee) [93]. An example of a tandem Heck reaction is shown below involving the arylation of dihydropyrrole 132 with 1-naphthyl triflate (133) [92]. Complete chirality transfer is observed for the arylation of 134 to 135. 

Dihydropyrrole triflate 55, which we have encountered earlier in this chapter, undergoes a Pd-catalyzed carbonylation reaction to give ester 158 [53, 81]. A similar carbonylation sequence in the presence of the hydride donor n-BusSnH gives the corresponding aldehyde in 56% yield [81]. 

Cyclization of amino alcohol 177 leads to efficient chirality transfer into product dihydropyrrole 178 [126]. 

Larock has described the reaction of diphenylacetylene with iodosulfonamides 189 to give alkylidene dihydropyrroles 190 [130], This ring-forming reaction is similar to the large number... 

With regard to the Pd-catalyzed arylation of dihydropyrroles presented in Section 2.5, it is noteworthy that the readily available 2,5-dihydropyrroles 197 can be smoothly isomerized to 2,3-dihydropyrroles 198 under the influence of Pd [144],... 

The intermolecular Heck reaction of 3-bromofuran and tosylallyamine 88 gave adduct 89 under the classical Heck conditions [79], Subsequent Rh-catalyzed hydroformylation with ring closure occurred regioselectively to furnish the hydroxypyrrolidine, which was dehydrated using catalytic HC1 to afford dihydropyrrole 90. 

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