Synthesis of dihydropyrroles

Scheme 10.10 Synthesis of dihydropyrroles through hydrogen-bonding-activation mode.

Scheme 42.47 Synthesis of dihydropyrroles by 1,3-dipolar cycloaddition using conjugated ynones catalyzed by phosphoric acid catalyst 101a.

Very recently, Sun et al. developed a cascade reaction with a binary catalytic system combining a secondary amine and a palladium catalyst for the synthesis of dihydropyrrole enantioselectively [54]. The reaction began with a Jprgensen-Hayashi catalyst promoted N-Ts propargyl amine-involved aza-Michael addition to cinnamaldehydes and ended with subsequent PdCl and Jprgensen-Hayashi catalyst co-promoted car-bocyclization (Scheme 9.59). The chemistry presented here also involved a DYKAT process and provided an alternative to chiral dihyropyrrole synthesis. 

Double alkenylatirai of amides with (lZ,3Z)-l,4-diiodo-l,3-dienes 124 could produce di- or trisubstituted Al-acylpyrroles 125 with good to excellent yields (Scheme 44) [80]. The same idea has been applied in the synthesis of dihydropyrroles and carbazoles [81]. 

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]... 

Many other examples, even with less reactive imine precursors as electrophiles, demonstrate that this type of dihydropyrrole synthesis has a very broad range. Eqs 8.21-8.24 present selected examples of the addition of lithiated methoxyallene 42 to... 

The unique reactivity pattern of alkynyl iodonium salts discussed in Sections II,A.2 and II,D,la can also serve as two-carbon conjunctive reagents in the synthesis of pyrroles, dihydropyrroles, and indoles. Feldman et al. found that combination of alkyl or aralkyl tosylamide anions 101 with phenyl(propynyl)iodonium triflate (102) furnishes the corresponding dihydropyrroles 103 (95JOC7722) (Scheme 28). 

Methoxyethyltosylamide also participates in the [3 -I- 2] addition reaction with 102, although it does not give any of the expected dihydropyrrole derivative 104. Instead, the major product was found to be pyrrole 105, which presumably results through ready elimination of methanol from the putative intermediate 104. Thus, this addition holds promise for the synthesis of 2-substituted tosylpyrroles (Scheme 29). In addition to 105, a minor product 106 (12%) is also formed in this reaction. 

A very interesting modification of method B was applied to the stereospecific synthesis of ( )-pseudoheliotridane.27 Condensation of ethyl bromoacetate with l-methyl-2-ethyl-4,5-dihydropyrrole (42) afforded the quaternary salt 43, which was reduced, without isolation, with formic acid to give ethyl /3-(Ar-methyl-2-pyrrolidyl)butyrate (44). The amino alcohol (45), obtained by reduction of 44 with lithium... 

As shown above, insertion of alkylidene carbenes is highly regioselective. However, when the normal 1,5-C-H insertion pathway is blocked, 1,4- or 1,6-C-H insertion takes place [Eq. (109)]. Thus, the cyclobutene 121 [192] and the six-membered enol ether 123 [193] were obtained in modest yields. Intramolecular insertion into carbon-carbon double bond provides a method for synthesis of cyclopenten-annulated dihydropyrrole 124, which results from homolytic scission of a methylenecyclopropane intermediate [194]. 

A similar intermolecular cyclization was recently utilized in the synthesis of highly substituted dihydropyrrole derivatives [133 -135]. In a specific example, the addition of pentadienyltosylamide derivatives 177 to propynyl(phenyl)iodo-nium triflate initiates a sequence of transformations that furnishes the complex, highly functionalized cyclopentene-annelated dihydropyrrole products 178 in moderate yields with complete stereoselection (Scheme 66). Under similar reaction conditions, the isomeric isoprene-derived tosylamide 179 reacts with propynyl(phenyl)iodonium triflate to give azabicyclo[3.1.0]hexane 180 as the final product [134]. 

The stereogenic center in a dihydropyrrol derivative was used as the key directing element in the synthesis of natural product (+)-preussin via a [2+2] photocycloaddition with benzaldehyde [154]. 

RCM reactions are most frequently employed in the synthesis of 2,5-dihydrofurans as well as dihydropyrrole derivatives . Likewise, RCM provides the most general approach to 3,6-dihydropyrans . In a specific example, dihydropyran 127 bearing a chiral oxacyclic diene can be constructed via enyne metathesis of the chiral ether 126 (Scheme 68) <2002T5627>. The analogous tetrahydropyridine derivatives are prepared by a similar RCM procedure . 

Bach T, Brummerhop H (1998) Unprecedented facial diastereoselectivity in the Paterno-Buchi reaction of a chiral dihydropyrrol—A short total synthesis of (+)-preussin. Angew Chem 110 3577-3579, Angew Chem Int Ed 37 3400-3402... 

Electrophile-mediated cyclization reactions of alkynes tethered to pendant heteroatom nucleophiles is an emerging strategy for the synthesis of heterocycles. This methodology has now been applied to the synthesis of pyrroles. The iodocyclization of 3-aminoalkynes 1 led to the formation of dihydropyrrole 2 <07TL7906>. Treatment of the latter with mesyl chloride in the presence of triethylamine then gave (i-iodopyrrolcs 3. 

Readily accessible 5-alkylidene-2,5-dihydropyrrol-2-ones 32 are transformed into functionalised pyran-4-ones on treatment with aq. HC1. The method is adaptable to the synthesis of dihydro- and tetrahydrochromones and benzo[/z]chromones <07T12975>. 

The synthesis of )-A -BOC-2-hydroxymethyl-2,5-dihydropyrrole )-923 with ee up to 98% was achieved by its irreversible acetylation catalyzed by Pseudomonas fluorescens lipase (Scheme 179) <1998TA403>. Precursor ( )-922 for compound 923 can be easily prepared from commercially available pyrrole-2-carboxylic acid 921 by Birch reduction, followed by esterification and reduction according to literature procedure <1996JOC7664>. 

Fig. 7.1. The strategy used to develop GGTI. A pilot library consisting of 171 compounds were screened for the ability to inhibit GGTase-I using RhoA as a substrate. This led to the identification of two groups of compounds, one with tetrahydropyridine scaffold and the other with dihydropyrrole scaffold. Solid-phase split-and-pool combinatorial synthesis of a large number of analogs of these initial hits led to the identification of P3-E5 and P5-H6. More than 700-fold increase in IC50 value for the inhibition of GGTase-I was obtained in the case of P3-E5 compared with the initial compound. Further derivatization of P5-H6 and P3-E5 led to cell active compounds P61-A6 and P61-E7, respectively.

Although the Birch reduction (alkali metals in liquid NH3) of the pyrrole ring is apparently unknown (c/. equation 8), the partial reduction of pyrroles to 2,5-dihydropyrroles using Zn/HCl has been of considerable utility. For example, pyrrole gives 2,5-dihydropynole as the major product upon treatment with Zn dust/20% aq. HCl (equation 9), and Lemal and McGregor observed that 2,5-dimethylpyrrole gives a mixture of trans- (78%) and c/5-2,5-dimethyl-2,5-dihydropyrrole (22%) under similar conditions (47% yield). In one of these studies, Hudson and Robertson demonstrated that 2,5-dihydropyrrole is not reduced to pyrrolidine under these reaction conditions. Using these same conditions, Schumacher and Hall reported the reduction of 2-benzylpyrrole to the 2,5-dihydro derivative (67%) in a synthesis of the antibiotic anisomycin. ... 

Further progress towards the stereoselective synthesis of chhydrooxazines has also been reported by Reissig and coworkers who exploited the formal [3 + 3] reaction of lithiated methoxyallene with nitrones derived from (R)-glyceraldehyde [97,98]. Subsequent transformations enabled the synthesis of enantiomerically pure pyrrolidine and 2,5-dihydropyrrole derivatives incorporating one asymmetric unit of the chiral template. 

Pulz, R, Watanahe, T, Schade, W, Reissig, H U, A stereoconvergent synthesis of enantiopure 3-methoxypyrrolidines and 3-methoxy-2,5-dihydropyrroles from 3,6-dihydro-27/-1,2-oxazines, Synlett, 983-986, 2000. 

Palladium-catalyzed asymmetric allylic alkylation [529] of suitable amines with two equivalents of racemic butadiene monoxide ((-r)-411) allows for the expedient synthesis of trans-and cA-2,5-dihydropyrroles derivatives 416 and 417 that are versatile chrrons towards the s)m-thesis of a wide variety of iminosugars [530]. In the presence of 0.4% [(allyl)PdCl)2], 1.2% of enantiomerically pure diphosphine (/ ,/ )-ligand, and Na2C03 a 1 1 mixture of ( )-411 and phthalimide reacted in CH2CI2 at room temperature giving (5)-412 in 99.6% yield and... 

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