Elimination pyrrolines

The regioselectivity observed in these reactions can be correlated with the resonance structure shown in Fig. 2. The reaction with electron-rich or electron-poor alkynes leads to intermediates which are the expected on the basis of polarity matching. In Fig. 2 is represented the reaction with an ynone leading to a metalacycle intermediate (formal [4C+2S] cycloadduct) which produces the final products after a reductive elimination and subsequent isomerisation. Also, these reactions can proceed under photochemical conditions. Thus, Campos, Rodriguez et al. reported the cycloaddition reactions of iminocarbene complexes and alkynes [57,58], alkenes [57] and heteroatom-containing double bonds to give 2Ff-pyrrole, 1-pyrroline and triazoline derivatives, respectively [59]. 

A good example of a concerted cheletropic elimination is the reaction of 3-pyrroline with IV-nitrohydroxylamine, which gives rise the the diazene 21, which then undergoes elimination of nitrogen. 

Petrillo reports that the reaction of l,4-diaryl-2,3-dinitrobutadienes 42 with representative primary amines leads to //-alkyl-3-alkylamino-2,5-diaryl-4-nitropyrrolidines 43 presumably via a disfavored 5-endo-trig ring closure <00EJOC903>. Acid catalyzed elimination of the amine led to the corresponding trans-2,5-diaryl-3-nitro-3-pyrrolines 44 which could be dehydrogenated to the corresponding pyrroles 45. 

In 1955, Guthrie and co-workers (131) erroneously assigned pyrroline structure 87 to the crystalline compound obtained by treating aminoacetal 86 with sulfuric acid (Scheme 14). The structure assignment was revised by Battersby and Yeowell (69) to 35, who named it isopavine, since the structure had already been proposed but eliminated for the isomeric compound pavine (34) (95,97). The Battersby structure was conclusively confirmed through a study of the chem-... 

The cyano-substituted nitrile ylides 123 have been generated via 1,1-elimination reactions. For example, the benzyhdene derivative 122 (R=Ph) eliminated benzene on vapor phase pyrolysis to give 123 (R=Ph), which reacted via 1,5-electrocycli-zation [see also (66)] to give the isoindole 124 (41%) (67). In a similar way, 122 [R=(CH2)3CH=CH2] gave the corresponding nitrile yhde that reacted via intramolecular cycloaddition to give the pyrroline derivative 126. 

The pyrido[3,4- pyridazine 40 was also reacted with l-methyl-2-methylthio-2-pyrroline, at room temperature within 30 min, to give the two isomeric pyrroline-annulated isoquinolines 49 and 50, in an overall yield of 65% with ratio 1 2.3, via elimination of nitrogen and methanethiol from the initially formed cycloadducts <1994H(38)1845>. 

Elimination of nitric oxide from 3-carbamoyl-2,2,5,5-tetramethyl-pyrroline 1-oxyl (69) was observed on photolysis in benzene, and an almost quantitative yield of the diene (70) was obtained.61 Ring-saturated nitroxides appear to be unaffected by irradiation of the same wavelength. 

Vinyl azide intramolecular cycloaddition is further illustrated by the formation of azidotriazoline 32 as a minor product in the thermolysis of the bisvinyl azide 31 (Scheme 41).200 An analogy is provided by the formation of 2,5-diphenylpyrrole from the slow decomposition of a-azidostyrene.202 Pyrrole formation is interpreted in terms of cycloaddition of the azide onto the electron-rich double bond of a second molecule to give a triazoline that loses nitrogen and rearranges to a pyrroline followed by hydrogen azide elimination (Section IV,D).203... 

Aryl-A3-iodane oxidation of amines to imines also involves a combination of ligand exchange and successive reductive -elimination. Oxidation of pyrrolidine with iodosylbenzene 18 affords quantitatively an equilibrium mixture of 1-pyrroline and its trimer [72]. When oxidation of piperidine with 18 (2 equiv) was carried out in water, 2-piperidone was produced [73]. In the latter reaction, a sequence of ligand exchange and reductive -elimination was repeated two times [Eq. (38)]. 

From a secondary amide, formation of a nitrile ylid because of plausible elimination of trimethylsilanol prior to cyclization might be expected. However, it is possible that this elimination occurs after cyclization. Thus, the true 1,3-dipole would be the imidate methylide. In any case, the final product will be a A -pyrroline.458... 

Generally, dehydrogenation prevailed in secondary amines when treated with one equivalent of IOB in dichloromethane in this way ACt-butylbenzylamine gave its imine (PhCH = NBu , 88%), whereas pyrrolidine was converted into a mixture of 1-pyrroline and its trimer. Hydrogen elimination followed Hofmann s rule, for example in the following transformation [41] ... 

Another synthetic route to ( )-retronecine (27) has been developed by Vedejs and Martinez.11 The protected hydroxy-lactam (22) was prepared from 2-methoxy-1-pyrroline by known methods. The key ylide intermediate (24) was then generated from the salt (23) by desilylation with caesium fluoride (Scheme 6). This ylide (24) reacted with methyl acrylate in a 1,3-dipolar cycloaddition to afford the unsaturated pyrrolizidine (25) in 57% yield from the lactam (22). Catalytic hydrogenation of the ester (25) gave an unstable endo-product, which epimerized to the exo-form (26). Introduction of the 1,2-double-bond into (26) was carried out by insertion and thermal elimination of a phenylseleno-group.12 Reduction then yielded ( )-retronecine (27). 

Treatment of the aldehyde 19 with amines in the presence of TiCU furnished the precursor 20, which was converted to the 2-pyrrolines 21. The products 21 could thereafter be exposed to methoxide, leading to the corresponding /3-chloropyrroles after elimination of cyanide (Scheme 3) <2005T2879>. A series of pyrroles has also been prepared by a procedure featuring acid-induced cyclization of precursors constructed by sequential lithiation and alkylation of 1-benzylbenzotriazoles with 2-bromoacetaldehyde diethyl acetal and A -benzylideneani-line <1997JHC1379>. 

Taking advantage of an intramolecular Wittig reaction, the a-amidoketones 316 underwent annulation to the 3-pyrrolines 317 upon treatment with the ylide 318 <199581151>. These intermediates could be further elaborated to the pyrroles 319 by base-induced elimination of benzenesulfinic acid (Scheme 37) <2000TL8969>. It should also be mentioned that a set of unusual 3-pyrroline-2-ones have been synthesized by Ugi s four-component reactions from phenacylamine hydrochloride, cyanoacetic acid, cyclohexyl isocyanide, and aldehydes, involving final formation of the C(3)-C(4) bond <1999H(50)463>. 

It was soon realized that the far more readily available 1-chloro and bromo acetylenes could be used too and in fact phenylchloroacetylene gives with lithium dimethylamide in ether, 87 % of the corresponding ynamine Similarly, N-lithium pyrroline affords 67 % of the corresponding ynamine In the following example (Eq. 7) P—CgH4 means styrene polymer where a di-ethylaminoethynyl moiety is built up via a formylation, Wittig reaction with dichloro-methylene phosphorane and elimination-substitution steps. This polymer-bound ynamine is till now unique... 

The imines of a-aminonitriles are lithiated with butyllithium or LDA at — 78°C in THF. The anionic intermediates 144 generated are captured in the regio- and stereoselective, and stereospecific cycloaddition with a number of olefins to give 4,5-cis-l-pyrrolines 145 after the elimination of lithium cyanide... 

Similarly, the imines of a-aminonitriles are activated by LDA as N-lithiated azomethine ylides 144, which undergo smooth cycloadditions, even with inactive olefins at — 78°C, to furnish 1-pyrrolines 145 (87BCJ3359). The ylide geometry with respect to the cyano-substituted carbon is not clear, since this carbon becomes an sp hybrid through the elimination of lithium cyanide after cycloaddition. However, selective construction of 4,5-cis stereochemistry in the cycloadducts 145 is important in organic synthesis. 

Equally selective cycloadditions occur, at -78°C, between cyano-stabilized ylides 144 and the above olefinic esters. As lithium cyanide is eliminated immediately after the cycloaddition is over, 4,5-cis-l-pyrrolines 145 are obtained (87BCJ3359). The stereochemistry of 145 arises from the initial regio- and endo-selective cycloadducts 267. 

Achiwa reported a short synthesis of pyrrolizidine derivatives by the cycloadditions using a nonstabilized azomethine ylide 23 (m = 1) (82CPB3167). When the trimer of 1-pyrroline is treated with a silylmethyl triflate, N-alkylation of the 1-pyrroline takes place. Then the resulting iminium salt is desilylated with fluoride ion in the presence of ethyl acrylate to give ethyl pyrrolizidine-l-carboxylate 295 as a mixture of stereoisomers (28%). After the epimerization of 295 with LDA, the ester moiety is reduced with lithium aluminum hydride in ether to provide (+ )-trachelanthamidine (296). A double bond can be introduced into 295 by a sequence of phenyl-selenylation at the 1-position, oxidation with hydrogen peroxide, and elimination of the selenyl moiety. The 1,2-dehydropyrrolizidine-l-carboxylate 297 is an excellent precursor of (+ )-supinidine (298) and (+)-isoretronecanol (299). Though in poor yield, 297 is directly available by the reaction of 23 with ethyl 3-chloropropenoate. 

Besides, in view of the ascertained knowledge of the stability of simpler systems of this type, the imine structure should be the preferred one (128, 129). In line with this evidence is the finding of Cerny and Sorm (98), who demonstrated that the elimination of the hydrochloric acid from the chloramine corresponding to JV-demethylconanine led to the 20(A )-pyrroline (see Section II,G). Thus, the double bond in conkurchine could not be in the 17,20- or 20,21-positions. Jarreau et al. (74a, 75,130) ruled out the 20(A)-position by the synthesis of 3 -methyl-amino-A-demethylcona-5,20(V)-diene and 3 -aminodemethylcona-5,(20)iV-diene which are not identical with conessidine and conkurchine, respectively. 

Methadone undergoes significant hepatic metabolism by N-demethylation and cycliza-tion to form pyrrolidines and pyrroline (23). Propoxyphene is also hepatically metabolized predominantly by N-demethylation and renally eliminated. The metabolite norpropoxy-phene is cardiotoxic and produces arrhythmias and pulmonary edema that have led to reports of cardiac arrest and death (59). This is especially problematic because of the long half-life of norpropoxyphenethat accumulates with repeated doses of the parent drug. Methadone is excreted in the urine but also in the bile (23). 

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