Novel Stereoselective Syntheses of Highly Functionalized Benzannulated Pyrrolizidines and Indolizidines by Samarium Diiodide Induced Cyclizations of Indole Derivatives

Gross, Steffen; Reißig, Hans‐Ulrich

doi:10.1021/ol0355581

Cited by 79 publications

(69 citation statements)

References 11 publications

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“…The SmI 2 -induced 6-exo-trig to 8-exo-trig cyclisations of precursors 7-9 (Scheme 11) furnished compounds 34-36 as single diastereomers in good to very good yields after workup and column chromatography. [9] Scheme 11. Results for the SmI 2 -induced 6-exo-trig to 8-exo-trig cyclisations of N-alkylated indole derivatives 7-9 with either tBuOH or phenol as proton source.…”

Section: Smi 2 -Induced Cyclisations Of N-alkylated Indole Precursorsmentioning

confidence: 99%

“…[7] In view of the importance of N-heterocycles, indole-and pyrrole-derived compounds in particular, [8] we subsequently turned our interest from aniline derivatives to the cyclisations of ketones containing indole or pyrrole moieties (Scheme 1). [9] Although a variety of methods have ferent proton sources SmI 2 -induced cyclisations afforded mainly one major type of diastereomer (thermodynamic control), so the formation of three or four stereogenic centres is controlled in one step. The mechanism of the SmI 2 -induced ketyl coupling is discussed in more detail on the basis of these observations and two possible mechanistic pathways are compared.…”

Section: Introductionmentioning

confidence: 99%

“…[9] These SmI 2 -induced cyclisations hence constituted a new method for the stereoselective conversion of easily available indole and pyrrole derivatives into functionalised nitrogencontaining polycyclic products. Encouraged by these results we started a systematic investigation of these reductive cyclisations and studied various appropriately substituted indole derivatives with success.…”

Section: Introductionmentioning

confidence: 99%

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Highly Diastereoselective Samarium Diiodide Induced Ketyl Cyclisations of Indole and Pyrrole Derivatives – Scope and Limitations

et al. 2010

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Here we summarise our results for SmI 2 -induced 5-exo-trig to 8-exo-trig reductive cyclisations of suitably substituted indole and pyrrole derivatives. All precursors were easily prepared by simple N-alkylation or N-acylation of indole and pyrrole derivatives with the corresponding iodo alkanones, acid chlorides or lactones. The SmI 2 -induced cyclisations in most cases provided tri-and tetracyclic derivatives, even in the absence of HMPA, in good to very good yields and with excellent diastereoselectivities. Extensive investigations of the reaction conditions revealed that in the presence of dif-

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Section: Smi 2 -Induced Cyclisations Of N-alkylated Indole Precursorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Highly Diastereoselective Samarium Diiodide Induced Ketyl Cyclisations of Indole and Pyrrole Derivatives – Scope and Limitations

et al. 2010

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“…However, if one cut off the second aryl ring, thereby going to indole derivatives such as 159 and 160, the reductive cyclization proceeded again and provided the expected diastereomerically pure benzannulated pyrrolizidine 161 and indolizidine 162 in good yields. 38,44 Since NOE measurements proved that again the bridgehead hydrogen and the hydroxyl group are cis-oriented, it is also the 'normal' configuration one observes for these indole derived compounds. For the cyclization of these indole derivatives we employed phenol as a proton source.…”

Section: Scheme 29 8 Reductive Cyclizations With Indole and Pyrrole Dmentioning

confidence: 92%

New Samarium Diiodide-Induced Ketyl Couplings - From Analogous Reactions to Serendipitously Discovered Processes

Berndt¹,

Gross²,

Hölemann³

et al. 2004

Synlett

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Analogous applications of samarium diiodide as a promoter for ketyl cyclizations led to the discovery of several new and synthetically interesting reactions. Whereas samarium ketyl cyclizations with alkyne and allene units could be expected -though they have not been known before -the unplanned cyclization of the ketyl towards an aromatic ring uncovered a new mode of reaction. The resulting hexahydronaphthalene derivatives were formed in excellent diastereoselectivities and are synthetically very valuable building blocks. This new method was systematically investigated and extended to polycyclic compounds and those with heteroatoms in the spacer between the carbonyl group and the aromatic ring. The cyclizations involving indole and pyrrole derivatives are most promising for the stereoselective construction of alkaloid skeletons.

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“…4 Furthermore, suitably substituted Naroylindoles are used as precursors for the synthesis of benzannulated indolizidines. 5 A variety of methods have been reported for the direct Naroylation of indoles. When neither the aroylating agent nor the indole contains an electron-donating substituent, several procedures are satisfactory.…”

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confidence: 99%

Efficient N-Aroylation of Substituted Indoles with N-Aroylbenzotriazoles

Katritzky¹,

Khelashvili²,

Mohapatra³

et al. 2007

Synthesis

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Stable and easily accessible N-aroylbenzotriazoles react with indoles in the presence of a base to afford the corresponding Naroylindoles in yields averaging 70%. This method is effective even when both coupling reagents possess electron-donating substituents.N-Aroylindoles are well-known nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., indomethacin, a 5-methoxyindole derivative). 1 N-Aroyl-5-nitro-1H-indoles are utilized as intermediates for the synthesis of 2-aryl-5-nitro-1H-indoles effective as bacterial NorA efflux pump inhibitors. 2 5-Substituted N-aroylindoles also exhibit selective cyclooxygenase-2 inhibitor activity, 3 and 5-amino-1-(3,5-dimethylbenzoyl)-1H-indole possesses antiangiogenic activity. 4 Furthermore, suitably substituted Naroylindoles are used as precursors for the synthesis of benzannulated indolizidines. 5 A variety of methods have been reported for the direct Naroylation of indoles. When neither the aroylating agent nor the indole contains an electron-donating substituent, several procedures are satisfactory. 6 However, useful Naroylations of indoles to a product in which either the aryl group or indole nucleus contains a strong electron-donor substituent are rare. N-Aroylindoles have been prepared by (i) indolide anion formation with sodium hydride followed by reaction with an acid chloride (36-82%), 6a (ii) direct aroylation of indoles with carboxylic acids using boric acid (50-82%), 6c and (iii) phase-transfer-catalyzed aroylation of indoles (77-94%). 6d Most recently, Bremner et al. 6b N-aroylated 5-substituted indoles with an electronwithdrawing substituent (NO 2 , CN or F) in the 5-position with carboxylic acids via DCC/DMAP coupling to give 73-95% yields of the N-aroylindoles. However, the yields for the 5-unsubstituted indoles, were 32-46% and for 5-methoxyindole only 0-15%.N-Acylbenzotriazoles are easily prepared activated derivatives of carboxylic acids. 7 Applications of N-acylbenzotriazoles include (i) N-acylation of amines, amides, 8 and sulfonamides; 9 (ii) O-acylation of aldehydes, 10 steroids, 11 hydroxyterpenes, and alcohols; 12 (iii) many C-acylations, viz: pyrroles and indoles, 13 ketones and heteroaromatics, 14 alkyl sulfones, 15 alkyl cyanides, 16 alkyl azines, 17 a-nitroalkanes, 18 furans, and thiophenes; 19 and (iv) syntheses of peptides, 20 oxazolines, 21 esters, 22 benzodioxin-4-ones, 23 ketones, 24 benzodiazepin-2-ones, 25 thiol esters, 26 alcohols, 27 hydrazides, 28 and heteroaromatics. 29Earlier we 13a,14b and others 12 have reported regiospecific C-acylation of pyrroles and indoles using N-acylbenzotriazoles. Herein, we report the efficient synthesis of electron-rich N-aroylindoles from N-aroylbenzotriazoles in the presence of a base via N-aroylation of indoles.Commercially available indole (1a) and 5-methoxyindole (1b) were used as substrates for N-aroylation reactions. NAroylbenzotriazoles 2a-c (Figure 1) were readily prepared from 1H-benzotriazole (BtH) and the corresponding carboxylic acid in yields of 85-95% according to a literature procedure. 20 Reac...

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Novel Stereoselective Syntheses of Highly Functionalized Benzannulated Pyrrolizidines and Indolizidines by Samarium Diiodide Induced Cyclizations of Indole Derivatives

Cited by 79 publications

References 11 publications

Highly Diastereoselective Samarium Diiodide Induced Ketyl Cyclisations of Indole and Pyrrole Derivatives – Scope and Limitations

Highly Diastereoselective Samarium Diiodide Induced Ketyl Cyclisations of Indole and Pyrrole Derivatives – Scope and Limitations

New Samarium Diiodide-Induced Ketyl Couplings - From Analogous Reactions to Serendipitously Discovered Processes

Efficient N-Aroylation of Substituted Indoles with N-Aroylbenzotriazoles

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