Intramolecular [4+2] and [3+2] Cycloadditions in Organic Synthesis

There are basically two kinds of hetero atoms in organic molecules: one kind confers electrophilic character upon the carbon atom to which it is bound, and the other kind turns it into a nucleophilic site. The development of methods permitting transitions between the two resulting categories of reagents has become an important task of modern organic synthesis. The scope of such umpolung of the reactivity of functional groups is discussed for the case of amines as an example. A method of preparing masked α-secondary amino carbanions consists in nitrosation of the secondary amine, followed by metalation of the resulting nitrosamine α-to the nitrogen, reaction with electrophiles, and subsequent denitrosation. Many examples are given for each of these steps which illustrate the wide scope of the overall synthetic operation (electrophilic substitution at the α-C atom of the secondary amine). Preliminary applications and a method for avoiding the handling of nitrosamines are presented, and the report concludes with a brief account of the significance of nitrosamines in the study of carcinogenesis and mutagenesis.

Umpolung of Amine Reactivity. Nucleophilic α-(Secondary Amino)-alkylation via Metalated Nitrosamines†‡

Zahlreiche Beispiele intramolekularer Cycloadditionen von 1,3-Dienen, Nitronen und Azomethiniminen bezeugen den praparativen Wert dieser Varianten zur regio- und stereoselektiven Synthese anellierter sowie uberbruckter Ringsysteme. Die Gemeinsamkeiten, Unterschiede und Grenzen dieser Reaktionstypen werden systematisch umrissen.

Intramolekulare [4 + 2]‐ und [3 + 2]‐Cycloadditionen in der organischen Synthese

3.06 – Pyrroles and their Benzo Derivatives: (iii) Synthesis and Applications

Es gibt prinzipiell zwei Arten von Heteroatomen in organischen Molekulen: Die einen machen das mit ihnen verbundene Kohlenstoffatom zu einem elektrophilen, die anderen zu einem nucleophilen Zentrum. Die Entwicklung von Methoden zum Uberwechseln zwischen den beiden darauf beruhenden Kategorien von Reagentien ist eine wichtige Aufgabe der modernen organischen Synthese. Moglichkeiten dieser Umpolung der Reaktivitat funktioneller Gruppen werden am Beispiel der Amine diskutiert. Eine Methode zur Herstellung von maskierten α-sek.-Aminocarbanionen besteht darin, das man das sekundare Amin nitrosiert, das entstandene Nitrosamin in α-Stellung zum Stickstoff metalliert, mit Elektrophilen umsetzt und entnitrosiert. Fur jeden dieser Schritte wird eine Anzahl von Beispielen gegeben, die die grose Anwendungsbreite der synthetischen Gesamtoperation (elektrophile Substitution am α-C-Atom des sekundaren Amins) belegen. Erste Anwendungen und ein Verfahren zur Umgehung des Hantierens von Nitrosaminen werden vorgestellt, und zum Schlus wird die Bedeutung der Nitrosamine fur die Carcinogenese- und Mutageneseforschung kurz erortert.

Umpolung der Reaktivität von Aminen. Nucleophile α‐sek.‐Aminoalkylierung über metallierte Nitrosamine

The N-alkylated 2-benzoylamino-benzophenones 2a–e on treatment with lithium diisopropylamide in tetrahydrofuran at − 78° gave the cyclic alchols 3a–e which were dehydrated with phosphorous oxychloride/pyridine to give the indoles 4a–e in 30–72% yield (Scheme 1).

Intramolekulare Additionen α-lithiierter Amide; eine neue Synthese von 2-Aryl- und 2-Vinylindolen

Alkylation of the sodium salt of mesitol with 2-bromomethyl-buta-1,3-diene (7) in benzene and subsequent refluxing of the reaction mixture gave 7% 2-methylene-3-butenyl-mesitylether (8), 12% 5-methylene-1,3,8-trimethyl-tricyclo[4,3,1,03,7]-8-decen-2-one (9) and 44% 9-methylene-1,3,5-trimethyl-tricyclo[4,4,0,03,8]-4-decen-2-one (10), a twistane derivative. The same procedure, when applied to the sodium salt of 2,6-dimethyl-4-methoxyphenol, gave in 73% yield a 26:18:54 mixture of 2,6-dimethyl-4-methoxyphenyl-(2-methylene-3-butenyl)-ether (11), 1,3-dimethyl-8-methoxy-5-methylene-tricyclo[4,3,1,03, 7]-8-decen-2-one (12), and 1,3-dimethyl-5-methoxy-9-methylene-tricyclo[4,4,0,03, 8]-4-decen-2-one (13). The tricyclic ketones 9 and 10, or 12 and 13, were also obtained on heating 8 or 11 respectively at 176° in decane solution. Alkylation of the sodium salt of 2,6-dimethylphenol with 3-butenylbromide in boiling toluene gave 1,3-dimethyl-tricyclo[4,3,1,03,7]-8-decen-2-one (17) as the only tricyclic product in 8% yield. The structures of the twistane derivatives 10 and 13 as well as those of the ketones 9, 12 and 17 were mainly deduced from spectroscopic data. Furthermore, the ketones 10 and 13 could be converted to the twistane derivatives 20 and 22, possessing C2-symmetry. On the other hand, compounds 9 and 17 gave only the asymmetric derivatives 18 and 21.

Intramolekulare Diels‐Alder‐Additionen in 6‐(But‐3‐enyl)‐6‐methyl‐cyclohexa‐2,4‐dien‐1‐on‐Systemen; eine neue Synthese von Twistanderivaten

Thermal rearrangement of trans-penta-2,4-dienyl mesityl ether (trans-1) gave, besides trans, cis-2 and trans, trans-2, the homotwistanone derivative 1,3,10-trimethyl-tricyclo[5.4.0.03,9]undeca-5,10-dien-2-one (3) as well as its isomer 1,3,9-trimethyl-tricyclo[5.3.1.03,8]undeca-5, 9-dien-2-one (4). The tricyclic ketones 3 und 4 were shown to be products of intramolecular Diels-Alder addition in the intermediate 2,4,6-trimethyl-6-(penta-2,4-dienyl)cyclohexa-2,4-dien-1-one (5). Preparation of 2,6-methyl-6-(3-methyl-penta-2,4-dienyl)-cyclohexa2,4-dien-1-one (6) and subsequent heating of 6 in benzene gave the homotwistanone derivative 1,3-6-trimethyl-tricyclo5.4.0.03,9]undeca-5,10-dien-2-one (7) together with its isomer 1,3,6-trimethyl-tricyclo[5.3.1.03,8]undeca-5,9-dien-2-one (8) in good yield.

Intramolekulare Diels‐Alder‐Additionen in 6‐Methyl‐6‐(penta‐2,4‐dienyl)‐cyclohexa‐2,4‐dien‐1‐on‐Systemen. Vorläufige Mitteilung

Reduction of the pyridinium salts 1b-f in methanolic sodium hydroxide solution with sodium borohydride gave the dimeric dihydropyridine derivatives 3b-f. Heating these dimers in hydrocarbon solvents at 110–207° resulted in the formation of the tricyclic amines 4c–f, which were shown to be products of an intramolecular Diels-Alder addition within the intermediate dihydropyridines 2c–f. The structures of 4c–f were deduced from spectroscopic, mainly NMR. data.

Intramolekulare Diels-Alder-Additionen von 1,2-Dihydropyridinen

Synthesis of new polycyclic compounds by means of intramolecular Diels-Alder reactions of cyclohexa-2,4-dien-1-one derivatives



Thermal rearrangement of mesityl penta-2,4-dienyl ether (1), consisting of the isomers E (93%) and Z (7%), furnished, besides mesitol, the two mesityl penta-1,3-dienyl ethers 2 (24%) and 3 (3%), and the two tricyclic ketones 4 (4,5%) and 5 (12,5%) (Scheme 1). A probable mechanism for this formation of 2 involves a [1,5]-hydrogen shift in (Z)-1. Isomerisation of (E)-1 to (Z)-1 at 145° occurs via reversible sigmatropic [3,3]- and [5,5]-rearrangements of (E)-1 to the cyclohexadienones 38 and 39 respectively (see Chapter A p. 1710, and Scheme 15). Formation of 3 from either (Z)-1 or 2 is rationalized by a series of pericyclic reactions as outlined in Chapter A and Scheme 16.



The tricyclic ketones 4 and 5 are undoubtedly formed by internal Diels-Alder reactions of the 6-pentadienyl-cyclohexa-2,4-dien-1-one 6 (Scheme 2). In fact, at 80° 6 is converted into 4 (5%) and 5 (35%). At 80° the cyclohexadienone derivative 7 furnished the corresponding tricyclic ketones 8 (15%) and 9 (44%) (Scheme 2). 5 and 9 contain a homotwistane skeleton. 8 and 9 are easily prepared by reaction of sodium 2,6-dimethylphenolate with 3-methyl-penta-2,4-dienyl bromide at ambient temperature, followed by heating, and finally separation by cristallization and chromatography.



The cyclohexadienones 6 and 7 have mainly (E)-configuration. Here too (E) (Z) isomerization is a prerequisite for the internal Diels-Alder reaction, and this partly takes place intramolecularly through reversible Claisen and Cope rearrangements (Scheme 17). On the other hand, experiments in the presence of 3,5-d2-mesitol have shown (Table 1) that intermolecular reactions, involving radicals and/or ions, are also operating (see Chapter B, p. 1712).



Two different modi (I and II) exist for intramolecular Diels-Alder reactions (Scheme 18). Whereas only modus I is observed in the cyclization of 5-alkenyl-cyclohexa-l,3-dienes, in that of (2)-cyclohexadienones 6 and 7 (Scheme 2) both modi are operating. Only in modus 11-type transitions is the butadienyl conjugation of the side chain retained, so that modus 11-type addition is preferred (Chapter C p. 1716).



Analogously to the synthesis of the tricyclic ketones 4, 5, 8 and 9, the tricyclic ketone 15 (Scheme 4) and the tetracyclic ketone 11 (Scheme 3) are prepared from mesitol, pentenyl bromide and cycloheptadienyl bromide, respectively.



From the polycyclic ketones derivatives such as the alcohols 16, 17, 18, 19, 23, 24 and 25 (Schemes 9 and 11), policyclic ethers 20, 21, 22 and 26 (Scheme 10), epoxides 30, 32 (Scheme 13), diketones 31, 33 (Scheme 13) and ether-alcohols 35 and 36 (Scheme 14) have been prepared. Most of these conversions show high stereoselectivity.

Hans Greuter

Papers

Intramolekulare Additionen α-lithiierter Amide; eine neue Synthese von 2-Aryl- und 2-Vinylindolen

Intramolekulare Diels‐Alder‐Additionen in 6‐(But‐3‐enyl)‐6‐methyl‐cyclohexa‐2,4‐dien‐1‐on‐Systemen; eine neue Synthese von Twistanderivaten

Intramolekulare Diels‐Alder‐Additionen in 6‐Methyl‐6‐(penta‐2,4‐dienyl)‐cyclohexa‐2,4‐dien‐1‐on‐Systemen. Vorläufige Mitteilung

Intramolekulare Diels-Alder-Additionen von 1,2-Dihydropyridinen

Herstellung neuer polycyclischer Verbindungen durch intramolekulare Diels‐Alder‐Reaktionen von Cyclohexa‐2,4‐dien‐1‐on‐Abkömmlingen