Cycloaddition of /?-enaminones

The 4 + 2-cycloaddition of enaminones could be extended to many tertiary alicyclic derivatives and by using benzylsulphonyl chlorides271 as sulphene precursors. The resulting 4-amino-3-phenyl-l,2-benzoxathiin-2,2-dioxides are a mixture of cis- and fra/w-isomers (equation 200). 

Cycloaddition of enaminone carboxaldehyde (formylenaminone) with a vinyl ether leads to pyrans as hetero-Diels-Alder adducts303,304. The stereochemistry is dependent on the substituents of the N-acyl group and on the reaction temperature (equation 227). 

Photochemical cycloaddition of enaminones with olefines leads to 1,4-dihydronicotime acids305 (equation 228). With cycloalkenes, fused pyridines are available, too306. 

The gas-phase pyrolysis of vinylogous systems of isopropylidene amino-methylenemalonates (1280,1287, and 1290), prepared from the appropriate enaminone or dienaminone and Meldrum s acid in pyridine, was studied by McNab etal. at 500°C and 10 2 torr (87CC140). Flash vacuum pyrolysis of 1280 gave l//-azepinones (1283) in —60% yields, together with a small amount of cyclopentadienone dimer (1284). They suggested that the azepi-nones (1283) were formed by electrocyclization from dipolar intermediates (1282) produced from the methyleneketenes (1281) by hydrogen transfer (Scheme 54). Cycloaddition of 1282 yielded bicyclics (1285), which col-... 

By suitable substitution the enaminones can often serve as precursors for heterocycles and preparation of indoles, carbazoles, quinolines, acridines and phenaNthridines can be achieved easily. However, this part of enaminone chemistry can lead to surprising and unexpected reactions if the multifunctional properties of the enaminones are ignored, e.g. ring contraction, ring expansion and other rearrangements are observed. In some cases jft-ketoenamines react as the ene-component in cycloaddition. Enaminones are even suitable synthones for building aromatic rings. 

Another special example in the use of enaminones of the aminomethylene type as dienes in the Diels-Alder cycloaddition is the stereoselective reaction with several dienophiles to yield substituted cyclohexenes279 (equation 204). 

Examples of the equivalent intramolecular cycloaddition have also been reported. The conversion of enaminone (90) into... 

Dihydrospiro[cyclopropane-l,5 -isoxazoles] 41 can be prepared by cycloaddition of nitrile oxides to methylenecyclopropanes 40. Thermolysis of the spiro-compounds led, in general, to the formation of mixtures of enaminones 42 and pyridones 43. However, the proportion of the enaminone 42 was much reduced when the rearrangements were carried out by flash-vacuum pyrolysis at 400 °C, and good yields of pyridones 43 were isolated (see Section 1. A.5.2.3.1 ... 

The cycloaddition of 2,2-dimethyl-3,4-dihydro-2/jT-pyrrole A-oxide to 1-methylenecyclopropanes illustrated for the example of 1-methylene-2-phenylcyclopropane (44) gave mixtures of isomeric spiro[cyclopropane-pyrroloisoxazolidines] 45 and 46, which on refluxing in toluene for several hours, rearranged to give mixtures of indolizidinones 47 and enaminones 48. ... 

Cycloaddition of ketene to enamines affords cyclobutanones, which upon distillation readily rearrange to enaminones (61JOC4775 63JOC1468). For... 

Few examples of azirine synthesis via enaminones are found in the literature, as azirines tend to undergo further reactions to give more stable compounds. One important method is the vinyl azide-olefin cycloaddition where the azides can be considered as derivatives of enaminones. The chemistry of this unique reaction has been reviewed (75AGE775). A recent example is included in Scheme 17, in which intramolecular cycloadditions of vinyl azides 53 furnish azirines 54 (87CB2003). In a similar reaction, the aziridinoindoies 56 are synthesized from 55 by insertion of the azide-derived nitrene into the olefinic bond (89H2029). 

Other reported methods for isoxazole synthesis are the 1,3-cycloaddition of nitrile oxides to 1,3-cyclohexadione-derived enaminones (78S43), the thermolysis of 2,2-diacyl-N-(l-pyridinio)vinylamidines [73JCS(P1)2580] and the Knoevenagel condensation of enaminones with isoxazolinone acetate (85JHC127). 

Triazoles can be prepared by the [3 + 2]-cycloaddition of azido-arenes to enaminones followed by deamination. As outlined in Scheme 91,... 

The 1,4-cycloaddition of ketenes to A, A -disubstituted enaminones allows a general synthesis of pyranones. Berchtold and co-workers (61JOC4776 65JOC2642) showed that treatment of ethyl 3-pyrrolidinocrotonate 341 (R = EtO) or 4-pyrrolidino-3-penten-2-one 341 (R = Me) with an excess of ketene resulted in the formation of pyranones 342, Scheme 96. The mode of formation of 342 apparently involves initial acetylation with one mole of ketene at the enaminone fi position followed by cycloaddition with a second mole of ketene. 

A one-pot thionation/cycloaddition was reported recently [92JCS(P1)-2603]. Treatment of enaminones 386 with Lawesson s reagent generated in situ the thioenaminones, which were added to dienophiles to give thiopyrans 387, Scheme 107. However, no thiopyrans could be isolated... 

Enaminones 83 undergo an IDA reaction with 1,3,5-triazine 5, allowing access to functionalized quinazolinones as intermediates in the synthesis of CNS agents (Equation 8). This reaction is highly dependent upon the solvent 1,3,5-triazine 5 undergoes single or double [4+2] cycloadditions with enaminones, and quinazolinones 84 or acridinediones 85 could be obtained selectively <2002TL3551>. 

Jurij Svete was born in Ljubljana, Slovenia, in 1962. He received his diploma in chemistry in 1986 and his Ph.D. in 1990 under supervision of Professor Stanovnik. He continued to work as a researcher with the group of Professor Stanovnik. In 1997, he spent one year as a Humboldt Fellow at the University of Stuttgart, Germany, working with Professor Jager on the synthesis of imonopolyols fom furan-nitrile oxide cycloadducts. In 1996, he became an assistant professor at the University of Ljubljana and a full professor in 2006. His research interests include synthesis of heterocyclic compounds with emphasis on chiral functionalized heterocycles, stereoselective synthesis, chemistry of enaminones, 1,3-dipolar cycloadditions, and combinatorial synthesis. 

Intramolecular cyclization of (76) in the presence of NaH gave exo (77) and endo (78) products (Equation (9)) <90SL584). Allene-based electrophile-mediated cyclization afforded iV-tosyl iodohexa-hydroazocines <94JCS(Pl)3549>. Photochemical intramolecular cycloaddition of phthalimide in acetone afforded the ring-opened product <82TL498l>. An unstable enaminone azocine derivative (81) was formed after the desulfurization of the bicyclic aminal (80), which in turn was synthesized from... 

Georg and coworkers reported a C=C bond cycloaddition with a ketene to provide six-membered enaminones, under mild conditions (Scheme 92) (2010JA15512). From this intramolecular cycloaddition of a ketene created from diazoketone 289, employing a silver-catalyzed Wolff rearrangement, a six-membered enaminones such as 290 was obtained. 

The reaction of (chlorocarbonyl)phenylketene 126 with enaminones takes place effectively in refluxing toluene, furnishing a facile and rapid synthesis of 4-hydroxy-3,4,6-trisubstituted-2(lfJ)-pyridinone 346 in high yield via ring closure of intermediates 344—345 (Scheme 107) (2009JHC96). On the other hand, the cycloaddition of 4-[(2-aminoethyl) amino]-3-penten-2-one 347 with 126 led to the generation of ethyl... 

Mechanistically, these processes involve Lewis-acid activation of the enone, subsequent 1,3-dipolar cycloaddition of the enone with azide, and ring opening of the nnstable triazoline (Scheme 7.30). In the case of exocyclic enaminone formation, antiperiplanar arrangement of the methylene gronp (path a) with the diazoninm ion facilitated ring contraction a 1,3-H shift nltimately provided product via path a. On the other hand, migration of an axially oriented R gronp led to the observed endocyclic enaminones (path b). 

C-H Insertion. Catalytic C-H functionalization is a powerful approach for C-C bond formation. As described in the previous update, [Cu(acac)2]-catalyzed cycloaddition of a,j8-enones with dimethyl diazomalonate would afford dihydrofurans through carbonyl ylide formation (eq 24). Yet, when enaminone was employed as substrate in the same reaction, naphthalen-l(4//)-one was obtained as major product (eq 55). The authors suggested that the product formation may arise from the unusual carbenoid C-H insertion followed by aromatic nucleophilic substitution. 

C-l,4-addition/Mannich-type cyclization through respective intermediates 303 and 304. This finding invoked historical perspectives from Prelog s work in 1949 [139] and the enamine work of Stork et al. in the 1950s [140]. With the latter case, a distinct contrast could be generalized whereby cycloadditions of a,(3-unsaturated carbonyl systems with enamines mostiy led to carbo-[3+3] cycloaddition [138], and those with enaminones, or vinylogous amides, almost exclusively proceeded down the pathway of an aza-[3+3] cycloaddition. 

It has been observed that Mg-Al-hydrotalcite is an efficient catalyst for microwave-assisted region-selective 1,3-dipolar cycloaddition of nitrillimines with the enaminone derivatives to produce pyrazole derivatives (Saleh et al., 2013). 

In a similar process, tertiary enaminones react with alkynylcarbene complexes to give the corresponding pyranylidene complexes following a reaction pathway analogous to that described above. First, a [2+2] cycloaddition reaction between the alkynyl moiety of the carbene complex and the C=C double bond of the enamine generates a cyclobutene intermediate, which evolves by a conrotatory cyclobutene ring opening followed by a cyclisation process [94] (Scheme 49). 

Triazines are generally more reactive in [2 + 4] cycloaddition in comparison with 1,2,3-tria-zines. The wide variety of dienophiles can be employed enamines, enaminones, vinyl silyl ethers, vinyl thioethers, cyclic ketene jV,O-acetals, /V-phenylmaleimide, 6-dimethylaminopentafulvene, 2-alkylidene-imidazolidines (cychc ketene aminals), cyclic vinyl ethers, arynes, benzocyclopropene, acetylenes, and alkenes like ethylene, (Z)-but-2-ene, cyclopentene, cyclooctene and bicyclo[2.2.1]hept-2-ene, hexa-1,5-diene, cycloocta-1,5-diene, diallyl ether, cyclododeca-l,5,9-triene,... 

In a variant of the Hantzsch synthesis N-substituted enaminones gave aminocyclohex-enone derivatives, which were convertible with Mn02 to the corresponding substituted diphenyls (see Section II.A.l.e and see equation 63). For an aromatic product resulting from cycloaddition, see Section II.A.4 (equation 144). 

Attack of nucleophiles at the a-position of the enaminone predominates, leading to Michael addition which mostly results in substituted, mainly cyclic end-products. Also observed are subsequent amine elimination and reactions at the carbonyl. Some initial reactions of nucleophilic reagents at the enaminone carbonyl carbon are known. Enaminones are often better starting materials for several reactions than the corresponding dicarbonyls. As a result, a-aminomethylene ketones act as 1,3-biselectrophiles. Due to their combined electrophilic and nucleophilic properties, enaminones act as 1,3-bisnucleophiles as well. The assumed first step in the following reactions is the one used for classification of the reactions. In addition, enaminones are used as heterodienes in 4 + 2-cycloaddition mostly with electron-deficient dienophiles. 

Due to their two electron-withdrawing groups, / ,/ -diketoenamines are reactive towards nucleophilic reagents. Attack usually occurs at the a-carbon. With dinucleophiles, the substitution of the amino group is followed by ring closure to 5- or 6-membered heterocycles. However, due to the enaminedione structure, few successful reactions with electrophiles are known. Only if an electrophilic group is incorporated into the enaminone molecule is such intramolecular reaction observed. Enaminediones are also suitable heterodienes in 4 + 2-cycloaddition. Their electron-deficient character as heterodienes requires the use of electron-rich dienophiles. The result is a Diels-Alder reaction with inverse electron demand. 

Secondary ketoenamines react with electrophilic diazenes to give products which undergo rearrangement to an adduct which affords benzimidazolinones after subsequent cyclization322. In the case of tertiary a-enaminones, l,3,4-oxadiazole-2-ones, as unstable intermediates of a [4 + 2]-cycloaddition, can be obtained323 (equation 241). 

In the case of cyclic tertiary enaminones as dienophiles in the reaction with nitroalk-enes as heterodienes, [4 + 2]-cycloaddition yields tetrahydrobenzo >][l,2]oxazin-8-ones nearly quantitatively. Heating in aprotic solvents affords substituted diaster-eoisomeric pentalenones by ring contraction of the six-membered ring326 (equation 244). 

---