Enamines cycloadditions with alkynes

Oxotetrahydrothiophenes form enamines (78S368). Such 3-amino-4,5-dihydrothio-phenes undergo [2 + 2] cycloaddition with alkyne derivatives (Scheme 210) (77AHC(21)253>. 

Again, it is noteworthy that 4-substituted 5-hydrdxythiazoles (24) react like 5-hydroxy-THISs with alkynes to give pyrroles and sometimes with alkenes to give exo-cycloadducts (Scheme 22). In the latter case other processes compete with the cycloaddition, becoming dominant when 24 is treated with azo-compounds, enamines, or heterocumulenes (31). 

Cyclobutanones (11, 560-561). Ketenimium salts are more reactive than ke-tenes in [2 + 2] cycloadditions with alkenes to prepare cyclobutanones. The salts are readily available by in situ reaction of tertiary amides with triflic anhydride and a base, generally 2,4,6-collidine. The cycloaddition proceeds satisfactorily with alkyl-substituted alkenes and alkynes, but not with enol ethers or enamines.1... 

The reaction of 77 with alkynes has further been elaborated for the synthesis of substituted phthalonitriles 81. An alternative for the synthesis of these compounds is the cycloaddition reaction of 77 with enamines followed by a retro-Diels-Alder loss of N2 and elimination of the amine (Scheme 16). Generally, more forcing reaction conditions are required and lower yields are obtained in reactions with alkynes than in reactions with enamines, for example, 4-ethyl-5-methylphthalonitrile is obtained in 51% yield from 2-pentyne (xylene, 150°C, 18 days) and in 73% yield from 4-(l-ethylprop-l-en-l-yl)morpholine (CHCI3, 70°C, 7 days) <1998T1809>. The mechanism of the reaction with enamines has been studied in detail. This revealed a [1,5] sigmatropic rearrangement in the cyclohexa-2,4-dien-1-amine intermediates formed after the loss of N2 <1998T10851>. 

The 1,2-dihydropyridines are also known to undergo [2 + 2] cycloadditions of the enamine double bond with alkynes (74JCS(P1)2496). The products of these reactions are azocine derivatives such as (259), which, after removal of the A-protecting group, have been used as intermediates in pyrrolizine synthesis (Scheme 47) (77JOC2903). 

Similarly, 1-azabutadienes 303 with an A-alkyl substituent react with enamines 304 to give a range of 3,5-disubstituted pyridines 305 in moderate to good yields (Scheme 153) <1984JOC2691>. 2-Azabutadienes are popular choices for [4 + 2] cycloaddition reactions ab initio calculations are available <1992JOC6736>. Electron-rich 2-azabutadienes react with alkynes to give pyridines, e.g., 306 (Scheme 154) <1982JA1428>. 

The three approaches can be compared with the same isoxazoles. 1,3-Dipolar cycloaddition with the alkyne 82 gives a mixture of regioisomers 83 and 84. If the chloroalkene 85 is used instead, only 84 is formed while the enamine 86 gives 83 only.7... 

The preparation of the quinoline system by pericyclic reactions is less important than the previous syntheses. Some cyclization/elimination reactions of iV-phenylimines 95 and 96 with alkynes, enol ethers or enamines are of preparative interest. Although they correspond to [4+2] cycloadditions, they are likely to proceed by SeAt mechanisms and are usually catalysed by Lewis acids. In the enolether cycloaddition to imines 95 ytterbium(III)triflate proved to be particularly effective [104]. 

In modifications of the click synthesis of 1,2,3-triazoles, enol ethers (esters), or enamines have been introduced as alkyne equivalents in the thermal cycloaddition with azides [496]. Primarily, 4,5-dihydro-l,2,3-triazoles 29 are formed, which are transformed to the triazoles 27 by HX-elimination. 

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

The types of cycloadditions discovered for enamines range through a regular sequence starting with divalent addition to form a cyclopropane ring, followed by 1,2 addition (i) of an alkene or an alkyne to form a cyclo-cyclobutane or a cyclobutene, then 1,3-dipolar addition with the enamine the dipolarophile 4), and finally a Diels-Alder type of reaction (5) with the enamine the dienophile. 

Terminal alkynes with no electron-withdrawing group next to the acetylenic linkage when treated with enamines merely add across the double bonds of the enamines (9i). But electrophilic alkynes (those with an electron-withdrawing group next to the acetylenic linkage) undergo cycloaddition reactions with enamines. 

Quinoline derivatives are of major interest as bioactive compounds. A new method for the synthesis of polycyclic fused quinolines 4-207 was developed by Rossi and coworkers [71], who used the [2+2] cycloaddition of an alkyne 4-204 with enamines 4-205 to give 4-206 (Scheme 4.45). Thereby follows an annulation, with the formation of 4-207a-c. 

One of the classic approaches toward cyclobutanes and cyclobutenes, [2+2] cycloaddition between electron-rich and electron-poor alkenes or alkynes, is mirrored by the in situ reaction of [W(CO)5] adducts of electron-deficient phosphaalkenes with enamines, enol ethers, ynamines, and ethoxyacetylene to yield the corresponding phosphetanes and 1,2-dihydrophosphetes.21 Prior... 

Simple a,3-unsaturated aldehydes, ketones, and esters (R = C02Me H > alkyl, aryl OR equation l)i, 60 preferentially participate in LUMOdiene-controlled Diels-Alder reactions with electron-rich, strained, and selected simple alkene and alkyne dienophiles, - although the thermal reaction conditions required are relatively harsh (150-250 C) and the reactions are characterized by the competitive dimerization and polymerization of the 1-oxa-1,3-butadiene. Typical dienophiles have included enol ethers, thioenol ethers, alkynyl ethers, ketene acetals, enamines, ynamines, ketene aminals, and selected simple alkenes representative examples are detailed in Table 2. - The most extensively studied reaction in the series is the [4 + 2] cycloaddition reaction of a,3-unsaturated ketones with enol ethers and E)esimoni,... 

Sulfenes, e.g. phenylsulfene (98), also react with the alkynic analogues of enamines termed ynamines e.g. (110), to give the four-membered cyclic sulfones, e.g. (Ill), by [2 + 2] cycloaddition (Scheme 72). 

The cycloaddition of 1-pyrrolidylcyclopentene with activated alkynes, such as dimethyl acctylcne-dicarboxylate, is reported to occur at room temperature. In contrast, the less reactive diethyl 1-alkynylphosphonates require reaction temperatures of at least 85°C to permit cycloaddition. Under such conditions, spontaneous ring opening of the thermally unstable cyclobutene intermediate yields the ring-enlarged product. Acid hydrolysis of the product enamine gives the unsaturated P-keto-phosphonate (Scheme 1.22). The best results for the cycloaddition are obtained with rigorous exclusion of moisture and with temperatures held below 100°C. Reaction times varied from 24 h (Rl = H) to 8 days (Ri = MOM). -... 

Thennal [2 + 2] cycloadditions proceed to give cyclobutenes either when an alkyne bearing an electron-withdrawing group is reacted with an electron-rich alkene such as an enamine or enol ether (equation 5), or when the alkyne substituted with an electron-donating group, such as dimethylamino, is heated with electron-poor alkenes (equation 6). Crood to excellent yields of cyclobutenes are generally obtained. 

Dipolar cycloadditions can, of course, only produce five-membered rings. Addition of dipolarophiles can generate tetrahydro, dihydro or aromatic oxidation level heterocycles, as illustrated above. Alkene dipolarophiles, with a group that can be eliminated following cycloaddition, give the same result as equivalent alkyne dipolarophiles, for example enamines as the dipolarophile, interact with azides, as the 1,3-dipole, with subsequent elimination of the amine, affording 1,2,3-triazoles. ... 

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