Ynamines cycloaddition reactions

The hetero Diels-Alder [4+2] cycloaddition (HDA reaction) is a very efficient methodology to perform pyrimidine-to-pyridine transformations. Normal (NHDA) and Inverse (IHDA) cycloaddition reactions, intramolecular as well as intermolecular, are reported, although the IHDA cycloadditions are more frequently observed. The NHDA reactions require an electron-rich heterocycle, which reacts with an electron-poor dienophile, while in the IHDA cycloadditions a n-electron-deficient heterocycle reacts with electron-rich dienophiles, such as 0,0- and 0,S-ketene acetals, S,S-ketene thioacetals, N,N-ketene acetals, enamines, enol ethers, ynamines, etc. 

The reaction of several substituted imidazo[4,5-c/]-, pyrazolo[3,4-r/]- and triazolo[4,5-zf]pyrid-azines 3 with ynamines, in competition with [4 + 2] cycloaddition, leads to [2 + 2] derivatives 4, which rearrange to l,2-diazocines5.7 8 The reaction seems to be sensitive to the substituents, as replacement of the electron-withdrawing group R on the pyridazine ring of the pyrazolo compound (A = N, B = CH) by chlorine completely inhibits both the [4 + 2] and [2 + 2] cycloaddition reactions. The X-ray structure of the imidazo derivative 5 (R = Ms, A = CH, B = N) reveals a tub conformation of the eight-membered ring. 

The betainic imidazo[l,2- 7][l,2,4]triazinium-olate 107 was found to react as a 1,3-dipole in 1,3-dipolar cycloaddition with ynamines to yield a bridged skeletone 108 <1999T13703> as shown in Scheme 15. This cycloadduct 108 underwent subsequent rearrangement upon heating, and resulted in formation of a fused eight-membered heterocycle 109. With acetylenes other than ynamines, the transformation was found to proceed slowly and in bad yields. The fact that ynamines were used successfully, as well as theoretical considerations (cf. Section 11.17.2) in this chapter, indicated that these Diels-Alder reactions are of inverse electron demand. 

Cycloaddition reactions of 3-diazopyrazoles and 3-diazoindazoles with ynamines led to the corresponding 4-aminopyrazolo- and 4-aminoin-dazolo-triazines of type 268 (77S556 83JOC2330). The yields are higher in the case of the 3-diazoindazoles (Scheme 79). 

Both 3-diazO 1,2,4-triazoles and 4-diazo-l,2,3-triazoles easily give cycloaddition reactions with ynamine leading to 4-aminotriazolo-triazine 284 and the yields are generally higher than in the pyrazole and imidazole series (77S556) (Scheme 85). 

Thiete sulfones show an irregular behavior pattern when involved in cycloaddition reactions. With 1,3-dienes, dienamines, enamines, ynamines, diazoalkenes, cyclopropadiene, and its substitution products, furan, and anthracene, the addition proceeds in the normal fashion. With certain Diels-Alder reagents such as tetraphenylcyclopentadienone (tetracycloneX however, the cyclic sulfones react anomalously. The Diels-Alder adducts undergo decomposition with SO 2 and CO extrusion to a seven-membered ring, the tetraphenylcycloheptatriene 223. Bicyclic octadienone is produced as well (Eq. 62). The mechanism of this unusual reaction is proposed by... 

Another well-studied cycloaddition of 1,2,4-triazines is the reaction with ynamines (423). In this the dienophile often attacks the 1,2,4-triazines across the 2- and 5- rather than the 3- and 6-positions. This can perhaps be due to the transition state of the cycloaddition with ynamines being more polar than that in the cycloaddition with alkenes, and a partial negative charge in the 1,2,4-triazine ring is better stabilized at a nitrogen (N-2) than at a carbon (C-6). The products isolated from these reactions are pyrimidines (424). It was shown by using lsN-labelled 3-methyl-l,2,4-triazine that the reaction is in fact a [4 + 2] cycloaddition to N-2 and C-5 and not a [2 + 2] cycloaddition to the N(4)—C(5) bond (72LA(758)125). 

Neunhoeffer and Lehmann have shown that it is possible to reverse the diene character of the 1,2,4-triazine ring by introducing alkoxy or dialkylamino groups into the ring. Alkoxy-, dialkoxy- and dialkylamino-1,2,4-triazines are therefore less reactive toward ynamines but they still react with these dienophiles. Bis(dialkylamino)-, trialkoxy- and tris(dialkylamino)-l,2,4-triazines (425) behave as electron-rich dienes and give cycloaddition reactions with acetylenedicarboxylate (426) but not with ynamines. Compounds (425) and (426) afford the 2,4-bis(dialkylamino)pyrimidine-5,6-dicarboxylates (427) (77LA1413). 

A few cases of [4 + 2] cycloaddition reactions of 1,2,4-triazines with C=N double bonds have been reported. Reaction of 1,2,4-triazines (441) with benzamidine (442) in boiling toluene led to the isolation of the 1,3,5-triazines (443). It may be supposed that here the dienophile adds to the 2- and 5-positions of the 1,2,4-triazine, as in the reaction with ynamines, then a nitrile (R6CN) is eliminated and aromatization follows by loss of ammonia. In one case, the initially formed 1,3,5-triazine (443) reacted with a second molecule of benzamidine by [4 + 2] cycloaddition and elimination of R3CN and ammonia, resulting finally in triphenyl-1,3,5-triazine (444). This is a known reaction in the 1,3,5-triazine series (see Chapter 2.20) (81TL1393). 

Cycloadditions of ynamines to nitroalkenes, 1-Nitrocyclopentene condenses with ynamine 1 in the expected manner (5, 219 7, 107-108) to afford cyclobutene 2 in 40 Xi yield. This reaction is not general, however, since nitroalkencs 3 and 4... 

Since the report by Carboni and Lindsey in 1959 on the cycloaddition reaction of tetrazines to multiple bonded molecules as a route to pyridazines, such reactions have been extensively studied. In addition to acetylenes and ethylenes, enol ethers, ketene acetals, enol esters and enamines, and even aldehydes and ketones have been used as starting materials for pyridazines. A detailed investigation of various 1,2,4, 5-tetrazines in these syntheses revealed the following facts. In [4 + 2] cycloaddition reactions of 3,6-bis(methylthio)-l,2,4,5-tetrazine with dienophiles, which lead to pyridazines, the following order of reactivity was observed (in parenthesis the reaction temperature is given) ynamines (25°C) > enamines (25-60°C) > ketene acetals (45-100°C) > enamides (80-100°C) > trimethylsilyl or alkyl enol ethers (100-140°C) > enol... 

Stereoselective Diels-Alder reactions have been performed variously, using chirally modified sulfines as dienophiles, chiral ynamines, SMP enamines, SMP acrylamides, and the in situ preparation of SMP A-acylnitroso dienophiles. The [2 + 2] cycloaddition reactions of chiral keteniminium salts obtained from SMP amides with alkenes have been studied. ... 

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,... 

Over the last twenty years, the cycloaddition reactions of 1,2,4-triazines have been studied intensively. 1,2,4-Triazincs arc clcctron-dcficicnt systems and readily undergo Diels-Alder reactions with inverse electron demand with electron-rich dienophiles, such as enamines and ynamines, or with systems containing strained double bonds. Inter- and intramolecular cycloaddition reactions have been observed, giving pyridines and pyrimidines or condensed pyridines and pyrimidines. 

Triethyl l,3,5-triazine-2,4,6-tricarboxylate and 2,4,6-tris(methylsulfanyl)-1,3,5-triazine react in an inverse electron demand Diels-Alder reaction with several electron-rich dienophiles.6 The tricarboxylate 9 (R1 = C02Et) undergoes a well-defined [4 + 2] cycloaddition reaction with ynamines and enamines. In the case of ynamines, the [4 -1- 2] cycloaddition is followed by a retro Diels - Alder reaction at 40 100 °C with direct formation of the substituted pyrimidines 11. In the case of enamines, the cycloaddition provides stable, isolable [4 + 2] adducts 12. The subsequent retro Diels-Alder reaction and the final aromatization step is catalyzed by a mixture of hydrochloric acid and dioxane, anhydrous p-toluencsulfonic acid or acetic acid. This two-step process can be reduced to a single operation by conducting the reaction in a solution of dichloromethane and acetic acid at 40-100 °C.6 Electron-deficient dienophiles like dimethyl acetylenedicarboxylate or 1,4-naphthoquinone do not react with this triazine. 

Figure 8 connects the kinetic data obtained in the tetrazine series with those measured for 1,2,4-triazines <90TH 621-01). The numbers at the triazine nucleus show the diene system which is involved in these cycloaddition reactions the dimethylamino group of the ynamine always orients to the C02Me substituents in the addition step. The triazine triester with a total rate constant of 10 A2 = 4.17 X 10 comes close in rate to the tetrazine diester. In general, triazines are less reactive than tetrazines by some powers of ten. 

The methods for generating acyl ketenes (Scheme 7-V) and their subsequent in situ participation in [4 + 2] cycloadditions with a wide range of hetero- or olefinic and acetylenic dienophiles (Scheme 7-VI), including acyl ketenes,185 186,197 carbonyl compounds, 86-188 nitriles,1874,189,191 isocyanates and isothiocyanates,1864,190,191 ketenes,191 imines,1864,1874,191,192 carbo-diimides,l87c 190,191,193 ynamines,194 ketene acetals,1864,195 enol ethers,1864,191,196 and V-sulfinylamines197 have been extensively reviewed.5,9,12 Two reports have detailed the 4-n- participation of allenic ketones in [4 + 2] cycloaddition reactions [Eq. (51)].198,199... 

For preliminary studies on the scope of the [4 + 2] cycloaddition reactions of 1,2,4-triazines with electron-rich dienophiles including enol ethers, enamines, ketene acetals, ynamines and strained or reactive olefins, see Dittmar, W., Sauer, J., and Steigel, A. (1969). Tetrahedron Lett., 5171 Reim, H., Steigel, A., and Sauer, J. (1975). Tetrahedron Lett., 2901. 

Early extensive accounts of the 4v participation of a,/)-unsaturated carbonyl compounds in [4 + 2] cycloadditions detailed their reactions with electron-deficient dienophiles including a,/3-unsaturated nitriles, aldehydes, and ketones simple unactivated olefins including allylic alcohols and electron-rich dienophiles including enol ethers, enamines, vinyl carbamates, and vinyl ureas.23-25 31-33 Subsequent efforts have recognized the preferential participation of simple a,/3-unsaturated carbonyl compounds (a,/3-unsaturated aldehydes > ketones > esters) in inverse electron demand [4 + 2] cycloadditions and have further explored their [4 + 2]-cycloaddition reactions with enol ethers,34-48 acetylenic ethers,48 49 ke-tene acetals,36-50 enamines,4151-60-66 ynamines,61-63 ketene aminals,66 and selected simple olefins64-65 (Scheme 7-1). Additional examples may be found in Table 7-1. 

In another group of (2 + 2)-cycloaddition reactions, the heterocyclic nucleus reacts via an electron-deficient carbon-carbon or carbon-nitrogen double bond with electron-rich aminoacetylenes (ynamines). For instance, thiete 1,1-dioxides, JV-benzylmaleimide, and 2,3-bis(methoxycarbonyl)-7-oxabicyclo( 2.2.1 lhepta-2,5-diene reacted with 1-diethylamino-l-propyne and with 1 -phenyl-2-( 1 -pyrrolidinyl)-acetylene to give the (2 + 2)-cycloadducts 48, 49, and 50, respec-tively.35,37,53 The latter product was thermally rather unstable, and its structure was identified on the basis of its conversion with 2,4,6-tri-methylbenzonitrile oxide into 51.53 (2 + 2)-Cycloaddition via a carbon-nitrogen double bond has been reported to take place in the reactions of 3,3-dimethyl-3//-indoles and 3,4-dihydroisoquinoline with ynamines, e.g., l-dimethylamino-2-phenylacetylene, in the presence of boron trifluoride.54 The (2 + 2)-cycloadducts 52 and 53 were not isolated, but... 

A similar reaction of a cyanoynamine with phenylsulfene also gave the four-membered cyclic sulfone (equation 93)205. Formation of the four-membered sulfones from cycloaddition of ynamines-sulfenes is again proposed to occur through a zwitterionic intermediate205. 

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