Ynamine cycloaddition

An application of the ynamine cycloaddition is found in a synthesis of dihydro-antirhine [167]. The transition state with matching polarized addends is adopted. The cycloadduct becomes fragmentable upon hydrolysis. 

Since 1,3-dipolar cycloadditions of diazomethane are HOMO (diazomethane)-LUMO (dipolarophile) controlled, enamines and ynamines with their high LUMO energies do not react (79JA3647). However, introduction of carbonyl functions into diazomethane makes the reaction feasible in these cases. Thus methyl diazoacetate and 1-diethylaminopropyne furnished the aminopyrazole (620) in high yield. 

The following compounds have been obtained from thiete 1,1-dioxide Substituted cycloheptatrienes, benzyl o-toluenethiosulfinate, pyrazoles, - naphthothiete 1,1-dioxides, and 3-subst1tuted thietane 1,1-dioxides.It is a dienophile in Diels-Alder reactions and undergoes cycloadditions with enamines, dienamines, and ynamines. Thiete 1,1-dioxide is a source of the novel intermediate, vinylsulfene (CH2=CHCH=SQ2). which undergoes cyclo-additions to strained olefinic double bonds, reacts with phenol to give allyl sulfonate derivatives or cyclizes unimolecularly to give an unsaturated sultene. - Platinum and iron complexes of thiete 1,1-dioxide have been reported. 

Analogously to ynamines and o, /3-acetylenic ketones, 4-aminobut-3-yn-2-ones react with 1,3-dipoles (68HCA443 73HCA2427 92KGS867). The reaction of 4-dimethylaminobut-3-yn-2-one with diphenylketene follows a route of [2-1-21-cycloaddition (30°C, THF, 1 h) to give 2-acetyl-3-dimethylamino-4,4-diphenyl-cyclobut-2-en-l-one (377) in 15% yield. With ethyl azidoformate (30°C, THF, 3 h), the tiiazole 378 is formed in 82% yield, whereas with phenyl isocyanate, the quinoline 379 is the product (by a [2- -4] scheme) in 70% yield (68HCA443). 

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. 

On the other hand, the known facts point to an alternative interpretation. The stereochemical course of the reaction may be explained in terms of a polar [2s + 2s] cycloaddition15 which is observed in reactions between very electron-poor and very electron-rich alkcnes. Namely, polar [2 + 2] cycloadditions usually proceed with high regioselectivity ( head to head ) and stereoselectivity under mild conditions33 35. This mechanism is also supported by the fact that a closely related reaction (between an ynamine and iminium salts) passes through a cyclic 4-membered intermediate36, which is probably the result of a polar [2 + 2] cycloaddition (see refs 10 and 37). 

As expected, 1 1 (2 + 2) cycloadducts are obtained in the reactions of thiete dioxides with some typical electron-rich olefins, e.g. enamines and ynamines, although this cycloaddition has not proven to be general190. 

A key step in the synthesis in Scheme 13.11 was a cycloaddition between an electron-rich ynamine and the electron-poor enone. The cyclobutane ring was then opened in a process that corresponds to retrosynthetic step 10-IIa 10-IIIa in Scheme 13.10. The crucial step for stereochemical control occurs in Step B. The stereoselectivity of this step results from preferential protonation of the enamine from the less hindered side of the bicyclic intermediate. 

An elegant method for the preparation of some cyclopropenone imines reported by Krebs118 is the (1 + 2) cycloaddition of isonitriles (as divalent carbon species) to activated triple bond of ynamines and certain cycloalkynes, e.g. ... 

The various transitions of triafulvenes to pentafulvenes achieved by addition of electron-rich double bonds is complemented by the reaction of triafulvenes with ynamines and yndiamines299, which gives rise to 3-amino fulvenes 539. This penta-fulvene type deserves some interest for its merocyanine-like inverse polarization of the fulvene system and its formation is reasonably rationalized by (2 + 2) cycloaddition of the electron-rich triple bond to the triafulvene C /C2 bond (probably via the dipolar intermediate 538) ... 

The calicene derivative 185 shows ambiguous behavior toward ynamines. Whilst reacting with yndiamine 542 according to the above (2 + 2) mode to give the fulvalene 545300), with ynamine 544 a (4 + 2) cycloaddition mode appears to operate which leads to the naphthalene derivative 545301. This is in accordance with the reactivity of other calicenes toward ADD shown earlier (p. 93). 

In the course of investigation of reactivity of the mesoionic compound 44 (Scheme 2) the question arose if this bicyclic system participates in Diels-Alder reactions as an electron-rich or an electron-poor component <1999T13703>. The energy level of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) orbitals were calculated by PM3 method. Comparison of these values with those of two different dienophiles (dimethyl acetylenedicarboxylate (DMAD) and 1,1-diethylamino-l-propyne) suggested that a faster cycloaddition can be expected with the electron-rich ynamine, that is, the Diels-Alder reaction of inverse electron demand is preferred. The experimental results seemed to support this assumption. 

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. 

Group 6 allenylidenes also react with the carbon-carbon triple bond of ynamines to yield similar cyclobutenylidene derivatives 88 along with the corresponding alkenyl-aminoallenylidenes 89 (Scheme 32) [286]. These aminoallenylidene complexes result from a formal [2-1-2] cycloaddition between the ynamine C=C and allenylidene Cp=Cy bonds followed by cycloreversion. A stepwise cyclization initiated by the addition of the nucleophilic R C=CNEt2 carbon at the C or Cy position has been proposed in the formation of these isomeric products. As commented previously, unlike their Cr and W counterparts, the reactions of... 

Employing ynamines, the cycloaddition-extrusion reaction can be extended to heterocondensed 1,3-oxazinones, resulting in a smooth, simple annulation of a pyridine ring to an existing heterocyclic system (87CB1427). 

The most recent extension of the 4 + 2 cycloaddition to aromatic quaternary salts has been carried out with isoquinolinium salts (42), in effect, dispensing with ring A of the acridizinium ion. Although there was an earlier claim that the addition of an ynamine to 2-methyl-isoquinolinium iodide led to a 2 1 adduct, the assigned structure... 

The only example found of an aromatic quaternary salt undergoing 4 + 2 cycloaddition, outside those discussed in Sections A and B above, is the reaction of 1-methylquinolinium iodide (47) with ynamines to afford l-methyl-3-substituted-4-dialkylaminoquinoliniura salts (49), presumably via loss of a C2 unit from the cycloadduct (48). A systematic search of aromatic quaternary salts using strongly nucleophilic addends will likely afford additional examples of this type of cyclization. 

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). 

Cycloaddition of ynamines with sulfenes (generated from sulfonyl chlorides) to give thiete sulfones 132 and 133 has been reported by Truce et (Eq. 21). Acid hydrolysis yields the corresponding enols (134). Other compounds that have been prepared in this manner are 135 and 136. Sulfene... 

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... 

When deprotonated dimethyl sulfone is reacted with 2 equiv of benzonitrile, compound 109 is obtained in low yield (Equation 91) <1973JOM(59)53>. Compounds of the general structure 179 can be prepared from two molecules of enamino esters 288 and sulfur dichloride or disulfur dichloride <1984JOG4780> or in low yield using chlorocarbo-nylsulfenyl chloride 289 as the source of sulfur <1985JHC1621> (Equation 92). A series of cycloadditions lead to the formation of 131 from 290 and two molecules of the ynamine 291 (Scheme 69) <1995LA1795>. 

Nitrooxazoles 271a-C also react with electron-rich ynamines to yield isoxazo-lines. °° The proposed reaction mechanism involves the Michael addition of the ynamine to give 275, followed by rearrangement to a nitrile oxide 277. Intramolecular 1,3-dipolar cycloaddition of 277 accounts for the exclusive cis stereochemistry observed in the products 278a-c (Scheme 8.78). 

The other diazines can also undergo cycloaddition with ynamines an example of a pyridazine addition is shown in equation (94) (72TL1517), and of an addition to a pyrazine in equation (95) (72LA(761)39). Pyrazinediones react with the electron-deficient acetylenedicar-boxylic ester, with subsequent expulsion of isocyanic acid, as shown in equation (96) (73JCS(P1)404). 

Upon reaction with ynamines 2-methyl-7-tosylfuro[2,3-4]pyridazine 21 undergoes [2-1-2] cycloaddition-ring-expan-sion reactions to afford 22 (Equation 7) <1996H(43)199> as one of three products isolated. 

Some examples dealing with the [4 + 2] cycloaddition of ketenimines have been recorded (Scheme 58). Thus, thioketones and ynamines reacted with N-aryl ketenimines 257 through the carbon—nitrogen and the conjugated aromatic carbon—carbon double bonds to yield benzothiazine derivatives 258 (80JOC3766 82JOC3998) and substituted quinolines 259 (73JA5417), respectively. Simple ketenimines 261 were formed by reaction... 

---