Reactions with electron-deficient alkynes

Scheme 11.4 PK reaction with electron-deficient alkynes.

Cycloaddition of trimethylsilylketene 108 with benzoylisocya-nate 282 was suggested to give 4-trimethylsilyloxy-l,3-oxazin-6-one 283. Interestingly, this six-membered heterocycle can be subjected to the Diels—Alder reaction with electron-deficient alkynes to afford 2-pyridone... 

Ag-catalyzed in situ generation of azomethine ylides from alkynyl A-benzylidene glycinates 35 and their reaction with electron-deficient alkynes 36 were demonstrated by Su and Porco (Scheme 16.17) [26]. This reaction is supposed to be initiated by cycloisomerization of alkynyl imines 35 to isoquinolinium species A with the assistance of AgOTf. Subsequent proton transfer would afford azomethine ylides B with regeneration of Ag(I). 1,3-Dipolar cycloaddition with alkynes 36 followed by aerobic oxidation may furnish pyrroloisoquinoline products 37. It is worth noting that various types of electron-deficient alkynes, irrespective of internal and terminal alkynes, are applicable to this reaction. 

Hydroxy-THISs react with electron-deficient alkynes to give nonisol-able adducts that extrude carbonyl sulfide, affording pyrroles (23). Compound 16 (X = 0) seems particularly reactive (Scheme 16) (25). The cycloaddition to benzyne yields isoindoles in low- yield. Further cyclo-addition between isoindole and benzyne leads to an iminoanthracene as the main product (Scheme 17). The cycloadducts derived from electron-deficient alkenes are stable (23, 25) unless highly strained. Thus the two adducts, 18a (R = H, R = COOMe) and 18b (R = COOMe, R = H), formed from 7, both extrude furan and COS under the reaction conditions producing the pyrroles (19. R = H or COOMe) (Scheme 18). Similarly, the cycloadduct formed between 16 (X = 0) and dimethylfumarate... 

The exploration of the chemistry of azirines has led to the discovery of several pyrrole syntheses. From a mechanistic viewpoint the simplest is based upon their ability to behave as a-amino ketone equivalents in reactions analogous to the Knorr pyrrole synthesis cf. Section 3.03.3.2.2), as illustrated in Schemes 91a and 91b for reactions with carbanions. Parallel reactions with enamines or a-keto phosphorus ylides can be effected with electron-deficient 2//-azirines (Scheme 91c). Conversely, electron-rich azirines react with electron deficient alkynes (Scheme 91d). 

Recently, Li et al. have reported an efficient 1,3-dipolar cycloaddition of azides with electron-deficient alkynes without any catalysts at room temperature in water.128 The reaction has been applied successfully to the coupling of an azido-DNA molecule with electron-deficient alkynes for the formation of [l,2,3]-triazole heterocycle (Eq. 4.66). 

Imino-1,2,4-thiadiazoles such as 27 react with electron-deficient alkynes to afford arylimino thiazoles such as 28. There has been some speculation as to the mechanism of this reaction, which may involve a 1,3-dipolar cycloaddition or a stepwise nucleophilic addition (Equation 6) <1996CHEC-II(4)307>. 

Nitroalkanes react with Jt-deficient alkenes, for example, p-nitro ketones are produced from a,P-unsaturated ketones [41], whereas allylic nitro compounds have been prepared via the Michael-type addition of nitroalkanes with electron-deficient alkynes (Table 6.19). The reaction in either dimethylsulphoxide [42] or dimethyl-formamide [43] is catalysed by potassium fluoride in the presence of benzyltriethyl-ammonium chloride the reaction with dimethyl acetylenedicarboxylate is only successful in dimethylsulphoxide [42], Primary nitroalkanes produce double Michael adducts [42,44], A-Protected a-aminoacetonitriles react with alkynes under catalysed solidiliquid conditions to produce the Michael adducts [45] which, upon treatment with aqueous copper(Il) sulphate, are converted into a,p-unsaturated ketones. 

Since the PK reaction with electron-defident alkynes was also problematic, even when stoichiometric Co2(CO)g was employed, promoters such as trialkylamine N-oxide were required for the reaction to proceed [14]. Alternatively, W(CO)5-THF may be employed semi-catalytically for this class of substrates [9cj. The rhodium catalyst [RhCl(CO)2]2, has shown great versatility for electron-deficient alkynes (Scheme 11.4) the reaction times are much shorter (1-3 h) than those of the usual examples (Tab. 11.3). This rhodium-catalyzed PK reaction may be extended to the synthesis of 6,5-fused ring analogs, as exemplified in the synthesis of bicyclo[4.3.0]nonenone 2o from the 1,7-enyne lo (Eq.4) [13 bj. 

The thiadiazoline (50) (Ar = p-Tol) reacts with electron-deficient alkynes (51) to give arylimino-thiazoles (53). It has been suggested that the reaction proceeds via a 1,3-dipolar cycloadduct (52) (Scheme 13) <75TL459> or by a stepwise nucleophilic substitution reaction <84CHEC-I(6)463>. 

A thorough study of the cycloaddition reactions of S4N4 with electron deficient alkynes has appeared <87JCS(P1)1579>. A clear mechanistic hypothesis is proposed along with the report of a high yielding synthesis of the versatile 3,4-diformyl-l,2,5-thiadiazole (73) (Scheme 15). 

V-Aminopyrroles, easily prepared from the reaction of azoalkenes with enamines and /3-dicarbonyl compounds, have been shown to react with electron deficient alkynes to afford substituted benzenes (79TL2969). While the N-methoxycarbonylaminopyrrole (208) reacted with DM AD under rather vigorous conditions to afford (211) in only 13% yield, the N-unsubstituted aminopyrrole (209) prepared from (208) by NaCN treatment reacted with DMAD in CHC13 solution at room temperature to give (211) in 50% isolated yield. The formation of the aromatic system probably occurs by extrusion of the heteroatom bridge from (210) to afford a relatively stable nitrene (212 Scheme 45). 

Reactions of Phosphonic and Arsenic Ylides with Electron Deficient Alkynes and Synthesis of Polyfunctional Fluoroorganics ... 

The formation of trans-products is observed to a lesser extent in the reaction of 3-alkoxycarbonyl-substituted cyclohexenones, in the reaction with electron-deficient alkenes and in the reaction with olefinic reaction partners, such as alkynes and allenes, in which the four-membered ring is highly strained (Scheme 6.11). The ester 26 reacted with cyclopentene upon irradiation in toluene to only two diastereomeric products 27 [36]. The exo-product 27a (cis-anti-cis) prevailed over the endo-product 27b (cis-syn-cis) the formation of trans-products was not observed. The well-known [2 + 2]-photocycloaddition of cyclohexenone (24) to acrylonitrile was recently reinvestigated in connection with a comprehensive study [37]. The product distribution, with the two major products 28a and 28b being isolated in 90% purity, nicely illustrates the preferential formation of HH (head-to-head) cyclobutanes with electron-acceptor substituted olefins. The low simple diastereoselectivity can be interpreted by the fact that the cyano group is relatively small and does not exhibit a significant preference for being positioned in an exo-fashion. 

Hector s base (3a) and (73 Ar = C6H4Me-4) react with electron deficient alkynes (74) to give 2-arylaminothiazoles (76). The intermediacy of a 1,3-dipolar cycloadduct (75) has been suggested (75TL459) to explain this result (Scheme 35). In order to provide support for the intermediate formation of (75), the reactions of 2-imino-3,4-diphenylthiazoline (77) with alkynes were studied. No 1,3-dipolar addition product (78) could be isolated instead, simple addition products (79) were obtained in high yields (Scheme 36). 

Drawn from these examples it is apparent that controlling the chemose-lectivity in inter-intermolecular Heck-Diels-Alder reactions of two different alkenes can be tedious if the alkenes show comparable reactivities. Nevertheless, the stepwise approach was realized in several other cases. In a synthesis of a derivative of cephalostatin 1 containing a central benzene instead of the pyrazine ring, Winterfeldt et al. linked two steroidal systems by a Heck coupling and subsequently performed high pressure Diels-Alder reactions of the conjugated diene with electron-deficient alkynes [34], Another example, reported by Hayashi et al., involves a selective Heck reaction of a bromoglu-cal with ethylene or acrylic acid derivatives followed by cycloadditions with maleic anhydride or N-phenylmaleimide [35]. 

Numerous transition and rare earth metal triflates were screened as catalysts for the alkenylation of arenes with alkynes, a transformation that can be performed only with difficulty in conventional solvents, see Scheme 9.23. Particularly with electron deficient alkynes such as p-trifluormethylphenylacetylene and />-chlorophenylacetylene the presence of an ionic liquid was found to be mandatory to observe any catalysis. Highest activity was obtained with Hf(OTf)3, In(OTf)3 and Sc(OTf)3 and the reaction proceeded smoothly, even at relatively low catalyst loadings. It is proposed... 

The uncoordinated 3-vinylpyrrole complexes (e.g., 1133) resemble an electron-rich diene and, as such, undergo a facile Diels-Alder reaction with electron-deficient alkenes and alkynes under mild conditions, for example T-phenylmaleimide 1134 to generate, after decomplexation and oxidation, a highly functionalized indole 1135 in ca. 60% overall isolated yield (from pyrrole) (Scheme 221) <1996JA7117>. 

Reaction rates of quadricyclanes 11 with electron-deficient alkynes are high with yields ranging between 74 and 84%. 

The Diels-Alder reaction with inverse electron demand has been one of the most intensively studied reactions of 1,2,4-triazines. In this reaction 1,2,4-triazines behave as electron-deficient dienes and react with electron-rich dienophiles to give, generally, pyridines (see Houben-Weyl, Vol. E7b, p 471 ff). [4 + 2] Cycloadditions of 1,2,4-triazines have been observed with alkenes, alkynes, strained double bonds, electron-rich double and triple bonds, but in a few cases also with electron-deficient alkynes C—N double and triple bonds can also be used as dienophiles. In addition to intermolecular Diels-Alder reactions, intramolecular [4 + 2] cycloaddition reactions of 1,2,4-triazines have also been studied and used for the synthesis of condensed heterocyclic systems. A review on the intermolecular Diels-Alder reaction was published by Boger and Weinreb 14 Sauer published a review on his studies in 1992,381 and E. C. Taylor published a summary of his own work on intramolecular Diels-Alder reactions in 1988.382... 

Furans react with electron-deficient alkynes giving 7-oxabicyclo[2.2.1]heptadienes (30). Whereas it is possible to induce thermally a retro cycloaddition <62ioc3520.89CC1238>, normally these intermediates are reduced at the less hindered side, yielding 7-oxabicyclo[2.2.1]heptenes (31) (Scheme 30). Elimination of ethylene (Alder-Rickert reaction <37CB1354> yields substituted furans (Scheme 30) <6814501, 85JHC1233, 87BSF131>. 

The regiochemistry of oxazole-alkyne cycloadditions is ill-defined except for the reactions of electron-rich 5-alkoxyoxazoles with electron-deficient alkynes. In these cases, as for the analogous oxazole-olefin cycloadditions, the major product results... 

Pd-catalyzed hydroarylation of alkynes via aromatic C—bond activation has been reported by Fujiwara. The reaction offers a good synthetic method of arylalkenes, which are usually prepared by Heck reaction of alkenes. Electron-rich arenes bearing more than one OH, OMe, and alkyl groups react with electron-deficient alkynes [6], The reaction proceeds with a catalytic amount of Pd(OAc)2 in trifluoroacetic acid (TEA) at room temperature. Hydroarylation of ethyl propiolate (15) with / -dimethoxybenzene yielded ethyl (Z)-3-(2,5-dimethoxyphenyl)-2-propenoate (16). Mesitylene (17) is an active arene and the reaction of 17 with 3-butyn-2-one (18) afforded the imsaturated ketone 19 which has f-form [7]. 

Compared with chiral nonracemic a-amino carbonyl compounds - which are not suitable substrates for MBH reaction, mainly due to their racemization under normal conditions after prolonged exposure times to catalyst or due to poor diastereoselectivity " a-keto lactams, enantiopure 3-oxo-azetidin-2-ones 168, readily react with various activated vinyl systems promoted by DABCO to afford the corresponding optically pure MBH adducts 169 without detectable epimerization (Scheme 1.69). " However, the Lewis acid-mediated reaction of electron-deficient alkynes with azetidine-2,3-diones 168 as an entry to p-halo MBH adduets was not very sueeessful the coupling product 170 was achieved with concomitant acetonide cleavage as a single ( )-isomer in low yield, in the presence of trimethylsilyl iodide under BF3 OEt2-induced catalysis (Scheme 1.69). 

In demanding crosselectron-deficient alkynes, the Stille coupling frequently gives better results than the preparatively simpler Sonogashira reaction [200]. Furthermore, the neutral conditions of the Stille reaction mixture are particularly suitable for base-sensitive substrates that may otherwise decompose under the conditions used in the Sonogashira coupling. 

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