Reactions of Enynes

Complex 38 also turned out to be an efficient catalyst for cycloisomerization reactions of enynes 41 (Scheme 8) [16, 17]. This seems reasonable if one considers the fact that Fe(0) is isoelectronic to Rh(+1), which is also a catalyst for Alder-ene cycloisomerizations [18, 19]. 

The substituent effects on the alkene were investigated in the reaction of enyne 12 and chromium carbene complex 2c [8]. In the reaction of enyne -12a having a phenyl group on the alkene with Fischer chromium carbene complex 2c, metathesis product 13a was obtained as a main product along with cyclopropane 14 and cyclobutanone 15 (Eq.4). The reaction of Z-12a with 2c gave only... 

Table 2. Reaction of enyne 12 with Cr-carbene complex 2c... 

The 1,5-substitution of l-chloro-2-en-4-ynes with Grignard reagents has been described by Dulcere and co-workers [41] but lacks generality with regard to the nucleophile (see Section 2.3). In contrast, the regioselective reaction of enyne acetates 47 with various lithium cuprates proceeds smoothly in diethyl ether, furnishing exclusively vinylallenes 48 with variable substituent patterns (Scheme 2.17) [42],... 

The reaction of enynes with Fischer-type carbene complexes can also lead to the formation of cyclobutanones (Figure 2.23) [315]. The mechanism for this reaction is likely to be rearrangement of the intermediate, non-heteroatom-substituted vinylcarbene complex to a vinylketene, which undergoes intramolecular [2 -i- 2] cycloaddition to form the observed cyclobutanones. 

Particularly interesting is the reaction of enynes with catalytic amounts of carbene complexes (Figure 3.50). If the chain-length between olefin and alkyne enables the formation of a five-membered or larger ring, then RCM can lead to the formation of vinyl-substituted cycloalkenes [866] or heterocycles. Examples of such reactions are given in Tables 3.18-3.20. It should, though, be taken into account that this reaction can also proceed by non-carbene-mediated pathways. Also Fischer-type carbene complexes and other complexes [867] can catalyze enyne cyclizations [267]. Trost [868] proposed that palladium-catalyzed enyne cyclizations proceed via metallacyclopentenes, which upon reductive elimination yield an intermediate cyclobutene. Also a Lewis acid-catalyzed, intramolecular [2 + 2] cycloaddition of, e.g., acceptor-substituted alkynes to an alkene to yield a cyclobutene can be considered as a possible mechanism of enyne cyclization. 

Highly enantioselective 1,5-substitution reactions of enyne acetates are also possible under carefully controlled conditions (Eq. 4.31) [46]. For example, treatment of enantiomerically pure substrate 70 with the cyano-Gilman reagent tBu2CuLi-LiCN at —90 °C provided vinylallene 71 as a 1 3 mixture of E and 2 isomers with 20% and 74% ee, respectively. This mediocre selectivity might be attributable to race-mization of the allene by the cuprate or other reactive copper species formed in the reaction mixture. The use of phosphines as additives, however, can effectively prevent such racemizations (which probably occur by one-electron transfer steps) [47]. Indeed, vinylallene 71 was obtained with an ee of 92% for the E isomer and of 93% for the 2 isomer if the substitution was performed at —80 °C in the presence of 4 eq. of nBusP. Use of this method enabled various substituted vinylallenes (which are interesting substrates for subsequent Diels-Alder reactions Sect. 4.2.2) to be prepared with >90% ee. 

By contrast, in 2000 Shibata reported the Ir-catalyzed enantioselective Pauson-Khand-type reaction of enynes [30aj. The chiral Ir catalyst was readily prepared in situ from [lrCl(cod)]2 and tolBINAP (2,2 -bis(di-p-tolylphosphino)-l,T-binaphthyl), both of which are commercially available and air-stable, and the reaction proceeded under an atmospheric pressure of carbon monoxide. The Ir-catalyzed carbonylative coupling had a wide generality in enynes with various tethers (Z), substituents on the alkyne terminus (R ) and the olefinic moiety (R ). In the case of less-reactive enynes, a lower partial pressure of carbon monoxide achieved a higher yield and ee-value (Table 11.1) [30b]. 

Cycloisomerization represents another approach for the construction of cyclic compounds from acyclic substrates, with iridium complexes functioning as efficient catalysts. The reaction of enynes has been widely studied for example, Chatani et al. reported the transformation of 1,6-enynes into 1-vinylcyclopentenes using [lrCl(CO)3]n (Scheme 11.26) [39]. In contrast, when 1,6-enynes were submitted in the presence of [lrCl(cod)]2 and AcOH, cyclopentanes with two exo-olefin moieties were obtained (Scheme 11.27) [39]. Interestingly, however, when the Ir-DPPF complex was used, the geometry of olefinic moiety in the product was opposite (Scheme 11.28) [17]. The Ir-catalyzed cycloisomerization was efficiently utilized in a tandem reaction along with a Cu(l)-catalyzed three-component coupling, Diels-Alder reaction, and dehydrogenation for the synthesis of polycyclic pyrroles [40]. 

One of the major advantages of the rhodium(I)-catalyzed Alder-ene reaction is that mild conditions are used to effect the cycloisomerization process thus increasing the likelihood of being able to facilitate an asymmetric reaction. In fact, Zhang has demonstrated convincingly that the Alder-ene reaction of enynes can indeed be performed with excellent enantioselectivity and with similar efficiency. These examples are highlighted below in chronological order. 

On the other hand, it has been shown that ruthenium carbene complexes lb and Ic are also effective for enyne metathesis. Intramolecular reaction of enyne metathesis is now a useful method for synthesizing cyclic compounds having a diene moiety, and intermolecular enyne metathesis has provided a method for synthesis of 1,3-dienes. 

Scheme 2 Reaction of enyne having teminai aikyne with 1c.

Scheme 11 Reaction of enyne having aikynyi boronate.

Blechert carried out a tandem reaction of enynes in the presence of olefins instead of ethylene (Scheme 21). Treatment of cyclopentenol derivative 58a with Ic in the presence of an alkene affords 59a. The five-membered ring in estrone 58b is cleaved by Ic to give 59 and an alkene part is introduced on the six-membered C ring. However, cycloalkenyl amine derivative 60 is treated in a similar manner in the presence of an allyl alcohol derivative to give pyrrolidine derivative 61, and in this case, an alkene part is introduced on the diene moiety. Presumably, ruthenium carbene complex XVI reacts with an alkyne part to produce the pyrrolidine ring with a regioselectivity opposite to the other cases. 

Dixneuf used [RuCl2(/>-cymene)]2 as a catalyst for the reaction of enyne 72a in the presence of imidazolium salt and CS2CO3 and obtained the enyne metathesis product 73a in a high yield. The enyne silyl ether 72b is converted under similar reaction conditions into r/i7ra-compound 73b which after the Tamao oxidation gives diol 74 (Scheme 28). In this reaction, V-heterocyclic carbene should be generated to coordinate to the ruthenium metal, but the actual species for this reaction is not well documented. 

PtCl2 constitutes an efficient and practical catalyst for skeletal rearrangement reaction of enynes. This includes a formal enyne metathesis reaction delivering 1,3-dienes. Skeletal reorganization of enyne 75a having a carbon chain in... 

The intramolecular iron-catalyzed Alder-ene reaction of enynes in the carbocy-clization reaction was recently reported by Furstner et al. (Scheme 9.8) [20], A low-valent cyclopentadienyliron catalyst, specifically the [CpFe(C2H4)2][Li(tmeda)] complex, is a reactive catalyst for enyne cydoisomerization reactions. Bicyclic products, also incorporating large ring systems, are thereby accessible, and the Thorpe-Ingold effect seems to be helpful for these types of reactions. 

Rhodium-catalysed asymmetric cyclization/hydroboration followed either by Pd-catalysed arylation or by oxidation was applied to the synthesis of a number of chiral, non-racemic carbocycles and heterocycles. Thus, reaction of enyne (28) with catecholborane, catalysed by a 1 1 mixture of [Rh(COD)2]+ Sbly,- and (S)-BINAP (5 mol%), followed by Pd-catalysed arylation with /7-IC6H4CF3, afforded benzyli-denecyclopentane (29) in 65% yield with 88% ee.46... 

Also, the [4+2] benzannulation of enyne 154 with diyne 155 proceeds chemo- and regioselectively to afford 156 [66], A similar reaction of enyne silyl enol ether 157 with the diyne offers a good synthetic route to polysubstituted phenols 159 via 158 [67]. In this reaction enol silyl ethers having the (E) configuration as shown in 157 give satisfactory results. 

Pauson-Khand-type reactions of enynes are mediated by other metal complexes, such as Fe(CO)5 [100], [W(CO)5THF] and Mo(CO)6 [101]. Cyclization of the allene-yne system 227 to the a-methylenecyclopentenone 228 is promoted by Mo(CO)6. The products depend on the substituents of the allene, and the cyclization of 229 afforded 230 as the main product [102]. 

Reaction of the carbene complex 148 with alkyne affords vinylcarbene 150 via metallacyclobutene 149. In the intramolecular reaction of enyne 152, catalysed by carbene complex 151, the triple bond is converted to vinylcarbene 153 which then reacts with the double bond to give the conjugated diene 154. Generation of 154 is expected by the formation and cleavage of cyclobutene 155 as a hypothetical intermediate. Based on this reaction, Ru-catalysed intramolecular metathesis of enyne 156 gave the N-containing cyclic diene 157, from which (—)-stemoamide (158) was synthesiszed. The reaction can be understood by assuming the formation of the hypothetical cyclobutene 159 from 156 [52],... 

The reaction of enyne with either an Au(I) or Au(III) catalytic promoter gave a 6-oxabicyclo[3.2.1]octane (Scheme 98).141 The use of Au(PPh3)Cl in combination with AgC104 is equally effective. The possible involvement of the conjugate Brpnsted acid in the alkyne activation of the alcohol was excluded since treatment with HC1 in the absence of AuC13 gave exclusively tetrahydrofuran. 

The introduction of a double bond between the triple bond and the leaving group of a propargyl electrophile leads to enyne electrophiles (e.g., 198) which would give access to vinylallenes 199 if the attack of the nucleophile takes place at the triple bond in an Sn2" (l,5)-substitution reaction (Scheme 48). Besides the regioselectivity, two types of stereoselectivity have to be considered in this transformation, that is, the configuration of the olefinic double bond of the vinylallene and the (relative or absolute) configuration of the allenic chirality axis. In the event, the reaction of enyne acetates 198 with various lithium cuprates proceeds... 

One of the major practical issues associated with the PK reaction is the use of carbon monoxide. In 2002, two groups independently published details of intramolecular PK-type reactions of enynes and alkenes where CO... 

A Pauson-Khand type reaction of enynes, where the CO source is an aldehyde, has been reported by Morimoto and coworkers. This CO-transfer carbonylation system was carried ont with monomeric or dimeric rhodium complexes supported by monodentate or chelating phosphine ligands (e g. [RhCl(cod)]2/dppe or dppp [RhCl(CO)PPh3]). This reaction is snccessfiil for a series of enynes and aldehydes (Scheme 28). 

Reaction of enyne-esters and -amides and 2-alkynyl-substituted aromatic ketones in a related fashion led to pyrranylidene complexes (Scheme 8). Compounds with a stabilized anion or a trialkylsilyl enolate in the 4- or 5-position relative to the alkyne can be used in related reactions to give carbocyclic products (Scheme 9). 

Double bonds of enynes act as nucleophiles and for ene-allenes perform similarly. Actually, some of the reactions of enynes with propargylic carboxylate substitution may... 

Alkenylpyrroles 23, which readily underwent hydrolysis to 24, have been prepared via reaction of enyne-imines 25 or the corresponding enyne-A.A -dimethylhydrazones with the Fischer carbene complex 26. The hydrazones were found to be the more useful synthons, generally giving higher yields <030L2043>. 

The results presented above indicate that the Zr-promoted bicyclization reactions of enynes and diynes constitute novel and attractive synthetic methods. The corresponding reaction of dienes remains to be developed. Somewhat unexpectedly, the reactions of monoalkynes and monoalkenes can, in many cases, be highly pair selective and regioselective. Many aspects of these reactions also need to be further developed. Besides being attractive from the viewpoint of organic synthesis, the chemistry of ZrCp2 provides a number of novel structural and mechanistic features that broaden the horizon of organometallic chemistry. 

The cobalt-mediated cycloaddition of an alkyne, an alkene, and CO leading to a cyclopentenone has been known as the Pauson-Khand (PK) reaction [78], Due to its synthetic importance, numerous variants - especially catalytic reactions - have been developed to date [79]. The first ruthenium-catalyzed PK reaction of enynes has been achieved using Ru3(CO)i2 by two research groups independently (Scheme... 

---