Alkylidenes, carbene synthesis

Insertions into tertiary C—H bonds can be carried out with moderate yields. Among other less common reactions improved by the use of PTC-generated CCI2 are the carbylamine synthesis (RNH2 — R NC) (33). Alkylidene carbene (R2C=C ) and alkenyUdene carbene (R2C=C=C ) adducts have also been prepared (34,35). 

Stang etal. (94JA93) have developed another alkynyliodonium salt mediated approach for the synthesis of y-lactams including bicyclic systems containing the pyrrole moiety. This method is based on the formation of 2-cyclopentenones 114 via intramolecular 1,5-carbon-hydrogen insertion reactions of [/3-(p-toluenesulfonyl)alkylidene]carbenes 113 derived from Michael addition of sodium p-toluenesulfinate to /3-ketoethynyl(phenyl) iodonium triflates 112 (Scheme 32). Replacing 112 by j8-amidoethynyl (phenyl)iodonium triflates 115-119 provides various y-lactams as outlined in Eqs. (26)-(30). 

Scheme 1.3.18 Asymmetric synthesis of monocyclic 2,3-dihydrofurans via O—Si bond insertion of alkylidene carbenes.

As shown above, insertion of alkylidene carbenes is highly regioselective. However, when the normal 1,5-C-H insertion pathway is blocked, 1,4- or 1,6-C-H insertion takes place [Eq. (109)]. Thus, the cyclobutene 121 [192] and the six-membered enol ether 123 [193] were obtained in modest yields. Intramolecular insertion into carbon-carbon double bond provides a method for synthesis of cyclopenten-annulated dihydropyrrole 124, which results from homolytic scission of a methylenecyclopropane intermediate [194]. 

Alkylidenecarbenes are valuable intermediates for intermolecular C-H insertion reactions. They allow for a stereo-controlled synthesis of 2,5-diyhdrofurans, since C-H insertion proceeds with retention of configuration at an existing stereocenter. Upon using the Seyferth method for alkylidene carbene formation with the ketoaldehyde 32, the alkylidene intermediate of the aldehyde underwent 1,2-hydride shift, whereas the alkylidene formed from the keto function underwent 1,5-C-H insertion to give the dihydrofuran product (Equation 52) <2005TL7483>. 

The first preparative use of intramolecular C—insertion in organic synthesis was developed by Dreiding, who reported in 1979 that, on flash vacuum pyrolysis, a conjugated alkynyl ketone such as (36) is smoothly converted to a mixture of the cyclized enones (37) and (38) (equation 15). This elegant reaction apparently proceeds via isomerization of the alkyne to the corresponding alkylidene carbene. 

While this compound would have to be classified as a carbene rather than an alkylidene complex, the synthesis involves an intramolecular H atom transfer, which is a recurring phenomenon in metal-alkylidene complex synthesis. 

Carbon-carbon bond formation ortho to a directing group has a long history in organic synthesis. Tsuyoshi Satoh of the Tokyo University of Science has reported (Tetrahedron Lett. 2004,45, 5785) a new protocol, based on the reaction of a deprotonated aniline such as 8 with a chloro sulfoxide such as 7. An N-methyl aniline works equally well. The reaction may be proceeding by way of a coordinated alkylidene carbene. 

A significant development for the selective synthesis of alkenes makes use of alkene metathesis. Metathesis, as applied to two alkenes, refers to the transposition of the alkene carbon atoms, such that two new alkenes are formed (2.110). The reaction is catalysed by various transition-metal alkylidene (carbene) complexes, particularly those based on ruthenium or molybdenum. The ruthenium catalyst 84, developed by Grubbs, is the most popular, being more stable and more tolerant of many functional groups (although less reactive) than the Schrock molybdenum catalyst 85. More recently, ruthenium complexes such as 86, which have similar stability and resistance to oxygen and moisture as complex 84, have been found to be highly active metathesis catalysts. 

Insertion reactions of alkylidene carbenes offer a useful entry to cyclopentene ring systems (4.81). Insertion is most effective with dialkyl-substituted alkylidene carbenes (R = alkyl), since rearrangement of the alkylidene carbene to the alkyne occurs readily when R = H or aryl. A number of methods have been used to access alkylidene carbenes. One of the most convenient uses a ketone and the anion of trimethylsilyl diazomethane. Addition of the anion to the ketone and eUmination gives an intermediate diazoalkene, which loses nitrogen to give the alkylidene carbene. For example, a synthesis of the antibiotic (-)-malyngolide started from the ketone 102 (4.82). The insertion reaction takes place with retention of configuration at the C—H bond. 

Various flve-membered heterocycles can be prepared by inter- or intramolecular addition/cyclizations of appropriate nucleophiles with alkynyliodonium salts via alkylidene carbene intermediates [856, 978, 979]. The intermolecular variant of this cyclization has been employed in the synthesis of 3-substituted-5,6-dihydroimidazo[2,l-( ]thiazoles [997], 2-substituted imidazo[l,2-a]pyrimidines [998] and 2-substituted-imidazo[l,2-fl]pyridines [999]. In a representative example, 2-substituted imidazo[l,2-fl]pyridines 744 were synthesized in good yield by cyclocondensation of 2-aminopyridine (742) with alkynyl(phenyl)iodonium tosylates 743 under mild conditions (Scheme 3.293) [999]. The mechanism of this cyclization involves... 

The intramolecular variant of the alkylidene carbene cyclization is achieved by treating functionalized alkynyliodonium salts with a suitable nucleophile. These cyclizations are exemplified by the following works the preparation of various functionalized 2,5-dihydrofurans by treatment of 3-alkoxy-l-alkynyl-(phenyl)iodonium triflates with sodium benzenesulfinate [1002], employment of the alkylidene carbene cyclization in the total syntheses of natural products agelastatin A and agelastatin B [1003] and preparation of the tricyclic core of ( )-halichlorine through the use of an alkynyliodonium salt/alkylidenecarbene/1,5 C—H insertion sequence [1004]. In particular, Wardrop and Fritz have employed the sodium benzenesulfinate-induced cyclization of alkynyliodonium triflate 751 for the preparation of dihydrofuran 752 (Scheme 3.295), which is a key intermediate product in the total synthesis of ( )-magnofargesin [1002]. 

In the area of carbocyclic nucleoside antibiotics, hydrolysis of the racemic esters 40 (R= n-Bu or ii-CeHis) by the lipase from Candida rugosa proceeds with very high enantiomeric selectivity, and from the resolved materials both enantiomers of aristeromydn were made by an established route. The authors report that a previous similar method (Vol.21, p. 182) is not as enantioselective. In a new synthesis of neplanocin A (43), the alcohol 41, derived from D-ribose, was converted to the cyclopentene 42 using an intramolecular insertion reaction of an alkylidene carbene. The new stereocentre in 42 was mostly of the wrong P-configuration, but could be corrected by a process of desilylation, oxidation and borohydride reduction. The biosynthesis of neplanocin A (43) and aristero-mycin has been reinvestigated, and the cyclopentenone 44 has been proposed as an intermediate, which is converted to aristeromycin via neplanocin A without any bifurcation. The 3-deaza-analogue 45 of 5 - or-aristeromydn has been prepared, and the antiviral activity of it and of the 7-deaza-compound (Vol.27, p. 235) are reported. ... 

Ullrich Jahn of the Academy of Sciences of the Czech Republic observed (Chem. Eur. J. 2009,15, 58) that the free-radical cyclization of 11 proceeded to give mainly the diaste-reomer 12 ( 1 1 at the secondary allylic position). Daesung Lee of the University of Illinois at Chicago reasoned (J. Am. Chem. Soc. 2009, 131, 8413) that the stereochemical relationship between the O and the adjacent C-H of 13 was such that the C-H would be deactivated. The cyclization of the alkylidene carbene derived from 13 indeed proceeded to give 14, setting the stage for the synthesis of platensimycin. 

Ohira, S., Moritani, M., Ida, T., and Yamato, M. (1993) Novel synthesis of (—)-malyngolide using reactions of alkylidene carbenes. J. Chem. Soc. Chem. Commun., 1299-1300. 

A decade after Fischer s synthesis of [(CO)5W=C(CH3)(OCH3)] the first example of another class of transition metal carbene complexes was introduced by Schrock, which subsequently have been named after him. His synthesis of [((CH3)3CCH2)3Ta=CHC(CH3)3] [11] was described above and unlike the Fischer-type carbenes it did not have a stabilizing substituent at the carbene ligand, which leads to a completely different behaviour of these complexes compared to the Fischer-type complexes. While the reactions of Fischer-type carbenes can be described as electrophilic, Schrock-type carbene complexes (or transition metal alkylidenes) show nucleophilicity. Also the oxidation state of the metal is generally different, as Schrock-type carbene complexes usually consist of a transition metal in a high oxidation state. 

The synthesis and X-ray structural determination of a stable Ir111 hydride/alkylidene complex, (165), has been reported, in which the tridentate N3 ligand is TpMe2. 9 The complex undergoes reversible hydride migration onto the electrophilic carbene atom, as shown in reaction Scheme 20. 

Alkylidene complexes are generally considered to be reactive intermediates but the actual surface organometallic species have never been fully characterized. However, the synthesis of silica-supported tantalum(V) carbene complexes and their characterization have been reported.332... 

Other synthetic approaches have been explored for binding an alkylidene functionality to a metalla-calix[4]arene. Among them, the reaction of diazoalkanes with coordinatively unsaturated metalla-calix[4]arenes deserves particular mention. The synthesis of an unusual high-spin (5.2 BM at 292 K) iron(II)-carbene, 192, is displayed in Scheme 39,13 and its structure is shown in Fig. 22. 

Although transition metal alkylidene complexes, i.e., carbene complexes containing only hydrogen or carbon-based substituents, were first recognized over 15 years ago, it is only relatively recently that Ru, Os, and Ir alkylidene complexes have been characterized. Neutral and cationic complexes of these Group 8 metals are known for both metal electron configurations d8 and d6. The synthesis, structural properties, and reactivity of these compounds are discussed in this section. 

Enyne metathesis is unique and interesting in synthetic organic chemistry. Since it is difficult to control intermolecular enyne metathesis, this reaction is used as intramolecular enyne metathesis. There are two types of enyne metathesis one is caused by [2+2] cycloaddition of a multiple bond and transition metal carbene complex, and the other is an oxidative cyclization reaction caused by low-valent transition metals. In these cases, the alkyli-dene part migrates from alkene to alkyne carbon. Thus, this reaction is called an alkylidene migration reaction or a skeletal reorganization reaction. Many cyclized products having a diene moiety were obtained using intramolecular enyne metathesis. Very recently, intermolecular enyne metathesis has been developed between alkyne and ethylene as novel diene synthesis. 

Initial reports of cross-metathesis reactions using well-defined catalysts were limited to simple isolated examples the metathesis of ethyl or methyl oleate with dec-5-ene catalysed by tungsten alkylidenes [13,14] and the cross-metathesis of unsaturated ethers catalysed by a chromium carbene complex [15]. With the discovery of the well-defined molybdenum and ruthenium alkylidene catalysts 3 and 4,by Schrock [16] and Grubbs [17],respectively, the development of alkene metathesis as a tool for organic synthesis began in earnest. 

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