Diazocarbonyl Synthesis Essay

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  • Introduction

    The chemistry of transition metal carbene complexes has been a subject of intense activity over the past two decades [1]. Current interest in this field stems from the role of metal carbenes in alkene metathesis [2], in alkene and alkyne polymerization [3], in cyclopropanation chemistry [4], and as intermediates in an impressive array of synthetic methodology [5,6]. The intramolecular reactions of metal carbene complexes derived from α-diazo carbonyl compounds have been extensively studied from both a mechanistic and synthetic viewpoint [7]. Rhodium(II) carboxylates are particularly effective catalysts for the decomposition of diazo compounds and many chemical syntheses are based on this methodology [8]. Among the more synthetically useful processes of the resulting carbenoid intermediates are intramolecular C-H insertion [9], cyclopropanation [10], and ylide generation [11]. In contrast to these processes, the corresponding reaction of alkynes with metal carbenes has been far less studied. Only in recent years has some attention been focused on the intramolecular cyclization reactions of α-diazo ketones containing tethered alkynes (i.e., 1) in the presence of transition metal catalysts. The overall reaction observed is believed to proceed via an initial decomposition of the α-diazo ketone to generate a rhodium carbenoid intermediate 2. Attack on the carbenoid carbon by the tethered alkyne generates a new intermediate (3) in which carbene-like character has been transferred to the beta-carbon of the alkyne. The intermediate vinyl carbenoid may then react further in either an intramolecular or intermolecular fashion to give novel products. This article describes some of our work in this area.

    Scheme 1.


    Many of the earlier systems studied involved trapping the vinyl carbenoid intermediate as a cyclopropane via reaction with external or tethered alkenes [12,18,19]. What is most interesting about this reaction is the formation of three new rings in one step from an acyclic precursor. A typical example is outlined in Scheme 6. Treatment of 19 with a catalytic quantity of rhodium(II) acetate in the presence of two equiv of vinyl ether afforded cyclopropane 20 in 91% yield [18].

    Scheme 6.

    In the case of intramolecular trapping with tethered alkenes, two basic structural variations are possible. These will depend on the point of attachment of the alkenyl group and each variation will lead to very different cyclization products. In type I systems, the alkenyl group is tethered onto the alkynyl carbon atom and this is illustrated with α-diazo ketone 21. Treatment of 21 with a catalytic quantity of rhodium(II) acetate gave indenone 22 in 60% yield.16

    Scheme 7.

    Scheme 8.

    A number of experiments designed to probe the scope and generality of the intramolecular alkyne cyclopropanation reaction were carried out in an effort to exploit this tandem sequence as a synthetic method. Initial efforts focused on the rhodium(II) catalyzed reaction of o-(6,8-nonadien-1-ynyl)-α-diazoacetophenone 23. Treatment of 23 with a catalytic quantity of rhodium(II) mandelate gave cycloheptadiene 25 in 58% yield. In a similar manner, treating the closely related diazo ketone 24 (R=CH3) with rhodium(II) mandelate also gave cyclopent[g]azulenone 26 [13]. The formation of the fused cycloheptadienes 25 and 26 can be rationalized by assuming that the reaction proceeds through the divinylcyclopropane intermediate 28. When the internal double bond of the diene possesses the E-geometry, intramolecular cyclopropanation gives rise to a cis-divinyl cyclopropane, which rapidly undergoes a Cope rearrangement under the conditions used [13]. It should be noted that intramolecular cyclopropanation of dienes by simple carbenoids followed by rearrangement of the resulting vinylcyclopropane has been effectively in several elegant syntheses. The overall process is also closely related to work by Davies who developed a synthesis of fused seven membered carbocycles based on a formal intramolecular [3+4]-cycloaddition of vinyl carbenoids with dienes [20].

    Cyclization of vinyl carbenoids to produce cyclopropenes is another common reaction that is often encountered with these systems [21]. For example, treatment of α-diazo ketone 29 with a catalytic quantity of rhodium(II) acetate afforded cyclopropene 30 in 95% yield.

    Scheme 9.

    A double internal/external alkyne cyclization of acetylenic α-diazo ketone 31 with 1-hexyne was also studied in our laboratory. Stirring this mixture in the presence of rhodium(II) acetate at 25°C for 1 h afforded the novel cyclopentadiene derivative 33 in 81% yield. Control experiments established that the initial product that was first formed was indenone 32. This product is the result of the vinyl carbenoid adding across the acetylenic π-bond of 1-hexyne. When the reaction was carried out for only 10 min at 25°C, indenone 32 could be isolated in 85% yield. Further stirring of 32 with rhodium(II) acetate induced a subsequent rearrangement and ultimately produced 33 in 92% yield [22].

    Scheme 10.

    The ease with which these systems undergo the rhodium(II) catalyzed cyclization to give cyclopropenyl substituted indenones suggested that a similar transformation might occur with diacetylenic systems [23]. Such a study was carried out using diazo ketone 34. A critical issue is whether the cyclization will occur to give products derived from the fully rearranged carbenoid 36 or from the initially formed carbenoid 35. In fact, treatment of 34 with a catalytic quantity of rhodium(II) acetate at 25°C in the presence of ethyl vinyl ether afforded cyclopropane 37 with notable efficiency (90% chemical yield) and selectivity (>95% isomeric purity). No signs of the isomeric cyclopropane 38 could be detected in the crude reaction mixture [24]. The exclusive formation of cyclopropane 37 was attributed to a slower rate of trapping of vinyl carbenoid 35 by ethyl vinyl ether, perhaps as a consequence of a more congested transition state. Another possibility is that the equilibrium between the two carbenoids lies completely in favor of the more stable phenyl substituted isomer 36.


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