Enediyne cycloaromatization reaction

Scheme 7-3 The system designed by Bergman to study the enediyne cycloaromatization reaction (1972).

Another example of a zwitterionic product of a cycloaromatization reaction was given by Kerwin and coworkers. Their skipped (aza)enediynes rearranged to yield (aza)eneyne-allenes that subsequently cyclized under addition of methanol (in a byproduct), which is consistent with a partitioning between a diradical and a zwitterionic reaction pathway (Scheme 15).66... 

Bergman cycloaromatization reaction Thermal or photochemical cycloaromatization of enediynes to form substituted benzene rings. 56... 

The discovery of the remarkable biological activity of natural enediynes and enyne allenes has further fueled interest in understanding the fundamentals that govern these transformations. Indeed, cycloaromatization reactions have served as a productive playground for testing numerous concepts related to structure and reactivity of organic and organometaUic compounds [2]. Furthermore, the... 

In the absence of the competing coordination with arene, the Ru- and Fe-catalyzed reactions of nonbenzannelated enediynes proceed quickly and efficiently, although photochemical liberation of the arene ligand occurs more effectively with Fe due to its lower arenophihcity relative to ruthenium (Scheme 30.18). Facile photochemical dissociation of the prodnct-metal complexes can be used for the creation of catalytic cycles. A fascinating feature of this approach is that it allows incorporation of trans/cis isomerization in the catalytic cycle. The possibihty of using trans enediynes in cycloaromatization reactions has the potential of dramatically increasing the scope of these reactions. 

Kovalenko and Alabugin reported that Cj-C cyclization of benzannelated enediynes with tetra-fluoropyridinyl (TFP) substituents at the terminal alkyne carbons forms indenes rather than fulvenes (Scheme 30.22). The radical/anionic Cj-Cj cyclization of enediynes represents a new type of cycloaromatization reaction—the cyclorearomatization process driven by rearomatization in the vicinity of the TS. This process is triggered via photoinduced electron transfer (PET) [35-38]. Expaimental work unambiguously established PET as the triggering event for the Cj-C cascade and the intermediacy of the second PET step in the indene-forming cascade [39]. Unlike the stable benzene product... 

Selective photochemical initiation is a viable option for inducing cycloaromatizations of enediynes and related compounds. Although increasing the efficiency of photochemical cycloaromatizations has been shown to be feasible, further research is needed to fully elucidate the electronic factors that control these processes. The presence of two orthogonal x-systems in alkynes is important for the understanding and control of photochemical cycloaromatization reactions since the two x-systems play complementary and important roles. 

The above section considered anionic cyclization of enediynes and related molecules in a one-pot process, in contrast to the known classical multi-step methods [260, 327-329]. One-step anionic cycloaromatization of enediynes is also an effective method for the synthesis of biarenes [328]. Depending on the reaction conditions and substrate structure, the process can go by two routes. For example, when a methoxide ion attacks the nitrile function of enediyne 3.691, there follows a cascade of cycloaromatization reactions by an anionic pathway, affording phenanthridinones 3.692 in 50% yield after chromatographic purification. On the other hand, reaction of enediyne 3.691 with sodium methoxide in methanol in the presence of two equivalents of tetra-butylammonium iodide at reflux leads to biaryl derivative 3.693 in 56-64% yield. Diynes 3.691 were synthesized in 40-98% yield by the Pd-catalyzed coupling reaction of 2-ethynylbenzonitrile 3.689 with 2-alkynyliodbenzenes 3.690 (Scheme 3.72) [327]. A similar procedure was applied to the cycloaromatization of a series of (Z)-l-aryl-3-decene-l,5-diynes 3.694 to produce biphenyls 3.695 in yields from 14% to 34% (Scheme 3.73) [327]. 

This cyclization occurs with only enediynes bearing a terminal alkyne and a nonbulky second alkynyl group (R = H, Me, Et). Substrates with a long internal alkyne group may react at a C-H bond of the substituent in the cycloaromatization reaction. 

Scheme 3.139 Base-promoted cycloaromatization reactions of enediynes 3.941.

Scheme 3.140 Cycloaromatization reactions of aryl-annulated enediynes 3.947 and 3.950.

The cycloaromatization of enediynes, having a structure like 1, proceeds via formation of a benzenoid 1,4-diradical 2, and is commonly called the Bergman cyclization. It is a relatively recent reaction that has gained importance especially during the last decade. The unusual structural element of enediynes as 1 has been found in natural products (such as calicheamicine and esperamicine) which show a remarkable biological activity... 

Other researchers have reported that the cyclization step is believed to be rate determining in the cycloaromatization (Bergman) reaction of aliphatic enediynes." It has been found that the rate-limiting step is hydrogen abstraction by benzannelation. This effect should be attributable to the faster rate of retro-Bergman cyclization from the aromatic ring-condensed 1,4-didehydrobenzene diradicals and/or the slower rate of hydrogen abstraction by them. 

The key transformation of 3-ene-l,5-diynes is a thermal rearrangement that was disclosed in the early 1970s by Darby et al. and Lockhart and Bergman, and which is commonly called the Bergman cycloaromatization (Scheme 19.3). In the classical Bergman experiment, the deuterated enediyne 6 was transformed into the isomer 7 or, in the presence of a hydrogen donor, into deuterated benzene 9. This reaction is believed to proceed through a diradical benzenoid species (a 77-benzyne). ... 

A series of thia enediynes have been recently prepared. The cycloaromatization was in this case promoted by an added base (EtsN). Moreover, the sulfone 56 was 1500-fold more reactive than the sulfoxide 55 and the sulfide was inert. These results indicate that in this case a different kind of cycloaromatization, the Saito-Myers reaction, is operating, as depicted in Scheme 19.14. This reaction is better illustrated in Section 19.5. 

Only few examples of bridged polycyclic enediynes belonging to this family are known and they cannot be assimilated to specific natural derivatives. However, they have the same safety catch, that is the absence of the double bond conjugated with the two triple bonds. In order to prevent cycloaromatization the double bond had to be introduced as the last step by a suitable reaction. This can be done by the action of a base, causing an elimination reaction as in compound 99 (when R = S02Me) ° or by a DDQ-mediated benzylic oxidation as in compound 100 (Scheme 19.26). The latter compound cycloaromatizes when heated at 80° C and shows some cytotoxicity with respect to rat embryo fibroblast cells. 

Shibuya, M. Wakayama, M. Naoe, Y. Kawakami, T. Ishigaki, K. Nemoto, H. Shimizu, H. Nagao, Y. Cycloaromatization of enediyne model compounds via a reaction cascade triggered by hydrolysis of the a-alkynylmalonates. Tetrahedron Lett. 1996, 37, 865-868. 

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