Arynes reactions

The question of the occurrence of cine or aryne substitution in some of these reactions has been raised but not answered adequately. The normal product, 2-methoxynaphthalene was shown to be formed from 2-chloronaphthalene and methoxide ion, and the normal 6- and 8-piperidinoquinolines were proved to be products of piperidino-debromination of 6- and 8-bromoquinolines, all in unspecified yield. More highly activated compounds were then assumed not to react via the aryne mechanism. Even if the major product had been characterized, the occurrence of a substantial or predominant amount of aryne reaction may escape notice when strong orientation or steric effects lead to formation of the normal displacement product from the aryne. A substantial amoimt of concurrent aryne reaction may also escape detection if it yields an amount of cine-substituted material easily removed in purification or if the entire reaction mixture is not chromatographed Kauffman and Boettcher have demonstrated that activated compounds such as 4-chloropyridine do indeed react partially via the aryne mechanism (Section I,C,1). 

It seems that the repulsive steric interactions play a more dominant role in regioselectivity of aryne reactions than is sometimes realized. In fact, it has been argued that in nucleophilic addition to arynes, the transition state is reached early, while the incipient bond is still very much extended. Consequently, steric effects were considered not to be of great importance.80 81 It should, however, be noted that the dehydro bond orbitals are so oriented that the optimal approach trajectory for the nucleophile lies in the... 

Adejare, A. Miller, D. D. Synthesis of fluorinated biphenyls via aryne reaction. Tetrahedron Lett. 1984, 25, 5597-5598. Skowronska-Ptasinska, M. Verboom, W. Reinhoudt, D. N. Effect of different dialkyl-amino groups on the regioselectivity of lithiation of O-protected 3-(dialkylamino)phenols. 

With the discovery of benzyne formation by pyrolysis of phthalic anhydride, a new field was opened for the investigation of aryne reactions at high temperatures. A first concern was to determine the generality of aryne formation from aromatic acid anhydrides. Such syntheses could be of considerable significance because of the enormous quantities of aromatic mono- and polyanhydrides available from petroleum aromatics by oxidation. 

During a study of several arynic reactions in aprotic solvents9, i0 we made some curious observations summarized in Scheme 2. 

It is clear that complex bases strongly favor arynic reactions. Moreover, NaNH2-/-BuONa always gives better overall yields and higher ratios monocondensation/ dicondensation than NaNH2. Note that the chlorine dance is nearly always encountered with 70. 

On the other hand, arynic reactions are also of interest in the synthesis of benzocyclenones substituted on the aromatic ring by an alkyl group in the ortho position of the carbonyl group. In these syntheses, ortho alkyl bromobenzenes must be used and arynic condensation intermediaries are of the 108 type ... 

Continuing in the condensations of nucleophilic complex base NaNH2-ketone enolates we have to note that, as in arynic reactions, there is a particular behaviour of aromatic ketone enolates. Thus, besides the usual reactions, we found101 that internal cyclisation may happen as pictured in Scheme 61. 

It is noteworthy that at the difference of what we met for arynic reactions, alcohols with a strained ring are isolated with cyclooctanone and with aliphatic ketones. Since the obtaining of these alcohols by us for the first time, a synthesis by photolysis of cyclenones has been published102. However, this last method seems, for the present time, much less general and above all much less stereoselective. 

One of the two reaction types which dominate the synthetic utility of arynes as reactive intermediates is cycloaddition. Cycloadditions can be subdivided into several categories. For example, benzynes undergo [4+2] and [2+2] cycloadditions as well as 1,3-dipolar cycloadditions, the ene reaction, and miscellaneous others. These reactions may occur in an inter- or intramolecular mode. Further, multiple and tandem aryne reactions can be used for multiple-bond construction in a single step. Each of these reaction types, as well as a few miscellaneous reactions, is discussed in the following sections. 

A particularly interesting feature of the diene-aryne reaction is revealed when 2,5-dimethylthiophene (410) is used as the trapping agent during the FVT of the anhydride 229." " In addition to the 4,7-dimethylthianaphthene (412)... 

In a sense, the difficulty of generating five-membered hetarynes could be totally discussed in terms of kinetic factors. If these arynes are of very high energy content due to whatever electronic or geometric effect, then their rate of formation will be slow and other reactions will have the opportunity to intervene before aryne formation can occur. In this section two types of kinetic effects on potential five-membered hetaryne precursors will be discussed, those which stabilize toward aryne formation and those which labilize toward non-aryne reactions. 

As the intermolecular multicomponent reactions, three-component cycloaddition reactions (21.2 [2+2-1-2] cycloaddition and 21.3 [3+2+1] cycloaddition) and two-component cycloaddition reactions (21.4 [4+2] cycloaddition) are described. As the intramolecnlar single-component reactions, cycloaromatization reactions (21.5 intramolecular hydroarylation of alkynes and cychzation via transition metal vinybdenes) are described. Aromatic ring constrnction reactions involving aryne reactions (Chapter 12), rearrangement reactions (Chapters 16 and 18), metathesis reactions (Chapter 17), and coupling reactions (Chapters 19 and 20) are described in these different chapters. 

A straightforward synthesis of benzoxazinones has been achieved by Yoshida, Kxmai, and coworkers by the MCR between arynes, aromatic imines, and CO2 [74]. This is a rare example of incorporating CO2 in aryne reactions. This reaction was initiated by the nucleophilic attack of aromatic imines to arynes generating the 1,3-zwitterionic intermediate 102, which was intercepted by CO2 generating the intermediate 103 followed by the cyclization to deliver... 

SCHEME 69 Synthesis of polysubstiluted chromones by aryne reaction with allenoic acids [95]. 

K.M. AUan, C.D. Gilmore, B.M. Stoltz, Benzannulated bicycles by three-component aryne reactions, Angew. Chem. Int. Ed. 50 (2011) 4488 91. 

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