Myers-Saito and Schmittel Cyclization

Limited thermochemical data are available for these two cyclization variants. Myers examined the thermolysis of (4Z)-l,2,4-heptatrien-6-yne (59) to give the diradical intermediate 61, which then abstracts hydrogen atoms from 

4-cyclohexadiene to give toluene. For this parent Myers-Saito cyclization, A.lfi = 21.8 0.5 kcal mol and = -11.6 1.5 eu. The Schmittel cyclization 

TABLE 4.12 Computed Energies (kcal mol for the Prototype Myers-Saito (59 61) and Schmittel (55 61) Cyclizations 

Method Myers- TS -Salto Product Schmittel TS Product  

In the experimental thermolysis of 59, no Schmittel product was detected. Computational estimates for the activation enthalpy for the Schmittel cyclization of 59 range from 31 to 35 kcal mol , significantly higher than the barrier for the Myers-Saito cyclization of 20-22 kcal mol . Furthermore, the Schmittel cyclization is predicted to be endothermic (AH = -I-IO - -I-19 kcal mol ), while the Myers-Saito cyclization is exothermic. Therefore, the Myers-Saito cyclization of 59 is both theamodynamically and kinetically favored over the Schmittel reaction. 

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Product stabilization is much more pronounced when the enediyne or ene-yne-allene starting materials are not already part of an aromatic system, since forming an aromatic system constitutes a much higher degree of stabilization than expanding an aromatic system (Fig. 24). Conjugation of the radical center provides additional stabilization to the 71-radical formed by the Myers-Saito and Schmittel cyclizations. 

The switch from Myers-Saito to Schmittel cyclization occurs with phenyl or bulky groups attached to the alkynyl position of the enyne-allene. Engels compared the Myers-Saito and Schmittel cyclization for the parent reaction with R=H, phenyl, and f-butyl (Fignre 4.15) at B3LYP/6-31G. The activation enthalpy for the Myers-Saito reaction increases from 21.4 kcal mol" when R=H to 26.7 kcal mol" for R=phenyl, and 27.9 kcal mol for R=f-butyl. Conversely, the phenyl group decreases the activation enthalpy for the Schmittel reaction from 29.0 to... 

In an analogy to the relationship between Myers-Saito and Schmittel cyclization, Schreiner proposed another cyclization path of an endiyne, C, -Cj, as an alternative to the Cj-Cg Bergman cyclization (Figure 4.17). For the case where the terminal group is a hydrogen atom (38 40), the barrier is 27.1 kcal mol ... 

Lipton et al. noticed that the switching of cyclization pathways observed by Schmittel takes place due to a combination of effects. The calculations of the energies of diradicals formed by Myers-Saito and Schmittel cyclization indicate that benzannulation of the eneyne-allene as in 15 plays a significant role in promoting C2-C6 cyclization. The energy of diradicals for the benzannulated system is 10.5 kcal/mol less as compared to those for the parent monocyclic diradicals (16 vs. 13, and 17 vs. 14). ... 

Competition between the Myers-Saito and Schmittel cyclization is also observed for phosphorus-substituted allenes. Terminal alkynes 18 give naphthalene derivatives 19. 

The photochemical cyclization of the Myers-Saito and Schmittel cyclization of enyne was described much later than the Bergman... 

However, for the cyclization of the oxyanion substituted enyne-allene, substitution causes both the Myers-Saito and Schmittel cyclizations to switch their product formation preferences from diradicals to polar intermediates, as established by The stabilization of the oxyanion-... 

For enyne-cumulenes, the thermal Myers-Saito is favored over the C -C cyclization [421]. Replacing the terminal carbon atom in a cumu-lene by a heteroatom decreases the activation barrier for both Myers-Saito and Schmittel cyclizations, for example, by approximately 7.9 and 16.5 kcal/mol in the case of oxygen (3.958, B = O) and by 6.0 and 12.2 kcal/mol for nitrogen (B = N) (Scheme 3.143) [421]. The effect is even greater when both terminal carbon atoms are replaced by the heteroatoms, as in the following examples. The barriers are decreased by approximately 14.3 and 23.7 kcal/mol when A = N and B = O and by 10.5 and 18.0 kcal/mol when A — B — N. At present, nonstatistical dynamic effects for most of these systems are unknown but Schmittel et al. [420a] have published studies on these effects. 

Lu, Y.-X., Zou, J.-W., Wang, H.-Q. and Yu, Q.-S. (2005) Myers-Saito and Schmittel cyclizations of enyne-(hetero)-l,2,3-trienes a DFT study on the structure-reactivity relationship.of Molecular Structure THEOCHEM., 732(1-3), 233-238. Hopf, H. and Kruger, A. (2001) Synthesis of cyclo-1, 3-dien-5-ynes. Chemistry—A European Journal, 7(20), 4378-4386. 

Schreiner and Prall examined a series of cyclic enyne-allenes (67) and find that ring strain lowers the barrier for both the Myers-Saito and Schmittel cycUzations. The lowest barrier and most exothermic reaction is found for the Myers-Saito cycUzation of the nine-membered ring. Cramer and Squires examined the Myers-Saito cycUzation of cyclonona-l,2,3,5-tetraen-7-yne (68) using the BD(T)/cc-pVDZ method. The activation enthalpy for 68 is about 10 kcal mol less than for 59, which they attribute to ring strain. They note that the cyclization of 68 leads to a [Pg.254]

Masch, P.W., Remenyi, C., Helten, H. and Engels, B. (2002) On the regioselectivity of the cyclization of enyne-ketenes a computational investigation and comparison with the Myers-Saito and Schmittel reaction. Journal of the American Chemical Society, 124(8), 1823-1828. 

This reaction is related to the Myers-Saito Cyclization and Schmittel Cyclization. 

Schmittel, M., Mahajan, A.A. and Bucher, G. (2005) Photochemical Myers-Saito and C -C cyclizations of enyne-allenes direct detection of intermediates in solution. Journal of the American Chemical Society, 127(15), 5324-5325. 

The most obvious effect on cycloaromatization, as the name implies, is the formation of an aromatic system. By delocalizing electrons in an aromatic ring, the product gains a high degree of stability, which is reflected in the small endothermicity of the Bergman cyclization and the exothermicity of the Myers-Saito cyclization. Since the Schmittel and Schreiner cyclizations are not true cycloaromatization reactions per se, they do not have the beneficial effect of the formation of an aromatic system and are therefore much are more endothermic than their counterparts. 

Many of the allenic parent systems mentioned in Schemes 5.1-5.3 have been of interest in mechanistic studies. Thus, the Z-isomer of 27 can either cyclize by the Myers-Saito route to the aromatic diradical 339 or under the so-called Schmittel cyclization conditions to yield the fulvene diradical 338 (Scheme 5.51) [141], both processes being discussed thoroughly in Chapters 13 and 20. 

The ability of (Z)-l,2,4-heptatrien-6-ynes (enyne-allenes) and the benzannulated derivatives to undergo cyclization reactions under mild thermal conditions to produce biradicals has been the main focus of their chemical reactivities [1-5]. With the development of many synthetic methods for these highly conjugated allenes, a variety of biradicals are readily accessible for subsequent chemical transformations. Cyclization of the enyne-allene 1 could occur either via the C2-C7 pathway (Myers-Saito cyclization) leading to the a,3-didehydrotoluene/naphthalene biradical 2 [6-10] or via the C2-C6 pathway (Schmittel cyclization) producing the fulvene/benzofulvene biradical 3 [11] (Scheme 20.1). 

This (7,o-diradical lacks the benzylic radical stabilization found in 61, and therefore cyclization of 68 is less exothermic than that of 59. Musch and Engels note that the Schmittel cyclization (AG (CCSD(T)/cc-pVDZ) = 18.6 kcal mol ) of 68 is favored over the Myers-Saito cyclization (AG (CCSD(T)/cc-pVDZ) = 21.1 kcal mor ). This is opposite to the case for the open chain analog 69, where the barrier for Myers-Saito cyclization is 9.7 kcal mol below the barrier for the Schmittel cyclization. However, fusing a cyclopentane ring with the eneyne-butatriene (70) favors the Myers-Saito cyclization over the Schmittel cyclization, AG (UB3LYP/6-31G(d) = 22.2 versus 22.8 kcal mol . Since neocarzinostatin chromophore follows the Myers-Saito pathway exclusively, nature has carefully balanced many factors in creating this system. 

Schmittel, M. Keller, M. Kiau, S. Strittmatter, M. A surprising switch from the Myers-Saito cyclization to a novel biradical cyclization in enyne-aUenes formal Diels-Alder and ene reactions with high synthetic potential, Chem. Eur. J. 1997, 3, 807-816. 

Schreiner, P. R. Prall, M. Myers-Saito versus —C ( Schmittel ) cyclizations of parent and monocyclic enyne-aUenes challenges to chemistry and computation, J. Am. Chem. Soc. 1999,121, 8615-8627. 

Stahl, F. Moran, D. Schleyer, P.V. Prall, M. Schreiner, P.R. Aromaticity of the Bergman, Myers-Saito, Schmittel, and directly related cyclizations of enediynes. J. Org. Chem. 2002, 67, 1453-1461. 

For the case of oxyanion, two factors were found to play a role. The size and nature of the ring in which enyne-allene is embedded as well as the steric bulk of the substituents of the allene and alkyne affects the competition between the two cyclizations. The Myers-Saito product is not observed for alkynes with the trimethylsilyl substituent even for cyclohexane-annulated compounds. However, when the alkynyl substituent is changed to phenyl, the resulting relief of steric strain in the C2-C7 transition state permits the cyclization of 25 to occur at low temperature and yields the styrene derivative 26 The cyclopentane-annulated compounds give the Myers-Saito product, or fail to react when a bulky silyl substituent is present at the alkynyl terminus. In contrary, the benzene-annulated compounds undergo rapid the Schmittel cyclization dominantly or exclusively. The cyclizations of oxyanion-substituted enyne-allenes studied in the cited article occured at far lower temperatures than the analogous cyclizations of neutral enyne-allenes. The presence of the oxyanion presumably stabilizes, by resonance, the diradical in the transition state. ... 

An aza-variant of the cycloaromatization of propargyl azaeneynes, such as 50, via azaenyne-allenes 51, has been reported by Kerwin et al. The aza-Myers-Saito cyclization provides a,5-didehydro-3-picoline diradical 52, which affords either polar or radical-based trapping products 53 and 54, depending on the reaction solvent. The facility of the aza-Myers-Saito cyclization relative to the parent Myers-Saito cyclization was predicted based on DFT calculations these results also indicate that the corresponding C2-C6 (aza-Schmittel) cyclization, although disfavored in the case of 51, is... 

These studies were extended for the synthesis and DNA cleavage chemistry of pyridinium aza-enediynes (2-alkynyl-iV-propargyl pyridinium salts). The 2-alkynyl-iV-propropargyl pyridinium triflate 55 cleaves DNA by hydrogen atom abstraction from the deoxyribose backbone, presumably tlu ough the intermediacy of diradicals formed by either aza-Myers-Saito or aza-Schmittel cyclization. Attempts to identify trapping products of these intermediates were unsuccessful. ... 

Other methods of forming six-mem bered rings include the Myers-Saito C -C cycloaromatization of enyne-allenes (Scheme 3.4) [25, 27, 29]. A possible pathway of enyne-allene 3.430 involves a,3-didehydrotoluene diradical 3.431. The acyclic enyne-allene 3.430 (Z-1,2,4-heptatrien-6-yne) undergoes the Myers-Saito cyclization at 37°C with ti/2 = 24 hours and at 75°C with tj/2 = 30 minutes to afford toluene [29]. The alternative Schmittel C -C cycloaromatization via diradical 3.432 is discussed in Section 3.3.3. 

Even in 1989 the mechanism of reactions concerning enyne-allene and cumulene-enyne bond systems, known as the Myers-Saito cycloaromatization, had been thoroughly investigated [3,17,18,267,268]. Thermal cycloaromatization of the enyne-allene 3.535 (Myers-Saito C -C ) to give naphthalene 3.536 competes with the Schmittel C -C enyne-allene cyclization to give indene 3.537 [18] (Scheme 3.34). Since the discovery of these cyclizations, they have been intensively studied, in particular. 

Thermal and Photochemical C -C Cyclization of Enyne-Allenes Switching the Regioselectivity from C -C (Myers-Saito) to C -C (Schmittel) Cyclization Mode... 

Earlier in this chapter different ways of cyclizing enyne-allenes were considered (Scheme 3.4). Depending on the sites of the newly formed carbon-carbon bond, they are classified as C -C (Schmittel) and C -C (Myers-Saito) cyclizations. Schmittel and coworkers [18] performed modern computational analysis of the cyclization mechanism and estimated various effects on the regioselectivity. 

Like the case of Bergman and Myers-Saito cyclizations, the geometry of the transition state of the C -C (Schmittel) cyclization of enyne-allenes is close to the reaction product but its electronic state is close to... 

The Myers-Saito reaction of nonsubstituted enyne-allenes is kinet-ically and thermodynamically favored as compared to the Schmittel reaction while the concerted [4+2] cycloaddition is only 1.32 kcal/mol higher than the C -C cyclization and more exothermic (Ar = —69.38 kcal/mol). For the substituent = CH3 and Bu, the increasing barrier of the C -C cyclization is higher than that for the C -C cyclization because of the steric effect, so the increased barrier of the [4+2]... 

Scheme 3.143 Schmittel and Myers-Saito cyclizations of enyne-(hetero) cumulenes [18, 421],...

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