Steric effects in the thermal C 2 -C 6 diradical cyclization of enyne-allenes

The thermal reaction of enyne-allenes 1 carrying bulky substituents ( tert -butyl, trimethylsilyl, triisopropylsilyl) at the acetylene terminus uniquely leads to C 2 -C 6 cyclization products in high yields independent of other structural motifs at the enyne-allene ( e.g . benzannulation, substituents at allene). The thermal cyclization can also be set up in a continous process, the latter protocol explored with a Cellular Process Chemistry (CPC) reactor. Bulky groups ( e.g . t Bu, TMS, TIPS) at the alkyne terminus stabilize the enyne-allene against cyclization, while the exchange of a hydrogen by a methyl group at the inner locus of the allene unit destabilizes the enyne-allene. DFT calculations at B3LYP/6-311G** level suggest that the observed acceleration is mostly brought about by increasing the equilibrium amount of the reactive s-cis conformer.

Over the last few years theoretical investigations 8,12,14,[16][17][18]34 have largely contributed to our understanding of the switch from the Myers-Saito to the C 2 −C 6 cyclization and of the character of the fulvene diradical intermediate. Subtituent effects (aryl substituents at the acetylene, 12 ring size and ring strain, 14,[35][36][37] benzannulation, 16 oxy-anion substitution 15,17 ) on the kinetics and the thermodynamics and character of the diradical have been elucidated.In contrast, steric effects exerted by bulky substituents at the alkyne terminus or at the allene have received less attention although the first experimental observations go back several years.27 A recent study on oxyanion-accelerated cyclization of tert-butyl and silyl substituted enyne-allenes 15 unfortunately is less informative in this respect because the cyclization does not involve diradical but closed−shell zwitterionic intermediates.17 Stimulated by our earlier results 27a and a recent theoretical investigation by Engels et al. 38 we have prepared a series of enyne-allenes to probe the effect of steric bulk on the regioselectivity of cyclization.
ARKAT USA, Inc. Herein, we would like to detail our findings that bulky substituents at the alkyne terminus and at the inner allene locus 9 can be used to change dramatically the temperature for diradical cyclization.Whereas bulky groups at the alkyne terminus thermally stabilize the enyne-allene, the simple exchange of a H for a methyl group at the inner locus of the allene unit leads to destabilization.In addition, we also wanted to check which one of these two counter-running effects would dominate in controlling the thermal stability of enyne-allenes.

Results
Synthesis of enyne-allenes.So called "masked" enyne-allenes, in which the ene substructure is part of an aromatic system, 39 were readily available in a three or four step synthesis.For example Sonogashira couplings with o-bromobenzaldehyde or o-bromoacetophenone 40 afforded compounds 2-5 that were further reacted with an additional acetylide, either nBuC≡CMgBr or (PhC≡C) 2 AlH 2 Na, 41 to furnish the resultant propargyl alcohols 6a-h.Enyne-allenes 1d-i were obtained in a different manner.Propargyl alcohols 6b,e-h were first treated with acetic anhydride in presence of DMAP and NEt 3 to furnish the propargyl acetates 7d-h that were subsequently reacted with arylzinc or alkylzinc chloride in the presence of palladium(0) 27b,42 to yield enyne-allenes 1d-i in moderate yields.In contrast, the thermolysis of enyne-allenes 1e-f in presence of 20 eqs. of 1,4-CHD in toluene (1e: 110 °C, 4 h, 86%; 1e´: 110 °C, 14 h, 91%; 26b 1f: 80 °C, 4 h, 79%) produced only one C 2 −C 6 cyclization product.Due to a methyl group at the inner locus of the allene, 1g-i were not stable at room temperature.It was, however, possible to isolate their cyclization products 10g,h and 11i.Cyclohex-enyne-allenes 1j,k were isolated and subjected to thermolysis at reflux temperature in toluene (48 h) affording only formal ene-products 11j,k, while no formal Diels-Alder products were detected.
The implementation of the enyne-allene thermolysis into a continuous process was investigated by using a CPC systems (Cellular Process Chemistry Systems) microreactor. 43,44he high yield thermal conversion of enyne-allene 1e´ to 10e´ was chosen as a test case for a flow reactor process.Due to the slow reaction of 1e´ at 95 °C, significantly higher temperature had to be realized in the CPC microreactor as the dwell time in the mixing chamber of the microreactor at a flow rate of 0.4 mL min -1 does only allow for a reaction time of a few minutes.By using xylene at a high flow rate and high temperature (5 mL min -1 , 145 °C) full conversion of 1e´ to 10e´ could be effected in the CPC system.The yield was quantitative as judged from the pure compound, traces of the solvent had to be removed by chromatography finally furnishing 10e´ in 80% yield.
The structures of the isolated cyclization products were assigned on the basis of H,H and C,H COSY techniques, combined with mass spectroscopy.Thermolysis of enyne-allene 1d afforded a mixture of products 10d and 11d, which could not be separated using various chromatographic techniques (column chromatography, MPLC and HPLC).Fortunately, characterization of the structures was nevertheless possible by assigning the individual signals in the mixture in comparison with those of the known cyclization products 10l and 11l 45 (scheme 9, table 1) using 1 H NMR and high resolution mass spectroscopy.

Discussion
While the factors controlling the regioselectivity of monoradical cyclizations are rather well understood, 46 the role of substituents on the regioselectivity of diradical cyclizations is still a widely unexplored area.Ten years ago we disclosed that aryl substitution at the alkyne terminus does change the course of the thermal enyne-allene diradical ring closure from the Myers-Saito (C 2 -C 7 ) to the C 2 −C 6 cyclization mode.In our first interpretation, 9 this switch was ascribed to the possibility that the aryl group at the alkyne may stabilize the incipient vinyl radical center, 47 and as a consequence the TS of the C 2 −C 6 cyclization was expected to fall beneath that of the Myers-Saito cycloaromatization.However, later calculations by Engels 34 and Schreiner 14 clearly indicated that the TS of the C 2 −C 6 cyclization has no unpaired spin.Hence, substituent effects that lead to the stabilization of monoradicals may not be applicable for the TS of biradical cyclizations.An additional motif for a switch from the Myers−Saito to the C 2 −C 6 cyclization may arise from steric effects exerted by the substituents at the alkyne and allene termini, as they must experience a repulsive interaction as ortho-substituents (R---B in scheme 1) in the TS of the Myers−Saito process, resulting in a tangible destabilization of the TS.Indeed, enyne-allenes 1ak, all of them characterized by bulky groups at the alkyne terminus, exhibited exclusively C  9 in agreement with recent calculations. 38This provides the following order of reactivity: tBu < SiMe 3 < pTol.Formation of products 10 and 11 demonstrates that the switch from the Myers-Saito cyclization to the C 2 -C 6 cyclization cannot only be brought about by aryl substituents but systematically by sterically demanding groups at the alkyne terminus.27a This outcome is surprising at first in light of calculations by Engels et al., 38 since they predict a lower activation barrier for the Myers-Saito pathway in case of tert-butyl substituents at the alkyne terminus.Moreover, Wang et al. 48clearly demonstrated that bulky substituents at the allene terminus still allow for a cyclization along the Myers-Saito pathway.Apparently, a switch towards the C 2 -C 6 cyclization requires enough steric bulk at both the alkyne and allene terminus in order to sufficiently increase the ortho-repulsion in the Myers-Saito transition state, a result that is summarized in scheme 11.
ARKAT USA, Inc.It is instructive to look at the cyclization of enyne-allene 1d with a tert-butyl group at the alkyne, as both formal ene and formal Diels-Alder products are formed.The concurrent formation of 10d and 11d suggests a common intermediate for both processes.Interestingly, this contrasts to the exclusive formation of formal ene-products 10e,h found in the thermolysis of enyne-allenes 1e,h, having a similar terminal substitution at the allene as 1d and a TIPS group at the alkyne terminus.Due to intermolecular kinetic isotope effects observed in the thermolysis of enyne-allene 1e', 26b it is reasonable to assume a stepwise process for 1e.Hence, to rationalize the exclusiveness of the formal ene reaction pathway in presence of the bulky TIPS group, it is illustrative to have a look at the full mechanistic scheme.Once diradical 12e,h is formed, two reaction channels open up: either a radical recombination (ring closure reaction with subsequent rearomatization to the formal Diels-Alder product 11e,h) or a hydrogen abstraction to the formal ene-product 10e,h may take place.Since both steps should be irreversible, one has to assume that steric demands brought about by the groups at the alkyne and allene termini lead to a strong kinetic bias towards the hydrogen transfer reaction.Steric bulk at the inner allene locus.While the energetic situation of the C 2 -C 6 TS itself will clearly be influenced by steric and electronic effects conveyed by the adjacent groups, the activation energy should also be biased by ground state effects, as one has additionally to consider the equilibrium between the s-cis and s-trans conformers (Scheme 13).
As noted in the experimental section, enyne-allenes 1g-i are not stable at room temperature and undergo thermal C 2 -C 6 cyclization to products 10g,h and 11i.It is interesting to compare the former to the structurally similar, but isolable enyne-allenes 1e,f whose stability was investigated by DSC measurements.Exothermic peaks corresponding to the cyclization process were observed only far above room temp.(1e: 116 °C; 1f: 80 °C), in agreement with thermolysis conditions to form products 10e and 11f.Obviously, replacing a hydrogen by a methyl group at the inner allene locus leads to a dramatic thermal destabilization of enyne-allenes.DFT calculations on the ground state equilibrium (Scheme 13) using B3LYP/6-311G** suggest that by changing X = H to Me the s-cis conformer will be present in a much higher equilibrium concentration.If one considers that the s-cis conformer will additionally be activated by back-strain effects, then the fast reaction of enyne-allenes 1g-i becomes readily understandable.
Another comment is warranted on the initial concept presented in scheme 1. Apparently, the stabilizing effect of the TIPS group on the kinetics of enyne-allenes 1g-i is overruled by the much more pronounced thermal destabilization of enyne-allenes caused by Me substitution at the inner allene locus.
In summary, the thermal cyclization of enyne-allenes 1 carrying bulky substituents (tertbutyl, trimethylsilyl, triisopropylsilyl) at the acetylene terminus uniquely follows the C 2 -C 6 cyclization pathway independent of other structural motifs at the remainder of the enyne-allene (e.g.benzannulation, substituents at allene).The alternative Myers-Saito pathway is not available due to severe ortho-repulsion in the transition state.Bulky groups at the alkyne terminus thermally stabilize the enyne-allene, while the exchange of a hydrogen by a methyl group at the inner locus ARKAT USA, Inc.
of the allene unit severely destabilizes the enyne-allene due to increased amounts of the reactive cis-conformer present in the equilibrium mixture.

Scheme 9 .
Scheme 9.Comparison of unknown and well characterized cyclization45 products.

Cyclohexene derived enyne-allenes 1j,k were prepared starting from 8 via propargyl acetate 9. As for 1d-i, the
last step involved a palladium catalyzed addition of arylchlorozincate to the propargyl acetate 9.