The Effect of Conjugation on the Reactivity and Selectivity

clo[1.1.0]butanes activated with an aromatic ring responding unsubstituted analogs, or bicyclo[1.1.0]butanes hydrogen at the terminal position. Keeping in mind the radical mechanism of the ene and [2+2] reactions, the resonance stabilization of the high-energy diradical interme-

The present study demonstrates that bicy are much more reactive than their cor

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diate by aromatic groups in conjugated the bicyclo[1.1.0]butanes may contribute to the lowering of the energy of the diradical intermediate. In addition to transition state stabilization, the aro- matic group is responsible for the increased reactivity of the bicyclo[1.1.0]butane due to conju- gation of the central bond with the aromatic system. The effect of the conjugation on the elec- tronic structure of bicyclo[1.1.0]butane can be studied by an analysis of the parent molecule and its substituted analogues. The structures of the model systems were optimized at the AM1 level, and selected geometrical parameters and energies of the frontier orbitals are represented in Figure 22. HOMO LUMO _1.75 -10.28 1.65 -9.94 -0.24 -9.33 Me Ph C1C3 1.498 Å 1.503 Å 1.508 Å

]butanes and selected geometrical parameters. Structures were optimized at the AM1 level of theory and the energies are given at the same lev- el in eV

Figure 22. Frontier orbitals of bicyclo[1.1.0 .

Figure 23. X-ray structures of 120b and 123c.

Selected Geometrical Parameters for : C1C2 – 1.333 Å, C1C3 – 1.456 Å; : C1C2 1.494

Å, C1C3 – 1.517 Å, C1C4 – 1.500 Å.

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c of conjugation on the reactivity of the strained system can be gain

s- pond the ease of electron fransfer in the intermolecular reactions. In order to relate these observa- tions to

]butane ring. The dih

Substitution of the terminal position with an aromatic ring is responsible for raising the energy of the HOMO and shortening the energetic gap between the frontier orbitals as compared to the parent bicyclo[1.1.0]butane. The LUMO of 1-phenylbicyclo[1.1.0]butane is mainly lo- cated on the aromatic ring and is lower in energy compared to the unsubstituted analog. Addi- tional information about the influen e

ed by the analysis of the geometrical parameters of bicyclo[1.1.0]butanes. The parent mo- lecule or the 1-methylbicyclo[1.1.0]butane substituted with a simple alkyl group are characte- rized by similar bond lengths of the central bond whereas introduction of the phenyl group in- creased the bond length in 1-phenylbicyclo[1.1.0]butane to 1.51 Å. If the pericyclic reactions of bicyclo[1.1.0]butanes proceed via radical intermediates, the HOMO-LUMO gap would corre

our systems, 120b and 123b were crystallized from Et2O and their single-crystal struc-

tures were obtained using X-ray crystallography. Figure 23 depicts their molecular structures, including selected geometrical parameters.

The length of the central bond in 120b is 1.456 Å, whereas the same bond 123b is signif- icantly longer – 1.517 Å.30,35,351-353 _{Due to the symmetry of the orbitals forming the central bond,}

the aromatic ring must adopt a perpendicular orientation relative to the bicyclo[1.1.0

edral angle between aromatic ring and bicyclo[1.1.0]butane is 88.3o (98o) and a small deviation from the optimal 90o is caused most likely by the crystal packing forces. Furthermore, the interflap angles α defined as the angles between two cyclopropane rings for 120b and 123b are 117.8o and 122.4o, respectively. Since the reacting alkene approaches the bicyc- lo[1.1.0]butane from the inside of the ring, 123b characterized by a larger α is also more access- ible for the incoming alkene due to reduced steric interactions. A correlation between the length

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rrolidine ring.

ased on the observed stereochemistry, we considered four possible transition states where the allyl chain is oriented in boat (277a,c) or chair (277b,d) conformations (Scheme 87). Since the stereochemistry of the endocyclic double bond in cyclobutene is coupled with the orientation of the allyl chain (intramolecular transfer of the endo proton of bicyclo[1.1.0]butane), formation of only two diastereoisomer 278a and 278b was considered. Additionally, the nitrogen atom of the P,P-diphenylphosphinamide is known to adopt a tetrahedral geometry as can be de- of the central bond and α in bicyclo[1.1.0]butane has also been noted by Gassmann30 _{– elonga-}

tion of C1C3 bond, as a consequence of steric or electronic bias, results in larger α. Analysis of

the factors responsible for different reactivity of conjugated and non-conjugated systems indi- cates that the lower kinetic stability may be the major contributor to the observed reactivity of conjugated bicyclo[1.1.0]butanes.

Previous results show that a significant difference in the reaction pathway is observed if the allyl group is substituted with an aromatic ring. Conversion of the bicyclo[1.1.0]butane into the azatricyclo[5.1.11,5]nonane is faster, as might be expected for the systems that display a lower kinetic barrier due to a low-laying LUMO. The second step in these reaction is a recombination of stabilized radicals that is a consequence of the conformational preference of the allyl chain.

Diastereoselectivity in Ene and [2+2] Reactions. In addition to high chemoselectivity, intramolecular pericyclic reactions of bicyclo[1.1.0]butanes show very high diastereoselectivity. Because only electronic factors control the ene vs. [2+2] selectivity, the discussion of the diaste- reoselectivity of the pericyclic reactions of allyl amides is only presented for the ene reaction. A parallel stereochemical analysis can be carried out for the [2+2] reactions as the products of both pericyclic reactions possess analogous stereochemistry around the py

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duced from the analysis of crystal structures (e.g. 242) as well as from NMR spectra of the amides that do not show the presence of rotamers at room temperature. Given that the bulky amide group occupies a pseudo-equatorial position, the α-substituent R is forced to accept an e the reacting alkene approaches the strained system from the inside of the bicyclo[1.1.0]butane. The pr

ot only the methyl group experiences severe steric interactions with the methy- lene gr

axial orientation so that the ene reaction must proceed via the boat-type conformer 277a wher

eference of the allyl chain to adopt the axial conformation is a consequence of the steric interaction between R and the methylene group of the allyl chain that become more severe in the transition state. However, if R is predominantly in an equatorial form (277a or 277d), this type of interaction is diminished and the allyl chain would exist in a more stable s-trans form leading to formation of the observed product 278a. The presented model accounts also for a lack of dif- ference in the selectivity of the reaction of (E)- and (Z)-alkenes since the terminal substituents are located away from the methylene groups and the vinyl carbon undergoes a pyramidalization in the transition state orienting the alkyl groups away from the reacting bicycle. However, the high selectivity (>95:5) was significantly reduced in the reaction with 2-methylallyl amide (Scheme 73). N

oups of the bicyclo[1.1.0]butane, but a similar size of the Me and CH2 groups leads to a

low discrimination of the two possible conformers 277a and 277b.

N R Ph₂(O)P 277a N Ph2(O)P Ar R 278a major Ar R _R 277c N Ar R Ph₂(O)P R

Ar 119 N )P Ar Ph2(O R N 277b R 278b minor Ar Ph2(O)P R _R N R Ph2(O)P R 277d

Scheme 87. Mechanistic rationale for the diastereoselctivity in the ene reaction of allyl amides.

Finally, the reversal of the diastereoseselctivity in the intramolecular reactions of propar- gyl amides is at first somewhat surprising. Also, the high level of transfer of the stereochemical information across the pyrrolidine ring is very interesting since the alkyne sp hybridized carbon

in bicyclo[1.1.0]butane. The bicyclo[1.1.0]butyl ring can, however, be tilted by the α- substitu

273b into the orients the propargyl chain into a conformation where the triple bond parallels the central bond

ents, thus preexposing one of the methylene groups towards the reaction with the propar- gyl group. Although the crystal structures of 120b and 123b did not provide a conclusive support for a well-defined conformer (at least in the solid state), the conformational bias of the bicyc- lo[1.1.0]butane may play an important role in determining the stereochemistry of the newly formed bonds.

Two conformers of the N-propargyl bicyclo[1.1.0]butane are depicted in Scheme 88. Like in the case of allyl group, the axial orientation of R substituent in 279a caused by the amide moiety led to formation of a stabilized radical that subsequently underwent a fast proton transfer reaction with a more accessible methylene group. The crystal structure of 244a shows that the t- Bu group is oriented in axial position whereas the P,P-diphenylphosphinyl group is in an equa- torial orientation, thus supporting the hypothesis that even a bulky group can be accommodated into an axial orientation. Based on this analysis, the configuration of the cyclobutene ring is de- termined by the axial substituent which forces one of the methylene groups in

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proxim y of the vinyl radical. The stereochemistry of the exocyclic double bond is a conse- quence of the intramolecular proton transfer.

it N R N R _Ar 279a R R 280a major Ph₂(O)P Ph2(O)P Ar N R _Ar R 279b Ph2(O)P

Scheme 88. Mechanistic rationale for the diastereoselctivity in the ene reaction of propargyl amides.

argyl amides (Scheme 89). We envisioned that bicyc- [1.1.0]butane 281 would react with propargyl bromide to afford the ene product that subse- quently undergoes a 4e-electrocyclic opening followed by 6e-closure. The unsaturated tetrahy- droisoindole 282 would be then treated under thermal conditions with an activated alkyne that should induce a Diels-Alder/retro-Diels-Alder reaction sequence to afford the desired polysubsti-

tuted benzene derivative 28 ituted with groups

f similar electronic and steric properties,354 a low torquoselectivity may be envisioned resulting the formation of a mixture of (E)- and (Z)-isomers during the initial opening step. In order to test the feasibility of this reaction sequence, conditions for the conversion of bicyc- lo[1.1.0]butane 282 into the tetrahydroisoindole derivative had to be established.