2+2 photocycloaddition

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[2+2] Photocycloaddition is the combination of an excited state enone with an alkene to produce a cyclobutane. Although the photochemical concerted [2+2] cycloaddition is allowed, the reaction between enones and alkenes is stepwise and involves discrete diradical intermediates.[1]

Introduction

In 1908, Ciamician discovered that upon exposure of carvone to sunlight for one year, carvone camphor resulted.[2] After this finding was confirmed in the 1950s, a flurry of research identified the synthetic value of the photochemical [2+2] cycloaddition between enones and alkenes for the construction of complex molecular frameworks.[3][4] In spite of the stepwise, radical mechanism, both stereoselective intra- and intermolecular variants have emerged. Cyclic enones must be used to prevent competitive cis-trans isomerization.

[2+2] Photocyclization may produce two constitutional isomers, depending on the orientation of substituents on the alkene and the enone carbonyl group. When the enone carbonyl and substituent of highest priority are proximal, the isomer is termed "head-to-head." When the enone carbonyl and substituent are distal, the isomer is called "head-to-tail." Selectivity for one of these isomers depends on both steric and electronic factors (see below).

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Prevailing Mechanism

The mechanism of [2+2] photocyclization begins with photoexcitation of the enone to a singlet excited state. The singlet state is typically very short lived, and intersystem crossing to the triplet state then occurs. At this point, the enone forms an exciplex with the ground-state alkene, eventually forming a triplet diradical intermediate. Spin inversion to the singlet diradical must occur before closure to the cyclobutane product can take place.[5]

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Scope and Limitations

The regiochemistry of the reaction is controlled primarily by two factors: steric interactions and electrostatic interactions between the excited enone and alkene. Excited enones exhibit polarity reversal with respect to the ground state, so that the β carbon possesses a partial negative charge. In the transition state for the first bond formation, the alkene tends to align itself so that the negative end of its dipole points away from the β carbon of the enone.[6]

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Steric interactions encourage the placement of large substituents on opposite sides of the new cyclobutane ring.[6]

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If the enone and alkene are contained in rings of five atoms or less, double-bond configuration is preserved. However, when larger rings are used, double bond isomerization during the reaction becomes a possibility. This energy-wasting process competes with cycloaddition[7] and is evident in reactions that yield mixtures of cis- and trans-fused products.

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Diastereofacial selectivity is highly predictable in most cases. The less hindered faces of the enone and alkene react.[8]

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Intramolecular [2+2] cyclizations may give either "bent" or "straight" products depending on the reaction regioselectivity. When the tether between the enone and alkene is two atoms long, bent products predominate due to the rapid formation of five-membered rings.[9] Longer tethers tend to give straight products.[10]

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The tether can also be attached at the 2 position of the enone. When the alkene is tethered here, bulky substituents at the 4 position of the enone enforce moderate diastereoselectivity.[11]

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A major difficulty of [2+2] photocycloadditions is the possibility of side reactions associated with the diradical intermediate or excited enone. These side reactions can often be minimized by a judicious choice of reaction conditions.

Synthetic Applications

[2+2] photocyclization has been used to synthesize organic compounds with interesting topology. It is used as a key step, for instance, in a synthesis of cubane.[12] Favorskii rearrangement established the carbon skeleton of cubane, and further synthetic manipulations provided the desired unfunctionalized target.

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Experimental Conditions and Procedure

Typical Conditions

A wide variety of solvents can be used, although solvents should be deoxygenated to prevent radical reactions with oxygen. Acetone is a useful solvent, because it can serve as a triplet sensitizer. Olefin-free hexanes (obtainable by treating bulk hexanes with sulfuric acid overnight, then washing with saturated sodium bicarbonate) may be useful for intramolecular reactions. Reaction temperature is not critical, although regioselectivity and stereoselectivity may depend on temperature. The wavelength of light employed is also important, as the cycloadduct must not absorb photons and engage in photochemistry of its own. For intermolecular reactions, an excess of the alkene should be employed to avoid competitive dimerization of the enone.

Example Procedure[13]

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A solution of 5-fluorouracil (0.39 g, 3 mmol) and 4 mL of methylenecyclopentane in 150 mL of acetone was placed in a standard photochemical reactor equipped with an immersion well, Corex filter sleeve, and a 450-W Hanovia mercury lamp. The solution was irradiated for 2 hours and the solvent was removed. The residue was recrystallized from ethyl acetate to give 0.47 g (76%) of the photoadduct, mp 265–266°. IR 1700 cm−1. 1H NMR (DMSO-d6) δ 1.0–1.9 (8H, br m), 2.0–2.6 (m, partially obscured by DMSO), 3.95 (1H, d, J = 21 Hz), 8.02 (1H, s), 10.44 (1H, br s). Anal. Calcd for C10H13N2O2F: C, 56.6; H, 6.2; N, 13.2. Found: C, 56.7; H, 6.2; N, 13.2.

References

  1. Crimmins, M. T.; Reinhold, T. L. Org. React. 1993, 44, 297. doi: (10.1002/0471264180.or044.02)
  2. Ciamician, G.; Silber. P. Ber. 1908, 41, 1928.
  3. Buchi, G. M.; Goldman, I. M. J. Am. Chem. Soc., 1957, 79, 4741.
  4. Cookson, R. C.; Crundwell, E.; Hudac, J. Chem. Ind., 1958, 1003.
  5. Loutfy, R. O.; DeMayo, P. Can. J. Chem., 1972, 50, 3465.
  6. a b Corey, E. J.; Bass, J. D.; LeMahieu, R.; Mitra, R. B. J. Am. Chem. Soc., 1964, 86, 5570.
  7. DeMayo, P.; Nicholson, A. A.; Tchir, M. F. Can. J. Chem., 1969, 47, 711.
  8. Baldwin, S. W.; Crimmins, M. T. J. Am. Chem. Soc., 1982, 104, 1132.
  9. Tamura, Y.; Kita, Y.; Ishibashi, H.; Ikeda, M. J. Chem. Soc. D., 1971, 1167.
  10. Coates, R. M.; Senter, P. D.; Baker, W. R. J. Org. Chem., 1982, 47, 3598.
  11. Becker, D.; Haddad, N. Tetrahedron Lett., 1986, 27, 6393.
  12. Eaton, P. E.; Cole, T. W., Jr. J. Am. Chem. Soc., 1964, 86, 3157.
  13. Wexler, A. J.; Balchunis, R. J.; Swenton, J. S. J. Org. Chem. 1984, 49, 2733.