Patai S., Rappoport Z. 1997 The chemistry of functional groups. The chemistry of double-bonded functional groups / 1281 135

22. Radical anions and cations derived from CDC, CDO or CDN groups 1291

In an extremely clever study, Tanner and collaborators have estimated rate constants for fragmentation of a series of ˛-haloacetophenones41. These rate constants were determined by the intramolecular competition outlined in Scheme 9. Radical ion 4 was generated by reaction with 1,3-dimethyl-2-phenylbenzimidazoline (DMBI). The rate constant ratio (k1/k2) was determined by the relative yields of the two products 5 and 6. With the assumption that the ˛-substituent does not affect the magnitude of k2, k2 was assumed to be equal to 3 ð 107 s 1 (which had been measured earlier by Wipf and Wightman for the dehalogenation of p-bromoacetophenone radical anion)42.

SCHEME 9

Some of the results of these experiments are summarized in Table 2. The results reveal that the rate increases as the basicity of X decreases. For X D Br or Cl, it is assumed that fragmentation occurs via dissociative electron transfer, i.e. fragmentation and electron transfer is concerted; the radical anion Ph(CDOž )CH2X has no significant lifetime.

Mathivanan, Johnston and Wayner examined the effect of substituents on the rates of cleavage of ˛-phenoxyacetophenone radical anions (equation 6)43. In this study, the radical anions were generated by trapping solvated electrons produced by laser-induced photoionization of 4,40 -dimethoxystilbene in CH3CN and DMF. Their results show that the fragmentation rate is enhanced when Y is electron withdrawing, but retarded when X is electron withdrawing.

Dehalogenation of ˛-substituted ketones and esters via radical anions has also been examined for its synthetic utility. As reported by Molander, Sml2 is an especially effective reagent for this transformation (equation 7)44. Yields are typically high (70 100%) for X D Cl, OAc, OSiMe3, OCOCH2Ph, OTs, etc.). A mechanism for the reduction of esters (Scheme 10) has been suggested.

a Reference 41.

Reductions of ˛-bromo ketones and esters can also be accomplished in a free radical chain process (Scheme 11) using 2-propanol or 2-methyldioxolane45. The 2- hydroxypropyl radical is an effective reducing agent with E° D 1.11 V vs Ag/AgCl. An application of this chemistry to yield spiro- -lactones has been reported (Scheme 12)46.

(ii) Long-range cleavage involving >CDOž . The presence of the >CDOž functionality may induce cleavage of distant C X bonds, presumably via intramolecular electron transfer. Examples include dehalogenations of ring-substituted benzophenone and acetophenone radical anions which yield aryl radicals. Results from a recent study from the Tanner group are summarized in Table 341. General trends emerge from these results such as leaving group abilities (l > Br > Cl ; p-X > m-X). Because of extended conjugation in ArCOPhž , these radical anions fragment at a rate one to two orders of magnitude slower than ArCOCH3ž .

DIMER− 2

(ion-pair) Cl

SCHEME 13

involve ketyl anion intermediates49.

Li

NH3

(8)

O O

There has been considerable interest in ring opening of cyclopropyl-containing ketyl anions from both a mechanistic and synthetic viewpoint. Cyclopropyl substituents are often

1296

TABLE 4. Effect of substituents on the rate of ring opening of cyclopropylcarbinyl radicals and related radical anions

22. Radical anions and cations derived from CDC, CDO or CDN groups 1297

equilbrium constant favoring the ring-closed form (Keq D 2 ð 10 8; k0 D 2 s 1)30. It was suggested that the relief of cyclopropane ring strain upon ring opening did not sufficiently compensate for the loss of resonance energy of the highly delocalized ketyl anion.

In a subsequent study, it was found that placement of radical stabilizing substituents on the cyclopropane ring partially compensates for the loss of resonance energy (by stabilizing the radical portion of the resulting distonic radical anions), but the rate constants for ring opening were still substantially slower than that of the analogous cyclopropyl carbinyl free radicals (Table 4)52.

Moreover, it appears that phenyl substitution on the cyclopropane ring does not solve the problem of reversibility. Tanner demonstrated that the radical anion derived from (C)-trans-1-benzoyl-2-phenylcyclopropane (9) isomerizes to (š)-trans and (š)-cis (presumably via ring-opened radical anion 10), providing definitive evidence that even for the substituted systems, ring opening is reversible. Rate constants for ring opening and closing were reported (Scheme 16).

A substrate which appears to solve many of these difficulties has recently been reported. The radical anion generated from spiro compound 12 undergoes ring opening to 3° distonic radical 14 with a rate constant >107 s 1 (equation 9)55. For this system, relief of cyclopropane ring strain and an increase in resonance energy provide the thermodynamic impetus for ring opening ( H° for ring opening of this radical anion is estimated to be20 kcal mol 1).

Cyclopropyl groups have been used to probe for ketyl anion intermediacy in reactions of Sml2 with ketones. In 1991, Molander reported that treatment of cyclopropyl ketone 15 with Sml2 yields ring-opened product 16 in 81% overall yield (equation 10)56 Timberlake and Chen reported that several cyclopropyl-ring-opened products result from treatment of 17 with Sml2 (Scheme 17)57.

Sml2

(17)

+

SCHEME 17

A number of synthetically interesting transformations involving Sml2-induced ring opening of cyclopropyl ketones were reported by Batey and Motherwell, involving subsequent cyclization of the ring-opened radical ion onto a remote CDC or C C. One example from this study is illustrated in equation 1158a. Moreover, these authors also demonstrated that it was possible to alkylate the ring-opened enolate anion with electrophilic reagents (equation 12).

22. Radical anions and cations derived from CDC, CDO or CDN groups 1299

Analogous ring opening of cyclopropyl esters with Sml2 were also reported in 1994 by Imamoto, Hatajima and Yoshizawa (equation 13).58b

(b) Oxirane ring openings. Although analogous to cyclopropanes, ring opening of radical anions generated from ˛,ˇ-epoxyketones are more complicated mechanistically because (in principle) either C C or C O bond cleavage may result. In the case of neutral free radicals, this competition is highly substituent-dependent. For unsubstituted oxiranylmethyl radicals, C O bond cleavage is observed. Radical-stabilizing substituents (vinyl, phenyl) on the oxirane ring tend to favor C C bond cleavage59.

There have been very few studies involving ring opening of radical anions generated from ˛,ˇ-epoxyketones, and in all of these, only C O bond cleavage has been found. This method has been successfully applied to the synthesis of ˇ-hydroxyketones or esters. These C O cleavages are thought to produce an enoyl radical and alkoxide anion (path d, Figure 3), although it is not clear that the available experimental evidence rules out path c. (Presumably C C bond cleavage would proceed according to path a on the basis of thermodynamic considerations.) The influence of substituents, counterion and solvent on the relative importance of these (potentially competitive) pathways, or whether any of these ring openings are reversible, is currently unknown.

In 1992, Hasegawa’s group60 found that irradiation of ˛,ˇ-epoxyketone 18 in the presence of triethylamine led to ring-opened products, the nature of which varied as a function of solvent and counter-ion (Table 5).

The proposed mechanism for this reaction is summarized in Scheme 18. Irradiation of 18 in the presence of Et3N yields SSRIP (21). Oxirane ring opening is suggested to yield 22, which, via CRIP (23), abstracts a proton from Et3NžC to yield 25. Diketone 19 is suggested to arise from a 1,2-hydrogen shift (22 ! 24), followed by back electron transfer. (Note: Since 1,2-hydrogen shifts are virtually unknown in free radical chemistry, it might be more reasonable to formulate this sequence according to equation 14). The effect of LiC on the product distribution is attributed to the fact that LiC favors SSRIP