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The reaction of enols with superoxide anion radical [02???]1. Synthesis of 2,3-unsaturated-δ-valerolactones.
Tetrahedron Printed in
Letters,Vol.23,No.l2,pp Great Britain
0040-4039/82/121301-04$03.00/0 01982 Pergamn Press Ltd.
1301-1304,1982
THE REACTION OF ENOLS WITH SUPEROXIDE ANION RADICAL tO2'?. SDXHF,SIS
OF 2,3-UNSATURATED-&VALEROLACTONES.
Aryeh A. Frimer*, Pessia Gilinsky-Sharon and Gladis Aljadeff Department of Chemistry, Bar Ilan University, Ramat-Gan, Israel
Abstract: 3- and 4-Hydroxycoumarin (& and 2) as well as 2-hydroxy-2,5-cyclohexadien-l-ones a-6 were reacted with K02/18-crown-6 in benzene. Initial deprotonation of the enol hydrogen was followed by nucleophilic attack by 0 (for &,and ,$ and/or autoxidation of the resulting anion (for 4 and ,&-q). A convenieng synthesis of 2,3-unsaturated-6-valerolactones from the corresponding 2-cyclohexen-l-onesis also described. There is little doubt any longer that superoxide anion radical plays a crucial role in a vast spectrum of metabolic processes and that itsswift disproportionation
to oxygen and
hydrogen peroxide is mediated by a group of enzymes called superoxide dismutases (SOD)2. There has, however, been some heated debate on the question of superoxide's toxicity3 which
. an in-depth exploration of the chemical capabilities of 02- should help to resolve. Indeed, . recent research on the organic chemistry of 0 - in aprotic media has revealed four basic 2 modes of action including deprotonation,nucleophilic attack, electron transfer and in some cases hydrogen atom abstraction4. Regarding the first mode, 02- can effect proton transfer from substrates to an extent 4d equivalent to that of a conjugate base of an acid with a pKa of approximately 23 . We would expect,therefore,thateven some weakly acidic organic compounds can be deprotonated by I 4d Thus primary alcohols', even those as weakly acidic as n-butanol (pK, = 33 DMF) , O2 * . apparently
cause the instantaneous
disproportionation
of O,- (equations
1 and 2).
‘
I
RH+
O2
H02' +o2
-HO-+0
R-+H02'
2
(1) (2)
2
. Enols, too, undergo facile proton removal by 0 -. Thus when 3-hydroxycoumarin(&) or -2 It-hydroxycoumarin (2, Aldrich) are reacted with 02- (generated from K02/18-crown-6 in benzene), deprotonation of the enolic hydrogen with concomitant evolution of O2 is the first step.
.
This is followed by subsequent nucleophilic attack by 02- at the lactone carbonyl carbon. In the case of &, autoxidation of the resulting anion 5 ultimately generates salicyaldehyde. The same is not true however for anion $ which like the enolates of 1,3-diketones (e.g. 1,3-cyclohexanedione and dibenzoylmethane)resints further oxidation by either molecular oxygen' . or 0 -. The course of these reactions was followed by trapping the intermediate anions with 2 CH31 prior to work-up. In a simple aqueous work-up, anions $ and ,$are returned to starting material.
1301
1302
4 N
Similarly, cr-ketoenols a-,$ (with the notable exception of G)
. als6 react with 02-
Prating the corresponding lactols ,&-e as the major product (Table I). The identity of ie lactols was consistent with the spectral data (NMR: H-5 at 6 = $ 5.3 ppm; IR (CHC13) 1 and 1640 cm-') and confirmed by their conversion to the corresponding aldehydo esters J,, 8 :ones &J, and acetates 2 .
E:
FePh, R'=H
9 #.A
1303
TALUX I:
Reaction of 4,4-Disubstituted-2-hydroxy-2,5-cyclohexadien-l-ones 5 with 02* e
Reaction Conditions*
2:l:l
4:2:1
4:2:1
50
80
80
lactol yield (X)
2.5:1:1 50
4:2:1
10:5:1
90
N.R.
* Ratio of KO : 18-Crown-6: Substrate. Reactions were carried out at ambient temperature2for 16 hrs under dry air. . One indication of the fact that 02- is acting as a base in the above reaction is that the same products are obtained with potassium hydroxide and t-butoxide with the order of decreasing rates t-butoxide > superoxide > hydroxide. Additional evidence comes from the ob-
.
servation that the rate of the 02- reaction is essentially the same whether carried out in air or under argon (after carefully degassing the solvent via 5 freeze-thaw cycles). This . is consistent with an acidic substrate induced disproportionationof 02- to molecular oxygen The resulting substrate anion then combines with the O2 generated' 10 yielding, in reactions typical of base catalyzed autoxidations , the correspondingperoxy 11 anion. A plausible mechanism for the oxidation of enols 2 to lactols & is outlined below . (equations 1 and 2).
It should be noted that enols z-;E were prepared in turn by 02- mediated base catalyzed
autoxidation
of 4,4- and 5,5-disubstitutedcyclohex-2-en-l-onesE
and 5
(Table TT).12-14
The conversion of enones l$,and && to the corresponding lactols 6 can in fact be carried
&
$&,$a
or
p’
out
ot*$>@
and f Q
J&M and r; &-gR in one step if the enol is not isolated and allowed to react further. The facile oxidation of ,#,directly to t and the subsequent reduction of the latter to 8 represents a convenient two'I,
step method for the conversion of 4,4-disubstftuted-2-cyclohexen-l-ones to their 6-oxa (2,3-unsaturated-+valerolactones).
analogs
A practical application of such an approach has been used in the synthesis of the pharmacologicallyactive 2-oxa-3-oxo-A4- steroids15_ 16
1304
z
TABLE II:
Reaction of Selected Cyclohex-Z-en-l-oneswith 0 2
ENONE
REACTION CONDITION*
BNOL YIELD (2)
ENONE
KOH (7 hr)
85 **
&I&
K02 K02 (2 hr)
&
&%
K02 (1.3 hr)
95
KO (16 hr) KO$ (16 hr)
80 75
ENOL YIELD (z)
&@
89 55
84
REACTION CONDITIONS*
78 32
KO (5 hr) KOS (16 hr)
KO2 (1 hr)
in Benzene
KO (7 hr) KO$ (16 hr)
&&
&gC
and HO
KOH (7 hr)
88 85 **
K02
* Ratio of KX (X=OH or 0 ): 18-Crown-6: Substrate was 4:2:1 for ga-t, 2:l:l for &, 8:2:1 for and F an% 4:1.5:1 for 116. Reactions were carried out at ambient temperature under q ry air. ** The enol cannot be isolated in appreciable yields in this instance because further oxidation to the corresponding lactol competes. References and Notes 1.
2.
3. 4.
5. 6. 7. 8. 9. 10. 11.
Presentedin part at the International Conference on Oxygen and Oxy-Radicals, University of Texas at Austin, May 1980. For recent review see: a) "Superoxide and Superoxide Dismutase", A.M. Michelson, J.M. McCord and I. Fridovich eds., Academic Press: New York, 1977; b) I. Fridovich, Science, 201, 875 (1978); c) I.B. Afanas'ev, Russ. Chem. Rev., 48, 527 (1979); d) "Biological and Clinical Aspects of Superoxide and Superoxide Dismutase", Developments in Biochemistry Series, Vol. 11A and llB, W.H. Bannister and J.V. Bannister, eds., Elsevier - N. Holland, 1980; e) "Oxygen and Oxy-Radicals in Chemistry and Biology", M.A.J. Rodgers and E.L. Powers eds, Academic Press: New York, 1981. See for example the papers of I. Fridovich and J.A. Fee and the ensuing discussion in reference 2e pages 197-239. For recent reviews see: a) E. Lee Ruff, Chem. Sot. Rev., 2, 195 (1977); b) A.A. Frimer and I. Rosenthal, Photochem. Photobiol., 25, 711 (1978); c) J.A. Fee and J.S. Valentine in reference la, p.19; d) D.T. Sawyer and M.J. Gibian, Tetrahedron,35, 1471 (1979); e) Reference lc; f) A.A. Frimer in "Superoxide Dismutase", L.W. Oberley ed., Chemical Rubber Co., Florida (In Press); f) A.A. Frimer in "Peroxides", Chemistry of the Functional Groups series, S. Patai ed., Wiley: New York (In Press). J.P. Stanley, J. Org. Chem., 45, 1413 (1980). K.N.F. Shaw, A. McMillan and M.D. Armstrong, J. Org. Chem., 2, 601, 604 (1956). Cf. G.A. Russel, A.J. Moye and K.L. Nagpal, J. Am. Chem. Sot., 86, 4154 (1962). Cf. M. Kocar, A. Kurek, and I. Dabrowski, Tetrahedron,2, 4257 (1969). Cf. E.J. Nanni, M.D. Stallings and D.T. Sawyer, J. Am. Chem. Sot., l$, 4481 (1980). G.A. Russel, E.J. Janzen, A.G. Bemis, E.J. Geel, A.J. Moyes, S. Mak and E.T. Strom, Adv. Chem. Ser., 11, 112 (1965). Cf. a) M. Utaka, S. Matsushita, H. Yamasaki and A. Takeda, Tetrahedron Let. 1063 (1980); b) R. Hanna and G. Ourisson, Bull. Sot. Shim. Fr., 1945 (1961); c) A. Nishinaga, T. Tojo and T. Matsuura, J. Chem. Sot. Perkin I, 251 (1979).
12. ;;;ln~,A;oFar%: g; f4b;;$&: ~r~~dronl~~~t~~~14~3~~d':~:91i! 13. were prepared by liter,$& ature melds. %ne &$% commercially availaby(Fluka).a) M.S. Newman, An Advanced Organic Laboratory Course, Mamillan: N.Y., 1972, p. 181; b) E. Winkert, N.F. Goloh, S.S. Sothe and R.A.J. Smith, Synth. Comm., 2, 205 (1973); c) W-G. Dauben, G.W. Shaffer and N.B. Vietmeyer, J. Org. Chem., 33, 4060 (1968); d) W.F. Gannon and H.O. House, Org. Syn. Coll. Vol. V, Wiley: New York, 1973, 294; e) Ibid p.593. 15. A.A. Frimer and P. Gilinsky in reference 2e, p.639. 16. We acknowledge the support of the Israel National Council for Research and Development. 14.
(Received
in UK 15 January
1982)
Letters,Vol.23,No.l2,pp Great Britain
0040-4039/82/121301-04$03.00/0 01982 Pergamn Press Ltd.
1301-1304,1982
THE REACTION OF ENOLS WITH SUPEROXIDE ANION RADICAL tO2'?. SDXHF,SIS
OF 2,3-UNSATURATED-&VALEROLACTONES.
Aryeh A. Frimer*, Pessia Gilinsky-Sharon and Gladis Aljadeff Department of Chemistry, Bar Ilan University, Ramat-Gan, Israel
Abstract: 3- and 4-Hydroxycoumarin (& and 2) as well as 2-hydroxy-2,5-cyclohexadien-l-ones a-6 were reacted with K02/18-crown-6 in benzene. Initial deprotonation of the enol hydrogen was followed by nucleophilic attack by 0 (for &,and ,$ and/or autoxidation of the resulting anion (for 4 and ,&-q). A convenieng synthesis of 2,3-unsaturated-6-valerolactones from the corresponding 2-cyclohexen-l-onesis also described. There is little doubt any longer that superoxide anion radical plays a crucial role in a vast spectrum of metabolic processes and that itsswift disproportionation
to oxygen and
hydrogen peroxide is mediated by a group of enzymes called superoxide dismutases (SOD)2. There has, however, been some heated debate on the question of superoxide's toxicity3 which
. an in-depth exploration of the chemical capabilities of 02- should help to resolve. Indeed, . recent research on the organic chemistry of 0 - in aprotic media has revealed four basic 2 modes of action including deprotonation,nucleophilic attack, electron transfer and in some cases hydrogen atom abstraction4. Regarding the first mode, 02- can effect proton transfer from substrates to an extent 4d equivalent to that of a conjugate base of an acid with a pKa of approximately 23 . We would expect,therefore,thateven some weakly acidic organic compounds can be deprotonated by I 4d Thus primary alcohols', even those as weakly acidic as n-butanol (pK, = 33 DMF) , O2 * . apparently
cause the instantaneous
disproportionation
of O,- (equations
1 and 2).
‘
I
RH+
O2
H02' +o2
-HO-+0
R-+H02'
2
(1) (2)
2
. Enols, too, undergo facile proton removal by 0 -. Thus when 3-hydroxycoumarin(&) or -2 It-hydroxycoumarin (2, Aldrich) are reacted with 02- (generated from K02/18-crown-6 in benzene), deprotonation of the enolic hydrogen with concomitant evolution of O2 is the first step.
.
This is followed by subsequent nucleophilic attack by 02- at the lactone carbonyl carbon. In the case of &, autoxidation of the resulting anion 5 ultimately generates salicyaldehyde. The same is not true however for anion $ which like the enolates of 1,3-diketones (e.g. 1,3-cyclohexanedione and dibenzoylmethane)resints further oxidation by either molecular oxygen' . or 0 -. The course of these reactions was followed by trapping the intermediate anions with 2 CH31 prior to work-up. In a simple aqueous work-up, anions $ and ,$are returned to starting material.
1301
1302
4 N
Similarly, cr-ketoenols a-,$ (with the notable exception of G)
. als6 react with 02-
Prating the corresponding lactols ,&-e as the major product (Table I). The identity of ie lactols was consistent with the spectral data (NMR: H-5 at 6 = $ 5.3 ppm; IR (CHC13) 1 and 1640 cm-') and confirmed by their conversion to the corresponding aldehydo esters J,, 8 :ones &J, and acetates 2 .
E:
FePh, R'=H
9 #.A
1303
TALUX I:
Reaction of 4,4-Disubstituted-2-hydroxy-2,5-cyclohexadien-l-ones 5 with 02* e
Reaction Conditions*
2:l:l
4:2:1
4:2:1
50
80
80
lactol yield (X)
2.5:1:1 50
4:2:1
10:5:1
90
N.R.
* Ratio of KO : 18-Crown-6: Substrate. Reactions were carried out at ambient temperature2for 16 hrs under dry air. . One indication of the fact that 02- is acting as a base in the above reaction is that the same products are obtained with potassium hydroxide and t-butoxide with the order of decreasing rates t-butoxide > superoxide > hydroxide. Additional evidence comes from the ob-
.
servation that the rate of the 02- reaction is essentially the same whether carried out in air or under argon (after carefully degassing the solvent via 5 freeze-thaw cycles). This . is consistent with an acidic substrate induced disproportionationof 02- to molecular oxygen The resulting substrate anion then combines with the O2 generated' 10 yielding, in reactions typical of base catalyzed autoxidations , the correspondingperoxy 11 anion. A plausible mechanism for the oxidation of enols 2 to lactols & is outlined below . (equations 1 and 2).
It should be noted that enols z-;E were prepared in turn by 02- mediated base catalyzed
autoxidation
of 4,4- and 5,5-disubstitutedcyclohex-2-en-l-onesE
and 5
(Table TT).12-14
The conversion of enones l$,and && to the corresponding lactols 6 can in fact be carried
&
$&,$a
or
p’
out
ot*$>@
and f Q
J&M and r; &-gR in one step if the enol is not isolated and allowed to react further. The facile oxidation of ,#,directly to t and the subsequent reduction of the latter to 8 represents a convenient two'I,
step method for the conversion of 4,4-disubstftuted-2-cyclohexen-l-ones to their 6-oxa (2,3-unsaturated-+valerolactones).
analogs
A practical application of such an approach has been used in the synthesis of the pharmacologicallyactive 2-oxa-3-oxo-A4- steroids15_ 16
1304
z
TABLE II:
Reaction of Selected Cyclohex-Z-en-l-oneswith 0 2
ENONE
REACTION CONDITION*
BNOL YIELD (2)
ENONE
KOH (7 hr)
85 **
&I&
K02 K02 (2 hr)
&
&%
K02 (1.3 hr)
95
KO (16 hr) KO$ (16 hr)
80 75
ENOL YIELD (z)
&@
89 55
84
REACTION CONDITIONS*
78 32
KO (5 hr) KOS (16 hr)
KO2 (1 hr)
in Benzene
KO (7 hr) KO$ (16 hr)
&&
&gC
and HO
KOH (7 hr)
88 85 **
K02
* Ratio of KX (X=OH or 0 ): 18-Crown-6: Substrate was 4:2:1 for ga-t, 2:l:l for &, 8:2:1 for and F an% 4:1.5:1 for 116. Reactions were carried out at ambient temperature under q ry air. ** The enol cannot be isolated in appreciable yields in this instance because further oxidation to the corresponding lactol competes. References and Notes 1.
2.
3. 4.
5. 6. 7. 8. 9. 10. 11.
Presentedin part at the International Conference on Oxygen and Oxy-Radicals, University of Texas at Austin, May 1980. For recent review see: a) "Superoxide and Superoxide Dismutase", A.M. Michelson, J.M. McCord and I. Fridovich eds., Academic Press: New York, 1977; b) I. Fridovich, Science, 201, 875 (1978); c) I.B. Afanas'ev, Russ. Chem. Rev., 48, 527 (1979); d) "Biological and Clinical Aspects of Superoxide and Superoxide Dismutase", Developments in Biochemistry Series, Vol. 11A and llB, W.H. Bannister and J.V. Bannister, eds., Elsevier - N. Holland, 1980; e) "Oxygen and Oxy-Radicals in Chemistry and Biology", M.A.J. Rodgers and E.L. Powers eds, Academic Press: New York, 1981. See for example the papers of I. Fridovich and J.A. Fee and the ensuing discussion in reference 2e pages 197-239. For recent reviews see: a) E. Lee Ruff, Chem. Sot. Rev., 2, 195 (1977); b) A.A. Frimer and I. Rosenthal, Photochem. Photobiol., 25, 711 (1978); c) J.A. Fee and J.S. Valentine in reference la, p.19; d) D.T. Sawyer and M.J. Gibian, Tetrahedron,35, 1471 (1979); e) Reference lc; f) A.A. Frimer in "Superoxide Dismutase", L.W. Oberley ed., Chemical Rubber Co., Florida (In Press); f) A.A. Frimer in "Peroxides", Chemistry of the Functional Groups series, S. Patai ed., Wiley: New York (In Press). J.P. Stanley, J. Org. Chem., 45, 1413 (1980). K.N.F. Shaw, A. McMillan and M.D. Armstrong, J. Org. Chem., 2, 601, 604 (1956). Cf. G.A. Russel, A.J. Moye and K.L. Nagpal, J. Am. Chem. Sot., 86, 4154 (1962). Cf. M. Kocar, A. Kurek, and I. Dabrowski, Tetrahedron,2, 4257 (1969). Cf. E.J. Nanni, M.D. Stallings and D.T. Sawyer, J. Am. Chem. Sot., l$, 4481 (1980). G.A. Russel, E.J. Janzen, A.G. Bemis, E.J. Geel, A.J. Moyes, S. Mak and E.T. Strom, Adv. Chem. Ser., 11, 112 (1965). Cf. a) M. Utaka, S. Matsushita, H. Yamasaki and A. Takeda, Tetrahedron Let. 1063 (1980); b) R. Hanna and G. Ourisson, Bull. Sot. Shim. Fr., 1945 (1961); c) A. Nishinaga, T. Tojo and T. Matsuura, J. Chem. Sot. Perkin I, 251 (1979).
12. ;;;ln~,A;oFar%: g; f4b;;$&: ~r~~dronl~~~t~~~14~3~~d':~:91i! 13. were prepared by liter,$& ature melds. %ne &$% commercially availaby(Fluka).a) M.S. Newman, An Advanced Organic Laboratory Course, Mamillan: N.Y., 1972, p. 181; b) E. Winkert, N.F. Goloh, S.S. Sothe and R.A.J. Smith, Synth. Comm., 2, 205 (1973); c) W-G. Dauben, G.W. Shaffer and N.B. Vietmeyer, J. Org. Chem., 33, 4060 (1968); d) W.F. Gannon and H.O. House, Org. Syn. Coll. Vol. V, Wiley: New York, 1973, 294; e) Ibid p.593. 15. A.A. Frimer and P. Gilinsky in reference 2e, p.639. 16. We acknowledge the support of the Israel National Council for Research and Development. 14.
(Received
in UK 15 January
1982)