Edmund C. Keung and Howard Alperl
State University of New York at Binghamton Binghamton, New York 13901
1
II
The Ene Synthesis
Diels and Alder received the Nobel Prize in 1950 for the 4+2 cycloaddition reaction named after them (1). An example is the reaction of the diene, cyclopentadiene, with the dienophile, maleic anhydride
diene
dienophile
11
0
Although the reaction has been extensively investigated with a wide variety of dienes (e.g., acyclic, cyclic, heterodienes) and dienophiles (e.g., alkenes, alkynes, nitroso compounds), the mechanism hap not been firmly established (8). This article is concerned with developments of a somewhat related reaction classified by Alder in his Nobel lecture as an "indirect substitutive addition" or "ene synthesis" (3). Unlike the Diels Alder reaction, relatively few publications have appeared on the ene synthesis and it is generally ignored in elementary organic texts (4). Most olefins, under thermal conditions, do not undergo 2+2 cycloaddition to form cy~lobutanes.~
However, Alder found that propylene reacts with maleic anhydride in benzene at elevated temperature and pressure to give dlyl succinic anhydride (11) as the only product (5).
In both cases, the double bond occupies the same relative position after the reaction is completed. In the formation of the six-membered ring V, two new u bonds are formed at the expense of two n bonds (2a -t 2u), whereas for VI, one u bond is formed at the expense of one a bond (In lu). It is not surprising, therefore, that similar mechanistic and stereospecific problems are encountered in both reactions. In fact, the similarities between these two reactions enabled Alder to combine both in a single reaction (6). Maleic anhydride combines with 1,4-pentadiene to give VII (ene synthesis).
Similar behavior is exhibited by 2-pentene, isobutylene, cyclopentene, and cyclohexene. Further reactions with unsymmetrical olefins such as allybenzene and 1hexene indicate that the ene synthesis proceeds by direct addition of maleic anhydride to an olefinic carbon with a "shift" of the double bond and transfer of an allylic hydrogen to the anhydride. Thus allylbensene gives (111) instead of (IV), as would be expected from direct addition of maleic anhydride to the allylic carbon with a simultaneous transfer of an olefinic hydrogen. A comparison of the ene to the well-known diene synthesis brings out some interesting similarities.
The migration of the double bond leads to the formation of a conjugated diene system necessary for diene
-
' Address correspondence to this author.
2 Olefins with electron-withdrawing groups may form cyclobutanes with olefins containing electron-donating groups. Reaction conditions usually require high temperature and pressure or ultraviolet irradiation.
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synthesis, thus resulting in cycloaddition with additional maleic anhydride.
Benzyne, suitably generated, undergoes the ene, rather than the diene synthesis with 2,5-dimethyl-2,4hexadiene to give X (9).
Similar coupling of substituting addition and diene synthesis takes place with a-allylnapthalene. The aromatic nature of the latter compound is completely destroyed through successive 2+4 cycloaddition initiated by substituting addition (MA = Maleic Anhydride).
It has been suggested that the two isobutylene groups assume a trans configuration and one of the two is oriented properly with benzyne to undergo the ene synthesis. Since Alder first used dimetbyl azodicarboxylate as a dienophile for the ene synthesis, a variety of heterodienophiles have been found to he capable of undergoing this reaction. Electronegatively suhstituted aldehydes, ketones and thioketones such as hexafluorothioacetone ( l o ) , pyruric ester ( l l ) , perfluorocyclobutanone (12),formaldehyde (15),chloral ( 1 4 , azo ester (15), and carbonyl cyanide (16) take part in ene synthesis readily, e.g.
Like Diels-Alder reactions, ene synthesis presents an interesting and challenging mechanistic problem for chemists. An ionic mechanism was first proposed for these reactions (17). According to this mechanism, both olefin and dienophile are polarized. The negative end of the olefin attacks the relatively positive bond of the dienophile to form an ionic intermediate XI.
Ene synthesis also takes place with negatively substituted dienophiles such as acrylonitrile, methyl vinyl ketone, ethyl vinyl sulfone, and acrylic acid (7). Sauer and Sauer (8) found that this suhstitive addition of allylic hydrogen takes place readily with negatively substituted acetylenes as well, e.g. 98 / lournol o f Chemical Educofion
Although this ionic mechanism accounts for the reactivity of a-substituted maleic anhydride with olefins through steric an' inductive consideration, it fails to give a satisfactory explanation for the stereochemical orientation of the reactions. Koch (18) and Arnold and Dowdall (19) proposed a concerted six-centered, cyclic process to account for the stereochemistry of the reaction.
Hill and Rabinovitz (80) verified this mechanism by reacting optically active olefins with maleic anhydride. In each cme, optically active products were obtained. erythro
anism did not completely eliminate the possibility of the ene synthesis occurring by a stepwise process involving an ionic intermediate such as XV. R-CH,
These workers concluded that the transfer of an optical asymmetric center from the olefin to a dierent position in the product agrees with a concerted six-center cyclic mechanism. Moreover, for XI1 (R = C&), if the ionic intermediate was formed, it would undergo either a hydride or methyl shift to give the more stable benzylic ion XIV (not observed). The absolute configurations of XI11 [R = CB&, (CHa)&H(CHJa-] suggest that orientation is controlled by simple steric factors.
XN
In each case, the bulky group is oriented away from the dienophile.
Berson and co-workers (ZI) found that there is a preference for endoid addition in the ene synthesis. Maleic anhydride reacts with cis-hutene to give the threo diasteriomer, and with trans-butene to form the eythro diasteriomer. Similarly the cyclopentene-maleic anhydride adduct has been shown to have the erythro configuration. Despite the above evidence, Berson carefully noted that "the preservation of asymmetry in the product of ene syntheses with optically active olefins are necessary but insufficientconditions, since a stepwise mechanism in which the carbon-carbon bond is formed first is also compatible with them." Moreover, Arnold and Dowdall (IS), who first proposed the concerted cyclic mech-
\ /C=CH,
R-CH,
+
R-CH,,@
-
H\,C=O H Q
/C-CH~CH~-O R-CH,
-
R-CH,
'c-CH~CH,-OH
R-C@
A free-radical mechanism is less likely. It is known that the formation of oxetanes by cycloaddition of olefins and aldehydes (or ketones) by ultraviolet irradiation involves a diradical triplet (88). Ene adducts are found to be absent in these types of reactions. Conversely, oxetane formation is not observed in ene syntheses involving aldehydes or ketones. In conclusion, the concerted six-center "no mechanism" mechanism is the most acceptable a t the present time.a Literature Cited 1942-1962:' Elmvier Publiehi% Go., Amsterdam-London-Ns\v York, 1964, pp. 253-305. ( 2 ) MARCH.J., "Advanced Organic Chemistry: Reactions. Mechaniama, and Structure." MeGrarv-Hill, New York. 1968, pp. 630-3. ( 3 ) For aoomorehensive treatment of thissubieot, aee: H O F ~ U NH. , M. R., Anceo. Chem.Int. E d . End..8,556 (1969). (4) E.g.. (4 MOBRIBON. R. T..AND BOYD.R. N.. "Organi0 Chemiatr~," (2nd ed.), Aliyn and Bacon, Inc., Boston, 1966; (b) RoaeBTs. J. D., AND C ~ a ~ n rM. o . C.,"Basia Princiulea of Orgsoic Chemistry." Benjsmin. Ino., New York, 1961: (4 Hmonrcasoli, J. B.. CRAM.D. J.. A N D HAMMOND, G. 6.. "Organic Chemistry" (3rd ed.), Ino.. 1970. A,, Cham. BET., 7 6 , 2 7 (1943). ( 5 ) A L D E ~K.. . PAscaen. F.. A N D SOXM~TK, ( 6 ) ALDER.K.. AND MUAS.F.. Ann. Chirn.. 565, 126 (1949). (7) ALDISETTI,C. J.. FISEER. N. G.. H O ~ S E DM , . J., AND JOYCE. a. M.. (1) "Nobel Lecture-Chemistry,
. I Amer. . Chem.Soc..78.2637 (1956).
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(8) S.&asn.J.C.. AND SAOEB.G . N . , J . OR. Cham..27,2730 (1962). (9) Anaem, E.M.,J . 0 7 0 . Chcm.,25, 324 (1960). W. J.. HOW*^ E. G.. *NU SH*RKWW. H., J . Arne?. (10) MIDDLETON. Cham.Soc.,83,2589(1961). R. T.,AND v ~ n n ~ v ~ Po.,uJ, . Amer. Chcn. sac., 82, 5411 (11)~nrrom, (1960). D. DC., , J. Am?.Chem.Soe..83,2205 (19611. (12) E N ~ L A N (13) RAIN,J. P.. J . Amcr. Chem.Soc.,68,638 (19461. T ,*NO VILK*~.M., Bd1. SOC.Chim. F?., 799 (14) D u ~ o u R.. . D ~ P O NG., (1955).
0.. A N D AOXX*TOIRIOZ, O., ROC%. Chcm.,36,1791 (1962); (15) ACXM*TOWIO~, 37,317(1963); Cham.Abstr., 59,8610b.12655e (1963). G . I., Chem.I%d. London, Ill6 (1961). (16) Brnrmha~, (17)R O N - D ~ ~ T V E D TC., s., FIDEY, A,, J . them., 19,548 (19541. (18) Koon. H.P., J. Chcm.Soc.,1111 (1948). J. F., J . Amm. Chsm. SOC., 70, 2590 (191 Aniro~n,R T.,A N D DOWDALL, (1948). z .. , J . Amer. Chsm. Soe..86,966 (1964). (20) Hmb. R. K . . m o R ~ n r i r o v l ~M . A.. WALL.R. G..AND PERLMUTTER. H. D.,J . A ~ Vmcm. . (21) B e n a o ~ J. Soc.,88, 188(1966). (22) BUCHI.G..INDIAN. C.G..A N D LIPIN~RY. E.6.. J . Amer. Chem.Soo., 76, 4327 (1954).
