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The Ene Reaction.

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The Ene Reaction
By H. M. R. HoffmannI*]
The ene reaction is defined as the indirect substituting addition of a compound with a
double bond (enophile) to an olefin with an allylic hydrogen (ene). For a long time the
reaction has been neglected and has remained overshadowed by the related Diels-Alder
addition. It is shown that the ene reaction possesses wide scope and applicability ranging
from industrial to biosynthetic processes. Preparative aspects are summarized and current
views on the mechanism are discussed.
1. Introduction
Although the ene reaction is one of the most simple
and versatile reactions of organic chemistry, it is surprisingly little known and virtually ignored in all textbooks. Isolated examples such as certain reactions of
olefins with formaldehyde (Prins reaction ; cf. also
Section 3.4) (11 as well as retro-ene reactions, e.g., the
decarboxylation of P-ketoacids and the formation of
olefins by ester pyrolysis have been known at least
since the beginning of the century, but many further
examples have been buried in the patent literature 127
and in a number of obscure journals. Only after a
paper by Alder131 in 1943 did the scope of the ene
reaction begin to be recognized. However, until today
the “ene synthesis” has remained unfashionable and
overshadowed by the related Diels-Alder addition
(“diene synthesis”). Furthermore, much of the early
work is insecurely based, because the by now common
analytical and spectroscopic tools were not available.
It is the purpose of this review to discuss what results
and mechanistic insight are now available on this
reaction.
The ene reaction is the “indirect substituting addition” 131 of a compound with a double bond (enophile)
to an olefin possessing a n allylic hydrogen (ene) and
involves aIlylic shift of one double bond, transfer of
the allylic hydrogen to the enophile and bonding between the two unsaturated termini (Scheme 1). Formally the reaction is not only related to the Diels-Alder
addition, but can also be regarded as a n intermolecular
variant of the symmetry-allowed 1,5-hydrogen shift 141
Scheme 2.
AH*
=
35.4 kcal/mole, AS* = -7.1 e.u. [6].
(Scheme 2), although the transition state geometry of
all three reactions is different (Section 6.5). It must be
stressed from the very beginning that the ene reaction
need not necessarily proceed in concerted fashion. If,
for example, the ene component is so constituted that
simultaneous bond-making at its carbon and hydrogen termini is geometrically unfavorable, the stepwise
reaction involving a biradical ( I ) may occur (Scheme
3). Such a mechanism will usually betray itself on
careful product analysis, since it seems clear from the
elegant work of Bartlett 151 that a biradical such as ( 1 )
will at least partly leak into the cyclobutane derivative
(2). Conversely, current theory suggests that in the
absence of any cyclobutane derivatives the ene reaction is most likely to take a concerted course. The
other mechanistic extreme, i.e., formation of an intermediate allylic radical by slow transfer of the hydrogen
to the enophile, appears to be extremely rare (Section 6.5).
/
\
I1
c
i;
(2)
Scheme 3
2. The Ene Component
Scheme 1
2.1. Monoolefins
[*] Dr. H. M. R. Hoffmann
William Ramsay and Ralph Forster Laboratories,
University College,
Gower Street, London W. C. 1 (England)
[l] €3.J. Prins, Chem. Weekblad Id, 1510 (1919); see also ref. [83].
[21 See C. P. A . Kappelrneier, J . H. van der Neut, and W. R. van
Goor, Kunststoffe 40, 81 (1950); see also 131, footnotes 1 and 2.
[31 K. Alder, F. Pascher, and A . Schmitz, Ber. dtsch. chem. Ges.
76, 27 (1943).
[41 R. 8. Woodwardand R . Hoffmann, J. Amer. chem. SOC.87,
2511 (1965).
556
The most simple ene reaction, that of propylene with
ethylene (Scheme l),appears to be unknown and only
the reverse reaction, i.e., decomposition of I-pentene
can be achieved at elevated temperatures 161. However,
[5] P. D . Bartlett, Science (Washington) 159, 833 (1968).
[6] W. R. Roth, Chimia 20, 229 (1966).
Angew. Chem. internat. Edit.
Vol. 8 (1969)I No. 8
Entry
under high pressure acetylene has been proved to
react with a number of simple olefins to form 1,4dienes 171. For instance, 2-methyl-1,4-pentadiene (4)
can be isolated in 40% yield when a large excess of
isobutylene (3) is treated with acetylene in a flow
reactor at 170 atm.
I-butene (entry 9), which can only donate its crowded
isopropyl hydrogen to the enophile, reacts very slowly
despite the fact that the abstracted hydrogen is tertiary.
In fact, in the latter reaction it is difficult to isolate the
monoadduct, which, having six primary hydrogen
atoms, forms the bisadduct very smoothly.
Thaler and Franzust81 have treated a number of isomeric butenes and pentenes with diethyl azodicarboxylate (Scheme 4) and identified the products by
NMR spectroscopy and gas-liquid chromatography
(Table 1). These data demonstrate that the azo ester
Substituent effects at the nonterminal vinylic carbon
of the ene component have been investigated less
thoroughly. However, relative rates obtained from
competition experiments indicate that feeding electrons into this position increases rates. Note also that
2-methyl-2-butene forms the adduct in which Y is
attached to the secondary but not the tertiary carbon
(entry 5 ) and that trans-2-butene reacts faster than the
cis isomer (entries 2,4).
Substituted allylic compounds such as 1,3-diarylpropenes react with diethyl azodicarboxylate according to
Scheme 4[9J, and with selenium dioxide in acetic
acid[lol, but have been claimed not to react with
maleic anhydride 1111, which admittedly is a less effective enophile.
Table 1. Monoadducts, yields, and relative rates of the reaction
of diethyl azodicarboxylate with butenes and pentenes;
Y = N(CO2C2HS)-NHC0&HS 181 (cf. Scheme 4).
Olefin
-
Rate
Relative
.o cisBut-2-ene
Monoadducts
I
17.2
1
2
\
"y
Y
3.73
2.2. Methylenecycloakanes and 1-Methylcycloallcenes
2.57
3
4
\=/
-
1.00
"(
Y
cr
Rate
Relative
to Pent1-ene
5
4.33
6
3.64
48%
I
Methylenecyclobutane affords a 1:2 adduct with maleic
anhydride (MA) in easily discernible fashion. The 1:l
adduct which is formed in a side reaction, is visualized
W
y
Y "
17%
35%
7Y-l
@Yn
Y
2.13
1 .oo
8
9
slow
[a] Not clear whether trans and/or cis adduct formed.
attacks the least substituted allylic position preferentially. In other words, a primary hydrogen is abstracted
more readily than a secondary and much faster than
a tertiary one (entries 1, 3, 9). The thermodynamic
stability of the product is not decisive here. 3-Methyl[7] N. F. Cywinski, J. org. Chemistry 30, 361 (1965).
[8] W. A. Thaler and B. Franzus, J. org. Chemistry 29, 2226
(1964).
Angew. Chem. internat. Edit. f Vol. 8 (1969)1 No. 8
d
q
0
0o
IMA
Scheme 5
[9] R. Huisgen and H. Pohl, Chem. Ber. 93,527 (1960).
[lo] J . P. Schaefer, B. Horvath, and H. P. Klein, J. org. Chemistry 33, 2647 (1968).
[ll] C. S . Rondestvedt j r . and B. H. Wark, J. org. Chemistry
20, 368 (1955).
557
to arise from rearrangement to I-methylcyclobutene,
opening to isoprene, and Diels-Alder trapping (Scheme 5) 1121. Methylenecyclopentane gives rise to (5)
and (6) on heating with, respectively, maleic anhydride
and formaldehyde to 200 "C for 2-4 hours. In contrast, the sulfonic acid (7) is formed simply on leaving
methylenecyclopentane and sulfur trioxide in dioxane
at 0 "C1131. Under the same conditions and with the
same reagents methylenecyclohexane forms the adducts corresponding to (5), (6),and (7)1141.
(5)
reactions are abnormal in that they can be catalyzed
by radical initiators such as dibenzoyl peroxide and
retarded by radical inhibitors (p-benzoquinone, acrylonitrile) [*,91 (see also Section 6.5). Indan and tetralin
0
Naturally-occurring P-pinene (8) is particularly reactive towards enophiles. It readily forms adducts
with maleic anhydride, dimethyl maleate and fumarate,
methylenemalonic ester r15a3, formaldehyde [15bI, trichloroacetaldehyde 1 1 5 ~ 1 , carbonyl cyanide [15dl, butyl
HNCO~C~H,
Scheme 6
react with maleic anhydride to form diastereomeric
glyoxylate [15e1, and benzyne c15fI. If these reactions
were to proceed via a carbonium ion such as (9) (or
the corresponding radical), much rearranged product
would arise. In fact, it has been found that the isolated
products retain the pinene carbon skeleton. Presumably, in all these reactions the axial hydrogen which is
on the more accessible endo face, is abstracted from
p-pinene. The homologous myrtenol formed from
formaldehyde and P-pinene is valued in the perfumery
industry under the trivial name of nopol.
Unlike (8), the endocyclic isomer a-pinene (lo),
which is thermodynamically more stable, reacts not at
all or only very reluctantly. For example, the powerful
enophile singlet oxygen gives a minor amount of ene
adduct only 1161, and paraformaldehyde reacts at
180°C in the absence of solvent to give (11) in 12%
yield only [17J. In these reactions u-pinene is attacked
generally from the less hindered endo side.
Cyclopentene and cyclohexene react with diethyl azodicarboxylate according to Scheme 6. However, these
[12] K. Alder and H. Dortmann, Chem. Ber. 85, 556 (1952).
[13] R. T. Arnold, R. W. Amidon, and R. M. Dodson, J. Amer.
chem. SOC.72, 2871 (1950).
[14] R. T. Arnoldand J. F. DowdaN, J. Amer. chem. SOC.70,2590
(1948); see also K. Alder, H. Soll, and H. Soll, Liebigs Ann.
Chem. 565, 73 (1949).
1151 a) R. T. Arnold and J. S. Showell, J. Amer. chem. SOC.79,
419 (1957); b) J. P. Bain, J. Amer. chem. SOC.68, 638 (1946); N.
0. Brace, ibid. 77, 4666 (1955); c) M. Vilkas, G. Dupont, and R.
Dulon, Bull. SOC. chim. France 1955, 799; d) G. I. Birnbaum,
Chem. and Ind. (London) 1961,1116; e) E. I. Klimova and Y. A.
Arbuzov,
org. Chim. 1968, 4 (lo), 1787; see Chem. Abstr. 70,
20228d (1969); f) L. Friedman and J . Miller, private communica-
z.
tion.
[161 C. S. Foote, Accounts chem. Res. I, 104 (1968); and references cited therein.
071 A. T. Blomquist, J. Verdol, C. L. Adami, J . Wolinsky, and
D. D. Phillips, J. Amer. chem. SOC.79, 4976 (1957).
558
1:l adducts in which the double bond is unshifted
(Scheme 7) [18J.
n
$0
Scheme 7
I-Methylcyclohexene (12) reacts with formaldehyde
at 165 "C,when acetic acid-acetic anhydride is used as
a solvent, to give an approximately equal mixture of
acetates (13) and (14) [17,191. It has been reported in an
earlier paper that (12) and maleic anhydride afford
(15) as a mixture of two diastereoisomers, but not the
adduct corresponding to (14)with an exocyclic double
bond [201. Recently, Blomquist and his co-workers have
considerably improved the experimental conditions
for inducing ene reactions with formaldehyde. For
example, the thermal ene reaction of (+)-limonene
(16) with formaldehyde in an autoclave at 180-200 "C
is completely unsatisfactory. However, if (16) is treated with formaldehyde in solvent dichloromethaneacetic anhydride in the presence of boron trifluoride
dihydrate, the adduct (17) is formed in 69% yield
after 70 minutes at autogeneous temperature [211!
Interestingly, the disubstituted double bond of (16)is
inert to singlet oxygen, which selectively attacks the
more electron-rich internal double bond [20aJ.
[18] K. Alder and 0. Wolff, Liebigs Ann. Chem. 576, 182 (1952).
[19] a) G. Ohlof, Liebigs Ann. Chem. 627,79 (1959), footnote 29;
b) Chem. Ber. 93,2673 (1960).
[ZO] K.AIder and A. Schmitz, Liebigs Ann. Chem. 565, 99 (1949).
[ZOa] G. 0. Schenck, K. Gollnick, G. Buchwald, S. Schroeter, and
G. Ohloff, Liebigs Ann. Chem. 674, 93 (1964).
[211 A. T. Blomquist and R. J . Himics, J. org. Chemistry 33, 1156
(1968).
Angew. Chem. internat. Edir. 1 Vol. 8 (1969)/ No. 8
trans configuration, produces some cis isomer in
photostationary equilibrium 1261; cis azo derivatives
are generally much more reactive in both 4 + 2 126,271
and 2 + 2 cycloadditions 1281.
A comparison of the benzoannelated dienes (25), (29),
and (32) is informative. Styrene (25) and maleic anhydride first form the Diels-Alder adduct (26), which
apparently cannot be isolated, since it possesses a
On treatment with formaldehyde in dichloromethane
containing boron trifluoride dihydrate or, alternatively,
stannic chloride, camphene (18) forms adduct (19)
as the main product (57%)[22a3. In contrast, on
heating (18) to 105 "C with formaldehyde in acetic acid
one obtains (19a) in 75 % yield; (19a) is also formed
from (19) in hot acetic acid[22bl. Consequently, the
conversion of (18) into (19) could represent the first
example of a homo-ene reaction as formulated here,
although Blomguist has suggested a stepwise mechanism
via a carbonium ion intermediate [22al.
-
0w0
0
0
carbon-hydrogen bond weakened by both ally1 and
pentadienyl resonance. Reaction with a second molecule of maleic anhydride yields the ene product (27)
2.3. 1,3-Dienes
Special factors are required if the ene reaction is to
proceed with conjugated dienes in preference to the
Diels-Alder addition. It was reported originally that
1,3-cyclohexadiene (20) forms exclusively the ene
product (21) with diethyl azodicarboxylate and no
Diels-Alder adduct (22) 1231. Reinvestigation revealed
that (22) is formed albeit in low yields (5-15 %) [241.
However, cycloadduct (22) may be obtained in 87 %
HNC02CzH5
I
0
0
a
C,II,02("N
>
C2H502cC'A
(20)
+ &q,c02c2H5
dCZ
(33)
and the 4 + 2 adduct (28) in a ratio of ca. 8:1[291. In
contrast, styrene and diethyl azodicarboxylate form
the bisadduct corresponding to (27) only [301.
+
0.
NHCOzCzH,
I
NHCO2CZHS
%02C2H,
(211 (80Yd
(22) (10Yo)
yield without any admixed (21) if the reaction solution is irradiated below room temperature 1231. It has
been shown that UV irradiation of diethyl azodicarboxylate which normally possesses the more stable
[22] a) A. T. Blomquist and R . J . Himics, Tetrahedron Letters
1967, 3947; b) A . T. Blomquist, R. J. Himics, and J . D. Meador,
J. org. Chemistry 33, 2462 (1968).
[23] a) B. T. Gillis and P . E. Beck, J. org. Chemistry 27, 1947
(1962); b) B. Franzus and J . H . Surridge, ibid. p. 1951.
1241 B. Franzus, J. org. Chemistry 28, 2954 (1963).
[25] R. Askani, Chem. Ber. 98, 2551 (1965).
Angew. G e m . internat. Edit.
*
(32)
N-COzCzH,
N-co~c~H,
€1 C 0 2 C2H5
~,C02C211,
Vol. 8 (1969) J No. 8
(23)
(24)
[26] G. 0. Schenck, H.-R. Kopp, B. Kim, and E. Koerner von
Gustorf, Z . Naturforsch. 206, 637 (1965).
[27] R. C . Cookson, S. S. H. Gilani, and I. D. R. Stevens, J. chem.
SOC.(London) C, 1967, 1905; see also Tetrahedron Letters 1962,
615.
[28] a) G. 0. Schenck and N . Engelhard, Angew. Chem. 68, 71
(1956); b) A. H . Cook and D. G . Jones, J. chem. SOC.(London)
1941,184.
1291 K . Alder and R . Schmitz-Josten, Liebigs Ann. Chem. 595,
l(1955).
I301 K . AIder and H. Niklas, Liebigs Ann. Chem. 585, 97 (I 954);
this paper has been partly criticised by Huebner et al. [31a].
559
Indene (29) and tetracyanoethylene afford the 2 + 2
adduct (30) [31al. Originally, the reaction with diethyl azodicarboxylate was assumed to yield the analogous 2 + 2 product [31aI, but more recent work has
shown that the 4 + 2 adduct (31) is formed instead [ 3 W
1,2-Dihydronaphthalene (32) does not undergo a
Diels-Alder addition with diethyl azodicarboxylate
but forms (33) [91. In this reaction free radical initiators
and inhibitors have shown no effect [91. Not surprisingly, the Diels-Alder addition is completely suppressed
for conjugated dienes including a variety of steroidal
dienes 134-361, which are highly alkylated at the carbon
termini. Apparently, only ene products have been
isolated for the reactions listed in Table 2.
by only 600 cal[24,36al. This free energy difference
corresponds to a ratio of (20):(34)= 2.85:l at equilibrium!
70ZCZH5
"C02C2I1,
(34)
(35)
ox.
0
(34) 3 5
5
0
m
o
o
0
\
0
(36)
0
0
(37)
Table 2. Ene reactions of stericallr hindered 1.3-dienes.
I
No. Reactions
I
Ref.
__
\
\
,
I321
I331
[341
The competition of ene and diene synthesis in the
thermal and catalyzed reactions of acyclic 1,3-dienes
with carbonyl compounds is described in Section 6.4;
see also Table 3.
Maleic anhydride is generally less effective as an enophile than diethyl azodicarboxylate, but more efficient as a dienophile. Consistently, the reaction of 1,4cyclohexadiene (34) and maleic anhydride cannot be
stopped at the stage of the monoadduct (36), and (37)
2.4. 1,4-Dienes
1,4-Cyclohexadiene (34) reacts some fifteen times less
readily with diethyl azodicarboxylate than 1,3-cyclohexadiene although conjugation energy is gained in
the former and lost in the latter reaction. The equilibration of (34) and (20) with strong base has revealed
that the conjugated diene (20) is more stable than (34)
[31] a) C. F. Huebner, P . L . Strachan, E. M . Donoghue, N. Cahoon, L. Dorfman, R. Margerison, and E. Wenkert, J. org. Chemistry 32, 1126 (1967); b) E. Koerner von Gustorf, D. V. White,
B. Kim, D . Hess, and J . Leitich, J. org. Chemistry 1969, in press;
C.F. Huebener, E. M. Donoghue, C. J. Novak, L . Dorfman, and
E. Wenkerr, ibid., in press.
[321 E. M . Arnett, J. org. Chemistry 25, 324 (1960).
1331 B. T. Gillis and P. E. Beck, J. org. Chemistry 28, 3177 (1963);
see also [23b].
[34] A . van der Gen, J. Lakeman, M . A . M . P . Gras, and H . 0.
Huisman, Tetrahedron 20, 2521 (1964); see also A . van der Gen,
W . A . Zunnebeld, U. K. Pandit, and H. 0 . Huisman, ibid. 21,
3651 (1965).
1351 A. M . Lautzenheiser and P. W . LeQuesne, Tetrahedron Letters 1969, 207.
1361 D . N . Jones, P. F. Greenhalgh, and I. Thomas, Tetrahedron
24, 5215 (1968).
560
is isolated as the final product [371. Similarly, heating
of 1,4-pentadiene (38) with maleic anhydride affords
in 40% yield the bisanhydride (40), which is decarboxylated to the spirodilactone (41) by traces of alkali 1381. On heating to 120 "C in benzene solvent, maleic
anhydride forms the normal ene product with 1,4-dihydronaphthalene [391 and cinnamylsuccinic anhydride
[36a] H . Oberhammer and S. H. Bauer, J. Amer. chem. SOC.91,
10 (1969).
(371 K . Alder and F. Mum, Liebigs Ann. Chem. 565, 126 (1949).
[38] R. K. Hill and H. J . Barjer j r . , J. org. Chemistry 30, 2558
(1965).
[39] K . Alder, H . Wollweber, and H . Spanke, Liebigs Ann.
Chem. 595, 38 (1955).
Angew. Chem. internat. Edit.
Vol. 8 (1969) I No. 8
0
(421
(43)
(43) with allylbenzene (42) 1401. Whether (43) is formed as the trans and/or cis isomer is unknown.
In norbornadiene (44) a shift of the double bond is
forbidden by Bredt's rule. With diethyl azodicarboxylate the 2 + 2 + 2 adduct (44a) and an isomeric compound have been detected in approximately equimolar
quantities 1411. Later,?work
has suggested the unusual
yields the Diels-Alder adduct (48) only 144aI. Clearly,
any cisoid diene component of triene (45) contains at
least one terminal cis alkyl group, an unfavorable
situation in a Diels-Alder addition 1451. On the other
hand, the cis configuration of the vicinal methyl
groups in (47) impedes the ene reaction (Table 1,
entry 4), while the methyl and isobutenyl group
attached to the reacting cisoid diene system are trans
and probably promote the cycloaddition. Interestingly, the less hindered and more reactive singlet
oxygen gives only one stable ene adduct with either
allocimene; cycloperoxides are not formed [44b7.
Not surprisingly, triene (49) undergoes the ene rather
than diene synthesis 1461.
(444
structure (446) for the second adduct, i.e., the azo
ester behaves as a heterodiene 1421 analogous to the
formation of (31).
2.5. Conjugated Trienes
The allocimene (45) (431, a naturally occurring triene,
reacts cleanly with diethyl azodicarboxylate to form
(46) under self-heating, while the isomeric triene (47)
r"
t
d
(45)
m*O
f 48)
(47)
MA_
0
(49)
O
0
m
o
0
o
0
(50)
[40] C. S. Rondestvedt jr., Org. Syntheses 31, 85 (1951); see also
1111.
[41] S. J. Cristol, E. L . Allred, and D. L . Wetzel, J. org. Chemistry 27, 4058 (1962); R. M. Moriurfy, ibid. 28, 2385 (1963).
(421 J. J . Tufariello, T. F. Mich, and P. S. MilIer, Tetrahedron
Letters 1966, 2293.
[431 For a discussionof the nomenclature and configuration of the
alloocimenessee K. J. Crowley, J . org. Chemistry 33,3679 (1968).
Angew. Chem. internat. Edit. J Vol. 8 (1969)1 No. 8
Cycloheptatriene reacts with a variety of dienophiles
such as maleic anhydride [47a947bl, 4-phenyl-l,2,4-triazoline-3,Sdione Q71, fumaryl chloride [47aI, and dimethyl and diethyl acetylenedicarboxylate147~1 to
form Diels-Alder adducts of the general structure (52),
in which the cyclopropane ring is oriented syn to the
double bond. Recently, Woodward and Houk 1481 have
concluded that (52) arises from a 2 + 2 + 2 cycloaddition rather than from attack on the norcaradiene
valence tautomer as had been frequently suggested 1491.
Dimethyl acetylenedicarboxylate does not only form
the Diels-Alder product (26% yield); in addition, a
minor product (55) (12%) has been observed which
seems to arise from an ene reaction followed by electrocyclic closure and a 3,3-sigmatropic process 1501.
With diethyl azodicarboxylate 151 a,bl :and singlet oxygen [51b1 cycloheptatriene undergoes the ene reaction
exclusively to form adducts (56a) and (56b), respectively. It is of interest how (56a) is actually formed. By
using [7-D]-cycloheptatriene, Koerner von Gustorf has
[44] a) E. Koerner von Gustorf, Tetrahedron Letters 1968, 4693;
see also E. Koerner von Gustorf and J. Leitich, ibid. 1968, 4689;
b) E. Koerner von Gustorf, F.-W. Grevels, and G. 0. Schenck,
Liebigs Ann. Chem. 719, 1 (1968).
[45] J . Suuer, Angew. Chem. 79, 76 (1967); Angew. Chem. internat. Edit. 6, 16 (1967).
[46] D. T. Longone and F.-P. Boettcher, J. Amer. chem. SOC.85,
3436 (1963).
[47] a) K. Alder and G . Jacobs, Chem. Ber. 86, 1528 (1953);
b) E. P . Kohler, M . Tishler, H . Potter, and H. T. Thompson,
J. Amer. chem. SOC.61, 1057 (1939); c) M . J. Goldstein and A . H.
Gevirtz, Tetrahedron Letters 1965, 441 7.
[481 K. N. Houk, Ph. D. Thesis, Harvard University, Cambridge,
Massachusetts 1968.
1491 See G . Muier, Angew. Chem. 79,446 (1967); Angew. Chem.
internat. Edit. 6,402 (1967).
[SO] M . J . Goldstein and A . H. Gevirtz, Tetrahedron Letters
1965, 4413.
[ X I a) J. M . Cinnamon and K. Weiss, J. org. Chemistry 26, 2644
(1961); b) G . 0. Schenck, E. Koerner von Gustorf, B. Kim, G. v.
Binau, and G. Pfundt, Angew. Chem. 74, 510 (1962); Angew.
Chem. internat. Edit. I, 516 (1962); c) E. Koerner yon Gusto%
private communication; d) E. Koerner von Gustorf and D . V.
White, unpublished.
56 1
3,3-shift
___j
(55)
(54)
(53)
propyne (59) inter alia affords (61)and (62). The two
bis-adducts seem to arise from the reaction of the intermediate allene (60) with an excess of benzynec531.
Whether the allenes (58) and (60) are formed in a
concerted process or not is presently not clear. A
further "record enophile" is perfluorocyclobutanone
which undergoes the ene reaction with methylacetylene
and allene (Scheme 8) 1541. Tetramethylallene reacts
(56 d/
(56~)
shown recently that (56c) and (56d) arise in a ratio of
7 3 , no deuterium being detectable at the C-3 and C-4
carbon. Apparently, the ene reaction cannot only
proceed via a 6-membered ring, but also a 10-membered one, provided the loss in entropy is not too high.
Clearly both reaction modes are symmetry allowed[slc]. (Cf. also the ene reaction in Scheme lZa,
which may be regarded as a 10-electron or even a 14electron process.)
2.6. Propynes and Allenes
Fz
Fz
Scheme 8
smoothly with azodicarboxylic esters and 5-phenyl1,2,4-triazoline-3,5-dioneto give the corresponding
ene adducts at room temperature f51dl; in these reactions the enophile attacks the central carbon of tetramethylallene.
2.7. Strained x - and o-Bonds
Only the most powerful enophiles react with propynes in
the sense of the ene reaction and few examples have been
reported. 1-Hexyne(57) reacts with benzyne to form the
allene (58) in less than 4 % yield [521, while 1-ethoxy-
C,H,-CH2-C=CH
0
<4%-
Olefins with strained double bonds seem particularly
prone to enter into ene reactions. For example, the
naturally occurring sesquiterpene caryophyllene
(63), which contains a strained trans double bond,
H\
C=C=CH-C,H,
+
(59)
other
products
c62H55m
C H O
(62)
[52] M. Stiles and A . Haag, private communication to R. w.
Hoffmann, cited in: Dehydrobenzene and Cycloalkynes. Academic Press, New York 1967, p. 198.
562
1531 H . H. Wasserman and J. M . Fernandez, J. Amer. chem. SOC.
90, 5322
[54] D. C. England, J. Amer. chem. SOC. 83, 2205 (1961).
Angew. Chem. internat. Edit.
/ Vol. 8 (I969) / No. 8
H5c6@C6H5
D
H5C6w
c
6
H
5
c6H5
reacts smoothly with maleic anhydride in refluxing
benzene. Originally the product was formulated as
a Diels-Alder adduct [55b,c,dI but after the structure
of caryophyllene had been elucidated Nickon deduced
structure (64) for the product 15SaI. However, when
the comparatively energy rich singlet oxygen is used
as the enophile, caryophyllene reacts only about 5-6
times faster than its cis isomer (iso-caryophyllene)[55eI.
The exocyclic double bond is not attacked by singlet
oxygen [55fI,although it is more accessible.
The deuterated triphenylcyclopropene (65) dimerizes
in 20% yield on heating in toluene; the product has
been formulated as the cis dimer (66)rather than (67)
because in the formation of (66) the deuterium is
transferred to the less hindered face of the second
cyclopropene system [561. Even more spectacular is the
dimerization of the parent cyclopropene, which has
been observed recently by Dowd and Gold[571. Such
is the reactivity of this hydrocarbon that it polymerizes
with explosive violence at room temperature. However, if it is allowed to react in dilute dichloromethane
CsH5
(68) of benzene and isoprene dimerizes to (69), a
single compound or a mixture of two stereoisomers
being formed below room temperaturersgal! In contrast, olefin (70), which contains a less crowded trans
double bond, affords (71)[58bl in a symmetry-allowed
x2s + K2acycloaddition [591.
Considerable interest has focused recently on reactions of strained hydrocarbons such as bicyclo[l.l .O]butanes and bicyclo[2.1.O]pentanes, in which the zero
bridge exhibits a major degree of unsaturation [601.
3-Methylbicyclo[l.l.O]butanecarbonitrile (72) has
Scheme 9
solution at -25 “C, the extremely labile dimer can be
isolated (Scheme 9). This reaction is probably not a
free radical process as had been suggested earlier, since
neither added nitrobenzene nor p-benzoquinone have
been treated with a variety of olefins and carbonyl
shown any effect on the rate of dimerization.
compounds; with hexafluoroacetone in ether solution
The behavior of some bridged cis,trans-l,5-cycloocta- the cyclobutene derivative (74) is formed in 82%
dienes whose trans double bond is considerably
yield below room temperature [61al; dicyanoacetylene
twisted is also of great interest. Thus, the photoadduct
[ 5 5 ] a) A. Nickon, J. Amer. chem. SOC.77, 1190 (1955); b) L.
Ruzicka, P . A . Plattner, and G . Balla, Helv. chim. Acta 24, 1219
(1941); c) L. Ruzicka and W. Zimmermann, ibid. 18, 219 (1935);
d) H. N. Rydon, J. chem. SOC.(London) 1939, 537; e) F. A. Lift
and A . Nickon, Adv. Chemistry Ser. 77, American Chemical
Society 1968, p. 118; f ) K . H . Schulte-Elte and G . Ohloff, Helv.
chim. Acta 51, 594 (1968).
[56] R. Breslow and P . Dowd, J. Amer. chem. SOC.85, 2729
(1963).
1571 P. Dowd and A . Gold, Tetrahedron Letters 1969, 85.
Angew. Chem. internat. Edit.
/ VoI. 8 (1969)1 No. 8
1581 a) K . Kraft and B. Koltzenburg, Tetrahedron Letters 1967,
4723; b) ibid. 1967, 4357.
1591 R. B. Woodward, Lectures held at the IUPAC Symposium
on “Valence Isomerization”, Karlsruhe, Sept. 1968, and the
Symposium on “Orbital Symmetry Correlations in Organic Reactions”, Cambridge, England, January 1969.
[60] M . Pomerantz and E. W. Abrahamson, J. Amer. chem. SOC.
88, 3970 (1966).
I671 a) E. P . Blanchard j r . , and A. Cairncross, J. Amer. chem.
SOC.88, 487 (1966); b) P . G . Gassman and K . T. Mansfield, ibid.
90, 1517 (1968).
563
A
6.5
:
1
Scheme 10
to 1,3-dimethylbicyclo[I.l.O]butane, which under the
same conditions yields the ene adduct only [62al.
gives rise to (75) and three unidentified very minor
by-products f61bI.
In analogous fashion 1,3-dimethylbicyclo[l.l.O]butane
reacts with dehydrobenzene [62aI, hexafluoroacet-
I
CN
6.7%
(12%)
one [62bI, and maleic anhydride C62bI. The propanobridged bicyclobutane (76) and dehydrobenzene
afford (77) in 61 % yieldC631 while hydrocarbon (78)
which contains the structural element of bicyclo[2.1.0]pentane reacts with dicyanoacetylene (79) to form
(80) in 46 % yield C641.
Frequently, bicyclobutanes and bicyclopentanes react
with olefins to give not only ene products, but also
cycloadducts. In these cases a stepwise mechanism
involving biradical intermediates seems assured, at
least for the formation of the cycloadducts (cf. also
Scheme 3). For example, the reaction of bicyclobutane
with dehydrobenzene gives rise to benzobicyclo[2.1.1]hexene as a by-product 1651 (Scheme lo), in contrast
[62] a) M . Pomerantz, G . W . Gruber, and R. N . Wilke, J. Arner.
chem. SOC. 90, 5040 (1968); b) M . R. Rifi, ibid. 89, 4442 (1967).
[631 P. G. Gassman and G. D . Richmond, J. Amer. chem. SOC.
90, 5637 (1968).
[64]P. G. Gassman and G . D. Richmond, Chem. Commun. 1968,
1630.
[65]M. Pomerantz, J. Amer. chem. SOC.88, 5349 (1966).
564
Five of seven products have been identified in the reaction of bicyclo[2.1.O]pentane with maleonitrile and
fumaronitrile, respectively (Scheme 11; the yields in
brackets refer to the reaction with fumaronitrile).
Clearly, the three isomeric 2,3-dicyanonorbornanes are
formed in either reaction, and hence rotation about
the central bond of maleonitrile and fumaronitrile
must have occurred at some stage during the reaction.
Since a concerted formation of the cycloadducts is also
forbidden by orbital symmetry conservation, the experimental findings are best accommodated by a biradical intermediate, in which rotation about a carboncarbon single bond may compete with intramolecular
radical combination [661. 1:1 Cycloadducts which are
derived from the bicyclo[2.l.l]hexane skeleton (8Z)
H
0.3%
(2 .I%)
CN
0.4%
(3.0%)
Scheme 11
can also be isolated in reactions of 3-methylbicycloE1.1.O]butane-1-carbonitrile (72) with ethylene, butadiene, styrene, acrylonitrile, maleonitrile, fumaronitrile, and I-(N,N-dimethy1amino)cyclopentene1671.
endo
(82)
As regards stereochemistry the enophile could attack
the zero bridge from the exo or endo direction (82).
The formation of the endo adducts (77) and (80)
demonstrates for two specific examples that it is the
backlobe of the zero bridge which is most vulnerable
[66] P. G. Gassman, K . T. Mansfield, and T. J . Murphy, J. h e r .
chem. SOC. 91, 1648 (1969).
[67]A . Cairncross and E. P. Blanchard jr., J. Amer. chem. SOC.
88, 496 (1966).
Angew. Chem. internat. Elfit. I Vol. 8 (1969) J No. 8
to attack from enophiles. In fact, much further work
with deuterium labeled substrates suggests that endo
attack is a general feature of these reactions[6*.691
[cf. also the pyrolysis of (118)l.
3. TheEnophile
3.1. Alkenes
One of the most widely used enophiles of this type is
maleic anhydride. In fact, its reactions with caryophyllene [55l and with naturally occurring unsaturated
fatty acids and esters [2,31 represent the first recorded
examples of ene reactions in all-carbon systems, and
much further work has been reported since
then [12,14,701. Typical conditions for reactions of
simple allylic compounds are 20 hours and 220"C,
an aromatic solvent generally being used. Trichlorobenzene is a particularly suitable solvent owing to its
high boiling point (200-210 "C) which makes an autoclave unnecessary. Polymerization of the reactants and
products can be inhibited by adding thionine or phenothiazine. Under these conditions the ene adducts have
been isolated in up to 80% yield[711. Tetracyanoethylene appears to have been used only rarely as an
enophile 135,721. m,P-Unsaturated ketones [731, esters [73J,
and nitriles [73al, in which the olefinic bond is activated
by only one electron-attracting group, are less reactive
than maleic anhydride.
3.2. Akynes
The parent acetylene has been shown to react with
isobutene at 350 "C under special conditions [71.
Acetylenedicarboxylic esters 150, 73b7741, propiolic ester [73b, 743, and dicyanoacetylene[61b3641 generally
react below 200°C, even with unactivated ene components. Hexafluoro-2-butyne readily forms 1,4dienes with isobutene and 2-butene according to
Scheme 12; in fact, it seems somewhat difficult to isolate the monoadduct in these reactions. Trifluoropropyne is less reactive, requiring temperatures of ca.
225 "C 1741.
Dehydrobenzene is strongly electrophilic and is also
one of the most powerful enophiles. Simple olefins
such as isobutene [75a1,2,3-dimethyl-2-butene[75b1, and
cyclohexene 175c3 are readily phenylated with shift of
the double bond. The ene synthesis can also compete
favorably with the Diels-Alder addition in reactions
of dehydrobenzene with open-chain dienes, but less so
with cyclic dienes, where the cisoid conformation
Table 3. Ene synthesis w r m s Diels-Alder addition in reactmns of
dehydrobenzene with conjugated dienes.
Nu.
-
I Products
Olefine
1
Ref.
1
2
3
19%
50%
necessary for a 4 + 2 addition is enforced (Table 3).
Apparently, in all three reactions listed in Table 3,
further as yet unidentified products are formed L75a, 75dl.
Interestingly, even alkylarenes enter into ene reactions
with dehydrobenzene as could be shown recently by
Friedman et al. For example, the major product (46 %)
in the reaction of dehydrobenzene with toluene is 1benzyl-2-phenylbenzene, which is formed in a "doubleene reaction"; Diels-Alder addition and insertion to
diphenylmethane (trace) are less important here
(Scheme 12a). Ethylbenzene and isopropylbenzene
r
1
L
46%
Scheme 12
1681 a) W. R. Roth and M . Martin, Tetrahedron Letters 1967,
3865,4695; Liebigs Ann. Chem. 702,l (1967); b) E. L. Allred and
R. L. Smith, J. Amer. chern. SOC.89,7133 (1967).
[69] See also M . Pomerantz and R . N . Wilke, Tetrahedron Letters 1969, 463.
1701 J. Ross, A. I. Gebhart, and J . F. Gerecht, J. h e r . chern.
SOC.68,1373 (1946); K . Alder and H. Soll, Liebigs Ann. Chem.
565, 57 (1949).
1711 W. StumpA F. Derichs, K . Rombusch, and W. Franke,
Liebigs Ann. Chem. 687,124 (1965).
[72] T . L. Cairns and B. C. McKusick, Angew. Chem. 73, 520
(1961).
[73] a) C. J. Albisetti, N . G. Fisher, M . J. Hogsed, and R. M .
Joyce, J. Amer. chern. SOC.78, 2637 (1956); b) K. Alder and H.
von Brachel, Liebigs Ann. Chem. 651, 141 (1962).
[74] J . C . Sauer and G . N . Sausen, J. org. Chemistry 27, 2730
(1962).
Angew.
Chem. internat. Edit. f Vol. 8 (1969)J No. 8
3 8%
+
16%
QfHz'o
trace
Scheme 12a
1751 a) G . Wittig and H. Dlirr, Liebigs Ann. Chem. 672, 55
(1964); b) G. Wittig and R. W. Hoffmann, Chern. Ber. 95, 2718
(1962); c) H . E. Simmons, I. Amer. chern. SOC. 83, 1657 (1961);
see also J . A. Kampmeier and A . B. Rubin, Tetrahedron Letters
1966, 2853; d) R. Huisgen and R. Knorr, Tetrahedron Letters
1963, 1017.
565
react similarly, but tert-butylbenzene, which does not
contain an allylic hydrogen, failed to give any ene
product, as expected. Tetrafluorobenzyne and tetrachlorobenzyne only yield Diels-Alder adducts with
toluene.
1-Methylnaphthalene undergoes (4 + 2) cycloaddition
exclusively with preferential attack (63 %) of the methylated ring. In contrast, 2-methylnaphthalene not only
forms Diels-Alder adducts, but also the double ene
product 2-benzyl-1-phenylnaphthalenein 38 % yield.
Apparently, this difference is due to a simple electronic
effect, i.e., enophiles, like electrophiles, attack preferentially the more electron-rich a-carbon of naphthalenes 1761.
Altogether, alkynes undergo the ene reaction more
readily than comparable alkenes (cf. also Section 6.1).
3.3. Azo Compounds
The most widely used derivative is diethyl azodicarboxylate, which reacts under rather mild conditions
with ene components, heating to 80°C for a few
hours being sufficient to complete the reaction [8,771.
The same compound also enters into ene reactions
aldehydes, ketones, disulfides, azobenzenes, and azobenzene, respectively, while itself being converted into
diethyl hydrazodicarboxylate 181al. Similarly, it abstracts hydrogen M to oxygen in ethersrslbl and cc to
sulfur in sulfides [81cl. Reaction with cyclohexanone
affords (84), the formation of which is weakly catalyzed by free radical initiators but strongly basecatalyzed [81dI.
3.4. Carbonyl Compounds
Thereaction of formaldehydewith olefins is of industrial
interest and has been studied with unusual intensity.
When the reaction is carried out thermallyin the absence
of catalyst, the products are generally those expected
from ene reactions. However, there still exists a great
deal of mechanistic :uncertainty and even confusion
about acid-catalyzed reactions (“Prins reactions”) 2831,
which appear to react1partly in the sense of the ene reaction, partly via an electrophilic addition of protonated
formaldehyde (cf. also Section 6.5 and Table 5, No. 5).
The reaction of cyclohexene with aqueous formaldehyde in sulfuric acid may serve as a n example for the
complexity of the product mixtures (Scheme 14) C821
that may be obtained.
,C6H5
’N-N(
N=N‘
C2H502C’
C2H50,C’
C02C2H5
Scheme 13
with conjugated dienes and trienes, 1,4-dienes (see
above) and with aldehyde hydrazones (Scheme 13) 1781.
If the azo-linkage is present in the cis-configuration
as in photochemically generated azodicarboxylate [25 26,791 and in 4-phenyl-l,2,4-triazoline-3,5-dione
(83) 1271 the dienophilic properties are considerably
enhanced. In fact, (83) is a “record dienophile” which
reacts smoothly with a variety of conjugated dienes C27,803 and cycloheptatrienet7-71.
Clearly, the presence of mineral acids makes it difficult
to determine the products of kinetic control and only
little mechanistic insight can be gained. Investigations
with Blomquist’s system of catalysts[211 could be of
interest.
24.0%
36.1%
22.3%
+G+@-)+
8
CHzOH
7.8%
7.270
2.870
Scheme 14
It must be mentioned that diethyl azodicarboxylate
has general hydrogen-abstracting properties. For
example, it smoothly oxidizes primary and secondary
alcohols, thiols, anilines, and hydrazobenzene to
[76] L. Friedman and J . M . Brinkley, private communication.
[77] 0. Achmatowicz and 0. Achmatowicr jr., Roczniki Chem.
37, 317 (1963).
1781 B. T . Gillis and F. A. Daniher, J. org. Chemistry 27, 4001
(1962).
1791 S e e B. T. Gillis in J. Hamer: 1,4-Cycloadditions. Academic
Press, New York and London, 1967, p. 143 for 1,4-cycloadditions of diethyl azodicarboxylate.
[80]J . Sauer and B. Schroder, Chem. Ber. 100, 678 (1967).
566
1811 a) F. Yoneda, K. Suzuki, and Y. Nitta, J. h e r . chern. SOC.
88, 2328 (1966); b) R. C. Cookson, 1. D . R. Stevens, and C. T.
Watts, Chem. Commun. 1965, 259; c) R . B. Woodward, K. Heusler, J. Gosteli, P. Naegeli, W. Oppolzer, R. Ramage, S. Ranganathan, and H. Vorbriiggen J. Amer. chem. SOC.88,852 (1966);
d) R. Huisgen and F. Jacob, Liebigs Ann. Chem. 590, 37 (1954).
[82] 0. Kovacs and I. Kovari, Magyar. kem. Folybirat 70, 223
(1964); Chem. Abstr. 61, 5528b (1964).
[83] C. W. Roberts in G . A . Olah: Friedel-Crafts and Related
Reactions, Interscience, New York 1964, Vol. XI, Part 2, p. 1175;
V. I. Isagulyants, T. G . Khaimova, V. R. Melikyan, and S. V.
Pokrovskaya, Usp. chim. 37, 61 (1968); E. Arundale and L. A .
Mikeska, Chem. Reviews 51, 505 (1952); see also L. J . Dolby,
C. L. Wilkins, and R. M . Rodia, J. org. Chemistry 33,4155 (1968);
B. Fremaux M . Davidson, M . Hellin, and F. Coussemant, Bull.
SOC. chim. France 1967, 4250; M . Heifin, M . Davidson, and
F. Coussemant, ibid. 1966, 1890, 3217.
Angew. Chem. internat. Edit. 1 Vol. 8 (1969) No. 8
Higher aldehydes react less readily and apparently
only if enolization is blocked. Trichloroacetaldehyde r15cl and phenylglyoxal [I41 react with monoolefins of the methylenecyclohexane type, but the
former has been reported not to react with less active
ene components [841, although it does react readily
if an electrophilic catalyst such as stannic chloride is
present (see Section 6.4).
react f89b3. Ene reactions with carbonyl chloride and
carbonyl fluoride have to the knowledge of the author
not yet been described or have failedf841. Possibly,
the ene components employed have not been sufficiently reactive, or alternatively the first formed adducts liberate acid which destroys reactants and products alike (cf also Scheme 17). The presence of a suitable acid trapping reagent might bring about a change.
A variety of ketones has been employed as enophiles.
Diethyl mesoxalate reacts with I-pentene (Scheme 15),
cyclohexene, and a-methylstyrene; as an enophile it
+
160°C
C~HS-CH~-CH=CHZ O=C(COzC2H& d
8h
C~HS-CH=CH-CH~C(CO~C~H~)~~H
CO(CN)>
H2c\,
Scheme 15
-HCN
appears to be superior to formaldehyde, but inferior
to carbonyl cyanide 1851. Methyl pyruvate and P-pinene
form an adduct ( 5 5 % ) in a readily reversible process
(Scheme 16) I861 (cf. also Section 5.2).
y
3
::
C-CH-C(CN)zOCCN
CsH:
R e C H = C H C H 3
(85u), R = CH,O
( M b ) , R = (CH,),N
(SSc), R = NO,
Scheme 17
H3F/COzCH3
P
Scheme 16
Perhaloketones such as hexafluoroacetone and symdichlorotetrafluoroacetone add to a variety of ene
components. The reaction with isobutene, P-pinene,
and isopropenyl methyl ether occurs already at room
temperature in high yields (80 %). It has been asserted
on rather little evidence that a stepwise rather than concerted mechanism best accounts for the experimental
observations f871. The most remarkable of all perhaloketones is perfluorocyclobutanone which reacts with
alkynes and allenes (Scheme 8) [541.
Ene reactions with carbonyl cyanide have been studied
in some detail by a Polish group. Generally, the first
formed adduct alcohols are not so easy to isolate; as
they are fairly acidic, they readily lose hydrogen
cyanide and react with a second molecule of carbonyl
cyanideL881 (Scheme 17). In analogy to Diels-Alder
additions electron-rich ene components such as the p methoxystyrene derivative (85a) and, even more so,
(856) react readily with carbonyl cyanide [89aI, while
the electron-deficientp-nitro derivative (85c) failed to
[84] 0. Achmatowicz and 0. Achmatowicz j r , , Roczniki Chem.
36, 1812 (1962).
[85] 0. Achmatowicz and 0 . Achmatowicz jr., Roczniki Chem.
36, 1791 (1962).
1861 R. T. Arnold and P. Veeravagu, J. Amer. chem. SOC.82,
5411 (1960).
1871 R. L. Adefman, J. org. Chemistry 33, 1400 (1968).
I881 0. Achmatowicz and K . BeIniak, Roczniki Chem. 39, 1685
(1965).
[89] a) 0. Achmatowicr, 0. Achmatowicz j r . , K . Belniak, and
J. Wrobel, Roczniki Chem. 35, 783 (1961); b) 0. Achmatowicz
and J . Szychowski, ibid. 37, 963 (1963).
Angew. Chem. internat. Edit. / Vol. 8 (1969) No. 8
Hexafluorothioacetone is not only a highly active
dienophile which reacts instantaneously with butadiene at -78"C, thus allowing a titration of the
diene [903, but also forms adducts with ene components
under similar conditions. It is worthy of note that the
orientation (Scheme 18) is the reverse of that for ene
reactions with carbonyl compounds [911 (cf. Section
6.1).
Scheme 18
3.5. Singlet Oxygen
The dye-sensitized photooxygenation of olefins and
dienes has long been known 116,921, but only recently
Foote
has shown that the reactive intermediate is
the first excited singlet state of molecular oxygen
[Oz(lAg)], which is only 22 kcal above the ground
state; Oz(1Ag) resembles ethylene electronically, but
is more electron-deficient. The reactions with singlet
oxygen have contributed substantially to our mechanistic understanding of the ene reaction and lead to
allylic hydroperoxides which can be reduced smoothly
1901 W. J. Middleton, J. org. Chemistry 30 1390 (1965).
[91] W. J. Middleton, J. org. Chemistry 30, 1395 (1965); W. J.
Middleton, E. G. Howard, and W. H . Sharkey, J. Amer. chem.
SOC.83, 2589 (1961).
1921 K. Gollnick and G. 0. Schenck, Pure Applied Chemistry 9,
507 (1964); K . Gollnick, Adv. Photochemistry 6 , 1 (1968); for the
behavior of singlet oxygen as a dienophile see K. Goflnick and
G. 0. Schenck in J . Hamer: 14-Cycloaddition Reactions, Academic Press, New York, 1967, p. 255.
567
to the allylic alcohols. The alcohols derived from
limonene (16) are natural products, and in the case of
the carveyl alcohols are formed via the carveyl hydroperoxides (85d) and (85e) with complete conservation
of chirality at the C-4 carbon, i.e., this reaction does
not involve a substituted cyclohexenyl radical intermediate (85f) which is symmetrical [20al.
(Scheme 19). What has been said above for the Prins
reaction is even more relevant to this reaction, i.e. the
products of kinetic control are hard to isolate.
4. Intramolecular Ene Reactions
4.1. 1,3- and 1,4-Dienes
The 1,s-hydrogen shift of cis-l,3-pentadienes (Scheme
2) occurs smoothly at about 150-200°C and may
be classified as an intramolecular ene reaction. The
most simple homovariant of this reaction is provided
3.6. Sulfur Trioxide and Selenium Dioxide
Sulfur trioxide reacts with a variety of ene componentsL931 and it has been suggested that the sulfonic acid (7) is formed from methylenecyclopentane
in concerted fashion C131. Until recently, selenium dioxide was believed to form cyclic selenones (86) with
RneZ\
0
R
+
0
SeOz
4.2. 1,CDienes
"PXO
R
o
various substituted butadienes. A reinvestigation has
revealed that unlike sulfur dioxide, selenium dioxide
possesses dienophilic properties and forms adducts
(87) instead [941. Therefore, it seems reasonable to
conclude that selenium dioxide also possesses enophilic properties and that allylic oxidations with this
compound proceed at least in part by an ene reaction.
In fact, Schaefer
and Trachtenberg [951 have proposed an ene type mechanism via a hypothetical selenium(r1) ester which is solvolyzed to the products
H
SeO2
C6H5CF
CH=CH
--t
OSeOH
I
CGHsCH=CH-CHCsH,
AcoH
C6H5~H-CH=CHC6H5+ H2Se02
OAc
Scheme 19
[93] F. G. Bordwell, C. M . Suter, and A. J. Webber, J . Amer.
chem. SOC. 67,827 (1945); for the behavior of sulfur trioxide
as a dienophile see F. G . Bordwell, R. D. Chapman, and C. E.
Osborne, ibid. 81, 2002 (1959).
[94] W.L. Mock and I. H . McCausland, Tetrahedron Letters
1968, 391.
1951 E. N. Trachtenberg in R. L . Augustine: Oxidation. Marcel.
Dekker, Inc.. New York 1969; see also G . Buchi and H. Wuest,
J. org. Chemistry 34, 857 (1969).
568
by the isomerization of cis-1,Chexadiene (88), which
on heating to 400 "C forms (90); a rapid pre-equilibrium of (88) and (89) is followed by irreversible
formation of the product (90)1961. Both 1,5-hydrogen
shifts 16,971 and their homocounterpart 16,97,981 have
been reviewed. 1,5-Dienes undergo 3,3 shifts (Cope
rearrangement).
1,6-Octadiene (91a) (a mixture of the cis and trans
form being used) has been reported to cyclize at elevated temperatures to the cis substituted cyclopentane
(92a) exclusively; similarly, (916) has been assumed
to furnish the cis isomer (926) only[W In contrast,
(91a), R = H
(91b). R = CHs
(%?a), R = H
(92b). R = CHs
3,7-dimethyl-l,6-octadiene(94), which may be prepared in 90 % yield [1001 from cis-pinane (93)via a 2 + 2
cycloelimination, cyclizes under the same conditions to
[96] W . R. Roth and J. Konig, Liebigs Ann. Chem. 688,28 (1965).
[97] D. S. Glass, R. S. Boikess, and S. Winstein, Tetrahedron
Letters 1966,999;H . M . Frey and R. Walsh, Chem. Rev. 69,103
(1 969).
[98] E.N. Marvell, D. R. Anderson, and J . Ong, J. org. Chemistry
27, 1109 (1962);A. Habich, R. Barner, R. M . Roberts, and H.
Schmid, Helv. chim. Acta 45, 1943 (1962);R. M. Roberts and R.
G. Landolt, J . h e r . chem. SOC. 87,2281 (1965);R. M. Roberts,
R . N. Greene, R. G. Landolt, and E. W. Heyer, ibid., p. 2282;
A. Habich, R. Barner, W . von Philipsborn, and H . Schmid, Helv.
Chim. Acta 48, 1297 (1965);G. Frdter and H . Schmid, ibid. 49,
1957 (1966);R. M . Roberts and R. G. Landolt, J . org. Chemistry
31, 2699 (1966);A. Jeffetson and F. Scheinmann, Chem. Commun. 1966,239,316.
[99] W . D. Huntsman, V. C . Solomon, and D . Eros, J. Amer.
chem. SOC. 80, 5455 (1958).
[lo01 a) R. Rienacker, Brennstoff-Chem. 45, 206 (1964); b) R.
Rienacker and G. Ohloff,Angew. Chem. 73,240 (1961).
Angew. Chem. internat. Edit. 1 Vd. 8 (1969) 1No. 8
give a mixture of isomeric cyclopentanes considered
to be (95) (main product) and (96) (minor product) [loll. The steric course of the cyclhation of linalool
(102) 4%
(103) 72%
I
(93)
(97) has been investigated in much greater detail and
it has been shown that all four possible diastereomeric
plinols (97a) -(97d) are formed. The formation
The two x-bonds of the birdcage homolog (IOSa) are
relatively strain-free, but they are held rigidly in almost parallel planes and separated by only about 2 A;
(I0Sa)
tendency of the four isomers can be related qualitatively to the number of conformations which are favorable
and unfavorable for the respective cyclizations [101aI.
6-Octen-l-yne (98) cyclizes at 400 "C to (99) in 65 %,
yield. Clearly, rupture of an acetylenic x-bond requires less energy than that of an ethylenic z-bond,
and the alkenyne is still sufficiently flexible for the
reaction to occur 11021. An interesting intramolecular
ene reaction of a 1,6-diene has been described by
Roth [61. On heating to only 250 "C the strained trans,
trans-l,6-cyclodecadiene (100) isomerizes to a mixture of (102), (103), (10.51, and cis,cis-1,6-cyclodecadiene (104). A product mixture of identical composition is obtained from cis,cis-l,6-cyclodecadiene at
320 "C. These Endings are best accommodated by the
biradical intermediate (lor), which not only forms
(103) (main product), but also collapses to the isomeric cyclobutanes (102) and (105) (cf. also Scheme
3). Molecular models show that a concerted intramolecular ene reaction of cis,cis-l,6-~yclodecadieneis
geometrically not feasible. The transformations of
(100) into (103) and of (104) into (103) represent two
examples of stepwise ene reactions which are conformationally enforced.
[loll H. Pines, N. E. Hoffman,and V. N. Ipafieff,J. h e r . chem.
SOC.76,4412 (1954); see also W. D. Huntsman and T. H. Curry,
ibid. 80. 2252 (1958).
[lola] H . Stiickler, G. Ohloff, and E. sz. Kovcfrs, Helv. chim.
Acta 50, 759 (1967).
11021 W. D . Huntsman and R . P. Hall, J. org. Chemistry 27,
1988 (1962).
Angew. Chem. internat. Edit. 1 VoI. 8 (1969) 1 No. 8
(10%)
(IOSa) has been found to cyclize to (10Sb) with a
half-life of about six hours at 45 "C [102aJ! The most
simple 1,6-diene, i.e., 1,6-heptadiene does not possess
a terminal methyl group and fails to cyclize up to
500 "C 1991.
4.3. 1,7-Dienes
A priori, the cyclization of 1,7-dienes can yield either
six- or eight-membered rings, and both reactions have
been observed. Generally, cyclohexane derivatives are
formed less readily than cyclopentanes in intramolecular ene reactions. Thus, 8-methyl-l,7-nonadiene
9-0
32OoC
(110)
(Ill)
[102a] J. M . Brown, J. chem. SOC.(B) (London) 1969,in press.
569
(106) fails to cyclize at 440"C, but on raising the
temperature to 490 "C an appreciable amount of (107)
is formed. However, the stereospecific formation of
the cis derivative could not be confirmed for related
examples which were investigated more thoroughly
(cf. below). The introduction of a terminal methoxycarbonyl group as in (108) facilitates cyclization, as
shown by the smooth formation of three diastereomeric menthene acetates (109) from (108). Which
stereoisomer(s) arise by kinetic control is not clear,
since the acetates (109) epimerize under the reaction
conditions 11031. 1,7-Octadiene (110) can be equilibrated with cyclooctene (111) above 320 "C. At higher
temperature the open chain isomer is favored
(cf.
also Section 5).
(+)- D- Citronella1
(-) -1sopulegol
(60%)
(+)-nee-
I sopulego1
(20%0)
(+ ) - iso- Isopulegol (+) -neoiso - Isopulegol
(15%)
(5%)
Scheme 19a
4.4. Unsaturated Carbonyl Compounds
Conia and his co-workers have cyclized a great
variety of ethylenic ketones of the general type (112)
to the corresponding cycloalkyl ketones (114). The
reactions proceed under comparatively mild conditions
(cu. 300"C, 1 h); cyclopentyl ketones (n = 5) are
generally formed quantitatively. Seven- and eightmembered rings (n = 7,8) can also be obtained, albeit
in lower yield. On heating to 390 "C for 30 min even
11-dodecen-Zone [(112), R = CH3, R1 = H; n = 91
forms the corresponding nine-membered ketone in a
respectable yield of 30 % [104dJ.Of necessity, the cyclization involves enol (113), the formation of which
from (112) via a concerted thermal 1,3-hydrogen shift
is forbidden 141. Interestingly, the formation of the
enol and hence cyclization can be accelerated by
catalytic amounts of water and by using reaction
vessels made of ordinary glass instead of Pyrex [104fJ.
If R1 + H, the product (114) cannot epimerize via
enolization and more detailed investigations have
shown very recently that not only the cis but also the
trans isomers are formed [104fI.
(1031 W. D. Huntsman, P. C. Lung, N. L . Madison, and D . A.
Uhrick, J. org. Chemistry 27, 1983 (1962).
[lo41 a) F. Rouessac, P. Le Perchec, and J.-M. Conia, Bull. SOC.
chim. France 1967,818; b) P. Le Perchec, F. Rouessac, and J.-M.
Conia, ibid. 1967, 822; c) p. 826; d) J.-M. Conia and F. Leyendecker, ibid. 1967, 830; e ) R . BIoch and J.-M. Conia, Tetrahedron
Letters 1967,3409 ;f) J.-M. Conia, Lecture held at the Symposium
on Synthetic Methods and Rearrangements in Alicyclic Chemistry,Oxford, July 1969, and personal communication of August 7,
1969; g) a good review has been written by J.-M. Conia, Bull.
SOC.chim. France 1968, 3057; for a description of the general
technique, see F. Leyendecker, G . Mandville, and J.-M. Conia,
ibid., in press.
570
Ohloffllo5al has investigated in detail the cyclization
of (+)-P-citronellal, an example of a 6-heptenal
[Scheme 19al. All four possible diastereomers are
formed in varying amounts. Isopulegol which is formed in 60% yield is a n intermediate in the technical
synthesis of (-)-menthol.
7-Octyn-2-one cyclizes at 260 "C to give two isomeric
cyclopentenes in practically quantitative yield (Scheme 20) [104~,1051.
5. The Retro Ene Reaction
5.1. Acyclic and Cyclic Olefins
On thermodynamic grounds the retro-ene reaction i s
favored with increasing temperature while the ene
reaction is facilitated by increasing pressure. The most
simple example, the decomposition of 1-pentene (cf.
Scheme 1) has been reported to occur above 400 "C.
However, whether the products of this reaction are
actually propene and ethylene, has not been investigated (1061. Intramolecular variants of this reaction
can be realized more readily, particularly in strained
medium-sized cycloalkenes (n = 8-11) which form
a,w-dienes (Scheme 21). For instance, above 320 "C
cis-cyclooctene (111) can be converted into 1,7-octadiene (110) 161. The more strained trans-cyclooctene
opens more easily, temperatures of cu. 250 "C being
[lo51 F. Rouessac, P. LePerchec, J.-L. Bouket, and J.-M. Conia,
Bull. SOC. chim. France 1967 3554; R. BIoch P. LePerchec, F.
Rouessac, and J.-M. Conia,Tetrahedron 24, 5971 (1968).
[105a] G. Ohioff,Tetrahedron Letters 1960,11,10; for the experimental part see K . H. Schulte-Eite and G. Ohioff, Helv. chim.
Acta 50, 153 (1967).
[lo61 J. F. Norris and G. Thomson, J. Amer. chem. SOC.53, 3108
(1931); see also ref. [6].
Angew. Chem. internat. Edit. VoI. 8 (1969) / No.8
n = 8-11
Scheme 21
sufficient to observe the diene. Pure trans-cyclononene
forms 1,8-nonadiene (85 %) and cis-cyclononene (15 %)
on heating to 500 "C, while under the same conditions
cis-cyclononene yields only ca. 20 % diene, 80 % of the
starting material remaining unchanged 11071. In contrast, cis-cyclodecene does not only afford 1,9-decadiene, but also vinylcyclooctane ( 5 % ) in a side reaction[lool (Scheme 22) (see also Section 6.5). It is advantageous to pyrolyze the cycloalkenes in a cyclic
extra aIIylic resonance or other factors facilitate the
breaking of the C-C bond (Table 5). The first two
reactions in Table 5 are clearly kinetically controlled,
while reactions 3 and 4 exemplify the competition of
the retro-ene reaction and the 3,3-shift (Cope rearrangement).
Table 5.
Entry
Retro-ene reactions ofy.8-unsaturated alcohols.
__
mc5H13
Reaction
+ C,H,,CH=O
78%
reactor, in which the dienes are removed immediately
as they are formed and the starting material can be
recycled continuously [100bl. Since the alkadienes boil
about 20 "C lower than the corresponding cycloalkenes, the product can be distilled off readily. Thus,
under reduced pressure and at temperatures around
600 "C it has been possible to isolate the a,w-dienes in
yields up to 90% and higher [lool!
1081
1091
rnI"i.Q+(-J--
Scheme 22
Ref.
co
(60%)
11
(4%)
1101
/
I
[I111
5.2. Heteroatom Analogs
Numerous heteroatom analogs of retro ene reactions
have been reported over a span of a hundred years or
so, and Table 4 [107aI summarizes the reaction types
generated by permutation of one oxygen atom. The
cleavage of y,&unsaturated alcohols represents the
reverse of the formation of unsaturated alcohols from
ene components and carbonyl compounds (see Section 3.4) and proceeds in the vicinity of 500 OC, unless
I
HP
Wbl
[lllal
(100%)
Table 4. Retro-ene reactions of
systems containing one oxygen atom.
Entry
1 Reactions
[lo71 A. T. Bfomquist and P. R . Taussig, J. Amer. chem. SOC. 79,
3505 (1957).
[107al For further examples, see A . T . Balaban, Revue roum.
Chim. 12, 875 (1967).
Angew. Chzm. internat. Edit. 1 Yol. 8 (1969) No. 8
Presumably, the ene cleavage in entry 5 is facilitated by
the rigidity of the allylic system, which allows the
transition state to be reached more readily (cf. also
Section 6.5). The retro-ene reaction in Scheme 1 6 could
be favored for the same entropy reasons as well as by
the methoxycarbonyl group which generates a retroClaisen-like system. The smooth ene cleavage of trans1,2-divinylcyclopentane-1,Z-diol (Table 5 , entry 6) is of
interest. However, with increasing ring size the retro[lo81 R . T . Arnold and G. Smolinsky, J. Amer. chem. SOC. 8 I ,
6443 (1959); ibid. 82, 4918 (1960); cf. also K . J . Voorhees, G . G.
Smith, R . T. Arnold, R . R . Covington, and D . G. Mikolasek,
Tetrahedron Letters 1949, 205.
[lo91 R. T . Arnold and G . Smolinsky, J. org. Chemistry 25, 129
(1960); see also G. G. Smith and R . Taylor, Chem. and Ind. (London) 1961,949.
[110]A . Viola, E . J . Iorio, K . K . Chen, G . M . Glover, U. Nayak,
and P. J . Kocienski, J. Amer. chern. Soc. 89,3462 (1967).
[ill] J . W. Wilson and S . A . Sherrad, Chem. Commun. 1968,
143; see also A. Viola and J. H. MacMiIfan, J. Arner. chem. SOC.
90, 6141 (1968).
57 1
ene reaction is completely suppressed in favor of the
3,3-shift [lllal. The decarboxylation of p,y-unsaturated acids requires temperatures in the range of
250-300 “C[1121. A more recent variant is the decarboxylative opening of cyclopropaneacetic acids. For
example, on heating above its melting point carboxylic
comparable to those required for unactivated analogs
(ca. 500 “C), while acetylenic ethers break up under
rather mild conditions (ca. 130°C) to form aldoketenes which are trapped by the starting material to
give ethoxycyclobutenones (Table 6 , entry 2).
The well-known pyrolysis of esters [1191 and xanthatesrl20J is related to the ene cleavage of carbonyl
compounds (Table 4, entry 4).
6. Reaction Mechanisms
acid (115) smoothly loses carbon dioxide to form
(116) with introduction of an angular methyl
group 11131. The steric requirements for decarboxylation
of bicyclobutanecarboxylic acids (cf. also Section 2.7)
are demonstrated nicely by the relative stability of the
6.1. Bond Energies and Reactivity
For a discussion of reactivities it is useful to consider
the change in bond energy during an ene reaction. In
the generalized Scheme 23 the debit side contains the
energy required for breaking the C3-H o-bond and
the X=Y x-bond, while energy is gained by making
Bond energy expended
exo acid (117) (no reaction up to 200”C), whereas the
structurally related endo acid (118) affords 1,3-diphenylcyclobutene (119) quantitatively on heating to
only 85 “C [1147.
The ene cleavage of ally1 ethers (Table 4, entry 2) constitutes the microscopic reverse of the “wrongly
oriented” addition of a carbonyl compound to an ene
component and has been investigated and discussed
recently by Cookson and WallisL1151.
The retro-ene reaction of vinyl ethers (Table 4, entry 3
and Table 6, entry 1) proceeds at temperatures [I161
Entr)
-
+
Scheme 23
the X-H and C1-Y bonds; the last items in each
column cancel on balance unless one of the two
double bonds is particularly strained (see below).
Provided that steric and solvent effects remain constant
in a series of related reactions (as is indeed frequently
the case; cf. Section 6.3) then
Table 6. Pyrolysis of vinyl ethers.
Reaction
Bond energy gained
D(C3-H)
D(X-H)
Dn(X=Y)
D(C1-Y)
Dn(Cz=Cd
Dn(cz=Cd
A F = AH-TAS;
D(C1-Y) - D(C3-H) - D,(X=Y)
A H = D(X-H)
BRAS= O [ * ] .
Hence,
~ R A F -~ R A H
1
i.e., the difference in free energy of two reactions is
equal to the corresponding differential heat of reaction [1211. One now assumes that the calculated ground
state energy term F R A F is proportional to the differential free energy of activation FRAFS. Such an
2
3
[a] Ea- 43.8 kcal/mole; AS+
-
-10.2 e.u. at 530OC.
[llla] P. Leriverend and J.-M. Conia, Tetrahedron Letters 1969,
2681 ; see also E. N. Marvelland T.Tao, ibid. 1969,1341;for retroene reaction of l-vinylcycloalkane-1,2-diolssee J.-M. Conia and
J.-P. Barnier, ibid. 1969,2679.
[112]R. T. Arnold, 0 . C. Elmer, and R. M. Dodson, J. Amer.
chem. SOC.72, 4359 (1950); see also K. Mackenzie in S. Pafai:
The Alkenes. Wiley, New York, 1964,p. 457.
[113] T. Hanafusa, L. Birladeanu, and S. Winsfein, J. Amer.
chem. SOC. 87, 3510 (1965); see also J. J. Sims, ibid., p. 3511.
11141 S.Masamune, Tetrahedron Letters 1965,945.
[115] R. C. Cookson and S. R. Wallis, J. chem. SOC.(London) B
1966, 1245;see also J. A . Berson and E. J . Wafshjr., J. Amer.
chem. SOC. 90, 4730 (1968), and [104b].
572
I1161 A. T . Blades and G. W. Murphy, J. h e r . chem. SOC. 74,
1039 (1952); A . T. Blades, Canad. J. Chem. 31, 418 (1953).
11171 R. H. Hasek, P. G. Gott, and J . C. Martin, 3. org.Chemistry
29, 2510 (1964); J. Nieuwenhuis and J. F. Arens, Recueil Trav.
chim. Pays-Bas 77, 761 (1958).
[118] H. J. Hagemeyer jr., and D. C. Hull, Ind. Engng. Chem.
41, 2920 (1949).
11191 C. H. DePuy and R. W. King, Chem. Reviews 60, 431
(1960).
I1201 H. R. Nace, “Organic Reactions” Vol. 12, 57, New York
1962.
[*I The reaction operator 8~ denotes the change of a thermodynamic quantity when two reactions are compared; see I. E.
Leffler and E. Grunwald Rates and Equilibria of Organic Reactions, Wiley, New York, 1963, p. 26.
[121] M . J. S. Dewar, Adv. Chem. Phys. 8, 65 (1965); see also
R. Huisgen, Angew. Chem. 75, 742 (1963); Angew. Chem. internat. Edit. 2, 641 (1963).
Angew. Chem. internat. Edit. 1 Vol. 8 (1969) 1 No. 8
approximation is more drastic, but presumably not
bad, if bond-making and bond-breaking, respectively,
have proceeded to about the same extent in the transition states of the reactions to be compared. Clearly,
this approximation allows that the new a-bonds are
formed with considerable asymmetry within one reaction class (see Section 6.2).
Several conclusions follow: First, the dependence of
the reactivity of the ene component on D(C3-H) has
been obvious throughout Section 1 and needs no more
comment. Further, the enhanced reactivity of acetylenic vis-bvis olefinic enophiles can be seen to be not
only the consequence of the reduced x-bond energy of
the triple bond, but also of the increased energy of the
vinylic carbon-hydrogen bond [D(C2H3-H) = 104 i 2
versus D(CzH5-H) = 98 1 kcal/mole] r1221.
The distinction of enophilic and dienophilic reactivity
now emerges also more clearly. For instance, it has
been seen that cycloheptatriene forms a 4 + 2 adduct
with maleic anhydride [47%47bl, while in the reaction
with acetylenedicarboxylic ester an ene adduct is
formed as a by-product [SO]. Since 0,(C -C) enters the
energy balance of both diene and ene synthesis, but a
new carbon-hydrogen bond is only made in the ene
reaction, alkynes are expected to be relatively more
enophilic than dienophilic when compared with
alkenes. That dehydrobenzene is such an efficient enophile should be the consequence of internal strain
Bond energies are also useful for predicting the orientation of enophilic attack. For instance, the exclusive
formation of the alcohol rather than the ether when
carbonyl compounds are used as enophiles (Scheme
24) can be rationalized by the greater gain in bond
energy for the observed reaction. Similarly, the reversal in orientation with thioketones 1911 as enophiles
is probably partly due to the fact that D(C-H) = 98,
while D(S-H) = 90 kcal/mole only [D(C-S) appears
to be unknown] [1221.
D(0-H)
D(C-C)
102 i 2 kcal/mole
88 f 2 kcal/rnole
190 kcal/rnole
L&
D(C-0)
79 kcaI/rnole
177 kcal/mole
f
Scheme 24
6.2. Orientation Phenomena
Little work has been reported here and the few observations of Alder and von Brache1173bl on propiolic
and acrylic ester are compiled in Table 7. Apparently,
Table 7.
Entry Ene
-
Ict;”
Enophile
Orientation phenomena in ene reactions 173bI.
I
Products
1
8 8%
12%
9 5%
5%
2
n- C,H9.(JCQCHs
3
75%
4
n-C,Hp
CH2=CH-CQCH,
25%
CH,=CH-CO,CH,
“OCO.&!H,
60%
40%
80%
20%
5
6
and, possibly, of a steric effect. Similarly, the quite remarkable reactivity of ene components with strained
or “soft” x-bonds (Section 2.7) appears to be primarily the consequence of a lowering of Dn(C2=C1)
(Scheme 23).
[1221 All bond energies are taken from J . A . Kerr, Chem. Rev.
66, 465 (1966).
Angew. Chem. internat. Edit. J Vol. 8 (I969) / No. 8
the linear isomer, in which the position of the ester
grouping is ‘‘para” with respect to the vinylic carbon
C2 (cf. Scheme 23), predominates over the branched
or “meta” isomer. Thus, in contrast to an earlier report[73al, a mixture of isomers rather than a single
product appears to be formed generally. The preferred
formation of the linear isomer suggests that bond-
573
making in the transition state is somewhat more efficient between the unsaturated termini than between the
allylic hydrogen and the corresponding carbon atom
of the enophile; or to rephrase, a double bond is a
better Michael-type donor than an allylic carbonhydrogen bond. Note that the analogy to the
Michael addition is purely formal, since, e.g., ene reactions are not catalyzed by bases. Furthermore, while
the clean orientation with carbonyl enophiles (Scheme 24) is consistent with advanced bond-making between the unsaturated termini, the observed opposite
orientation with hexafluorothioacetone probably indicates that the transition state may by variable.
6.2.1. T h e c i s - P r i n c i p l e
Table 8. Solvent effect on the ene reaction of diethyl
azodicarboxylic ester with I-phenyl-3-(p-tolyl)propene19).
~
~~
Rate constant
I04 kz [I mole-’ sec-11 at 50 “C
Solvent
cyclohexane
dioxane
dimethylformamide
acetonitrile
1,2-dichloroethane
nitrobenzene
1.02
1.12
2.0
2.2
3.2
4.0
e. u.) similar to Diels-Alder additions. As expected,
A s * is less negative for intramolecular ene reactions,
since less molecular motion has to be frozen in the
transition state (cf. Table 5 , entry 2, Table 6 entry 1,
and Scheme 2).
6.4. Catalysis of Ene Reactions
The Diels-Alder addition entails stereospecific cisaddition. Likewise, the adducts of I-hexene and 1heptene with acetylenedicarboxylic ester have been
found to be derivatives of maleic rather than fumaric
esters (Table 7, entry 5), and the linear isomer formed
in the reaction of ethyl propiolate with ene components
is a derivative of acrylic ester containing a trans double
bond (Table 7, entry 6) [see also Scheme 12 and the
formation of (53)].
It is worthy of mention that the antipnti ene reaction
[anti with respect to the ene and enophile; cf. (119c)l
is also symmetry-allowed. Obviously, such a transition
state is far less likely than (122) for steric reasons, but
(1194
it remains an interesting speculation for special cases
such as ene components containing twisted double
bonds and enophiles which are sterically readily accessible. In any case, such a reaction mode seems more
probable here than for the related and better investigated Diels-Alder addition, where, as implied above,
the anti, anti attack has never been observed.
6.3. Solvent Effects and Activation Parameters
I n analogy to other “no mechanism” reactions 11231 the
ene synthesis is little affected by solvent changes.
Huisgen and PohZr91 have measured the rate of reaction of 1,3-diarylpropenes with diethyl azodicarboxylate. On changing the solvent from cyclohexane to
nitrobenzene the rate increases by a factor of 4 only
(Table 8).
For the ene reaction of diethyl azodicarboxylate with
some cyclic dienes F r a n z u s r 2 4 3 has found a highly
negative entropy of activation ( A s * = -30 to -40
[I231 W. von E. Doering and W. R. Roth, Tetrahedron 18, 67
(1962).
574
The facilitation of intermolecular ene reactions by an
increase in pressure and that of the retro-ene reaction
by high temperatures needs no comment. Likewise,
the enhanced reactivity of certain enophiles in the
presence of organic and aqueous mineral acids is
familiar.
Attention is drawn to the catalyst system CH2CIz/
Ac20/BF3 . 2 HzO [21,221, in which the boron
trifluoride dihydrate is present presumably as
88
HBF30Ac t 3AcOH, as well as stannic chloride
[21 22,124,1251 and aluminum chloride, which has been
used as such and as the etherate[125cl. With these
catalysts the reaction times can be shortened dramatically, and it would be of preparative interest to
know whether allylic oxidations by selenium dioxide
can be catalyzed similarly.
The reaction of isoprene with trichloroacetaldehyde in
dichloromethane affords 5 % Diels-Alder (119a) and
95 % ene adduct (119b), if the reaction is run at room
temperature in the presence of stannic chloride. In the
absence of catalyst, however, the reaction requires
temperatures around 150 OC, and the ratio of ( 1 1 9 ~ ) :
(119b) is reversed completely, being 90:lO. A similarly
characteristic reversal in the composition of products
has been observed for other catalytic and thermal
reactions of isoprene and 2,3-dimethylbutadiene with
carbonyl compounds 1125al. As one possible reason for
this remarkable observation it should be considered
that the proportion of the cisoid diene conformer is
greater at higher temperature so that the cycloaddition
is preferred.
(1190)
(1196)
[124] N. C. Yang, D.-D. H . Yang, and C. B. Ross, J. Amer. chern.
SOC. 81, 133 (1959).
[I251 a) E. I. Klimova, E. G . Treshchova, and Y. A . Arbuzov,
Dokl. Akad. Nauk SSSR 180, 865 (1968); see Chem. Abs. 69,
67173b (1968); formula (11) in this abstract needs revision;
b) E. I . Klimova and Y. A . Arbuzov, Dokl. Akad. Nauk SSSR
173, 1332 (1967); see Chem. Abs. 67, 108156~(1967); c) E. I.
KIimova and Y. A . Arbuzov, Dokl. Akad. Nauk SSSR 167,1060
(1966); see Chem. Abs. 65, 3736h (1966).
Angew. Chem. internat. Edit.
VoI. 8 (1969) J No. 8
The interesting case of a photo-ene reaction has been
described for 2,6-dimethyl-7-octen-3-one, which on
irradiation with ultraviolet light forms terpinen-4-01
(2.5 %) amongst other products. Although the yield is
low the terpinen-4-01 arises with complete transfer of
chirality, suggestive of a concerted transformation of
the excited ketone into the product (Scheme 24a) 1126al.
-
OXH
p
H
,
menthene would have to be formed [cf. also the
formation of (85d) and (85e)l.
Microscopic reversibility demands that the reverse
reaction is also completely stereospecific. While the
reaction of (+)-Al-p-menthene with formaldehyde
requires acid catalysis, the y,s-unsaturated alcohol is
formed with more than 98 % retention of configuration
at the C-4 carbon[l9bl. Thus, it is proven that the
Prins reaction may proceed via a concerted enereaction
(cf. also Section 3.4).
The reaction of maleic anhydride with optically active
olefin (123) has been shown to give optically active
adduct (124); however, it is unknown to what extent
precisely chirality is preserved during this reaction [1281.
Scheme 24a
The reverse reaction proceeds thermally and also
entails complete induction of chirality [126bl.
To summarize, ene reactions proceed most readily if
the ene is electron-rich and the enophile electrondeficient. Ene reactions with inverse electron demand
have not yet been described.
6.5. The Geometry and Timing of Bond Changes in the
Transition State
The Diels-Alder addition, 1,Shydrogen shift, and the
ene reaction are structurally related cyclic six-electron
processes, although bonding in the transition state is
maximized in each reaction in a different way. The
transition state of the Diels-Alder reaction is boatlike 11271, i.e., the x-orbitals of the reactants overlap
partly x-wise, partly a-wise (120).
The optimum geometry for a 1,Shydrogen shift involves a planar carbon framework with a suprafacial[41 placement of the hydrogen (iZI), while a
concerted ene reaction maximizes allylic resonance by
turning the axis of the breaking carbon-hydrogen bond
parallel to the p-orbitals of the neighboring double
bond (122).
The ene cleavage of (-)-6-hydroxymethyl-Al-pmenthene smoothly forms (+)-Al-p-menthene with
100% conservation of chirality (Table 5 , entry 5). If
this retro-ene reaction were to proceed via a substituted cyclohexenyl radical intermediate, much racemic
[126a] K. H. Schulte-Elte and G. Ohloff, Tetrahedron Letters
1964, 1143; a related reaction has been described by N. C. Yang,
A . Morduchowitr, and D.-D. H . Yang, J. Amer. chem. SOC.85,
1017 (1963); however, these authors postulated a unified stepwise
mechanism via free radicals; cf. also N. J . Turro: Molecular Photochemistry. Benjamin, New York 1965, p. 155; for the photo-ene
reaction of methyl- and dimethylmaIeic anhydride with a-cedrene
see C. H . Krauch and H. Kiister, Chem. Ber. 97, 2085 (1964).
[126b] G. Ohloff, private communication.
Angew. Chem. internat. Edit.
1 Vol. 8 (1969) I No. 8
The ene reaction of cyclopentene and cyclohexene
with diethyl azodicarboxylate can be catalyzed by free
radical initiators and retarded by free radical inhibitors L8,91. However, whether cyclopentenyl and cyclohexenyl radicals are actually intermediates in these
reactions has not yet been shown clearly. Since one
would expect that shift of the double bond is incomplete if a free allylic radical is involved, experiments
with cycloalkenes possessing a positional or radioactive label might provide further clues.
Molecular models show that cyclopentene and cyclohexene are relatively rigid and that it may be difficult
to achieve the optimum geometry (122). Alternatively,
one could argue that the relative stability of the cyclopentenyl and cyclohexenyl radicals [I291 favors a stepwise process. However, 1,2-dihydronaphthalene (32)
and the 1,4-dihydro isomer seem to react in concerted
fashion (91 although any potential intermediate radical
would be even more stable. Models suggest a greater
flexibility for these two compounds so that the porbitals of the developing double bond can become
coaxial in the transition state.
A concerted mechanism is geometrically impossible for
the pyrolysis of trans,trans-l,6-cyclodecadiene(100)
and of (104). Presumably, cyclodecene rearranges also
at least in part via a biradical, which would account
for the formation of vinylcyclooctane (Scheme 22). In
any case, the thermal formation of vinylcyclooctane
from cyclodecene by a concerted suprafacial 1,3carbon shift is forbidden [41. The twisted bicyclobutane
and bicyclopentanes enter into stepwise ene reactions
also. However, to conclude that all bicyclobutanes and
bicyclopentanes react in a stepwise manner may be
premature, since these compounds appear to form
11271 H . M . R . Hoffmann and D. R . Joy, J. chem. SOC. (London)
B 1968, 1182.
[128] R . K. Hill and M . Rabinovitz, J. Amer. chem. SOC.86, 965
(1964).
I1291 C. Walling and W. Thaler, J. Arner. chem. Soc. 83, 3877
(1961).
575
exclusively the ene adduct without any admixed 2 +2
product in a number of reactions.
6.6. endo or ex0 Transition State?
It should be borne in mind that the initial rate-limiting
abstraction of an allylic hydrogen (possibly followed
in certain reactions of cyclopentene and cyclohexene;
cf. also Scheme 7) and the similarly rate-limiting formation of the biradical (Scheme 3) represent but two
mechanistic extremes which demarcate a broad spectrum of concerted ene reactions.
Since the ene reaction does not lead to cyclic adducts, a
distinction of endo and exo transition states is more
difficult than in the Diels-Alder addition. Only three
ene reactions have so far been scrutinized from this
point of view, and all three examples are due to the
work of Berson and his collaborators c1301. cis-2-Butene has been shown to react with maleic anhydride to
give two diastereomeric 3-(1-butenyl)succinic anhydrides (125) and (126) in a ratio of 80-85% to
15-20 %. trans-2-Butene and maleic anhydride, on the
other hand, afford 43% (125) and 57% (126). The
configurational assignments have been reached by a
six-step degradation to 3,4-dimethylhexane: (i) hydrogenation, (ii) hydrolysis, (iii) reaction with 2 CH2N2,
(iv) reaction with LiAlH4, (v) reaction with 2pCH3C6H4-S02CI in pyridine, and (vi) further reaction
with LiAIH4. (see Scheme 25). Clearly, the selectivity
A useful criterion forprobing the timing of bond changes is the deuterium isotope effectkH/kD, which hasbeen
measured for a few ene reactions. For the reaction of
1,4-dihydronaphthalene (32) with diethyl azodicarboxylate kH/kD = 2.8-4.1 between 60 and 80 "C 191, and
for the benzylic oxidation of 1,3-diphenylpropenewith
selenium dioxide in acetic acid at 115°C kH/kD =
3.2 [lo]. By comparison, for the intramolecular 1,5-hydrogen shift in cis-l,3-pentadiene (Scheme 2) kH/kD is
greater, being 12.2 at 25 OC, suggestive of a highly symmetric transition state with a half-transferred hydrogen in this case [GI. Clearly, carbon-hydrogen bondbreaking is energetically costly and presumably not
fully compensated by formation of the new H-X
bond, at least when X = carbon (cf. Scheme 23). The
limited data on orientational phenomena discussed
above (Section 6.2) seem to reinforce this conclusion
and suggest that within the province of concerted ene
reactions involving all-carbon systems, the making of
the new carbon-carbon bond may well be in the lead
in many cases.
For the reaction of two conformationally defined 1methylcyclohexene systems with singlet oxygen Nickon
has shown recently that kH/kD is also rather low
(1.1-2.4); chemical studies indicate that neither C-H
bond breaking nor C - 0 bond making have advanced
very far, i.e. the transition state is reactant-like in this
particular reaction [1311.
The few isotope effects measured for the retro-ene
reaction again seem to suggest a variable transition
state. For example ally1 cc-deuteriodiphenylmethyl
ether undergoes cleavage at 430 "C only about 10%
more slowly than the undeuterated compound (kH/
kD = 1.1)rllsl. On the other hand, kH/kD w 2 at
400-500°C for the pyrolysis of acetates. The latter
value appears to be close to the theoretical maximum
of 2.1 at this temperature [1191.
In summary, ene reactions may proceed by a broad
spectrum of transition states. While most Diels-Alder
additions are considered to be concerted 1451, the mechanism of the ene reaction is janus-faced in that both
concerted and stepwise routes may be followed. A
concerted course is generally preferred, but the stepwise process may occur, provided the optimum geometry of the transition state is inaccessible and, perhaps
less urgently, the intermediate radical or biradical is
stabilized.
I1301 J. A . Berson, R. G. Wahl, and H. D .
chem. SOC. 88,187 (1966).
Perlmutter, I. Amer.
I1311 A . Nickon, V. Chuang, P.J.L.Daniels,J. 3.DiGiorgio, H.G.
Vilhuber, and E. Werstiuk, to be published.
576
9
i
C'
d
H
(125) threo
(126) erythro
.1
1
optically active
optically inactive
(meso form)
Scheme 25
is considerably reduced with trans-2-butene, yet the
endo preference is qualitatively preserved, because the
major diastereomer from cis-2-butene is the minor one
from the trans isomer. For the ene reaction of cyclopentene with maleic anhydride there exists a 3.53
preference for the endo transition state 11301. The endo/
ex0 ratio in another ene reaction amounts to either
29:23 or 23:29 1361. Apparently the endo selectivity is
not particularly striking and is sensitive to steric effects (see below); any generalization on the preferred
steric course must be regarded with caution.
6.7. Steric Effects
Ene reactions are notoriously sensitive to steric effects,
just like cycloadditions [451. For example, the reduced
endo selectivity (57 %) for the reaction of trans-2-butene with maleic anhydride as compared with more
Angew. Chem. infernat. Edit. Vof. 8 (1969) 1 No. 8
than 80 % selectivity for the reaction with cis-Zbutene
(cf. Scheme 25) is probably the consequence of nonbonded repulsion between the nonreacting methyl
group of trans-Zbutene and the opposing carbonyl
grouping in the endo transition state. Similarly, the
formation of the endo adducts from u-pinene [cf. e.g.
( I I ) ] , the considerably enhanced reactivity of the
parent cyclopropene (Scheme 9) vis-a-vis its triphenyl
counterpart (6.5),the formation of the cis dimer (66)
from (65),and the different reactions of (68)and (70)
attest to the importance of steric effects.
In the ene reaction of dehydrobenzene with 1-octene
the trans isomer has been reported to be formed as the
major product (Scheme 26), although the other products were not identified. It has been suggested that
the bulky and flexible n-pentyl chain prefers to be
oriented away from the attacking dehydrobenzene [75cl
(cf. also Table 1, entry 3 for the translcis ratio with a
trans enophile).
Steric effects are also manifest in the data of Table 1
which suggest that the enophile attacks the least
crowded olefinic terminus preferentially and abstracts
the least crowded hydrogen most readily. Tnterestingiy, trans-2-butene reacts about 3.7 times faster than
the cis-isomer with diethyl azodicarboxylate. As can
be seen in Scheme 27, one ethoxycarbonyl grouping
of the azo ester (which is usually present in its more
stable trans form) and the opposing methyl group of
the cis-2-butene clash in the transition staterg]. In
Scheme 21
7. Outlook
Much further work is needed before we may claim to
understand the ene reaction. On the preparative side
further heteroatom analogs await discovery, and new
enophiles should be found which react in the presence
or absence of electrophilic catalysts. Much of what has
been said about the mechanism and particularly the
reactivity of the ene reaction has been based on fragmentary data and perhaps even some speculation.
Future work will have to explore in a more quantitative way the reactivities, orientation phenomena, and
steric effects as well as the variable transition state and
its geometry.
I thank Prof. R. B. Woodward for his hospitality at
Harvard University, where much of the work on this
paper was done, Prof. L. Friedman and Dr. G. Ohlof
for stimulating discussions, and Drs. 0.Achmatowicz,
Jr., R. Alder, J. M . Brown, Prof. J.-M. Conia, Dr. P.
Dowd, Dr. E. Koerner von Gudtorf, Prof. A. Nickon,
Prof. E. Trachtenberg, and Prof M. C. Whiting for
personal communications regarding the manuscript. The
support given by the Penrose Fund of the American
Philosophical Society is gratefully acknowledged.
Received: May 19, 1969
[A 717 IEI
German version: Angew. Chem. 81, 591 (1969)
contrast, no such repulsion is present in the reaction
of trans-2-butene so that the situation is exactly
reversed to that for the reactions with maleic anhy-
Angew. Chem. internat. Edit.
dride, which is a cis-enophile and would be expected
to react more readily with cis-2-butene than with the
trans isomer.
A distinction of endo and exo transition state is no
longer possible when alkynes and dehydrobenzenes act
as enophiles. It has been found that trans as well as cisalkoxypropenes and dehydrobenzenes afford 2 + 2
cycloadducts and also ene products. In all the reactions
studied the trans propene derivative enters the ene
reaction more readily than the cis isomer. Furthermore, the ene reaction is inhibited more with cisethoxypropene [132d than with cis-methoxypropene L132bl. That all these differences-are probably of
steric origin is suggested by an inspection of models.
Vol. 8 (1969) No. 8
[132] a) H . H. Wasserman, A . J . Solodar, and L. S . Keller,
Tetrahedron Letters 1968, 5597; b) L . Friedman, R. J. Osiewicz,
and P. W. Rabideau, ibid. p. 5735.
577
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