DIELS- ALDER REACTION

DIELS-ALDER
REACTION
VIPUL BATRA
1
+ O
91%
O
O
O
O
O
O

INTRODUCTION
 In the Diels-Alder reaction , a 1,3 diene reacts with a
dienophile to form a six membered ring adduct . Two new
σ bonds and a new ∏ bond are formed at the expense of
three ∏ bonds in the starting materials.
PERICYCLIC REACTIONS
CYCLOADDITION
REACTIONS
[4+2]-DIELS-ALDER REACTION
2
Tuesday,April11,2017VIPULBATRA

CHRACTERISTICS OF DIELS-
ALDER REACTION
 Versatility.
 Remarkable stereoselectivity.
 In most of the cases the reaction takes place easily at room
temperature by simply mixing the components or by warming
them at room temperature , but in the case of unreactive
components , more vigorous conditions may be necessary.
 This reaction is reversible and many adducts dissociate easily at
room temperature.
 A normal Diels-Alder reaction involves an electron rich diene and
an electron deficient dienophile.
3

MECHANISM
DIENE DIENOPHILE
HOMO
 ᴪ3
ᴪ2
LUMO
ᴪ2 ᴪ1
4

 A substituted alkene or alkyne is called a dienophile.
 The Dienophile is generally electron deficient .
 Its reactivity depends upon its structure , in general the greater the number of electron
attracting substituents on the double or triple bond , the more reactive is the dienophile.
 The most commonly used dienophiles are α,β-unsaturated carbonyl compounds such as
acrolein.
 Substituents exert a pronounced steric effect on the reactivity of dienophiles . Compative
experiments show that the yeilds of adducts obtained in such reactions decrease with the
introduction of substituents into the α-position of the dienophile or if substitution is present
on the doble bond as shown below in the case of reaction of benzoquinones with
butadienes.
THE DIENOPHILE
O
O
ON
NN
N
O
O
O
O
H
O
+
O
O
O
O
O
O
O
O
O
O
H
+
100 °C
86%
5

THE DIENOPHILE
 In contrast to the reactive dienophiles in which the double or triple bond is
activated by conjugation with electon withdrawing groups, ethylenic compounds
such as allylic alcohols and its esters and allyl halides are relatively unreactive ,
although sometimes they can be induced to react with dienes under forcing
conditions . Enol ethers or enamines in which the dienophile bears an electron
donating substituent , takes part in this reaction with inverse electron demand .
They react with electron deficient dienes and with α,β-unsaturated carbonyl
compounds , the latter to give dyhydropyrans as shown below :-
O
O
H
O
H
O
O
5 °C
48%
O
O
O
O
H O
+
O O O O
+
200 °C
400 °C
6

THE DIENOPHILE
 Isolated carbon-carbon double or triple bonds usually do not take part in inter-
molecular Diels- Alder reactions, but a number of cyclic alkenes and alkynes with
pronounced angular strain are reactive dienophiles. The driving force for these
reactions is thought to be the reduction in angular strain associated with the transition
state for the addition as shown below:-
 Benzynes also undergo Diels-Alder reactions . Benzyne is a highly reactive species
and reacts in situ with various dienes such as furan , cyclopentadiene , cyclohexadiene
and even with benzene and naphthalene.
 A good reagent that promotes effective cycloaddition and allows subsequent
conversion to the desired ketone is 2-chloroacrylonitrile .
H
H
+
0 °C
97%
+ plus other products
O OO
CHCl3 , 61 °C
50%
Na2S. 9H2O
EtOH
80%
7

THE DIENOPHILE
 Cationic dienophiles , in which the alkene is rendered electron deficient , are
good substrates for the Diels-Alder reactions . 2-vinyl-1,3-dioxolane is very
unreactive towards dienes, however on protonation , the acetal is in
equilibrium with the oxonium ion an effective dienophile . Cycloaddition and
re- formation of the acetal gives the adduct.
O O
catH+
O
+
OH
CH2Cl2,< 0 °C
O
O
8

THE DIENE
 The dienes are usually electron rich.
 A wide variety of dienes can take part in this reaction includind open chain and acyclic dienes .
 Heterodienes in which one or more of the atoms are heteroatoms are also known.
 Acyclic dienes can exist in cisoid or transoid conformation , and an essential condition for
reaction is that the diene can adopt the cisoid form . If the diene does not have or cannot adopt
a cisoid conformation then no Diels-Alder reaction occurs.
 Substituents in the butadiene molecule influence the rate of cycloaddition.
 The rate of reaction is often increased by electron-donating substituents.
 Bulky substituents that discourage the diene from adopting cisoid conformation hinder the
reaction.
O
O
+Na
-
cisoid transoid
9

THE DIENE
o Hetero-substituted dienes are excellent substrates for the Diels-Alder reaction. The
increased rate of reaction is ascribed to the higher energy HOMO of the hetero-
substituted diene , which therefore results in the reduction in the energy difference
between the HOMO of diene and LUMO of dienophile.
O
O
Si heat
O
H
H
OO
O
Si
H3O+
O
H
O
10

STEREOCHEMISTRY OF THE DIELS-
ALDER REACTION
 The great synthetic usefulness of the Diels-Alder reaction depends not only on the fact
that it provides easy access to a variety of six membered ring compounds but also on its
remarkable stereoselectivity. The stereochemistry of the adduct can be selected on the
basis of two empirical rules formulated by Alder and Stein in 1937.
 THE CIS PRINCIPLE- according to this principle , the relative stereochemistry of
substituents in both the dienophile and the diene is retained in the adduct. That is , a
dienophile with trans substituents will give an adduct in which the trans configuration
the substituents is retained while a cis di-substituted dienophile will form an adduct in
which the substituents are cis to each other. This aspect is often referred to as the
stereospecific nature of the Diels-Alder reaction.
+
O
O
O
O
H
O
O
O
O
H
+
H
H
O
O
O O
+
O
O
O
O
O O
O
O
H
H
11

ALDER REACTION
 Similarly with the diene component the relative configuration of the substituents in the 1-
and 4- positions is retained in the adduct ; trans ,trans-1,4-disubstituted dienes give rise
to adduct in which the 1- and 4- substituents are cis to each other , and trans-
disubstituted diene give adducts with trans substituents .
 THE ENDO ADDITION RULE:- In the addition of a 1-substituted diene to a dienophile, two
different products the endo and the exo stereoisomers , may be formed depending upon
the manner in which the diene and dienophile are arranged in the transition state .
According to the endo addition rule, the diene and the dienophile arrange themselves in
parallel planes , and the most stable transition state arises from the orientation in which
there is “ maximum accumulation of double bonds “ . The double bonds encompass all
the pi-bonds in the two components , including those in the activating groups of the
dienophile. This rule is by no means always followed and is perhaps best applicable to the
addition of cyclic dienes to cyclic dienophiles , but it is a useful guide in many other
cycloaddition reactions.
+
+
12

 To illustrate this aspect of stereoselectivity , the addition of maleic anhydride to
cyclopentadiene gave almost exclusively the endo product 18. the
thermodynamically more stable exo compound is formed in yields less than 2%.
 The products obtained in the cyclic diene furan and maleic anhydride and from diene
addition reactions of fulvene do not obey the endo rule . The reason for this is that
the initial endo adducts easily dissociate at moderate temperatures , allowing
conversion of the kinetic endo adduct into the thermodynamically more stable exo
isomer.
Tuesday,April11,2017
13
VIPULBATRA
ALDER REACTION
O
O
O
H
H
O
H
O
H
O
18
O
O
O
H
H
H
O
H
O
O
endo

THE RETRO DIELS-ALDER REACTION
 Diels-Alder reactions are reversible , and many adducts dissociate into their components
on heating . There are some interesting reaction's in which the original adduct is
modified chemically and subsequently dissociated to yield a new diene or dienophile.
Thus, in a synthesis of sacromycin methyl ester , the enantiomerically pure adduct was
elaborated in a number of steps to the diastereomers 1 and 2 . Retro Diels-Alder
reaction of 1 by flash vacuum pyrolysis gave optically pure sacromycin methyl ester (3)
with elimination of cyclopentadiene.
O
O
CH3
HO
O
CH3
O
+
HO
O
CH3
O
650 °C, 0. 02mm Hg
CH2
CH2
CH3O
O
CH3
+
1
2
3
14

THE RETRO DIELS-ALDER REACTION
 High temperatures are normally required for the Diels-Alder reactions and this is not
always convenient . Flash vacuum pyrolysis is carried out typically at temperatures in
the region of 400-600 ˚C, although the retro reaction can sometimes take place at
lower temperatures (180-250 ˚C) by refluxing in 1,2-dichlorobenzene or diphenyl ether
. In contrast Retro-Diels alder reaction of some anionic intermediates take place under
relatively mild conditions for example the adduct given below fragments at only 35˚C
after treatment with potassium hydride.
H O
OH
R
O
R
HO
O
CH3
CH3
KH, dioxane
35 °C, 12h
O
O
CH3
CH3
O
R
O
R
+
O
-
15

THE RETRO DIELS -ALDER REACTION
 The two sigma bonds that are cleaved in the Retro Diels-Alder reaction need not
necessarily be the same as those formed in the initial forward reaction. Many valuable
Retro Diels-Alder reactions involve the cleavage of one carbon-carbon and one carbon-
hetro atom bond , or two carbon-hetro atom bonds , that were not setup in the forward
Diels-Alder reaction for example…
N
O
CH
O
O
CH3
+
180 °C
N
O
O
CH3
90%
N
+
O
O
CH3 O
16

CYCLOADDITION REACTIONS OF
ALLYL CATIONS/ANIONS
 The Diels-Alder reactions are concerted [4+2] cycloadditions involving six pi-
electrons to give six membered rings. The possibility of analogous six pi-electron
cycloadditions involving allyl anions and cations to give five and seven membered
rings respectively is predicted by the Woodward Hoffmann rules . Examples of both
the processes have been observed, although the synthetic scope of the reactions ,
particularly with allyl anions , is limited.
 Allyl anions tend to react as nucleophilic carbanions rather than undergo
cycloaddition reactions, and the few known cycloaddition reactions with alkenes are
confined to allyl anions bearing an electron withdrawing group at C-2 of the allyl
unit. These and the better known examples of cycloaddition reactions of 2-aza-allyl
anions, may be stepwise rather than concerted processes . The 2-aza allyl anion adds
to a variety of alkenes to form pyrrolidine derivatives . Thus , proton abstraction at
the methyl group of the imine 4 gave an intermediate 2-aza-allyl anion , which
undergoes cycloaddition to give the 2,3-diaryl-pyrrolidine 5 .
+ - -
+ + +
17

 Cycloaddition of Allyl cations to conugated dienes provides a route to seven membered
carbocycles. One of several methods can be used to generate the allyl cation , such as
from the allyl halide and silver trifluoroacetate, or from an allyl alcohol by way of its
trifluoroacetate or sulfonate . Cycloaddition of the allyl cation proceeds best with a
cyclic diene, particularly for intermolecular reactions.
N
N LDA
THF
N
N
-
O
N
H N
O
4 5
+ I
CF3CO2Ag
30%
18

 The 2-oxyallyl cation has found a number of applications in organic synthesis. These
species can be produced from α,α’-dibromoketones , from α-halo-trialkylsilyl enol
ethers or from allyl sulfones and a Lewis acid . For example, the 2-oxyallyl cation 7 can
be prepared from the dibromide 6 and its cycloaddition with furan gave the adduct 8.
CH3
CH3
O
Br Br
Zn -Cu
or Fe2(CO)9
CH3
CH3
O
-
+
O
CH3 CH3
O
O
6 7 8
19

THE ENE REACTION
 The ene reaction involves the thermal reaction of an alkene bearing an allylic hydrogen
atom ( the ene component )with a compound containing an activated multiple bond (the
enophile). A new sigma bond is formed between the unsaturated centres with migration
of the allylic hydrogen atom to the other terminus of the enophile multiple bond. The ene
reaction , although not strictly a cycloaddition reaction , resembles the Diels-Alder
reaction in having a cyclic six electron transition state ,but with two electrons of the allylic
C-H sigma bond in place of two pi-electrons of the diene. As expected, therefore, the
activation energy is greater than the Diels-Alder reaction and high temperatures are
generally required to effect the ene reaction . However , many ene reactions are catalyzed
by Lewis acids and proceed under relatively mild conditions, often with improved stereo
selectivity.
 The best type of ene components are 1,1-disubstituted alkenes , although other
substitution patterns are possible , particularly with reactive enophiles . A typical example
is the ene reaction of maleic anhydride with 2-methylpropene, which occurs at a
temperature of 170˚ . The reaction of methyl acrylate with 2-methylpropene requires a
temperature of approximately 230˚C although, in the presence of Lewis acid such as ethyl
aluminum dichloride , adducts from reactive alkenes can be obtained at 25˚C as shown
below:-
20
H HH

THE ENE REACTION
o Further evidence of the concerted nature of the reaction comes from the observation
that the observation that the new C-C AND C-H Bonds are formed cis to each other .
The cis addition is exemplified in the reaction of 1-heptene with dimethyl
acetylenedicarboxylate to give the adduct 9 . In this reaction the adduct is formed
with the two ester groups on the same side of the alkene such that the hydrogen
atom and the allyl residue add to the same side of the triple bond of the enophile.
21
VIPULBATRA
H
O
O
O
+
170 °C
80%
O
O
O
O
O+
EtAlCl2
25 °C
40%
O
O
H
+
OO
O O
170 -190 °C
80%
O
O
O
O

 Intramolecular Diels-Alder reactions have found widespread use in organic synthesis
,the cycloaddition providing ready access to polycyclic compounds with excellent
levels of regio- and stereoselectivity. Intramolecular reactions often proceed more
easily as compared to intermolecular reactions owing to the favorable entropy
factor. Heating the E,E-dienyl-acrylate 10 gave the trans- and cis- hydrindanes 11 and
12 . Heating the E,Z-isomer 13 gave solely the cis- hydrindane 12 . In contrast to the
easy cyclization of 13 , intermolecular reactions with Z-1-substituted butadiene's
generally take place only with difficulty. This intramolecular reaction is most common
with 1-substituted butadiene's and favours the fused ring products.
22
VIPULBATRA
INTRAMOLECULAR DIELS- ALDER REACTION
CH2
O
O
CH3
H
H
O
O
CH3
+
H
H
O
O
CH3
10 11 12
150 °C
CH2
OO
CH3
180 °C
H
H
O
O
CH3
1213

 With two substituted butadiene's , intramolecular cycloaddition necessarily forms
bridged-ring compounds of this kind have been used to make bridgehead double
bonds. This substituted pattern allows access to natural product systems such as the
taxane ring system.
 Intramolecular cycloaddition reactions are possible in the absence of electron-
withdrawing substituents on the dienophile, although more vigorous conditions are
normally required. cycloaddition of the triene 15 at 200 Celsius gave , after
hydrolysis of silylether , diastereomeric trans-fused ring systems 16, which were
converted into the eudesmane sesquiterpene 17.
23
VIPULBATRA
O O
PhMe, 155 °C
70 - 80%
O
Si
200 °C
then H3O+
OH
H H
15 16 17

 An interesting variant of the tethered Diels- Alder reaction has been discovered that
uses vinyl magnesium species , such as 17 . In this case , the cycloadduct that is
obtained is formally the product of using ethene as the dienophile.
 The intramolecular version of this Diels-Alder reaction is particularly valuable in
synthesis . Imines as heterodienophiles are useful for the preparation of alkaloid ring
systems. For example,
24
VIPULBATRA
i, BuLi, THF
ii,
Mg
Br
OH O
Mg
80 °C
then H2O
OH
17
NH2
O
HCHO(aq)
65 °C N
O
N
O
N
O
+

DIELS- ALDER REACTION

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