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Methods for the Preparation of Bridgehead Olefins.

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[30] R . E. Dessy, T Chiuers, and W Kitching, J. Amer. Chem. SOC.88,
467 ( 1966).
[31] H . Frirrsche, U . Hnsserodt, and F. Korre, Angew. Chem. 75, 1205
(1963); Angew. Chem. internat. Edit. 3, 64 (1964).
[32] S. Nakayama, M . Yoshifuji, R . Okazaki,and N. Inamoro, Chem. Commun.
1971, 1186; J. C. S. Perkin I 1973, 2065, 2069.
[33] A. Ecker, I. Boie, and U . Schmidr, Angew. Chem. X3, 178 (1971); Angew.
Chem. internat. Edit. 10, 191 (1971); Monatsh. Chem. 104, 503 (1973).
[34] H . Tomioka, E Hirano, and E Izawa, Tetrahedron Lett. 1974, 1865.
[35] J . K . Srille, J . L. Eichelberger, J . Higgins, and M. E. Freeburger, J.
Amer. Chem. SOC.94, 4761 (1972).
Methods for the Preparation of Bridgehead Olefins[**l
methods (11)
By Reinhart Keese"]
During the past eight years, bridgehead olefins have attracted rapidly increasing attention.
In view of their significance with regard to the stereochemistry of aikenes, the study of certain
reaction mechanisms, and the nature of the double bond, detailed research into this structural
type appears highly desirable. Bridgehead olefins represent connective linkages between olefins
in the ground state and species which can arise in the deactivation of photochemically excited
alkenes and cycloalkenes and also contribute to our understanding of the structural conditions
prevailing during cis-trans isomerization of alkenes.
1. Introduction
In the course of experimental work subsequent to the structural elucidation of (+)-camphor, Bredt noted that all the
reactions in bicyclic ring systems which should lead to a
bridgehead olefin either failed to take place or yielded other
products. These findings, known as Bredt's rule, played an
important role in the structure determination of unsaturated
bi- and polycyclic natural products. Furthermore, this rule
prompted experimental work which led to a more precise
knowledge of the size of bicyclic ring systems which are compatible with a bridgehead double bond. The synthesis of 8methylbicyclo[5.3.1]undec-7-en-l1 -one and related studies by
Prelog towards the end of the 1940'~''~
represented a climax
of this development.
In 1950 this period came to a rather abrupt end with a
survey of the essential aspects of the Bredt rule by FawcettC2'.
Interest in bridgehead olefins'"'l was only reawakened in 1956
when E d w a r d ~ [found
~ I that lycoctonamic acid, which contains
a 2-oxobicyclo[3.3.l]nonane-l -carboxylic acid as a structural
component, undergoes ready decarboxylation This observation prompted Miller to study the decarboxylation of
[*] Dr. Reinhart Keese
Laboratorium fur organische Chemie.
Eidgenossische Technische Hochschule
CH-8006 Zurich (Switzerland)
Present address:
Institut fur organische Chemie der Universitat Bern
CH-3000 Bern 9, Postfach 89 (Switzerland)
[**I Based on the Habilitationsschrift of R. Keese, ETH Zurich 1974.
["'1
The common structural feature of bridgehead olefins is a bi- or polycyclic
skeleton with a double bond originating from the bridgehead. "Bredt olefins"
are bridgehead olefins having a bridged structure such as (2) and ( 7 ) ;
they diNer structurally (but not necessarily with regard to the magnitude
of their strain energy) from those having annelated ring systems, i.e. with
a "zero bridge" as in ( 1 4 8 ) and ( 1 4 9 ) (cf. Section 2.11, and also ref. [16]).
528
the corresponding unsubstituted B-keto acidI41. After a brief
induction period, a series of important studies were published
from 1967 which led t o the isolation of bicyclo[3.3.l]non-lene (2)f5r6];in 1971/72 it was proved that the classical bridgehead olefin 1-norbornene (bicyclo[2.2.l]hept-l-ene) (106) can
exist as a reactive intermediate"]. Very recently, intense
research has been directed to this exciting area with a focus
on problems of the stereochemistry of olefins and the structural
course of certain reactions as well as on the electronic nature
of highly strained double bonds. This article will deal with
some general aspects of Bredt's ruler'] and discuss methods
and structural prerequisites for the preparation of bridgehead
olefins.
The Bredt rulefE1may be briefly summarized'"] as follows :
In small bi- and polycyclic ring systems a normal (usual) double
bond cannot emanate from the bridgehead. A usual double
bond is characterized geometrically by two doubly bonded
carbon atoms and four ligands all of which lie in a common
plane. Twisting and changes in bond lengths and angles lead
to a geometrical distortion which is accompanied by
strain'"']. Twisting and pyramidalization (= out of plane
or wagging deformation) of the ligands produce a structure
corresponding to the typical geometry of a bridgehead double
bond in a Bredt olefin. To a first approximation it can be
assumed that the strain is largely localized in the distorted
double bond. Thus the maximum strain of a bridgehead olefin
is given by the rotational barrier to cis-trans isomerization of
an olefin (ca. 65 kcal/mol)['Ol. However, if it is borne in mind
that bi- or polycyclic systems are often also strained without
even having a bridgehead double bond then it is conceivable
that the overall strain of a bridgehead olefin makes it possible
for it to decompose to a dicarbene. Insofar as the Bell-EvansPolanyi principle" 'I or the Hammond postulate['*] are valid,
the Bredt rule applies to transition states of reactions in which
highly strained bridgehead olefins are formed.
['I Other review references are given in refs. [2. 9. 16. 321.
[**I A detailed discussion is given in R. Keese, Habilitationsschrift,
ETH
Zurich 1974.
[***I The concept of strain is based on comparison of energy with that
of a standard molecule, whereas the energy of vibronically excited molecules
is given relative to the vibronic ground state of the same species.
Angew. Chem. internut. Edit.
1 Vol. 14 ( 1 9 7 5 ) 1 No. 8
Thus, for example, elimination reactions initiated by rapid
formation of a carbenium ion must possess a particularly
high activation energy if strained bridgehead olefins are
formed; the poor x-conjugation of a twisted double bond
must manifest itself in the transition state of the reaction
leading t o its formation. This formulation is essentially identical to the stereoelectronic control[131of such elimination reactions.
The stereoelectronic restrictions of the Bredt rule also
extend to intramolecular 1,2-hydride shifts in bi- and polycyclic
carbenium ions[141and similar rearrangements (cf. Section
2.9). Concerted bimolecular eliminations of HX depend upon
the dihedral angle between the hydrogen and the leaving
group X. The reactions proceed most rapidly for syn- or antiplanar orientations, and least rapidly for a dihedral angle
of !No[’
51. During formation of bi- and polycyclic bridgehead
olefins by E2 reactions it must be considered that conformational mobility of the rings, especially the ring bearing the
leaving group, can in some circumstances affect the dihedral
angle in a manner crucial to the course of reaction. Nevertheless, from the standpoint of the Bredt rule one must consider
whether concerted bimolecular eliminations are possible at
all if the bonds to be cleaved are mutually orthogonal.
Likewise, we are almost completely ignorant of stereoelectronic prerequisites of eliminations which are initiated by
fast deprotonation of carbanion formation prior to the rate
determining step (cf., however, Section 2.7).
The Bredt rule also embraces bicyclic bridgehead olefins
in which one or two heteroatoms of the first or second row
of the Periodic Table participate in the double bond and
the special class of “Bredt compounds”, as defined by
Kiibrich1161,which are stable at room temperature [cf. (148)
and (149) in Section 2.1 I]. Participation of second row elements leads, for instance, to bi- or polycyclic alkylidenephosphoranes and -sulfuranes (cf. Section 2.5). Replacement of
carbon by elements of higher atomic number, especially those
of the transition series, is particularly relevant to the nature
of the double bond and must also be viewed in relation
to problems of bonding in metal-carbene c o m p l e x e ~ ~ ” ~ .
chair-boat conformation of (f)[’91; if so the EZreaction would
be subject to stereoelectronic acceleration. Compound (2)
must possess the quasi-boat-chair conformation (2a) for the
bridgehead double bond to be trans in the eight-membered
ring and cis in the six-membered ring. Predictably, (2) is
an olefin exhibiting enhanced reactivity which appears to
favor syn additions from the ex0 side.
Under comparable conditions the constitutionally isomeric
bicyclic ammonium bases (3) and (6) undergo elimination
to yield a mixture of the bridgehead olefins ( 4 ) and ( 5 ) ,
and (7) and ( 8 ) , respectively[z01.
The preferential formation of the presumably less stable
compound ( 4 ) [ ( 4 ) and ( 5 ) are formed in the ratio of 5: 1
respectively] during the thermolysis (3) is attributable
to the stereoelectronically favored syn-elimination in the fivemembered ring. The third possible olefin would be a derivative
of trans-cyclohexene and as such would possess considerable
strain energy. Thus its non-occurrence seems reasonable. The
olefins ( 7 ) and (8), which are comparable to trans-cyclohep
tene, possess a much lower thermal stability than ( 4 ) and
(S), corresponding to trans-cyclooctene. (7) and (8) dimerize
so rapidly that all attempts to isolate the pure compounds
have so far failed. In all cases of Hofmann eliminations cited
the desired bicycloalkenes were accompanied by various
amounts of the parent tertiary amines from which the quaternary ammonium salts had been prepared. Pyrolysis of (9)
for example regenerates the tertiary amine (10) in up to
99 %
2. Methods for Preparation of Bridgehead Olefins
R
2.1. Eliminations
The typical elimination reactions have considerably
extended out knowledge about bridgehead olefins in which
the double bond is formally located in a seven or preferably
larger-membered ring.
In particular, the Hofmann elimination has proved to be
a powerful method for preparing bicyclo[3.3.l]non-l-ene (2)
and its analogs in whicti the methylene bridge is replaced
by a heteroatom[’*].
Degradation reactions have established beyond all doubt
that (2) is indeed a bridgehead olefin. From a mechanistic
point of view it would be important to establish whether
or not (2) is formed by syn elimination from the less stable
Angew. Chem. internat. Edit. j Vol. 14 ( 1 9 7 5 ) j No. 8
0
( 9 ) , R = N(CH,), OHo
(101, R = N(CH3)z
Q
( I ] ) , R = 4 ( C H 3 ) , OH”
(12), R = N(CH,),O@
Thermolysis of the homoadamantane derivatives ( I 1 ) and
(12) also predominantly afforded products most probably
formed from nucleophilic substitution and Stevens or Meisenheimer rearrangement IZ
2!
Nevertheless, in either case four additional saturated hydrocarbons were isolated, of which two can be regarded as direct
dimerization products of 3-homo-1-adamantene ( 1 3 1 ) (cf. Section 2.9). It is hardly surprising then, that adamantene itself,
which is comparable with trans-cyclohexene, is not formed
either by Hofmann elimination from (13) or from (16). Furthermore (14) merely rearranges to the dithiocarbonic ester
(IS) under the conditions of the Tschugaeff reacti0n1~~’
(cf.
Sections 2.3 and 2.7).
529
R
0
( 1 3 ) , R = N(CH3)3 OH@
( I 4 ) , R = O-C(S)-S-CH,
(U),R = S-C(0)-S-CHI
tion and concomitant change of the bond angle [Fig. 1, formula
(21 a)]. A similar situation is encountered in the ketone ( 2 5 )
accessible from the triterpene catonic acid[31] and in the
bridged decapentaene (120). Apart from the specific effects
of the carbonyl group a deformation of this kind must be
a common feature of all strained bridgehead olefins [cf. Fig.
1, formulas ( 2 5 a ) and (Izoa)].
0
(16), R = N(CH3)3 OH@
In this context it should also be mentioned that pyrolysis
of O-bicyclo[3.3.1]non-l-yl 0-p-tolyl thiocarbonate does not
give the bridgehead olefin ( 2 ) but yields exclusively the more
stable bicycl0[3.3.1]non-2-ene[~~!
In certain cases however bridgehead olefins of this kind
can be formed not only by Hofmann elimination but also
by base-induced dehydrohalogenation. The 7-exo-chloro keto
ester ( I 7 ) affords a thermally labile bicyclic enone which
has been assigned structure (18)125!
(l20a)
Fig. I . Concerning the structure of ( 2 1 ) . ( 2 5 ) , and ( 1 2 0 )
(17)
(18)
If the stability of trans-cyclooctene and of bicyclo[3.3.l]non1-ene are taken as a yardstick, then bicyclo[5.3.l]undecane
is the smallest bicyclic ring system for which all three isomeric
bridgehead olefins should be capable of isolation. 8-Methylbicyclo[5.3.l]undec-7-en-l1 -one has been prepared previously[']; and (19), (20), and ( 2 2 ) have recently become
accessible by base-catalyzed elimination[*"!
The specific and structural situation, of course. also affects
the spectroscopic properties of bicyclic enones having a bridgehead double bond. These aspects have recently been the subject
of a detailed discussion[32! The presence of a-carbonyl groups
I S not absolutely essential for base-induced deprotonations
at the bridgehead of bicyclic ring systems. Reaction apparently
also proceeds after replacement of all methylene protons by
fluorine (cf. also Section 2.5). The exceptional properties of
the fluorine substituents increase the acidity to such an extent
that (26) and (27) readily incorporate deuterium at the bridgehead in basic s ~ l u t i o n ~ ~ ?
H
(19), R = COZC~H,
(20). R = H
(211, R CONH-CGH,Cl
122)
(23)
As expected, ( 2 2 ) is less stable than ( 2 0 ) and undergoes
rapid dimerization at room temperature; in this respect it
resembles the photochemically accessible trans-2-cyclooctenone12'] more than trans-cyclooctene. The diterpene taxicin
I ( 2 4 ) also belongs to the family of bicyclo[5.3.l]undec-1ene[281.Compound ( 2 3 ) , which contains ane ring member
less than (24), is formed on pyrolysis of 10-oxobicyclo[4.3.1]dec-7-yl benzoate[29!
(24)
(25)
The X-ray structure analysis of (21 )I3'], a modified precursor of (20), illustrates the geometrical changes affecting a
double bond in a bridgehead olefin discussed in the introduction. In addition to a torsional angle of ca. 32" between
the carbonyl group and the double bond, twisting of the
double bond is also observed, accompanied by pyramidaliza-
530
It is remarkable that ( 2 7 ) is merely deprotonated by methyllithium at room temperature, whereas under the same conditions ( 2 6 ) eliminates H F and in the presence of furan affords
two apparently inseparable adducts for which the structure
( 2 8 ) has been postulatedr3Z1.It would be interesting to know
the minimum number and positions of the fluorine substituents
necessary for deprotonation and elimination at the bridgehead
of bicyclo[2.2.2]octane and bicyclo[2.2. llheptane systems.
2.2. Bridgehead Olefins Having Adjacent Heteroatoms
Worthy of particular mention are olefins having the structure of bicyclo[3.3.l]non-l-ene ( 2 ) in which the methylene
bridge has been replaced by heteroatoms. The compounds
( 2 9 ) , (30). and (3/)..accessible from 5-substituted cyclooctanones, undergo base-catalyzed reaction to give the bridge-
0.
( 2 9 ) , X = N-CH3, Y = C1
( 3 0 ) , X = 0 , Y = OS02CH3
(31), X = S , Y OS02CH3
Angew Chem. infernal. Edit.
(32), X
(33). X
(34), X
= N-CH,
= 0
= S
1 Vol, 14 ( 1 9 7 5 ) 1 No. 8
head olefins (32), (33), and (34), respectively[341.They should
belong to the trans-cyclooctene family and accordingly possess
a quasi-boat-chair conformation.
Table 1 lists some spectroscopic data of these compounds.
The NMR signal of the olefinic proton in the bicyclic compounds (2) and (32)-(34)
is shifted downfield by varying
amounts relative to standard values of corresponding openchain ole fin^[^^! Attempts to parametrize these differences
with the aid of simple models of conjugational interaction
d o not appear very conclusive.
Table I. Spectroscopic data of selected bridgehead olefins
(40a), n = 9
(40b), n = 5
( 4 0 ~ )n. = 4
uv
'H-NMR
IR
(2)
(32)
1620 w [d]
1620 m [d]
5.62 t
5.86 t
7 [el
6
(33)
(34)
1640 w [el
1600 ~i [el
5.74 t
6.25 t
6 [el
7'[e]
[fl
206
240
184
I90
206
7500
1667
Csl
6200
7 500
:a] C=C stretching frequency: w, weak: m, medium
Zb] Olefinic proton: t, triplet.
-c] I n pentane; F., molar extinction coefficient.
-d] Liquid.
-el In carbon tetrachloride.
TI In chloroform.
[g] End absorption.
The heteroatoms clearly influence the reactivity of the bridgehead double bonds. Thus addition of acetic acid to (2)
at 25 "c' is complete in less than two minutes while the half-reaction time with (33) is 68h. The nonbonding electron pairs
on the oxygen of (33) are apparently incapable of stabilizing
adjacent carbenium ions by conjugation (cf. Section 2.61, as
in the case of open-chain enol ethers.
Base-catalyzed dehydrohalogenation of (35) and (37) in
tert-butyl alcohol unexpectedly affords products having differing configurations of the tert-butoxy
These surprising results are explained in terms of conformational differences.
(41a), n = 9
(41b), n = 5
(42), n = 9
can no longer cyclize. The immonium salt (41 a) undergoes
base-induced reaction to give ( 4 2 ) whereas (41 b ) reacts in
a different manner.
2.3. Fragmentations
It was mentioned in the introduction that (2) is accessible
from (1) by Hofmann elimination. At about the same time
(2) was also found to be formed by fragmentation reactions[38!
Thus the potassium or sodium salt of (43), on heating in
dimethyl sulfoxide, affords the strained olefin (2), as well
as the p-lactone ( 4 4 ) and the unsaturated carboxylic acid
( 4 5 ) . Since ( 4 5 ) is stable under the reaction conditions ( 2 )
must be formed directly from ( 4 3 ) . Presumably one of the
less stable conformations of (43 ) undergoes fragmentation.
The p-lactone ( 4 4 ) also decomposes above 260°C to give
( 2 ) but is photochemically inert.
(43)
(44)
It is remarkable that the diene ( 4 6 ) is formed in good
yield on reaction of 2-cyclooctenone with propenylidenetriphenylphosphorane in a one-pot, multistep process, terminated
by a n intramolecular Wittig reaction[391.
Bicyclic enamine ketones with a bridgehead double bond
are accessible by reaction of r$-unsaturated acyl chlorides
with medium and large ring enamines. Thus reaction
of acryloyl chloride and N-(I-cyclooctenyl)morpholine
affords ( 3 9 / , which is considerably more stable than (22).
Enamines of cycloheptanone merely afford bicyclo[4.3.1]de~ane-7,10-dione[~~!
Bicyclic immonium salts having a carbon-nitrogen double
bond at the bridgehead are formed by intramolecular condensation of type ( 4 0 ) if n > 5l3'I. As in the case of the enamine
ketones, ring size is again critical: the amino ketone (4Uc)
Angew. Chrm. infernal. Edit.
/ Vol. 14 ( 1 9 7 5 ) I N o . (I
While (47) is still isolable at room temperature, ( 4 8 ) and
( 4 9 ) dimerize on formation. They can however be trapped
by [4 + 21-cycloaddition with 1,3-diphenylisobenzofuran or
furan. It has recently also proved possible to prepare (2)
by intramolecular Wittig reaction[40! The long-sought adamantene (53 j , which can be regarded as a methylene-bridged
bicyclo[3.3.l]non-l(9)-ene having thedouble bond in the short
bridge, definitely belongs to the trans-cyclohexene structural
type. A first indication that it can exist was provided by
the observation that thermally induced fragmentation of the
di-tert-butyl ester of 1,2-adamantanediperoxycarboxylicacid
(50), in the presence of 2,5-dimethylfuran, affords products
having the constitution (54)1411.
531
It would seem that the success of this fragmentation method
is crucially dependent upon the comparable rates of cleavage
of the two peroxy ester groups which are certainly frequently
encountered in the formation of unstrained double bonds1421.
(54)
(53)
( S O ) , R' = R 2 = C(O)-O-O-C(CH3)3
having a dihedral angle between the carbonyl and the carboxyl
group of the order of 90".This arrangement is a prerequisite
for maximum possible conjugational stabilization of the incipient carbanion by the x-system of the adjacent carbonyl
group. If a conformational change of this kind is impossible,
as in the case of ( 6 4 ) , the corresponding enol is not
It is therefore highly probable that ( 6 2 ) can only decarboxylate
to ( 6 3 ) in the conformation (62b).
(51). R' = O - C ( O ) - C H ~ C ~ H SR2
, = H
(S2), R'
H, R 2 O-C(O)-CH2C,jH,
then no evidence for the expected bridgehead olefin 1-norbornene (106) is obtained from thermally induced fragmentation of the diester (57)[441. Photochemically induced fragmentation of 1-adamantyl phenylacetate ( 5 1 ) and the 2-adamantyl
ester (52) in monodeuteriomethanol gave 1% of l-methoxyadamantane having comparable deuterium contents in both
cases. Since only 1-substituted adamantane derivatives are
formed on photolysis of 1- and 2-substituted adamantyl esters,
a common intermediate is postulated, i. e. adamantene (53)[451
(cf. Sections 2.1 and 2.7).
(59)
(60)
6OOH
(63)
(64)
313
(58)
(626)
(62 a )
Preliminary measurements show that the fragmentation of
the tert-butyl ester of 2-adamantaneperoxycarboxylic acid is
about 10 times slower than that of l-adamantaneperoxycarboxylic
If the difference in reaction rate of the peroxy
ester groups is even greater, as in the case of (55) and (56)[431,
According to the generally accepted mechanism of decarboxylation of a P-keto acid, carbon dioxide is eliminated from
the cyclic structure (65) having an intramolecu' ir hydrogen
bond to form the e n o P 'I. However, consideration of models
reveals that a dihedral angle of 90" is only compatible with
an intramolecular hydrogen bond involving the x-system of
the carbonyl group, as in ( 6 6 ) , and not the lone pair of
the oxygen, as in (65). Moreover, such a hydrogen bond
is also required for a Huckel aromatic transition state for
decarboxylation.
go
0-
If the carbonyl group is replaced by an imino group, decarboxylation is accelerated so drastically that it has so far proved
impossible to detect simple p-imino carboxylic acids. In contrast, p-imino carboxylic acids having a bicyclic skeleton can
be isolated but decarboxylate about lo6 times faster than
comparable P-keto acids (Table 2)[521.However, this effect
is not pronounced enough to be able to induce the acids
( 6 9 ) and (70) to eliminate carbon dioxide.
(61)
Attempts to generate bicyclic bridgehead olefins by Norrish
type I1 cleavage have so far been unsuccessful. Only cyclobutanol derivatives can be detected on photolysis of the ketones
(58)-(61)[46,471. Apparently fragmentation of the 1,4-diradical formed by y-H abstraction during the photolysis is a
stereoelectronically highly demanding reaction.
(67a), x = 0
(67b), X = N - C ~ H S
(68a), X = 0
(68b), X = N-CBH,
24. Decarboxylations
All bi- and polycyclic 0-keto acids which should form a
bridgehead enol of the trans-cyclopenteneor trans-cyclohexene
series either fail to undergo decarboxylation or do so only
with extensive modification of the carbon ~keleton[~*-~*1
PI.
The limit imposed by ring size seems to be relatively clear-cut
since all known homologs potentially capable of forming an
enol of the trans-cycloheptene series readily eliminate carbon
dioxide above 200 0C1491.
For stereoelectronic reasons P-keto
acids have to undergo decarboxylation in a conformation
[*] Optically active 2,5-dioxobicyclo[2.2.2]octane-1 ,4-dicarboxylic acid racemizes on monodecarboxylation, thus ruling out intermediacy of the bridgehead
enol.
532
Table 2. Concerning the decarboxylation of bicyclic keto and imino acids.
(670)
(676)
(68a)
(68b)
(69)
(70)
Ring size of
the potential
enol
Decarboxylation
c'CI
AH+
[kcal/mol]
7
7
7
7
6
6
150-220
69-86
130-150
18-93
not below 300°C
not below 300°C
38.7
26.5
36.7
26.4
Angew. Chrm. internat.
-
Edit. 1 Vol. 14 (1975) 1 No. 8
2.5. Deprotonations
On acid catalysis a ketone affords an enol which should
be structurally and energetically identical to that formed from
decarboxylation of the corresponding P-keto acids. Accordingly, the deprotonation of a ketone should be subject to
the same conformational and stereoelectronic criteria as the
elimination of carbon dioxide from P-keto acids. No systematic
studies designed to support this relationship have been
reported. Apart from an exceptional case which proceeds via
a different mechanism[531,
there appear to be no bicyclic ketones
which undergo acid-catalyzed deuteration at the bridgehead if the carbon ring of the potential enol is eight-membered or smaller[541.Acid catalyzed enolization of ketones
(or at least that of bicyclic ketones) appears to be structurally
more selectivethan base-induced deprotonation. Thus in acidic
deuterium oxide ( 7 1 ) merely exchanges the two protons on
C-3 whereas deuterium is also incorporated at the bridgehead
in basic solution[55! This difference can be attributed both
to the comparatively slower acid-catalyzed reaction and to
the formation of a more rigid en01[~~'.
The minimum size of the carbocycle for which bridgehead
enolization can still be observed is 7. Thus ent-17-norcauran16-one (74), longicamphor (75), and especially copacamphor
( 7 6 ) can readily be deuterated at the bridgehead albeit under
drastic basic condition^[^'^ 581.
Deprotonation is affected not only by ring size but also
by the conformation of the bicyclic skeleton, especially that
of the carbonyl-containing ring. Although compounds having
a bicyclo[3.3.l]nonane structure appear to prefer a double
chair conformation in the crystalline state[591,formation of
the bridgehead enolate ion of ( 7 2 ) is stereoelectronically
favored only in the chair-quasi-boat geometry ( 7 2 b ) (6.
Section 2.4). The bridgehead enolate ion itself should largely
retain the conformation (73) in the case of strong double
bond character. Additional alkylene bridges which restrict
the conformational mobility only slightly or hardly at all,
do not interfere with base-induced bridgehead deprotonation.
Presumably the ketones (74)--(76), unlike (77)[601,can be
deuterated at the bridgehead for this reason.
Hitherto it was tacitly assumed that an incipient carbanion
at the bridgehead can be stabilized by a neighboring carbonyl
group via n-delocalization. However, other effects can become
dominant under certain conditions. An indication for this
is provided by the observation that the ketone ( 7 8 ) not only
undergoes the expected proton exchange of the cyclopropane
ring under drastic conditions at 200°C but is also partially
deuterated at the bridgehead, although the carbonyl group
Angew. Chem. internat. Edit.
1 Val. 1 4 (1975) J N o . 8
is in a conceivably unfavorable position for rc-conjugation
with the potential bridgehead carbanion[611.(79) is also partially deuterated at the bridgehead. Alternative mechanisms,
such as exchange on ring-opened intermediates with subsequent recyclization, are regarded as incompatible with experimental findings.
(78)
(79)
(80)
(81)
Not only carbonyl groups but also heteroatoms accelerate
deprotonation at the bridgehead of bicyclic ring systems. A
few noteworthy examples are cited.
The bicyclic trisulfide ( 8 2 ) is dedeuterated in the presence
of alkoxides even faster than ( 8 3 ) , whereas the oxygen analogs
(80) and ( 8 1 ) display no exchange[621.If the relative rate
of isotope exchange were to reflect the difference in pK, values
of these compounds[631then ( 8 2 ) would be more acidic than
(83). The converse applies to the trisulfones (84) and ( 8 5 ) :
the open-chain (85) is the stronger
The significance
of bridgehead deprotonation for the successful synthesis of
natural products in the gliotoxin and sporidesmin series has
recently become apparent : bridged diketopiperazines of type
(86) can be diastereoselectively deprotonated by n-butyllithium and thus readily substituted at the bridgehead[651.Bicyclic
compounds having just a single hetero substituent can likewise
be deprotonated at the bridgehead Both the sulfoxide (87)1661
and the sulfone (88)[671
are subject to base-catalyzed deutera-
tion. These reactions should proceed via compounds having
a C=S bond. Without exception, saturated and unsaturated
bicyclic sulfones of type (90) apparently form bridgehead
dianions on treatment with n-butyllithium since only the disubstituted derivatives can be isolated on subsequent treatment
with deuterioacetic acid or methyl iodide[681.
4
The bicyclic phosphonium salt (89) can also be easily deuterated in basic solution[69! The reaction should proceed
via an alkylidenephosphorane.
Attempts to interpret the acidity-enhancing effects of heteroatoms can be found in the more recent literature[66"01.
533
2.6. Solvolyses
The acceleration of a solvolysis by nonbonding electron
pairs of a-heteroatoms is explained by conjugational stabilization ofthe incipient carbocation. Thus while open-chain a-halo
ethers are generally isolable, they undergo extremely rapid
solvolysis. O n the other hand, the open-chain a-halo amines
are isolable only as immonium salts. It therefore seems appropriate to investigate the solvolysis of corresponding bicyclic
compounds, in order to establish whether intermediates having
bridgehead double bonds are formed.
The a m compounds (91), (93a), and ( 9 3 b ) solvolyze more
slowly than the carbocyclic codpounds (92), (94 a), and
( 9 4 b ) by a factor of 20, 10, and 2, respectively. However,
on comparison with values estimated for a retarding o-acceptor effect of the nitrogen they display an acceleration in the
order of lo3-lo8 which has been termed “n-a~celeration”[~‘I.
(91)
(92)
(93a),X = OTs
( 9 3 b ) , X = C1
(94a),X = OTs
( 9 4 b ) , X = C1
Presumably, additional effects also play a role here since
the a-chloro amine ( 1 2 6 b ) is in fact solvolyzed faster than
l-bromo-3,3-dimethylbicyclo[2.2.2]octane~72?It should be
mentioned in this context that ( 9 5 ) , in phenol, not only rearranges but also fragments to give (96)[73’.The fact that ( 9 5 )
is solvolyzed two to four times faster than (97) is attributable
not to a smaller activation energy but to a more positive
activation entropy. A comparatively unusual acceleration of
solvolysis has been observed for the a-chloro amine (101
The krel values given have been extrapolated to 29.1 “C. No
explanation has yet been offered for the striking difference
in relative rates.
intermediate (106) led to cycloadducts (107) and (108) in
a constant ratio. The structures of (107) and (108) were
established by oxidative degradation to bicyclo[2.2. Ilheptane1,2-exo-dicarboxylic acid, which in turn was synthesized by
a n independent route. The existence of (106) as a discrete
intermediate in these reactions is substantiated by the constant
adduct ratio and the finding that olefin formation is induced
in each case by lithium-iodine exchangec7].
X
(102),X
(103), X
=
=
Br
C1
(1041, X = B r
( I O S ) , X = C1
Attempts to bisdehalogenate (109) in the same manner
gave no indication of the transient formation of bicyclo[2.2.1]hept-1(7)-ene174! Both the magnesium and the lithium compound accessible from (110) are likewise stable up to 80”C[751.
Furthermore, in the homologous series the reaction of ( 1 11)
with an excess of tert-butyllithium under controlled conditions
gave, inter alia, the compounds ( 1 1 2 ~ )and ( 1 1 2 b ) which
1109)
(111)
(IIZa),X
=
C(CH,),,
Y = H
(Il2b), X = H,
Y = C(CH3)3
may be regarded as trapping products of bicyclo[2.2.2]oct-lene (129)1761.
As expected, bisdehalogenation becomes easier
and more specific with increasing ring size : 1,2-dibromobicyclo[3.3.l]nonane is cleanly reduced by sodium in alcohol to
the olefin (2)r771. On reductive bisdehalogenation of 1,2diiodo- and 1-bromo-24odoadamantane in the presence of
furan only two saturated hydrocarbons were isolated which
can be viewed as dimers of adamantene (53)[78? However,
if the reaction is carried out in butadiene the cycloaddition
product is formed[791(cf. Sections 2.1 and 2.3).
2.7. Reductive Eliminatiom
28. Oxidative Eliminatiom
Of the many variants of reductive elimination used for
the production of olefins only few have so far been applied
to the generation of olefins having bridgehead double bonds.
Bisdehalogenation of bicyclic 1,2-dihaloalkanes induced by
alkyllithium plays a prominent role in this context. This
method was first used in the case of 1,2-dihalonorbornanes
and led to the classical bridgehead olefin 1-norbornene (bicyclor2.2.1 Jhept-1-ene) (106) as intermediatef7’.
O n reaction of the diastereoisomeric pairs (102)/( 104) and
(103)/(105) with butyllithium in the presence of furan the
534
In the course of structural elucidation of alkaloids it was
observed that the methyl ester of homo-seco-daphniphyllic
acid is oxidized to the bridgehead imine ( 2 1 3 ) by lead tetraacetate[801. Other conceivable double bond isomers are ruled
out partly for steric reasons and partly on the basis of the
spectra. Rearrangement products are unlikely since ( 1 13) is
reduced practically quantitatively to the original amino ester
by NaBH4 or on catalytic hydrogenation. The formation of
( I 13), a bicyclic analog of trans-1-azacyclooctene, is presumaAngew. Chem. intemat. Edir. f Vol. 14 (I975)
/ No. 8
3
I”
,C OOCH3
R = CHi,
1/13)
gationally stabilized double bonds. The 1,6-bridged cyclodecapentaene (119) is cited as an exampler841.The structure of
the carboxylic acid (120), a derivative of ( 1 19), is characterized by ready twisting of the partial bridgehead double bond,
accompanied by pyramidalizati~n‘~~]
[Fig. 1, formula
(I 20 a ) ] .
CHz
bly promoted by both the fixed boat-chair conformation of
the 2-azabicyclo[3.3. llnonane skeleton-which has been verified by X-ray structure analysis of the saturated compoundand by the absence of any alternative reactions. In any case,
bicyclic bridgehead imines of the same type have hitherto
not been
(120), R
2.9. Rearrangements
Bicyclic compounds of type (I 1 4 ) can easily isomerize to
monocyclic dihalo olefins if n <3. The propellanes ( 1 15 a )
and ( 1 15 b ) of analogous structure are considerably more
stable since electrocyclic opening of the three-membered ring
entails formation of bridgehead olefins.
x
( 1 1 4 ) 3 X = C1, B r
R
(119), R = H
x
(IISa), X = C1
( I I S b ) , X = Br
“luc’
(116)
However, if the strain in the propellane increases more
rapidly than in the bicyclic bridgehead olefin with decreasing
ring size then the tendency to undergo rearrangement can
again increase. Nevertheless it is rather surprising that (1 16)
is unstable at room temperature and affords dimers which
are formally derivable from a bridgehead olefin (1 27)[821.
As shown by X-ray structure analysis of the major product
the predominant dimer formed from the twelve possible
alternatives is the mem form (I 18). Thus the dimerization
formally corresponds to [n2s+ n2,]-cycloaddition. It has been
estimated for a strain of about 20 kcal/mol in ( I 16) that
isomerization of (116) to ( 1 1 7 ) is exothermic to the extent
of about 10 kcal/mol.
It is to be expected that directed studies of the dimerization
of reactive bridgehead olefins should lead to considerable
refinement of the selection principles and mechanistic models
of [2 + 21-cycloadditions.
The rate of rearrangement of thermally stable dihalopropellanes of type ( 1 1 5 ) can be enhanced by acceleration of the
ring-opening solvolysis step: both ( 1 15 b ) and the corresponding saturated propellane are rapidly hydrolyzed in the presence
of silver ions. The products formed can be formulated in
terms of intermediate bridgehead ole fin^[^^!
The bridged annulenes accessible from certain unsaturated
propellanes can be classified as bridgehead olefins with conjuAngew. Chem. internat. Edit. 1 Val. 14 ( 1 9 7 5 ) 1 No. 8
(121)
(122)
= COOH
(/23a), n = 7
(123b), n = 6
The equilibrium between the cycloheptatriene and norcaradiene structure of bridged compounds of type (121) and
(122) must also be viewed in light of the Bredt rule186-901.
Meta- and paracyclophanes having small bridges[” 931
suchas (123a) and (123b), which have only become available
very recently and whose structure should prove particularly
informative, will at last put discussions of the flexibility of
aromatic rings on a firm basis.
The rearrangement of carbenes and nitrenes is developing
into a potent method for the preparation of highly reactive
bridgehead olefins. Thus, for example, photolysis of l-azidobicyclo[2.2.l]heptane in methanol affords the u-amino ethers
(126a) and ( 1 2 7 ) which are formally derivable from the
imines ( 1 2 4 a ) and (125), respectivelyr941.
(124a), R = H
( 1 2 4 b ) , R = CH3
(125)
( / 2 6 a ) , R‘ = H, R 2 = %H3
( 1 2 6 b ) , R’ = CH3, R 2 = C1
(127)
(128)
(129)
Products which could arise via bridgehead olefins are formed
from carefully dried salts of tosylhydrazones only under conditions of flash pyrolysis. 3-Methylene-l,6-heptadiene,which
is isolated on decomposition of the lithium salt of (128),
formally arises from bicyclo[2.2.2]0ct-l-ene (129) by retroDiels-Alder reaction[”!
(I3Oa), M = Li
( 1 3 0 b ) , M = Na
Pyrolysis of (130a) and (130b), however, does not give
unsaturated compounds but instead yields five hydrocarbons,
of which three are regarded as direct dimerization products
of 3-homo-I-adamantene (131)[961.Apart from their configur-
535
ation it remains to be established which of the dimers are also
formed on thermolysis of (il) and (i2)[22a1.
It should nevertheless be emphasized that potentially suitable carbenes only react to give bridgehead olefins if rearrangement is favored by stereoelectronic factors : thermolysis of
a-diazocamphor does not give an olefifi but instead the tricyclic
ketone ( 1 3 2 ) , and pyrolysis of the lithium salt of adamantanone tosylhydrazone essentially affords 2,4-didehydroadamantane ( 1 33Jr9". In the A1CI3-catalyzed reductive ring opening of l-(N,N-dichloro)amino-7,7-dimethylbicyclo[2.2.l]hep
tane to give ( 1 2 6 b ) , it is conceivable that the strained imine
( I 24 b ) or the corresponding bridgehead immonium ion is
formed as an
An unusual oxidative ring expansion was observed in the
reaction of hydroxy-B-norsteroid with lead tetraa~etate['~].
The bicyclic enol ether ( 1 3 4 ) having a 10-oxabicyclo[4.3.1]dec-1-ene skeleton was formed as major product.
go
&OAC
Acd
(132)
(133)
(134)
Sigmatropic rearrangements of order [2,3] are likewise subject to the stereoelectronic restrictions of the Bredt rule. The
isolable ammonium enolate ( 1 3 5 ) isomerizes readily to the
a-amino ketone ( 1 3 7 ) , which is assigned the configuration
shown on the basis of mechanistic arguments and NMR spectroscopic data"001. However, the corresponding Stevens rearrangement having the sigmatropic order [2,1] is apparently
stereoelectronically much more demanding since heating of
( 1 3 6 ) merely affords a complex mixture of products.
Since the torsional angle increases with decreasing bridge
length it is hardly surprising that the ammonium enolates
( 1 3 8 ) and ( I 3 9 ) are stable and no longer undergo sigmatropic
rearrangement.
2.10. Robust and Labile BridgeheadSubstituted Bicyclic and
polycyclic Compounds
As already mentioned, a series of elimination reactions have
been developed for preparing bridgehead olefins. In some
studies less interest is attached to the strained double bond
than to the functional group at the bridgehead. Since decomposition reactions such as p-eliminations, and nucleophilic
substitutions of course, are kineticallyhindered, if not completely suppressed, by the bi- or polycyclic system, the chemical
and physical properties of certain functional groups become
observable to study over a considerably greater temperature
range.
Thus the kinetic stability of the metal complex ( 1 4 0 ) is
comparable to that of pentacyanomethylcobaIt(m) while the
536
corresponding tert-butyl complex decomposes so readily that
it has so far evaded isolation['0'! The transition metal compounds of type ( 1 4 1 ) also owe their stability, at least in
part, to the lack of j3-elimination['02!
(141)
M = Hf, Z r , Ti, V,
C r , Mn, F e , C o
(142)
Since pyrolysis of alkyl sulfoxides with j3-hydrogens entails
ready &-elimination to give olefins their racemization can
only be investigated if the alkyl groups either bear no P-hydro.
gen or have a structure in which p-elimination is stereoelectronically hindered: the sulfoxide ( 1 4 2 ) racemizes without
simultaneous elimination[' 031. Dealkylation of tertiary amines
according to PoZono~ski~'~~1
is formulated as proceeding via
unstable N-acyloxyammonium salts which are transformed
rapidly into immonium ions on base catalysis, and afford
secondary amines after hydrolysis. In contrast, the salts ( 1 43 a )
and ( 1 4 3 6 ) accessible from quinuclidine N-oxide do not
undergo elimination because formation of the bicyclic bridgehead immonium ion is largely suppressed['04'.
Dialkylnitroxyls have long evaded any study of their physical properties because they rapidly decompose to nitrones
and hydroxylamines. However, bicyclic nitroxyls possess adequate stability since formation of nitrones having a strained
imine double bond is much slower. Thus ( 1 4 4 ) decomposes
about lo9 times more slowly than an acyclic dialkylnit r o ~ y l-'08].
~ ' ~ The
~ configuration of ( 1 4 4 ) is unknown.
(144)
(145)
(1461
On the other hand, compounds which are normally stabilized by conjugation can become highly reactive if the functional groups are incorporated into a bi- or polycyclic skeleton
in such a manner that n-delocalization is no longer possible.
The effect of this conformational difference on the chemical
and physical properties of the quinuclidones ( 1 4 5 ) and ( 1 4 6 )
is particularly striking. Thus ( 1 4 5 ) reacts with methanol in
basic solution about lo4 times faster than the bicyclic lactam
( 1 46)['O91.
2.11. "Annelated" Bridgehead Olefins
The strain in bridgehead olefins possessing a bridged polycyclic skeleton as common structural feature (Bredt olefins)
is largely attributed to twisting"]. "Annelated" bridgehead
olefins, on the other hand, are predominantly strained for
[*] The extent of twisting is overemphasized by formulas and models having
rigid bond angles.
Angew. Chum. internat. Edit. f Voi. 14 (1975)
1 No. 8
reasons of bond angle deformation and pyramidalization. The
polycyclic compound (147)'' 1' should be mentioned as a
prototype since in this case both bond angle narrowing and
pyramidalization are very pronounced [cf. formula (147a)I.
(1471
(147a)
Bicyclic compounds of type (148), whose chemistry has
recently been surveyed in
also belong to this class
of bridgehead olefins, as do (149)["'! For that matter, this
class really also embraces cephalosporinsf' and penicillins.
8
3. Outlook
The methods presented by no means exhaust the arsenal
for preparation of bridgehead olefins. Potential reactions
include both those which have proved of value in the preparation of 1,2-dehydrobenzene['131 and those which are suitable
for introduction of an additional double bond into cyclobutenel' l41.
Interest, however, will probably continue to be focused
upon development of methods providing an entry to highly
strained bridgehead olefins under conditions in which their
physical and chemical properties can be directly determined.
We can also expect the study of bridgehead olefins to make
a significant contribution to our understanding of the photochemistry of simple alkenes" 's.
and the reactivity of
strained olefind' 17. *I. Moreover, Bredt olefins themselves
will extend our knowledge about the structural course of
thermal cis-trans isomerizations of simple alkenes.
From the vantage point of preparative organic chemistry,
bridgehead olefins possess considerable interest whenever
they afford products that are otherwise accessible only with
difficulty. An impressive example is seen in the synthesis of
dimethyl bicyclo[2.2.l]heptane-l,2-exo-dicarboxylate from
norcamphor via l-norbornene['].
Received: September 2,1974,
in abbreviated form: December 30, 1974 [A 72 IE]
German version: Angew. Chem. 87.568 (1975)
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Angew. Chem. internat. Edit. / Vol. 14 (1975)
No. 8
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