The synthesis and transformations of fused bicyclo[2.2.2]octenes

The synthesis and transformations of bicyclo[2.2.2]octenes with the emphasis on substituted bicyclo[2.2.2]oct-7-ene-2,3,5,6-tetracarboxylic acid derivatives bearing a substituted amino group at the bridgehead carbon atom are presented. The main topic of this review is the Diels − Alder reaction, as the most important tool for preparing compounds of this type. The transformations of bicyclo[2.2.2]oct-7-ene-2,3,5,6-tetracarboxylic acid dianhydride derivatives with nitrogen-containing nucleophiles are discussed as well as the derivatisation of the olefinic C=C double bond


Introduction
Bicyclo[2.2.2]oct-7-enes (bicyclo[2.2.2]oct-2-ene when unsubstituted; structure 1, Scheme 1) represent a very interesting and synthetically challenging class of compounds that have attracted the attention of numerous organic chemists.The representatives of this class can be found in nature and their complete syntheses have also been published (for instance, eremolactone 2). 1 In many cases the bicyclo[2.2.2]octene skeleton is a part of a more complex polycyclic framework, like in kopsidasine (3), a representative of the naturally occurring Kopsia alkaloids. 2It is also worth mentioning that a random study of activities revealed that mitindomide (4) possessing the bicyclo[2.2.2]octene skeleton exhibited a strong and repeatable antitumor activity in vivo.Its water-soluble and structurally symmetrical counterpart 5, which lacks the cyclobutane fragment, also shows a certain antitumor activity. 3n this account we present some of the most efficient and attractive ways of constructing the bicyclo[2.2.2]octene moiety 4 as well as summarizing our recent work in the field of differently substituted bicyclo[2.2.2]oct-7-ene-2exo,3exo,5exo,6exo-tetracarboxylic acid 2,3:5,6dianhydrides 6 5 with various nitrogen nucleophiles (hydrazines and amines).A subsequent transformation of the products thus obtained, including the C=C double-bond reductions, will also be discussed.

The Synthesis of Various Bicyclo[2.2.2]oct-7-ene-2,3,5,6-tetracarboxylic Acid Dianhydride Derivatives
There are various ways of preparing bicyclo[2.2.2]oct-7-ene-tetracarboxylic acid dianhydride derivatives 6; one of the most usual being a double Diels−Alder cycloaddition of maleic anhydride (8), acting as a dienophile onto the 2H-pyran-2-one core 7 (Scheme 2). 4 The first intermediate in the synthesis is a bicyclic bridged lactone 9, which is formed through the usual thermal [4+2] cycloaddition reaction.Since these reactions are usually run at high temperatures (reflux in toluene, mesitylene, xylene, tetralin, etc.), 6 a spontaneous extrusion of CO 2 immediately follows the cycloaddition step and another diene 10 is formed.The latter reacts with a second molecule of maleic anhydride (8), thus forming a double cycloadduct 6.Other ways of preparing this system include the Diels−Alder reaction of a substituted cyclopentadienone system, which is prepared in situ from a stable precursor (4-hydroxy-3,4diphenylcyclopent-2-enone derivative) through a dehydration reaction. 7The subsequent addition of one molecule of maleic anhydride, the extrusion of carbon monoxide and the addition of the second molecule of the maleic anhydride leads to a system of type 6.Some pathways start with an appropriately substituted thiophene derivative, which is in turn oxidized to sulphone.After the first cycloaddition step the sulfur dioxide is eliminated and thus a new diene is formed.It again reacts with another molecule of dienophile, yielding the product with a bicyclo[2.2.2]octene skeleton. 8It is also worth mentioning that the starting diene does not need to be a cyclic compound.For example, the reaction of (1E,3E)-4-(trimethylsilyl)buta-1,3-dienyl acetate with maleic anhydride produced 6a (6: R 1 =R 2 =R 3 =R 4 =H) in a 95% yield after one hour of heating at 100 °C, and in the absence of a solvent. 9Vinylketene dithioacetal could also be used as a diene.Here, the regeneration of the diene system, which is necessary for the bicyclic product formation, is enabled through the elimination of thiomethanol. 10e reported the synthesis of a series of highly substituted double cycloadducts, bearing a protected amino substituent at the bridgehead carbon atom.These were obtained with the cycloaddition of maleic anhydride (8)  Our approach to the derivatives of the bicyclo[2.2.2]octene system involved the application of 3-benzoylamino-2H-pyran-2-ones 14a-j 12 as dienes in the reaction with maleic anhydride 8 (Scheme 4). 13With the use of refluxing tetralin we were able to synthesize the doublecycloaddition products 15a-k in short reaction times with good-to-excellent yields (Table 1).The products are formed as crystalline precipitates; their isolation requires only filtration and rinsing with methanol.It is also worth noting that the starting compounds containing either thienyl or furyl substituents (14b, 14c, 14h and 14k) react specifically only with the 2H-pyran-2-one ring as dienophile, yielding the products 15b, 15c, 15h and 15k as single isomers.The required reaction time seems to decrease if the substituents R 1 and R 2 are electron donating (for example, R 2 =4-MeOC 6 H 4 , Run 6), which is consistent with the normal electron demand of the Diels−Alder reaction.
Based on the 1 H NMR spectra of the compounds 15a−k a plane of symmetry was evident, but there was still some ambiguity.There were two possible types of products: I or II.The stereochemical configuration of the products was elucidated by an X-ray study of the compound 15e, which was shown to be of type I, in accordance with the previous reports. 4,6he formation of these products is also in accordance with the endo-kinetic control of the Diels−Alder reaction. 5There are just a few previously described examples involving maleimides as dienophiles in which unsymmetrical products were obtained under photochemical conditions.).The reaction toward 20 must therefore also include a retro Diels−Alder reaction followed by an aromatization reaction.It was also proven that the presence of Rh/C accelerates the reaction toward the products 20. 15 ARKAT USA, Inc.
We further expanded the library of bis(succinimide) derivatives of bicyclo[2.2.2]oct-7-enes 22 by employing differently substituted 2H-pyran-2-ones 14 and several N-alkyl substituted maleimides 17 as the starting materials and reacting them in water, as a solvent, and applying microwaves as the source of energy (Scheme 6, Table 2). 16 Microwave-assisted synthesis of bis(succinimide) derivatives of bicyclo[2.2.2]oct-7enes 22 in water.
Despite the negligible solubility of the substrates 14 in water at room temperature, most of the cycloaddition reactions were complete within one hour of the irradiation with microwaves at 150 ºC, affording the bicyclo[2.2.2]octene derivatives in very good yields.In runs 11 and 12 we found that neat reaction conditions were beneficial for the reactions as the reaction times and the formation of side-products were reduced considerably.The use of microwaves as the energy source and water as the reaction medium seems to have a large effect on the reaction times.If the syntheses of products 22d and 22h (runs 4 and 8) were carried out in refluxing decalin, bp 189−191 ºC, after 90−120 min 22d and 22h were obtained in 81 and 76% yields, respectively.This was good evidence that the use of water as the reaction medium and microwaves as a source of heating are beneficial in comparison with thermal reactions in decalin.We attempted to expand our methodology toward the library of fused succinimide derivatives of the bicyclo[2.2.2]octene system by further varying the substitution pattern on the starting 2Hpyran-2-ones 14 as well as the reaction conditions (Scheme 7, Table 3). 17Here, we have applied neat reaction conditions in the presence of a minor amount of a liquid additive (butan-1-ol) and microwave heating, a method which was previously shown to be beneficial in terms of the degree of conversion and the reaction time. 18We found that this was also the case in the double cycloaddition reaction of maleimides.In other words, the reactions in the presence of small amounts of butan-1-ol took place with higher conversions than the same reactions in the absence of any additive or in butan-1-ol as a solvent.The role of the liquid additive was to rinse the sublimed maleimides from the colder, upper parts of the closed microwave reaction vessel to the lower parts of the same vessel, where the reaction with nonvolatile 2H-pyran-2-ones takes place.It is also worth mentioning that this method does not require a large excess of maleimide (only 5% excess is needed) and, due to an easy work-up (filtration and washing), it is very appropriate for the synthesis of a large number of new compounds.We have thus synthesized a library of compounds with the use of microwaves and minimal solvent requirements (water and a small amount of additive) by a simple and eco-friendly green approach.

Reactions with hydrazines and amines
It is well known that anhydrides react with amines and hydrazines, producing the corresponding amides and imides. 19Before our investigation in this field started, to our knowledge there had only been one report on the utilization of the fused bicyclo[2.2.2]octene system (but not containing an amino group at the bridgehead) in a reaction with hydrazine hydrate and phenylhydrazine in an ethanolic solution. 20Only two products were prepared in this investigation and no details about the reaction times were given.Therefore, we decided to investigate the reactivity of the anhydride moieties of bicyclo[2.2.2]oct-7-ene-2exo,3exo,5exo,6exotetracarboxylic acid 2,3:5,6-dianhydrides 15 toward various hydrazines and amines.Our idea was to perfom this reaction in green conditions, i.e., in an aqueous mixture, and to apply microwaves as the source of heating.With the starting material 15 readily available from the previously mentioned double cycloadditions of maleic anhydride with 2H-pyran-2-ones, it proved to be an effective way of synthesizing a library of differently substituted, fused Naminosuccinimide derivatives of bicyclo[2.2.2]octene 27 (Scheme 8, Table 4). 21 NHCOPh Scheme 8. Synthesis of differently substituted N-aminosuccinimide derivatives 27 of bicyclo[2.2.2]octene from 15 and hydrazines 26 with water as the solvent and microwaves as the source of energy.
The reaction runs well in most cases, even with a small excess of hydrazine (1.2 eq.).In the case when we applied this transformation to the adduct 15e, the reaction of the carbonyl group proceeded as well (Scheme 9, Table 5).This reaction enabled us to obtain N-aminosuccinimide products 28 containing an additional hydrazono group.When we analyzed ( 1 H NMR) a non-completed reaction of 15e with hydrazine hydrate we found that the reaction mixture consisted of unreacted 15e and the product 28a, suggesting that the condensation runs simultaneously at all three reactive centers.Therefore, we have shown that this reaction, under the applied conditions, could not be undertaken in a chemoselective way.
We also wondered if the above-mentioned transformations would proceed with amines.When checking the literature we found that some reactions with representatives of these systems and amines occurred when using refluxing DMF as a solvent 22 or by heating an aqueous solution for a long reaction time 23 (Scheme 10).As amines are less nucleophilic than hydrazines, we expected that the transformations would run less smoothly than with hydrazines; however, we found that the transformation of starting 15 with a series of amines toward new bis(succinimide) derivatives of bicyclo[2.2.2]octene runs under similar conditions as with hydrazines, yielding products 25m-q (Scheme 11, Table 6).We were also wondering how the acetyl derivative 15e would react with amines under aqueous conditions.We thought about a possible chemoselective transformation of the additional acetyl group (the reactivity of keto versus anhydride functionality).When amines react with aldehydes or ketones imines are formed; they are known, on the other hand, to hydrolyze in the presence of water and at high temperatures back to oxo derivatives.Therefore, we applied aqueous reaction conditions and microwave heating to reactions of 15e with various amines (Scheme 12, Table 7).We found that substrate 15e reacts with amines under aqueous conditions in a different way than with hydrazines.With hydrazines, hydrazones 28 were formed (see Scheme 9), but with amines the reaction in water does not proceed on the keto group; both anhydride moieties react, producing 32 in high yields.On the other hand, we found that carrying out the same reaction in neat conditions in the presence of a minor amount of toluene, as an additive, with only 4 eq. of aniline derivative, enables the formation of imines 33 under green conditions. 24RKAT USA, Inc.  Optimization studies on the reaction of 15e with 4-chloroaniline 31c showed that toluene is a necessary additive.Without it, no suitable condition to finish the reaction could be found.However, the amount of toluene proved to be very important.The optimal quantity was shown to be around 100 mg/0.5 mmol of 15e in a 10-mL reaction tube.It seems that with such small amounts of toluene the water eliminated during the reaction is evaporated and deposited on the uppermost, coldest parts of the reaction vessel.Only 4-chloroaniline, with a higher boiling point than water, is rinsed back by the toluene to the lower parts of the vessel where the reaction takes place.The formation of 32c becomes significant with larger amounts of toluene, as too much additive also rinses the water back into the reaction mixture.Running the reaction using two-fold amounts was complete under identical conditions as on the 0.5-mmol scale.However, quadrupling the quantity of the reactants and running the reaction in a classical 10-mL sealed tube proved to be impossible.It resulted in unusual temperature profiles.Therefore, we decided to carry out this experiment in a larger, closed reaction vessel (a heavy-wall Ace pressure tube, 38 mL, Aldrich) and using the CEM Discover "open vessel" mode protocol.Again, the reaction was finished in 75 minutes and we isolated 33c as the sole product in an 83% yield.
The reactions proceeded with good yields and with reasonable reaction times.The imines 33 can be formed with aromatic (conjugated) amines only.An attempt to use nonconjugated amines (for instance, 31f) under neat reaction conditions with the substrate 15e to obtain a product similar to 33 was not successful.This was confirmed by the mass spectrum of the crude reaction mixture; an analysis using the 1 H NMR spectra was not possible, because of the large number of overlapping signals.The fact that imine-type products 33 were not formed could be attributed to the lower stability of the imine moiety when an aliphatic residue is bound to the imine nitrogen.It is also worth mentioning that the imine-type products are formed, presumably only as anti isomers, as their 1 H NMR spectra show only one set of signals.We presumed the anti orientation because such an isomer would be less sterically crowded, and with the aromatic and sterically demanding bicyclo[2.2.2]octene groups further apart.
Both sets of reaction conditions (aqueous and neat) complement each other nicely and products 32 and 33 can be prepared with complete selectivity by applying the appropriate reaction conditions.In aqueous mixtures only the anhydride moiety is transformed to the corresponding imide, whereas the neat reaction condition also enables the transformation of the acetyl moiety to the corresponding imine functionality.

The synthesis of tetraalkyl tetraesters of bicyclo[2.2.2]oct-7-ene-2,3,5,6-tetracarboxylic acid
A fused anhydride ring can serve as a useful synthon for the preparation of the ester derivatives of the corresponding acids.The transformation usually involves the anhydride ring opening with alcohols in the presence of an acidic catalyst.For example, Uno et al. developed a transformation of the dianhydride 6a into the corresponding tetramethyl tetraester 34a, employing trimethyl orthoacetate as the dehydrating agent and p-TsOH as an acidic catalyst (Scheme 13).For the preparation of the ethyl tetraester derivative 34b similar reaction conditions were applied.The only difference was that toluene was used to raise the temperature of the refluxing reaction mixture and molecular sieves (4 Å) were employed to remove the water from the reaction mixture (Scheme 14).The above reaction conditions can also be applied to the synthesis of the tetrabutyl tetraester derivative. 26

Other Transformations of Bicyclo[2.2.2]oct-7-ene-2,3,5,6-tetracarboxylic Acid Derivatives
There were some reports of further transformations of the above tetraesters. 27Base-catalyzed isomerisation of 34a yielded the all-trans 35 and the trans-cis-trans derivative 36 in the ratio 4:1 (35 obtained in an 83% total yield). 25Reduction of the main product 35 with LiAlH 4 proceeded smoothly to the corresponding tetraalcohol 37, which was further transformed to the corresponding chloro derivative 38.The latter gives, after an elimination reaction with KOH, a pentaene derivative 39 (Scheme 15). 25 Another interesting reaction of the fused bicyclo[2.2.2]octene ring system is a reduction of the bis(succinimide) derivative 30 with LiAlH 4 , which gives product 40, containing fused pyrrolidine rings (Scheme 16). 23The amine 40 can be further quaternized with ethyl bromide.The alcohol derivative 41 was oxidized to a ketone, which was further subjected to various rearrangement conditions (Beckmann, Baeyer−Villiger), yielding the corresponding amide and ester. 29Compound 38 was also subjected to an epoxidation reaction with m-CPBA in EtOAc and the racemic epoxide was obtained in a 90% yield. 30The double bond in the compound 34a was proven to be extremely unreactive towards epoxidation conditions as the only successful condition applied to this transformation was the HOF x MeCN complex (dimethyldioxirane and m-CPBA failed) yielding 42 (Scheme 18).It is worth noting that the olefinic bond in dianhydride 6a was unreactive, even to this extremely strong electrophilic reagent.
Two very useful oxidation transformations were applied for the preparation of the compounds used in a stereochemical study of substituted cyclohexanes.The first one was an oxidation of 6a to cyclohexane-1,2,3,4,5,6-hexacarboxylic acid 43 (Scheme 19).The second was a successful ozonation of 34a (and some of its isomers) followed by an oxidative work-up with hydrogen peroxide and diazomethane, as the esterification reagent, yielding different peresterified stereoisomers of 43. 32In our ongoing cooperations with other research groups our substrates were also successfully further transformed under hydrogenation conditions.It was possible to apply Rh ligands, immobilized on layered double-hydroxide (LDH) supports, for the hydrogenation of bis(succinimide) derivatives of bicyclo[2.2.2]octene.16a The supported Rh catalysts were prepared via ion-exchange ligand immobilization on LDH1 (Zn 3 AlCl) and LDH2 (Co 2 FeCO 3 ).As the metal ligands, anionic analogues of triphenyphosphane (TPPTS = trisodium salt of 3,3',3''-phosphanetriyl benzenesulfonic acid and TPPTC = trilithium salt of 3,3',3''phosphanetriyl benzencearboxylic acid) were chosen.The catalyst structures and their chemical composition were confirmed by XRD analysis and XPS spectroscopy.As starting materials the compounds 22c−f were chosen, which differ only in their substituent at both succinimide nitrogens.It was shown that these highly sterically constrained systems are very resistant toward hydrogenation.The activity of both catalytic systems and their selectivity (48 vs. 49) is also strongly dependent on the steric hindrances of the R groups (Scheme 22, Table 8).Recently, we have also investigated the possibility of the C=C double-bond hydrogenolysis of the substrates 22. Two catalytic systems were tested for this purpose: (a) platinum (Pt) colloids modified by the chiral ligand synphos and subsequently embedded in silica to form a heterogeneous catalytic system 34 and (b) Fe 3 O 4 colloids modified by the chiral ligand cinchonidine and also embedded in silica. 35No simple C=C or C=O double-bond hydrogenation products (48 or 49) were obtained, but complex mixtures of interesting products were formed, with different compounds (50, 51 or 52, Scheme 23) being predominant in each case.
ARKAT USA, Inc.It is evident that the ratio of different hydrogenolysis products depends to a large extent on the applied catalytic system.Though no enantioselectivity was observed in these reactions, we believe that the scope of these methodologies will receive further attention in the near future.

Conclusions
In this account we have summarized our results in the field of bicyclo[2.2.2]octene synthesis along with the selected work of some other research groups.The above discussion proves that the representatives of bicyclo[2.2.2]octene derivatives can be very efficiently synthesized from 2H-pyran-2-one derivatives using the double Diels−Alder reaction of maleic anhydride or substituted maleimides.Bicyclo[2.2.2]oct-7-ene-2exo,3exo,5exo,6exo-tetracarboxylic acid 2,3:5,6-dianhydrides as a starting material enable the synthesis of a wider variety of new bis(succinimide) derivatives through reactions with nitrogen nucleophiles (amines, hydrazines) in high yields.The use of water or neat reaction conditions with the assistance of microwave irradiation renders these syntheses environmentally benign and user friendly.Fused dianhydrides can be further transformed to the corresponding acids and their derivatives, which could serve as useful intermediates for the preparation of a variety of interesting products.Finally, reactions of the C=C double bonds of bicyclo[2.2.2]octenes have shown their potential for the synthesis of new products, valuable for organic synthesis, that are otherwise not easily obtained.It is also important to mention that the reported conversions bring about an additional insight into the chemistry of heterocyclic dehydro-α-amino acid derivatives. 36

29 Scheme 10 .
Scheme 10.Reactions of derivatives 6 with amines under various conditions.
Scheme 11.Microwave-assisted transformation of 15 with amines under aqueous conditions.

Scheme 12 .
Scheme 12. Chemoselective transformations of substrate 15e under aqueous or neat reaction conditions.

Scheme 23 .
Scheme 23.Hydrogenolysis products of 22 with modified Pt or Fe 3 O 4 colloids as catalyst.

Table 2
a Microwave irradiation at 150 ºC in a pressurized tube.b Yield of isolated products.c Neat reaction.d Yield after crystallization from EtOH.

Table 3
a Microwave irradiation at 150 ºC in a pressurized tube with the addition of 100 mg butan-1-ol.b Yield of isolated products.c Temperature was set to 160 ºC.

Table 4 26
Run Reaction of 15e with various hydrazines to the corresponding hydrazones.
a Microwave irradiation at 100 ºC.b Microwave irradiation at 150 ºC.c Microwave irradiation at 160 ºC.d Yields of isolated products are given.ARKAT USA, Inc. a Yields of isolated products are given.