THE SYNTHESIS AND REARRANGEMENT
REACTIONS OF 1-AMINOADAMANTANE ANALOGUES
A thesis submitted in part fulfilment of requirements for the degree of
MASTER OF CHEMISTRY
by
Ivy Sio Hang LAU
Supervisor: Dr R. Bishop
THE UNIVERSITY OF NEW SOUTH WALES
July 1985 THE SYNTHESIS AND REARRANGEMENT REACTIONS
OF 1-AMINOADAMANTANE ANALOGUES
CONTENTS
Page 1. SUMMARY 1
2. INTRODUCTION
2.1 Adamantane and 1-aminoadamantane 2
2.2 Synthetic approaches to 1-aminoadamantane analogues 6
3. DISCUSSION
3.1 Synthesis and rearrangement reactions of 10 3.3.7.7- tetramethylbicyclo[3.3.1]nonane-2,6-dione
3.2 Synthesis and rearrangement reactions of 17 3.3.7.7- tetramethyl-6-methylenebicyclo[3.3.1] nonan-2-one
3.3 Synthesis and rearrangement reactions of end.o-2, 21 en
3.4 Hydrolysis of 1,3-bis(acetamido)-4,4,8,8- 23 3 7 tetramethyltricyclo[3.3.1.1 * ]decane
4. CONCLUSIONS AND FUTURE STUDIES 26
5. EXPERIMENTAL 27
6. REFERENCES 42 -1-
1. SUMMARY
Three bicyclo[3.3.1]nonane derivatives were prepared in this project and their behaviour under Ritter reaction conditions investigated:
3.3.7.7- tetramethylbicyclo[3.3.1]nonane-2,6-dione (39)
3.3.7.7- tetramethyl-6-methylenebicyclo[3.3.1]nonan-2-one (44), and endo-2, en Ritter reaction on the tetramethyl dione (39) was found to give endo-6-acetamido-3,3,6,7-tetramethylbicyclo[3.3.1]non-7-en-2-one (54). Under different conditions a closely related hydroxyamide (55) or (56) was formed. The actual isomer produced is still uncertain. The tetramethyl ketoolefin (44) was found to give 1,3-bis(acet- amido)-4,4,8,8-tetramethyltricyclo[3.3.1.l^*^]decane (67) and 3,3,6,6,7- pentamethylbicyclo[3.3.1]non-7-en-2-one (70) under strong and weak Ritter conditions respectively. Reaction pathways are described explaining the formation of these four novel rearrangement products. Ritter reaction on the tetramethyl diol (82) gave a mixture of products in very low yields with none being isolable. Attempts to hydrolyse the diamide (67) to the diamine using basic hydrolysis conditions were unsatisfactory. -2- 2. Introduction 2.1 Adamantane and 1-aminoadamantane Adamantane, the trivial name for the hydrocarbon tricyclo- 3 7 [3.3.1.1 * ]decane (1), is derived from the Greek for diamond. At the turn of the Twentieth Century the structure of diamond was postu lated to be the now familiar arrangement of fused chair cyclohexane 12 3 rings (2) * . Decker , in 1924, proposed the synthesis of "dekaterpene" CigHig (1), a tricyclic hydrocarbon which would have the same part-structure as the diamond lattice and would be highly symmet- 4 rical and strain free. In 1933, Landa first isolated this substance from petroleum naphtha, where it constituted about 0.0004%, accompanied by equally small amounts of alkylated adamantanes. The isolation was made possible by the atypically high melting point of adamantane. Investigations into the chemistry of adamantane were hindered by its unavailability since total synthesis involved elaborate stepwise procedures giving very low overall yields^. In 1956 Schleyer and Donaldson who were studying the facile AlCl3-catalyzed isomerization of endo-tetrahydrodicyclopentadiene (3) to its exo-isomer (4), obtained adamantane in yields of 15-20% by chance. Since then, adamantane has become conveniently available because cyclopentadiene is a commercial product and its dimer can easily be hydrogenated. The driving force for the profound skeletal transformation leading to adamantane is the relief of the large amount of strain inherent in the bicyclo[2.2.1]heptane ring system. While an entirely satisfactory mechanism for this transformation is still absent, it is believed to involve a large number of carbonium ions and rearrangement reactions^. There may also be more than one pathway 9 TABLE I. HISTORY OF INFLUENZA 'PANDEMICS Year Virus 1658 1688 1710 1743 1762 1782 1803 1831 1833 1837 1889 1918 HswinelNl 1948 H1N1 1957 H2N2 'Asian' era 1968 H3N2 'Hong Kong' era 1977 H3N2 1978 H3N2 and H1N1 (possibly 'frozen' since 1950 in nature) 1980 H3N2 and H1N1 (possibly 'frozen' since 1950 in nature) Influenza A viruses are designated as type A, B or C. Influenza A viruses alone are able to cause world-wide epidemics or pandemics. Influenza B and C viruses are responsible for more localised outbreaks. Clinically they are not distinguishable, For influenza A viruses an index in the virus description describes the antigenic character of the haemagglutinin and neuraminidase, e.g. HswinelNl indicates that the H or haemagglutinin originated from a swine influenza virus, whilst the neuraminidase N1 had a human origin. -3- leading to adamantane . The discovery that 1-aminoadamantane (5) exhibited anti-viral g activity against several strains of influenza virus was made in the laboratories of E.I. du Pont de Nomours and Co. in the early 1960's. World-wide influenza pandemics have been documented for several 9 hundred years (see TABLE I). About half of the infections caused a febrile respiratory disease, but severe cases were rapidly fatal. The morbidity rate from influenza ( H2N2 strain) in the 1957 pandemic ranged from 18% to 87%^ in various geographic areas. Unlike other viruses such as measles, polio and smallpox, influenza virus has a 9 segmented RNA genome , making genetic recombination between different viruses very frequent. Many influenza A viruses co-exist in animal, 9 avian and human groups . The large genetic pool of influenza viruses makes its control by vaccine very difficult. This, coupled with the time required for vaccine development, makes chemotherapy all the more important. 1-Aminoadamantane (5) is marketed as the hydrochloride with trade names such as "Amantadine" and "Symmetrel". Its therapeutic indications now include influenza A virus strains, influenza A2 11 12 respiratory illness, rubella , Rous sarcoma, Esh sarcoma and 13 Parkinson's Disease . It is a thermostable water soluble solid. In man, the drug is absorbed rapidly after oral administration and there is nearly complete recovery from urine of an administered dose 14 14 in unaltered form . This excretion follows first order kinetics The precise mode of action of 1-aminoadamantane is still unknown. Tissue culture studies^ indicated that 1-aminoadamantane hydrochloride Activity in vivo* (18) ++ (19) + ++ = activity comparable to that of 1-aminoadamantane or better. + = significant activity but less than 1-aminoadamantane. - = inactive. -4- was not virucidal. In the presence of (5), adsorbed infectious viruses remained at the cell surface but were blocked from penetration^. 1-Aminoadamantane has also been reported to inhibit uncoating of viruses and the release of infectious virions^. Industrially, 1-aminoadamantane (5) is prepared from adamantane (1) in several steps. Koch-Haaf reaction on (1) produces the carboxylic acid (6) which is readily converted to the acid chloride (7) and reacted with ammonia to give the amide (8). Hoffmann rearrangement results in the urethane (9) which is hydrolyzed by base to give (5)^. Alternatively, (1) can be monobrominated to give 1-bromoadamantane (10), and this can undergo Ritter reaction to produce the amide (11) which is hydrolyzed to (5)^. Pharmacological screening involving the synthesis of new compounds and in vitro and in vivo testings have picked out those with 18 varying degree of antiviral activity. Aldrich and co-workers conducted a comprehensive study of the structure-activity relationship of some of the compounds related to 1-aminoadamantane. They class ified the structure variations into five types (12, 13, 14, 15, 16). In general, the antiviral activity diminished as the size of the N-substituent(s) in (12) increased. The presence of functional groups such as OH, NH2, Cl and COOCH3 on the alkyl moiety reduced activity. Substituents at one or more of the tertiary positions of (13) were highly detrimental to activity. The insertion of a single C as moiety "A" in (14) led to compounds of good activity. One of these, 1-amino- 3 7 ethyl-1'-tricyclo[3.3.1.1 * Jdecane (17) (rimantadine .HC1) was found by Tsunoda and co-workers to be more effective than (12) in vitro 19 against influenza A Japan 305 virus . In (15), the adamantane -5- 3 8 skeleton has been expanded to the tricyclo[4.3.1.1 * ]undecane (homo- adamantane) system. The 3-amino and 3-methylamino derivatives retained antiviral activity. Replacement of the amino group of (12) by H, OH, SH, CN, COOH, Cl or Br gave inactive compounds (16). The basicity of the nitrogen is important since acylation lowered the activity. The antiviral activity of the adamantanespiro-31-pyrrol- 20 idines (18) diminishes with increasing size of the N-substituents. 20 Of the analogous spiro-3'-pyrrolidines (19, 20, 21, 22), activity is highest for (20) which is structurally more related to adamantane. 20 That the cyclohexane derivative (22) is inactive stresses the importance of a bi- or tricyclic nucleus for antiviral activity. In summary, the antiviral activity of 1-aminoadamantane is shared by a whole range of amines attached to multicyclic systems. Thus, compounds related to 1-aminoadamantane are continuously being synthesised by investigators who then assess their activity and attempt to develop the rationale of how they work. c H302^ yPC2CH3 /C02Cn3 CH'CHfCH CK|=C / \ CH302C C02C'H3 ^co2ch3 (26) (23) Michael Addition '•C02CH- CH2Ch ch3o2' Dieckmann c,o2ch3 ------» condensation / \ /C02CH3 ch3o2c CHjCh 'C02ch3 /O2CH3 ChJC Michael Addition >/ Meerwein’s Ester 3 Jones Reagent (26) (31) (33) -6- 2.2 Synthetic approaches to 1-aminoadamantane analogues A simple way of synthesising the bicyclo[3.3.ljnonane system was 21 22 discovered by Meerwein and co-workers * who condensed formaldehyde and dimethyl malonate. The 1,1,3,3-tetracarbomethoxypropane (23) and dimethyl methylenemalonate (24) formed then underwent a sequence of Michael additions and Dieckmann condensations leading to 1,3,5,7- tetracarbomethoxybicyclo[3.3.1]nonane-2,6-dione (25), now generally known as Meerwein’s Ester. All four ester groups may be removed from the Meerwein's Ester to give bicyclo[3.3.1]nonane-2,6-dione (26) in 65% 23 yield . The bicyclo[3.3.1]nonane skeleton and its simple derivatives 24 25 adopt the double chair conformation ’ which is flattened to increase the distance between the endo-3 and endo-1 hydrogen atoms. The promixity of C3 and C7 makes transannular reactions between these sites 2 6 quite common. Stetter found that when 7-methylenebicyclo[3.3.1]- 27 nonane-3-one (27) or 3,7-dimethylenebicyclo[3.3.1]nonane (28) were treated with electrophiles, derivatives of adamantane (29) and (30) were formed in high yield. This transannular addition of the reagent HX provides a simple and convenient method of forming a specifically functionalised multicyclic ring system. Meerwein reacted bicyclo[3.3.1]nonane-2,6-dione (26) with sodium amalgam and produced a 1:1 mixture of bicyclo[3.3.1]nonane-2,6-diol (31) and tricyclo[4.3.0.0^’^]nonane-6,7-diol (32) (brexane-6,7-diol)^. This reaction requires the bicyclo[3.3.1]nonane skeleton to adopt the twin-twist boat conformation such that C2 and C6 are sufficiently close 28 for intramolecular cyclisation. Amini repeated Meerwein's reduction and confirmed the proposed structures of (31) and (32) and the acetate derivative (33) using spectral methods. Bicyclo[3.3.1]- nonane-2,6-dione (26) was regenerated when (32) was oxidised with (26) -7- 22 28 Cr03 or Jones reagent There are three possible diastereoisomers of the bicyclo[3.3.1] ■ nonane-2,6-diol (31): endo-2, en endo-ly exc>-6-dihydroxybicyclo[3.3. ljnonane (35) and exo-2, exc>-6-dihydroxybicyclo [3.3.1]nonane (36) . The stereochemistry of (31) produced in the reduction reaction was 22 controversial since Meerwein concluded it to be the "trans" isomer, 29 namely (35), but Schaefer and Honig advocated the exo3 exo-isomer 28 (36). Amini found that the 13C n.m.r. spectrum of the bicyclo[3.3.1] nonane-2,6-diol (31) obtained from the sodium amalgam reduction consisted of five carbon signals, consistent with either the endo3 endo- (34) or exo3 exo-isomer (36) being produced alone. Comparison of the 13C chemical shifts with those known for the exo3 exo-isomer (36) which had been synthesised by another route and studied by X-ray 30 crystallography , showed that endo-2, en Marvell and co-workers reacted bicyclo[3.3.1]nonane-2-one (37) with potassium t-butoxide and iodomethane to produce 3,3-dimethyl- bicyclo[3.3.1]nonane-2-one (38) as the only product. No methylation occurred at the bridgehead Cl position, although the rates of exchange 32 of the protons at C3 and Cl are comparable . Using similar condit- 2 8 ions, Amini converted bicyclo[3.3.1]nonane-2,6-dione (26) into its 3,3,7,7-tetramethyl derivative (39) where steric crowding of the endo-3 and endo-1 methyl groups ruled out the twin-chair conformation. TABLE II. 13C CHEMICAL SHIFT DATA FOR 3,7-SUBSTITUTED BICYCLO [3.3.1] NONANES 3-ew Cl/5 C2/6 C3/7 C4/8 C9 Other carbon atoms 3 s2 5K 9^N 1 28.0 31.7 22.6 - 35.1 7 :h3Xc h3 25.6 43.7 28.6 - 27.6 33.2, 37.0 (methyls) c 3Hq (b) ,■0H 33.6 71.1 31.2 22.6 32.3 HO :«3X^ H3 ,0' OH 32.4 78.7 33.5 36.0 26.9 26.0, 36.1 (methyls) 1" HO >< :H3 C H3 r” 43.5 212.7 37.1 26.6 31.4 0^9 Cl H3 ^0 42.2 218.3 43.2 41.4 27.5 28.4, 30.1 (methyls) 0- Cl h- (c) ,ch2 (a) (a) 37.6 152.8 31.0 32.7 36.1 107.5 (=CH2) 3 CH, 3 . ch2 36.2 161.4 34.8 45.5 29.0 106.7 (=CH ); 32.4, 35.2 CH p (methyls) Cl1-3 '- CH 3_ (a) Values may be reversed. (b) Spectra recorded in dg-DMSO, all others in CDCI3. (c) Data from ref. 37. (42 cb) (42 be) Q (43) (4A) -8- 28 Amini found that both the tetramethyl dione (39) and endo^ endo-tetramethyl diol (40) showed seven carbon signals in their 13C n.m.r. spectra which would be the number of signals expected of the twin-chair conformation (impossible due to crowding of the endo-3 and endo-1 methyl groups), the twin-boat or twin-twist boat, or for a boat-chair/chair-boat equilibrium. All thirteen carbon atoms would be non-equivalent if the molecules existed in a fixed boat-chair 33 conformation. Peters and co-workers found a correlation between the degree of chemical shift changes of C9 and substitution on C3 or C7 of the bicyclo[3.3.1]nonane system (TABLE II). An endo-3 substituent forces that ring into a boat which introduces steric compression effects between C3 and C7, causing the chemical shift of C9 to fall. If two very bulky groups are placed as endo-3 and endo-1 substituents, the twin-boat conformation is adopted (probably as the twin-twist boat) 33 (41-tbb) and the chemical shift of C9 falls further. Peters found that typical values of 6 for C9 were (cc) 33 to 35; (cb) 27 to 29; 28 and (bb) 24 ppm. Amini also compared the chemical shift value of C9 between four pairs of bicyclo[3.3.1]nonane derivatives and their tetra methyl substituted analogues (TABLE III). The 6 change between each pair was close to those found by Peters for the chair-boat conformation. 28 Amini concluded that the tetramethylbicyclo[3.3.1]nonanes (TABLE III) exist in a chair-boat/boat-chair equilibrium, for example (42cb) and (42bc). This was expected to increase the likelihood of transannular reactions between the C2 and C6 positions. 34 Wittig reaction of the tetramethyl diketone gave the diolefin (43) and ketoolefin (44). When the diolefin (43) was 35 subjected to typical Ritter reaction conditions (acetic acid/aceto- nitrile/sulphuric acid), a single product was found in 70% yield. CH^ migration ------> ^yClisation 4------ N H-CO- CH -9- X-ray diffraction showed this to be l-acetamido-3,4,4,8,8-pentamethyl- 28 adamantane (45), a result of a series of rearrangement reactions followed by transannular cyclisation, rather than a direct transannular cyclisation which would have produced a twistane derivative (46). Reacting the diolefin (43) under weaker Ritter conditions enabled the 28 isolation of a rearranged isomeric diolefin (47) in 74.5% yield. 28 This could further be reacted to give (45) in 84% yield showing that it was a genuine intermediate in the process. The diolefin (43) was 3 6 proposed to undergo sequential protonation, methyl migration and deprotonation yielding the intermediate (47). The generation of planar carbonium ions at either C3 or C7 removes the severe steric crowding originally present between the endo-3 and endo-1 methyl groups of (43). Further protonation and deprotonation would yield the 27 diolefin (48) or (49) which on protonation would be expected to undergo intramolecular cyclisation to the pentamethyl-l-adamantyl ion (50) which would undergo Ritter reaction to produce the amide product (45). o = ^ n -10- 3. DISCUSSION 3.1 Synthesis and rearrangement reactions of 3,3,7,7-tetramethyl- bicyclo[3.3.1]nonane-2,6-dione (39) 3,3,7,7-Tetramethylbicyclo[3.3.1]nonane-2,6-dione (39) was 28 prepared by the method of Amini . The dione (39) should adopt the chair-boat/boat-chair equilibrium (see Introduction). A solution of the tetramethyl dione (39) in acetonitrile and glacial acetic acid was reacted with concentrated sulphuric acid. 38 Burgess had found that the use of glacial acetic acid as a solvent in the Ritter reaction of diene (51) gave the amide (52) in consistently higher yield and greater purity than when glacial acetic acid was absent. In highly polar solvents the attacking nitrile is strongly polarized and becomes solvated, resulting in enhancement of 35 its nucleophilic reactivity After the reaction and recrystallisation of the crude product, colorless crystals were obtained in 23.3% yield. The i.r. spectrum showed absorption bands at 3340 (N-H stretch), 1660 (C=0 stretch) and 1530 cm ^ (amide II band) indicative of the presence of a secondary acyclic amide, and at 1700 cm ^ (ketonic C=0 stretch) showing the presence of a ketone group. The out of plane C=C-H absorption band at 870 cm 1 suggested that the compound was also a trisubstituted olefin. Results of elemental analysis of the product, melting point 159-160°C, conformed with the empirical formula C15H23NO2 which represents the addition of C2H3N to the tetramethyl dione (39). The formal addition of one molecule of acetamide C2H5NO and loss of one molecule of water would account for this. (53) (54) X-ray crystal structure of (54) -11- The presence of the CH3-CO-NH group in the compound was also shown by singlet absorption signals at 1.84 6 and 5.41 6 in the *11 n.m.r. spectrum. The doublet at 5.46 and 5.48 6 also indicated the presence of one olefinic proton. The remaining proton signals ranged from 1.11 to 3.09 and corresponded to the presence of four CH3 groups, two CH2 groups and two CH groups. The mass spectrum showed the molecular ion peak at m/z+ = 249. The loss of CH3> CH^C=0 and C^-C-m fragments were shown by fragment peaks at 234, 206 and 191 respectively. So far all the analytical results suggest that the compound is a bicyclic olefin with an acetamide group, a ketone group and four methyl groups. Isomers (53) and (54) are possible structures that conform with this information and the nature of the reactant. X-ray structure determination was subsequently carried out and the compound was revealed to be endo-6- 39 acetamido-3,3,6,7-tetramethylbicyclo[3.3.1]non-7-en-2-one (54) which adopted the double chair conformation. Reacting the tetramethyl dione (39) under different Ritter conditions produced some white crystals in 7.8% yield after column purification. These crystals had a melting range of 64-67°C. Their i.r. spectrum suggested the presence of an amide group (N-H stretch at 3400 cm ^, amide C=0 stretch at 1675 cm ^ and C-N stretch at 1470 cm 1), an alcoholic 0-H group (0-H stretch at 3290 cm ^ and C-0 stretch at 1060 cm ^) and an absorption peak at the 'normal* carbonyl vibrational frequency (1715 cm ^) indicative of the existence of a ketone group. (55) HC-OC-HN HC-OC-HN— -12- Elemental analytical results suggest that the compound had the empirical formula C15H25NO3, which corresponds to a formal addition of acetamide C2H5NO to the tetramethyl dione (39). The *11 n.m.r. spectrum showed the signals for CH3-CO and 0-H at 1.94 and 1.97 6, respectively. The other seven signals ranged from 1.02 5 to 2.54 6 and corresponded to four CH3 groups and three multiplets which were not easily identifiable. The location of the NH signal (which normally appears at approximately 5.00 6) was uncertain but perhaps was part of the 1.63 to 1.83 multiplet. The 13C n.m.r. spectrum of the product showed fifteen carbon signals in the proton-decoupled spectrum. The off-resonance decoupled spectrum enabled the identification of these fifteen signals as five CH3 , three CH2, two CH and five quaternary C's. Two of the quaternary C's (163.9 6, amide C=0 and 219.3 6, ketonic C=0) were significantly more downfield than the rest. These analytical results indicated that the compound was a bicyclic ketone with an acetamido and a hydroxyl substituent. From the nature of the starting tetramethyl dione (39), possible structures for this compound are (55), (56), (57) and (58). The simplicity of the n.m.r. spectra showed that the product consisted of a single isomer and not a mixture of two or more. The molecular weight of these isomers is 267. Although no such molecular ion peak existed for the compound in the mass spectrum, alcohols are known to often give a very weak parent molecular ion and instead show a pronounced (M-18)+ peak resulting from the loss of water. The presence of a peak at m/z = 249 with 16% intensity clearly showed the loss of 18 mass units. PATHWAY I -13- The loss of CH3 and H2O gave a fragment with m/z+ = 234. Loss of CH3-C-NH corresponded to a fragment with m/z+ = 209. The fragmentation 0 of CH3“C=0 together with H2O and CH3-C-NH together with OH gave II fragments at 206 and 192 respectively. The uncertainty surrounding the identity and conformation of the product necessitated X-ray study. Crystals were grown using ether, petroleum ethyl acetate and tetrahydrofuran as solvent in turn. They came out as fine needle-shaped crystals which were unsatisfactory for X-ray work. Ritter reaction on the tetramethyl diketone (39) was repeated using the same conditions that formerly gave the hydroxy- amide. After column purification and recrystallisation using ethyl acetate, some small colourless crystals with identical i.r. and t.l.c. characteristics as crystals from the previous experiment were obtained. However, these crystals, when examined under the microscope, were found to be involved in 'twinning' whence a number of crytals grow into one another in different directions so that no single crystal can be isolated. The crystals were grown from ether and again they 'twinned'. It was envisaged that the existence of hydrogen bonding in the molecule would favour the 'twinning' phenomenon. Therefore, water was then used as the solvent in recrystallisation in the hope of obtaining more regular single crystals, but they were found to 'twin' once again. Thus the exact identity of this product is still unknown. For the formation of (54), initial protonation of the tetra methyl diketone (39) would give the carbonium ion (59) which undergoes methyl migration to give (60). Deprotonation of (60) would create the ketoolefin (61). After protonation and the loss of water, nucleophilic attack of carbonium ion (62) by acetonitrile would give pathway II (55) (56) -14- (63), which on hydrolysis gave (54) (see PATHWAY I). The orientation of the OH and CH3 groups on C6 relative to the molecule was unimportant since subsequent elimination of water would have generated the planar carbonium ion (62). Sterically, aceto nitrile attack of (62) from the top should be more favourable than attack from the bottom. This would have resulted in the formation of (53). However, the configuration of (54), proved by X-ray diffraction, showed that attack actually occurred from the bottom. Compound (53) might still be formed but it could have continued reacting to give another product and was not isolated. It is difficult to compare the strength of the Ritter conditions for the formation of amide (54) and the hydroxyamide, one of the isomers (55) to (58). Although the amount of sulphuric acid used for (54) was larger, the hydroxyamide was formed after the Ritter reaction had been carried out under elevated temperature. If the hydroxyamide was formed after the formation of the mono amide (54), a reasonable reation pathway (PATHWAY II) would involve the protonation of (63) to give the carbonium ion (64). Subsequent acidic hydrolysis would give either (55) or (56) as the hydroxyamide product. Both the isomers (55) and (56) should be in a boat-chair conformation. Attack by the HSO4 group on carbonium ion (64) would be more likely to occur from the top; therefore the amide and hydroxy groups would be expected to be trans to each other producing (55). However attack from the underneath would result in the cis -product (56) . Initial Ritter reaction on the tetramethyl diketone (39) could have the acetonitrile attacking the carbonium ion (62) from the h-co-ch (65) pathway m (6 0) ch3cn, h2so4 h2o H-CO-Ch (65) PATHWAY IV CHq migration + h2o ' V (55) -15- top of the planar carbon C6 too. This, in turn, would give the hydroxyamide isomers (57) or (58). Since the exact identity of the hydroxyamide is not known, the hydroxy group could very well be on C6 instead of C7 and the acetamido group on C7 instead of C6 as in (65). Structure (65) comprises four possible structures analogous to structures (55) to (58) depending on the relative stereochemistry of the hydroxy and amide groups. Structure (65) could be produced by another reaction pathway (see PATHWAY III). Protonation of the tetramethyl diketone (39) would give carbonium ion (59). The migration of a methyl group then would create the isomer (60) and subsequent attack by acetonitrile would then yield (65). Alternatively, if the hydroxyamide was formed prior to (54), reaction PATHWAY IV could be proposed. Initial protonation of the tetramethyl diketone (39) would create the carbonium ion (59) which on methyl migration from C7 to C6 would then give the isomeric carbonium ion (60) as in PATHWAY III. Considering the difference in polarity between the carbonium ion on C7 and the hydroxy substituent on C6, the formation of an epoxy ring between C6 and C7 to give (66) would be expected. Since the protonated epoxide ring was part of a fused-ring system in (66), it must have a cis-geometry. Epoxides are strongly polar and strained. Their characteristic reaction is ring opening to give products of lower energy and higher stability. Nucleophilic attack by acetonitrile on C6 and subsequent cleavage of C6-0 bond and hydrolysis would then generate the hydroxyamide (55). Dehydration of -16- (55) would be expected to yield (54). In many ways this pathway seems to be the most attractive explanation for the formation of the two amide rearrangement products. -17- 3.2 Synthesis and rearrangement reactions of 3,3,7,7-tetramethyl-6- methylenebicyclo[3.3.1]nonan-2-one (44) The tetramethylbicyclic ketoolefin (44) was prepared using the 34 Corey modification of the Wittig reaction. Heating sodium hydride with dimethylsulphoxide (DMSO) generated the strong base sodium methylsulphinylmethylide which reacted with methyltriphenylphosphonium bromide to give methylenetriphenylphosphorane in DMSO solution. Reacting the diketone (39) with one equivalent of methylenetriphenyl phosphorane produced the ketoolefin (44) as the major product. A solution of the tetramethyl ketoolefin (44) in dry acetonitrile was treated with a small amount of concentrated sulphuric acid to see if Ritter reaction occurred. After the usual work up of the reaction and recrystallisation, a single product was isolated in 12.8% yield. The combustion analytical results of this product, melting point 270-272°C, suggested the empirical formula C18H30N2O2 which represents an addition of C4H8N2O during the reaction. This corresponds to the formal addition of two molecules of acetamide and loss of one molecule of water during the reaction. The i.r. spectrum showed absorption bands at 3360, 1645 and 1520 cm 1 indicative of the presence of a secondary amide and no olefinic signals were observed. The *H n.m.r. spectrum showed the signals for CH3-CO-NH- at 1.92 and 5.1 to 5.15 6, respectively. The 13C n.m.r. spectrum of the product showed ten carbon signals in the proton-decoupled spectrum. Comparison of the carbon types and the empirical formula of the product suggests that it is highly symmetrical. The carbon signals at 169.8 and 58.1 6 corresponded to amide C=0 and ^C-NH- respectively. The (69) X-ray crystal structure of (67) -18- remaining eight carbon signals ranged from 41.3 to 22.7 6. The off- resonance decoupled spectrum allowed the determination of the proton substitution of all ten carbon atoms. They consisted of one amide C=0; one quaternary ^C-NH-; one quaternary C; one C-H; three CH2 and three CH3 groups. The mass spectrum gave the parent mass number of 306 and clearly showed the fragmentation of CH3, CH3-C=0 and CH3-£-NH (one and two) o at 291, 263, 248 and 190 mass numbers respectively. All this information pointed to the product being a tricyclic- diamide with possible structure (67), (68) or (69), of which the first seemed most probable on mechanistic grounds. Both structures (68) and (69) would require addition of acetonitrile to take place from a specific direction, for which there is no obvious reason. Confirmation 39 of the structure was obtained by X-ray crystallography . This proved the product to be the adamantane derivative (67). In postulating the mechanism of formation of l-acetamido-3,4,4,8,8-pentamethyladamantane from 3,3,7,7-tetramethyl-2,6-dimethylenebicyclo[3.3.1]nonane as a series of rearrangement reactions followed by transannular cyclisation, 28 Amini anticipated that similar rearrangement and cyclisation might apply to ketoolefin (44) producing an adamantane derivative. Reacting the ketoolefin (44) under less vigorous conditions resulted in another product in 49.1% yield and with similar t.l.c. retention time to that of the reactant ketoolefin. Its i.r. spectrum, however, indicated no absorption bands characteristic of a vinylidene olefin, but rather that of a trisubstituted olefin (860 cm *). The *H n.m.r. spectrum showed the signals of an olefinic proton at 5.26 (70) -19- to 5.28 6 and that of a bridgehead C-H coupled with an olefinic proton at 2.86 to 2.87 <5. In the 13C n.m.r. spectrum, fourteen carbon signals were observed. The off-resonance decoupled spectrum allowed their identification as four quaternary C (one ketonic and one olefinic), three C-H (one olefinic), two CH2 and five CH3 groups. Chemical combustion data was consistent with the compound having C14H22O as formula. The rearranged ketone (70) fitted in nicely with all the above information. It was envisaged that Ritter reaction on the ketoolefin (44) produced the rearranged ketone (70) as an intermediate which reacted further to give a monoamide and then the diamide (67). Using conditions intermediate to those producing the rearranged ketone and the diamide, effort was made to trap the monoamide. In each case, a single product with similar t.l.c., m.p., i.r. and n.m.r. characteristics as those of the diamide (67) was obtained in decreased yield. This suggests that the monoamide, if it existed, lasted for such a short time that isolation was difficult and that the ultimate formation of the diamide was highly energetically favoured. As in the diene (43) and diketone (39) cases, the tetramethyl groups at C3 and C7 were not sufficiently large to force the keto olefin (44) to adopt the twin-twist boat conformation. A reaction pathway giving a twistane carbonium ion was therefore unlikely. A more plausible pathway again involved migration of methyl groups from C3 and C7 of the bicyclo[3.3.1]nonane system to positions (67) (81) -20- C2 and C6. Initial protonation of the ketoolefin (44) would give carbonium ion (7.1) which undergoes methyl migration from C3 to C2, producing carbonium ion (72), thereby partially relieving the steric crowding originally present between the endo-3 and endo-1 methyl groups of (44). This would have been followed by deprotonation to give the intermediate rearranged ketone (70). Another sequence of protonation and methyl migration would give carbonium ion (74) which would undergo Ritter reaction to give the hydroxyamide (76). Under the strong conditions required to start the reaction on the ketoolefin initially, the isolation of the hydroxyamide (76) would have been very difficult. The hydroxyamide (76) would react further very quickly through proton ation, deprotonation and then protonation, dehydration and methyl migration from C7 to C6 to produce the carbonium ion (79) which would be expected to undergo intramolecular cyclisation to the tetramethyl- acetamidoadamantyl ion (80). A second Ritter reaction via (81) would then yield the diamide product (67). -21- 3.3 Synthesis and rearrangement reactions of endo-2, gndfo-6-dihydroxy- 3,3,7,7-tetramethylbicyclo[3.3.1]nonane (82) Reduction of the tetramethyl diketone (39) with lithium 28 aluminium hydride, in a manner similar to Amini , gave the bicyclic diol (82) in 58% yield, more than twice that previously obtained. The tetramethyl diol (82) is the endo-2, endo-6-isomer and should be involved in a chair-boat and boat-chair equilibrium as described in the introduction. When the endo-2, endo-6-tetramethyl diol (82) was subjected to Ritter conditions, a yellowish gummy liquid in very poor yield was obtained. T.l.c. of the liquid showed it to be a mixture of substances. The use of intermediate and weak Ritter conditions also failed to obtain any single product. In all these attempts, i.r. spectra showed the presence of amide(s) after the reactions (absorption bands at 3300, 1645 and 1535 cm 1). The gummy liquid was purified by column chromatography and a very small quantity of white solid appeared. However, its *H n.m.r. spectrum was virtually unidentifiable except for the broad N-H peak at 4.28 6. Comparison with the D20-exchanged spectrum showed an 0-H signal at 1.64 6. It is not understood why the bicyclo diol (82) behaved differently from its dione (39), ketoolefin (44) and diene (43) 40 analogues under typical Ritter conditions. Glikmans found that alcohols, in general, gave lower yields than the corresponding olefins. Thus far, the formation of a single amide from each of the diene (43), dione (39) and ketoolefin (44) in reasonably good yield was postulated to involve a series of intramolecular rearrangement reactions and trans- annular cyclisation. In all three cases, rearrangement would continue -22- until the most stable carbonium ion was reached. Reaction of a nitrile source with the most stable carbonium ion would lead to the amide. With the diol (82), it is possible that the carbonium ions formed happened to be similar in energy so that no particular one was favoured. This would result in a mixture of amides as products. The absence of a single product and the low yield of products greatly reduce the synthetic value of the diol (82) in Ritter reactions. o R-C nhr'r -23- 3.4 Hydrolysis of 1,3-bis(acetamido)-4,4,8,8-tetramethyltricyclo [3.3.1.l^’^Jdecane (67) The Ritter reaction provides a very simple and direct approach to the synthesis of multicyclic amides. Although the yields of amides sometimes are moderate to low, it has the advantage of being a one-step process. A preliminary study was made on the hydrolysis of amide to amine. 38 Burgess showed that acidic hydrolysis of the multicyclic amide (52) using hydrochloric acid in ethanol was too slow and ineffective. The use of stronger conditions ( 50% aqueous sulphuric acid in ethanol) resulted in slow conversion to the alkane (83). This novel reduction proceeded in high yield for a number of different multicyclic amides, in preference to hydrolysis to the corresponding amines. The mechanism and kinetics of basic amide hydrolysis are well 41 known. Reid showed that the reaction was second order. Nucleophilic attack of the hydroxide ion on the carbonyl group gave a tetrahedral intermediate which collapsed to give either the amine product or 42 regenerate the reactants , since the amide residue is a poorer leaving group than either the hydroxy- or alkoxy- groups. 38 Burgess found that the optimum conditions for the formation of the amine hydrochloride (84) from amide (52) involved refluxing the amide (52) in a solution of sodium hydroxide in ethyleneglycol. The diamide (67) was therefore subjected to similar conditions but only slight change resulted after refluxing for 5 h. When the diamide (67) was refluxed for 6 h, t.l.c. indicated the formation of hcn/(chj,coh m ------—------^ 96% H,SO, l 4 (ch3)3cnh2 (98) (89) \y (5) -24- three products, all of which were more nonpolar than the reactant diamide. I.r. showed a C=0 stretch near the ’normal* aliphatic ketone absorption frequency. It is suspected that the ethylene glycol conditions were not harsh enough for the hydrolysis of the diamide (67), therefore the experiment was repeated using diethylene glycol as the medium. Refluxing the diamide for 5 h in diethylene glycol and sodium hydroxide gave little change. Refluxing for 15 h gave a mixture of four substances according to t.l.c.. One of them was the reactant diamide (67) while the other three were all less polar than the diamide (67). The presence of amide, amine and ketone groups were shown by i.r. spectroscopy. 43 Haaf when investigating the participation of isoparaffins as a carbonium ion source in the Ritter reaction, found that methyl- cyclohexane (85) reacted with hydrogen cyanide to give 1-methyl- (86) and 2-methylcyclohexylamine (87) in yields of 23% and 4% respectively. The major product was t-butylamine (88) (52% yield) when t-butyl alcohol was employed as a hydride acceptor. Using similar conditions, adamantane (1) gave 1-formylaminoadamantane (89) in 78% yield 43 instead . Hydrolysis of the formylaminoadamantane (89) to 1-aminoadamantane (5) occurs more easily than from the corresponding acetamide, and therefore future investigations should involve the use of HCN rather than acetonitrile. 18 Aldrich showed that the aminoadamantylamide (90) was bio logically active against influenza virus. This aminoadamantylamide (90) can be produced by a Ritter reaction on adamantane (1) using aminoacetonitrile (91). Conversion of the aminoadamantylamide (90) (92) (93) -25- to its hydrochloride salt (92) has the advantage of increasing the compound's solubility in aqueous fluids. At present, no rationalization behind the aminoadamantylamide's activity has been made, but as the lone pair of electrons present in the amide nitrogen is not available for nucleophilic attack, the biological activity of the aminoadamantyl amide (90) could very well come from the adamantyl ion (93) alone. If this were the case, it would not be necessary to carry out hydrolysis reactions of amide to amine, but rather the alternative synthesis of the aminoacetamidoadamantanes would solve all the problems. -26- 4. CONCLUSIONS AND FUTURE STUDIES The Ritter reaction on bicyclo[3.3.1]nonane derivatives provides a simple and convenient method of generating multicyclic amides. Unlike alternative synthetic routes, the Ritter reaction only involves a one-flask process. Ritter reaction on the tetramethyl dione was found to give a monoamide and a hydroxyamide under different conditions. The structure of the monoamide was elucidated by X-ray diffraction analysis but the hydroxyamide still needs to be identified. Future work may require the preparation of a derivative such as a 2,4-dinitro- phenylhydrazone to avoid the problem of crystal twinning. If the rearranged ketoolefin from the tetramethyl ketoolefin reaction can be reacted further to form the diamide, then that would comprise further proof of the reaction mechanism. Unexpected difficulty was encountered when attempts were made to hydrolyse the diamide under basic conditions. Since hydrolysis of 1-formylaminoadamantane to its amine derivative occurs more readily than from the corresponding acetamide, HCN may be used to replace acetonitrile in future. The necessity of hydrolysing multicyclic amides to amines should also be questioned. If the adamantyl ion alone were the source of antiviral activity, the alternative synthesis of the aminoacetamidoadamantanes would suffice. -27- 5. EXPERIMENTAL Thin layer chromatography used Merck Kieselgel HF254 * TYP 60 plates using diethyl ether as the developing solvent and visualising by iodine vapour. Chemical analyses were carried out in the School of Chemistry, University of New South Wales by Dr. H.P. Pham. Infrared spectra were recorded using a Perkin Elmer 298 Infrared spectrophotometer. Peak intensities are shown as: strong (s), medium (m) or weak (w). *H and 13C n.m.r. spectra were run by Mrs. H.E.R. Stender using a JEOL JNM-FX100 instrument (for both *H and 1 3C spectra) and a BRUKER CXP-300 (for ^ spectra). The data are reported as chemical shifts (6) relative to tetramethyl silane as internal standard. The substitution of carbon atoms in the 13C spectra were determined by off- resonance decoupling. N.m.r. peaks are designated as follows: singlet (s), doublet (d), triplet (t), quartet (q) and multiplet (m). Mass spectra were recorded using an A.E.I. MS12 instrument by Dr. J.J. Brophy. The molecular ion was designated M+ and the mass to charge ratio m/z+. The intensity was calculated as percentage of the base peak. -28- 3,3,7,7-Tetramethylbicyclo[3.3.1]nonane-2,6-dione (39) Potassium i-butoxide (66 g, 0.588 mol) was introduced into a 3-necked flask under a dry (H2SO4, KOH) nitrogen atmosphere and protected with a reflux condenser and drying tube. Melted t-butanol (700 ml) was added and the solution stirred to dissolve the butoxide. When bicyclo[3.3.1]nonane-2,6-dione (26) (15.8 g, 0.104 mol) was added, the reaction became exothermic and turned orange. After stirring for 10 mins, iodomethane (165.0 g, 1.16 mol) was added and the solution turned milky with evolution of heat. After stirring overnight, the t-butanol in the solution was removed by evaporation and water (200 ml) added. The solution turned brownish and solid appeared. More t-butanol was evaporated and the residue was acidified (~pH 6) with hydrochloric acid (2.5M) and thoroughly extracted with dichloro- methane, neutralised (NaHC03 solution), dried (Na2S04) and evaporated to give a yellowish oil which was distilled, b.p. 281°C (Lit. b.p. O O 280-285°C) , to give the pure dione (39) (17.45 g, 0.084 mol, 80.7%) as a colorless oil. v (liquid film) 2970(s), 2890(s), 1705(s), 1465(s), 1390(s), max 1267(m), 1217(m), 1102(m), 1072(m), 1000(s) cm"1. 6-Acetamido-7-hydroxy-3,3,6,7-tetramethylbicyclo[3.3.1]nonan-2-one (55) or (56)? Concentrated sulphuric acid (9 ml, 98%) was added dropwise to a stirred solution of the tetramethyl dione (39) (3 g, 0.014 mol) in acetonitrile (24 ml) and glacial acetic acid (30 ml) in a flask protected with a reflux condenser and drying tube. The solution turned from slight brown to reddish-orange with concomitant warming up. It was then heated at 80°C for 1 h, cooled and water (30 ml) -29- added when the solution heated up again. After cooling, the reaction was extracted with chloroform, neutralised (NaHC03 solution), washed (water), dried (Na2S0 4) and evaporated to give the crude product as a brownish oily liquid. The crude oil was eluted through an alumina column. The pure product came out as white crystals (55) or (56) when eluted with 45% diethyl ether/petrol and subsequent increase of ether (0.29 g, 1.09 mmol, 7.76%). M.p. 64-67°C. T.l.c. Rf = 0.59, 0.17, 0.09, 0 before chromatography. = 0.09 after chromatography. (Found: C, 67.28; H, 9.25; N, 5.22. C15H25NO3 requires C, 67.38, H, 9.42, N, 5.24%). v (paraffin mull) 3400(s), 3290(s), 1715(s), 1675(s), 1470(m), max 1445(m), 1395(s), 1270(m), 1060(s), 930(m), 660(m) cm"1. 6 (CDCI3) 1.02, s, 3H, CH3; 1.08, s, 3H, CH3; 1.17, s, 3H, CH3; n I. 32, s, 3H, CH3; 1.63 to 1.83, m, 5H?; 1.94, s, 3H, CH3-CO; 1.97, br.s, 1H, 0-H (exchanged with D2O); 2.06 to 2.17, m, 1H, C-H; 2.33 to 2.54, m, 3H. The location of the -NH- was uncertain, but perhaps was part of the 1.63 to 1.83 multiplet. 6c(CDC13) 14.8, q; 22.1, q; 24.6, q; 24.9, t; 27.7, q; 31.8, q; 36.9, t; 37.7, d; 38.4, t; 39.1, d; 41.7, s; 70.4, s; 87.7, s; 163.9, s; 219.3, s. m/z+ 250(3%), 249(M-18, 16), 234(9), 209(0.7), 206(21), 192(4), 190(6), 126(12), 112(12), 111(100), 84(14), 69(14), 43(40), 41(17). -30- Endo-6-acetamido-3,3,6,7-tetramethylbicyclo[3.3.1]non-7-en-2-one (54) Concentrated sulphuric acid (13.5 ml, 98%) was added dropwise to a stirred solution of the tetramethyl dione (39) (1.5 g, 7.2 mmol) in acetonitrile (12 ml) and glacial acetic acid (15 ml) in a flask protected with a reflux condenser and drying tube. The solution turned yellow, then red and finally brown and became very hot. It was stirred for 1 h, water (40 ml) added and the solution heated up again. When cooled, the reaction was extracted with chloroform, neutralised (NaHC03 solution), washed (water), dried (Na2S04), filtered and evaporated to give a crude gummy solid (0.53 g, 2.24 mmol, 31.1%). Recrystallisation from diethyl ether (2x) yielded the pure amide (54) (0.394 g, 1.68 mmol, 23.3%) as colorless crystals. These crystals were identified by X-ray diffraction analysis. M.p. 159-160°C. T.l.c. = 0.53, 0.23 before recrystallisation. = 0.53 after recrystallisation. (Found: C, 71.80; H, 9.51; N, 5.41. C15H23NO2 requires C, 72.25; H, 9.30; N, 5.41%). v (liquid film) 3340(m), 2980(s), 2940(s), 1700(s), 1660(s), 1530(s), max 1450(m), 1375(m), 1265(m), 1100(w), 1035(w), 870(w), 810(w), 760(m) cm"1. 6 (CDCI3) 1.11, s, 3H, CH3; 1.12, s, 3H, CH3; 1.68, s, 3H, CH3; n I. 70, br.s, 3H, =C-CH3; 1.75, m, 2H, CH2; 1.84, s, 3H, CH3; 2.0 to 2.15, m, 2H, CH2; 2.88 to 2.90, br.m, 1H, CH; 3.06 to 3.09, br.m, 1H, CH; 5.41, br.s, 1H, NH; 5.46 and 5.48, d, 1H, olefinic CH. m/z+ 250(M+l, 2%), 249(M, 5), 234(2), 221(4), 208(5), 207(3), 206(5), 192(12), 191(16), 190(89), 178(6), 175(47), 172(32), 162(20), 157(12), 150(8), 148(8), 147(44), 136(15), 130(10), 129(27), 124(19), 122(8), 121(20), 120(69), 119(94), 108(38), 107(80), 106(100), 105(43), 91(38), -31- 87(22), 60(79), 43(14). 3,3,7,7-Tetramethyl-6-methylenebicyclo[3.3.1]nonan-2-one (44) The mineral oil was removed from a suspension of sodium hydride in paraffin oil (14.95 g of 50% = 7.5 g, 0.31 mol) by washing with several portions of light petroleum under a dry nitrogen atmosphere. Dry dimethyl sulphoxide (DMSO) (100 ml, freshly distilled from calcium hydride) was added to produce a slurry which was stirred and heated (oil bath temp. = 70 ± 2°C) under a dry nitrogen atmosphere for 1 h. The sodium hydride reacted, evolving a gas and giving a blackish solution of sodium methylsulphinylmethylide. Methyltriphenylphosphonium bromide (17.85 g, 0.05 mol, previously dried over P2O5) in dry DMSO (50 ml) was stirred with the indicator triphenylmethane (ca. 5 mg) under a dry nitrogen atmosphere, and sufficient of the sodium methylsulphinylmethylide solution was added by syringe so that a permanent red colour (Na+Ph3C ) resulted. The dry diketone (39) (8.32 g, 0.04 mmol) was introduced via the condenser, the final traces washed in using dry DMSO (20 ml). The reaction flask became warm to touch and the solution became darker. The stirred solution was heated at 75°C for 2 h, cooled to room temperature and water (300 ml) added. This caused warming of the solution and precipitation of white solid (Ph3P=0). On cooling the solution was extracted with diethyl ether, the combined ether extracts washed (cold water), dried (Na2S04) and the ether evaporated. The product appeared as a crude oil mixed with some white solid (Ph3P=0) which was eluted through an alumina column. 3,3,7,7-Tetramethyl-6-methylene- bicyclo[3.3.1]nonan-2-one (44) was eluted with 50% diethyl ether/ petrol (5.6 g, 0.027 mmol, 68%). -32- v (liquid film) 3070(w), 1700(s), 1625(m), 1455(m), 1380(m), 1360(m), IT13.X 890(s), 675(m) cm *. 1,3-Bis(acetamido)-4,4,8,8-tetramethyltricyclo[3.3.1.1^*^]decane (67) Conditions A Concentrated sulphuric acid (2.8 ml, 98%) was added dropwise to a stirred solution of the ketoolefin (44) (0.84 g, 4.07 mmol) in aceto nitrile (5 ml) in a flask protected with a reflux condenser and drying tube. An immediate exothermic reaction resulted and the colour of the solution turned from colourless to yellow. The reaction was stirred for 1 h, water (25 ml) added, whereupon the reaction warmed up again and white solid appeared. The reaction was further stirred for 1 h and extracted with chloroform. The chloroform extracts were washed (water), dried (Na2S04) and evaporated to give white solid (0.59 g) . Recrystallisation from chloroform gave the pure amide (67) (0.16 g, 0.52 mmol, 12.8%) which was identified by single crystal X-ray diffraction analysis. M.p. 270-272°C. (Found: C, 69.95; H, 10.07; N, 9.12. C18H3oN202 requires C, 70.55; H, 9.87; N, 9.14%). v (paraffin mull) 3360(s), 1645(s), 1520(s), 1470(s), 1380(m), nicix 740(w) cm 1. <$H (CDC13) 1.08, s, 6H, CH3; 1.15, s, 6H, CH3; 1.61 to 1.79, m, 6H, CH2 and CH; 1.92, s, 6H, C0-CH3; 2.67 to 2.81, m, 4H, CH2; 5.15, br.s, 2H, NH. 6C (CDC13) 22.7, q; 23.3, q; 24.9, q; 27.3, t; 30.2, t; 34.1, t; 38.6, s; 41.3, d; 58.1, s; 169.8, s. -33- m/z+ 308(M+2, 3%), 307(M+l, 21), 306(M, 100), 291(47), 265(3), 263(51), 249(9), 248(9), 247(30), 232(82), 221(97), 207(12), 206(9), 204(24), 190(14), 178(24), 136(39), 83(47), 59(67), 44(45), 43(83), 32(50). Conditions B Concentrated sulphuric acid (0.6 ml, 98%) was added slowly to a stirred solution of the ketoolefin (44) (0.25 g, 1.21 mmol) in aceto nitrile (1.5 ml). The solution turned yellowish with no observable heating. The stirred solution was heated at 50°C for 15 min after which it was allowed to cool for 45 min. When water (30 ml) was added, white particles appeared and the solution was left to stir for another h. The white solid was extracted with chloroform, washed (water), dried (Na2S04) and solvent evaporated to give crude beige powder (0.19 g). Recrystallisation using ethyl acetate gave white solid (67) (47.9 mg, 0.16 mmo1, 12.9%). M.p. 272-275°C The i.r. and 13C n.m.r. spectra were identical with those of the diamide (67) obtained under Conditions A. Conditions C Concentrated sulphuric acid (0.5 ml, 98%) was added dropwise to a stirred solution of the ketoolefin (44) (0.25 g, 1.21 mmol) in aceto nitrile (1.5 ml). The solution turned from colorless to orange with concomitant warming. It was left to stir for 1 h, water (30 ml) added and the solution stirred for another h. The reaction was extracted with chloroform, washed (water), dried (Na2S04) and solvent evaporated to give beige powder (0.15 g). Recrystallisation using -34- ethyl acetate gave the pure white powder (67) (10.1 mg, 0.03 mmol, 2.48%). M.p. 271-273°C The i.r. spectrum was identical with that of the diamide (67) obtained using Conditions A. Conditions D Concentrated sulphuric acid (0.4 ml, 98%) was added slowly to a stirred solution of the ketoolefin (44) (0.25 g, 1.21 mmol) in aceto nitrile (1.5 ml). The solution turned from colorless to yellow and then orange and heated up mildly. After stirring for 1 h, water (30 ml) was added and the solution stirred for another h. The reaction was extracted with chloroform, washed (water), dried (Na2S04) and solvent evaporated to give some light yellow powder (0.13 g). Recrystallisation using ethyl acetate gave the pure product as white powder (67) ( 6 mg, 0.02 mmol, 1.65%). M.p. 270-272°C. The i.r. spectrum was identical with that of the diamide (67) obtained using Conditions A. 3,3,6,6,7-Pentamethylbicyclo[3.3.1]non-7-en-2-one (70) Concentrated sulphuric acid (0.8 ml, 98%) was added dropwise to a stirred solution of the ketoolefin (44) (0.57 g, 2.77 mmol) in acetonitrile (4.1 ml) in a flask protected with a reflux condenser and drying tube. The solution turned from colorless to yellow and finally orange-brown and heated up mildly. It was stirred for 1 h, water (30 ml) added whereupon it heated up again. After cooling, the reaction was extracted with chloroform; the chloroform extracts -35- combined, dried (Na2S04), filtered and evaporated under reduced pressure to give an oily semi-solid. T.l.c. showed two spots [R^ = 0.375 and 0.67 c.f. ketoolefin (44) 0.67]. Although one of the spots of the crude product had the same as the ketoolefin (44), the i.r. spectrum of the crude product was different from that of the reactant ketoolefin (44). The crude oil was purified by elution through an alumina column. The pure product came out as colorless liquid (70) (0.28 g, 1.36 mmol, 49.1%) after solvent evaporation. B.p. 281°C T.l.c. R^ = 0.72 cf. ketoolefin (44) 0.72 after chromatography. (Found C, 81.35; H, 10.63. C14H22O requires C, 81.50; H, 10.75%). v (liquid film) 2980(s), 2940(s), 1715(s), 1465(m), 1040(m), max 860(m) cm 1. 6 (CDCI3) 1.07, s, 3H, CH3; 1.10, s, 3H, CH3; 1.15, s, 6H, CH3; n 1.65, br.s, 3H, CH3; 1.7 to 2.25, m, 5H, CH2 and CH; 2.86, br.m, 1H, CH [bridgehead H-C(l)]; 5.26 and 5.28, d, 1H, olefinic H-C(8). 6c(CDC13) 19.0, q; 24.7, q; 27.1, t; 29.7, q; 30.3, q; 32.7, q; 37.7, s; 39.9, d; 40.8, t; 42.6, s; 48.2, d; 120.4, d; 145.0, s; 216.2, s. m/z+ 207(M+l, 1%), 206(M, 11), 191(12), 135(29), 134(100), 122(11), 121(69), 120(8), 119(34), 108(8), 107(51), 105(17), 96(11), 93(14), 91(26), 79(11), 77(11), 57(14), 43(11), 41(29), 39(11), 32(11), 29(11), 28(51). Endo-2, endo-6-dihydroxy-3,3,7,7-tetramethylbicyclo[3.3.1]nonane (82) The tetramethyl diketone (39) (5.41 g, 0.026 mol) in diethyl ether was added slowly to a solution of lithium aluminium hydride (7.0 g, -36- 0.18 mol) and diethyl ether (150 ml) in a flask protected with a condenser and drying tube. The reaction heated up mildly and was left to reflux for 48 h at reflux temperature, then cooled. The excess hydride was destroyed by wet ether, then 2.5M hydrochloric acid. The aqueous layer was extracted with ether and chloroform, the combined extracts dried (Na2S04) and evaporated to give a gummy crude solid, which on recrystallisation from diethyl ether, gave the pure diol (82) (3.2 g, 0.015 mol, 58%). O O M.p. 119-124°C. (Lit. 119-123°C) v (paraffin mull) 3420(s), 2920(s), 1470(m), 1385(w), 1365(w), max r 1050(s) cm 1. 1st Attempted conversion of gn Concentrated sulphuric acid (2 ml, 98%) was added dropwise to a solution of the diol (82) (0.25 g, 1.18 mmol) in acetonitrile (2 ml) and glacial acetic acid (2 ml) in a flask protected with a reflux condenser and drying tube . The solution turned brownish and was heated at 80°C for \ h and left to cool. Water (60 ml) was added and the solution stirred for another h. The reaction was extracted with chloroform, neutralised (NaHC03 solution), washed (water), dried (Na2S0i+) and evaporated to give a yellowish gummy liquid. T.l.c. Rf = 0.63, 0.47, 0.36, 0.19 and 0.05, cf. diol (82) 0.44. v (liquid film) 3330(m), 2980(s), 1670(s), 1525(m), 1470(m), 1385(m), max 1230(s), 1045(w), 770(s), 680(m) cm"1. Although i.r. showed the presence of amide, the small yield and the presence of mixtures made purification very difficult. -37- 2nd Attempted conversion of gre Concentrated sulphuric acid (3 ml, 98%) was added dropwise to a stirred solution of the diol (82) (0.75 g, 3.54 mmol) in acetonitrile (6 ml) and glacial acetic acid (6 ml) as described earlier. The solution then turned brownish and heated up mildly. Stirring was continued for 1 h, water (50 ml) added and the solution stirred for another h. The reaction was worked up as described before to give a yellowish liquid. T.l.c. R = 0.94 and 0.14 cf. diol (82) 0.89. v (liquid film) 3300(m), 2940(s), 1735(m), 1650(s), 1545(s), max 1450(m), 1370(s), 1240(s), 1040(s), 805(m) cm"1. The crude product was purified by column chromatography using alumina as the stationary phase and petroleum as the initial mobile phase. An increment of 5% diethyl ether to the mobile phase was made per fraction collected. A small quantity of white solid appeared when elution was carried out with 70% diethyl ether/petrol and subsequent increments of ether. 6 (CDCI3) Besides 4.28, br.s, 1H, NH; 1.64, br.s, 1H, OH, n (exchanged with D2O); other peaks were unidentifiable. 3rd Attempted conversion of g?2(io-2->gn(i(9-6-dihydroxy-3,3,7,7-tetra- methylbicyclo[3.3.ljnonane (82) to amide Concentrated sulphuric acid (4.5 ml, 98%) was added slowly to a stirred solution of the diol (82) (0.75 g, 3.54 mmol) in acetonitrile -38- (6 ml) and glacial acetic acid (6 ml) as described previously. The solution turned from colourless to yellowish and finally brownish and became exothermic. After stirring for 1 h during which the solution cooled, water (50 ml) was added and stirring continued for another h. The reaction was worked up as before to give a yellowish liquid. T.l.c. R = 0.20 and 0.95 cf. diol (82) 0.97. v (liquid film) 3300(m), 2930(s), 1720(m), 1645(s), 1535(m), max 1450(m), 1370(m), 1240(m), 1030(m), 755(s), 660(w) cm"1. The crude oil was purified by elution through an alumina column. A small quantity of white solid appeared on elution with 45% diethyl ether/petrol and subsequent increase of ether. These were combined and evaporated under reduced pressure to give the dry product The proton n.m.r. spectrum showed the presence of numerous impurities and identification was impossible. Attempted hydrolysis of 1,3-bis(acetamido)-4,4,8,8-tetramethyl- 3 7 tricyclo[3.3.1.1 * jdecane (67) with sodium hydroxide in ethylene glycol Conditions A The diamide (67) (0.024 g, 0.078 mmol) was added to a stirred suspension of powdered sodium hydroxide (0.49 g) in ethyleneglycol (8.0 ml) and the solution refluxed for 4 h (oil bath temp. 210°C) under a nitrogen atmosphere. The solution was allowed to cool, water (10 ml) added and the mixture extracted with diethyl ether. The combined ether extracts were washed (water), dried (Na2S04) and solvent evaporated to give traces of yellow solid. T.l.c. = 0.09 and 0.0, cf. diamide (67) 0.10. -39- Conditions B The diamide (67) (0.018 g, 0.058 mmol) was added to a stirred suspension of powdered sodium hydroxide (0.50 g) in ethyleneglycol (5.0 ml) and the solution refluxed for 6 h (oil bath temp. 210°C) under nitrogen atmosphere. The solution was allowed to cool, water (10 ml) added and extracted with ether. The combined ether extracts were washed (water), dried (Na2S04) and solvent evaporated to give traces of gummy yellow liquid. T.l.c. Rf = 0.98, 0.92 and 0.75, cf. diamide (67) 0.08. v (liquid film) 3400(m), 2960(s), 2940(s), 2860(s), 1730(s), max 1465(m), 1380(w), 1280(s), 1125(m), 1075(w), 1040(w), 800(w), 745(w), 705(w) cm 1. Conditions C The diamide (67) (0.02 g, 0.07 mmol) was added to a stirred suspension of sodium hydroxide (0.52 g) in ethyleneglycol (5 ml) and the solution refluxed for 5 h (oil bath temp. 210°C) under a nitrogen atmosphere. The solution was allowed to cool, water (10 ml) added and the mixture extracted with diethyl ether. The combined ether extracts were washed (water), dried (Na2S04) and solvent evaporated to give traces of colorless liquid. The i.r. spectrum showed these to be mainly water droplets. v (liquid film) 3400(s), 2100(w), 1650(s) cm 1. max -40- Attempted hydrolysis of 1,3-bis(acetamido)-4,4,8,8-tetramethyltricyclo 3 7 [3.3.1.1 * jdecane (67) with sodium hydroxide in diethyleneglycol Conditions A The diamide (67) (0.03 g, 0.098 mmol) was added to a stirred suspension of powdered sodium hydroxide (0.59 g) in diethyleneglycol (5 ml) and refluxed 5 h (oil bath temp. 250°C). The solution was allowed to cool, water (10 ml) added and the mixture extracted with diethyl ether. The combined extracts were washed (water), dried (Na2S04), filtered and the ether distilled off to give traces of brownish solid. T.l.c. = 0.07 and 0.0, cf. diamide (67) 0.07. The i.r. spectrum showed the product to be identical to the original diamide (67). Conditions B The diamide (67) (0.04, 0.12 mmol) was added to a stirred suspension of powdered sodium hydroxide (0.52 g) in diethyleneglycol (5 ml) and refluxed for 15 h (oil bath temp. 250°C). The solution was allowed to cool, water (10 ml) added and extracted with diethyl ether. The combined extracts were washed (water), dried (Na2S04), filtered and the ether evaporated to give traces of yellow liquid. T.l.c. Rf = 0.97 and 0.06, cf. diamide (67) 0.06. v (liquid film) 3400(m), 2940(s), 2860(s), 1730(m), 1465(m), nia.x 1380(w), 1265(w), 1125(m) cm”1. -41- Conditions C The diamide (67) (0.06 g, 0.2 mmol) was added to a stirred suspension of powdered sodium hydroxide (0.52 g) in diethyleneglycol (5 ml) and refluxed for 15 h (oil bath temp. 250°C). The solution was allowed to cool, water (10 ml) added and extracted with diethyl ether. The combined ether extracts were washed (water), dried (Na2S04), filtered and the ether evaporated to give traces of yellow liquid. T.l.c. Rf = 0.96, 0.87, 0.21 and 0.09, cf. diamide (67) 0.09. v (liquid film) 3360(m), 2940(s), 2870(s), 1720(w), 1662(m), max 1580(m), 1510(w), 1468(s), 1390(m), 1370(m), 1350(m), 1260(w), 1215(s), 1100(m), 1072(m), 1052(m), 880(m), 750(s), 665(s) cm"1. -42- 6. REFERENCES 1. Nold, A., Chem. Ztg.,( 1905), 29^, 174. 2. Mohr, E., c/. Prakt. Chem., (1918), 98, 315. 3. Decker, H., Z. Angew. Chem. , (1924) , 37_y 795. 4. 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