A STUDY OF THE DiELS-ALDER ADDITION OF NITROSOBENZENE T0 CYCUC DiENONES Thesis for the Degree of Ph. D. MICHIQAN S‘E’ME UNIVERSITY SAMBHARAMADOM K. RAMASWAM! 1970 a. i 1 LIB RA R Y Michigan Sta te University a, ‘ .1» «a n This is to certify that the thesis entitled A STUDY OF THE DIELS—ALDER ADDITION OF NITROSOBENZENE TO CYCLIC DIENONEIS presented by Sambharamadom K. Ramaswami has been accepted towards fulfillment of the requirements for Ph . D . degree in Chemis try Major professor Date June 51 1970 0-169 30:3!“ 3‘! ms & sous mm mm me. __- 'mv amoras ran. Items“ ' ‘ ‘7' - . ' l e '0 '. . VI ' -. v ,v .L ‘ h . ‘ \ V~ I . | ,_ ABSTRACT A swab! OF THE DIELS-ALDER ADDITION or NITROSOBENZENE TO CYCLIC DIENONES ' BY Sambharamadom K . Ramaswami ,_ The Dials-Alder addition of nitrosobenzene to five methyl-substituted 2,4—cyclohexadienones (1‘, 23' '12,, g; and w and one methyl—substituted 2,4—cycloheptadienone (3132) one 2,4-cyclohexadienol (1 derived from L) and one 2,4-cyclo- heptadienol (1?. derived from 122) was studied with regard ‘ to the ease of adduct formation, stability of the adducts r and the orientation of addition. 0 o ‘ OCOCH3 ' 3 H g 1.52. 12. o o 22. 1%. 1 l Sambharamadom K. Ramaswami H OH H OH 2. 9.9. The number and position of the methyl groups in the dienones influenced their reactivity, stability of the pro— duct and orientation of addition. Among the dienones, 1 was the most reactive and gg the least. Dienol Z'was exception- ally reactive and gave a single adduct, possibly due to hydrogen bonding between the hydrogen of the dienol 0—H bond and the nitroso oxygen. This may lower the transition state energy for adduct formation. The adducts from dienols Z,and gglas well as the di— enones §£u lg'and gl'were stable in solution, whereas those from L, lg'and 22'showed a tendency to dissociate into com— ponents. All the adducts were thermally unstable and decom— posed into the components almost quantitatively on heating, as during a vpc analysis. The orientation of addition (either the oxygen or the nitrogen of the nitrosobenzene may become attached to the diene carbon which is adjacent to the carbonyl or hydroxyl group) was elucidated by a combination of nmr spectral measurements and chemical degradation. For example, dienol Z,may give adduct gé'or §§.(neglecting the two epimeric possibilities for the alcohol function). 2 Sambharamadom K. Ramaswami H OH OH , OH H and/or H . C6H5 " I /° 2" O H N\c6r15 H 7. is £13. The bridgehead proton adjacent to the -CHOH group was a doublet and appeared at lower field than the other bridge- head proton, which was a singlet. Since Kresze1 has shown that in 3,6—dihydro—1,2—oxazines the proton adjacent to oxy- gen appears at lower field than the proton adjacent to nitrogen, structure §§_was assigned. I chemical degradation of the adduct from 1 supported uri.the assignment based on the nmr spectrum. Cleavage of the -'_ h-O‘bond with zinc and acetic acid gave a monocyclic amino diol. Further oxidation with sodium metaperiodate gave an open-chain dialdehyde, which further underwent facile intra- ;flholecular cyclization and dehydration to give pyrrole lg'in ”:4high yield. CHO ‘ H H OH HO / mama > NH-C5H5 ﬂ> \ u—Ceﬁs _ H .7: 2, 14 Sambharamadom K. Ramaswami This reaction sequence established the structure of the adduct as §A, Lithium aluminum hydride reduction of adduct from dienone ; also gave §gﬁ thus establishing its struc— ture as gé, O J / /0 8A N H \C6H5 1. 2}}. Similar nmr correlations and chemical degradation established that the adducts from iéx l2” §£ﬂ and §g_all had the A orientation. Structures with the B orientation are favored for the nitrosobenzene adducts of a; and gﬁ, In most cases the oxygen of the nitrosobenzene becomes attached to the diene carbon which has an adjacent electron- withdrawing oxygen function. In the absence of other fac— tors, this electronic effect seems to control the orienta- tion. However when C-5 of the dienone has a methyl substitu— / c1 0 + n . /0 \\\C6H5 N"\c3t15 Cycloheptadiene gave no adducts,8 whereas with cyclohepta— triene, 1,6-cycloaddition (a thermally disallowed process) occurs . (Ar = C6H4-prcl) This has been explained10 as a step-wise process, in which the first step was considered to be a nucleophilic attack by the cycloheptatriene on the positively polarized nitro— gen atom. (b) Nitroso Compounds Aromatic nitroso compounds are the most frequently used nitroso dienophiles because the addition in these cases proceeds much more smoothly than for aliphatic nitroso compounds. The reactivity of the aromatic nitroso compound depends on the substituents in the ring; electron—withdraw- ing groups such as N02 or halogen enhance the reactivity ,cna ‘CH3 decrease it. Aliphatic nitroso compounds react with dienes whereas electron—donating groups such as —OCH3 or —N only when the a—carbon atom carries an electron—withdrawing substituent, such as C1, CN, CC13 or CF3- (c) ggversibility of the Reaction As in the case of the C=C dienophiles, the diene addition with nitroso compounds is reversible. Cleavage into components occurs above the temperature range of 100-1500 in many cases. The adducts with cyclic dienes are particularly unstable thermally; 243; the adduct of cyclo- pentadiene with nitrosobenzene decomposes appreciably above 0°. Orientation of Addition when a nitroso compound adds to an unsymmetrically substituted butadiene, two positional isomers, having structures 3 and 3 may be obtained. 5 R1 R1 H R1 H /R o N + H --> I + N N \R \R R2 H R2 H R2 ‘3. E. with vinyl compounds as dienophiles, the orientation of addition has been well—studied and the results are dis— cussed in reviews.3'12'13 The conclusion in this case is that the polarity of the addends is not the deciding factor in the orientation of addition. The addition of nitroso compounds to 1,3—dienes offers an excellent opportunity to study orientation preferences in the Diels-Alder reaction. Since the addition proceeds smoothly with a large number of dienes under relatively mild conditions, the influence of various substituents on the diene or dienophile on the reaction rate and on the yield and orientation of the products can be investigated. In cases where both structural isomers 3' and 3. are formed, the more subtle influences caused by the variation of the substituents can be detected by using either chemical or spectroscopic methods to analyze the product mixtures. The nmr spectra of the isomeric adducts are very well dif- ferentiated, especially with regard to the signals of the protons at the 3- and 6-positions of the resulting 6 3,6-dihydro-1,2—oxazines. Integration of the intensities of these signals can be used to estimate the isomer ratio. Chemical transformations may change this ratio and are less useful as an analytical method. As a result of such studies, Kresze4 has observed the following general empirical rules for aromatic nitroso compounds. 1-Substituted Dienes The main product with all 1—substituted butadienes (except pentadiene, R1 = CH3) is the 6-substituted-3,66 dihydro-1,2-oxazine. Examples include R1 = E-Bu, CH3CO, R1 R1 H 0 II and Ar = C3115, E‘Cl‘C6H4 and E-Cl'la-CSH4. Thus the orientation is governed mainly by steric factors; the transi- tion state in which R1 and Ar are remote from one another is favored. 2-Substituted Dienes with all the 2-substituted butadienes, the 4-substituted adduct is obtained. R1 R1 = C113: CF31 C1: CN: CH30: C3115: E—CH3C6H4, E‘CH30C6H47 Ar = C6H5, B-Cl—C6H4, R—CH30C6H4- Whereas in the case of 1—substituted dienes, the isomer ratio can be attributed to steric factors, this cannot be logical for 2-substituted dienes. Here, polar substituents also do not operate in a simple predictable way; 343; groups that influence the diene system as donors or acceptors through resonance participation (OCH3, Cl, CN) or through their inductive effect (CH3, CF3) all lead to the same orientation. These results are similar to those obtained in the Diels—Alder reaction of dienes with vinylic dieno- philes of structure CH2=CHX (X is an electron—withdrawing group such as COOH, CN, C1 etc.); the carbon carrying the x-substituent is equivalent to the oxygen in the aromatic nitroso compound. At the moment there does not seem to be an adequate explanation for the marked orientation prefer- ence in additions to 2-substituted butadienes. 1,4—Disubstituted Dienes The adducts formed from 1,4-disubstituted dienes and aromatic nitroso compounds are usually mixtures of isomers. The factors which influence the isomer ratio can be separ- ately considered as follows: (a) Steric Factors The isomer ratio is influenced by steric factors, when both substituents differ in their size. Since both the diene and the dienophile are arranged in parallel planes in the transition state, the difference in energy content for the transition states for the two isomers could be large for bulky substituents, with the result that one isomer may predominate substantially over the other. This is exempli— fied in the case of 4-arylbutadiene carboxylic acid methyl COOCH3 H COOCH3 O > I N \ \ C6H5 A H Ar r A ester. In the series Ar = phenyl, a-naphthyl and 9-anthryl, the fraction of isomer A (in which the aryl residue and the N-aryl group are close to each other) decreases in this order from 80 to 74 to 5%. (b) Polar Factors A clear-cut separation of the polar influences is more difficult than the steric influences. However, some indica- tions have been obtained in the case of the following sorbinol derivatives as the dienes: H CH X CH2- X C 2x 2 f 6+ 6- 0 Ar N’/ + > + 6+ N 0 - \\ 6 Ar \ Ar CH3 CH3 A B x = OH Ar C3H5 OSi(CH3)3 g-cl—CGH4 OCOCH3 E-CH3—CGH4 OCOC5H4-N02(2) OCOCF3 ETCHso‘C6H4 The X-substituent in these cases are not bulky and should therefore exert no steric influence. orientation can be stated thus: The observed trend in the stronger the electron withdrawing nature of X, the greater the proportion of isomer A in which the O—atom of the C-atom carrying the x-group in the product. N=O group is bound to the This result is understandable if one considers that the inductive effect of the X-group polarizes the diene as indicated and bond ‘ formation occurs preferentially between the terminals with opposite polarities. However, the influence of polar ef- fects is often complex as for example in the case of pigg— substituted 4-phenylbutadienecarboxylic acid esters in which steric influences do not vary. Here, the isomer ratio A/B in the product decreases according to the following sequence for electron—withdrawing groups: H > p—Cl > E—CN > p-Noz. For electron-donors, the following sequence is observed: H > prCHs > p-OCHa > E-N(CH3)2. A linear dependence of log (A/B) on the substituent constant 0 or 0+ is not observed. Polar effects of pggg—substituents on the nitroso— benzene do not have any effect on the isomer ratio in the case of reaction of sorbinyl acetate with nitrosobenzenes. L OCOCH3 OCOCH3 OCOCH3 C6H4 ‘X o N / +|| -—> I + I N N o \C5H4-X \CeHrX CH3 CH3 L A B x=eu(i-em.nn=smw>cm.m-smwheegae= 82 Kinetic Studies t The influence of structural changes on the kinetics of the Diels—Alder reaction have been investigated using nitroso compounds as the dienophile. The kinetics is ‘ 11 second order up to 60-70% reaction;1‘*17 beyond that, com- plications from side reactions occur. A Hammett study18 of the reaction of 1,3—cyclohexadiene with substituted nitroso- benzenes showed that electron—withdrawing substituents in- crease the rate and electron—donating groups decrease it. Similar studies on aryl-substituted dienes have shown that the effect of substitution on the diene is considerably smaller than that in the case of the nitroso component. The p value for the reaction of cyclohexadiene with sub— stituted nitrosobenzenes has been found to be +2.57 at 2° and for 2,3—dimethy1butadiene +2.51 at 25° when the reac— tions are carried out in methylene chloride. For the reac— tion of 1- and 2-phenylbutadienes with p—chloronitroso— benzene, the p values vary between —0.25 to -0.43 (at 15-440). from these p values, there is support for the conclusion that electron deficienCy in the dienophile and electron availability in the diene favor the Diels— Alder reaction. As in the case of C=C dienophiles, high negative entropies of activation (about -35 e.u.) have also been estimated for reactions of unsubstituted dienes with para—chloronitrosobenzene.14r18 Mechanism The nature of the transition state in the reaction of dienes with nitrosobenzene has been discussed in detail by Kresze.4 It is presumed that the diene and the dienophile are in two parallel planes and bond formation results from r—* ——~_———.—.—..—. - pf-.. . 12 interaction of the bonding w—orbitals of the reacting com- ponents.19 The extent of bond formation on the individual reacting center is, however, dependent on the particular structure of the components. Changes in the nature of the substituents on the diene or nitroso compound can influence the bonding in the transition state. In principle, if the polarity of the dienophile X-Y is O- 6 + indicated as x - Y , then three limiting cases are possible. 5+ In A, simultaneous bond formation takes place at ‘C1 and C4. Preferred bond formation at C4 and partial charges at C1 and X is indicated in B. The reverse situation, 315. preferred bond formation at C1 and partial charges at C4 and Y are shown in C. For aromatic nitroso com- pounds as dienophiles (X = O; Y = NAr), the Observed orienta— tion rules can be generally explained by the assumption that polar forms such as 3 do contribute to the structure of the transition state, although not to a large extent. The transition state, therefore, in the first approximation in all cases, can be described by means of the non—polar 13 form A. The mechanism may vary within these limits accord- ing to the nature of the substituents. Contribution of the polar form C may be present only in the exceptional case of 1-arylbutadiene in which the pggg—position of the benzene ring has a -CN group and where the reaction rate is actually enhanced by this group, in comparison to, say, a CH3 group. From these results, it is clear that one single mechanism cannot fully explain all the observations in the Diels-Alder reaction with nitroso compounds. The details of the mechanism can be easily influenced by small structural changes in the components. Synthetic Utility From a synthetic point of View, the Diels-Alder reac- tion with nitroso compounds provides an easy route to a variety of heterocyclic structures. The adducts undergo facile transformations with various simple reagents and thus lead to many heterocyclic ring systems4 which are otherwise accessible only with difficulty. Photochemistry There has been great interest in recent years in the photochemistry of N-containing heterocyclic compounds. A recent article20 which appeared while the present work was in progress deals with the photochemistry of simple 3,6-di- hydro-1,2-oxazines resulting from the Dials-Alder reaction ‘— 14 of substituted 1,3—butadienes with nitrosobenzene. The following reaction is typical: CH3 c H N/ 8 5 h V I 254 mp. > CH3 CH3 0 N c H CH3 6 5 The reaction has been claimed to be useful in the synthesis of substituted pyrroles. The photochemistry of bridged bicyclic 1,2—oxazines has not been reported so far. Present Work Conjugated cyclohexadienones have been the subject of intensive studies in the past several years in our labora- tory. New methods have been discovered for preparation of various alkyl-substituted cyclohexadienones, and from these, many such compounds have now become easily available.21'23 Also under exhaustive study is the photochemistry of these dienones and their Diels—Alder adducts. The dienones form adducts with a variety of dienophiles, gyg; maleic anhydride?1 dimethyl acetylenedicarboxylate,2‘ diethyl azodicarboxylate?1 benzynes,24 2-butyne,25 diphenylacetylene,24 vinyl acetate,28 etc. The dienones, the adducts, and their derivatives under- go interesting rearrangements when subjected to ultraviolet irradiation.31'23v*‘°'32 ‘ 15 In the light of these interesting observations, the present work was undertaken with the following aims: (l) to see whether cyclohexadienones react with nitroso compounds to form Diels—Alder adducts: (2) if so, to study the orientation of addition; and (3) to investigate whether these adducts exhibit any useful ground state and photochemical reactivity. The results obtained from these investigations form the subject matter of this thesis. By using nitrosobenzene as the dienophile, Diels-Alder adducts have been prepared from the following dienes: 21- 22 z. ""1"?“ " .l: ‘ - z > t,‘ -~,. I . 4. .. ' 16 _ . _, H H 32 39 .3175 5, The structure elucidation of these adducts is discus sad ,wgdetail in the Results and Discussion section of this 'iuhgsis. Preliminary studies on the photochemistry of these 'W« hots indicate that they are photochemically reactive. ' . ..+, it: J! ‘F’ .: ‘ RESULTS The Dials-Alder Adduct from 3L4,6L6—Tetramethyl-2,4-cyclo— hexadienone {1! and Nitrosobenzengj' N-Phenyl—7-oxa—8-aza—- -3,3',5,6-tetramethylbicyclo[2.2.21oct—5-ene-2-one A simple cyclohexadienone available for the Dials-Alder studies appeared to be the tetramethyl derivative, 335., 3,4,6,6—tetramethyl-2,4—cyclohexadienone l, which is easily prepared from durene.22 The 2- and 5—positions in this dienone have hydrogens as substituents, and these, after 0 ——-> 1 ~ the Diels-Alder reaction, will form the bridgehead positions in the adduct. This should make the assignment of the orientation of the N and O in the adduct relatively easy by nmr methods. The tetramethyldienone l formed a single adduct, mp 62-630, in 51% yield. When attempts were made to recrystallize this product, however, partial dissociation into the components was observed, as indicated by the 17 18 appearance in solution of the green color of nitrosobenzene. This was a serious problem while working with this adduct in solution. A recrystallized sample from pentane had nmr signals (Figure 1) at T 5.92 (singlet, 1H) and 5.63 (sing- let, 1H) due to the bridgehead protons and two quartets q; = 1.2 Hz) at T 8.53 and 8.15 respectively due to the allylic methyl groups, in addition to the aromatic protons (5H) at 2.7-3.2. The question about the correct assignment of the chemical shifts of the bridgehead protons was solved by a combination of methods such as analogy to literature, labeling experiments and reduction of the carbonyl group to the alcohol. —.... ﬂ-’_._s- -__ The nmr results were compared with those obtained by Kresze and co-workers33 in their extensive studies with adducts obtained from open-chain 1,3-dienes and pfchloro— nitrosobenzene. These authors made use of the chemical shifts of the bridgehead protons as a distinguishing criterion to decide about the orientation of addition of the dienophile to the diene. As a general case, if a 1,3— diene such as 2 reacts with p-chloronitrosobenzene g, the ~ two possible structures can be represented by $§_and 22, R1 R1 H1 ‘R1 H5 0 /C5H4Cl O N + “ ___, ‘ and/or 1 N O N\ \ C H C]. C6H4‘C1(E) 6 4 R3 R2 H2 R2 H1 a it 2.23, :12 19 Starting with various dienes having different substi- tuents R1 and R2 , the authors prepared the corresponding adducts and elucidated the structures by chemical degrada- tion. Thus, from a knowledge of the orientation of addition from chemical evidence, a correlation between the nmr chemical shifts of the bridgehead protons and the structures corresponding to them was obtained. Some typical results are tabulated in Table I. From the table, it is evident that the proton adjacent to the oxygen, i;§;, H(1) is deshielded more than that adjacent to the nitrogen, 2:24! H‘z), and that attachment of electron withdrawing groups to the carbon atoms carrying these protons enhances this deshielding effect. It would be expected from these findings that in the [2.2.2] bridged heterocyclic systems formed from cyclohexadienones, the same effect would be present with the result that the bridgehead proton adjacent to oxygen would be deshielded relative to that adjacent to nitrogen. The bridgehead protons in the adduct from tetramethyl- dienone l'show signals at T 5.63 and 5.92. If the Kresze correlations are applicable in this bridged system, the assignments can be made that the T 5.63 signal is due to the bridgehead proton adjacent to the oxygen and the T 5.92 sig- nal is due to the bridgehead proton adjacent to the nitrogen. However, this assignment does not serve to decide between the two possible structures Qé'or §§'for the adduct since both structures are in accord with the Kresze correlations. ‘ 20 Table I. Chemical shifts of the ring protons signals in the nmr spectra of 3,6-dihydro-1,2-oxazines H1 H2 R1 R2 [C§(0)] [C§(N)] (a) Adducts with structure 4k'from 1—substituted dienes H H " 5.59 6.29 Me H 5.43 6.32 CMe3 H 5.75 6.30 cooue H 5.02 6.24 Ph H 4.55 6.29 OCOMe H 3.68 6.34 (h) Adducts with structure 3% from 1,4—substituted dienes Ph Me ' 4.54 5.92 Ph CHMe2 4.77 6.27 Ph Ph 4.40 4.99 COOMe Me 5.02 6.05 CH'CH-COOMe Me 4.87 5.97 CN Me 4.95 6.08 CONHz Me 4.98 5.95 C32C00Me Me 5.37 6.05 COOMe COOMe 4 .95 5 .25 COOMe Ph 4.98 5.12 CN Ph 4.90 5.14 (c) Adducts with structure 4% Me H " 5.70 6.08 COOMe Ph 4.54 5.20 COOMe a-Furyl 4.45 5.22 21 H T 5.92 .»C6H5 H T 5.63 EA 2% This question was unambiguously resolved by labeling the starting tetramethyldienone 1 with deuterium at C2 by heating under reflux with sodium methoxide in methanol-d (CH30D). O 331 U M can. -N=o CH3OD > ——“> Adduct H reflux CD3 H 1. s: The resulting labeled dienone g'had deuterium at the positions indicated, as revealed by nmr. The T 4.32 broad signal and the T 7.98 quartet22 were absent in the spectrum of the labeled dienone g. This was then reacted with nitroso— benzene and the nmr spectrum of the resulting adduct was examined. If the adduct had structure 5g” the T 5.63 signal should disappear: if it had structure 2g, the T 5.92 signal should disappear. Thus this experiment enables an easy 22 distinction between the two possible structures, provided that the assignments based on Kresze's observations are valid. The actual experimental result showed that the T 5.63 signal had disappeared, thereby indicating that the adduct was probably best represented by structure 5%; The labeling experiment also showed that the low—field allylic methyl at T 8.15 in 5A,also was absent in the labeled product, thus enabling a clear—cut assignment to this methyl as the one attached to C-7 in the adduct. This result is significant and will be considered in greater detail later. Thus by analogy to Kresze's correlations of chemical shifts of the ring proton signals in simple 3,6—dihydro—1,2— oxazines,33 it is concluded that the adduct from tetramethyl— dienone l'has structure 5A; However, this conclusion is based on the assumption that the correlations in the simple monocyclic system also apply to the bridged [2.2.2] system. A second independent method for verification of these chemical shift assignments was accomplished by reducing the dienone L to the dienol Z'with lithium aluminum hydride and conversiOn to an adduct With nitrosobenzene. The formation of the adduct from the dienol was complete in 2 hr at 0°. This is in contrast to the lesser reactivity of the dienone 1, which required at least 4 hr at room temperature. The enhanced reactivity may be explained as arising out of the improved dienic character of the dienol. The adduct, obtained in 78% yield, could be recrystallized conveniently from pentane (mp 82-830). It was thermally quite stable, could 23 be purified in good yield by sublimation, and did not show any evidence of dissociation in solution. The nmr spectrum (Figure 2) was particularly helpful in assigning a structure to the adduct. The low—field bridgehead proton appeared at T 5.77 as a doublet Q; = 1.6 Hz) as a result of coupling with the adjacent cgron proton. This coupling requires that the low—field bridgehead proton be adjacent to the hydroxyl—bearing carbon. The high-field bridgehead proton appeared as a singlet at T 6.47. A noteworthy feature in the spectrum is the greater separa- tion between the two bridgehead protons (0.7 ppm) whereas in the spectrum of the dienone—adduct, this separation was only about 0.3 ppm. These differences in the chemical shifts of the bridgehead protons in the two adducts are somewhat surprising and may be attributed to subtle changes in the conformation of the molecule and the resultant ring strain while going from the dienone-adduct having an sp2 hybridized carbon in the bridge to the dienol—adduct in which this is absent. The Kresze correlations may be more valid in the case of the dienol-adduct, and if this is true, structure §A_should be more favored than §§'for the dienol— adduct. 24 H OH OH ’j<:f/O T 5' 77 /:<;:: T 5.77 N/ C6H5 T 6.47 T 6.47 z. 54. 83 The allylic methyls in the adduct showed signals at T 8.62 and 8.22 as quartets Q; = 1.2 Hz). Reduction of the labeled dienone Q'with lithium aluminum hydride and conver- sion of the resulting labeled dienol to an adduct was then carried out to confirm the nmr assignments. The nmr spec— trum of the labeled dienol-adduct lacked the signals at T 5.77 and 8.22. H D 0 H OH D D CD3 /l< _> C6H5 -N=O o ——’ / CD 3 H H N\C3H5 E 24 The ir spectrum of the dienol-adduct (in very dilute solution in carbon tetrachloride) showed the O-H absorption as a ‘ 25 fairly sharp band at 3576 cm_1 which did not change position on dilution, indicative of intramolecular hydrogen bonding, as pictorially shown below. This effect may be partly re— sponsible for the spectacular reactivity of the dienol in that the transition state energy for formation of the adduct may thereby be lowered. Furthermore, it may also have a directing effect in obtaining the observed orientation. N‘\C8H5 §A The orientation of addition of nitrosobenzene to the dienol 1 has been shown to be the same as that to the dienone'l'by direct reduction of the dienone—adduct 5A to the dienOl—adduct 8A with lithium aluminum hydride. This reduction was done by rapid addition of a freshly prepared solution of the dienone-adduct in ice-cold ether to an ice- cold slurry of the reducing agent in ether, to minimize dissociation of the starting material into the components. Dissociation of the dienone—adduct to the components, reduc— tion of the dienone to the dienol and formation of the ad— duct within this short time is unlikely; moreover, the nitrosobenzene would also be reduced under these conditions 26 to hydroxylamine (which further condenses with nitroso— benzene to azoxybenzene very rapidly)34 and thus would not be available for reaction with the dienol. H Ar-N=0 , + Ar-N=O --——¢v Ar-NHOH ——-————> Ar-N -N-Ar I- 0 Thus, assuming that the Kresze correlations are also applicable to the [2.2.2] bridged systems, the nmr evi— dence strongly supports structures éé'and 8A'for the dienone- and the dienol-adducts respectively. However, independent chemical evidence was deemed desirable to sup- port this assumption. In the simple 3,6-dihydro—1,2—oxazine systems, the earliest method to cleave the N-O bond is the one used by Arbuzov and his co-workers35, gig. reduction with zinc and acetic acid, to form an amino alcohol. 0 OH NH-R' The dienol-adduct was found to be well suited for this type of degradation since it did not dissociate into its components under the conditions of the reduction. Moreover, the resulting amino diol turned out to be a key intermediate suitable for further degradation. The bicyclic adduct, now 27 designated as ég’from nmr evidence, was reduced with zinc and acetic acid and gave an oily product having all the spectral characteristics of the expected amino diol 2 (Note: the formulas E7Lg in Scheme I do not have any stereochemical implicatiOns). The ideal oxidant to cleave the resulting a—glycol (or a-amino alcohol from structure §E~) appeared to be sodium metaperiodate (the Malaprade reaction)35, since the oxida- tion is fast and specific, requires only very mild condi— tions, produces no side-products, and above all, work-up is simple. The crude amino diol obtained from zinc—acetic acid reduction of the dienol-adduct §§.reacted rapidly with the reagent, as shown by the formation of a precipitate of sodium iodate. Thus, reduction with zinc and acetic acid followed by cleavage with sodium metaperiodate appeared to be a useful sequence of reactions to determine the structure of the adduct. The bicyclic system can thus be opened up to an aliphatic system with great ease and further character— ization becomes relatively a simple matter. The reaction of periodates with a-glycols and a-amino alcohols in general is outlined in the following equations:36 a-glycols: OH OH I I R1\ /R3 R1—C—C-R3-—> c=o+o=c I I / \ R2 R4 R2 R 28 a—amino-alcohol (N-secondary amine) H R 0H ‘N’ I I R1\ /R3 R1 - C " C — R3 > /C=O + R-NHz + C=C\ I I R2 R4 R2 R4 The expected cleavage products from each of the struc- tures 8A,and ﬁg are given in Scheme I. H. OH H OH H H CH0 ,J<:;\ Ho CH0 0 Zn,HOAc NanI .._.___..> > / NH —c H N \ 6 5 H ~\C6H5 C6H5 H 8A 2 12 H OH H : H OH I /J<:\ HO CHO ' CeHs CHO ‘ N’En > ﬁg 51an4 x —— ., ...' _————— ? O/HOAC eeHs H > H ¥ H H H + CsHs-NHZ 22. ll 1% Scheme I Product expected from 8A.would be a single amino aldehyde, whereas that from §§.wuuld consist of two fragments, a hydroxy dialdehyde and aniline. 29 The actual product isolated from this two—step sequence of degradation from the dienol-adduct consisted of a single crystalline compound, obtained in 87% yield mp 59-600, which could be easily purified by either column or vapor phase chromatography. The ir spectrum (Figure 17) showed char- acteristic bands of an aliphatic aldehyde at 1715 and 2720 cm-1. The absence of absorption typical of an a,B-unsaturated aldehyde, an amine, or a hydroxyl indicated that neither lg'nor lg'was present. It is possible that the product of Cleavage might have undergone further reaction. This is in fact conceivable in the case of the product from Qé, as it is a y-amino aldehyde, in which the amino function can further react intramolecularly with the a,B-unsaturated aldehyde function to form a five—membered heterocyclic ring l2, which can further aromatize by loss of water and thus form'a stable pyrrole derivative 14. NH— —C6H5 NH'CeHs : éﬁﬂ HO Li 30 Many examples of such intramolecular reaction to form pyrroles from 3,6—dihydro-1,2-oxazines have been reported by Kresze and co-workers.37 Two typical examples are given below: _ ._ CH3OOC H CH3°°C 9?. 0 Base. gMeOH gl N \ IIReam-CHE) Ar R H coocn3 o > | > NH-Ar CH3 N C02CH3 1 CeH4'C1(E) OCOCH3 H 0 ! (3 Zn ACOH > —— N NH-C6H4-Cl(p) C6H4-Cl(2) ' CeH4'C1(E) In all these cases, the cyclization to pyrrole is so facile that the intermediate ymamino aldehyde of type $2 can not be isolated. The product obtained from the dienol-adduct was in fact -'u_ . found to be the expected pyrrole £$ from its mass spectrum (m/e 241, M+ C15H190N) and its nmr spectrum (Figure 3), which showed signals at T 8.80 (singlet, 6H, gem—dimethyls), 8.00 (multiplet, 6H, ring methyls), 3.60 (multiplet, 1H, ring 31 proton), 2.68 (multiplet, 5H, benzene protons) and 0.62 (singlet, 1H, aldehyde proton). The degradative formation of a pyrrole from the dienol- adduct conclusively proves that the adduct is represented by structure ﬁg, Structure gg'could not give rise to the pyrrole and is thus clearly ruled out. Synthesis of gé' from §§,also establishes the structure of the dienone adduct. The chemical evidence thus supports the nmr spectral evi- dence in favor of structures §§'and also proves that the Kresze correlations33 are applicable to the [2.2.2] bridged heterocyclic systems formed from cyclohexadienones and nitrosoaromatics. The sequence of reactions used for this degradation is also valuable for the synthesis of substituted pyrroles in good yields frOm cyclohexadienones. The Diels-Aldgr Adduct from 6-Acetoxy-2,4,6-trim§thy1-2,4- cyclohexadienone (12) and Nitrosobenzene The next cyclohexadienone chosen for Dials-Alder reac— tion with nitrosobenzene was the 6—acetoxy-2,4,6—trimethy1— dienone 123 The substitution pattern of this dienone is quite different from that of the tetramethyldienone l, thus offering the possibility for further understanding of the influence of substituents on the reactivity of the dienone, stability of the adduct, etc. The dienone was readily prepared by oxidation of 2,4,6-trimethy1phenol with lead tetraacetate:38 32 OH O Pb(0Ac)4 > ococn3 12 The Diels—Alder adduct is formed when the components are mixed and stirred together in a solvent for 9 hr at room temperature. The stability of the adduct was found to be the lowest of all the adducts prepared in this series. Simple dissolution of the adduct in most solvents resulted in partial dissociation into components as judged by the formation of the green color of the dienophile. Hence nmr spectral determination was hampered by the appearance of signals due to the starting dienone (Figure 4). Reduction of the adduct with lithium aluminum hydride in ether at 0° gave a crystalline diol having considerably better stability. It could be purified by sublimation to a stable solid mp 94-950. The nmr spectrum of this diol (Figure 5) could be analyzed since there was no evidence of any dissociation in solution. The only bridgehead proton in the diol showed a signal as a doublet at T 6.08 Q; = 1.8 Hz) due to coupling with the vinylic proton); the other signals were at T 8.80 (singlet, 3H), 8.50 (doublet, g = 1.4 Hz, 3H, allylic methyl), 8.45 (singlet, 3H), 7.08 (broad, 1H), 6.33 (broad, 1H), 5.73 (broad, 1H), 4.27 (broad, 1H, olefinic proton) and multiplet at T 3.05 (5H, aromatic protons). 33 The chemical shift of the bridgehead proton (1 6.08) favors structure 17A for the diol in preference to structure 173 when the Kresze correlation33 is considered. u 0 CHa-CO C6H5N=O /J<:\ OCOCH3 O / N\ H C6H5 15 16A 16B H H OH OH CH3 / CH3 OH 1 OH F K, K.-.” ﬁ/\\\\ﬁ<\C6H5 d/ r 6.08 17A 178 (Note: No stereochemistry is implied in these structures.) The diol IZA'was further degraded by using sodium meta- periodate. The cleavage products expected from 11% and 112 are indicated in Scheme II given below: The nmr spectrum of the cleavage product (Figure 6) showed a broad singlet at T 5.63 for the tertiary hydrogen which previously was at the bridgehead position in the diol. In structure 18B.the proton signal would be expected to be 34 shifted farther downfield, shifts of similar compounds recorded in Table I. from comparisons with the chemical Thus, from nmr evidence, 18A is the favored structure for the cleavage product, 17A for the diol and consequently 16A for the Diels—Alder adduct. H OH CH3 OH /*<:\ NaIO 0 4 - / N . \\C H H 6 5 17A H OH CH3 OH NaIO4 ) ' C6H5 N/ ' H 178 Scheme II CH3 CH0 \\ O _/’ //-N\ \\ C6H5 CHa-C H 0 18A CH3 CHO /C6H5 O CHa-C H O 183 The Diels-Alder adduct from 2,3,4,6,6-Pentamethyl-2,4—cyclo~ hexadienone (12) and Nitrosobenzene Oxidation of pentamethylbenzene with trifluoroperacetic acid yields a mixture of pentamethyldienones (12 to 2}) in the yields indicated:23 35 CP3COOH BF3-Et20 > + + 12, (37%) 2,9, (33%) ,2}, (7%) The individual dienones can be isolated in a pure state by a preliminary column chromatography followed by preparative scale vapor phase chromatography. Sufficient amounts of dienones 12 and glzwere prepared by this method for the Dials-Alder reaction with nitrosobenzene. The 2,3,4,6,6-pentamethyldienone (12) formed an adduct, mp 99-1000, in 38% yield on refluxing a Solution of the dienone and nitrosobenzene in methylene chloride. The nmr spectrum (Figure 7) had signals at T 8.87, 8.55 and 8.50 (all singlets, 3H each), 8.52 and 8.33 (quartets, g_= 1.2 Hz, allylic methyls), 5.98 (broad singlet, 1H, bridgehead proton), and T 2.95-3.1 (multiplet, 5H, aromatic protons). Considering the chemical shift of the bridgehead proton signal at T 5.98, application of the Kresze's correlations indicates that structure 22A is favored over structure 22B. 36 O O / ’J<:\O L:\N/CezH5 N/ O/ H \C6H5 H T 5.98 T 5.98 22A 22E This conclusion is mainly based on the similarity to the chemical shift of the bridgehead proton in adduct 5Q, obtained from tetramethyldienone l, reproduced below. 0- J< r 5 .63 /o H \C6H5 T 5.92 2,13; Labeling lg'at C-3 with CD3 by deuterium exchange, and forma- tion of adduct indicated exclusive formation of one crystal- line isomer, the nmr spectrum of which did not have the low- field allylic methyl at T 8.33. This result is similar to that for adduct géifrom the tetramethyldienone l; The ad— duct ggébwas reduced with lithium aluminum hydride in ether solution at 0° to the corresponding alcohol (gggjin almost quantitative yield. There was no evidence of dissociation 37 when 22g was dissolved in ether, in sharp contrast with 55; RecryStallization of the reduced product from pentane gave a solid, mp 113-1140 whose nmr spectrum (Figure 8) indicated it to be pure 22g; It had signals at 1 9.03 (singlet, 3H), 8.73 (singlet, 3H), 8.60 (quartet, g.= 1.2 Hz, 3H), 8.55 (singlet, 3H), 8.32 (quartet, g_= 1.2 Hz, 3H), 7.88 (broad, 1H), 7.05 (broad, 1H), 6.43 (singlet, 1H) and 2.73-3.23 (multiplet, 5H). The chemical shift of the bridgehead proton signal at T 6.43 is very similar to that in gé'repro— duced below: 0' 0 0 CD K __> > /9 CD3 H 2221:\C6H5 H H CD J< J / and/or / N \\C6H5 O g5 26A 2613 Labeling the starting dienone gé'with deuterium at the C-3 methyl group21 and conversion of the labeled dienone to the adduct showed that the T 8.57 quartet was absent in the nmr spectrum of the product. Labeling at both the 3- and 5- positions of the starting dienone21 showed that both the 40 T 8.57 and the 8.60 signals disappeared. This enables assignment of these two signals as follows in both 26A and 26B. 0 o O T 8.57 ' T 8.57 CD3 CD ,J<:\ \‘ /l<:\ 3 C6H5 > /O and/or 7/ CD3 CD3 1' 8.04 (3133 kcsHs T 8 04 CD3 T 8.60 T 8.60 25 26A 2613 It is significant here that labeling at C—3 of the dienone removes the high-field allylic methyl signal at T 8.57 from the nmr spectrum of the adduct. (Similar labeling of tetramethyldienone A'at C—3 and conversion to the nitrosobenzene adduct resulted in removal of the low- field allylic methyl signal, at T 7.98.) One of the methods used to degrade simple six-membered ring 3,6-dihydro-1,2-oxazines is catalytic hydrogenation.4 The reaction path is shown below: 0 ____>H2 O __,H2 OH I I Pt HR N\\ \\ R R It is thus possible to cleave the N-O bond and obtain an open-chain amino alcohol. 41 The adduct from the hexamethyldienone Zé'was catalytically hydrogenated in glacial acetic acid solution using a platinum oxide catalyst at room temperature and atmospheric pressure. The result was rather unexpected in that 4-5 moles of hydro— gen were absorbed under these conditions. The hydrogenated product was isolated and examined for its nmr spectrum, when surprisingly, no signals corresponding to aromatic protons were detected. There was some loss of material during work up which corresponded to the loss of aniline during removal of last traces of solvent under reduced pressure. The ir 1 and spectrum of the product had a strong band at 1700 cm- weak bands at 3500 and 1660 cm-1. These results can be ex- plained as arising partly from the initial dissociation of the adduct into the components (dienone gg'and nitrosoben- zene) followed by rapid uptake of hydrogen by these to form saturated materials, and partly by the cleavage of the N-O bond fallowed by the loss of water and aniline from the product. Considering 26A as a possible structure of the adduct, this scheme is given below: O O O ' H0 KO .2_H£_> —H9.O _ -C6H5NH2 ’ \\ H NH-C6H5 ‘\C6H5 H 26A 25, 1 H 1 H2 2 25 + C6H5NO > Hydrogenated derivatives 42 A similar reaction is also possible with structure 2&3, giving rise to the same products. Further hydrogenation experiments by using different catalyst (Pd/C) and solvent (ethyl alcohol) did not ap— preciably change the results. A homogeneous product useful for characterization was not obtained. In one case, by careful column chromatography of the hydrogenated product, one fraction characterized as aniline was actually isolated, along with fractions which did not contain nitrogen. The ease with which the elements of water and aniline are eliminated from the resulting amino alcohol after cleavage of the N—O bond is not surprising, as the O-H and the -NH-C6H5 are both attached to tertiary carbon centers. Thus, catalytic hydrogenation was found to be rather unsuitable for degradation of this adduct. The next degradative experiment attempted for the di- enone-adduct was reduction with zinc and acetic acid. This reaction has been used in simple cases with good results as shown in the following examples:4°'41 NH I 50 HO 1 . KMHO4 2.h drol E's Y Y ﬁO R / N zn' > / HOAC I, \ O OH 43 R / HOAC AC 0 . R ____mmo4> AcO N< P M212.) AcO /}—NR-Ac Ac I CHO CHO 1»; When the hexamethyldienone adduct was subjected to zinc acetic acid reduction, the product consisted of a complex mixture. The ir spectrum had strong bands at 1700, 1620, and medium bands at 3400 and 3500 cm-1. These data indi- cate that reduction to amino alcohol might have proceeded to some extent. However, the nmr spectrum was quite com- plex. A preliminary thin layer chromatography indicated the presence of at least four components. Chromatographic separation on a packed column gave fractions containing no aromatic protons, as in the case of catalytic hydrogenation. Here again, elimination of aniline seems to occur. Also, partial dissociation into components might readily proceed under the conditions of the experiment, which required main- taining a temperature of 40-500 for 4 hr. Attempts were then made to effect the reduction by metal hydrides at low temperatures. A report claims that lithium aluminum hydride is useful in cleaving the N-O bond.“2 However, when the dienone-adduct was reduced with 44 this reagent at 00 in ether solution, a simple reduction of the carbonyl group to the hydroxyl function was the only change observed. The product had a strong band at 3500 cm"1 and no carbonyl band in the ir spectrum (Figure 25 ) . The nmr spectrum had signals at T 9.17 (multiplet), 8.92, 8.77, 8.67, 8.58, 8.10 (multiplet) all integrating for 3H each, due to the six methyl groups, and in addition signals at T 8.30 (1H), 7.05 ( broad, 1H) and 2.85-3.10 (5H). The nmr spectrum indicated that the product was mainly a single component, gig, the [2.2.2] alcohol resulting from reduc- tion of the carbonyl group in the dienone—adduct, although the presence of epimers is not ruled out. No loss of the aromatic fragment was observed. Reduction with lithium aluminum hydride in tetrahydrofuran followed by refluxing for 4 hr did not produce any appreciable change in the nature of the products, as judged from the ir and nmr Spectra. To test whether any product resulting from cleavage of the N-O bond was formed even in small amounts, the reaction product was treated with sodium metaperiodate, which would instantly react with any a—glycol such as gz'(derived from Eggjto give keto aldehyde gg'or perhaps more sluggishly34 with the a- amino alcohol g§'(derived from §§§)to give keto aldehyde 32’ and aniline according to the following scheme: 45 O H OH . HO zl<::7) L1A1H4 > NaIO4> N ‘\C6H5 -C6H5 NH'CsHs 26A 27 O _ H OH K C6H5NH \/o CHO H N/CLBiAslH 331434.. + c H NH / .______L_> > 6 5 2 \. "O OH OH 2 B 28 30 W w ,w The ir spectrum of the product showed no carbonyl bands, and was identical to that of the starting material, indi— cating lack of any reaction. This would support one of two conclusions: (1) that the N-O bond did not cleave under these conditions and thus products that could react with periodate were not formed, or (2) that if any product was indeed formed, it could not be gz'but might be 28 which being an a-amino alcohol, is much less reactive toward periodate than an a-glycol. The adduct was found to be inert to both ozonolysis and epoxidation reactions at the double bond, possibly due to steric hindrance to the approach of the reagents. Since the alcohol obtained by reduction of the adduct was found to be more stable thermally than the dienone—adduct 46 itself, attempts were made to reduce this material further with zinc and acetic acid. The ir spectrum of the product from this reaction showed only a medium intensity band in the hydroxyl region at 3400 cm-1, but had in addition a medium intensity band at 1720 cm-1 indicating the presence of a carbonyl group. Thus one of the hydroxyl groups in the expected diol (gz'or 28) or the amino group might have been acetylated under these conditions. The nmr spectrum had a strong signal at T 7.80 confirming the presence of an acetoxy function, but was again complex indicating that the product contained more than one component. However, no loss of the aromatic protons was noticed. Oxidation of the product with sodium metaperiodate resulted in recovered starting material, thus showing absence of any oxidizable material. Attempts to separate this mixture by means of column chromatography did not give any pure material; more- over, loss of the aromatic fragment was indicated by nmr. Reduction of the entire mixture containing the acetates with lithium aluminum hydride was then tried with the aim of getting the expected diol gz'or 28, These attempts were also unsuccessful as no identifiable homogeneous product which would react with sodium metaperiodate to give a car- bonyl compound was obtained. From the degradative experiments so far described, it has not been possible to isolate any single identifiable product that may serve in deciding unambiguously between the two possible structures 2&A,and 262; However, the fol— lowing features have to be emphasized: 47 (1) The failure to react with periodate as readily as in the case of the a-glycol 8'from the tetramethyldienol- adduct 83 points to the possibility that a similar glycol was not formed and that the adduct from 88'may have the opposite orientation as in 882, (2) Examination of models reveals more steric crowding in the transition state for orientation 88A'than for 882; (3) The result of labeling the dienone 88 at C-3 is the same as for dienone 21;.XlE-I the high-field allylic methyl signal in the nmr spectrum of the adduct is removed. This is in contrast to the results from adducts 8g and 888” which have been assigned the opposite orientation.’ A posSible correlation of the chemical shift of the allylic methyl group with the orientation of the adduct is proposed on page 66 in the Discussion Section. From a consideration of these factors structure 882' is favored over 26A for the adduct. The Diels-Alder Adduct of Eucarvone (88) and Nitrosobenzene Eucarvone (88), being a seven-membered ring dienone, would be expected to give an adduct having a [3.2.2] bridged bi— cyclic structure which might be less strained and hence more stable than the [2.2.2] systems obtained from cyclohexadi— enones. Thus, a study of the Diels-Alder reaction of this dienone permitted a comparison of the stabilities of this adduct with those obtained from the cyclohexadienones. 48 Eucarvone 88’was readily prepared by hydrobromination followed by dehydrobromination of carvone (88), a commercially available natural product, according to the following sequence.“3 F. Br .T Br T o 2 H yo 0 HBr ACOH a > //JE<. / i g; 1, J i. .4 Br | /O -2HBr / > -———> Br 32 Eucarvone 88'reacted readily with nitrosobenzene at room temperature to give an adduct, mp 56-570, in 77% yield. Depending upon the orientation of addition, the adduct can be represented by one of the two possible structures 33A or 333. 49 O O O C _ 5H5 N=o > or / C6H5 / o N/ / - / O/ N-\ H C6H5 H T 6.02 {.3 33A 338 The nmr spectrum (Figure 11) of the adduct showed signals at T 8.93, 8.55 and 8.38 (singlets, 3H each) for the three methyl groups, 7.74 and 6.59 (doublets, 1 H each, g”: 22 Hz, Methylene protons), 6.02 (doublet, 1H,‘g_= 10 Hz, bridgehead proton), 3.72-3.95 (mulitplet, 2H, olefinic pro- tons), and 2.60-3.08 (multiplet, 5H, aromatic protons). When the Kresze correlation is applied to this [3.2.2] system, the bridgehead proton appears to be adjacent tola nitrogen, thus favoring structure 88A>rather than 888, This conclusion is substantiated by the isolation and characterization of an open—chain cleavage product from the bicyclic adduct as described below. Lithium aluminum hydride reduction of the adduct in ether at 00 yielded a 1:1 mixture of alcohols (epimeric), one of which crystallized as a light, white, fibrous solid, mp 159-1600, leaving the other isomer as a viscous liquid. The nmr spectrum (Figure 12) had signals at T 8.95 (singlet, 3H), 8.72 (singlet, 3H), 8.40 (singlet, 3H), 6.33 (broad, 1H, 50 hydroxyl proton), 6.11 (broad, multiplet, 1H, bridgehead proton), 3.85-4.17 (multiplet, 2H, olefinic protonsL and 2.80—3.18 (multiplet, aromatic protons). The two —CH2- protons and the CHfOH proton were not well-resolved and had signals in the region T 8.27-8.75. The appearance of the bridgehead proton signal at T 6.11 supports structure 82' for this alcohol. Alcohol 82 was further cleaved to a monocyclic seven- membered ring system by reduction with zinc and acetic acid to give quantitative yield of a crystalline amino diol 88'mp 118-119°. Similar reduction of the liquid iso— mer gave a different amino diol, mp 95~96°. These two compounds were distinctly different as shown by their mp, ir, and nmr spectra, and probably constitute the gig- and utgagg- diols. Oxidation of either of these two compounds with sodium metaperiodate in the usual manner gave the same cleavage product, characterized as 88, still containing the arylamine function. epimers here H r‘L‘ﬁ H OH Me OH )~=o CHO H > > / /° \ N\C H 6 5 ._ H NH C3H5 H NH-C6H5 34 35 36 51 Structure 888, on the other hand, would also give rise to a keto aldehyde, but having an additional hydroxyl func- tion, as in 88’yig_diol 81, Furthermore, aniline would be released as a separate fragment which would be lost during the work-up. C6H5-HN / 7‘1““ \ OH 338 37 38 Absence of O-H absorption in the ir spectrum of the product as well as the presence of aromatic protons in the nmr spectrum point to structure 8g'and not structure 88 for the product. The ir spectrum (Figure 31), in addition, showed two strong carbonyl bands at 1687 (a,B-unsaturated ketone) and 1715 cm.1 (aldehyde). The nmr spectrum (Figure 13) of the product was complex and could not be analyzed with accuracy. Repeated column chromatography failed to give a pure product. The cleavage product thus appears to be unstable and may have undergone secondary reactions. The amino function in 88'could react with either of the carbonyl functions to give a complex mixture of products. 52 Eucarvone was reduced to eucarveol 88'with lithium aluminum hydride, and the dienol thus obtained was allowed to react with nitrosobenzene. The addition proceeded quite well, although not as spectacularly fast as in the case of the tetramethyldienol Z, and the product consisted of a mixture of epimeric alcohols from which 17% yield of a solid alcohol-adduct mp 159-1600 could be obtained. This was found to be identical (mp, ir and nmr spectra) with the solid alcohol 82'obtained by lithium aluminum hydride reduction of the eucarvone-adduct 88A, Assuming that 82' is the major product of reaction, the orientation of addi- tion of nitrosobenzene to eucarvone and eucarveol is the same, as was found in the case of the six-membered ring dienone l'and the corresponding dienol Z, However, the differenCe between the two ring systems is manifested in the enhanced thermal stability of the [3.2.2] system derived from eucarvone as compared to the facile thermal reversibil- ity of the [2.2.2] system from the cyclohexadienone. The dienol—adducts in both cases, on the other hand, were found to be stable. Preliminaryggrradiation Studies‘ One of the objectives of the present study was to in— vestigate the photoisomerization of the various Diels-Alder adducts prepared in this work. The dissociation of some of the dienone-adducts in solution was a serious problem in the analysis of the products. As a typical example, 53 irradiation of the adduct 263 from hexamethyldienone 88 in ether solution in Pyrex with a 450 watt Hanovia lamp gave the bicyclic ketone 28, a product derived from photochemical transformation of the dienone 25.21 m 40 "W The two dienone-adducts which were fairly stable in solution at room temperature were 22A from pentamethyldi— enone 18, and 33A from eucarvone 88,’ O O / /° N \CSHS N\C6H5 22,22, 91s The adduct 888'showed Agzgﬁ 308 nm (e = 6489), 282 nm (e = 6561), 249 nm (e = 7987) and 208 nm (e = 10,700). The first attempts were directed towards selective excitation of the n -¢ 7* band in the molecule. When irradiated in 1% ether solution through Pyrex with a Hanovia type L mercury 54 lamp for two hours, the solution turned dark and a gummy residue was deposited on the walls of the vessel. The progress of the reaction was followed by uv and the results shown in Figure 33. The nmr spectrum of the product showed only slight change. When separation was attempted by vpc, only pure l8'(resulting from thermal dissociation of the adduct) was collected. Hence it is evident that the photo- reaction is extremely slow and accompanied by much tar formation. The above irradiation was repeated using acetone as the solvent. The progress was followed by uv and the re— sults shown in Figure 34. The photolysis appeared to be complete in 12 hr. The nmr spectrum of the product indi- cated that it was a mixture. Attempts to separate the product by chromatography were unsuccessful. The adduct 88A'from eucarvone 88'had xgng 285 nm (e = 162), 244 nm (e = 7558), and 208 nm (e = 10,400). Irradiation of a 1% solution in ether with a 450 watt Hanovia type L mercury lamp through vycor was attempted to see whether any reaction due to the excitation of the carbonyl function selectively could be detected. Slow reaction was observed in 8 hr and the progress was followed by uv (Figure 35). The nmr spectrum of the product appeared to be much less complex than in the previous cases; however, the product was still a mixture, and contained much start- ing material. In one experiment, the photolysis was 55 continued for 22 hr. The ir and nmr spectra of the product were quite similar to those of the starting material, and showed that there was no appreciable reaction after this long period. The lack of reaction in the [3.2.2]-nonenones comparable to that in the [2.2.2]-octenones may be ex— plained as due to the decreased electronic interaction between the orbitals of the carbonyl group and the B,y- double bond in this system. Attempts were then made to excite the N-O bond selec— tively in these adducts by irradiation in the Rayonet chamber with light of wavelength 2537 2.20 The adduct 888' from eucarvone 88'was irradiated in ether solution at this wavelength in a quartz test tube. The progress of the reaction was followed by uv and is shown in Figure 36. After 5 hr, separation of product was attempted by vpc, when only pure eucarvone was collected. Column chroma— tography failed to give any pure product. Attention was then turned to the dienol—adducts 88' from tetramethyldienol Z'and 88'from eucarveol 88, 88> showed (”3233 206 nm (e = 9063 ), 250 nm (e = 6889) and 284 nm (e = 91 ). Irradiation of 88 in methanol solution H H 56 at 2537 X was followed by uv (Figure 37). The maximum at 245 nm shifted progressively to 238 nm and a new shoulder developed at 282 nm. The ir spectrum of the product showed strong absorption at 3500 cm"1 (O-H) and medium absorption between 1710 and 1660 cm-1. Column chromatography of the product gave one fraction, eluted with ether, and from ir and nmr spectra, appeared to be a single photo-product. The ir Spectrum (Figure 32) had strong absorption at 3450 cm.1 (O-H) and medium absorption at 1660 cm-1. The nmr spectrum (Figure 14) had signals at 7 9.07, 8.92, 8.65 and 8.48, all singlets for the four methyl groups, 8.05 (sing— let, 1H), 6.98 (triplet, g.= 10 Hz), 6.30-6.50 (broad, 2H) and 2.8-3.4 (5H). The absence of two quartets for the allylic methyls would indicate absence of double bond in the product. The mass spectrum had parent peak at m/e 269 M+ C15H2102N, isomeric with starting material.. Further characterization was not possible due to paucity of material. Irradiation of adduct 88'from eucarveol 88'under simi- lar conditions was followed by uv as shown in Figure 38. Repeated attempts to isolate any pure photo-product by column chromatography were unsuccessful. DISCUSSION The present study has shown that cyclohexadienones readily react with nitrosobenzene to give Diels-Alder ad- ducts. The conditions required for the reaction vary de- pending on the nature and position of the substituents on the diene component. As expected, the carbonyl group retards the reaction; simple dienes carrying no electron- withdrawing substituents give good yields of adducts within a few hours at room temperature.4 The dienones examined in the present study were less reactive than such dienes, since most of them required heating the components in a solvent. The tetramethyldienone A'appeared to be most re— active, and formed an adduct at room temperature after 4 hr. The least reactive of the dienoneswas the hexamethyldienone o 0 0 ,1. 2,9 12, 0 o \ / 93 9,2. 57 58 88; it required refluxing the components in 1,2-dichloro- ethane (bp 92°). The pentamethyldienones 18 and gi’only required a lower-boiling solvent such as methylene chloride (bp 40°). The seven-membered ring dienone, eucarvone 88' showed comparable reactivity to the six—membered ring di— enones. Reduction of the carbonyl group to the CH-OH group produced a dramatic activating effect for dienol Z, This effect was less pronounced for eucarveol 39, however. H S OH H OH 2, 22. 'The stability of the adducts varies widely. In the solid state, the adducts can be sublimed under reduced pressure without decomposition, though adduct 16A from the acetoxydienone 88'was unstable at room temperature. The O COCH ‘/,/ ”L<;\ 0 3 O .— 59 most stable of all the adducts were those derived from eucarvone and eucarveol, possibly because these adducts with a three—carbon bridge are relatively less strained than the [2.2.2] systems from the cyclohexadienones. The behavior of the adducts in solution also varied. Adducts~88'(from tetramethyldienone 1) and 188 (from acet— oxydienone 88) partially dissociated when dissolved in most solvents. The adduct 26B from the hexamethyldienone 0 ° 0 o cnsco . ,csHs / /O / /O / /N 5A 16A 26B 88'showed similar behavior, though to a lesser extent. In contrast, adducts 888'from the pentamethyldienone 18, and 888'from 88'did not show any sign (green color of nitroso— .benzene) of dissociation in solution. This behavior is rather surprising and difficult to explain. The adduct 33A 22A 24B 33A 60 from eucarvone also shows no sign of dissociation in solution. The dienol-adducts 88, 118, 888'and 88'as well as the alcohol derived from the adduct (888) all behaved similarly and were stable in solution. A possible explana- tion for this difference is that a [2.2.2] system carrying an sp2 hybridized carbon of the carbonyl group may be more strained than a similar system with an sp3 carbon (CH-OH group). Two noteworthy features in the Diels—Alder reaction of nitrosobenzene with dienones are'the high specificity in orientation of the nitroso component with respect to the carbonyl group and the marked dependence of this orientation on the nature and position of substituents on the dienone. The results so far described have led to the following con— clusions with respect to orientation in the various Diels- Alder adducts: Orientation A (with the O-atom of the nitroso group bonded to C-2, the carbon carrying the electron—withdrawing substituent and the N-atom bonded to C-5 of the diene) has been observed with the dienes 1, Z, 18, 18, 88’and 88, 2H 0" 1D 61 .; L; H OH H OH J<‘ . o N H \‘CGHS ’7' 98 o OCOCH3 —'> £2 16A 0 o 62 2.9 34 Orientation B (with the N-atom of the nitroso group bonded to C-2 and the O-atom bonded to C-5 of the diene) has been observed with the dienes 81'and 88. 63 O -——> 22 9.9.3. For the tetramethyldienone 1, the orientation is according to expectation. The results with dienes such as the simple sorbinol derivatives studied by Kresze4 show that the O— atom of the N=O group attaches itself to the carbon carrying the electron-withdrawing group, in this case the carbonyl group. The formation of an adduct having the same orienta- tion from the tetramethyldienol Z'cannot be attributed solely to the inductive effect of the fCH-OH substituent, as it is much less electron-withdrawing than the C=O group. The same argument may be applicable for acetoxy-dienone 18' and eucarvone 88, The detection of intramolecular hydrogen bonding (as shown in 88) in the ir spectrum of this adduct indicates that the energy for transition state for the par— ticular orientation may thereby be lowered and as a result this orientation is favored. 64 The orientation in the case of the pentamethyldienones 18'and 81’and the hexamethyldienone 88'is probably controlled exclusively by the steric requirements of the ggm:dimethyl groups at C-6 and the methyl groups at C-2 and C-5 of the dienones, and the aromatic ring of the nitrosobenzene. In 18'and 81'opposite orientations are obtained because in the transition state the aromatic ring of the nitrosobenzene takes up the space where the methyl group is absent. In the hexamethyldienone 88, more drastic conditions are required to bring the components together, and the aromatic ring can only orient in the gap of the only small group in the molecule of the diene 315., the carbonyl group. In this connection, it may be worthwhile to compare the results of the Diels-Alder reaction of the hexamethyldienone 88'with the unsymmetrical dienophile, vinyl acetate. It was found26 that the product with vinyl acetate consisted of a mixture of both isomers, with 8' predominating in the ratio 4:1. 65 ‘1 + U ’// ‘OCOCH3 2.9 O + ’ / ococn3 h ,9 Major Minor It was mentioned in the Introduction (p. 7) that if the two dienophiles are arranged according to their polarity, the following parallel is obtained: 0+ 0— Ar—N = 0 0+ 0- CH2 =CH'OAC According to this scheme, if polar factors influenced the orientation of addition of the dienophiles in both cases, the following isomers would be expected from 88'for each orientation. 66 Orientation A > ,J<:\ and / OAC . / f / H :v z» Orientation B > OAc 2 B 8, W The result from the vinyl acetate addition is in agreement with the expectation, if it is assumed that polar factors influence the orientation. The acetate group is a much smaller group than the aromatic ring and hence the steric influence on the orientation would be much less than that for nitrosobenzene. If polar factors also influenced the orientation in the case of nitrosobenzene, the major expected product would be 888, The fact that 888'is the favored structure for the adduct actually isolated, supports the conclusion that polar factors are superceded by steric factors in this case. The results of the labeling experiments with the dienone- adducts reveal an interesting feature.. Labeling the starting dienone, §;g;_1'at C-3 with CD3 removes one of the two allylic methyl signals, in this case, the low-field one of 67 the adduct. In adducts having orientation A, this means that the nmr signal of the allylic methyl group opposite to the N-atom appears at higher field compared to the other, which is opposite the O-atom. Typical chemical shift 7 values are given below: OH K / /0 ﬁg” N 8.52 H \CeHs 8 .60 / \CsHs 22.8 29.8. This difference can be attributed to a shielding ef- fect, which is clearly discernable when a model of the adduct is examined. Here, the assumption is made that the aromatic ring is gg§g_to the boat—shaped 3,6—dihydro-1,2- oxazine ring of the bicyclic system, since in this arrange— ment, there is least steric interactions with the ggmfdi— methyl group on the adjacent carbon bridge. This favored 68 conformation is shown below in the diagram. 4P0 The allylic methyl giving the high-field signal is found to be in the region where the diamagnetic anisotropy of the benzene ring produces a shielding effect. If this explanation is valid, it is possible to determine the orientation of addition in such systems by this simple labeling experiment. In the hexamethyldienone—adduct (ten- tatively assigned structure 888), labeling removes the. high-field allylic methyl signal, in contrast to adducts having orientation A. If the above explanation is the real cause for the difference in chemical shifts, then the ori- entation in this adduct is opposite to that in 88, 88, 888} and 888, The chemical shift values of the allylic methyl groups in the Dials—Alder adducts prepared in this work have been discussed so far. It may now be relevant to compare these 69 results with similar values of various other Diels-Alder adducts prepared in this laboratory during the past few years. Representative examples of such adducts, their structures, the assigned chemical shift values of the allylic methyl groups, and the relevant references in parentheses are given below: 0 // 8.24 ‘/J<:\ COOMe / N/ / 8 ~07 N\ COOMe 8.32 8.23 (ref. 21) (ref. 44) The methyl group adjacent to the carbonyl group is at higher field as revealed by labeling. This indicates that the carbonyl group has a small shielding effect on the methyl group through its diamagnetic anisotropy. (Alterna— tively, the allylic methyl remote from the carbonyl function may be deshielded due to a homoconjugative interaction be— tween the carbon—carbon double bond and the carbonyl group.) The incorporation of a second carbonyl group on the remaining bridge of the [2.2.2]—octenones has an effect depending upon its position as indicated in the following two structures: the effect is additive when the two carbonyls are adjacent to each other and to the methyl group as in the first example. 70 In the second case, both allylic methyls are shielded by a carbonyl group and hence the chemical shift values are 8.38 8.27 8.18 (ref 26) shifted upfield to the same extent. When the carbonyl group in the [2.2.2]-adducts is reduced to the CH-OH group, this shielding effect is no longer present as shown in the following examples. H. OH 8.32{ / (Em) H (anti) (ref 24) OH (ref 24) 8.28{ /l\/ C6H5 (ref 24) 71 Thus it is evident that the carbonyl group in the Dials—Alder adducts from nitrosobenzene must also have a shielding effect on the allylic methyl group near to it and this effect should be absent for the corresponding alcohols. In the adducts prepared in this work, the chemi- cal shift value difference is much more (about 0.2 to 0.4 ppm) than in the case of the examples cited above and the explanation for this must lie in the anisotropy due to the aromatic ring on the nitrogen atom. As expected, this dif- ference is more pronounced for the alcohols than for the ketones as illustrated in the following two structures: 8 .33 K 8 .33 22A 23 From the synthetic point, the Diels-Alder reaction of nitrosobenzene with dienones and their derivatives provides access to novel heterocyclic bridged systems. Formation of pyrrole 18'in almost quantitative yield from 88'also offers synthetic utility. Further synthetic potential has not been explored in the present study. EXPERIMENTAL 1. General Procedures The nmr spectra were recorded with a Varian Model A-60 using CDC13 solutions (unless otherwise stated) with tetra- methylsilane as an internal standard. The ir spectra were obtained with a Unicam Model SP-200 Infrared Spectrophotometer, and the spectra were calibrated (polystyrene). The uv spectra were measured with a Unicam Model SP-800 Ultraviolet Spectro- photometer. The mass spectra were obtained by Mrs. Lorraine Guile with a Hitachi-Perkin Elmer RMU-G Mass Spectrometer. Elemental analyses were carried out by Spang Microanalytical Laboratory, Ann Arbor, Michigan or Clark Microanalytical Laboratory, Urbana, Illinois. Melting points were determined with a Gallenkamp Melting Point Apparatus and are uncorrected. 2. The Diels-Alder Adduct (88) from 3,4,6,6-Tetramethyl- 2,4-gyclohexadienone (1) and Nitrosobenzene The dienone 1?2 (1.5 g, 0.01 mol), nitrosobenzene a.07 g, 0.01 mol, Aldrich Chemical Co.) and methylene chloride (20 ml) were stirred together at room temperature until the green color of the solution had disappeared (about 4 hr). The solvent was evaporated at room temperature using a rotary evaporator and the last traces of solvent were 72 73 removed in vacuo. There was obtained a dark, viscous oil which was redissolved in the minimum amount of pentane: warming the mixture to effect dissolution was avoided to minimize the facile thermal dissociation of this adduct into its components. The solution was cooled in the refrig- erator overnight, which resulted in deposition of crystals of the adduct. These were removed by decantation: yield 1.35 g (51%). Recrystallization from pentane yielded light yellow crystals of the adduct, mp 62-63°. The ir spectrum (Figure 15, Nujol) indicated absorption at 1720 ( :c=0), 1600 (w), 1595 (m), 1220 (m), 1020 (w), 903 (m), 770 (s) and 700 cm_1 (s). The nmr spectrum (Figure 1, CCl4 solu— tion) had signals at 1 8.92 (singlet, 3H), 8.60 (singlet, 3H), 8.53 (quartet, 3H), 8.15 (quartet, g_= 1.2 Hz, 3H), 5.92 (singlet, 1H), 5.63 (singlet, 1H), and 2.7-3.2 (multi- plet, SH). 8821. Calcd. for C13H19N02: C, 74.68; H, 7.44; N, 5.44 Found: C, 74.59; H, 7.56; N, 5.44. 3. The Diels-Alder Adduct from 4,6,6-Trimethyl-3-methyl-dq- 2,4-cyclohexadienone-2d (g) Dienone 1'(1 g, 0.007 mol) in methanol-d (50 ml) containing sodium methoxide (1.25 g) was heated under reflux in an atmosphere of nitrogen for 24 hr. The methanol was evaporated under reduced pressure and the residue was extracted with hot benzene. The benzene extract was washed with water and dried. Removal of solvent yielded a yellow oil (0.85 g, 74 85% yield). Inspection of the nmr spectrum of the product indicated that the signals at T 4.32 (vinylic proton at C-2) and T 7.98 (C-3 methyl) were absent in the labeled product. The nmr spectrum of the Diels-Alder adduct from this labeled dienone 8'and nitrosobenzene lacked the signals at T 5.63 (bridgehead proton adjacent to oxygen) and T 8.15 (low-field allylic methyl at C—7 in 88). 4. The Diels-Alder Adduct (88j_from 2,3,6,6-Tetramethyl— 2,4—cyclohexadienol (Z) and Nitrosobenzene Tetramethyldienone 1'(1.5 g, 0.01 mol) dissolved in 80 ml of anhydrous ether was added gradually to a mechani— cally stirred slurry of lithium aluminum hydride (0.2 g, 0.005 mol, excess) in 40 ml of anhydrous ether at 0°. The reaction mixture was stirred at 0° for an additional 2 hr. Excess hydride was destroyed by addition of moist ether. Filtration of the white precipitate followed by evaporation of the clear filtrate at reduced pressure and room tempera- ture gave a quantitative yield of a light yellow syrupy liquid. The ir spectrum of the product (neat) indicated complete absence of absorption in the carbonyl region and presence of a strong band in the O-H region at 3400 cm-1. The dienol was found to be unstable at room temperature,22 but could be handled without decomposition for a few hours if kept in the refrigerator. In the present case, the dienol was reacted with nitrosobenzene immediately after 75 isolation. Thus, the above product (1.50 g, 0.01 mol) was dissolved in ice-cold methylene chloride (20 ml), and nitroso- benzene (1.05 g, 0.01 mol) was added. The mixture was stirred magnetically until all the nitrosobenzene dissolved to give a green solution. This solution was then kept in the refrigerator. The green color disappeared in 2 hr. The solvent was then evaporated at reduced pressure and the residue was dissolved in pentane. Cooling the pentane solution gave light yellow crystals of the adduct (yield 2.1 g, 78%), mp 98-990. Further purification was achieved by sublimation at 0.1 mm and 90-1000. The ir spectrum (Figure 16, Nujol) had principal bands at 3330 (O-H), 1597 (m), 1130 (m), 1065 (s), 964 (w), 833 (s), 765 (s), 730 1 (s). The nmr spectrum (Figure 2, (doublet, s) and 700 cm" CDC13 solution) showed signals at T 9.03 (singlet, 3H), 8.72 (singlet, 3H), 8.62 (quartet, g_= 1.2 Hz, 3H), 8.22 (quartet, g_- 1.2 Hz, 3H), 7.50 (broad, 1H, disappears when sample is shaken with D20), 6.85 (broad, 1H), 6.47 (singlet, 1H), 5.77 (doublet, g.= 1.6 Hz) and 2.67—3.28 (multiplet, 5H). Reduction of 4,6,6—trimethy1-3-methyl-d3-2,4-cyclo- hexadienone-2d (8) with lithium aluminum hydride and con- version of the resulting labeled dienol to the Diels-Alder adduct and inspection of its nmr spectrum showed that the 7 5.77 doublet and the T 8.22 quartet disappeared and the T 8.62 signal became a singlet. Found: C, 74.04; H, 8.13; N, 5.34. 76 5. Reduction of the Adduct (88) with Zinc and Acetic Acid: Biol (8) The adduct (1.3 g, 0.005 mol) was dissolved in glacial acetic acid (15 ml) in a 100 ml three-necked flask equipped with a mechanical stirrer. To this stirred solution, zinc powder (5 g) was added and stirring was continued for 6 hr. with the reaction flask immersed in an oil bath at 50°. The reaction mixture was then cooled, diluted with ether and the residual zinc was removed by filtration. The solvent and most of the acetic acid was removed under reduced pres- sure. Water (25 ml) was added to the residue and the re- maining acetic acid was neutralized with concentrated am- monium hydroxide. The neutralized mixture was then extracted with ether, the ether extract was washed with water, and dried (M9504). Evaporation of solvent yielded a brown oil (1.26 g). The ir spectrum (neat) of this product showed an intense band between 3450 and 3550 cm-1 (O—H). The nmr spectrum of the crude product (CDC13 solution) had signals at 1 9.10, 8.93, 8.68, 8.28 (each 3H), 5.70-6.78 (broad, 5H), and 2.83-3.47 (5H, aromatic protons). The product was not further purified, but was used directly in the next experiment. 6. Cleavage of the Biol (8) with Sodium Metaperiodate: gyrrole (14) The crude diol (8) obtained from the above reaction was oxidized with sodium metaperiodate without further 77 purification. The diol (1.25 g, 0.005 mol) was dissolved in absolute ethanol (20 ml) and to this stirred solution at room temperature was added a solution of sodium metaper- iodate (NaIO4, 1.1 g, 0.005 mol) in water (8 ml). Within 10 min, a white precipitate was deposited from the previously clear solution. Stirring was continued at room temperature for a further 30 min. The reaction mixture was then fil— tered and the clear filtrate was evaporated under reduced pressure, when a semi-solid residue contaminated by some inorganic material was obtained. This was diluted with water (5 ml) and extracted with ether. The ether extract was washed with water and dried. Removal of solvent yielded a dark, viscous oil (1.09 g, 87%). The ir spectrum (Figure 17, neat) of the crude product showed bands at 1715 (s, >c=0), 2720 (w, aldehyde), 1600 (m), 1500 (s), 1464 (m), 1402 (s), 1375 (s), 1220 (m), 1110 (m),920 (w), 788 (s), 755 (m), and 760 (s) cm-l. The nmr spectrum (Figure 3, CDC13 solution) showed signals at 7 8.80 (singlet, 6H), 8.00 (multiplet, 6H), 3.60 (multiplet, 1H), 2.68 (multiplet, 5H) and 0.62 (singlet, 1H). The mass spectrum had parent peak at m/e = 241 corresponding to M+, C13H19NO. The above product could be purified by vapor phase chromatography (10' x 1/4" SE-30 column at 220°, He flow rate of 85 ml/min) and had a retention time of 12 min. The pure material thus obtained was a solid, mp 59—600. Anal. Calcd. for C13H19NO: C, 79.63; H, 7.94; N, 5.80 Found: C, 79.44; H, 7.97; N, 5.75. 78 7. Reduction of the Adduct (88) with Lithium Aluminum Hydride The adduct (88) (0.257 g, 0.001 mol) was dissolved in ice—cold anhydrous ether (25 ml) and this solution was added rapidly to an ice-cold, mechanically stirred, slurry of 0.5 g (excess) of lithium aluminum hydride in dry ether (20 ml). Stirring was continued for 1/2 hr at 0°. Excess hydride was destroyed by the addition of moist ether and the white precipitate was removed by filtration through a sintered funnel. The filtrate was evaporated to give a yellowish brown oil (quantitative yield). The ir spectrum of this oil (neat) showed a strong band at 3500 cm"1 (O—H) and was identical to the spectrum of the adduct 88, This product was dissolved in a minimum volume of pentane and cooled; the crystals thus obtained were filtered (yield 0.211 g, 84%) mp 90-920.~ The nmr spectrum (CDC13 solution) had signals at T 9.04 (singlet, 3H), 8.73 (singlet, 3H), 8.62 (quartet, 8.: 1.2 Hz, 3H), 8.21 (quartet, g_= 1.2 Hz, 3H), 7.60 (broad, 1H), 6.83 (broad, 1H), 6.43 (singlet, 1H), 5.75 (broad, 1H), 2.70— 3.19 (multiplet, 5H). 8. The Diels—Alder Adduct (16A) from Dienone(18) and Nitrosobenzene The dienone 1538 w (4.16 g, 0.02 mol) and nitrosobenzene (2.14 g, 0.02 mol) were dissolved in methylene chloride 79 (20 ml) and the resulting green solution was stirred at room temperature until the green color completely disap- peared (9 hr). The solvent was removed under reduced pres— sure and the oily residue was redissolved in pentane (50 ml). On cooling the solution in the refrigerator overnight, yellow crystals of the adduct were deposited. These were removed by decantation (yield 3.60 g, 57%), mp 73-75°. The ir spec- trum (Figure 18, Nujol) had a broad band at 1720-1740 cm-1 0 (-O-C-CH3, >c=0) and bands at 1640 (w), 1590 (m), 1245 (s), 1115 (s), 1030 (s), 1003 (s), 980 (s), 850 (s), 780 (s), 765 (w), 706 cm“1 (s). The nmr spectrum (Figure 4, CDCl3 solu- tion) showed evidence for partial dissociation of the adduct into components; the adduct had signals at T 8.40 (singlet, 6H, methyls), 8.10 (quartet, g_= 1.2 Hz, 3H, allylic methyl), 7.87 (singlet, 3H, —O*CO-CH3), 4.5 (doublet, g.- 2 Hz, 1H, bridgehead proton), 4.20 (multiplet, 1H, vinylic proton) and 2.7-3.2 (multiplet, 5H, aromatic protons). Anal. Calcd.for C17H19NO4: C. 67.76; H. 6.36: N. 4.65 Found: C, 67.75; H. 6.39; N, 4.65. 9. Reduction of Adduct (16A) with Lithium Aluminum gydride: Diol (178) The adduct (16A) (0.5 9, 0.0017 mol) was dissolved in ice-cold dry ether (50 ml) and the resulting solution was added rapidly (2 min) to an ice-cold, stirred slurry of lithium aluminum hydride (0.35 g, excess) in 50 ml of dry 80 ether. The reaction mixture was stirred at 00 for 2 hr. The excess hydride was decomposed by cautious addition of water (5 ml) and the resulting white precipitate was re- moved by filtration. The filtrate was dried and evaporated to yield a viscous oil (yield 0.325 g).. The product was crystallized from pentane-ether mixture, mp 94-960. The ir spectrum (Figure 19, Nujol) indicated complete absence of carbonyl absorption and had an intense band at 3450 cm-1. The nmr spectrum (Figure 5. CDC13 solution) had signals at T 8.80 (singlet, 3H), 8.50 (doublet, g_= 1.4 Hz, 3H, allylic methyl), 8.45 (singlet, 3H), 7.08 (broad, 1H), 6.33 (broad, 1H), 6.08 (doublet, g_= 1.8 Hz, 1H), 5.73 (broad, 1H), 4.27 (broad, olefinic proton) and multiplet centered at 3.05 (5H). 10. Cleavage of Diol (17A) with Sodium Metaperiodate To a stirred solution of diol (11%) (0.322 g, 0.0012 mol) in absolute ethanol (30 ml) was added a solution of sodium metaperiodate (0.3 9. 0.0014 mol) in water (4 ml). Within a few minutes, a crystalline precipitate was de- posited from the solution. Stirring was continued for 1 hr and then the mixture was filtered. Evaporation of the fil— trate under reduced pressure gave a semi-solid residue. Water (5 ml) was added to this and then the mixture was extracted with methylene chloride. The extract was dried and evaporated to yield a brown viscous oil (yield 0.285 g, 81 90%). The ir spectrum (Figure 20, neat) showed a strong absorption between 1700 and 1735 cm—1. The nmr spectrum (Figure 6, CCl4 solution) had signals at T 8.60 (singlet, 3H), 8.23 (quartet, g_= 1.4 Hz, allylic methyl), 8.05 (singlet, 3H), 5.63 (broad, 1H), 4.17 (multiplet, 1H), 2.78 (multiplet, 5H, aromatic protons), and —0.67 (singlet, 1H. aldehyde proton). 11. The Diels-Alder Adduct (22A) from 2,3,4,6,6—Penta— methyl-2,4—cyclohexadienone'(12) and Nitrosobenzene The dienone lgfa (1.081 g, 0.006 mol), nitrosobenzene (0.705 g, 0.006 mol) and methylene chloride (15 ml) were re— fluxed for 4 hr when the green color of the solution disap- peared. The solvent was removed by using a rotary evaporator and the oily residue was diluted with petroleum ether (30- 600). The clear solution at the top was decanted from some sludge which separated. Cooling the solution overnight in the refrigerator gave some solid crystals of the adduct. This was removed and once again recrystallized from the same solvent. The recrystallized product had a light brown color, yield 0.628 g (38%), mp 99—1020. The ir spectrum (Figure 21, Nujol) indicated bands at 1720 (s), 1590 (m), 1210 (w), 1030 (m), 800 (w), 765 (s), 720 (w), and 700 cm—1 (w). The nmr spectrum (Figure 7, CDC13 solution) had sig— nals at T 8.87, 8.55 and 8.52 (all singlets, each 3H), 8.52 and 8.33 (quartets,_g = 1.2 Hz, each 3H), 5.98 (sing— let, 1H) and 2.95-3.10 (multiplet, 5H). 82 Anal. Calcd. for C17H21N02: c. 75.35; H, 7.82; N. 5.18 Found: C. 75.24; H, 7.80; N, 5.16. Dienone lg'was labeled at C-3 with CD3 by deuterium exchange under mild conditions.21 Thus 0.811 g (0.005 mol) of lg'was dissolved in 10 ml of methanol-d containing 0.2 g of sOdium and the clear solution was kept for 4 hr at room temperature. It was then diluted with 200 ml of methylene chloride and washed thrice with ice-cold water and dried (M9804). Removal of solvent yielded 0.727 g of the labeled dienone, the nmr spectrum (CDC13 solution) of which lacked the T 7.97 quartet due to the allylic methyl group at C-3.23 Preparation of the adduct with nitrosobenzene from the labeled dienone and inspection of its nmr spectrum showed that the low-field allylic methyl signal at T 8.33 was absent. 12. Reduction of Adduct22A with Lithium Aluminum Hydride: Alcohol 23A The adduct (1.36 g, 0.005 mol) dissolved in 25 ml of ice-cold ether was added to a slurry of 1 g (excess) of lithium aluminum hydride in 50 ml of ether at 0° within 5 min. No evidence of dissociation of the adduct was noticed when it was dissolved in ether. Stirring was continued at 0° for 2 hr. Excess hydride was decomposed cautiously with water, and the mixture was filtered. Evaporation of fil- trate gave quantitative yield of a solid product. Recrys- tallization from pentane gave a crystalline material, mp 113-114°, yield 1.16 g (85%). The ir spectrum 83 (Figure 22, Nujol) had principal bands at 3300 (s, O-H), 1598 (s), 1205 (m), 1170 (m), 1140 (m), 1060 (s), 1035 (m). 1000 (w), 920 (m), 820 (m), 780 (s), 760 (s) and 700 (s) cm-1. The nmr spectrum (Figure 8, CDC13 solution) had sig- nals at T 9.03 (singlet, 3H), 8.73 (singlet, 3H), 8.60 (quartet, g_- 1.2 Hz, 3H). 8.55 (singlet, 3H), 8.32 (quar- tet. g_= 1.2 Hz, 3H), 7.88 (broad, 1H), 7.05 (broad, 1H), 6.43 (singlet, 1H), and 2.73-3.23 (multiplet, 5H). 13. The Diels-Alder Adduct 24B from 3,4,5,6,6—Pentamethyl— 244-cyclohexadienone (glj'and Nitrosobenzene The dienone 2123 (0.250 g, 0.015 mol), nitrosobenzene (0.164 g, 0.015 mol) and methylene chloride (2.5 ml) were stirred together at room temperature. The green color of the solution disappeared after 18 hr. The solvent was evaporated at reduced pressure and the viscous oil that was obtained was dissolved in petroleum ether (30-60°) and cooled in the refrigerator. After several days, crystals were deposited and these were removed. The recrystallized adduct had a mp of 70°. The ir spectrum (Figure 23, Nujol) had principal bands at 1730 (s, :>c=0), 1630 (:Tc=c:;), 1600 (m), 1395 (m, doublet, g2m:dimethyl), 1300 (w), 1170 (m), 1120 (m), 870 (w), 300 (s), 725 (s) and 710 (m) cm‘l. The nmr spectrum (Figure 9, CC14) showed signals at T 9.07 (singlet, 3H). 8.83 (singlet, 3H), 8.60 (singlet, 3H), 8.52 (quartet, g_= 1.1 Hz, 3H), 8.23 (quartet, g_= 1.1 Hz, 3H), 5.93 (singlet, 1H), and 2.7-2.9 (multiplet, 5H). 84 14. The Diels—Alder Adduct (263) from 2,3,4,5,6,6-Hexa- methyl—2,4-cyclohexadienone (22) and Nitrosobenzene The dienone 22?1'39 (1.78 g, 0.01 mol), and nitroso- benzene (1.07 g, 0.01 mol) were dissolved in 1,2-dichloro— ethane (25 ml) and the green solution thus formed was re— fluxed in an oil bath at 100-110° until the color disap— peared (2 hr). The solvent was removed using a rotary evaporator, leaving a residue as a brown viscous oil. This was dissolved in petroleum ether (30-600) and cooled over— night in the refrigerator. The first crop of crystals that were deposited were removed (yield 1.4 g, 50%) and had mp 77-780. The ir spectrum of the mother liquor was identical to that of the crystalline adduct. This was further redis— solved in petroleum ether and cooled when a second crop of crystals of the adduct was obtained (0.42 g, 15%). The ir spectrum (Figure 24, Nujol) indicated absorption at 1720 (c=o), 1640 (w), 1590 (m), 1392 (s), 1300 (w), 1220 (m), 1120 (w), 1090 (m), 1080 (m), 1035 (m), 950 (w), 815 (w), 788 (s), and 707 (s) cm—l. The nmr spectrum (Figure 10, CCl4) had signals at T 9.03 (singlet, 3H), 8.89 (singlet. 3H). 8.76 (singlet, 3H), 8.60 (singlet, 3H), 8.57 (quartet. g.= 1.2 Hz, 3H). 8.04 (quartet, g.= 1.2 Hz, 3H) and 2.94- 3.00 (multiplet, 5H). 5331, Calcd. for clsnzauoz; c. 75.75; H, 8.12; N, 4.91 Found: C, 75.85; H, 8.25; N, 4.92. 85 15. The Diels-Alder Adduct from 2,4,6,6-Tetramethyl-3.5— dimethyl-dﬁ;2,4-cyclohexadienone The labeled dienone was prepared from gé'according to the procedure reported in lit.21 The labeled adduct was prepared from 1.74 g (0.01 mol) and nitrosobenzene (1.07 g, 0.01 mol) as described before. The adduct was obtained in crystalline form only after cooling the solution in petroleum ether for several days in the refrigerator. Inspection of the nmr spectrum of the product (CDC13) showed that the signals at 7 8.60 and 8.57 were absent, and that the quartet at T 8.04 became a singlet. 16. Catalytic Hydrogenation Studies on the Adduct (26B) The adduct (0.57 g, 0.002 mol) was dissolved in 25 ml of glacial acetic acid and hydrogenated at atmospheric pres— sure using pre-reduced Adams' catalyst («v40 mg). The volume of hydrogen absorbed corresponded to 5 mols. Work up of the product yielded 0.33 g of an oil having a typical amine-like odor. The ir spectrum showed strong absorption at 1700 cm"1 (ketone) and weak absorption at 3500 cm-1. The hydrogenation was repeated in ethanol solution using the same catalyst. Uptake of hydrogen corresponded to 2 mols under these conditions. Work-up of product gave a low yield (0.22 g) of an oil. The ir spectrum had strong absorption at 1660 cm.1 and medium absorption at 3400- 3500 cm-1. 86 Column chromatography of the hydrogenated product gave fractions rich in aniline (characterized by ir and nmr) and products arising out of hydrogenation of the starting dien- one. The later fractions exhibited bands in the ir (neat) in the 1700 cm—1 region and gave no signals for aromatic protons in the nmr. 17. Reduction of Adduct (268) from Hexamethyldienone_22' with Zinc and Acetic Acid The adduct (2.85 g, 0.01 mol) was dissolved in glacial acetic acid (120 ml) in a 500-ml three-necked flask. Zinc dust (25 g) was then added portionwise in the course of 1/2 hr while the mixture was stirred with a mechanical stirrer. Stirring was continued for 3 hr and the product worked up by dilution with ether, followed by filtration. The clear filtrate was evaporated using a rotary evaporator until all the ether and most of the acetic acid was removed under reduced pressure. The residue was diluted with water, neutralized with sodium bicarbonate and extracted twice with benzene and the benzene extract was dried. Removal of solvent gave a reddish oil (yield 2.247 g). The ir spectrum (liquid film) had strong bands at 3500, 3400 (N-H and O-H). 1700 (carbonyl), 1620 and 1600 cm-1. The nmr spectrum of the product indicated that the product was impure. The product was then subjected to column chromatography using 50 g of Florisil. The first fractions eluted with methylene chloride had strong bands in the ir spectrum at 1700 cm"1 87 and no aromatic protons in the nmr spectrum. The subsequent fractions from the column were rich in aniline as judged from ir and nmr spectra and comparison with an authentic sample. 18. Reduction of Adduct 26B with Lithium Aluminum Hydride The adduct (0.285 mg, 0.001 mol) was dissolved in 15 ml of dry ether and added dropwise in 1/2 hr to a slurry of 0.5 g of lithium aluminum hydride in 20 ml of dry ether. The mixture was stirred for a further period of 1 hr at 0°. Excess hydride was decomposed by cautious addition of water, and the resulting suspension was filtered through a sintered funnel. The filtrate was dried (M9304) and solvent re— moved under reduced pressure. The product was a yellow viscous oil, yield 241 mg (85%). The ir spectrum of the crude product (Figure 25, neat) showed complete absence of carbonyl absorption; a strong band at 3500 cm-1 indicated presence of O-H. The nmr spectrum (CDC13) had signals at T 9.17 (multiplet), 8.92, 8.77, 8.67, 8.58 (quartet, g_= 1.2 Hz), 8.10 (quartet, g.= 1.2 Hz) all integrating to ap- proximately 3H each, due to the six methyl groups. None of the methyl signals were sharp singlets, as would be ex- pected from a pure product; additional signals were noted at 1 8.30 (1H), 7.05 (broad, 1H) and 2.85-3.10 (5H). In another experiment. the adduct (285 mg, 0.001 mol) was dissolved in 20 ml of dry tetrahydrofuran and this solu- tion added dropwise to 0.3 g of lithium aluminum hydride in 88 50 ml of tetrahydrofuran with stirring and cooling. Addi- tion was completed in 15 min. After being stirred at 0° for 2 hr, the mixture was refluxed for 4 hr. It was then cooled, and excess hydride was decomposed by careful addi- tion of water. The suspension was then filtered and the filtrate was evaporated to yield an oil (260 mg). The ir and nmr spectra of the product were very similar to those of the product from reduction in ether solution. 19. Attempted Oxidation of the Alcohol with Sodium Metaperiodate The product obtained from the lithium aluminum hydride reduction (in tetrahydrofuran. as described above) was sub- mitted to periodate cleavage. Thus 480 mg (0.0017 mol) of the reduction product was dissolved in 25 ml of absolute ethanol and to this stirred solution, an aqueous solution of 0.5 g (excess) of sodium metaperiodate in 5 ml of water was added and the mixture was stirred for 1/2 hr. Some sus- pended matter separated from the solution. This was removed by filtration and the filtrate was evaporated under reduced pressure. The residue consisted of a white solid and a yellow Oil. This was further diluted with water and ex- tracted with methylene chloride. The extract was washed with water and then dried (MgSO4). Removal of solvent yielded 430 mg of a viscous liquid. The ir spectrum did not show any carbonyl absorption and was identical with that of the starting material. 89 20. Reduction of the Alcohol (from Lithium Aluminum Hydride Reduction of Adduct 2§§)with Zinc and Acetic Acid, and Attempted Oxidation The alcohol (409 mg, 0.0014 mol) from lithium aluminum hydride reduction of 262', was dissolved in 10 ml of glacial acetic acid in a 100-ml three-necked flask and to this mechanically stirred solution was added 1.8 g of zinc dust. The flask was warmed in an oil bath at 50° and stirring continued for 9 hr. The product was worked up as described in the reduction of the adduct 222; the yield of a brown mobile liquid was 352 mg. The ir spectrum indicated a strong carbonyl band at 1720 cm“1 (acetate) and a strong hydroxyl band at 3400—3500 cm-l. The nmr spectrum had a strong sig- nal at T 7.80, but was otherwise complex and pointed to the presence of more than one component. Column chromatography on silica gel (10 9) resulted in obtaining fractions having no aromatic protons in the nmr spectra, but having vinylic protons between T 4.75 and 5.05. Periodate oxidation as described for the dienone-adduct 2§§,above did not give any carbonyl-containing fragment. The oxidation was repeated after further reduction of the acetates with lithium aluminum hydride. In this case also no identifiable single product was obtained. The ir spec- trum of the product showed no carbonyl absorption. 90 21. The Diels-Alder Adduct (33A) from Eucarvone (32) and Nitrosobenzene Eucarvone (32) was prepared according to the method of Corey and Burke.43 The nmr spectrum (CCl4 solution) had signals at T 8.93 (singlet, 6H), 8.13 (doublet, g_= 1.7 Hz), 7.43 (singlet, 2H), 4.0-4.5 (2H, multiplet) and 3.6 (1H, doublet, further split to quartets).45 Eucarvone (7.5 g, 0.05 mol), nitrosobenzene (5.35 g, 0.05 mol) and methylene chloride (150 ml) were stirred together at room temperature for 10 hr, by which time the green color of the solution disappeared. The solvent was removed at reduced pressure and the residual oil was redissolved in pentane and cooled overnight in the refrigerator. The crystals which were deposited were removed and amounted to 9.8 g (77% yield). Recrystallization from the same solvent yielded light yellow crystals of the adduct, mp 56-57°. The uv spectrum had xﬁggﬁ 285 nm (shoulder), a - 162; 244 nm, e - 7558; 208 nm, e - 10,400. The ir spectrum (Figure 26, Nujol) had strong absorption at 1705 (:0-0), 1655 (:c=c:), 1595, 1375, 1240, 1180, 1090, 1020, 862, 770 and 700 cm-1. The nmr spectrum (Figure 11, CDCl3) had signals at T 8.93 (singlet, 3H), 8.55 (singlet, 3H), 8.38 (singlet, 3H), due to the three methyl groups, two doublets at 7.74 and 6.59 (1H each, g_= 22 Hz, geminal coupling of the methylene protons; the former doublet was split into further doublets with g_= 1 Hz due to long-range coupling with the bridgehead proton), 1 91 6.02 (doublet, 1H,)g.- 10 Hz, further split into multiplets, bridgehead proton), 3.72-3.95 (multiplet, 2H, olefinic pro- tons) and 2.60—3.08 (multiplet, 5H, aromatic protons). ’ Agai, Calcd. for clsnlguoz; c, 74.68; H, 7.44; N, 5.44 Found: C, 74.86; H, 7.60; N, 5.55. 22. Reduction of Adduct (33A) with Lithium Aluminum Hydride: Alcohol (33)" A solution of the adduct (1.3 g, 0.005 mol) in dry ether (100 ml) was added dropwise to a mechanically stirred slurry of lithium aluminum hydride (0.5 g, excess) in 200 ml of ether at 0°. Stirring was continued for a further period of 2 hr at 0°. Excess hydride was decomposed by cautious addition of water and the product was filtered through a sintered funnel. The solvent was removed at reduced pres- sure when a semi-solid residue was obtained in quantitative yield. This was recrystallized from a 1:1 mixture of ether- petroleum ether (40-60°). The yield of a light, white, fibrous solid amounted to 0.65 g (50%), mp 159-1600. The ir spectrum (Figure 27, Nujol) had principal bands at 3250 (O-H). 1600, 1230, 1055, 1035, 1020, 850, 760, and 700 cm’l. The nmr spectrum (Figure 12, CDC13 solution) showed signals at T 8.95 (singlet, 3H), 8.72 (singlet, 3H), 8.40 (singlet, 3H) for the three methyl groups. The two -CH2- protons and the -C§OH proton were not well resolved and had signals in the region 8.27-8.75; other signals were at T 6.33 (broad, 1H, hydroxyl proton), 6.11 (broad, multiplet, 1H, 92 bridgehead proton), 3.85-4.17 (multiplet, 2H. olefinic protons) and 2.80-3.18 (multiplet, 5H. aromatic protons). 523;. Calcd. for C13H21N02: C, 74.10; H. 8.16; N, 5.40 Found: C, 74.14; H, 8.10; N, 5.37. The liquid portion which failed to crystallize had principal bands in its ir spectrum (Figure 28, neat) at 3450 (O-H), 1600. 1220, 1145, 1040, 950, 860, 820, 760 and 700 cm-1. The nmr spectrum (CDC13) showed signals at T 9.02 (singlet, 3H), 8.62 (singlet, 3H), 8.45 (singlet, 3H) due to the three methyl groups, 8.30 (doublet, g_= 6 Hz, 2H. -CH2-), 7.35 (broad, 1H) and 6.38 (broad, 1H), 6.17 (multip- let, 1H, bridgehead proton), 3.93-3.95 (multiplet, 2H, ole— finic protons) and 2.83-3.15 (multiplet. 5H. aromatic protons). 23. Reduction of Alcohol gg'with Zinc and Acetic Acid: Amino Diol 35 The crystalline alcohol 34'(1.30 g, 0.005 mol) was dissolved in 55 m1 of glacial acetic acid in a three-necked flask fitted with a mechanical stirrer and a reflux condenser. Zinc dust (5 g, excess) was added and the mixture was stirred at 50-55° (oil bath) for 14 hr. It was then cooled. extracted with ether and the ether extract was filtered. Ether was removed at reduced pressure, the residue was diluted with water and neutralized with concentrated ammonium hydroxide. The neutral mixture was then extracted with ether and the ether extract was washed with water and dried. 93 Removal of solvent gave a light pink solid material in quantitative yield. This was recrystallized from ether and had mp 118-119°. The ir spectrum (Figure 29, Nujol) had principal bands at 3400 (O-H), 3260 (N-H), 1600, 1520, 1325, 1100, 1055, 1020, 950, 760 and 700 cm‘l. The nmr spectrum (CDCl3 solution) had signals at T 8.93 (singlet, 3H), 8.90 (singlet, 3H), 8.63 (singlet, 3H). 8.18 (doub- let, g = 6 Hz, 23, -cn2-), 7.15 (broad, 23). 6.00-6.35 (unresolved. 3H), 4.15-4.85 (multiplet, 2H, olefinic pro- tons) and 2.77-3.58 (multiplet, 5H, aromatic protons). Anal, Calcd. for C15H23N02: C, 73.53; H, 8.87: N, 5.36 Found: C, 73.37; H, 8.77; N, 5.30. Similar reduction of the liquid alcohol gg'with zinc and acetic acid gave a quantitative yield of a different amino diol, mp 95-96°. The ir spectrum (Figure 30, Nujol) had principal bands at 3380 (O-H), 3260 (N-H), 1600, 1310, 1260, 1140, 1030, 900, 760 and 730 cm-1. The nmr spectrum (CDC13) had signals at T 8.98 (singlet, 3H), 8.88 (singlet, 3H), 8.62 (singlet, 3H), 7.63-8.40 (multiplet, 3H), 6.25- 6.53 (broad, 4H), 4.34-4.37 (multiplet, 2H, olefinic protons) and 2.77-3.50 (multiplet, 5H, aromatic protons). ﬁnal, Calcd. for C13H23N02: C, 73.53; H, 8.87; N, 5.36 Found: C, 73.31; H, 8.87; N, 5.23. 24. Oxidation of Amino Diol (32) with Sodium Metaperiodate The isomer mp 118-119° of the crystalline amino diol 35' (261 mg, 0.001 mol) was dissolved in 30 ml of methanol and" 94 to this was added a solution of 0.45 g (0.002 mol) of sodium metaperiodate dissolved in 5 ml of water. The mixtures was stirred magnetically at room temperature for 3 hr. Precipi- tation of sodium iodate was observed within a short time. This was filtered, and the filtrate was evaporated at reduced pressure. The residue was diluted with water and extracted with methylene chloride. The extract was washed twice with 10-ml portions of water and dried. The solvent was removed at reduced pressure and the residue was evacuated at 0.1 mm for 30 min to remove any volatile fragments resulting from the oxidation. Final yield of product did not change as a result of the evacuation, indicating that fragments such as aniline were not formed. The product was obtained as a brown oil. This was chromatographed through a column of silica gel (5 g) and the first fraction eluted with benzene (yield 105 mg) was collected as a yellow oil. The ir spec— trum (Figure 31, neat) had principal bands at 3050 (aldehyde), 1718 (aldehyde), 1690 (a.B-unsaturated ketone), 1600, 1185, 1050, 770 and 690 cm-1. The nmr spectrum (CC14) indicated that the product was still contaminated with probably secondary products. However, the signal due to the aldehyde proton was clearly noticeable at T 0.60 as a triplet (g_= 3 Hz) due to coupling with the adjacent methylene protons. Oxidation of the isomeric amino diol 35“ mp 102-103°, also gave the same unstable aldehyde in comparable yield, after column chromatography, in a purer state. The nmr spectrum (Figure 13, CC14) had prominent sharp bands at 95 0 T 8.82 (singlet, ggmfdimethyls), 8.23 (singlet. CH3-8-), 7.82 (doublet. -CH2-), 4.23 (multiplet, olefinic protons), 2.75 (aromatic protons) and 0.60 (triplet, g_= 3 Hz). The integration was approximately in agreement with this as- signment. However, there were a few other signals also in the nmr spectrum with much lower intensities. 25. Reduction of_§ucarvone by Lithium Aluminum Hydride: Eucarveol (32) Eucarvone (1.5 g, 0.01 mol) dissolved in 30 ml of dry ether was added during 15 min to a well stirred slurry of 0.5 g (excess) of lithium aluminum hydride in 100 ml of ether at 0°. The mixture was stirred for a further period of 2 hr. Excess hydride was destroyed by cautious addition of water and the mixture was filtered. Evaporation of sol- vent under reduced pressure, followed by removal of last traces of solvent and moisture at 0.1 mm gave an oil (yield 1.36 g). The ir spectrum (neat) had principal bands at 3400 (O-H), 1640, 1620 (::C=Ci:), 1135, 1080, 1030, 930 and 760 cm-1. The nmr spectrum (CDC13 solution) had signals at T 8.97 (singlet, 3H) and 8.92 (singlet, 3H) due to the _ggm-dimethyls, 8.15 (quartet, g;= 1.5 Hz, 3H. allylic methyl), 8.03-8.25 (multiplet, 2H. -CH2-), 6.78 (broad, 1H, disap- pears on shaking with D20, hydroxyl proton), 5.77 (broad doublet, g_= 15 Hz, CHkOH) and 4.62 (singlet, 3H, vinylic protons). ‘1— '_...E E x 96 26. The Diels—Alder Reaction of Eucarveol (32) with Nitroso- benzene: Adduct (32) Eucarveol (1.36 g, 0.009 mol). nitrosobenzene (0.91 g, 0.009 mol) and methylene chloride (50 ml) were stirred together at room temperature for 24 hr. The solvent was evaporated under reduced pressure and the residual oil redissolved in 1:1 mixture of ether-petroleum ether (40-60°) and cooled in the refrigerator overnight. Crystals de- posited and were filtered (yield 0.4 g, 17%, mp 159-160°). The ir and nmr spectra were superimposable with those of alcohol 32, A mixed mp did not show any depression. The liquid portion which did not crystallize even on prolonged cooling was found to contain some unreacted starting mater- ials and was not further investigated. 27. Irradiation of Adduct 26B fromgﬁexamethyldienone 22' The uv spectrum of the adduct 26B had xﬁng 308 nm (e = 5698), 281 nm (e = 6045) and 208 nm (e = 12610). The adduct (100 mg) was dissolved in 10 ml of ether and degassed with purified N2 for 15 min. It was then irradiated in a Pyrex test tube with a 450 watt Hanovia L Type lamp for 2 hr. The uv spectra indicated a new maximum at 245 nm. The product was separated by vpc. The ir and nmr spectra of the product indicated it to be pure 1,3,4,5,6,6-hexamethyl- bicyc1o[3.1.0]hex-3-ene-2-one (42).”1 97 28. Irradiation of Adduct 22A from Pentamethyldienone 12' The adduct 22A'(67 mg) was dissolved in anhydrous ether to make up a 1% solution, and after degassing with N2 for 1/2 hr, the solution was irradiated in.a Pyrex test tube with a 450 watt Hanovia Type L lamp. The progress of the reaction was followed by uv measurements (Figure 33). The maxima at 308 nm and 282 nm gradually decreased while that at 249 nm increased during 45 min. The nmr spectrum of the product indicated that much of the starting material was still unchanged. Vpc separation gave only one fraction which was identified as the dienone lg'resulting from thermal dissociation of the adduct. When the irradiation was repeated under the above conditions, but using acetone as solvent, photolysis ap- peared to be complet in 12 hr, as shown by uv analysis (Figure 34). The nmr spectrum of the product was complex. Attempts to separate the product by chromatography were unsuccessful. 29. Irradiation of Adduct 33A frongucarvone 32' The adduct (70 mg) was dissolved in 7 ml of ether, and after degassing by flushing with N2 for 15 min, irradiated using a 450 watt Hanovia lamp through vycor. Progress of reaction was followed by uv (Figure 35). At the end of 22 hr, product was worked up. The ir and nmr Spectra indicated mainly starting material. 98 Irradiation of égéywas then repeated in ether solution using light of wavelength 2537 2 in a Rayonet chamber. Thus 60 mg of adduct dissolved in 10 ml of dry ether in quartz test tube was irradiated for 5 hr. The progress ‘was followed by uv (Figure 36). Separation of product by vpc gave pure eucarvone, resulting from thermal dissociation. 30. Irradiation of Adduct Qé'from Tetramethyldienol Z The adduct (518 mg) was dissolved in 50 ml of methanol. The solution was flushed with purified N2 for 45 min. The solution was taken in the inner chamber of a quartz well and closed with a two-holed rubber stopper carrying an inlet tube for purified N2. The gas was bubbled into the solution throughout the photolysis to keep the solution stirred. The progress of reaction was followed by taking uv spectra at frequent intervals (Figure 37). At the end of 5 1/2 hr the photolysis was stopped and the product subjected to column chromatography using Florisil. Nine fractions were collected, using progressively polar solvents. Only the ether fraction (107 mg) showed spectra that could be at- tributed to a reasonably pure material. The ir spectrum (Figure 32) had strong absorption at 3450 (O-H), and medium absorption from 1700-1640 cm-l. The nmr spectrum (Figure 14, CDCls) had signals at T 9.12 (singlet, 3H), 8.93 (singlet, an), 8.70 (singlet, 3H), 8.53 (singlet, an), 8.17 (singlet. 1H). 6.77-7.20 (broad, an) and 2.75-3.33 (5H). ’ 99 31. Irradiation of Adduct 32 from Eucarveol 32’ In a typical experiment, 518 mg of the adduct was dissolved in 100 ml methanol. The solution was flushed with N2 for 1/2 hr and then irradiated in the Rayonet chamber at 2537 X for 10 hr. The uv spectra are given in Figure 38. The product was chromatographed over silica gel. No fraction, sufficiently pure for characterization was obtained. 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A. m . a . ﬁ _ . an 0 £ 28 . . . . .. _ . A3 9 8. 8a 8. 8s . . u o... nol . , . . . 2°- .— P rrrrrr h h ’’’’’’ p FL rrlrrb p P h \7 If .' rrh rrrrrrrr krilr . h L Pb’rp - h ’ n F b}. A b! y F ’ ~ D _ bL ’ \PL! ’. FFFFF ..I- IfHEFEEEEATt..prb—pthrLFu>u>H>Pu?L’>rPJb[ .... 24... O 0- Oh On 01 on 00 GS transmittance ‘ 8 8 8 0 4000 2000 I800 1600 Moo K300 800 650 wavenumlnr ...-......- Figure 15. Ir spectrum (Nujol) of adduct 2A" from 3,4,6,6— tetramethyl-Z ,4-cyclohexadienone (L) . 886 trammittante 6 1 - . "In: at m 5000 4000 1400 200 IOOO 0C0 ‘3 wavenumber ...... .. :- 0 Figure 16. Ir spectrum (Nujol) of adduct Q]: from 3,4,6,6- tetramethy1—2 , 4—cyclohexadienol ' (£13) 116 no 8 530 E20 VI 3 GI I- “ 10 u 0 5 O 4000 3000 2000 ‘800 500 MOO 200 ‘000 650 wavenumlgev; --~- - '- Figure 17. Ir spectrum (neat) of pyrrole £3. 6 40 3 530 3° .‘1 52° 20 m = n b a $0 10 unu- u n- - O 2000 1600 1600 1400 i200 000 800 650 an.“ I. II 5000 > 4000 wavenumber Figure 18. Ir spectrum (Nujol) of adduct 16A from 6-acetoxy- 2,4,6-trimethyl-2,4-cyclohexadremone. 117 transmittance 8 8 8 6 "null n n- 5000 6000 3000 2000 BOO I600 MOO I200 000 900 650 wavenumbcr ...-... - ... Figure 19. Ir spectrum (Nujol) of diol 17A. 6 S trans—lgittante 6 $00 "00 200 000 800 3000 2000 1500 650 uni-[u .- m 5000 4000 wavenumber Figure 20. Ir spectrum (neat) of periodate-cleavage product 18A from diol 17A. a '1 ‘0 n 12 [3» ‘1 ‘0 40 3 :30 10 3 .2 520 PO 2 C 5 n n 5000 l 4000 2000 $00 ‘00 1‘00 ROD 000 650 "ad-nun m Figure 21. Ir spectrum (Nujol) of adduct 22A from 2,3,4, ~w 6,6-pentamethyl-2,4-cyclohexadienone (lg). transmittante 6 8 8 5 0 500 M00 1200 ‘000 Figure 22. Ir spectrum (Nujol) of alcohol 23A from ad— duct 22A. 119 l 1 . __ O $000 ‘000 3000 2000 1800 1600 H00 1200 000 800 650 .wavcnumber ...... . - m Figure 23. Ir spectrum (neat) of adduct 24B from 3,4,5, 6 , 6-pentamethyl-2 , 4-cyclohexa3ienone (2;) . lldllillllttdlltt 8 8 5 Figure 24. Ir spectrum (Hujol) of 26B from 2,3,4,5,6,6- hexamethy1-2 ,4-cyclohexaa ienone (g3) . 7O transmittiite 3 8 6 6 ' amu- u no 120 :70 o . . . . ' o 5000 4000 3000 2000 $800 $00 “00 1200 ‘000 800 650 wavenumber ____..___, .... ...- .. .. -..- ....-. _ ...— f .-- ...:.....z..wﬁ Figure 25. Ir spectrum (neat) of alcohol from reduction of adduct 263. k 24—C31ﬁ9327E-Fﬁﬁi‘ti- g 4 5 W. ‘—"— _"' (1 '"' 7 a ' 0 :o u 1.3 13 14 1:5 ‘00 ' 3 ' - f“? 1 ' 1: if: '1. .100 9o i 915 { 13ft" .90 so : - r ..., . . .. «~94».- so .-- :9. 3‘- . _ r... so '1: ‘3' so . "f , h‘ M .No so I ‘1'; j 1 so [I I Ali JIU1.~.~L.CO 40 ”M g 1"" , g g .— o :11 ‘ 1 A , . r 40 33° .. . ‘ . 1 ' w : --.--._ 30 £3 I p ' l . .. a. 52° C.“‘ J' 20 .3 . , 1 2 J ‘ 010 m . 4~—-— -——~« 0 o ;I-Itnusf.xot; . , ' I ll ..1 . L ‘ o 5000 4000 30 2000 1800 moo I woo 200 000 coo 650 wavenumhcr ...-.... .. ..- Figure 26. Ir spectrum (Nujol) of adduct 33A from eucarvone 22, 121 ' "Inn III. "a O I . 5000 ‘000 ‘600 I200 000 Figure 27. Ir spectrum (Nujol) of solid alcohol from reduction of adduct 33A. 8 S 6 transmittance 5 ‘..:u-- n no ‘ i . . ' Q00 ‘000 600 6 50 5000 . 4000 3000 2000 B00 ‘600 K00 Figure 28. Ir spectrum (neat) of liquid alcohol from reduction of adduct 33A. 122 6 Nil-(2.8, 8 :53. mp 118-119° transgﬁttante 6 u 2000 1600 1600 M00 000 uni-".1" Figure 29. Ir spectrum (nujol) of amino diol mp 118-119°. 5000 4000 wavenumber 6 urn-ca. 8 ‘ 92 Ip 95-96' transtgittance 6 non-- n. nu I 5000 wavenumber Figure 30. 1r spectrum (Nujol) of amino diol mp 95-960. transmittance 123 8 8 6 0 ”0° 3°00 200° '00 1600 H00 200 . 000 500 Kiwan- Figure 31. Ir spectrum (neat) of periodate-cleavage product 522. from amino-diol £33. 70 transmittahce' 6 8 8 6 O l . "00 I200 000 600 650 Figure 32. 11: spectrum (neat) of photo-product from adduct QA. absorbance absorbance 124 20 . w . to 14 12 1o ‘- 03 'I:; W lit 5 2°” 06 E: ' 3 I”; : a x. 1 ' m 51:: .. a. °‘ W ‘°:= 2:! ' a; .E' ' 3 . 02 cos i. f i " ‘ so 00 1 20: 225 400 «so m wavelength millimicrons «...-mum Figure 33. Photoleis of adduct 22A: in ether: uv spectra as a function of irradiation time. io'o ‘ as 256 275 1 300 3'25 :30 .300 ' 4w wavelength milﬁmlcrgngm ,, _. awn-num- Figure 34. Photolysis of adduct 22A in acetone: uv spectra as a function of irradiation time. 3 6 aouzugwsucn 8 §8 u absorbance 9 » absorbancc 9 A 9 » 00 125 __VL:vc!cnggl_\__mi.l[imjgcrons_ .. ...... Figure 35. Q . O 9 A 9 o wavelength Figure 36. Photolysis of adduct 33A in ether: uv spectra as a function of irradiation time. cum-..- In com) Photolysis of adduct 33A in ether at 2537 R; uv spectra as a function of irradiation time. 3 6 03“!)JHUSUIJ) 382 8 so 8 uuzngwsuu) 833 126 absorbance 9 9 A O 9 n 9 0 Figure 37. Photolysis of adduct ﬁg in methanol at 2537 R; uv spectra as a function of irradiation time. (...-.... ... mu: millimicrons absorbance 9 A 9 N 00 run... ... wavdength millimicrons Figure 38. Photolysis of adduct ﬁg in methanol at 2537 R; uv spectra as a function of irradiation time. 8 8 aautngwsuu: 933 8 so 6 nucugmsuu: 33$ 127 Table II. lNomenclature of compounds described in this thesis. Compound N Jer Structure Name 0 H N-Phenyl-7-oxa-8-aza-3,3',5,6- Qé' tetramethylbicyclo[2.2.2]oct-5- O ene-Z-one ' N’ ‘\C H H s 5 H OH H N-Phenyl-7-oxa-8-aza-3,3',5,6- §§> tetramethylbicyclo[2.2.2]oct-5- / 7 -2 -01 N H ‘\5635 CHO ZeMethyl-2[N-phenyl-3'.4'-dimethyl- 14 1” 2'-pyrry1]propanal N-Phenyl-7-oxa-8-aza-3-acetoxy- 1,3,5-trimethylbicyclo[2.2.2]oct- 5-ene-2-one Table II. (Cont.) 128 Compound Number Structure Name 23A H 7,0H 7 N~\ H CsHs CH3 CHO j ‘0 N\ CsHs CH3-C H ll 0 0 ﬂ /0 N- H ‘\C6H5 H OH N-Phenyl-7-oxa-8—aza—1,3,5-tri- methylbicyclo[2.2.2]octa—5-ene- 2,3-diol N-Phenyl-4,6—dimethyl—6—formyl- 3-acetyl—3,6-dihydro-1,2—oxazine N-Phenyl-7-oxa-8-aza-1,3,3',5,6— pentamethylbicyclo[2.2.2]oct-5— ene-Z-one N-pheny1-7-oxa-8—aza-1,3,335,6— pentamethylbicyclo[2.2.2]oct-5- ene-Z-ol 129 Table II. (Cont.) Compound Number Structure Name /p // N-Phenyl—7-aza—8-oxa—3,3,4,5,6— 24B ‘/J<:? pentamethylbicyclo[2.2.2]oct—5- ene-Z-one ‘/CGH5 ,C6H5 N-Phenyl-7-aza-8-oxa-1,3,3,4,5,6- 26B // hexamethylbicyclo[2.2.2]oct-5- ene-2-one - O N-Phenyl-B-oxa—Q-aza-l,4,4-tri— 33A methylbicyclo[3.2.2]non-6-ene—2- /0 one H OH N-Phenyl-S-oxa—Q-aza-l,4,4-tri— Qg, -\ methylbicyclo[3.2.2]non—6—ene-2- \0 ol N‘\C6H5 130 Table II. (Cont.) Compound Number Structure Name H OH Me H0 2,6,6-Trimethyl-5—anilino— 35 cyclohept-3—ene-1,2-diol NH-C6H5 0 CH0 3,3-Dimethyl-4-anilino— 36 oct-5-ene-7-one-1-a1 LITERATURE CITED 1. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. LITERATURE CITED A. Yu. Arbusow, Russ. Chem. Rev., ﬁg“ 407 (1964). J. Hamer and M. Ahmed, "1,4-Cycloaddition Reactions," J. Hamer, Ed., Academic Press, New York, N.Y., 1966, Chapter 12. S. B. Needleman and M. C. Chang Kuo, Chem. Rev., 62 405 (1962) . "" G. Kresze and J. Firl, Fortschr. Chem. Forsch., ii, 245 (1969). J. Sauer, Angew. Chem. Int. Ed., 2” 211 (1966). J. Sauer, Angew. Chem., Int. Ed., 6, 16 (1967). N G. Kresze and G. Schulz, Angew. Chem., 22” 576 (1960). G. Kresze and G. Schulz, Tetrahedron, 125 7 (1961). G. Kresze, G. Schulz and H. Walz, Ann. Chem. Liebigs, 66 , 45 (1963). P. Burns and W. A. Waters, J. Chem. Soc. (C), ZZ.(1969)' M. Ahmed and J. Hamer, J. Org, Chem., g1” 2831 (1966). Yu. A. Titow, Russ. Chem. Rev., §lu 267 (1962). A. S. Onishchenko, "Diene Synthesis,“ Israel Program for Scientific Translations, Jerusalem, 1964. J. Hamer, M. Ahmed and R. E. Holliday, J. Org, Chem., gﬁﬂ 3034 (1963). M; Ahmed and J. Hamer, J. Chem. Educ., 4;, 249 (1964). G. Kresze et al., Tetrahedron, 22“ 1605 (1964). G. Kresze and O. Korpium, Tetrahedron, 22“ 2493 (1966). M. Ahmed and J. Hamer, J. Org. Chem., 6}“ 2829 (1966). R. Hoffmann and R. B. Woodward, J. Amer; Chem. Soc., §Z” 2046 (1965. 131 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 132 P. Scheiner, O. L. Chapman and J. D. Lassila, J. Org. Chem., 34, 813 (1969). H. Hart, P. M. Collins and A. J. Waring, J. Amer. Chem. Soc., 88“ 1005 (1966). H. Hart and R. M. Lange, J. Org. Chem., 31” 3776 (1966). . P. M. Collins and H. Hart, J. Chem. Soc. (C), 895 (1967). T. Kakihana, M. S. Thesis, Michigan State University, 1966. E. Perry, Michigan State University, unpublished work, 1969. M. Petschel, Jr., Ph.D. Thesis, Michigan State University, 1969. J. Griffiths and H. Hart, J. Amer. Chem. Soc., 92/ 3297 (1968). J. Griffiths and H. Hart, J. Amer. Chem. Soc., 20, 5296 (1968). R. K.)Murray Jr., and H. Hart, Tetrahedron Lett., 4995 1068 . ' H. Hart and R. K. Murray, Jr., J. Amer. Chem. Soc., 21” 2183 (1969). H. Hart and R. K. Murray, Jr., Tetrahedron Lett., 379 (1969). H. Hart, R. K. Murray, Jr., and G. D. Appleyard, Tetrahedron Lett., 4785 (1969). G. Kresze and J. Firl, Tetrahedron, 22“ 1043 (1968). P. A. S. Smith, "Open—Chain Nitrogen Compounds" Vol. 2, W. A. Benjamin Inc., New York, 1966, p. 375. A. I. Finkel'shtein, Yu. A. Arbuzov and P. P. Shorygin, Zhur. Fiz. Khim;J 24” 802 (1950). A. S. Perlin in "Oxidation" Vol. I, R. L. AuguStine, Ed., Marcel Dekker Inc., New York, 1969, p. 189. J. Firl and G. Kresze, Chem. Ber., 22x 3695 (1966). 38. 39. 40. 41. 42. 43. 44. 45. 133 E. Zbiral, O. Saiko and F. Wessely, Monatsh. Chem., 95, 512 (1965). H. Hart, R. M. Lange and P. M. Collins, Org. Synth. 48, p. 87 (1968). Gd Kresze, G. Schulz and G. Firl, Angew. Chem., Int. .(Engl. ), 2, 321 (1963). G. Kresze, G. Schulz and H. Zimmer, Tetrahedron, 18, 675 (1962). O. Wichterle and M. Kolinsky, Chem. Listyj 41” 1787 (1953), Chem. Abstr. 42, 201 (1955). E. J. Corey and H. J. Burke, J. Amer. Chem. Soc., Z8” 174 (1956) R. K.)Murray, Jr. and H. Hart, Tetrahedron Lett., 4781 1969 . A. A. Bothner—By and F. Moser, J. Amer. Chem. Soc., 90, 2347 (1968). R" E V" mm3 U." 4 17